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MANAGEMENT GUIDELINES FOR ANXIETY

DISORDERS IN CHILDREN AND ADOLESCENTS

Prabhat Sitholey1 , Anil Nischal2

Anxiety disorders represent one of the most common categories of psychopathology in children and
adolescents. Apart from separation anxiety disorder, a well recognized problem of childhood, it is now
widely accepted that generalized anxiety disorder, social phobia, specific phobia, posttraumatic
stress disorder, obsessive compulsive disorder and panic disorder all occur during the childhood and
adolescent years. Numerous studies examining the nature and treatment of anxiety disorders have
appeared during the recent years. Significant advances in this area include the investigation of
pharmacological agents and development of effective psychosocial interventions. Prevalence rates
for having at least one childhood anxiety disorder vary from 6% to 20% over several large
epidemiological studies (Costello et. al., 2004). Co-morbidity is extremely common among children
and adolescent suffering from anxiety disorders. A recent study of children aged 8 - 13 years, having
a primary diagnosis of anxiety disorder revealed that 79% of the sample also had another co-morbid
anxiety disorder, mood disorder or behavior disorder (Kendall et. al., 2001). In view of such findings,
consideration needs to be given to co-morbidities as their presence will guide selection of specific
treatments.

The objective of these guidelines is to provide up-to-date information about management of anxiety
disorders. Literature was reviewed by a computerized search in the month of June 2007 using the
keywords child, adolescent, anxiety disorder, treatment, and management. The search covered a
period of 10 years (1997 through 2007).Articles retrieved and their relevant references were reviewed
for the purpose of framing these guidelines. The information has been presented in two sections -
Assessment and Treatment. Certain statements in this guideline are followed by abbreviations MS or
CG. MS stands for minimal standards and reflects that the statement is based on rigorous empirical
evidence while CG stands for clinical guidelines indicating that the statement is based on empirical
evidence and/or strong clinical consensus.

ASSESSMENT
Defining the boundary between extremes of normalcy and psychopathology is a dilemma that
pervades all psychiatry. In many cases of childhood anxiety disorder this dilemma is at its zenith. The
defining point for caseness is often ambiguous as many childhood anxieties are not only common but
also have an adaptive role in human development. It is strongly recommended that psychiatric
assessment of children and adolescents should routinely include screening questions about anxiety
symptoms [MS]. If the screening indicates significant anxiety, then the clinician should do a formal
evaluation to determine subtype of anxiety disorder, the severity of anxiety symptoms and functional

1. MD Professor and Head, 2. MD Assistant Professor, Department of Psychiatry, CSM Medical


University UP, Lucknow, India

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impairment [MS] (Connolly et. al., 2007). Anxiety may be considered symptomatic when it is impairing
and prevents / limits developmentally appropriate adaptive behavior. A useful rule for determining
diagnostic threshold is the child's ability to recover from anxiety and to remain anxiety-free when the
provoking situation is absent. The child's lack of flexibility in affective adaptation is an important
pathological indicator. In addition, the degree of distress and dysfunction associated with anxiety also
help in reaching a diagnosis. Anxiety disorders impair emotional, cognitive, physical and behavioral
functioning in multiple areas and are usually chronic in nature. Hence, the child needs to be evaluated
in context of his family, school, community, and culture. Important areas of assessment include
history of onset and development of anxiety symptoms, associated stressors, medical history, school
history, family psychiatric history and mental status examination. The psychiatric assessment should
always consider differential diagnosis of physical conditions & psychiatric disorders that may mimic
anxiety disorders [MS]. Early detection and effective treatment may reduce the impact of anxiety on
academic and social functioning in youth and may reduce the persistence of anxiety into adulthood.

INSTRUMENTS FOR ASSESSMENT


Earlier, determination of childhood anxiety largely relied on rating scales or interviews inquiring about
multiple unrelated fears and worries generating a count without a clear clinical meaning (Lapouse &
Monk, 1958). The emphasis has now shifted to the study of diagnostic groups that reflect explicit
clinical criteria. A comprehensive evaluation should include a detailed structured or semi structured
psychiatric interview to establish the anxiety disorder diagnosis and detect co-morbid psychiatric
disorders. In addition, clinical rating scales, self report scales and parent report instruments may be
used to determine the type and severity of anxiety symptomatology. This practice also allows for
monitoring of these symptoms over time.

Over the last two decades there has been a proliferation of instruments to determine the presence of
anxiety disorders in children or quantify levels of anxiety. Assessment instruments include paper-
and-pencil scales for children, parents and teachers, as well as child and parent interviews.
Interested readers are referred to a review of commonly used instruments by Brooks & Kutcher, 2003.
An overview is provided below.

Rating scales:
Rating scales serve diverse purposes. They are used to screen large groups, to examine the relative
contribution of genetics and environment, to assess severity and as outcome measures of treatment
efficacy. Rating scales that anteceded the present nosology of anxiety disorders were designed to
assess a plethora of factors such as worry, physiological anxiety, fear of bodily harm, etc. rather than
anxiety syndromes. These include the Revised Children's Manifest Anxiety Scale (RCMA; Reynolds
&Richmond, 1985), the State Trait Anxiety Inventory for Children (STAIC; Spielberger, 1973) and the
Revised Fear Survey Schedule for Children (FSSC-R; Scherer and Nakamura 1968; Ollendick 1983).
In addition, the Child Behavior Checklist (CBCL; Achenback 1991) which generates a non specific
factor of emotional disturbance, called the internalizing factor" may be used as a rating scale.

The limitations of the older rating scales and increasing interest in childhood anxiety disorders has
led to development of more sensitive and diagnostically relevant measures of childhood anxiety.
Recent efforts reflect the classification of anxiety disorders and a move towards specificity of content,
with relevance to diagnostic grouping. Newer scales devised with these considerations include the
Social Anxiety Scale for Children (La Greca et.al., 1988; La Greca & Stone, 1993) and for
Adolescents( La Greca & Lopez, 1998), the Multidimensional Anxiety Scale for Children (MASC;
March et. al., 1997; March & Albano,1998) and the Screen for Child Anxiety Related Emotional
Disorders (SCARED), which has a parent version also (Birmaher et. al.,1997; Monga et. al., 2000).
The MASC and SCARED appear to be promising for clinical purpose according to Research Unit on

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Pediatric Psychopharmacology Anxiety group study, 2001.

A major clinical challenge is to differentiate between anxiety and depression. Anxiety scales do not
adequately distinguish between children with anxiety disorders and those with other diagnosis (Klein,
1994). Therefore, though anxiety scales may provide an overall estimate of anxiety levels, they
cannot be viewed as contributing to the diagnosis of anxiety disorders, and clinicians would be
unwise to rely on them only for differential diagnostic decisions.

Diagnostic Interviews:
Several systematic diagnostic interviews for children and for parents as informants have been
devised to meet different purposes and vary accordingly. The Diagnostic Interview Schedule for
Children (DISC; Shaffer et. al, 1996) was developed for use in epidemiological studies. It is highly
structured and can be used even by individuals who have no clinical training. A computer based
version is also available. The Diagnostic Interview for Children and Adolescents (DICA; Herjanic &
Reich, 1982; Reich et. al., 1991) is another highly structured instrument. The Child and Adolescent
Psychiatric Assessment (CAPA; Angold & Costello, 1995) also devised for epidemiological studies,
requires adequate training as it is less structured than DISC. The CAPA, in comparison to other
instruments, additionally covers assessment of functioning in school, social relationship, etc. along
with specific symptoms, allows for clarification of questions and more closely resembles usual clinical
interview. The Kiddie Schedule for Affective Disorder and Schizophrenia (K-SADS) has been
developed from a clinical perspective. Its present and lifetime version allows full latitude of inquiry.
(Chambers et. al. 1985, Kaufmen et al, 1997). The Anxiety Disorder Interview Schedule for Children
(ADIS) originally prepared to assess anxiety disorders has been expanded to provide diagnosis for
other major disorders. This can be employed to collect detailed information in a flexible clinical fashion
(Silverman & Albano 1996).

All the instruments described above have demonstrated modest to adequate test-retest reliability
with anxiety disorders faring no better or worse than most other diagnosis. There is little to guide
selection of instruments in terms of better reliability or validity but the DISC is the most widely used
worldwide.In Lucknow K-SADS-PL (Kaufmen et al, 1997) is the preferred tool. We understand that
many of the above mentioned tools not be available easily, others might not be suitable for use in
Indian population due to variety of reasons. The authors recommend use of K-SADS for diagnostic
assessment, CGI for severity evaluation and CGAS (Shaffer et al, 1983) for global assessment of
functioning as a minimal standard. Additionally, DOTES may be used for monitoring medication side-
effects (Campbell et al, 1985). Although conceived for research purposes, diagnostic interviews may
be useful to clinicians as they provide a comprehensive coverage of symptomatic status, are
excellent teaching tools and allow comparisons. In the end it needs to be said the though many
instruments are available all of them have not been conclusively shown to distinguish between
various anxiety disorders or anxiety disorders and other child psychiatric disorders. As such, a
sufficient level of precision for diagnostic classification has not been reached. Available evidence
only supports the diagnostic validity of social phobia but not other disorders.

OUTLINE OF DIAGNOSTIC ASSESSMENT

A. Obtain history from parents, patient, and other pertinent informants.


1. Note onset and development of symptoms and the context in which symptoms occur and are
maintained.
a. DSM - IV target symptoms, with particular attention to the following:
i. Determination of whether anxiety is stimulus specific, spontaneous, or anticipatory.
ii. Evaluation for avoidant behavior (degree of constriction of daily life).

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b. Biopsychosocial stressors.
c. Co morbid psychopathological symptoms, maladaptive personality traits, and internal
conflicts.
d. Impact of symptoms on the daily life of the patient and family.
e. Social and familial reinforcers of symptoms.
2. Emphasize developmental history with special consideration of the following:
a. Temperament
b. Ability to sooth self or be soothed.
c. Quality of attachment.
d. Adaptability.
e. Stranger and separation responses.
f. Childhood fears.
3. Obtain medical history, especially noting the following:
a. Numbers of visits to physician or emergency room for these or other symptoms.
b. Medications taken by the patient that could produce anxiety symptoms.
c. Medical disorders
4. Obtain school history.
a. Academic, athletic, social and behavioral functioning.
b. Disparity between potential and actual achievement.
c. Patterns of attendance.
5. Obtain social history.
a. Environmental stressors such as disorganized home, presence of child abuse
(physical, emotional or sexual) or neglect, mental or physical illness or death in family
members, or exposure to danger or violence.
b. History of separations and losses.
c. Degree of involvement with peer group and social competence.
6. Obtain family history with particular attention to the following:
a. Patient's past and present role in the context of family functioning.
b. Family stresses, resources, and coping style.
c. Family psychiatric history with emphasis on the following:
i. Anxiety disorders (including obsessive compulsive disorders).
ii. Mood disorders.
iii. ADHD.
iv. Psychoactive substance use disorders.
v. Tic disorders.
vi. Psychotic disorders.
vii. Suicidal behavior.

B. Interview the patient, including a mental status examination with special note of the
following:
1. Patient's reports of symptoms, including self-assessment of impairment.
2. Objective signs of anxiety, including motor tension, autonomic hyperactivity, vigilance and
scanning, variations in speech patterns and production and separation difficulty.
3. When developmentally appropriate, communication of anxiety through play and drawings.
Play techniques can be used to understand a child fears and reasons for anxiety.

C. Conduct family assessment.


1. Evaluation of family interactions and dynamics.
2. Assessment of parent -child relationship.

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D. Administer structured or semi structured interview for anxiety and comorbid diagnosis.

E. Administer clinical, self-report, and parent-report instruments for severity of anxiety


symptoms.

F. Refer for IQ and psychological testing if indicated clinically and for learning disability,
and speech and language testing if required and facilities are available.

G. Conduct physical evaluation of the child or adolescent.


1. Physical examination.
2. Consultation and collaboration with family practitioner, pediatrician or other specialties
as per need.
3. Evaluation of medical and neurological conditions as indicated. (See sec II.A below)

DIFFERENTIAL DIAGNOSIS

A. Consider physical conditions that may mimic anxiety disorders.


1. Documented hypoglycemic episodes.
2. Hyperthyroidism.
3. Cardiac arrhythmias
4. Caffeinism.
5. Pheochromocytoma.
6. Seizure disorders.
7. Migraine.
8. Central nervous system disorders (e.g., delirium or brain tumors).
9. Medication reactions: antihistamines, antiasthmatics, sympathomimetics, steroids,
SSRIs, anti-psychotics (akathisia), and nonprescription preparations, including diet pills
and cold medicines.

B. Screen for psychiatric disorders that may be comorbid with or misdiagnosed as anxiety
disorders.
1. Mood disorders.
2. ADHD.
3. Adjustment disorder.
4. Substance use disorders, including alcohol, nicotine, marijuana, cocaine, stimulants,
inhalants, and hallucinogens.
5. Borderline or other personality disorders.
6. Eating disorders.
7. Somatoform disorders.
8. Tic disorders.
9. Trichotillomania.
10. Reactive attachment disorder.
11. Pervasive developmental disorders.
12. Schizophrenia.
13. Sleep Terror Disorder.

C. Establish diagnosis of specific type of anxiety disorder. More than one may be present.

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1. Anxiety disorder beginning in childhood and adolescence: separation anxiety disorder.
2. Anxiety disorders affecting children, adolescents and adults.
a. Generalized anxiety disorder (inclusive over-anxious disorder of childhood).
b. Specific phobia.
c. Social phobia.
d. Panic disorder.
e. Obsessive - compulsive disorder.
f. Posttraumatic stress disorder.

Treatment
The evidence that childhood anxiety disorders cause suffering and impairment and may entail long
term liability highlight the need for effective treatments. Some interventions, such as CBT, are based
on theoretical models of anxiety while others such as medication, follow demonstrated efficacy in
adult anxiety disorders. Child and adolescent psychiatrists usually employ an integration of several
approaches in treating patients with anxiety disorders. In general, treatment planning should
consider severity of and impairment produced by the anxiety disorder. A multimodal approach is
advisable and psychotherapy should be considered an integral part of the management of childhood
anxiety disorder [CG] (Connolly et. al., 2007). Literature is replete with case reports and studies
evaluating various approaches. Wherever controlled studies are available, case reports have not
been considered in framing the recommendations. We initially brief the different approaches followed
by disorder-specific recommendations.

BEHAVIOR THERAPY:
Behavior therapy targets the patient's overt behavior and emphasizes treatment in context of family
and school instead of focusing on intrapsychic conflicts. (Bernstein et. al., 1997). Etiology is not the
focus of attention (Kazdin, 1991).Two comparative studies demonstrate efficacy of behavior therapy
(systematic desensitization) in treatment of children with school refusal. (Miller, 1972; Blagg and Yule,
1984).

CONGNITIVE BEHAVIOUR THERAPY:


CBT is the most well studied intervention. It integrates the behavioral approach with an emphasis on
changing the cognitions associated with the patient's anxiety. The basic notion is that distorted
cognitions about the dangerousness of the environment underlie anxiety symptoms. The aim is to
replace negative beliefs with more neutral realistic ones. The technique encourages the patients to
restructure their thoughts into a more positive framework resulting in more assertive and adaptive
behavior (Bernstein et. al., 1997). Cognitive interventions include identifying anxious feelings and
thoughts, recognizing somatic responses to anxiety, and devising a plan to deal with these
symptoms. Behavioral interventions include modeling, role-playing, relaxation techniques, exposure
and rewards. CBT has been used for a variety of childhood anxiety disorders and is said to be
effective (Roblek & Piacentini ,2005; Cartwright-Hatton et. al., 2004). Another major advantage of
CBT is availability of treatment manuals that allow comparison across studies. The controlled studies
of CBT may be divided into those that have used a no-treatment waiting list control group, and those
that have compared CBT to a non-specific control intervention. Early trials often used waiting list
controls. The problem with this methodology was that this confirms to patients that they require
treatment, but withholds it. Another limitation is that this control does not reveal the specific
usefulness of an intervention, because there is no way of determining whether treatment was
effective because of its particular nature, or because of non-specific factors such as therapist's
interest and concern, or the family mobilizing itself to bring the child for treatment. Even if control
psychotherapy is used, it should be equivalently appreciated by recipients, so that treatment effects

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are not due to difference in treatment credibility. The most informative studies are those which rely on
a comparison treatment that is reasonable and credible i.e. use attention controls. CBT was
examined in two systematic studies by Kendall (Kendall 1994, Kendall et al. 1997) and he reported
that the group receiving CBT had significantly better outcome. However, two other studies of CBT
using attention controls reported no difference in efficacy (Last 1998; Silverman et. al., 1999). Other
studies have examined parental involvement (Bernstein et. al.,2005, Spence et. al., 2000,
Mendlowitz et. al. 1999) and report benefits of the same. In a study on family cognitive behavioral
therapy for childhood anxiety disorders Wood et. al., 2006 report that family CBT may provide
additional benefit over and above child-focused CBT. These findings provide preliminary support and
encourage further research in parental participation in treatment for childhood anxiety. Many other
studies are available, most of them suffer from methodological limitations, but there is evidence of
improvement which is sustained over time (Kendall et al. 1996, Barrett et al.2001, Kendall et al. 2004).
A recent review of CBT studies concluded that cognitive behavioral therapy appears an effective
treatment for childhood and adolescent anxiety disorders in comparison to waiting list or attention
control. There was no evidence for a difference between an individual, group or parental/family
format. CBT can be recommended for the treatment of childhood and anxiety disorders, although with
only just over half improving, there is a need for further therapeutic developments (James et. al.,
2005).

PSYCHOANALYSIS AND PSYCHODYNAMIC PSYCHOTHERAPY:


Clinical data on psychoanalysis consists largely of case reports and most accounts report favorable
results. Systematic studies of psychoanalysis (Heinicke and Ramsey-Klee, 1986; Target and
Fonagy,1994) relevant to childhood anxiety disorders report improved capacity for relationships,
frustration tolerance, balanced use of defenses and improvement in adaptation.

Psychodynamic psychotherapy is a derivative of psychoanalysis with modifications such as less


frequent appointments, greater participation of parents in treatment, and more explicit use of active
support, practical guidance and environmental interventions (Bemporad, 1991). Anxious children
generally benefit from mastering themes of separation, autonomy, self-esteem, and age appropriate
behavior (Bernstein et al., 1997). Studies documenting efficacy in children are available (Muratori et.
al.2003, Barett et. al., 1998, Hampe et al 1973, Miller et al, 1972). Overall, it is an effective but time
consuming approach. Until recently this approach was widely practiced and accepted but has been
overtaken by CBT now.

PARENT CHILD INTERVENTIONS AND FAMILY THERAPY:


Early temperamental traits of passivity, shyness, behavioral inhibition, fear & withdrawal in unfamiliar
situations and insecure mother-child relation have been associated with increased risk of developing
anxiety disorders during childhood (Capsi et al, 1995; Kagan et al 1988; Biederman et al, 1993;
Warren et al, 1997; Prior et.al. 2000; Williams et. al. 1990). Therefore, attention to temperament and
parent- child relationship is vital. Parent child interventions include helping parents encourage the
child to face new situations, refraining from excessive criticism and intrusiveness, responding to
child's emotional needs and encouraging child to engage in activities despite anxiety (Ginsburg et.
al.,2002; Barrett P M, 1996; Crawford et. al. 2001).
Family theory views anxiety symptoms in interpersonal terms and postulates that anxiety
symptoms reflect problems in the family system (Last et. al. 1991). Bernstein et al .1990 in a study of
76 families identified family difficulties in areas of role performance, values and norms. It has been
suggested that working with the family is a key to decrease anxiety symptoms experienced by the
child. The aim of the therapy is to disrupt the dysfunctional family interactions that promote insecurity
and to support areas of family competence (McDermott et. al. 1989).

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PHARMACOLOGICAL TREATMENT:
Pharmacotherapy should preferably be used as adjunct to behavioral or psychotherapeutic
interventions rather than as a sole intervention. This approach is important to prevent symptom return
after discontinuation of medications. SSRI's have been extensively used for adult anxiety disorders
and have documented safety and efficacy. Although several open trials of SSRI's in children have
appeared, the most important study till date is a large multicentric, placebo controlled study
(Research Unit on Pediatric Pharmacology Anxiety Group, 2001) documenting efficacy of
fluvoxamine in children with mixed anxiety disorders (Social phobia, separation anxiety and
generalized anxiety disorder), without major depression. 79% of the children on medication
improved, as compared to 28% on placebo over a period of 8 weeks. Williams & Miller, 2003 after
reviewing evidence state that the serotonin selective reuptake inhibitors should be considered first-
line pharmacological treatment for anxiety disorders in children and adolescents [CG]. However,
medications other than SSRIs may also be considered for treatment of anxiety disorders in children
and adolescents [CG]. Klein, 1994 in his review of literature on TCAs states that the support for the
efficacy of TCAs in children with separation anxiety is inconsistent. Bernstein el. at., 2000 reported
efficacy of imipramine compared to placebo in adolescents with school refusal and anxiety disorders.
Although there are reports supporting efficacy of benzodiazepines in childhood anxiety disorders,
the safely profile of SSRIs and evidence of their recent usefulness weaken consideration of
benzodiazepines. However, they may be used on short term basis for immediate respite from anxiety
symptoms. Less commonly buspirone and -blockers may be employed if required. At this time, there
are no specific dosing guidelines for children and adolescents with anxiety disorder. Experts
recommend starting at low doses, monitoring side effects closely, and then increasing the dose
slowly on the basis of treatment response and tolerability. Clinicians need to appreciate that anxious
child and anxious parents may be especially sensitive to any worsening in the child's somatic
symptoms or emergence of even transient side effects of medications. Selection of medication is
guided by several factors, primarily co morbidity and side effect profile (Connolly et. al., 2007).

DISORDER SPECIFIC RECOMMENDATIONS


Separation Anxiety Disorder, Generalized Anxiety Disorder and other Anxiety Disorders:
Majority of pharmacological studies of children and adolescents with anxiety disorders enroll a mixed
diagnostic group including with SAD, GAD and/or Social phobia. Several trials support efficacy of
SSRIs in treatment of anxiety disorders in children. Efficacy and safety of fluovoxamine & Paroxetine
in children and adolescent with SAD, GAD and/or social phobia, of sertraline for youth with GAD, and
of fluoxetine for youth with SAD, GAD and/or social phobia has been documented in well designed
trials (Reinblatt et.al.,2007; Seidel et.al.,2006; Muller et. al., 2005; Wagner et.al.,2004; Birmaher et. al.
2003; Brent D A, 2003; Pine DS, 2002; RUPP study, 2001; Rynn et. al. 2001). The most common side
effects reported were abdominal discomfort and headache. No major problems were reported.
Currently, an SSRI is the first line choice medication for children and adolescent with anxiety
disorders, including those with SAD. Fluoxetine has also been reported to be clinically effective as
maintenance treatment of anxiety disorders in children and adolescents (Clark et. al., 2005).
Preliminary findings from controlled trials of extended release venlafaxine in treatment of youths with
generalized anxiety disorder (Rynn et. al.2002, Rynn et. al.2007) and social phobia (Tourian
et.al.2004) suggest it may be well tolerated and effective. Tricycles antidepressants are an alternative
choice. However, scientific data for this group is much less convincing than that for SSRI's. Controlled
studies for TCA's in SAD and/or school refusal report contrasting findings (Bernstein et. al. 1996). A
study comparing CBT + Imipramine and CBT + placebo for adolescent school refusal with co-morbid
anxiety and depression reported response rate of 70% and 28% respectively after 8 weeks of
treatment. The point to be noted is that these patients did not suffer from pure anxiety problems
(Bernstein et. al. 2000). Use of BZD's in treatment of youth with anxiety disorders is backed by limited

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data. Due to dependence potential this class of medications is reserved for short term use, typically in
combination with an SSRI's or TCA while waiting for the onset of therapeutic effect of SSRI / TCA. It
has been recommended that the SSRI should be continued for approximately one year after
remission of target symptoms. Subsequently, during a low stress period a watchful medication free
trial may be given. If relapse occurs SSRI should be immediately reinstated (Pine D S, 2002).

In terms of psychotherapeutic interventions, CBT has the greatest empirical support (Albano et. al.,
2002; Bernstein et. al., 2000; Dadds et. al. 2001; Velting et. al. 2004; Barrett PM, 1998; Kendall et. al.
1996; Last, 1998). The common components are 1. Education about nature of anxiety. 2. Activities to
increase recognition of anxious thoughts and feelings. 3. Coping strategies such as adaptive self talk
(cognitive-modification), progressive muscular relaxation and diaphragmatic breathing, and 4.
Exposure to anxiety-provoking stimuli. The role of family therapy as a positive addition has also been
documented along with efficacy in group format for SAD, GAD and social phobia (Barrett et. al. 1996;
Dadds et. al. 2001; Kearney et. al. 2003). Data strongly supports short term efficacy of group/
individual CBT and SSRI's for youth with anxiety disorders. In anxiety disorders of mild severity, CBT
should be initiated first, followed by SSRI in case of non-response. In practice, the two approaches
are often combined for severe, impairing anxiety disorders. In cases of Generalized Anxiety Disorder
CBT or CBT plus medication both are appropriate approaches based on severity of the case.
Medication alone is not recommended. In mild to moderate cases CBT alone usually suffices
(Connolly et. al., 2007).

Social Phobia:
CBT and SSRIs are the first line treatments. To our knowledge there is no published study examining
efficacy of SSRIs in a sample of pure social phobia. However, studies of CBT in such samples are
available and report CBT to be effective (Dadds et. al. 2001; Velting et. al. 2004; Beidal et. al. 2000).
Depending on presentation, treatment may begin with CBT alone or CBT plus an SSRI (Mancini C. et.
al., 2005). CBT here consists of social skills training, increased social opportunities, relaxation
techniques, adaptive self-talk (cognitive restructuring), exposure and response prevention.
Individual, group and school-based all interventions have found to be effective (Albano et. al. 1999;
Masia et. al. 2001; Baer et. al. 2005)

Specific Phobia:
Treatment for specific phobias differs from CBT of SAD, GAD and social phobia. It primarily involves
graded exposure to the feared stimuli, imaginary or actual, according to hierarchy constructed by the
child progressing gradually from mild to most significant fears (Velting et. al. 2004). When exposure is
paired with relaxation the technique is referred to as systematic desensitization. Other treatments
include modeling, and cognitive exercises to facilitate adaptive thoughts. These also can be paired
with graded exposure. Outcome studies report significant and sustained improvement with these
approaches (Muris et. al. 1999; Bernstein et. al. 2005; Silvermann et. al. 1999; Berman et. al. 2000).

Panic Disorder:
CBT again is the first line of treatment. Components include 1. Education about the physical
experience associated with panic attacks. 2. Breathing and relaxation exercises. 3. Interceptive
exposure (i.e. exposure to cues associated with panic). 4. In vivo exposure. 5. Cognitive modification
to reduce catastrophic misinterpretation. Ollendick, 1995 reported efficacy of this approach in a
multiple-baseline design analysis. In practice an SSRI may be added to CBT (Masi et. al. 2001). Masi
et. al. 2006 after reviewing the empirical evidence of pharmacotherapy in early-onset panic disorder,
including selective serotonin re-uptake inhibitors, benzodiazepines and tricyclics conclude that the
data supporting efficacy are still limited, and no controlled studies are available. Research in this area
is wanting.

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Posttraumatic Stress Disorder
Although only some of the children and adolescents exposed to traumatic life events develop full-
blown posttraumatic stress disorder, many others experience some PTSD symptoms and associated
functional impairments. A variety of psychopharmacological and psychosocial treatments are
currently available for this group of anxiety disorders but the effectiveness of most of those
interventions has not been adequately evaluated. Only trauma-focused cognitive behavioral
interventions and SSRIs enjoy empirical evidence of efficacy.

Psychotherapeutic treatments:
Trauma-Focused CBT: Widely regarded as the first line treatment for PTSD. Several RCTs proving
trauma focused CBT to be superior to other treatment are available. It decreases PTSD, depressive
and behavioural symptoms, and /or functional impairment in traumatized children. Majority of
research has been done on sexually abused children (Cohan et al, 2004). Typically 10-16 treatment
sessions are given. The major components of this treatment are
- Psycho education about traumatic reactions and PTSD
- Stress-inoculation- including affective modulation, muscle relaxation, focused
breathing, thought stopping, and cognitive coping techniques.
- Gradual exposure- consisting of carefully calibrated efforts to encourage the child to
recall and describe increasing details about the traumatic events as well as thoughts,
feelings and physical sensations experienced at the time of the original trauma as well
as during retelling.
- Cognitive processing
- Parental treatment component
Eye Movement Desensitization And Reprocessing (EMDR): Variant of trauma focused CBT, in
which exposure and cognitive reprocessing interventions are paired with directed eye movements;
fewer sessions are required.
Crisis Intervention: Consist of one to three sessions provided in the immediate aftermath of a
traumatic event. It is often provided in a community setting and includes encouragement to discuss
feelings, provision of emotional support and psycho education about common reaction to stress and
advice about managing these reactions.
Play Therapy: Therapists do not direct the form or content of child's play but rather interpret
themes in it thought to be representative of certain inner conflicts.
Other Techniques
Psychodynamic & psychoanalytical technique
Parent-child interaction therapy
Dialectical behaviour therapy
Relationship based conjoint parent-child treatment

Pharmacological treatment:
The data supporting efficacy of pharmacotherapy in early-onset panic disorder, including selective
serotonin re-uptake inhibitors, benzodiazepines & tricyclics is limited (Masi et. al.,2006). Only one
randomized trial has been conducted. This study evaluated the comparative impact of imipramine vs
chloral hydrade on development of PTSD in acutely burnt children and demonstrated the efficacy of
imipramine (Robert et. al, 1999). Several open trials have demonstrated clinical improvement with
adrenergic blockers (PPNL), clonidine, dopamine antagonists (risperidone) and opiates. In practice
SSRI's, TCA's, venlafaxine, bupropion or any of the above mentioned medications may be used. No
information is available with regard to optimal length of treatment, need for maintenance treatment or
use of multiple medications in treatment of childhood PTSD.

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Obsessive Compulsive Disorder:
It is now being increasingly appreciated that although OCD in children is often chronic and can be
severe, the outlook for patients receiving prompt diagnosis and appropriate treatment is quite
positive. Considerable progress has been made in testing and refinement of both pharmacological
and psychosocial treatments. Both forms of treatment are very effective in symptom relief and
produce improvements in functioning, Clinical consensus suggests that combined treatment has
added benefits. Treatments should begin with educating the family of the child about how to handle
their child's behavior, which may be disrupting family life. On the internet www.ocdresource is a useful
source of information about the disorder. If the disorder is hampering school performance, teachers
need to be told about the child's problem and if possible be involved in the child's behavioral program.
Choice of first line therapy depends on the symptom pattern, severity, and the patient's and family's
preference. Whatever is used, it is important to urge flexibility, as combination therapy may be
eventually required.

Cognitive-Behavior Therapy:
The technique of CBT needs to be modified in accordance with the developmental age of the child.
CBT for pediatric OCD basically encompasses three techniques
1. Exposure and Response prevention
2. Cognitive therapy and
3. Relaxation training.

ERP is the most recommended and effective approach. Cognitive therapy, which involves changing
false beliefs, challenging reality of obsessions and necessity of compulsions, is usually ineffective as
a sole treatment for OCD. However, it is a useful complement in most cases. Relaxation therapy is
primarily used to manage anxiety produced by exposure but has no direct affect on O.C. Symptoms.
Older children and adolescents respond well to CBT modeled on approaches used for adult OCD.
However, younger children require a number of modifications. These include additional efforts to
educate child and family about the nature of excessive anxiety and the role of treatment, sensitizing
the child to the impact of OCD on his/her life and fostering motivation for change through his/her co-
operation and perseverance in treatment, building a shared language to better communicate the
nature of associated feelings or cognitions, and including behavioral rewards for maintaining
engagement in treatment. Manuals for modified CBT for OCD suitable for children are available.
Methodology, though undergoing continued refinement currently involves.
1. Daily exposure to cues avoided because of associated discomfort and rituals, and
2. Maintaining exposure and not ritualizing for at least an hour or until discomfort subsides.

Developmentally modified forms of CBT for children appear to confer similar benefits in children as
observed for adult population (O'Kearney et. al., 2006). Uncontrolled trials of CBT appear highly
promising, with excellent response in up to 75% of the patients. Although, gains from ERP persist
beyond discontinuation, booster treatment may help long term progress, and additional treatment
may be needed for relapses brought on by stress. O'Kearney et. al., 2007 after reviewing evidence on
benefits of cognitive-behavioural therapy for children and youth with obsessive-compulsive disorder
report that CBT should be regarded as a first line equivalent to anti-OCD medication with the potential
to lead to better outcomes when combined with medication than medication alone can provide.
Additional studies are needed to further clarify CBT's benefits and to investigate how it can be made
more available as a treatment option for children and youth who suffer from OCD.

Pharmacological Treatment:
Although pediatric trials of SSRIs have lagged behind those in adults, there is now extensive
substantiation of the utility of pharmacotherapy in pediatric OCD. An initial trial of Serotonin Reuptake

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Inhibitor (SRI), most often an SSRI is the treatment of choice. If there is inadequate response at 10-12
weeks, another SSRI may be tried.

Serotonergic Agents:
Clomipramine was the first agent shown to be effective in O.C.D. A meta-analysis suggested that it
may possess greater efficiency for pediatric OCD than the SSRIs (Allen, 1994; Practice Parameters
for OCD, 1998). De Veaugh-Geis et.al, 1992 documented the efficacy of clomipramine in pediatric
O.C.D in randomized controlled trial. However, being a tricyclic, it is associated with significantly
greater risk of side effects and therefore is relegated to a second or third line treatment choice in
children and adolescent with OCD. The evidence base supporting the efficacy and safely of SSRIs
has considerably strengthened over the last few years (Geller et. al. 2004; Geller et. al. 2003; Practice
Parameters for OCD, 1998). Anti-obsessive efficacy of fluoxetine, fluvoxamine and sertraline has
been reported by controlled trials (March et.al.1998 Geller et. al. 2002; Liebowitz et. al. 2002, Riddle
et. al. 2001). Similar benefits have been reported for Paroxetine (Geller et. al. 2003) and for
Citalopram (Mukkades et. al. 2003). Low initial doses, with slow upward titration, are the rule.
Patients should be told trials of more than one agent may be required, at times with augumenting
agents. In controlled trials reduction in baseline symptom rating with treatment of upto 16 weeks has
been relatively consistent, although modest, ranging from 18 to 44 percent (Geller et. al. 2003; Geller
et. al. 2002; Liebowitz et. al. 2002; Riddle et. al. 2001). Studies including long term observation report
continued symptom reduction upto one year. Data suggests that treatment benefits with SSRIs are
stable and can be expected to strengthen in many with continued treatment. Overall, SSRIs have
been found to be well tolerated by child and adolescent patients with OCD. However, almost 50% of
the children and adolescents treated with an SSRI continue to have interfering symptoms and may
require trials of alternative SSRIs, combined pharmacotherapy and addition of psychotherapeutic
interventions.

Augmenting Strategies and Adjunctive agents:


Up to 50% childhood OCD cases show no or partial response to SRI treatment, even if two different
SRIs are used (Geller et.al ,2003). Hence, augmentation strategies may be required. There are no
randomized controlled trials of the utility of augmentation strategies in Pediatric OCD. However,
based on experiences in adult patients, augmentation of an SRI might be considered for pediatric
patients with a partial response or intolerance to higher doses. In adults, three agents, Clonazepam,
Haloperidol, and Risperidone (Mc Dougle et.al., 1995; Pigott et.al.,1992) have been shown to be
effective in controlled trials. These agents are worth a try. Another strategy, addition of a second
concurrent SRI, has been used to a limited extent in children. An open table trial of six adolescents
(Simeon et.al. 1990) combined fluoxetine and clomipramine and reported decreased doses
requirement for both medications and fewer side effect. Figueroa et.al., 1998 described an open
series of seven patients given clomipramine and SSRI (fluoxetine, sertraline or paroxetine) and
followed through 5-22 months. Combination therapy appeared to be more effective than
monotherapy for all cases. Adjunctive treatment may be indicated for children and adolescent with
OCD with comorbidities. The comorbidity of tic disorders may require the addition of a-agonists or
neuroleptics. Co-morbid anxiety symptoms are benefited by addition of BZDs or Buspirone.
Depressive Symptoms may improve with lithium addition.

Treatment Planning:
Many experts and consensus guidelines recommend CBT as the first line approach for the majority of
children and adolescents with OCD. However, more severe symptoms, comorbid depression or
limited cooperation may prompt the clinician to consider medication alone or in combination with CBT.
One half or more of the young patients with OCD usually require combined therapy at some point of

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time to achieve complete remission. OCD is often chronic and long-term medication treatment is
often required to maintain symptom control (Leonard et.al. 1991). Whenever discontinuation is
attempted, tapering should be gradual usually over several weeks. Long term (indefinite) drug
maintenance is suggested after 2-4 relapses. Concomitant CBT has been observed to assist
medication discontinuation in some patients (Stanley & Turner 1995; Wever & Rey 1997). Periodic
resumption of CBT may be necessary to combat symptom exacerbation in response to stress or
development transitions. In general, OCD in children & adolescent is very responsive to treatment.
Majority of patients should experience significant relief and return to functioning. Reducing delays in
diagnosis and aggressive treatment, often with combined approaches goes a long way in minimizing
impact of the disorder on children development.

Selective Mutism:
Data on treatment of selective mutism is mostly limited to single case studies. Controlled trials are
lacking. In spite of this, the conviction that behavioral techniques are an essential component of
management of selective mutism is widespread. Reports describe successful use of techniques such
as contingency management, stimulus fading, systematic desensitization, negative reinforcement
and shaping. A combination of behavioral techniques is probably the most common and successful
treatment approach (Anstending K, 1998; Dow et. al. 1995; Holmbeck et. al. 1992; Watson et. al.
1992). A hierarchy of situations in which the child has difficulty speaking is prepared. Then, the child is
guided to systematically engage in speaking- related behaviors (e.g. mouthing speech, making
sounds , whispering and so on.) in increasingly more difficult situations. With repeated attempts,
associated anxiety dissipates through autonomic habituation. When the feared consequences of
speaking fail to occur anxiety is further reduced. Typically, child is given rewards after attempts to
engage in desired behaviors. The young age of most children with selective mutism and the fact that
most of these children initially do not speak to the therapist necessitates parental involvement in
treatment. Traditional anxiety-reducing behavioral techniques like shaping, gradual exposure and
reinforcement are often used in initial sessions. Involvement of school personnel for providing regular
communication and support in school is also highly recommended.

Other Psychosocial therapies:


Although behavior therapy is most commonly employed, accounts of successful treatment of
selective mutism with use of play therapy, family therapy, psychodynamic therapy, and group therapy
are also available (Watson et.al. 1992; Tatem et.al. 1995; Dow et. al.; Bozigar & Hansen, 1984;
Anstendig et. al. 1998). These strategies may be used as per need. It is common for children with
selective mutism to have some degree of speech or language difficulties which exacerbate speech-
related anxiety. In such cases speech therapy should be considered as an adjunct to other
interventions.

Pharmacological Treatments:
SSRI medications appear to be effective. A double-blind, placebo controlled trial of fluoxetine in
children with selective mutism indicated significant benefit (Black & Uhde, 1995). In addition,
fluvoxamine was also found to be efficacious in a large multicentric study of anxiety disorders (RUPP
Anxiety Group Study, 2001). Several open trials and case reports also support the use of SSRIs for
selective mutism (Cartson et.al. 1999; Dow et. al. 1995). As of now, behavior therapy when available
and practical should be considered the initial intervention strategy. In resistant cases, a combination
treatment may be used.

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REVIEW Open Access

Canadian clinical practice guidelines for the


management of anxiety, posttraumatic stress and
obsessive-compulsive disorders
Martin A Katzman1*, Pierre Bleau2, Pierre Blier3, Pratap Chokka4, Kevin Kjernisted5, Michael Van Ameringen6,
the Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/
Association Canadienne des troubles anxieux and McGill University

Abstract
Background: Anxiety and related disorders are among the most common mental disorders, with lifetime
prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated.
Methods: These guidelines were developed by Canadian experts in anxiety and related disorders through a
consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were
obtained through MEDLINE, PsycINFO, and manual searches (19802012). Treatment strategies were rated on
strength of evidence, and a clinical recommendation for each intervention was made, based on global impression
of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines.
Results: These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and
management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder,
agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder,
and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents,
pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions.
Conclusions: Anxiety and related disorders are very common in clinical practice, and frequently comorbid with
other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and
side effect profiles of pharmacological and psychological treatments.

Introduction evidence-based recommendations. This guideline docu-


Anxiety and related disorders are among the most com- ment is not focused on any individual type of clinician
mon of mental disorders. Lifetime prevalence of anxiety but rather on assessing the data and making recommen-
disorders is reportedly as high as 31%; higher than the dations. Subsequent user friendly tools and other
lifetime prevalence of mood disorders and substance use initiatives are planned.
disorders (SUDs) [1-5]. Unfortunately, anxiety disorders The guidelines include panic disorder, agoraphobia,
are under-diagnosed [6] and under-treated [5,7,8]. specific phobia, social anxiety disorder (SAD), generalized
These guidelines were developed to assist clinicians, anxiety disorder (GAD), as well as obsessive-compulsive
including primary care physicians and psychiatrists, as disorder (OCD), and posttraumatic stress disorder
well as psychologists, social workers, occupational thera- (PTSD). Also included are brief discussions of clinically
pists, and nurses with the diagnosis and treatment of relevant issues in the management of anxiety and related
anxiety and related disorders by providing practical, disorders in children and adolescents, women who are
pregnant or lactating, and elderly patients, and patients
with comorbid conditions.
* Correspondence: mkatzman@startclinic.ca
1
Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1,
Canada
Full list of author information is available at the end of the article
2014 Katzman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Methods Table 2 Treatment recommendation summary


These guidelines are based on a thorough review of First-line Level 1 or Level 2 evidence plus clinical support for
the current literature and were developed by a panel of efficacy and safety
Canadian experts in anxiety and related disorders Second-line Level 3 evidence or higher plus clinical support for
efficacy and safety
through a consensus process. Data on the epidemiology,
Third-line Level 4 evidence or higher plus clinical support for
diagnosis, and treatment (psychological and pharmacolo- efficacy and safety
gical) were obtained through MEDLINE searches of Not Level 1 or Level 2 evidence for lack of efficacy
English language citations (19802012), using search recommended
terms encompassing the specific treatments and specific
anxiety and related disorders. These searches were supple-
mented with data from PsycINFO and manual searches of and the evidence upon which they had been based were
the bibliographies of efficacy studies, meta-analyses, and reviewed at a meeting of the panel in December 2012;
review articles. Treatment strategies were rated on subsequently, draft guidelines were prepared by the sub-
strength of evidence for the intervention (Table 1). A clini- panels which were then circulated to the entire group
cal recommendation for each intervention was then made, for consensus ratification during 2013. Preliminary
based on global impression of efficacy in clinical trials, recommendations were also presented to the Canadian
effectiveness in clinical practice, and side effects, using a psychiatric community for input in September 2012 at
modified version of the periodic health examination guide- the Canadian Psychiatric Association annual conference.
lines (Table 2). These guidelines are presented in 10 sections, the first
The guidelines were initiated prior to the introduction of which is this introduction. In the following section, the
of the American Psychiatric Associations (APA) fifth edi- principles of diagnosis and management of anxiety and
tion of the Diagnostic and Statistical Manual of Mental related disorders are covered. That section provides an
Disorders (DSM-5) and the committee was sensitive to overview of the differential diagnoses associated with
potential changes to the nosology of anxiety and related anxiety and related disorders in general, discusses issues
disorders and its impact on the guidelines. However, it that affect all anxiety disorders, and presents the general
was agreed that, since the evidence for treatment is based advantages and disadvantages of psychological treatment
on studies using DSM-IV criteria (or earlier), the intro- and pharmacotherapy options. In the subsequent six sec-
duction of the DSM-5 would not fundamentally alter the tions (Sections 3 through 8), the specific diagnosis and
evidence and recommendations at this time. Whether management of the individual anxiety and related disor-
using DSM-5 diagnostic criteria for the inclusion patients ders (panic disorder, specific phobia, SAD, OCD, GAD,
in clinical trials in the future will have an impact on out- and PTSD) are reviewed and recommendations are made
comes, remains to be seen. for psychological and pharmacological treatments. Sec-
The panel of Canadian experts in anxiety and related tion 9 discusses issues that may warrant special attention
disorders responsible for the development of these pertaining to anxiety and related disorders in children
guidelines via consensus process included 10 psychia- and adolescents, pregnant or lactating women, and the
trists and seven psychologists who were organized into elderly. The last section of these guidelines addresses
subpanels based on their expertise in particular anxiety clinical issues that may arise when treating patients with
or related disorders as well as in treating specific patient anxiety and related disorders who are also diagnosed
populations. Preliminary treatment recommendations with comorbid psychiatric conditions such as major
depressive disorder (MDD), bipolar disorder, or other
psychoses, and attention deficit/hyperactivity disorder
Table 1 Levels of evidence (ADHD), or medical comorbidities, such as pain syn-
1 Meta-analysis or at least 2 randomized controlled trials (RCTs) that dromes, cardiovascular disease, and diabetes/metabolic
included a placebo condition syndrome.
2 At least 1 RCT with placebo or active comparison condition
3 Uncontrolled trial with at least 10 subjects Principles of diagnosis and management of
4 Anecdotal reports or expert opinion anxiety and related disorders
Levels of evidence do not assume positive or negative or equivocal results, Epidemiology
they merely represent the quality and nature of the studies that have been Prevalence and impact
conducted.
Anxiety and related disorders are among the most com-
Level 1 and Level 2 evidence refer to treatment studies in which randomized
comparisons are available. Recommendations involving epidemiological or risk mon mental disorders, with lifetime prevalence rates as
factors primarily arise from observational studies, hence the highest level of high as 31% [1-5] and 12-month prevalence rates of
evidence for these is usually Level 3. Recommendations, such as principles of
care, reflect consensus opinion based on evidence from various data sources,
about 18% [3,4]. Rates for individual disorders vary
and therefore are primarily Level 4 evidence. widely. Women generally have higher prevalence rates
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for most anxiety disorders, compared with men [4,5,9]. Asking patients if they are feeling nervous, anxious or
Anxiety and related disorders are associated with an on edge, or whether they have uncontrollable worry, can
increased risk of developing a comorbid major depres- be useful to detect anxiety in patients in whom the clini-
sive disorder [10-12]. cian suspects an anxiety or related disorder [7]. The
Anxiety and related disorders put a significant burden DSM-5 suggests the questions shown in Table 4 for the
on patients and their family members [13]. They are identification of anxiety-related symptoms; items scored
associated with substantial functional impairment, which as mild or greater may warrant further assessment [26].
increases as the severity of anxiety [14] or the number of If anxiety symptoms are endorsed, they should be
comorbid anxiety disorders increases [7,15]. In addition, explored in more detail by including questions about
studies have demonstrated quality of life impairments in the onset of the anxiety symptoms, associations with life
patients with various anxiety and related disorders events or trauma, the nature of the anxiety (i.e., worry,
[16,17]. Anxiety has a considerable economic impact on avoidance, or obsession), and the impact they have had
society as well, being associated with greater use of health on the patients current functioning.
care services [5,18] and decreased work productivity Table 5 presents suggested screening questions for
[18,19]. individual anxiety and related disorders, from various
Importantly, studies report that about 40% of patients validated screening tools [27-30], some of which are
diagnosed with anxiety and related disorder are freely available online (e.g., http://www.macanxiety.com/
untreated [5,7]. online-anxiety-screening-test).
Suicide risk Conduct differential diagnosis
In large surveys, anxiety and related disorders were The differential diagnosis of anxiety and related disor-
independently associated with a significant 1.7-2.5 times ders should consider whether the anxiety is due to
increased risk of suicide attempts [20-23]; however, data another medical or psychiatric condition, is comorbid
are conflicting as to whether the risk is moderated by with another medical or psychiatric condition, or is
gender [20,23]. Increased risk of suicide attempts or medication-induced or drug-related [32].
completed suicide has been reported for patients with When a patient presents with excessive or uncontrolla-
panic disorder, PTSD [20,24], and GAD [24], even in ble anxiety it is important to identify other potential
the absence of a comorbid mood disorder. These data causes of the symptoms, including direct effects of a sub-
indicate that patients with an anxiety disorder warrant stance (e.g., drug abuse or medication) or medical condi-
explicit evaluation for suicide risk. The presence of a tion (e.g., hyperthyroidism, cardiopulmonary disorders,
comorbid mood disorder significantly increases the risk traumatic brain injury), or another mental disorder [26].
of suicidal behavior [22,25]. However, since comorbid conditions are common, the
presence of some of these other conditions may not pre-
Initial assessment of patients with anxiety clude the diagnosis of an anxiety or related disorder.
The management of patients presenting with anxiety Certain risk factors have been associated with anxiety
symptoms should initially follow the flow of the five and related disorders and should increase the clinicians
main components outlined in Table 3. index of suspicion (Table 6) [4,9,33-37]. A family [33] or
Screen for anxiety and related symptoms personal history of mood or anxiety disorders [34,35] is
Anxiety and related disorders are generally characterized an important predictor of anxiety symptoms. In addi-
by the features of excessive anxiety, fear, worry, and avoid- tion, family history is associated with a more recurrent
ance. While anxiety can be a normal part of everyday life, course, greater impairment, and greater service use [33].
anxiety disorders are associated with functional impair- A personal history of stressful life events is also asso-
ment; as part of the key diagnostic criteria for anxiety dis- ciated the development of anxiety and related disorders
orders is the requirement that the symptoms cause [36,37], in particular, childhood abuse [37].
clinically significant distress or impairment in social, occu- Women generally have higher prevalence rates across
pational, or other important areas of functioning [26]. all anxiety and related disorders, compared with men
[4,5,9]. The median of age of onset is very early for some

Table 3 Overview of the management of anxiety and


related disorders Table 4 General screening questions
Screen for anxiety and related symptoms During the past two weeks how much have you been bothered by
Conduct differential diagnosis (consider severity, impairment, and the following problems?
comorbidity) Feeling nervous, anxious, frightened, worried, or on edge
Identify specific anxiety or related disorder Feeling panic or being frightened
Psychological and/or pharmacological treatment Avoiding situations that make you anxious
Perform follow-up
Adapted from reference [26].
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Table 5 Screening questions for specific anxiety and related disorders


Panic disorder MACSCREEN [29,30]
Do you have sudden episodes/spells/attacks of intense fear or discomfort that are unexpected or out of the blue?
If you answered YES then continue
Have you had more than one of these attacks?
Does the worst part of these attacks usually peak within several minutes?
Have you ever had one of these attacks and spent the next month or more living in fear of having another attack or worrying about
the consequences of the attack?
SAD (Based on Mini-SPIN [28])
Does fear of embarrassment cause you to avoid doing things or speaking to people?
Do you avoid activities in which you are the center of attention?
Is being embarrassed or looking stupid among your worst fears?
GAD [31]
During the past 4 weeks, have you been bothered by feeling worried, tense, or anxious most of the time?
Are you frequently tense, irritable, and having trouble sleeping?
OCD MACSCREEN [29,30]
Obsessions:
Are you bothered by repeated and unwanted thoughts of any of the following types:
Thoughts of hurting someone else
Sexual thoughts
Excessive concern about contamination/germs/disease
Preoccupation with doubts (what if questions) or an inability to make decisions
Mental rituals (e.g., counting, praying, repeating)
Other unwanted intrusive thoughts
If you answered YES to any of the above Do you have trouble resisting these thoughts, images, or impulses when they come into
your mind?
Compulsions:
Do you feel driven to perform certain actions or habits over and over again, or in a certain way, or until it feels just right? Such as:
Washing, cleaning
Checking (e.g., doors, locks, appliances)
Ordering/arranging
Repeating (e.g., counting, touching, praying)
Hoarding/collecting/saving
If you answered YES to any of the above Do you have trouble resisting the urge to do these things?
PTSD MACSCREEN [29,30]
Have you experienced or seen a life-threatening or traumatic event such as a rape, accident, someone badly hurt or killed, assault,
natural or man-made disaster, war, or torture?
If you answered YES then continue
Do you re-experience the event in disturbing (upsetting) ways such as dreams, intrusive memories, flashbacks, or physical reactions to
situations that remind you of the event?

phobias and for separation anxiety disorder (seven to and almost 30% will have three or more comorbid anxiety
14 years), but later for GAD, panic disorder, and PTSD or related disorders [3]. Anxiety is often comorbid with
(24-50 years) [1,2]. substance use and mood disorders [3,40]. An estimated
Loneliness [38], low education [38], and adverse parent- 52% of patients with bipolar disorder [43], 60% of patients
ing [39], as well as chronic somatic illnesses, such as cardi- with MDD [44], and 47% of those with ADHD [45] will
ovascular disease, diabetes, asthma, and obesity may have a comorbid anxiety or related disorder. Therefore,
increase the risk for a lifetime diagnosis of anxiety [34,40]. anxiety disorders should be considered in these patients.
Comorbid medical and psychiatric disorders Anxiety The high frequency of comorbidity must be consid-
and related disorders frequently co-occur with other psy- ered when diagnosing anxiety and related disorders
chiatric disorders [3]. More than half of patients with an since this can have important implications for diagnosis
anxiety disorder have multiple anxiety disorders [3,15], and treatment [32]. Anxiety disorders comorbid with
other anxiety or depressive disorders are associated with
poorer treatment outcomes, greater severity and chroni-
Table 6 Common risk factors in patients with anxiety and city [46-49], more impaired functioning [46], increased
related disorders health service use [50], and higher treatment costs [51].
Family history of anxiety [33] The impact tends to increase with an increasing number
Personal history of anxiety or mood disorder [34,35]
Childhood stressful life events or trauma [36,37] of comorbid conditions [46].
Being female [4,9] Patients with anxiety disorders have a higher preva-
Chronic medical illness [34,40] lence of hypertension and other cardiovascular condi-
Behavioral inhibition [41,42]
tions, gastrointestinal disease, arthritis, thyroid disease,
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respiratory disease, migraine headaches, and allergic con- related disorders and trauma- and stressor-related disor-
ditions compared to those without anxiety disorders ders, respectively [26].
[16,52]. Comorbid anxiety and related disorders have a Table 8 provides a brief summary of the key DSM-5
significant impact on quality of life (QoL) in patients diagnostic features of the anxiety and related disorders
with medical conditions [52]. that are included in these guidelines [26]. While the
Baseline assessment Baseline assessment should include DSM-5 is the most up-to-date diagnostic criteria, it is
a review of systems, prescribed medications, over-the- important to note that the evidence for treatment is
counter agents, alcohol use, caffeine intake, and illicit based on studies using DSM-IV criteria (or earlier) for
drug use, in addition to evaluation of the anxiety symp- inclusion of patients. However, most of the diagnostic
toms and functioning [32]. Table 7 lists potential investi- criteria have not changed substantially (see Sections 39
gations that can be considered based on an individual for more information on diagnosis); the exception being
patients presentation and specific symptoms (e.g., dizzi- agoraphobia, which is now designated as a separate
ness or tachycardia). Ideally, a physical examination and diagnosis.
baseline laboratory investigations should be performed Specific individual anxiety and related disorders
before pharmacotherapy is initiated, with repeat assess- should be diagnosed with the DSM-5 criteria in the sec-
ments according to best practice guidelines [32]. Patients tions devoted to each anxiety disorder. An accurate
with anxiety and related disorders should be monitored diagnosis is important to help guide treatment.
initially every one to two weeks and then every four Psychological and pharmacological treatment
weeks for weight changes and adverse effects of medica- Treatment options for anxiety and related disorders
tions, as this is a major factor contributing to disconti- include psychological and pharmacological treatments. All
nuation of medication. patients should receive education about their disorder,
Closer monitoring may be required in children younger efficacy (including expected time to onset of therapeutic
than 10 years of age, older or medically ill patients, effects) and tolerability of treatment choices, aggravating
patients on medications associated with metabolic factors, and signs of relapse [32]. Information on self-help
changes, and those on multiple medications [32]. materials such as books or websites may also be helpful.
Identify specific anxiety or related disorder The choice of psychological or pharmacological treat-
The fifth edition of the Diagnostic and Statistical Manual ment depends on factors such as patient preference and
of Mental Disorders (DSM-5) has been finalized by the motivation, ability of the patient to engage in the treat-
American Psychiatric Association (APA) [26]. The new ment, severity of illness, clinicians skills and experience,
DSM-5 provides diagnostic criteria for psychiatric disor- availability of psychological treatments, patients prior
ders based on scientific reviews of the literature, field response to treatment, and the presence of comorbid med-
trial data, internal evaluations, public comments, and a ical or psychiatric disorders [32].
final review by APAs Board of Trustees. A brief overview of psychological and pharmacological
The anxiety disorders chapter now includes panic treatments is provided below, with more specific recom-
disorder, agoraphobia, GAD, selective mutism, separation mendations in the individual sections for each anxiety
anxiety disorder, SAD (social phobia), specific phobia, and related disorder.
substance/medication-induced anxiety disorder, as well Overview of psychological treatment Psychological
as anxiety disorder due to another medical condition or treatments play an important role in the management of
not elsewhere classified. OCD and PTSD have been anxiety and related disorders. Regardless of whether for-
moved to separate chapters on obsessive-compulsive and mal psychological treatment is undertaken, patients should
receive education and be encouraged to face their fears.
Meta-analyses have demonstrated the efficacy of psycholo-
Table 7 Considerations for baseline laboratory gical treatments in group and individual formats in
investigations (as needed based on patients presenting patients with panic disorder [54-56], specific phobia [57],
symptoms) SAD [58,59], OCD [60-63], GAD [55,64,65], or PTSD
Basic lab tests [66-69], particularly exposure-based and other cognitive
Complete blood count Fasting glucose behavioral therapy (CBT) protocols [70,71], as well as
Fasting lipid profile (TC, vLDL, LDL, HDL, TG) Thyroid-stimulating mindfulness-based cognitive therapy (MBCT) [72]. When
hormone
choosing psychological treatments for individual patients,
Electrolytes Liver enzymes
the forms of therapy that have been most thoroughly eval-
If warranted
uated in the particular anxiety or related disorder should
Urine toxicology for substance use
be used first.
Adapted from references [32,53]. HDL = high density lipoprotein; LDL = low
density lipoprotein; TC = total cholesterol; TG = triglyceride; vLDL = very low
CBT is not a single approach to treatment, but rather
density lipoprotein. a process that focuses on addressing the factors that
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Table 8 Key features of specific anxiety and related disorders


Disorder Key features
Panic disorder Recurrent unexpected panic attacks, in the absence of triggers
Persistent concern about additional panic attacks and/or maladaptive change in behavior related to the attacks
Agoraphobia Marked, unreasonable fear or anxiety about a situation
Active avoidance of feared situation due to thoughts that escape might be difficult or help unavailable if panic-like
symptoms occur
Specific phobia Marked, unreasonable fear or anxiety about a specific object or situation, which is actively avoided (e.g., flying,
heights, animals, receiving an injection, seeing blood)
Social anxiety disorder (SAD) Marked, excessive or unrealistic fear or anxiety about social situations in which there is possible exposure to
scrutiny by others
Active avoidance of feared situation
Generalized anxiety disorder Excessive, difficult to control anxiety and worry (apprehensive expectation) about multiple events or activities (e.g.,
(GAD) school/work difficulties)
Accompanied by symptoms such as restlessness/feeling on edge or muscle tension
Obsessivecompulsive Obsessions: recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted
disorder (OCD) and that cause marked anxiety or distress
Compulsions: repetitive behaviors (e.g., hand washing) or mental acts (e.g., counting) that the individual feels driven
to perform to reduce the anxiety generated by the obsessions
Posttraumatic stress disorder Exposure to actual or threatened death, serious injury, or sexual violation
(PTSD) Intrusion symptoms (e.g., distressing memories or dreams, flashbacks, intense distress) and avoidance of stimuli
associated with the event
Negative alterations in cognitions and mood (e.g., negative beliefs and emotions, detachment), as well as marked
alterations in arousal and reactivity (e.g., irritable behavior, hypervigilance)
Adapted from reference [26].

caused and maintain the individual patients anxiety Psychotherapy and pharmacotherapy generally demon-
symptoms [73]. Some of the core components of CBT strate about equivalent efficacy for the treatment of most
are shown in Table 9 [73]. anxiety and related disorders [71,82]. Results with combi-
CBT can be effectively delivered as individual or group nation therapy vary for the different anxiety disorders,
therapy for most anxiety and related disorders. In addi- and results have been conflicting [82,83] (see Sections 3
tion, a variety of self-directed or minimal intervention 9 for evidence and references regarding combination
formats (e.g., bibliotherapy/self-help books, or internet/ therapy). Therefore, current evidence does not support
computer-based programs with or without minimal the routine combination of CBT and pharmacotherapy as
therapist contact) have demonstrated significant initial treatment. However, when patients do not benefit
improvements in anxiety symptoms [74-79]. Meta-ana- from CBT or have a limited response, a trial of pharma-
lyses have also shown that exposure therapy can be cotherapy is advisable. Similarly, patients who show lim-
effectively administered in a virtual reality format ited benefit from pharmacotherapy may benefit from
[80,81]. These strategies may be particularly useful in CBT. All patients being treated with pharmacotherapy
cases where real-life exposure is difficult due to inconve- should be instructed to gradually face their fears (expo-
nience, expense, or patient reluctance. sure to decrease avoidance).

Table 9 Components of cognitive behavioral interventions


Exposure Encourage patients to face fears
Patients learn corrective information through experience
Extinction of fear occurs through repeated exposure
Successful coping enhances self-efficacy
Safety response Patients restrict their usual anxiety-reducing behaviors (e.g., escape, need for reassurance)
inhibition Decreases negative reinforcement
Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy
Cognitive strategies Cognitive restructuring, behavioral experiments, and related strategies target patients exaggerated perception of danger
(e.g., fear of negative evaluation in SAD)
Provides corrective information regarding the level of threat
Can also target self-efficacy beliefs
Arousal management Relaxation and breathing control skills can help patient control increased anxiety levels
Surrender of safety Patient relinquishes safety signals (e.g., presence of a companion, knowledge of the location of the nearest toilet)
signals Patients learn adaptive self-efficacy beliefs
Adapted from reference [73].
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Overview of pharmacological treatment This section to short-term use, and generally dosed regularly rather
provides a general overview of some of the commonly than as-needed [32].
recommended pharmacological agents. Evidence and Several anticonvulsants and atypical antipsychotics
recommendations for specific medications are described have demonstrated efficacy in some anxiety and related
in the individual sections for each of the anxiety and disorders, but for various reasons, including side effects,
related disorders. as well as limited randomized controlled trial (RCT)
Table 10 shows medications that have Health Canada data and clinical experience, these agents are generally
approved indications for use in different anxiety and recommended as second-line, third-line, or adjunctive
related disorders [84], and dosing suggestions are shown therapies (see Sections 39 for evidence and references).
in Additional file 1. Various antidepressants including The choice of medication should take into considera-
selective serotonin reuptake inhibitors (SSRIs), serotonin tion the evidence for its efficacy and safety/tolerability
norepinephrine reuptake inhibitors (SNRIs), noradrenergic for the treatment of the specific anxiety and related dis-
and specific serotonergic antidepressants (NaSSAs), tricyc- order, as well as for any comorbid conditions the patient
lic antidepressants (TCAs), monoamine oxidase inhibitors might have, in both acute and long-term use.
(MAOIs), and reversible inhibitors of monoamine oxidase Safety and side effects Antidepressants: The most com-
A (RIMAs) have demonstrated some efficacy in the treat- mon side effects seen with SSRIs and SNRIs include
ment of anxiety and related disorders (see Sections 39 headache, irritability, gastrointestinal complaints, insom-
for evidence and references). SSRIs and SNRIs are usually nia, sexual dysfunction, weight gain, increased anxiety,
preferred as initial treatments, since they are generally drowsiness, and tremor [85-88]. Patients report that the
safer and better tolerated than TCAs or MAOIs [32]. most common bothersome side effects are sexual dys-
Benzodiazepines may be useful as adjunctive therapy function, drowsiness, fatigue, and weight gain [87,88].
early in treatment, particularly for acute anxiety or agi- Most side effects occur early and transiently during the
tation, to help patients in times of acute crises, or while first two weeks of treatment, but others, such as sexual
waiting for onset of adequate efficacy of SSRIs or other dysfunction and weight gain, may persist for the dura-
antidepressants [32]. Due to concerns about possible tion of treatment [85,87,89].
dependency, sedation, cognitive impairment, and other Use of SSRIs or SNRIs has been associated with an
side effects, benzodiazepines should usually be restricted increased risk of upper gastrointestinal bleeding,

Table 10 Medications with Health Canadaapproved indications for anxiety and related disorders
Anxiety Panic Social anxiety Obsessivecompulsive Generalized anxiety Posttraumatic stress
disorders disorder disorder disorder disorder disorder
ANTIDEPRESSANTS
SSRIs
Escitalopram (Cipralex) X X
Fluoxetine (Prozac) X
Fluvoxamine (Luvox) X
Paroxetine (Paxil) X X X X X
Paroxetine CR (Paxil CR) X X
Sertraline (Zoloft) X X
TCAs
Clomipramine X
Other antidepressants
Venlafaxine XR (Effexor X X X
XR)
Duloxetine (Cymbalta) X
AZAPIRONES
Buspirone (BuSpar, X
Buspirex)
BENZODIAZEPINES* X
Data from respective Canadian product monographs [84].
*Multiple generic and brand name products, consult product monographs: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, lorazepam, and
oxazepam are indicated for anxiety disorders; alprazolam is also indicated for panic disorder.
CR = controlled release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release.
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particularly when used in combination with nonsteroidal cognitive dysfunction in patients using, versus those not
anti-inflammatory drugs (NSAIDs) [90,91]. SSRI use has using, antipsychotics [117].
also been associated with low bone mineral density Because of the risks of diabetes and weight gain, and
[92,93], as well as an increased risk of fractures [94] and the fact that there is limited RCT evidence of the effi-
hyponatremia [95]. cacy of these agents in anxiety and related disorders,
Abrupt discontinuation of SSRIs or SNRIs can lead to atypical antipsychotics are generally recommended as
a discontinuation syndrome with gastrointestinal, psy- second-line, third-line, or adjunctive therapies (see Sec-
chiatric, vasomotor, and other symptoms [85,96]. tions 39 for evidence and references).
Health Canada and the US Food and Drug Administra- Anticonvulsants: Anticonvulsants are associated with
tion (FDA) require antidepressants to include a warning gastrointestinal side effects, somnolence, weight gain,
regarding an increased risk of suicidal ideation and beha- tremor, as well as dermatologic and hematologic side
vior in children and adolescents [97,98]. The increased effects [111,118]. In addition, several anticonvulsants
risk of suicidal behavior reported in pediatric patients [99] have a potential risk of serious rash, erythema multi-
does not appear to be seen in adults, and may in fact be forme, Stevens-Johnson syndrome, or toxic epidermal
decreased [99,100]. Careful monitoring for evidence of necrolysis [111]. Regular monitoring of serum medica-
self-harming or suicidal thoughts or behaviors is impor- tion levels and liver function is required for patients on
tant in both adult and pediatric patients. divalproex [84,111].
SSRIs and SNRIs are generally better tolerated and Follow-up
safer than TCAs and MAOIs, having less anticholinergic Anxiety and related disorders are often chronic and a
effects, toxicity, lethality, and psychomotor or cognitive systematic approach to treatment should include patient
impairment [85,101]. MAOIs are generally reserved for education, assessment of comorbidities, and evidence-
second- or third-line treatment because of side effects, based pharmacological and psychological interventions
drug interactions, and dietary restrictions [32]. with adequate monitoring and duration. Pharmacological
Anxiolytics: The most common side effects associated treatment is often associated with a delay of about two to
with benzodiazepines include primarily sedation, fatigue, eight weeks in onset of symptom relief, with full response
ataxia, slurred speech, memory impairment, and weak- taking up to 12 weeks or more. Longer-term therapy has
ness [85]. Benzodiazepines are associated with withdra- been associated with continued symptomatic improve-
wal reactions, rebound, and dependence, with the risk ment and the prevention of relapse, and therapy should be
being greater with short- and intermediate-acting com- continued for at least 12-24 months for most patients [32].
pared to long-acting agents [102]. These agents should Medication should be initiated at low doses and
be used with caution in patients with SUDs [85,103]. titrated to the recommended dosage range at one- to
Older patients (generally over 65 years of age) may be at two-week intervals over four to six weeks. Once the
high risk for falls and fractures due to psychomotor therapeutic range has been achieved, improvement is
impairment associated with benzodiazepines [104,105]. usually seen over the next four to eight weeks. Follow-
Cognitive impairment has been reported [106], some of up should occur at two-week intervals for the first six
which may persist after cessation of therapy [107]. In par- weeks and monthly thereafter [32].
ticular, memory impairment has been associated with For a patient undergoing psychotherapy, the treatment
high-dose or high-potency benzodiazepines, particularly schedule is structured around weekly contact with a thera-
in older people [102,107]. pist for about 12-20 weeks, although shorter protocols and
Reported side effects of azapirones (buspirone) include minimal intervention programs have also proven effective
dizziness, drowsiness, and nausea [32,108]. (see Sections 39 for evidence and references). A follow-
Atypical antipsychotics: Atypical antipsychotics are up appointment four weeks later and then every two to
associated to varying degrees with weight gain, diabetes, three months is usually sufficient [32].
and other metabolic side effects, including alterations in Assessing response to treatment Therapy should seek to
glucose and lipid levels [109-116]. Metabolic disturbances improve symptoms and distress. The optimal goal is full
generally appear to be higher with olanzapine, intermedi- remission of symptoms and return to a premorbid level
ate with risperidone and quetiapine, and lower with aripi- of functioning [32,85]. However, goals may need to be
prazole, asenapine, lurasidone, and ziprasidone [109-114]. individualized for some patients with disorders that have
Atypical antipsychotics have varying sedative effects, been present since childhood as they may never have had
with quetiapine, clozapine, asenapine, and olanzapine gen- adequate premorbid functioning. A response to therapy
erally causing more sedation than ziprasidone, risperidone, is often defined as a percentage reduction in symptoms
lurasidone, or aripiprazole [111,115]. Data on cognitive (usually 25-50%) on an appropriate scale. Remission is
effects are conflicting, with some studies suggesting often defined as loss of diagnostic status, a pre-specified
improvements [111], while other data suggest greater low score on an appropriate disorder-specific scale, and
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no functional impairment in fully recovered patients as or related disorder, mood disorder, impulse-control disor-
measured by a scale such as the Sheehan Disability Scale der, or SUD [121,137]. MDD is very common, occurring
or SF-36 [32,119,120]. in an estimated 35-40% of patients with panic disorder
Objective scales can be used to help assess a patients [121]. Panic disorder also frequently co-occurs with agora-
progress. The Clinical Global Impression (CGI) scale is phobia [138].
brief, comprehensive, and can easily be used at each Panic disorder is more prevalent in patients with med-
appointment to assess improvement. The clinician-rated ical conditions, including thyroid disease, cancer,
Hamilton Anxiety Rating Scale (HARS) can assess anxi- chronic pain, cardiac disease, irritable bowel syndrome,
ety symptoms in general and is often used in clinical migraine, as well as allergic and respiratory diseases
trials but is less practical in clinical practice. A variety compared with the general population [85,139-141]. The
of self-report and clinician-rated scales are available to presence of medical comorbidity is associated with
assess the specific anxiety or related disorder. greater severity of panic disorder symptoms and disabil-
ity [140,142].
Panic disorder and agoraphobia
Epidemiology Diagnosis
The lifetime and 12-month prevalence of panic disorder For a diagnosis of panic disorder, a patient must have
have been estimated at 4.7-5.1% and 2.1-2.8%, respec- had recurrent, unexpected panic attacks (Table 11), fol-
tively [121,122]. The estimated prevalence of panic lowed by at least one month of persistent concern or
attacks is considerably greater at 28.3% (lifetime) and worry about further attacks or their consequences, or a
6.4-11.2% (12-month) [121,123]. Youth with panic significant maladaptive behavioral change related to
attacks (which often do not meet diagnostic criteria for attacks (Table 12) [26].
panic disorder) will frequently have or develop other A panic attack continues to be considered a noncod-
psychiatric disorders including mood disorders (bipolar able event in the DSM-5, with only minor revisions,
disorder and MDD), other anxiety or related disorders, including removal of the 10-minute window, changing
SUDs, eating disorders, psychotic disorders, and person- hot flushes to heat sensations, and the re-ordering of
ality disorders [122,124,125]. Annually, 8-10% of the gen- the list of symptoms to increase clinical utility [26,143].
eral public will have a panic attack without ever Compared to the DSM-IV-TR [144], changes to the
developing any identifiable psychopathology [126]. About diagnostic criteria for panic disorder largely consisted of
40-70% of patients with panic disorder experience noc- minor phrasing changes to improve clinical utility, with
turnal panic (waking from sleep in a state of panic) [127]. the most substantial change being the title of the disor-
Rates of 12-month and lifetime agoraphobia (without der [26,143]. The DSM-5 now lists agoraphobia (anxiety
panic) are quite low, at 0.8% and 1.4%, respectively [2,3]. about having a panic attack in certain situations, which
The risk of panic disorder and agoraphobia is higher are avoided or endured with marked distress) as a sepa-
in women than men, and patients who are middle-aged, rate codable disorder, whereas previously panic disorder
widowed/divorced, and those of low income [122]. In could be diagnosed as panic disorder with agoraphobia
the Canadian Community Health Survey 1.2 (CCHS 1.2) or panic disorder without agoraphobia [26,145].
there were no differences in the rates of panic disorder For a diagnosis of agoraphobia, a patient must have
or agoraphobia in urban versus rural settings [128]. intense fear about at least two different types of
Panic disorder has a negative impact on both psycho-
logical and physical functioning, and puts a substantial
Table 11 DSM-5 criteria for panic attacks
burden on the patients family [13]. Patients with panic
An abrupt surge of intense fear or intense discomfort that reaches a
disorder have more QoL impairment and dissatisfaction peak within minutes, and includes 4 of the following symptoms:
[16,17], greater likelihood of suicide attempts [20], and (1) Palpitations, pounding heart, or accelerated heart rate
increased cognitive and emotional dysfunction [129-133] (2) Sweating
(3) Trembling or shaking
compared to healthy controls. Panic disorder is also (4) Sensations of shortness of breath or smothering
associated with substantial societal costs [134], both in (5) Feelings of choking
terms of health care utilization [135] and loss of work- (6) Chest pain or discomfort
(7) Nausea or abdominal distress
place productivity [136]. In a 2012 survey, panic disor- (8) Feeling dizzy, unsteady, light-headed, or faint
der conferred a substantial rate of work absenteeism (9) Chills or heat sensations
(mean: 36.0 days/year) [136]. (10) Paresthesias (numbness or tingling sensations)
(11) Derealization (feelings of unreality) or depersonalization (being
Comorbidity
detached from oneself)
Patients with panic disorder, or those experiencing panic (12) Fear of losing control or going crazy
attacks, have significantly increased odds of being diag- (13) Fear of dying
nosed with a comorbid disorder, including another anxiety Adapted from reference [26].
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Table 12 DSM-5 diagnosis of panic disorder may be PTSD [26,85], and those related to being kid-
The person has experienced both of the following: napped by extraterrestrials may be schizophrenia [26].
Recurrent unexpected panic attacks Some medical conditions that can be associated with
1 of the attacks followed by 1 month of 1 or both of the
following:
panic symptoms include hyper- or hypothyroidism,
Persistent concern or worry about additional panic attacks or hypoglycemia, seizure disorders, and cardiac conditions
their consequences [26,85]. Panic attacks may also be associated with intoxi-
Significant maladaptive change in behavior related to the
attacks
cation or withdrawal from drugs of abuse, medications
such as decongestants, stimulants, or beta-adrenergic
Adapted from DSM-5 [26].
agonist inhalers, or caffeine [85].
situations, with the fear resulting from thoughts that
Psychological treatment
escape may be difficult or help may be unavailable if
CBT has been extensively studied, and is an efficacious
panic-like symptoms occur (Table 13) [26,145]. The situa-
psychological treatment for panic disorder (Level 1)
tions provoke anxiety and are avoided or endured with
[56,70,146,147]. In fact, CBT was significantly favored
intense fear or anxiety, or may require that a companion
over medications for the treatment of panic disorder in a
be present. The resultant fear or anxiety is out of propor-
meta-analysis [71]. In a meta-analysis of 42 studies, expo-
tion to any actual danger from the situation, causes sub-
sure and combinations of exposure, cognitive restructur-
stantial functional impairment, and usually lasts for six
ing and other CBT techniques had the most consistent
months or longer [26].
evidence of efficacy for the treatment of panic disorder
While the most up-to-date DSM-5 diagnostic criteria
[56]. Strategies that included exposure were the most
are presented here, the treatment data described within
effective for panic measures. For measures of agorapho-
this section are based on studies involving patients
bia, combined strategies were more effective than single
meeting DSM-IV panic criteria (or older).
techniques, which did not result in significant improve-
Establishing the context in which panic attacks occur,
ments. Factors that improved the effectiveness of treat-
and whether there is any prior history of recurrent,
ments were the inclusion of homework and a follow-up
unexpected panic attacks, is important for accurate diag-
program [56]. Another meta-analysis also found that
nosis. Panic attacks frequently occur in other psychiatric
CBT that included interoceptive exposure was superior
disorders (e.g., MDD, PTSD), and medical conditions
to relaxation therapy for panic symptoms [55]. CBT can
(e.g., cardiac, respiratory), and the DSM-5 has identified
be effectively delivered in both individual and group set-
panic attacks as a specifier to be used in the absence of
tings [56,148,149]. Conducting exposure in virtual reality
a diagnosable panic disorder [85]. Another disorder may
appears to be effective when used as part of a CBT proto-
better account for the panic attacks; for example, panic
col [150-154].
attacks in social situations may be SAD, those related to
Minimal intervention formats, such as self-help books
defined phobic objects or situations may be specific
(bibliotherapy) [75,76,155-158], treatment via telephone/
phobia, those related to reminders of traumatic events
videoconferencing [75,159-161], and internet-based CBT
(ICBT) [75,79,162-169] have been shown to be more
Table 13 DSM-5 diagnosis of agoraphobia effective than wait-list or relaxation controls, as effective
Marked fear or anxiety about 2 of the following 5 groups of as face-to-face CBT, and may be cost-effective options
situations:
(1) Public transportation (e.g., traveling in automobiles, buses, trains,
particularly for agoraphobic patients who are unwilling
ships, or planes) or unable to attend a clinic. When using bibliotherapy,
(2) Open spaces (e.g., parking lots, market places, or bridges) providing information all at one time was as effective as
(3) Being in shops, theatres, or cinemas
(4) Standing in line or being in a crowd
pacing [157], and therapist support does not appear to
(5) Being outside of the home alone in other situations be essential [75,158]. Most ICBT programs have some
The individual fears or avoids these situations due to thoughts that therapist contact by either telephone or email, and once
escape might be difficult or help might not be available in the event of weekly contact appeared to be as effective as more fre-
panic-like symptoms
quent contact [168].
The agoraphobic situations almost always provoke fear or anxiety
CBT panic disorder protocols usually involve 12-14
The situations are actively avoided, require presence of a companion,
or endured with marked fear or anxiety
weekly sessions, but briefer strategies of six to seven ses-
The fear or anxiety is out of proportion to actual danger posed by
sions have been shown to be as effective [148,149,170].
agoraphobic situation In addition, compressing the duration of therapy by
The fear, anxiety, or avoidance is persistent, typically lasting 6 months administering 13 sessions over three weeks has also
The fear, anxiety, and avoidance cause clinically significant distress or been shown to be as effective as traditional weekly CBT
functional impairment [171]. Patients with higher baseline severity, disability,
Adapted from DSM-5 [26]. or comorbidity may have better outcomes with standard
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CBT [172]. CBT programs sometimes include one or [191], while another found an acceleration of symptom
more follow-up or booster sessions [170,173]. reduction in severely ill patients but no significant
Predictors of decreased response to CBT were severity improvement in outcomes overall [192] compared to
of panic disorder, strength of blood/injury fears, earlier CBT plus placebo. Another compound acting at the
age of initial onset of panic symptoms, comorbid social N-methyl-D-aspartate (NMDA) receptor, Org 25935,
anxieties, and degree of agoraphobic avoidance [174,175]. demonstrated no benefit over placebo in augmenting
Changes in symptoms are preceded by changes in beliefs CBT for panic disorder [193].
during therapy [176], and change in beliefs and avoidance Long-term effects of psychological treatment
behaviors are considered key process variables [170,176]. In naturalistic long-term follow-up studies, the benefits of
Eye movement desensitization and reprocessing CBT were maintained for up to three years [148,169,
(EMDR) does not appear to offer advantages over the 170,188]. At two-year follow-up, individual, group, and
same strategy without the eye movement component for brief CBT were associated with lower relapse rates com-
the treatment of panic disorder [177,178]. pared to the wait-list control [148]. A long-term follow-up
Combined psychological and pharmacological treatment study of patients who had become panic-free with expo-
A meta-analysis of 21 trials found that combination psy- sure therapy found that 93% remained in remission after
chotherapy and pharmacotherapy with antidepressants two years and 62% after 10 years [194].
was superior to CBT or pharmacotherapy alone during A meta-analysis found that at six to 24 months follow-
the acute treatment phase and while medication was con- up, remission/response rates with the combination of
tinued [179,180]. After termination of treatment, com- psychotherapy and antidepressants continued to be
bined therapy was more effective than pharmacotherapy superior to antidepressants alone, or to psychotherapy
alone and was as effective as psychotherapy [179,180]. as long as therapy was continued [179,180].
Prior meta-analyses have reported similar findings
[54,146,181], suggesting that CBT alone or CBT combined Pharmacological treatment
with pharmacotherapy should be considered as first-line The management of patients with panic disorder should
treatment. follow the principles discussed in Section 2. Pharmaco-
A meta-analysis of the combination of psychotherapy logical interventions that have good evidence for efficacy
and benzodiazepines included only three trials, and in treating panic disorder include SSRIs, TCAs, and
found no benefit to combination therapy compared with other antidepressants, as well as benzodiazepines. Treat-
psychotherapy or medication alone [182]. The follow-up ments that have been investigated for use in panic disor-
data suggested that the combination might be inferior to der have been assessed according to the criteria for
behavior therapy alone [182]. strength of evidence (Tables 1 and 2) and are summar-
Adding self-administered CBT to SSRI therapy did ized in Tables 14 and 15.
not result in significant improvements overall, but First-line agents
patients did report a significantly greater rate of SSRIs: Evidence from meta-analyses [195-197] and RCTs
decline in fear of bodily sensations compared to medi- supports the use of the SSRIs citalopram [198-200],
cation alone [183]. Early results suggest a benefit of fluoxetine [201-204], fluvoxamine [195,205-210], paroxe-
MBCT as an adjunct to pharmacotherapy in relieving tine [211-219], and sertraline [183,220,221,223,224] (all
anxiety and depressive symptoms in patients with Level 1), as well as escitalopram [198] and paroxetine
panic disorder [184,185]. controlled-release (CR) [225] (both Level 2) for the
Providing CBT sessions around the time of medication treatment of panic disorder. In meta-analyses, SSRIs
discontinuation was associated with a lower relapse rate demonstrated significant improvements in panic symp-
during follow-up among patients treated with antidepres- toms, agoraphobic avoidance, depressive symptomatol-
sants [186]. In addition, CBT has been shown to be helpful ogy, and general anxiety [195-197,226]. Effect sizes for
in facilitating benzodiazepine discontinuation [187,188]. SSRIs and TCAs are similar [195,196], although dropout
A cost-effectiveness study found that combined CBT rates may be lower with SSRIs [195].
and pharmacotherapy was associated with a robust clini- SNRIs: Venlafaxine extended-release (XR) has been
cal improvement compared to usual care, with only a shown to be useful in reducing the severity of panic dis-
moderate increase in costs [189]. order symptoms in RCTs (Level 1) [215,216,227-229].
In a RCT, buspirone enhanced the effects of CBT in Two studies found significantly greater rates of panic-
the short-term, but had no significant benefit over CBT free patients compared with placebo [215,216] while two
alone during long-term follow-up [190]. did not [228,229].
Data on the efficacy of d-cycloserine as an adjunct to Second-line agents
CBT are conflicting, with one study suggesting signifi- TCAs: There is good evidence from RCTs to support the
cant benefits at posttreatment and one-month follow-up use of the TCAs clomipramine [199,211,213,232,233]
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Table 14 Strength of evidence for pharmacotherapy for panic disorder


Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Citalopram [198-200] 1 Clomipramine [199,211,213,232,233] 1
Fluoxetine [201-204] 1 Imipramine [207,224,233-240] 1
Fluvoxamine [195,205-210] 1 MAOIs and RIMAs
Paroxetine [211-219] 1 Phenelzine [240] 2
Sertraline [183,220-224] 1 Moclobemide [204,232,241,242] 1*
Escitalopram [198] 2 Tranylcypromine [243] 3
Paroxetine CR [225] 2 Other antidepressants
SNRIs Reboxetine [200,219,244] 1
Venlafaxine XR [215,216,227-229] 1 Mirtazapine [203,245,246] 2
Duloxetine [230] 3 Bupropion SR [247,248] 3*
Milnacipran [231] 3
Other therapies
Anxiolytics Atypical antipsychotics
Benzodiazepines Risperidone [217,267] 2
Alprazolam [234,249-254] 1 Olanzapine [268] 3
Clonazepam [218,250,255-258] 1 Quetiapine [267] 3
Lorazepam [251,259,260] 1 Adjunctive aripiprazole [269] 3
Diazepam [261-263] 1 Adjunctive olanzapine [270] 3
Adjunctive clonazepam [264,265] 1 Adjunctive risperidone [271] 3
Adjunctive alprazolam ODT [266] 3 Anticonvulsants
Other treatments Divalproex [272-275] 3
Buspirone [254,282] 1 (-ve) Levetiracetam [276] 3
Trazodone [283] 2 (-ve) Gabapentin [277] 2 (-ve)
Propranolol [262,284,285] 2 (-ve) Tiagabine [278,279] 2 (-ve)
Adjunctive pindolol [286] 2 Carbamazepine [280] 3 (-ve)
Adjunctive divalproex [281] 3
*Conflicting data. No significant superiority over placebo in overall population, but significant benefits in subgroup of more severely ill patients. CR = controlled
release; MAOI = monoamine oxidase inhibitor; ODT = orally disintegrating tablets; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin
norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release;
(-ve) = negative.

and imipramine [207,224,233-240] in panic disorder Other antidepressants: Although there is level 1 evi-
(Level 1). In meta-analyses, TCAs have demonstrated dence to support the use of reboxetine [200,219,244],
efficacy for the treatment of panic symptoms and agora- limited experience with this agent in Canada, and its
phobia [195-197,226]. Efficacy is generally equivalent to side effect profile, which includes dry mouth, constipa-
SSRIs, however, since TCAs tend to be less well toler- tion, and insomnia [244], led to its recommendation as
ated and have higher discontinuation rates than SSRIs a second-line option. Mirtazapine has demonstrated effi-
[195], they are recommended as second-line options. cacy for the treatment of panic disorder in several open

Table 15 Recommendations for pharmacotherapy for panic disorder


First-line Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, paroxetine CR, sertraline, venlafaxine XR
Second-line Alprazolam, clomipramine, clonazepam, diazepam, imipramine, lorazepam, mirtazapine, reboxetine
Third-line Bupropion SR, divalproex, duloxetine, gabapentin, levetiracetam, milnacipran, moclobemide, olanzapine, phenelzine, quetiapine,
risperidone, tranylcypromine
Adjunctive Second-line: alprazolam ODT, clonazepam
therapy Third-line: aripiprazole, divalproex, olanzapine, pindolol, risperidone
Not Buspirone, propranolol, tiagabine, trazodone
recommended
CR = controlled release; ODT = orally disintegrating tablets; SR = sustained release; XR = extended release.
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trials [245,246] and one small RCT [203] (Level 2). It In a RCT, pindolol added to fluoxetine therapy in
appears to be as effective as fluoxetine [203] and may be patients with treatment-resistant panic disorder was
a useful second-line choice. associated with significant improvement in panic disor-
Benzodiazepines: Alprazolam [234,249-254], clonaze- der symptoms compared with fluoxetine plus placebo
pam [218,250,255-258], lorazepam [251,259,260], and (Level 2) [286]. Open-label data also support the use of
diazepam [261-263] have demonstrated efficacy for the the atypical antipsychotics aripiprazole [269], olanzapine
treatment of panic disorder (Level 1). While it has been [270], and risperidone [271] (all Level 3), as well as the
suggested that alprazolam may be more effective, a meta- anticonvulsant divalproex [281], as adjunctive strategies
analysis found no evidence that it was superior to other for patients with treatment-resistant panic disorder.
benzodiazepines for the treatment of panic disorder Not recommended
[252]. Although benzodiazepines are second-line options, Buspirone (Level 1, negative) [254,282], propranolol
they may be useful at any time during therapy for the (Level 2, negative) [262,284,285], tiagabine [278,279]
short-term management of acute or severe agitation or (Level 2, negative), and trazodone (Level 2, negative)
anxiety. They may also be useful at the initiation of SSRI [283] have not demonstrated efficacy and are not recom-
treatment to hasten response (Level 1) [264-266]. mended for the treatment of panic disorder. Carbamaze-
Third-line agents pine (Level 3, negative) [280] also does not appear to be
MAOIs and RIMAs: Results with moclobemide for the effective in this disorder.
management of panic disorder have been conflicting Maintenance pharmacological treatment
(Level 1). In clinical trials, moclobemide demonstrated In long-term, open, follow-up studies, citalopram
efficacy similar to that of clomipramine and fluoxetine [287,288], fluoxetine [204,288], fluvoxamine [288], par-
[204,232], but was not superior to placebo [241,242]. oxetine [288-290], and moclobemide [204], as well as
However, significant efficacy in more severely ill patients clomipramine [287,289] and imipramine [291,292]
[241], suggests it may be useful in treatment-resistant demonstrated maintenance of benefits and continued
patients. In a RCT, phenelzine was more effective than improvements over six months to three years of ongoing
placebo and as effective as imipramine (Level 2) [240]. In treatment. In a RCT, sertraline and imipramine were
a small randomized, uncontrolled trial, tranylcypromine equally effective over a six month period [224]. How-
demonstrated efficacy for patients with comorbid panic ever, in another RCT, imipramine was not superior to
and social anxiety disorders (Level 3) [243]. placebo in the proportion of panic-free patients after
Atypical antipsychotics: There is some evidence that eight months of therapy [293].
atypical antipsychotics may have some benefits in the Venlafaxine XR [294] and imipramine [295] have been
treatment of patients with refractory panic disorder shown to prevent relapse in randomized, placebo-con-
[217,267,268]. In a RCT, risperidone monotherapy was as trolled, discontinuation studies. After three months of
effective as paroxetine (Level 2) [217]. Open-label data acute treatment, relapse rates were significantly lower
also support the use of risperidone [267], olanzapine with ongoing venlafaxine XR [294] or imipramine [295]
[268], and quetiapine [267]. There are also open-label therapy compared with switching to placebo during six
data supporting the use of some atypical antipsychotics to 12 months of follow-up.
as adjunctive therapy (see below). Benzodiazepines are generally recommended for short-
Other therapies: The antidepressants duloxetine [230], term use only. However, several trials have demon-
milnacipran [231], and bupropion sustained release (SR) strated the benefits of up to two years of alprazolam
[247,248] have shown some efficacy in open trials, as maintenance therapy [291,293]. There was no evidence
have the anticonvulsants divalproex [272-275] and leve- of tolerance, but up to one-third of patients were unable
tiracetam [276] (all Level 3). In a RCT, gabapentin was to discontinue therapy [293]. The efficacy of clonazepam
superior to placebo in patients who were more severely was maintained over a three-year course of treatment
ill, but not in the overall group (Level 2, negative) [277]. [290], and patients who had been asymptomatic for at
These agents are recommended only as third-line least one year were able to successfully discontinue the
options in patients with refractory panic disorder. medication, using a slow tapering strategy over four to
Adjunctive therapy seven months, and improvement in panic disorder was
There is good evidence that adjunctive clonazepam maintained [296].
[264,265] (Level 1), and open-label evidence that adjunc-
tive alprazolam orally-disintegrating tablet (ODT) [266] Biological and alternative therapies
(Level 3), used short-term (<8 weeks including taper) at Biological therapies: In open-label case series, noninvasive
the initiation of SSRI treatment, can lead to a more brain stimulation using a radioelectric asymmetric con-
rapid response [264-266]. veyor (REAC) demonstrated efficacy for panic symptoms
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and agoraphobia (Level 3) [297,298]. A small case series maintained during follow-up. In addition, data suggest
suggested repetitive transcranial magnetic stimulation that combination of psychotherapy and pharmacotherapy
(rTMS) could improve panic and anxiety in patients with may be superior to pharmacotherapy alone during fol-
panic disorder with comorbid MDD (Level 4) [299]. How- low-up.
ever, a small RCT found no additional benefit of rTMS Pharmacotherapeutic approaches should begin with a
compared to sham rTMS as an add-on to SSRI therapy in first-line agent. If response to optimal dosing is inade-
patients with panic disorder (Level 2, negative) [300]. quate or the agent is not tolerated, treatment should be
Alternative therapies: In a RCT, capnometry-assisted switched to another first-line agent before considering
respiratory training was as effective as cognitive training second-line medications. First-line options for the treat-
in reducing panic symptom severity and panic-related ment of panic disorder include citalopram, fluoxetine,
cognitions and improving perceived control (Level 2) fluvoxamine, paroxetine, sertraline, venlafaxine XR, esci-
[301]. However, breathing training did not significantly talopram, or paroxetine CR. Second-line choices include
improve reactivity or recovery after a respiratory chal- the TCAs (clomipramine and imipramine), mirtazapine,
lenge in another small trial (Level 2, negative) [302]. In reboxetine, or benzodiazepines (alprazolam, clonazepam,
a RCT, patients with panic disorder randomized to the lorazepam, and diazepam).
exercise groups (plus paroxetine or placebo) had a trend Patients who do not respond to first- or second-line
toward better improvement compared to relaxation agents are considered to have treatment-refractory ill-
training, but this was not significant (Level 2, negative) ness. In such patients it is important to reassess the diag-
[303]. However, in an open cross-over study, acute aero- nosis and consider comorbid medical (e.g., ischemic
bic exercise was found to reduce anxiety as well as heart disease) and psychiatric conditions (e.g., SUDs) that
panic attack frequency and intensity in patients with may be affecting response to therapy. Third-line agents,
panic disorder compared to a quiet rest condition (Level adjunctive therapies, as well as biological and alternative
3) [304]. These therapies may be useful for some therapies may be useful when patients fail to respond to
patients; however, more data are needed. an optimal treatment trial of first- and second-line thera-
pies used alone and in combination.
Summary
As much as 40% of the general population has experi- Specific phobia
enced a panic attack at some point in their lifetime. Epidemiology
However, patients with actual panic disorder experience A specific phobia is an intense fear of a specific object or
recurrent, unexpected panic attacks as well as persistent situation and is usually associated with avoidance of the
concern or behavioral change around further attacks. feared object. The most prevalent phobia types include
Data support pharmacotherapy, CBT alone, and CBT animal (e.g., insects, snakes), natural environment (e.g.,
combined with pharmacotherapy as initial treatments for heights, storms, water), situational (e.g., flying, enclosed
panic disorder. CBT alone may be insufficient in patients spaces), and blood-injection-injury (B-I-I) (e.g., blood,
with comorbid moderate-to-severe major depression, or dentists, hospitals) [305,306]. Large US and European
in those with severe, frequent panic attacks, or rapid wor- epidemiologic surveys report lifetime prevalence esti-
sening of agoraphobia, and/or suicidal ideation, as well as mates of 10-13% and 12-month prevalence rates of 7-9%
in situations where one might consider initial rescue [2,3,305,307]. Rates among adolescents may be particu-
treatment with a benzodiazepine to minimize or stop the larly high with lifetime prevalence estimates of 36.5% and
panic attacks while waiting the 4-12 weeks for the first- 12-month prevalence rates of 27.3% being reported [308].
line pharmacotherapy to become effective. Also there are Specific phobias are more common in women than men
patients who are not motivated to participate in CBT [306]. Age of onset is usually in the range of five to 12
(preferring medication as initial treatment) or are too years (median: seven years) [2]; however, this varies by
fearful to engage in any kind of exposure before being type of phobia. Animal and B-I-I phobias generally begin
treated with a first-line pharmacotherapeutic agent. At in childhood, whereas situational phobias (e.g., driving
the very least, if agoraphobic distress or avoidance per- phobia, claustrophobia) have a later onset, typically dur-
sists, these patients need instruction and support to ing late adolescence or early adulthood [306].
engage in exposure exercises. For panic symptoms, stra- Specific phobias are associated with significant dis-
tegies should include exposure; and combined strategies tress, regardless of the number of feared stimuli
should be considered for patients with agoraphobia. CBT reported [305]. Specific phobias have a negative impact
can be effectively delivered in both individual and group on social/occupational functioning and lead to restric-
settings, as well as via self-help books, virtual reality, and tion of usual daily activities, which increases with an
internet-based programs. The benefits of CBT are increasing number of fears [305].
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Comorbidities Table 17 Specific phobia specifiers in DSM-5


Specific phobias tend to co-occur with other specific Specifier Examples
phobias, with less than 10% of patients having only one Animal Spiders, insects, dogs
fear [305]. The mean number of fears, in one survey, Natural Heights, storms, water
was three [305]. In addition, specific phobias are fre- environment
quently comorbid with other psychiatric disorders, Blood-injection- Needles, invasive medical procedures
including SUDs, mood disorders, and other anxiety or injury
related disorders (particularly panic disorder, SAD, and Situational Airplanes, elevators, enclosed spaces
GAD), as well as personality disorders [305,309,310]. Other Choking or vomiting. In children, loud sounds or
costumed characters
Diagnosis Adapted from DSM-5 [26].
To receive a DSM-5 diagnosis of specific phobia a
patient must experience marked (intense) fear or anxi-
ety about a specific object or situation, which is asso- Psychological treatment
ciated with significant distress or functional impairment Psychosocial interventions, particularly exposure-based
(Table 16) [26]. The object or situation will be actively treatments, are the treatments of choice and are asso-
avoided or endured with intense anxiety. Compared to ciated with a high degree of success in providing remis-
the DSM-IV-TR criteria for specific phobia [144], few sion of specific phobias [311]. Both in vivo exposure and
changes were made in the DSM-5 [26,306]. Of note, virtual reality exposure (VRE) can be effective
recognition that the fear is excessive or unreasonable [57,311,312], with in vivo exposure being shown to be
has been removed and a new criterion stating the fear superior to alternative types (e.g., imaginal, virtual rea-
or anxiety is out of proportion to danger posed has lity, etc.) at posttreatment but not at follow-up [57].
been added. Avoidance has been clarified as actively In general, exposure-based therapy has been shown to
avoided to distinguish the avoidance seen in specific be more effective if: sessions are grouped closely together;
phobias from passive avoidance that may occur for exposure is prolonged, real (not imagined), and provided
other reasons [26,306]. in multiple different settings; and there is some degree of
While the most up-to-date DSM-5 diagnostic criteria therapist involvement (not entirely self-directed) [32,311].
are presented here, it is important to note that most of While one-session treatments have demonstrated efficacy
the treatment data described within this section are [313], a meta-analysis found that a greater number of ses-
based on patients meeting DSM-IV criteria (or older). sions predicted more favorable outcomes [57].
Specific phobias are delineated into five types: animal There is no evidence that either flooding or gradual
type, natural environment type, B-I-I type, situational exposure is more effective [314], however, progressive
type, or other type (Table 17) [26]. The fear of contract- exposures are generally more tolerable to patients [311].
ing an illness has been removed because of high related- An example of graded exposure in a patient with ara-
ness to OCD and anxiety disorder related to medical chnophobia would be to look at pictures of spiders, hold
condition [26]. a rubber spider, look at a live spider in a jar, touch the jar
Specific phobias can be difficult to distinguish from containing the spider, stand two feet from a live spider,
panic disorder [311]. It is important to consider the and finally touch a live spider. This approach can be used
focus of apprehension (e.g., fear of crashing while on an to guide exposure depending on the patients symptom
airplane versus fear of having a panic attack on an air- severity and tolerance to each level of exposure.
plane), the types of panic attacks experienced (e.g., While a meta-analysis of 33 RCTs of psychological
expected versus unexpected), and the range of situations approaches found that treatment outcomes were not
associated with fear and avoidance [311]. moderated by type of specific phobia [57], studies have
suggested that certain subtypes may respond more
favorably to specific types of treatment (Table 18).
Table 16 DSM-5 diagnosis of specific phobia For patients with B-I-I phobias, exposure therapy
Marked fear or anxiety about a specific object or situation (e.g., flying, combined with muscle tension exercises (applied ten-
seeing blood)
The phobic object or situation almost always provokes immediate fear
sion) designed to prevent fainting [311] has been shown
or anxiety and is actively avoided or endured with marked fear or to be effective [315,316]. Use of stress-reducing medical
anxiety devices, such as decorated butterfly needles and syr-
The fear or anxiety is out of proportion to the actual danger posed by
the specific object or situation
inges, has been shown to significantly reduce needle
The fear, anxiety, or avoidance is persistent, typically 6 months phobia and stress in both pediatric and adult patients
There is marked distress or functional impairment [317]. CBT reduced avoidance of oral injections and
Adapted from DSM-5 [26]. decreased anxiety in patients with dental phobias [318].
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Table 18 Psychological treatments with demonstrated efficacy in specific phobias


Psychological treatment Phobia
Exposure-based treatments All specific phobias [57,311,312]
Virtual reality exposure Heights [327-329], flying [319,321-324], spiders [331,332], claustrophobia
[330]
Computer-based self-help programs Spiders [334,335], flying [323], small animals [336,337]
Applied muscle tension (exposure combined with muscle tension Blood-injection-injury type [311,315,316]
exercises)
Cognitive therapy and exposure Dental [318], flying [319,320]

Fear of flying has been effectively treated with group (n=40) [340] and arachnophobia (n=20) [341], with evi-
CBT [319,320]. In addition, computer-generated VRE has dence suggesting that cortisol may facilitate the extinc-
demonstrated efficacy [319,321-324], which was compar- tion of phobic fear at follow-up.
able to standard exposure therapy in several studies Enhanced emotional memory may be stimulated
[322,324], and can have long-term benefits [325,326]. through elevated noradrenaline levels, and data suggest
Bibliotherapy was found to be less effective than VRE or that yohimbine hydrochloride, a noradrenaline agonist,
CBT for patients with fear of flying [319]. VRE has also can facilitate fear extinction. In RCTs, there were no sig-
been shown to be effective for patients with a fear of nificant VRE-enhancing effects with adjunctive yohim-
heights [327-329], and those with claustrophobia [330]. bine compared with placebo in patients with fear of
This approach may also be useful for treating fears for flying (n=48) [342] or claustrophobia (n=24) [343]. How-
which in vivo exposure may not be practical (e.g., fear of ever, in the claustrophobia study, patients treated with
storms) [32]. yohimbine showed greater improvements in outcomes at
Arachnophobia has been successfully treated with in the one-week follow-up [343].
vivo [331] and VR [331,332] exposure, with little differ- In contrast, naltrexone was found to render one-ses-
ence between the two modalities [331]. A spiderless form sion exposure therapy less effective compared with pla-
of VRE, which presented images that were not spiders, cebo or no treatment in 15 patients with specific phobias
but had some of the characteristics of spiders, was shown (animals) [344].
to be useful in patients with severe arachnophobia who Long-term effects of psychological treatment
were reluctant to undergo direct exposure or VRE [333]. Long-term treatment of specific phobia is rare. As dis-
An internet-based self-help program was associated with cussed above, CBT and exposure therapies have demon-
improvement, but was not as effective as one session of strated sustained benefits at long-term follow-up
in vivo exposure at the post-treatment assessment, assessments [325,326].
although results were similar at follow-up [334]. How-
ever, even one session of VRE was associated with greater Pharmacological treatment
fear reduction compared to a control group, and may be There is a minimal role for pharmacotherapy in the
a useful self-help intervention to reduce fear of spiders treatment of specific phobias, largely due to the lack of
[335]. Computer-based self-help has also shown promise research on medications in this condition, and the suc-
for other small-animal phobias (e.g., cockroaches, mice) cess of exposure-based therapies [32,311].
[336,337]. Antidepressants have been investigated in two small
Combined psychological and pharmacological treatment RCTs [345,346]. In a small RCT, paroxetine was signifi-
It has been speculated that d-cycloserine, a partial agonist cantly more effective than placebo in resolving anxiety
at the NMDA receptor, may improve extinction of fear in in patients with specific phobias (n=11) [345]. Similarly,
patients with phobias undergoing behavioral exposure escitalopram was associated with a strong treatment
therapy [338]. In a RCT (n=28), d-cycloserine as an effect in a small RCT (n=12); however, the trial was
adjunct to VRE resulted in significantly larger reductions under-powered to show statistically significant superior-
of acrophobia symptoms compared with VRE alone [338]. ity over placebo on the primary outcome [346]. In addi-
In another study (n=100), adjunctive d-cycloserine did not tion, cases of successful treatment of flying phobias with
improve the reduction of spider fears compared to expo- fluoxetine [347], and storm phobia with fluvoxamine
sure-based therapy alone, however, patients had heigh- [348], have been reported.
tened, but subclinical, spider fears [339]. Benzodiazepines have usually been assessed as
In two RCTs, use of adjunctive cortisol, a glucocorti- adjuncts to exposure therapy, and these studies have
coid, significantly enhanced the benefits of exposure ther- found no additional benefit with medication [349-351].
apy compared with placebo in patients with acrophobia Benzodiazepines are often used in clinical practice to
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provide acute symptom relief when it is necessary for a Diagnosis


patient with a specific phobia to face a feared situation SAD is characterized by a persistent fear that in social
(e.g., dental procedure, magnetic resonance imaging and performance situations the individual will say or do
[MRI], unexpected flight) [32]. Nasal midazolam has something that will lead to humiliation, embarrassment,
proven useful in facilitating MRI in claustrophobic or negative evaluation by others (Table 19) [26]. Social
patients [352,353]. situations are actively avoided or endured with distress,
and the individual recognizes the fears as excessive or
Summary unreasonable. The avoidance or anxiety induced by
Specific phobia is quite common, particularly among these fears incurs significant functional impairment and
adolescents. Patients with specific phobia exhibit an distress [144]. Compared to the DSM-IV-TR [144],
intense fear or anxiety about a specific object or situa- changes to the diagnostic criteria for SAD in the DSM-5
tion which is associated with significant distress or func- have been minimal, largely consisting of minor phrasing
tional impairment. The most prevalent phobia types changes to improve clinical utility [26]. The criterion
include animal, natural environment, situational, and that the person recognizes that the fear is excessive or
B-I-I. unreasonable has been changed to out of proportion
Exposure-based techniques, including virtual exposure, to the actual threat posed by the social situation. Since
are highly effective, and are the foundation of treatment patients with SAD are often unable to recognize that
for specific phobias. Pharmacotherapy is generally their fear may be excessive the clinician may be in a bet-
unproven, and thus not a recommended treatment for ter position to judge this.
most cases. The DSM-IV-TR criteria excluded social fears/avoidance
associated with and secondary to medical conditions,
Social anxiety disorder however, the DSM-5 recognizes that SAD may be sec-
Epidemiology ondary to a medical condition. Some patients experience
SAD is one of the most common anxiety disorders, with excessive social anxiety about their medical symptoms
lifetime prevalence estimates ranging from 8-12% (e.g., stuttering, tremulousness from Parkinsons disease,
among the international general population [2,354-356]. obesity, disfigurement from burns or injury), and may
It is more common in women than men [355,357-360], experience disability due to their social anxiety [26].
and higher rates have been reported in developed (6.1%) In addition, the generalized subtype specifier
versus developing (2.1%) countries [361]. SAD has an included in DSM-IV-TR has been removed, while the
early age of onset, typically during adolescence (mean performance only specifier has been added [26,380] for
12 years), and tends to have a chronic and unremitting DSM-5. This change was made because there was little
course [2,362,363]. Factors such as low educational supporting evidence for the generalized specifier, and
achievement, low socioeconomic status, being single or the evidence that SAD symptoms fall along a continuum
separated, and having comorbid MDD have been asso- of severity characterized by the number of fears [380].
ciated with a higher prevalence of SAD in epidemiologi- The performance only specifier appears to represent
cal studies [359,360,364]. a subset of SAD patients typically experiencing
SAD is associated with significant impairments includ-
ing problems with educational and occupational perfor-
mance, family functioning, and an overall reduced QoL Table 19 DSM-5 diagnosis of SAD (social phobia)
[14,15,17,354,363,365-369]. SAD also confers a substan- Marked fear or anxiety about social situations in which the person
tial economic burden upon afflicted individuals and may be exposed to scrutiny by others
society in terms of work days missed and health care Fear that actions or showing anxiety symptoms will cause negative
costs [370,371]. Canadians with SAD were twice as evaluation (e.g., embarrassment, humiliation) or offend others
likely to report at least one disability day in the past two The social situation:
Almost always provokes fear or anxiety
weeks, compared to those without SAD [356]. Is actively avoided or endured with marked fear or anxiety
Psychiatric comorbidity
The fear, anxiety, or avoidance:
SAD is associated with significant comorbidity, with up Is out of proportion to the actual threat posed by the social
to 72% of patients reporting criteria for another psychia- situation
Is persistent, typically 6 months
tric disorder [372]. The highest rates of comorbidity Causes significant distress or functional impairment
have been found with MDD and other anxiety or related If another medical condition is present (e.g., stuttering, obesity), the
disorders [355,356,360]. Avoidant personality disorder disturbance is unrelated or out of proportion to it
[373], body dysmorphic disorder [374,375], SUD Specify performance only if the fear is restricted to speaking or
[356,376], ADHD [377,378], and schizophrenia [379] performing in public
also commonly occur with SAD. Adapted from DSM-5 [26].
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impairment from performance fears primarily related to patients to disengage from negative social cues, but data
their professional lives [26]. are conflicting [402,403].
While the most up-to-date DSM-5 diagnostic criteria ICBT is a newer treatment that may increase the avail-
are presented here, it is important to note that all of the ability of CBT for anxiety and mood disorders in the
treatment data described within this section are based future. Studies have evaluated this treatment in compari-
on patients meeting DSM-IV criteria (or older). son to individual and group CBT. ICBT has demon-
strated efficacy in RCTs of SAD, significantly improving
Psychological treatment social anxiety symptoms compared to wait-list control
Psychological treatment, in the form of CBT, is consid- conditions [404-410]. Most ICBT programs include mini-
ered to be the gold-standard nonpharmacological treat- mal therapist contact via email [404-410] or telephone
ment in SAD. Cognitive techniques involved in CBT for [405,409]. Many programs involve a component of inter-
SAD include restructuring and challenging of maladap- action with other participants through the use of internet
tive thoughts, while the behavioral component is typi- discussion groups [411]. However, it remains unclear
cally in the form of exposure therapy. The efficacy of whether the therapist component is necessary, and stu-
CBT compared with placebo, treatment-as-usual, or dies comparing guided with unguided ICBT have yielded
wait-list conditions, is supported by many RCTs as well conflicting results. In one RCT, clinician-assisted ICBT
as meta-analytic evidence [58,59,70,71,381]. Although was more effective than a self-guided ICBT, and the
results vary, several studies of acute SAD treatment self-guided ICBT was not significantly better than the
have also found a similar efficacy between CBT and wait-list condition [406]. Similarly, a self-help program
pharmacotherapy [382-387]. Some reports suggest that augmented with minimal therapist contact was more use-
after treatment discontinuation, gains achieved with ful than a pure self-help strategy [412]. However, several
CBT may persist longer than those achieved with phar- other RCTs have found that unguided ICBT self-help
macotherapy [388,389]. CBT for SAD can be adminis- was as effective as ICBT with therapist involvement
tered in group or individual formats. Although some [410,411]. A few ICBT programs included face-to-face in
studies have reported that individual CBT is superior to vivo exposure sessions [409,413], but one RCT found
group CBT [390,391], meta-analyses have failed to find that adding this component did not significantly improve
significant differences in efficacy between the two mod- outcomes versus ICBT with self-directed exposure [413].
alities [58,59,381]. In addition, several RCTs have shown ICBT (with mini-
The treatment literature has also examined the efficacy mal therapist contact) to be as effective as face-to-face
of the individual components of CBT. There is evidence CBT [414,415], while being more cost-effective [416]. As
to support the effectiveness of exposure therapy alone with other RCTs, research on ICBT has involved pre-
[389,392], however the efficacy of exposure alone com- screening of participants in-person or by telephone, with
pared with CBT is equivocal in the current treatment lit- posttreatment and follow-up assessments by telephone or
erature [392-395]. through self-report measures. Little is known about the
There are several variants of CBT that have been exam- effectiveness of self-administered treatments (ICBT or
ined in the literature. For example, videotaped feedback self-help books) used with no pre-screening or planned
was not shown to enhance the effects of exposure-based follow-up contacts.
treatment [396]. However, CBT with VRE was found to
be more effective than wait-list control and as effective as Combined psychological and pharmacological treatments
CBT with imaginal or in vivo exposure according to two When used in combination, pharmacotherapy has not
meta-analyses [80,150]. been shown to add to the benefits of CBT in some studies
A form of CBT focused on interpersonal behavior [387,417], while one study found the combination of phe-
found similar improvements in social anxiety compared nelzine and CBT superior to either modality alone [418].
to standard CBT but also increased relationship satisfac- D-cycloserine has also been found to enhance treatment
tion and social approach behaviors [397]. Evidence to outcomes when used during exposure exercises as an
support interpersonal therapy (IPT) in SAD is conflicting adjunct to exposure alone [419,420]. In addition, a study
[398-400]; while some results have been negative [398], it of psychodynamic group therapy with or without the addi-
is likely that IPT is more effective than wait-list control tion of clonazepam also found combination treatment to
[399], but less effective than traditional CBT [399,400]. be superior to clonazepam treatment alone [421].
Similarly, while less effective than traditional CBT,
mindfulness-based therapy (MBT) has been associated Long-term effects of psychological treatment
with improvements in symptoms of SAD [401]. In addi- The benefits of CBT have been found to be maintained at
tion, small studies of attentional bias training suggest six to 12 month follow-up visits [58,382,390,393,409,
there may be some benefit associated with training 413,422,423], with sustained improvement being reported
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at five years posttreatment [424,425]. Long-term assess- First-line agents


ments post-ICBT have shown sustained improvement at Antidepressants: Meta-analyses demonstrate that SSRIs
one to five years follow-up [409,413,423,424]. Long-term and SNRIs are significantly more effective than placebo
benefits with psychotherapy appear to be more enduring [58,426-429] and RIMAs [426,428] for the treatment of
than those of pharmacotherapy after treatment disconti- SAD. There is level 1, RCT evidence supporting the use
nuation [388,389]. of the SSRIs escitalopram [430,431], fluvoxamine
[433-435], fluvoxamine CR [436,437], paroxetine
Pharmacological treatment [431,438-444], and sertraline [445-448], as well as the
The management of patients with SAD should follow SNRI venlafaxine XR [439,441,454-456], for the first-line
the principles discussed in Section 2. Pharmacological treatment of SAD. There is also good evidence for the
interventions that have good evidence for efficacy in efficacy of paroxetine CR (Level 2) [452].
treating SAD include SSRIs, SNRIs, anticonvulsants, and Pregabalin: Pregabalin has also demonstrated efficacy
benzodiazepines. Treatments that have been investigated versus placebo for the treatment of SAD in RCTs at higher
for use in SAD have been assessed according to the cri- (600 mg/day) but not lower dose levels (150-300 mg/day)
teria for strength of evidence (Tables 1 and 2) and are (Level 1) [474,475]. Although there is Level 1 evidence for
summarized in Tables 20 and 21. pregabalin, it is not clear how its efficacy compares to that

Table 20 Strength of evidence of pharmacotherapy for SAD


Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs [58,426-429] 1 TCAs
Escitalopram [430-432] 1 Clomipramine [458,459] 3
Fluvoxamine [433-435] 1 Imipramine [460] 3 (-ve)
Fluvoxamine CR [436,437] 1 MAOIs and RIMAs
Paroxetine [431,438-444] 1 Phenelzine [384,386,418,461,462] 1
Sertraline [445-448] 1 Moclobemide [417,462-466] 1*
Fluoxetine [382,387,449] 1* Other antidepressants
Citalopram [450,451] 2 Mirtazapine [467,468] 1*
Paroxetine CR [452] 2 Bupropion SR [469] 3
Adjunctive paroxetine [453] 3
SNRIs
Venlafaxine XR [439,441,454,255,456] 1
Duloxetine [457] 2
Other therapies
Anxiolytics Anticonvulsants
Benzodiazepines Pregabalin [474,475] 1
Clonazepam [385,470,471] 1 Gabapentin [476,477] 2
Alprazolam [386] 2 Levetiracetam [478-480] 2 (-ve)
Bromazepam [472] 2 Divalproex [481] 3
Adjunctive clonazepam [473] 2 (-ve) Tiagabine [477,482] 3
Topiramate [483] 3
Other treatments Atypical antipsychotics
Atenolol [461,484] 1 (-ve) Olanzapine [493] 2
Buspirone [383,485] 1 (-ve) Quetiapine [494,495] 2 (-ve)
Atomoxetine [486,487] 1* Adjunctive aripiprazole [496] 3
Propranolol [488] 2 (-ve) Adjunctive risperidone [271] 3
Selegiline [489] 3
Pergolide [490] 3 (-ve)
Adjunctive buspirone [491] 3
Adjunctive pindolol [492] 2 (-ve)
*Conflicting data. CR = controlled release; MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin
norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release;
(-ve) = negative.
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Table 21 Recommendations for pharmacotherapy for SAD


First-line Escitalopram, fluvoxamine, fluvoxamine CR, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR
Second-line Alprazolam, bromazepam, citalopram, clonazepam, gabapentin, phenelzine
Third-line Atomoxetine, bupropion SR, clomipramine, divalproex, duloxetine, fluoxetine, mirtazapine, moclobemide, olanzapine, selegiline,
tiagabine, topiramate
Adjunctive Third-line: aripiprazole, buspirone, paroxetine, risperidone
therapy Not recommended: clonazepam, pindolol
Not Atenolol*, buspirone, imipramine, levetiracetam, propranolol*, quetiapine
recommended
CR = controlled release; SR = sustained release; XR = extended release.
*Beta-blockers have been successfully used in clinical practice for performance situations such as public speaking.
Note: although there is limited evidence for citalopram in SAD, it is likely as effective as the other SSRIs, in contrast there are negative trials of fluoxetine in SAD
suggesting it may be less effective than other SSRIs [382,449].

of SSRIs. In addition, SSRIs may have a broader spectrum with moclobemide compared with placebo (Level 1)
of efficacy for common comorbid conditions. [462-464], while others have not [465,466]. Moclobemide
was found to be superior to CBT early in treatment; how-
Second-line agents ever, after six months CBT was found to be superior.
Benzodiazepines: In RCTs, the benzodiazepines clonaze- Data from two small RCTs assessing mirtazapine were
pam (Level 1) [470][385,471], alprazolam [386], and bro- also mixed (Level 1, conflicting), with one showing sig-
mazepam [472] (both Level 2) have demonstrated nificant improvements over placebo [468] and the other
efficacy in the treatment of SAD. showing no differences [467].
Although, a meta-analysis found benzodiazepines to be In a dose-finding study in which patients treated with
as effective as SSRIs [58], these agents are recommended open-label duloxetine 60 mg/day were randomized to
as second-line options because of the lack of effect on continue or double their dose, both doses improved
common comorbidities and the potential for abuse/ symptoms, but there was no significant advantage to the
dependence in individuals with a history of SUDs. higher dose (Level 2) [457].
Antidepressants: In RCTs, citalopram was found to be Small open-label trials have also suggested that bupro-
significantly more effective than placebo [451], and as pion SR [469] and clomipramine [458,459] (both Level 3)
effective as moclobemide [450] (Level 2). Although there may be effective in patients with SAD.
is limited evidence for citalopram in SAD, it is likely as Anticonvulsants: Open-label studies have demonstrated
effective as the other SSRIs. some efficacy with divalproex [481], topiramate [483],
The efficacy of phenelzine has been established in mul- and tiagabine [482] (all Level 3). In addition, tiagabine
tiple RCTs (Level 1) [384,386,418,461,462]; however, this was comparable to gabapentin in a small RCT, crossover
agent is recommended as a second-line option because of study in eight adults [477].
concerns regarding dietary restrictions, drug interactions, Other treatments: Olanzapine was effective in a small
and the potential for hypertensive crisis. RCT (Level 2) [493], and selegiline demonstrated efficacy
Anticonvulsants: Gabapentin was significantly more in a small, open-label trial (Level 3) [489]. In a RCT, ato-
effective than placebo in a RCT [476], and as effective moxetine significantly improved SAD symptoms com-
as tiagabine in a small cross-over study (Level 2) [477]. pared with placebo [487]; however, in a another small
RCT, atomoxetine showed no significant difference in out-
Third-line agents comes compared with placebo (Level 1, conflicting) [486].
Antidepressants: Results with fluoxetine have been All of these agents are recommended as third-line
mixed (Level 1, conflicting) [382,387,449]. A large RCT options, and may be useful in refractory patients after
found that fluoxetine was more effective than placebo first- and second-line monotherapies and adjuncts have
and as effective as CBT [387]. However, in two other been unsuccessful.
small RCTs, fluoxetine alone or when added to self-
exposure showed no benefit over placebo, with or with- Adjunctive therapy
out self-exposure [382,449]. These negative trials with Adjunctive strategies have generally been studied in
fluoxetine suggest it may be less effective than other patients who have had an inadequate response to anti-
SSRIs [382,449]. depressant therapy and can be considered for patients
Similarly, results with moclobemide have also been with treatment-resistant SAD.
mixed (Level 1, conflicting) [417,462-466], with some Third-line adjunctive therapies: Open-label studies and
RCTs demonstrating significantly higher response rates case series have suggested that patients with refractory
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SAD may benefit from adjunctive therapy with aripipra- outcomes, and is often associated with other comorbid
zole [496], risperidone [271], buspirone [491], or paroxe- disorders, including MDD and other anxiety and related
tine [453] (all Level 3). disorders. SAD is characterized by intense fear or anxi-
Not recommended adjunctive or combination therapies: ety relating to social or performance situations where
In RCTs, clonazepam [473] combined with paroxetine and the individual is exposed to scrutiny by others. These
pindolol augmentation of paroxetine [492] (both Level 2, situations are often actively avoided.
negative) were not significantly superior to placebo in aug- CBT and exposure therapy alone are effective first-line
menting the effects of SSRI treatment for SAD. options for the treatment of SAD, although limited data
suggest that CBT may be more effective in maintaining
Not recommended benefits during follow-up. VRE and internet-based pro-
In RCTs there was no evidence of benefits with the beta- grams have also demonstrated efficacy. The benefits of
blockers atenolol (Level 1, negative) [461,484] or proprano- CBT are maintained over one to five years of follow-up.
lol (Level 2, negative) [488], or for the following treatments: CBT and pharmacotherapy appear to have similar effi-
buspirone [383,485], levetiracetam [478-480] (both Level 1, cacy for the acute treatment of SAD, but after treatment
negative), or quetiapine (Level 2, negative) [494,495]. These discontinuation, gains achieved with CBT appear to per-
agents are not recommended for SAD. Imipramine [460] sist longer than those achieved with pharmacotherapy. In
and pergolide (both Level 3, negative) [490] also do not most studies, adding pharmacotherapy has not been
appear to be effective in this disorder. shown to increase the benefits of CBT.
Pharmacotherapeutic approaches should begin with a
Maintenance pharmacological treatment first-line antidepressant such as escitalopram, fluvoxa-
Long-term therapy has been evaluated in relapse preven- mine, fluvoxamine CR, paroxetine, paroxetine CR, sertra-
tion and naturalistic follow-up studies. Relapse-prevention line, or venlafaxine XR, or the anticonvulsant pregabalin.
studies are those in which responders to medication are If response to optimal doses is inadequate or the agent is
randomized to continued active treatment or placebo. not tolerated, therapy should be switched to another
A meta-analysis of four relapse prevention studies first-line agent before considering a second-line medica-
included 760 patients with SAD and found a highly signifi- tion. Second-line choices include the benzodiazepines
cant reduction in relapse rates with continued SSRI treat- alprazolam, bromazepam, and clonazepam, as well as
ment compared with placebo over three to six months. citalopram, gabapentin, and phenelzine. Pregabalin has
The relative risk (RR) for relapse was 0.39 (95% CI 0.30 also been shown to maintain benefits and prevent relapse
0.49) and number needed to treat (NNT) was 3.57 (95% in a six-month study.
CI 2.944.76) [497]. The anticonvulsant pregabalin has Patients who do not respond to several medication
also demonstrated reductions in relapse rates over six trials and/or CBT are considered to have treatment-
months [498]. refractory illness. In such patients it is important to
In RCTs, escitalopram [431], fluvoxamine CR [499], reassess the diagnosis and consider comorbid medical
and venlafaxine XR [456] have demonstrated continued and psychiatric conditions that may be affecting
improvement compared with placebo over approxi- response to therapy. Third-line agents and adjunctive
mately six months. Additional open follow-up data sup- therapies may be useful when patients fail to respond to
port the long-term efficacy of moclobemide over six to optimal treatment trials of first- and second-line thera-
24 months [464,500]. pies used alone and in combination.

Biological and alternative therapies Generalized anxiety disorder


Biological therapies: In an open-label study, neuro psy- Epidemiology
cho physical optimization-radio electric asymmetric con- The estimated 12-month prevalence of GAD ranges from
veyor (NPPO-REAC) (a brain stimulation technique) 1-4%, and the lifetime prevalence is approximately 6%
was as effective as sertraline for the treatment of SAD [2,3,16,503]. GAD is more frequent in Caucasians com-
(Level 3) [501]. pared to other groups [504]. The usual age of onset varies
Alternative therapies: St Johns wort failed to demon- and may be bimodal with the median age of onset being
strate superiority over placebo, and is not recommended approximately 31 years [2] and mean age of onset being
for the treatment of SAD (Level 2, negative) [502]. 32.7 years [505]. The prevalence of GAD is estimated to
be 3% in children and 10.8% in adolescents [506], with
Summary the age of onset for children and adolescents being
SAD is one of the most common anxiety disorders, between ages 10 and 14 [507]. Some data suggest that
occurring more often in women than men. SAD has a women may be two to three times more likely to suffer
negative impact on QoL, functional and occupational from GAD than men [16,508], and GAD may be more
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common in older adults [509,510]. This disorder is than placebo or wait-list control conditions for GAD
reportedly frequently under-recognized with less than (Level 1) [55,64,65,70,520]. Few studies have compared
one-third of patients being adequately treated [511,512]. CBT and pharmacotherapy alone in the same trial, but
This is further complicated in children because of the the magnitude of benefits appear to be comparable for
previous designation of Overanxious Disorder of Child- both groups [521-523]. Individual and group therapy
hood and its possible differentiation of childhood GAD appear to be equally effective in terms of anxiety symp-
from GAD in adults. tom reduction, but individual therapy may lead to ear-
GAD is associated with functional [15,511,513], occupa- lier improvement in worry and depression symptoms
tional [511], and QoL impairments [16,511], as well as sub- [65,520].
stantial economic costs [511,514]. In addition, in primary The intensity of therapy was assessed in a meta-analy-
care 60-94% of patients with GAD report painful physical sis of 25 studies [65]. Regimens including fewer than
symptoms [515,516], and these were the main reason for eight sessions were as effective as those of eight or more
initial presentation to a physician in 72% of cases [516]. for anxiety symptoms, but the more intense regimens
Comorbidity were more effective in improving symptoms of worry
GAD is associated with high rates of comorbid psychia- and depression compared with fewer sessions [65].
tric conditions including other anxiety or related disor- Several studies have demonstrated the utility of internet-
ders and MDD [16]. The risk of medical conditions is based or computer-based CBT programs [79,524-526].
also elevated [16], including pain syndromes [16,517], ICBT has been shown to be significantly more effective
hypertension [16], as well as cardiovascular and gastric than wait-list control [79,524,525], with benefits being
conditions [16,518]. The presence of comorbid depres- maintained at long-term follow-up [525]. In addition, a
sion increases the severity of illness, functional impair- peer-to-peer cognitive self-therapy program was as effec-
ment [519], and economic costs [514]. tive as treatment-as-usual, with a decreased need for
therapist contact [527].
Diagnosis A meta-analysis of five trials found no significant differ-
GAD is characterized by excessive anxiety and worry ences between CBT and relaxation therapy [55]. How-
about multiple events or activities such as school or work ever, more recent studies suggest that applied relaxation
difficulties, which is apparent on a majority of days over has limited efficacy [528-530]. One RCT found little evi-
the previous six months (Table 22) [26]. In addition, GAD dence that patients with GAD can learn to relax in ther-
is associated with restlessness, muscle tension, fatigue, apy or that a decrease in activation is associated with a
concentration difficulties, irritability, and sleep issues [26]. reduction in anxiety [529]. Balneotherapy, a relaxation
The diagnostic criteria for GAD underwent one minor therapy involving spa-related treatments, demonstrated
revision in the DSM-5 [26] compared to the DSM-IV- potential advantages over SSRI pharmacotherapy in
TR [144], the requirement that the disturbance not improving anxiety scores and response rates in patients
occur exclusively during a mood, psychotic, or pervasive with GAD in a large RCT [531]; however, while this
developmental disorder was removed. However, it study may be interesting, concerns pertaining to blinding
remains important to note that most of the treatment and potential bias indicate further study is needed [531].
data described within this section are based on patients Several research-based variables have been specifically
meeting DSM-IV criteria (or older). identified among individuals with GAD in order to gener-
ate evidence-based CBT protocols for GAD, including:
Psychological treatment intolerance of uncertainty, poor problem-solving confi-
Meta-analyses clearly demonstrate that CBT significantly dence, as well as positive and negative metacognitive
reduces GAD symptoms and is markedly more effective beliefs about the function or utility of worry [532]. Specific
psychotherapeutic protocols based upon models of the
Table 22 DSM-5 diagnosis of GAD disorder that target variables underlying GAD have been
Excessive anxiety and worry (apprehensive expectation) about a
developed to individualize therapy. Acceptance-based
number of events or activities (e.g., school/work performance) behavior therapy [533], meta-cognitive therapy [528,534],
The individual finds it difficult to control the worry CBT targeting intolerance of uncertainty [530], and
Excessive anxiety and worry are associated with 3 of the following adjunctive MBCT [184] have demonstrated efficacy for the
symptoms (with at least some occurring more days than not for 6 treatment of GAD. Targeting worry and relaxation [535],
months):
Restlessness or feeling keyed-up or on edge, being easily fatigued,
as well as looming vulnerability (the tendency to generate
difficulty concentrating, irritability, muscle tension, or sleep disturbance and maintain internal scenarios of increasing risk and dan-
The disturbance causes clinically significant distress or functional ger) [536], may also be beneficial.
impairment Psychodynamic therapy may also be of benefit, how-
Adapted from DSM-5 [26]. ever the research findings to date are unclear. A RCT
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found that short-term psychodynamic psychotherapy First-line agents


was as effective as CBT in improving anxiety scores, but Antidepressants (SSRIs & SNRIs): Evidence from RCTs
CBT was superior on measures of worry and depression supports the use of SSRIs including escitalopram
[537]. Another study found no significant differences [544-552] and sertraline [556,559-561], as well as the
between brief psychodynamic therapy, pharmacotherapy, SNRIs duloxetine [566-571] and venlafaxine XR
or the combination [523]. [548,553,570-580] (all Level 1) for the first-line treat-
No significant benefits were found with the addition of ment of GAD. Similar evidence exists for paroxetine
interpersonal and emotional processing therapy to CBT [546,547,553-558] supporting its use as a first-line
when compared with CBT plus supportive listening option. Paroxetine CR has a similar active ingredient,
[538]. However, pretreatment motivational interviewing and although there are less data supporting its use, it is
as an adjunct to CBT was shown to help reduce resis- likely interchangeable with paroxetine as a first-line
tance to therapy, improve homework compliance, and agent (Level 3) [564,565]. In head-to-head comparisons,
improve worry outcomes this strategy may be particu- the efficacy of SSRIs and SNRIs appear to be similar
larly useful in more severe cases [539,540]. [546,547,549,556,558,570,571]. Some data suggest that
In clinical practice, the approach may need to be indi- escitalopram may be less effective than venlafaxine XR
vidualized to the problems experienced by the patient. [548] or quetiapine XR [551]. Efficacy of venlafaxine was
Psychological and pharmacological treatment similar to pregabalin in one RCT [576], but less effective
Few data are available on the use of combined psycholo- in another [577].
gical and pharmacological treatment. A meta-analysis Other antidepressants: In two 12-week, double-blind
concluded that combination pharmacotherapy and CBT RCTs, agomelatine was found to be more effective than
was more effective than CBT alone at posttreatment but placebo (Level 1) [584,585], and as effective as escitalo-
not at six-month follow-up [83]. While large effect sizes pram [585].
were found for GAD, data were available from only two Pregabalin: The anticonvulsant pregabalin was more
studies, and these compared CBT plus diazepam or effective than placebo in RCTs [576,577,592,593,597,613]
buspirone with CBT alone [83]. Compared to pharma- and as effective as benzodiazepines [592,593,597] in
cotherapy alone, the few studies that have assessed the patients with GAD (Level 1). Pregabalin was more effective
benefits of adjunctive psychotherapy have been conflict- than venlafaxine XR in one RCT [577], but equivalent in
ing [184,523,541,542]. One study suggested benefits of another [576].
the combination [184], while two other studies did not Second-line agents
[523,541]. However, adjunctive CBT was shown to facili- Benzodiazepines: Alprazolam [589-593], bromazepam
tate benzodiazepine tapering in patients with GAD [542]. [589,594], diazepam [583,589,595,596], and lorazepam
There is no current evidence to support the routine [589,593,597-601] all have demonstrated efficacy for the
combination of CBT and pharmacotherapy. However, as treatment of GAD (all Level 1). While these agents have
in other anxiety and related disorders, when patients do level 1 evidence for efficacy, they are recommended as
not benefit from CBT or have a limited response, a trial second-line therapy, and usually only for short-term use,
of pharmacotherapy is advisable. Similarly, patients who because of side effects, dependence, and withdrawal issues.
show limited benefit from pharmacotherapy may benefit TCAs and other antidepressants: In RCTs, imipramine
from CBT. was superior to placebo and as effective as benzodiaze-
Long-term effects of psychological treatment pines for the treatment of GAD (Level 1) [553,581-583].
Long-term follow-up data from a meta-analysis [520] However, because of side effects and potential toxicity
and RCTs [523,525,535,543] suggest that benefits of psy- in overdose, imipramine is recommended as a second-
chological treatments are maintained at one to three line option. While there are little data on bupropion XL
years follow-up after treatment. (Level 2), in a 12-week RCT in patients with GAD it
was as effective as escitalopram (a first-line option), sup-
Pharmacological treatment porting its use as a second-line option [549].
The management of patients with GAD should follow Vortioxetine is a so-called serotonin modulator
the principles discussed in Section 2. Pharmacological because of its activity in a variety of serotonin receptors.
interventions that have good evidence for efficacy in Results from two similar, eight-week, placebo-controlled
treating GAD include SSRIs, SNRIs, TCAs, benzodiaze- RCTs with vortioxetine were conflicting, with one trial
pines, pregabalin, quetiapine XR, and other therapies. being positive [587] and the other negative (Level 1,
Treatments that have been investigated for use in GAD conflicting) [586]. The differences in outcomes may be
have been assessed according to the criteria for strength related to differences in recruitment between the two
of evidence (Tables 1 and 2) and are summarized in studies [623], and data suggest that vortioxetine may be
Tables 23 and 24. useful in GAD.
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Table 23 Strength of evidence for pharmacotherapy for GAD


Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Escitalopram [544-552] 1 Imipramine [553,581-583] 1
Paroxetine [546,547,553-558] 1 Other antidepressants
Sertraline [556,559-561] 1 Agomelatine [584,585] 1
Citalopram [562] 3 Vortioxetine [586,587] 1*
Fluoxetine [563] 3 Bupropion XL [549] 2
Paroxetine CR [564,565] 3 Trazodone [583] 2
SNRIs Mirtazapine [588] 3
Duloxetine [566-571] 1
Venlafaxine XR [548,553,570-580] 1
Other therapies
Anxiolytics Atypical antipsychotics
Benzodiazepines Quetiapine XR [551,557,602,603] 1
Alprazolam [589-593] 1 Adjunctive quetiapine [565,604,605] 1*
Bromazepam [589,594] 1 Adjunctive risperidone [606,607] 1*
Diazepam [583,589,595,596] 1 Adjunctive olanzapine [608] 2
Lorazepam [589,593,597-601] 1 Adjunctive aripiprazole [269,609] 3
Adjunctive quetiapine XR [610] 3
Adjunctive or monotx ziprasidone [611,612] 2 (-ve)
Anticonvulsants Other treatments
Pregabalin [576,577,592,593,597,613] 1 Buspirone [108,561,572,589,598,618,619] 1
Divalproex chrono [614] 2 Hydroxyzine [594,619,620] 1
Tiagabine [615,616] 1 (-ve) Pexacerfont [552] 2 (-ve)
Adjunctive pregabalin [617] 2 Propranolol [621] 2 (-ve)
Memantine [622] 4 (-ve)
*Conflicting data. SNRI = serotoninnorepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XL = extended
release; XR=extended release; (-ve) = negative.

Quetiapine XR: There is good evidence for the efficacy adverse events compared with placebo or antidepressants
of quetiapine XR for the management of GAD (Level 1) [115,116]. Due to tolerability and long-term safety con-
[551,557,602,603]. Two meta-analyses [115,116] concluded cerns with atypical antipsychotics, this treatment is recom-
that quetiapine was significantly superior to placebo and mended as a second-line option for patients who cannot
equivalent to antidepressants [115] for the treatment of be provided antidepressants or benzodiazepines.
GAD. However, quetiapine was associated with more Other treatments: Buspirone was more effective than
weight gain and sedation, and higher dropout rates due to placebo and as effective as benzodiazepines in several

Table 24 Recommendations for pharmacotherapy for GAD


First-line Agomelatine, duloxetine, escitalopram, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR
Second-line Alprazolam*, bromazepam*, bupropion XL*, buspirone, diazepam*, hydroxyzine, imipramine, lorazepam*, quetiapine XR*,
vortioxetine
Third-line Citalopram, divalproex chrono, fluoxetine, mirtazapine, trazodone
Adjunctive Second-line: pregabalin
therapy Third-line: aripiprazole, olanzapine, quetiapine, quetiapine XR, risperidone
Not recommended: ziprasidone
Not Beta blockers (propranolol), pexacerfont, tiagabine
recommended
CR = controlled release; XL = extended release; XR=extended release.
*Note: These have distinct mechanisms, efficacy and safety profiles. Within these second-line agents, benzodiazepines would be considered first in most cases,
except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy,
but given the metabolic concerns associated with atypical antipsychotic, it should be reserved for patients who cannot be provided antidepressants or
benzodiazepines. Please refer to text for further rationale for the recommendations.
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RCTs (Level 1) [108,561,572,589,598,618,619]. There are treatment-refractory cases of GAD, and other than que-
limited data comparing buspirone to antidepressants, tiapine XR, used only as an adjunctive treatment.
with it being less effective than venlafaxine XR in one Not recommended adjunctive therapies: Ziprasidone
study [572], but as effective as sertraline in another does not appear to be effective as adjunctive therapy
[561]. Limited effectiveness in clinical practice relegates (Level 2, negative) [611].
buspirone to a second-line agent. Not recommended
Hydroxyzine has demonstrated efficacy superior to Propranolol [621] and pexacerfont [552] (both Level 2,
placebo and similar to benzodiazepines and buspirone in negative) have not demonstrated efficacy and are not
RCTs (Level 1) [594,619,620]; however, clinical experience recommended in the treatment of GAD. While a small
with this agent in the treatment of GAD remains limited. randomized, open-label trial suggested that tiagabine was
Third-line agents as effective as paroxetine, the results of three placebo-
The following agents are recommended as third-line controlled RCTs do not support the efficacy of tiagabine
options because of limited data, side effects, or lack of in patients with GAD (Level 1, negative) [615,616]. Mem-
clinical experience as a primary therapy for the treat- antine also does not appear to be effective in this disorder
ment of GAD. (Level 4, negative) [622].
Antidepressants: In open-label studies or case series, the Maintenance pharmacological treatment
antidepressants citalopram [562], fluoxetine [563], paroxe- Long-term therapy has been evaluated in relapse preven-
tine CR [564,565], and mirtazapine [588] have demon- tion and naturalistic follow-up studies. Relapse-prevention
strated efficacy in patients with GAD (all Level 3). In a studies are those in which responders to SSRI therapy are
RCT, trazodone was as effective as diazepam (Level 2) randomized to continued active treatment or placebo. A
[583]. meta-analysis of three relapse prevention studies included
Other treatments: Divalproex chrono was superior to 1342 patients with GAD and found a highly significant
placebo for the treatment of GAD (Level 2) [614], how- reduction in relapse rates with continued SSRI treatment
ever this formulation is not widely available. compared with placebo over six to 12 months (odds ratio
Adjunctive therapy for relapse was 0.20) [497].
Adjunctive strategies have generally been studied in In RCT discontinuation studies, duloxetine [624], esci-
patients who have had an inadequate response to SSRI talopram [625], paroxetine [626], and venlafaxine XR
therapy, and can be considered for patients with treat- [627] have demonstrated significantly lower relapse rates
ment-resistant GAD. over six to 18 months in the range of 10-20% with active
Second-line adjunctive therapies: Adjunctive pregabalin treatment compared to 40-56% with placebo. Pregabalin
demonstrated good efficacy in a large RCT in patients [628] and quetiapine XR [629] have also demonstrated
with GAD who had an inadequate response to prior significantly lower relapse rates over six to 12 months of
treatments (Level 2) [617]. continued treatment in discontinuation trials.
Third-line adjunctive therapies: A meta-analysis of five In long-term RCT studies, escitalopram [546], paroxe-
RCTs of adjunctive atypical antipsychotics found no sig- tine [546], and venlafaxine XR [578,579] have demon-
nificant improvement in response rates but higher dis- strated continued improvement compared with placebo
continuation rates versus placebo in patients with over approximately six months.
refractory GAD [116].
Two RCTs suggest that adjunctive risperidone (Level 1, Biological and alternative therapies
conflicting) [606,607] may be useful in some patients, but In general, these therapies may be useful for some
in the larger RCT it demonstrated superiority over pla- patients; however, more data are needed.
cebo only in patients with moderate to severe residual Biological therapies: In a small open trial, rTMS was
symptoms at baseline [607]. Similarly, data on adjunctive effective as monotherapy or as an adjunct to SSRIs in
quetiapine have been inconsistent (Level 1, conflicting) patients with GAD (Level 3) [630], and improvements
[565,604,605], with one RCT being negative [565], while were largely maintained six months after treatment [631].
another, unblinded RCT showed some, but limited bene- Alternative therapies: Several herbal preparations have
fits [605]. Adjunctive olanzapine demonstrated efficacy in demonstrated efficacy comparable to lorazepam for
a small RCT in patients who remained symptomatic after the treatment of GAD including silexan (lavender oil)
six weeks of SSRI therapy [608]. Adjunctive treatment (Level 1) [600,632] and Galphimia glauca extract (Level 2)
with quetiapine XR [610] or aripiprazole [269,609] (both [601]. Cochrane meta-analyses found two studies of passi-
Level 3) also had some benefit in open trials. flora (passion flower) indicating it was as effective as
Because of the limited evidence for efficacy and their benzodiazepines (Level 2) [633], and one study of valerian
potential for weight gain and metabolic side effects, which found no significant differences between placebo,
atypical antipsychotics should be reserved for highly valerian, or diazepam (Level 2, negative) [634,635].
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Unfortunately, because these preparations are poorly stan- diagnosis and consider comorbid medical and psychia-
dardized and have substantial variation in proportion of tric conditions that may be affecting response to ther-
the active ingredient in different products, they cannot be apy. Third-line agents, adjunctive therapies, as well as
widely recommended. biological and alternative therapies may be useful when
A RCT of adjunctive resistance training (weightlifting) patients fail to respond to an optimal treatment trial of
or aerobic exercise found significant symptomatic first- and second-line therapies used alone and in
improvements compared to a wait-list condition (Level 2) combination.
[636]. A systematic review included four studies of
acupuncture in GAD or anxiety neurosis, and while all Obsessive-compulsive disorder
trials reported positive findings, methodological details Epidemiology
were lacking and the authors concluded that there was OCD is a relatively uncommon, yet severe, mental disor-
insufficient evidence to determine efficacy (Level 2) [637]. der, with an estimated lifetime and 12-month prevalence
Open-label studies suggest that adjunctive meditation and of 1.0-2.3% and 0.7%-1.2% in adults, respectively
yoga-based treatments may be useful in patients with [2,3,641,642]. Mean age of onset of OCD is ~20 years of
GAD (Level 3) [638,639]. age, but symptoms can occur below the age of 10, with
Not recommended alternative therapy: In a RCT, there few new cases after the early 30s [2,641,643]. Rates of
were no significant improvements with bright light ther- treatment-seeking have been estimated to be only about
apy compared with placebo (Level 2, negative) [640], 14-56% of patients, suggesting that OCD may be under-
and this treatment is not recommended. recognized and under-treated [644,645]. Social isolation,
history of physical abuse, and negative emotionality are
Summary risk factors for the development of OCD [646].
The lifetime prevalence of GAD is approximately 6%, it OCD is associated with a substantial negative impact
is more frequent in women than in men, with age of on QoL for both patients [647,648] and their caregivers
onset reflecting a bimodal distribution (onset in late- [649]. Patients experience cognitive, social, and occupa-
teens to early-twenties, and again in the 30s and 40s). tional impairments [642,645,650,651]. In addition, up to
GAD is associated with substantial functional impair- one-quarter of patients with OCD have attempted suicide
ment and a high prevalence of comorbid psychiatric and [645,652]. OCD symptoms are associated with increased
medical disorders. According to DSM-5 criteria, GAD is rates of health care utilization compared to those without
characterized by excessive anxiety and worry about mul- OCD symptoms [642], with health care costs estimated
tiple situations and is associated with restlessness, mus- at $10.6 billion/year (2005) in the US [653].
cle tension, and behavioral changes. Comorbidity
CBT is an effective first-line option for the treatment of About 60-90% of patients with OCD also have a comorbid
GAD and is as effective as pharmacotherapy. Internet- disorder [641,645]. Patients with OCD or OCD symptoms
based and computer-based CBT have also demonstrated have a three-times higher rate of comorbidity compared to
efficacy. Evidence does not support the routine combina- those without OCD symptoms [642]. Common comorbid-
tion of CBT and pharmacotherapy, but when patients do ities include mood, anxiety, and somatoform disorders, as
not benefit from CBT, a trial of pharmacotherapy is advi- well as SUDs, psychotic disorders, and bipolar disorders
sable, and vice versa. [641,642,645].
Pharmacotherapeutic approaches should begin with
one of the first-line options including an SSRI such as Diagnosis
escitalopram, paroxetine, or sertraline, an SNRI such as A diagnosis of OCD requires the presence of obsessions
duloxetine or venlafaxine XR, or other antidepressant and/or compulsions (Table 25) [26]. Obsessions are
such as agomelatine. The anticonvulsant pregabalin is defined as recurrent, persistent, and intrusive thoughts,
also a recommended first-line therapy. images, or urges that cause marked anxiety, and compul-
If response to optimal doses is inadequate or the agent is sions are defined as repetitive behaviors or mental acts
not tolerated, therapy should be switched to another first- that the patient feels compelled to perform to reduce the
line agent before considering second-line medications. obsession-related anxiety [26]. The obsessions or com-
Second-line choices include bupropion XL, buspirone, pulsions are time consuming and cause significant
hydroxyzine, imipramine, quetiapine XR, vortioxetine, as impairment in social or occupational functioning.
well as the benzodiazepines, alprazolam, bromazepam, In the DSM-5, OCD has been moved from the anxi-
diazepam, and lorazepam. ety disorders [144] to a new diagnostic category called
Patients who do not respond to multiple courses of obsessive-compulsive and related disorders. In addition
therapy are considered to have treatment-refractory to OCD, this new category also includes diagnostic cri-
illness. In such patients it is important to reassess the teria for body dysmorphic disorder, hoarding disorder,
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Table 25 DSM-5 diagnosis of OCD (danger ideation reduction therapy, DIRT), was found to
Presence of either obsessions, compulsions, or both be more efficacious than ERP [661,662]. Cognitive interven-
Obsessions are defined by the following: tions may be important in patients who do not have overt
Recurrent and persistent thoughts, urges, or images that are
experienced as intrusive and unwanted and that cause marked anxiety
compulsions, which can make ERP more difficult. One
or distress meta-analysis found that exposure in vivo combined
The individual attempts to ignore or suppress such thoughts, with imaginal exposure was better than exposure in vivo
urges, or images, or to neutralize them with other thoughts or actions
Compulsions are defined by the following:
alone [60].
Repetitive behaviors (e.g., hand washing, ordering, checking) or Several meta-analyses have demonstrated no significant
mental acts (e.g., praying, counting, repeating words silently) that the differences in efficacy between group and individual CBT
individual feels driven to perform in response to an obsession or
according to rigid rules
[60,62,663]. However, results of head-to-head trials are
Compulsions are aimed preventing or reducing anxiety or conflicting, with some RCTs finding no significant differ-
preventing some dreaded situation or event; however, they are not ences in efficacy between group and individual therapy
connected in a realistic way with what they are designed to neutralize
or are clearly excessive
[663,664], and others showing individual therapy to be
The obsessions or compulsions are time-consuming (e.g., take >1
superior [665-667]. Differences in results may be explained
h/day) or cause clinically significant distress or functional impairment by the fact that in individual therapy the therapist may
Specify patients degree of insight as to reality of OCD beliefs: have the advantage of being more aware of the patients
Good or fair insight (i.e., definitely or probably not true) dysfunctional beliefs, however, the group therapy setting
Poor insight (i.e., probably true)
Absent insight (i.e., completely convinced beliefs are true)
may offer the advantages of group encouragement, reci-
Specify if tic-related OCD
procal support, imitation, and interpersonal learning
which may result in an increased motivation and reduced
Adapted from DSM-5 [26].
discontinuation of treatment [62].
An important practical question concerns the intensity
hair-pulling disorder (trichotillomania), and skin picking and duration of treatment. The intensive ERP program
disorder [26]. described by Foas group involves 15 two-hour sessions
Most of the other modifications to the OCD diagnostic scheduled five days a week over three weeks [658,668]. A
criteria in the DSM-5 were minor wording changes similar program administered twice-weekly (a more prac-
designed to enhance clarity or further operationalize con- tical approach for many patients and therapists) was as
cepts that were considered too vague [26]. In particular, effective at the end of follow-up as the intensive five-
the definitions of obsessions and compulsions were clari- days/week strategy [669]. A step-care approach in which
fied and simplified [26,654]. The requirement that the patients received six weeks of low-intensity counseling
patient recognizes that the obsessions or compulsions are with ERP bibliotherapy followed by standard ERP for
excessive or unreasonable has been deleted, since these non-responders only was found to be as effective as
terms are subject to interpretation and patients can have initial therapy with standard ERP (17 sessions twice
varying levels of insight. As a result, the previous DSM- weekly), but was significantly less costly [670].
IV-TR specifier of poor insight has been expanded to Other techniques that may be useful include accep-
include: good or fair, poor, and absent insight [26]. Finally, tance and commitment therapy (ACT) [671], modular
a specifier of tic-related OCD has been added [26]. cognitive therapy (CT) addressing OCD beliefs [672,673],
While the most up-to-date DSM-5 diagnostic criteria CT addressing obsessional doubt [674], organizational
are presented here, it is important to note that most of training [675,676], and mindfulness training [677]. RCTs
the treatment data described within this section are on the benefits of adding motivational interviewing to
based on patients meeting DSM-IV criteria (or older). CBT have been conflicting, with one showing no addi-
tional benefits [678], while another demonstrated
Psychological treatment improved symptom reduction and remission rates com-
Meta-analyses support the beneficial effects of psychologi- pared with CBT alone [679]. While EMDR was more
cal treatment for OCD, mainly CBT, generally including effective than an SSRI in a RCT [680], data are limited
exposure with response prevention (ERP) [60-63,70,71, and this technique is not generally recommended for
655-657]. CBT is equivalent or superior to pharmacother- patients with OCD.
apy [71,658-660]. Results with CBT were generally similar Data suggest that therapist-guided exposure is better
in comparisons of interventions with an emphasis on ERP than self-exposure [60]. While both treatment condi-
and those with an emphasis on cognitive elements tions showed significant symptom reduction, therapist-
[60,63,655]. A treatment specifically designed to address administered ERP was superior to self-administered ERP
fear of contamination with infectious substances, using a in improving OCD symptoms and self-reported func-
cognitive intervention that includes no direct exposure tional impairment [681]. Other data suggest that ERP
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delivered by telephone is equivalent to face-to-face ERP Pharmacological treatment


[682]. Bibliotherapy in the form of self-help manuals The management of patients with OCD should follow
delivered to patients via email has demonstrated signifi- the principles discussed in Section 2. SSRIs are recom-
cantly greater improvements in OCD symptoms mended first-line pharmacological interventions for
compared with wait-list control groups in two RCTs OCD, while SNRIs, clomipramine, and other antidepres-
[683,684]. sants are recommended second- and third-line treat-
ICBT is an easily accessible treatment that has the ments. Treatments that have been investigated for use
potential to reach untreated patients and motivate them in OCD have been assessed according to the criteria for
for face-to-face psychotherapy if necessary [684,685]. strength of evidence (Tables 1 and 2) and are summar-
Several RCTs have demonstrated that ICBT programs ized in Tables 26 and 27.
are significantly more effective than supportive therapy First-line agents
or relaxation control strategies [685-687]. ICBT was as SSRIs: Evidence from RCTs and meta-analyses support
effective as therapist-led CBT only when patients com- the use of SSRIs, including escitalopram [705-709], fluox-
pleted at least one self-exposure session [687]. ICBT was etine [660,710-716], fluvoxamine [711,713,714,717-719],
associated with significantly better outcomes when it paroxetine [705,720-722], and sertraline [659,710,711,
included brief, scheduled, therapist-initiated telephone 713,714,723-725] (all Level 1), in the treatment of OCD.
support compared with on-demand phone support [688]. In meta-analyses, response rates with SSRIs are generally
Family accommodation (i.e., family members taking twice those of placebo [809], at 40-60% with treatment
part in the performance of rituals, avoidance of anxiety- versus <20% with placebo [711,713,714,740,741]. Pooled
provoking situations, or modification of daily routines to response rates are not significantly different between
assist a relative with OCD) has been associated with SSRIs [809]. In meta-analyses and head-to-head trials,
poorer response to both behavioral and pharmacological compared with clomipramine, the SSRIs fluoxetine, flu-
treatments [689]. Clinicians may want to consider target- voxamine, paroxetine, and sertraline had similar efficacy
ing family accommodation in order to improve treatment but better tolerability [711,713,714,716-718,720,724].
outcomes for some patients. Dimensional analyses have suggested that symmetry/
Although hoarding disorder is now a separate diagnosis hoarding symptoms may be associated with a poorer
[690], the limited data available on the treatment of response to SSRI therapy [810,811], while aggressive/
hoarding will be mentioned in this section on OCD. One religious/sexual symptoms may predict better outcomes
RCT found that group CBT significantly reduced hoard- [810,812]. It has been hypothesized that the symmetry/
ing and depression symptoms while bibliotherapy alone hoarding symptom dimension may be mediated by the
was associated with very limited improvements [691]. dopamine system and aggressive behaviors by the sero-
The addition of posttreatment, nonclinician, home assis- tonin system [810,812].
tance did not significantly improve outcomes. Second-line agents
Combined psychological and pharmacological treatment Clomipramine: There is good evidence to support the
The combination of psychological and pharmacological use of clomipramine in the treatment of OCD (Level 1)
treatment has been shown to be superior to medication [658,711,713,714,716-718,720,724,740,741]. Clomipra-
alone [657,658,692-694], but not to CBT alone [83,658, mine has efficacy similar to SSRIs, but SSRIs are gener-
692,694,695]. These findings suggest that if pharma- ally better tolerated [711,713,714,716-718,720,724]. Side
cotherapy is required or preferred, adding CBT to phar- effects and safety are issues with clomipramine and there-
macological treatment of OCD may enhance response fore it is recommended as a second-line choice. Common
rates and reduce relapse rates. Unlike in some anxiety adverse effects include anticholinergic effects such as dry
and related disorders, there does not appear to be any mouth, constipation, and blurred vision, as well as urinary
contraindication to combining CBT with medications in retention, orthostatic hypotension, weight gain, and seda-
patients with OCD [696], and combined treatment may tion [813,814]. The major safety concerns are cardiac
improve relapse prevention [697]. arrhythmias, seizures, drug interactions, and toxicity in
Adding d-cycloserine may hasten the onset of improve- overdose [813,814].
ments with ERP, with significant benefits over placebo Antidepressants: In RCTs, citalopram was more effec-
during the first four or five ERP sessions [698-700], but tive than placebo but less effective than psychotherapy
this effect has not been seen in all studies [701]. (Level 2) [680,726]. Additional data from augmentation
Long-term effects of psychological treatment studies support the efficacy of citalopram for the treat-
Follow-up studies suggest that the benefits of CBT are ment of OCD [727,728]. However, given that other
maintained at one to five years of follow-up [664,695, SSRIs have much stronger evidence, citalopram was
702-704]. designated a second-line option. The only RCT data on
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Table 26 Strength of evidence of pharmacotherapy for OCD


Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs MAOIs
Escitalopram [705-709] 1 Phenelzine [737,738] 2*
Fluoxetine [660,710-716] 1 Tranylcypromine [739] 4
Fluvoxamine [711,713,714,717-719] 1 TCAs
Paroxetine [705,720-722] 1 Clomipramine [658,711,713,714,716-718,720,724,740,741] 1
Sertraline [659,710,711,713,714,723-725] 1 IV clomipramine [742-744] 2
Citalopram [680,726-728] 2 Desipramine [723,745] 2 (-ve)
IV citalopram [729] 3 Adjunctive clomipramine [746,747] 2 (-ve)
Adjunctive citalopram [730] 3 Other antidepressants
SNRIs Mirtazapine [748] 2
Venlafaxine XR [721,731-733] 2 Bupropion [749] 3 (-ve)
Duloxetine [734-736] 4 Adjunctive mirtazapine [727] 3
Other therapies
Antipsychotics Anxiolytics
Adjunctive aripiprazole [750-755] 1 Benzodiazepines
Adjunctive risperidone [755-761] 1* Clonazepam [771] 2 (-ve)
Adjunctive olanzapine [760,762,763] 1* Adjunctive clonazepam [772] 2 (-ve)
Adjunctive quetiapine [728,746,747,764-768] 1* Other treatments
Adjunctive haloperidol [758,769] 2 Clonidine [773] 2 (-ve)
Adjunctive amisulpride [770] 3 Adjunctive pindolol [774-776] 1*
Adjunctive ziprasidone [767] 4 Adjunctive celecoxib [777] 2
Anticonvulsants Adjunctive granisetron [778] 2
Adjunctive topiramate [795-798] 1* Adjunctive IV ketamine [779,780] 2
Adjunctive lamotrigine [799,800] 2 Adjunctive memantine [622,781-783] 2
Adjunctive pregabalin [801,802] 3 Adjunctive ondansetron [784,785] 2
Adjunctive gabapentin [803,804] 3 (-ve) Adjunctive N-acetylcysteine [786,787] 2
Opioids Adjunctive riluzole [788,789] 3
Tramadol [805,806] 4 Adjunctive lithium [790,791] 1 (-ve)
Naltrexone [807] 3 (-ve) Adjunctive buspirone [792,793] 2 (-ve)
Adjunctive morphine [808] 2 Adjunctive minocycline [794] 4 (-ve)
*Conflicting data. IV = intravenous; MAOI = monoamine oxidase inhibitor; SNRI = serotoninnorepinephrine reuptake inhibitor; SSRI = selective serotonin
reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

the use of mirtazapine in OCD are from a discontinua- the treatment of OCD (Level 2) [721,731-733]. In RCTs,
tion study in which continued mirtazapine was associated venlafaxine XR was more effective than placebo [732],
with continued improvement (Level 2) [748]. There is and as effective as paroxetine [721] and clomipramine
some evidence to support the use of venlafaxine XR for [731]. In a double-blind extension of a RCT [721],

Table 27 Recommendations for pharmacotherapy for OCD


First-line Escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Second-line Citalopram, clomipramine, mirtazapine, venlafaxine XR
Third-line IV citalopram, IV clomipramine, duloxetine, phenelzine, tramadol, tranylcypromine
Adjunctive First-line: aripiprazole, risperidone
therapy Second-line: memantine, quetiapine, topiramate
Third-line: amisulpride, celecoxib, citalopram, granisetron, haloperidol, IV ketamine, mirtazapine, N-acetylcysteine, olanzapine,
ondansetron, pindolol, pregabalin, riluzole, ziprasidone
Not recommended: buspirone, clonazepam, lithium, morphine
Not Clonazepam, clonidine, desipramine
recommended
IV = intravenous; XR = extended release.
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paroxetine was more efficacious than venlafaxine in the other studies. Considering the tolerability concerns of aty-
treatment of non-responders to previous treatment with pical antipsychotics, these data reinforce that this augmen-
the alternate antidepressant [733]. tation strategy should be reserved for patients with
Third-line agents treatment-resistant OCD.
Intravenous clomipramine: In a RCT, intravenous (IV) Second-line adjunctive therapies: RCT evidence
clomipramine was more effective than placebo in demonstrated that adjunctive memantine was superior
patients with OCD (Level 2) [742]. Initiating therapy to placebo (Level 2) [783]. Additional open-label data
with IV then switching to oral therapy does not appear also support this therapy [622,781,782]. Another option
to be associated with greater benefit compared with oral which may be useful as an adjunctive therapy in those
therapy alone [743,744]. with refractory OCD is the atypical antipsychotic quetia-
Other agents: IV citalopram [729] (Level 3), as well as pine (Level 1, conflicting) [728,746,747,764-766,768].
duloxetine [734-736], tramadol [805,806], and tranylcy- Data from small RCTs suggest that topiramate may be
promine [739] (all Level 4) have demonstrated some a useful adjunctive therapy, but data are conflicting
efficacy in open trials or case reports. Results with phe- (Level 1) [796,797]. In one RCT, adjunctive topiramate
nelzine have been inconsistent. In one RCT, phenelzine significantly improved Yale-Brown Obsessive Compul-
was not significantly better than placebo [738], but in sive Scale (Y-BOCS) scores compared with placebo
another it was as effective as clomipramine (Level 2) [797], while in another trial, adjunctive topiramate sig-
[737]. In the placebo-controlled trial, post-hoc analysis nificantly improved compulsions but not obsessions
suggested that phenelzine may be beneficial in patients [796]. Additional open-label data support the use of
with symmetry or other atypical obsessions [738]. adjunctive topiramate [795,798].
These agents are recommended as third-line options, Third-line adjunctive therapies: The agents discussed
and may be useful in refractory patients after first- and below are recommended as third-line adjunctive options,
second-line monotherapies and adjuncts have been since some data are available to suggest they may be
unsuccessful. useful but there is conflicting or inadequate evidence to
Adjunctive therapy warrant stronger recommendations. These agents may
Adjunctive strategies have generally been studied in be useful for some patients, but more data are needed.
patients who have had an inadequate response to SSRI Other atypical antipsychotics have been assessed as
therapy, and can be considered for patients with treat- adjunctive therapies in patients with refractory OCD,
ment-resistant OCD. A meta-analysis demonstrated that including olanzapine (Level 1, conflicting) [760,762,763],
response rates with adjunctive medication were twice amisulpride (Level 3) [770], and ziprasidone (Level 4)
those of placebo, however these were still quite low [767].
(31.8% versus 13.6%) [815]. Meta-analyses of RCTs There is level 2 evidence to support the use of adjunc-
found that adding risperidone (and possibly quetiapine) tive haloperidol in patients with refractory OCD
to antidepressants increased efficacy but decreased toler- [758,769], and although it may be as effective as adjunc-
ability, while adjunctive olanzapine did not improve tive risperidone, it is a third-line choice because it was
response rates [816,817]. less well tolerated [758].
First-line adjunctive therapies: In RCTs, adjunctive ari- Adjunctive mirtazapine was associated with an earlier
piprazole was significantly more effective than placebo onset of response of OCD symptoms compared with cita-
(Level 1) [750,754], and may be as effective as risperi- lopram alone, but there was no advantage of the combi-
done [755]. Additional open-label data also support the nation over time (Level 2) [727]. Some data also support
beneficial effects of adjunctive aripiprazole [751-753]. the efficacy of adjunctive citalopram for treatment-
As adjunctive therapy for treatment-resistant OCD, ris- resistant OCD (Level 3) [730].
peridone was more effective than placebo (Level 1) Adjunctive anticonvulsants may be useful for some
[756-759] and as effective as olanzapine [760] and aripi- patients with refractory illness [799-802]. In a small
prazole overall [755]. Compared with aripiprazole, risperi- RCT, adjunctive lamotrigine improved both obsessions
done may provide greater improvement in obsessions and compulsions compared to SSRI therapy (Level 2)
[755]. Risperidone was also as effective as haloperidol for [799]. Open-label data also suggest that adjunctive preg-
obsessions, but less so for compulsions, however it was abalin may be useful (Level 3) [801,802].
better tolerated [758]. More recently an open, randomized Other agents that have been studied as adjunctive
study found that while augmentation with ERP was super- therapy for treatment-resistant OCD include celecoxib
ior to risperidone or pill placebo, risperidone was not sig- [777], granisetron [778], IV ketamine [779,780], ondan-
nificantly more effective than placebo [761]. However, setron [784,785], N-acetylcysteine [786,787] (all Level 2),
patients in this study had some response to SSRI therapy and riluzole (Level 3) [788,789]. There is little clinical
and may have been less refractory compared to those in experience with these agents for refractory OCD,
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therefore they are recommended as third-line adjunctive suggested that rTMS may be a promising adjunctive
options only. therapy in patients with treatment-refractory OCD
Results with pindolol augmentation have been inconsis- [825,826]. However, results of sham-controlled trials are
tent, with significant improvements in one small RCT conflicting, with some trials finding significant improve-
[774], but not in other randomized or open trials (Level 1, ments [827,828] and others concluding that rTMS was
conflicting) [775,776]. ineffective for treatment-resistant OCD (Level 1, con-
In two randomized, quetiapine-controlled trials, flicting) [829-831]. Some data suggest that rTMS may
adjunctive clomipramine was not superior to SSRI ther- improve comorbid depressive symptoms in patients with
apy (Level 2, negative) [746,747]. Clinical experience OCD [829,830].
suggests that some patients may benefit from adjunctive Several very small studies have suggested that deep
clomipramine; however, plasma levels should be moni- brain stimulation may improve symptoms and function-
tored because of the risk of drug interactions with SSRIs ality in up to two-thirds of patients with highly treat-
[747,813]. ment-refractory OCD (Level 4) [832-834].
Not recommended Open trials suggest that capsulotomy (Level 3)
Clonazepam [771], clonidine [773], and desipramine (all [835-839] or cingulotomy (Level 3) [840-842] may be
Level 2, negative) [723,745] have not demonstrated effi- effective in reducing symptoms in patients with severe,
cacy and are not recommended in the treatment of treatment-refractory OCD, however these treatments are
OCD. Bupropion [749] and naltrexone (both Level 3, usually considered last resorts.
negative) [807] also do not appear to be effective in this Alternative therapies: A meta-analysis of meditation
disorder. therapies found only two small studies and showed that
Adjunctive buspirone [792,793], clonazepam [772] transcendental meditation and Kundalini yoga were
(Level 2, negative), or lithium [790,791] (Level 1, nega- likely no more effective than other kinds of relaxation
tive) have not demonstrated efficacy for the treatment of therapies in treating OCD (Level 3, negative) [843].
OCD. There is currently no evidence for the efficacy of Open studies suggest that adjunctive moderate-intensity
adjunctive gabapentin (Level 3, negative) [803,804] or aerobic exercise may help improve OCD symptoms
minocycline (Level 4, negative) [794], but there are insuf- (Level 3) [844,845].
ficient data to make recommendations at this time. In a Small RCTs and open trials have suggested that herbal
RCT, adjunctive once-weekly oral morphine was effective therapies such as milk thistle (Silybum marianum L.
in patients who had failed six SSRI trials (Level 2) [808], Gaertn.) (Level 2) [715], valerian root (Valeriana offici-
however, morphine is not generally recommended nalis L.) (Level 2) [846], and St Johns wort (Hypericum
because of its potential for abuse. perforatum) (Level 3) [847] may be useful in patients
Maintenance pharmacological treatment with OCD. Unfortunately, because these preparations
Long-term therapy has been evaluated in relapse preven- are poorly standardized and have substantial variation in
tion and naturalistic follow-up studies. Relapse-prevention the proportion of the active ingredient in different pro-
studies are those in which responders to SSRI therapy are ducts, they cannot be widely recommended. These
randomized to continued active treatment or placebo. A therapies may be useful for some patients; however,
meta-analysis of six relapse prevention studies included more data are needed.
951 patients with OCD and found a highly significant
reduction in relapse rates with continued SSRI treatment Summary
compared with placebo over six to 12 months (odds ratio OCD is a relatively rare, yet severe, mental disorder,
for relapse was 0.38) [497]. In RCTs, escitalopram [818], with an onset in the 20s or earlier. It is characterized by
paroxetine [722], sertraline [819], and high-dose fluoxetine the presence of obsessions (persistent, intrusive
[820] have demonstrated reductions in relapse rates. In thoughts) and/or compulsions (repetitive behaviors the
RCT discontinuation studies, mirtazapine [748] and clomi- individual feels compelled to perform). OCD is asso-
pramine [821] have demonstrated continued improvement ciated with substantial functional impairment and a high
compared with placebo over approximately six to prevalence of comorbid disorders.
12 months. Additional data support the long-term efficacy CBT, and notably ERP, are effective first-line options for
of fluoxetine, fluvoxamine XR, and sertraline over six to the treatment of OCD, being equivalent or superior to
24 months [710,822-824]. pharmacotherapy. CBT can be effectively delivered in both
individual and group settings, as well as via self-exposure,
Biological and alternative therapies self-help books, telephone, and internet-based programs.
Biological therapies: Biological therapies may be useful The benefits of CBT are maintained over one to five years
in patients with OCD who have not responded to CBT of follow-up. The combination of psychotherapy and phar-
and multiple medication trials. Open trials have macotherapy appears to be superior to pharmacotherapy
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alone, but not to CBT alone, and data suggest that adding Comorbidity
CBT to pharmacological treatment may yield better long- An estimated 75% of patients with PTSD have another
term outcomes. comorbid psychiatric disorder [3,848]; and rates are par-
Pharmacotherapeutic approaches should begin with a ticularly high for other anxiety and related disorders
first-line SSRI such as escitalopram, fluoxetine, fluvoxa- [3,849,859,869,870], MDD [3,849,859,871,872], opposi-
mine, paroxetine, or sertraline. If response to optimal tional defiant disorder [3], ADHD [3], SUD [849], alco-
doses is inadequate or the agent is not tolerated, therapy hol dependence [3,873], and borderline personality
should be switched to another first-line agent before con- disorder (BPD) [874]. Comorbid panic or mood disor-
sidering second-line medications. Second-line choices ders have been associated with greater functional
include citalopram, clomipramine, mirtazapine, and venla- impairment than PTSD alone [870,871]. Patients with
faxine XR. OCD can be difficult to treat; therefore, in comorbid PTSD and BPD had a poorer QoL, more
order to preserve any benefits of a therapy, adjunctive stra- comorbidity with other psychiatric conditions, and
tegies may be important early in treatment. increased odds of a lifetime suicide attempt versus
Patients who do not respond to multiple courses of ther- patients with either condition alone [20,874].
apy are considered to have treatment-refractory illness. In
such patients it is important to reassess the diagnosis and Diagnosis
consider comorbid medical and psychiatric conditions that By definition PTSD requires exposure to trauma, includ-
may be affecting response to therapy. Third-line agents, ing actual or threatened death, serious injury, or sexual
adjunctive therapies, as well as biological and alternative violation [26]. It is characterized by intrusive and distres-
therapies may be useful when patients fail to respond to sing memories or dreams, dissociative reactions, and sub-
optimal treatment trials of first- and second-line therapies stantial psychological or physiological distress related to
used alone and in combination. the event (Table 28) [26]. A diagnosis of PTSD requires
the disturbances to be present for longer than one
Posttraumatic stress disorder month; symptoms of >3 days but less than one month
Epidemiology may be diagnosed as acute stress disorder (ASD), if the
The lifetime prevalence of PTSD in Canada was esti- required ASD criteria are met [26].
mated to be 9.2%, and current (1-month) rates were 2.4% Compared to the DSM-IV-TR [144], changes to the diag-
[848]. Over 76% of Canadians reported exposure to a nostic criteria for PTSD in the DSM-5 include adjusting
significantly traumatic event [848]. US and European the symptom clusters, adding some new symptoms, and
community studies report lifetime prevalence rates of re-classifying PTSD as a trauma- and stressor-related dis-
6.4-6.8% and 12-month rates of 1.1-3.5% [2,849,850]. The order instead of an anxiety disorder [26,875]. In addition
most common forms of trauma resulting in PTSD to PTSD, this new category also includes diagnostic criteria
included unexpected death of someone close, sexual for reactive attachment disorder, disinhibited social engage-
assault, serious illness or injury to someone close, having ment disorder, ASD, and adjustment disorders [26]. The
a child with serious illness, and being beaten by a partner DSM-5 diagnostic criteria for PTSD sharpens the definition
or caregiver [848-850]. Onset is generally in the mid to of traumatic event, and there are now four symptom
late 20s [2], and the prevalence is about twice as high clusters rather than three with the avoidance and numb-
among women versus men [849,851]. ing of responsiveness being separated (Table 28). The
PTSD was associated with significant QoL [852] and DSM-5 also eliminated the acute and chronic PTSD speci-
functional impairments [848,853-855], which increase fiers. The PTSD diagnostic criteria apply to adults, adoles-
with increasing severity of symptoms [855]. In addition, cents, and children >6 years of age. A subtype has been
PTSD is associated with high rates of chronic pain added for children 6 years of age, as well as a dissociative
[856-859], sleep problems [860], and sexual dysfunction symptoms specifier for patients of all ages [26].
[861], as well as cognitive dysfunction [862,863] and While the most up-to-date DSM-5 diagnostic criteria
alexithymia [864]. The risk of suicide attempts is are being presented here, it is important to note that
increased two- to three-fold by the presence of PTSD the treatment data described within this section are
[20,849,865]. based on patients meeting DSM-IV criteria (or older).
In primary care, PTSD was associated with more and PTSD is frequently comorbid with other psychiatric
longer hospitalizations as well as a greater use of mental disorders, including other anxiety and related disorders,
health care [866]. Among Canadian military personnel, MDD, and SUDs, which may complicate diagnosis and
greater use of mental health care was associated with management [849,859]. In addition, patients with PTSD
cumulative lifetime trauma exposure, index trauma type, frequently present with somatic symptoms and pain
PTSD symptom interference, suicidal ideation, female [859]. It is important to ask patients with psychological
gender, and comorbid MDD [867,868]. or somatic symptoms about trauma [32,859].
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Table 28 DSM-5 diagnosis of PTSD


The person has been exposed to actual or threatened death, serious injury, or sexual violation in 1 of the following ways:
Directly experienced or witnessed the traumatic event, learned that trauma occurred to close family member or friend (actual or threatened
death must have been violent or accidental), experienced repeated exposure to aversive details of trauma
Presence of 1 of the following intrusion symptoms associated with the trauma:
Recurrent, involuntary, and intrusive distressing memories, distressing dreams, dissociative reactions (e.g., flashbacks), psychological or
physiological distress at reminders of trauma
Persistent avoidance of stimuli associated with the trauma, including 1 of the following:
Avoidance of distressing memories or feelings and external reminders (e.g., people, places) of the trauma
Negative alterations in cognitions and mood associated with the trauma, including 2 of the following:
Inability to recall important aspect of the trauma, diminished interest or participation in activities, feeling of detachment or estrangement from
others, persistent negative beliefs, distorted blame, and negative emotional state
Marked alterations in arousal and reactivity associated with the trauma, including 2 of the following:
Irritable or aggressive behavior, reckless or self-destructive behavior, hypervigilance, exaggerated startle response, problems with concentration,
sleep disturbance
Duration of disturbance >1 month
Symptoms cause clinically significant distress or impaired functioning
Specify whether with dissociative symptoms (depersonalization or derealization) or with delayed expression (full criteria not met until at least 6
months after the event)
Adapted from DSM-5 [26].

Prevention and early intervention likelihood of developing subsequent PTSD [889]. SSRI
A number of studies have assessed early intervention therapy was significantly more effective than placebo in
with psychological and pharmacological strategies for preventing PTSD symptoms according to parent reports
the prevention of PTSD. Meta-analyses do not support but not child reports in a RCT in children [890]. Cohort
the efficacy of wide spread use of single-session studies suggest that the early use of morphine during
[876,877] or multiple-session [878] psychological trauma care may reduce the risk of the subsequent devel-
debriefing after trauma in preventing or reducing the opment of PTSD in children and adults [891-894].
intensity of PTSD in individuals who have been exposed
to a traumatic event but have not been identified as suf- Psychological treatment
fering from any specific psychological difficulties. In Psychological therapies for PTSD generally include educa-
fact, these interventions may have an adverse effect on tion about the disorder and its treatment, as well as expo-
some individuals [876,878]. These findings pertain to sure to cues relating to the traumatic event. Psychotherapy
individual debriefings only; there is insufficient evidence has demonstrated significant efficacy, although a meta-
to comment on the utility of group debriefings. analysis suggested it may be less effective than pharma-
Conversely, meta-analyses have demonstrated the ben- cotherapy in improving PTSD and comorbid depression
efit of multisession trauma-focused-CBT (TF-CBT) in symptoms [895].
patients with ASD or PTSD [879,880]. Therefore, debrief- Meta-analyses of over 30 RCTs of psychological inter-
ing of all trauma victims is not recommended, rather, ventions provide evidence of the efficacy of several CBT
screening and treating appropriate individuals is pre- approaches for the management of chronic PTSD com-
ferred [876]. For the prevention of chronic PTSD in pared with wait-list or usual care control groups [66,67].
patients with ASD or acute PTSD, brief TF-CBT was There was evidence that individual TF-CBT, EMDR, stress
more effective than both wait-list and supportive coun- management, and group TF-CBT were effective, while
seling interventions, but there was no evidence of the other nontrauma focused psychological treatments (sup-
effectiveness of structured writing compared to minimal portive therapy, nondirective counseling, psychodynamic
intervention [880]. therapy, and hypnotherapy) did not reduce PTSD symp-
There are few data on the use of pharmacotherapy for toms as significantly [66,67]. Individual TF-CBT and
the prevention of PTSD. In a cohort study and a RCT, EMDR appeared to be equally effective, but superior to
the early use of benzodiazepines following trauma was stress management in the treatment of PTSD [66]. Another
not beneficial, and may increase the risk of developing meta-analysis also found EMDR and TF-CBT were equally
PTSD [881,882]. Similarly, retrospective data suggested effective [68]. However, in a head-to-head RCT, EMDR
that gabapentin or pregabalin had no effect on PTSD resulted in faster recovery compared with the more gradual
development [883]. Data from cohort studies on the use improvement with brief TF-CBT [896]. Cognitive therapy
of the beta-blocker propranolol have been conflicting approaches have been used effectively in treating PTSD fol-
[884-888], but one small RCT did show a significant lowing sexual or interpersonal violence [897-901], civilian
decrease in the severity of PTSD symptoms and lower trauma [902-908], and military trauma [909-914].
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Cognitive processing therapy (CPT) is an effective pro- behaviors allowing over half of patients to become suita-
tocol that combines cognitive therapy and written ble candidates for PTSD treatment [929].
accounts [899-901,910-913]; however, an analysis of the Another study [931] demonstrated some success with
components found no differences in outcomes with PE treatment of PTSD and comorbid substance abuse.
either component alone or the combined protocol [899]. Results of a recent expert clinician survey on best prac-
Prolonged exposure (PE) is a widely studied CBT tices suggests that CBT is useful for fear-based PTSD,
approach. A meta-analysis of 13 RCTs concluded that PE while this treatment approach may require an additional
therapy was more effective than wait-list or psychological treatment module targeting affective regulation for
placebo control conditions, and as effective as other patients presenting with a diagnosis of Disorders of
active treatments (e.g., CBT, CPT, EMDR) [69]. One Extreme Stress (DESNOS) or complex PTSD [932].
study found that 30-minute imaginal exposure sessions Internet-based treatments are being increasingly investi-
were as effective as 60-minute sessions [915]. Imaginal gated, in part because they can be administered remotely
appears to be as effective as in vivo exposure [69,916]. and anonymously to under-served or disaster-stricken
Data are conflicting as to the benefits of adding cogni- areas at a relatively low-cost [933]. RCTs have shown that
tive restructuring to exposure therapy; several studies therapist-assisted ICBT is more effective than wait-list or
suggest that exposure alone is superior to the combina- supportive care control strategies in improving PTSD
tion [917-919], however, another large RCT found the symptoms, depression, anxiety, and disability [934-940].
combination to be significantly better than imaginal or In addition, a strong therapeutic relationship can be estab-
in vivo exposure alone [916]. When used as an adjunct to lished through the internet, which improved the treatment
exposure therapy, cognitive restructuring may improve process [936]. VRE therapy has also demonstrated
non-fear problems like anger and guilt, and may be a use- some utility in improving PTSD symptoms [941-943].
ful adjunct in patients in which these emotions predomi- Compared to face-to-face CBT, video-conference CBT
nate [920,921]. Similarly, the addition of social emotional was equally effective [944] but telehealth CBT was less
rehabilitation to exposure therapy did not improve PTSD effective [914]; however, both were effective compared
symptoms but did improve social functioning in male with pre-treatment.
combat veterans with chronic PTSD [922]. Combined psychological and pharmacological treatment
Meta-analyses and systematic reviews reveal two cur- Research evaluating combined treatment in PTSD is lim-
rent limitations of CBT for PTSD. The first is that about ited; a meta-analysis found only four small trials [945].
one-third to one-half of patients experience substantial Combination SSRI plus psychotherapy was not superior
residual symptoms and functional impairments posttreat- to psychotherapy alone in two RCTs [946,947], but was
ment, still report symptoms meeting diagnostic criteria at superior to pharmacotherapy alone in the other two trials
follow-up, or relapse and require booster sessions [948,949]. In contrast, a more recent RCT found that
[923-925]. The second issue pertains to external validity. combination therapy was superior to psychotherapy
While CBT for PTSD has been shown to be efficacious in alone [950]. The role of combining psychotherapy and
RCTs, there is a dearth of effectiveness studies to suggest medication requires further study.
that CBT can be generalized to many patients commonly Adjunctive propranolol with trauma reactivation therapy
found in clinical practice. Many RCTs have excluded was found to help prevent reconsolidation of the traumatic
patients with complex clinical profiles including child- memory and thus decreased physiological responses and
hood abuse histories, current SUDs, personality disor- PTSD symptoms during subsequent follow-up in rando-
ders, suicidality or self-injurious behavior, homelessness, mized and open trials [951,952]. Two RCTs have found
refugees, intimate partner violence, and significant disso- that use of d-cycloserine did not enhance the overall treat-
ciative symptoms among others [926,927]. In this regard, ment effects of exposure therapy [953,954], and may in
Bradley et al. [923] found a positive association between fact decrease response to psychotherapy [954].
the number of exclusion criteria and the strength of Long-term effects of psychological treatment
effect sizes, such that studies with stricter inclusion cri- Open follow-up data of psychological treatments suggest
teria tended to report larger treatment effects. Addition- that benefits are maintained at six- to 18-month assess-
ally, numerous studies fail to report whether patients ments after treatment [923,955-958]. Longer-term fol-
experience any adverse effects from psychological treat- low-up of patients treated with EMDR showed that
ments [66], or whether dropout rates (ranging between benefits were maintained at three years, with the majority
0-50%) result from treatment demands. of patients who had initially remitted being at full work-
Dialectical behavior therapy (DBT), which was devel- ing capacity [959]. Very long-term follow-up showed that
oped to reduce self-harm behavior in patients with BPD, improvements in PTSD and related symptoms achieved
was shown to be useful in patients with PTSD [928-930]. with CPT and PE were maintained over an extended five
When used as a pretreatment, DBT reduced self-harm to 10 year period [901].
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Pharmacological treatment PTSD. Data with fluoxetine are mixed, with both posi-
The management of patients with PTSD should follow tive [960-962] and negative [963-965] RCTs (Level 1,
the principles discussed in Section 2. Pharmacological conflicting). Similarly, RCTs with sertraline have yielded
interventions that have good evidence for efficacy in both positive [971,972,975,976,978] and negative
treating PTSD include fluoxetine, paroxetine, sertraline, [973,974,977] results (Level 1, conflicting). However,
and venlafaxine XR. Treatments that have been investi- there appear to be sufficient data from the larger RCTs
gated for use in PTSD have been assessed according to to suggest that these agents can be effective first-line
the criteria for strength of evidence (Tables 1 and 2) options. Conflicting results may be related to the types of
and are summarized in Tables 29 and 30. traumas, symptom clusters, and comorbidities included
First-line agents in the various studies.
Antidepressants (SSRIs & SNRIs): Evidence from meta- Second-line agents
analyses [895,1060] and RCTs supports the use of the Antidepressants: The efficacy of mirtazapine was demon-
SSRI paroxetine [966-970] and the SNRI venlafaxine XR strated in one small RCT (Level 2) [1000] and three
[975,989] (both Level 1) for the first-line treatment of open trials [999,1001,1002]. In a randomized, open-label

Table 29 Strength of evidence of pharmacotherapy for core symptoms of PTSD


Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Fluoxetine [960-965] 1* Imipramine [992,993] 1
Paroxetine [966-970] 1 Amitriptyline [994] 2
Sertraline [971-978] 1* Desipramine [970,995] 2*
Fluvoxamine [979-984] 2 MAOIs and RIMAs
Escitalopram [985] 3 Phenelzine [992,993,996] 1*
Citalopram [974,986,787,988] 2 (-ve) Moclobemide [997,998] 3
SNRIs Other antidepressants
Venlafaxine XR [975,989] 1 Mirtazapine [999-1002] 2
Duloxetine [990,991] 3 Reboxetine [984] 2
Bupropion SR [1003] 3
Tianeptine [997,1004] 3
Adjunctive bupropion SR [1005] 2 (-ve)
Other therapies
Anxiolytics Anticonvulsants
Benzodiazepines Topiramate [1009,1010] 1*
Alprazolam [1006] 2 (-ve) Lamotrigine [1011] 2
Clonazepam [881,1007,1008] 3 (-ve) Carbamazepine [1012,1013] 3
Atypical antipsychotics Divalproex [1014-1017] 1 (-ve)
Risperidone [1030] 2 Tiagabine [1018] 2 (-ve)
Aripiprazole [1031-1033] 3 Adjunctive gabapentin [1019,1020] 4
Quetiapine [1034,1035] 3 Adjunctive levetiracetam [1021] 4
Olanzapine [1036-1038] 2 (-ve) Adjunctive pregabalin [1022] 4
Adjunctive risperidone [1039-1044] 1* Adjunctive tiagabine [1023-1025] 4
Adjunctive olanzapine [1045] 2 Adjunctive topiramate [1026-1029] 2 (-ve)
Adjunctive aripiprazole [1033,1046,1047] 3 Other treatments
Adjunctive quetiapine [1048-1050] 3 Buspirone [1051,1052] 4
Trazodone [1053] 4
Memantine [1054] 4
Adjunctive eszopiclone [1055] 2
Adjunctive clonidine [1056] 3
Adjunctive guanfacine [1057,1058] 1 (-ve)
Adjunctive zolpidem [1059] 2 (-ve)
*Conflicting data. MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotoninnorepinephrine reuptake
inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR=extended release; (-ve) = negative.
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Table 30 Recommendations for pharmacotherapy for core symptoms of PTSD


First-line Fluoxetine, paroxetine, sertraline, venlafaxine XR
Second-line Fluvoxamine, mirtazapine, phenelzine
Third-line Amitriptyline, aripiprazole, bupropion SR, buspirone, carbamazepine, desipramine, duloxetine, escitalopram, imipramine,
lamotrigine, memantine, moclobemide, quetiapine, reboxetine, risperidone, tianeptine, topiramate, trazodone
Adjunctive Second-line: eszopiclone, olanzapine, risperidone
therapy Third-line: aripiprazole, clonidine, gabapentin, levetiracetam, pregabalin, quetiapine, reboxetine, tiagabine
Not recommended: bupropion SR, guanfacine, topiramate, zolpidem
Not Alprazolam, citalopram, clonazepam, desipramine, divalproex, olanzapine, tiagabine
recommended
SR = sustained release; XR = extended release.

trial, response rates were significantly higher with mirta- Other therapies: Small, open case series have suggested
zapine than sertraline [1001]. benefits with trazodone [1053], buspirone [1051,1052],
Fluvoxamine demonstrated efficacy for PTSD in open and memantine [1054] (all Level 4).
trials [979-983], and in a RCT was as effective as rebox- Adjunctive therapies
etine (Level 2) [984]. Adjunctive strategies have generally been studied in
Phenelzine was more effective than placebo in two RCTs patients who have had an inadequate response to ade-
[992,993], but not significantly different from placebo in a quate antidepressant therapy, and can be considered for
RCT crossover study (Level 1, conflicting) [996]. Caution patients with treatment-resistant PTSD.
is needed when using MAOIs because of the dietary Second-line adjunctive therapies: In a RCT, adjunctive
restrictions and potential for drug interactions. eszopiclone was significantly more effective than placebo
Third-line agents in improving PTSD and sleep symptoms (Level 2) [1055].
The following agents are recommended as third-line There is RCT evidence for the use of adjunctive atypical
options because of limited data, side effects, or lack of antipsychotics, including risperidone (Level 1, conflicting)
clinical experience as a primary therapy for the treatment [1039-1044] and olanzapine (Level 2) [1045], for patients
of PTSD. with treatment-resistant PTSD. While a number of small
Antidepressants: In small RCTs, imipramine (Level 1) RCTs demonstrated benefits with adjunctive risperidone
[992,993] and amitriptyline (Level 2) [994] demonstrated [1039-1042], a large, six-month trial in approximately 250
some efficacy in patients with PTSD. Data with desipra- patients failed to show improvements in PTSD symptoms
mine are mixed, with one RCT showing significant benefit, compared with placebo [1043].
which were comparable to paroxetine [970], and the other Third-line adjunctive therapies: Open-label trials and
showing improvements in depression only [995]. While case series suggest that adjunctive quetiapine [1048-1050]
RCTs with the TCAs suggest some benefit with these or aripiprazole [1033,1046,1047] (both Level 3) are useful
agents, it appears to be limited. in patients with refractory PTSD.
Reboxetine and fluvoxamine were equally effective in a Similarly, there are some data suggesting adjunctive
small RCT (both Level 2) [984], and open-label studies anticonvulsants including: gabapentin [1019,1020], levetir-
suggest that bupropion SR [1003], duloxetine [990,991], acetam [1021], pregabalin [1022], or tiagabine [1023-1025]
escitalopram [985], moclobemide [997,998], and tianep- (all Level 4), as well as the alpha-adrenergic agonist cloni-
tine [997,1004] (all Level 3) may be useful in PTSD. dine (Level 3) [1056], can improve symptoms in patients
Anticonvulsants: Data on topiramate are mixed, with with treatment-resistant PTSD.
one RCT finding significant benefits over placebo [1010], Not recommended adjunctive therapies: Small RCTs
while the other did not [1009] (Level 1, conflicting). failed to show the superiority of adjunctive therapy with
There are also limited data suggesting efficacy of other guanfacine (Level 1, negative) [1057,1058], bupropion SR
anticonvulsants, including lamotrigine (Level 2) [1011] [1005] (Level 2, negative), or zolpidem [1059] (Level 2,
and carbamazepine (Level 3) [1012,1013]. negative). While case series suggested that adjunctive
Atypical antipsychotics: Some data suggest that the atypi- topiramate [1026,1027,1029] may be effective in treat-
cal antipsychotics, risperidone (Level 2) [1030], aripiprazole ment-resistant PTSD, a RCT failed to show superiority
(Level 3) [1031,1032], and quetiapine (Level 3) [1034,1035] over placebo [1028] (Level 2, negative).
may be a useful alternative to SSRIs for some patients with Treatments for specific PTSD-associated symptoms
PTSD. A meta-analysis of seven RCTs using atypical anti- Several agents have been used to target particular symp-
psychotics, either as monotherapy or adjunctively, con- toms associated with PTSD. Prazosin has demonstrated
cluded that these agents may be beneficial in the treatment significant efficacy for reducing trauma nightmares and
of PTSD, particularly for the symptom of intrusion [1061]. improving sleep quality in patients with PTSD compared
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with placebo (Level 1) [1035,1062-1066]. Some open- PTSD benefited from transcendental meditation
label data suggest that naltrexone may help reduce flash- (Level 4) [1085].
backs (Level 3) [1067-1070], and fluphenazine may
improve trauma re-experiencing symptoms (Level 3) Summary
[1037]. The lifetime prevalence of PTSD is around 6-9%; it is
Cyproheptadine was not effective for nightmares or more frequent in women than in men, with an onset gen-
sleep problems in patients with PTSD and may actually erally in the mid to late 20s. PTSD is associated with high
exacerbate sleep disturbance (Level 2, negative) [1071]. rates of functional impairment, somatic complaints, sui-
Not recommended cide risk, and comorbid psychiatric disorders. A diagnosis
In general, data do not currently support the use of dival- of PTSD requires evidence of exposure to trauma, and is
proex [1014-1017] (Level 1, negative), alprazolam [1006], characterized by intrusive and dissociative symptoms.
citalopram [974,986-988], olanzapine [1036-1038], tiaga- Evidence does not support the wide spread use of early
bine [1018] (all Level 2, negative), or clonazepam (Level 3, intervention with psychological strategies for the preven-
negative) [881,1007,1008]. tion of PTSD. Debriefing of all trauma victims is not
Maintenance pharmacological treatment recommended, rather, screening and treating appropriate
Long-term therapy has been evaluated in relapse- individuals is preferred. In general, there is little evidence
prevention and naturalistic follow-up studies. Relapse- supporting the use of pharmacotherapy for the preven-
prevention studies are those in which responders to tion of PTSD, with most studies suggesting no preventive
SSRI therapy are randomized to continued active treat- benefits.
ment or placebo. A meta-analysis of three relapse- CBT is an effective first-line option for the treatment of
prevention studies included 272 patients with PTSD, PTSD. Effective approaches include TF-CBT, EMDR, PE,
and found a highly significant reduction in relapse and stress management therapy. ICBT and VRE have also
rates with continued SSRI treatment compared with demonstrated efficacy. Benefits are maintained during
placebo over approximately six months (odds ratio for long-term follow-up of up to one to 10 years after treat-
relapse was 0.25) [497]. ment. Research evaluating combined psychological and
In RCT discontinuation studies, fluoxetine [1072,1073] pharmacological treatments in PTSD is limited, and this
and sertraline [1074] have demonstrated significantly requires further study.
lower relapse rates over six months in the range of Pharmacotherapeutic approaches should begin with
5-22% with active treatment compared to 16-50% with one of the first-line options which include SSRIs such as
placebo [1072-1074]. However, in a small discontinua- fluoxetine, paroxetine, or sertraline, or the SNRI venla-
tion RCT, tiagabine was not superior to placebo in pre- faxine XR. If response to optimal doses is inadequate or
venting relapse [1075]. the agent is not tolerated, therapy should be switched to
Open follow-up studies with paroxetine [1076] and another first- or second-line agent, or a second-line agent
sertraline [1077] have demonstrated sustained and con- should be added. Patients with PTSD may make few
tinued improvement over six to 12 months of continued gains during treatment, and it is important to preserve
SSRI therapy. even small gains achieved with initial therapy. Therefore,
augmentation with second- or third-line agents may be
Biological and alternative therapies important early in treatment.
In general, these therapies may be useful for some Patients who do not respond to multiple courses of ther-
patients; however, more data are needed. apy are considered to have treatment-refractory illness. In
Biological therapies: In RCTs, rTMS was effective as such patients it is important to reassess the diagnosis and
monotherapy or as an adjunct to SSRIs in patients with consider comorbid medical and psychiatric conditions that
PTSD (Level 1) [1078-1080], and at least some improve- may be affecting response to therapy. Third-line agents,
ments were maintained at two to three months after treat- adjunctive therapies, as well as biological and alternative
ment [1078,1079]. Open prospective and retrospective therapies may be useful when patients fail to respond to
data suggest that adjunctive electroconvulsive therapy may an optimal treatment trial of first- and second-line thera-
be helpful in patients with refractory PTSD (Level 3) pies used alone and in combination.
[1081,1082].
Alternative therapies: In a RCT, acupuncture was Special populations
more effective than a wait-list control and as effective as Women during pregnancy and the postpartum period
group CBT (Level 2) [1083]. Adjunctive use of symp- Epidemiology
tom-oriented hypnotherapy [1059] or mantra repetition Women have been found to be at higher risk for anxiety
[1084] (both Level 2) improved PTSD symptoms in and related disorders than men [2]. Anxiety disorders
small trials; and in a small case series, patients with during the perinatal period are increasingly gaining
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research attention. Although further investigation is that is gaining increasingly more research attention.
needed, data from a large national survey suggest the Treatment decisions should attempt to optimize out-
overall prevalence of anxiety and related disorders is comes for both mother and baby.
unchanged in women during pregnancy [1086]; however, Detailed recommendations on the use of psychiatric
other data have found an increased risk for individual medications during pregnancy and lactation are available
disorders, such as GAD [1087,1088]. Similarly, some from the American Congress of Obstetricians and Gyne-
data suggest that anxiety disorders are also not more cologists (ACOG) Practice Bulletin [1108]. Although it is
prevalent during the postpartum period [1086], but over five years old, risks associated with various psychotro-
other studies suggest higher rates of OCD and GAD pic medications are summarized [1108]. The FDA preg-
during this period [1089,1090]. In addition, PTSD can nancy risk category system has been criticized as being
develop as a result of pregnancy complications that are insufficient [1109] and is currently under the process of
experienced as traumatic [1091,1092]. revision. The Canadian Hospital for Sick Children
Anxiety and related disorders during pregnancy or Motherisk website (http://www.Motherisk.org) is also a
postpartum may have a negative impact on the preg- useful resource.
nancy, the child, or the mother. While studies report that Antidepressants: There appears to be little evidence of an
maternal anxiety disorders are associated with adverse association between maternal antidepressant use and
pregnancy outcomes such as a shorter gestational age, increased risks of congenital malformations in general, and
premature delivery, or elective cesarean delivery major congenital malformations in infants [1110-1113].
[1093-1095], a meta-analysis found no relationship The exception is a statistically increased risk of cardiac
between anxiety symptoms per se and adverse perinatal defects with antidepressants, and with paroxetine specifi-
outcomes [1096]. Anxiety symptoms during pregnancy cally, although the clinical significance of this has been
have been associated with depressive symptoms, sub- questioned [1108,1113-1117]. There have been reports of
stance use, and anemia, as well as decreased use of prena- increased rates of spontaneous abortion following antide-
tal vitamins [1093,1097-1099]. pressant use during pregnancy; in the most recent meta-
Parenting may also be affected by maternal anxiety and analysis, this was not supported using data from studies
related disorders. Mothers with anxiety disorders have with higher study quality but found by others who included
been found to be less promoting of psychological auton- all studies [1118-1120]. In terms of delivery outcomes, a
omy than those mothers without anxiety [1100]. Maternal recent meta-analysis found a statistically increased risk for
anxiety has been found to be predictive of child cognitive preterm birth, lower gestational age, birth weight, and
development [1101], associated with behavioral/emotional APGAR scores but the effects were small, generally in
problems in childhood [1101,1102], and maternal anxiety the normal range, and of questionable clinical significance
and related disorders have been found to be related to [1118]. However, data support an increased risk for poor
subsequent development of an anxiety disorder in the neonatal adaptation syndrome (PNAS) [1121-1123], while
child [1103]. findings of increased risk for persistent pulmonary hyper-
Treatment issues tension in the antenatally exposed infant have not been
Psychosocial treatments, with CBT specifically, have consistent [1124-1127]. Systematic reviews suggest that
strong empirical support for the treatment of anxiety and overall prenatal exposure to antidepressants does not
related disorders [63,70,71,1104], but evidence of their appear to be associated with changes in long-term neuro-
efficacy in perinatal women with anxiety disorders is cognitive or behavioral development in children
lacking. Cohort studies have shown beneficial effects of [1128-1130] and that illness itself appears to play a role in
group CBT in pregnant women with B-I-I phobia [1105], negative outcomes (although this study examined the
and individual CBT in women with OCD in the postnatal effects of maternal depression) [1131]. Two reports link
period [1106]. Arch et al. argued that although exposure- prenatal antidepressant use to childhood autism spectrum
based CBT or behavioral therapy may have been avoided disorders [1132,1133] and two others link bupropion expo-
in the past because of concerns of potential harm, they sure to childhood ADHD [1134,1135]. These studies have
likely can be viable, safe alternatives in pregnancy [1107]. limitations and further research is required.
The lack of data on the use of structured psychosocial In terms of breastfeeding, potential risks of antidepres-
interventions for anxiety and related disorders during the sant use during lactation must be weighed against the
perinatal period is a significant gap in the literature. recognized benefits for the infant. Antidepressants are
It is important to consider the risks and benefits of excreted into breast milk and although data are limited,
pharmacotherapy during pregnancy and while breastfeed- the majority are found in very low amounts with few iso-
ing during the postpartum period. Risks to the fetus and lated instances of adverse signs [1108]. If antidepressant
newborn should be weighed against that of the potential treatment is indicated, sertraline or paroxetine is preferred
harm of untreated anxiety and related disorders, an area [1136]. Long-term data on potential neurobehavioral
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effects are lacking. Clinicians can consult LactMed at be counseled about PNAS and its management. Less is
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT for known about the risk of benzodiazepine and atypical
the latest information available. antipsychotic exposure during pregnancy as the data are
Benzodiazepines: The data on benzodiazepines remain more limited. Treatment must be individualized and
more limited. A recent meta-analysis did not find an decisions should be made with the most up-to-date infor-
increased risk of major malformations or cardiac defects mation with the best course of action decided upon with
following prenatal benzodiazepine exposure, but con- the patient. Poorly or untreated psychiatric illness carries
cluded the significant increase in risk of oral cleft remains its own risks, both in the short- and long-term.
based on data derived from case-control studies [1137],
although another meta-analysis reported the absolute Children and adolescents
risk is small (<1%) [1138]. A case-control study published Epidemiology
in 2002 examining exposure to five benzodiazepines Anxiety and related disorders were the most common
(including clonazepam) and not included in the above psychiatric disorders noted in the National Comorbidity
meta-analyses, with over 60,000 infants, did not find an Survey-Adolescent supplement (NCS-A) (age 13-18
association with various congenital malformations or oral years), with a lifetime and 12-month prevalence of
clefts [1139]. Although there are a lack of meta-analytic 31.9% and 24.9%, respectively [1155,1156]. Prevalence
data, neonatal withdrawal or toxicity syndrome has been rates for individual anxiety and related disorders are
described with antenatal benzodiazepine exposure and shown in Table 31 [1155,1156].
close monitoring of the infant has been recommended Specific phobias are very common in children. How-
[1108]. The neurobehavioral effects on the child over the ever, although most adolescents reported at least one
long-term due to antenatal exposure have been topics of fear (77%), lifetime prevalence rates are in the range of
debate and remain uncertain [1108]. Benzodiazepines are 10-35% [308,1156]. A study including children as young
excreted into breast milk at low levels generally. A recent as five years of age found lower rates of diagnosed speci-
study with 124 mothers documented low levels of fic phobias (1%) [1157]. B-I-I and animal fears are the
adverse effects (sedation in particular) and supported the most common types reported in pediatric populations
initiation of breastfeeding [1140]. Caution may be advised [308,1157]. The prevalence of OCD is only 0.25% in
regardless however in infants who poorly metabolize ben- children [1158], but is 1-2% in adolescents, which is
zodiazepines [1108]. comparable to the rate seen in adults [2,1159,1160].
Atypical antipsychotics: Data on the use of antipsycho- In the adolescent population, anxiety and related dis-
tics during pregnancy continue to be limited [1141]. orders were found to have the earliest median age of
Thus far, there does not appear to be an increased risk onset (six years), compared to other psychiatric disor-
for malformations although inconsistent data have been ders (11-15 years) [1156]. Similarly, in the adult popula-
reported with some suggesting the data are inconclusive tion, the median age of onset was earliest for anxiety
[1141-1143]. These drugs have been found to be asso- and related disorders (11 years) compared to other psy-
ciated with both increased and decreased birth weight as chiatric disorders (20-30 years) [2]. Separation anxiety
well as increased risk for preterm birth [1144-1149]. The disorder and the phobias (seven to 14 years) have much
second-generation antipsychotics can increase the risk of earlier median ages of onset compared to OCD, GAD,
complications given the risk of metabolic syndrome, and panic disorder, or PTSD (20-30 years) [1,2,1161].
thus diabetes, in the mother. Monitoring has been Anxiety and related disorders can have a substantial
recommended [1150]. Both the FDA and Health Canada long-term impact, putting children at elevated risk for
have issued safety alerts advising of the potential risk for
abnormal muscle movements and withdrawal symptoms Table 31 Prevalence estimates of anxiety and related
in infants exposed to antipsychotic medications during disorders among youths in the NCS-A (age 13-18 years)
the 3 rd trimester of pregnancy [1151-1153]. Data on Anxiety and related disorder Estimated prevalence (%)
breastfeeding are more limited, but levels in breast milk 12-month Lifetime
have typically been shown to be low although adverse Any anxiety disorder 24.9 31.9
effects have been reported [1154]. Separation anxiety disorder 1.6 7.6
Summary Specific phobia 15.8 19.3
The management of anxiety and related disorders in Social anxiety disorder 8.2 9.1
women who are pregnant or lactating requires careful Posttraumatic stress disorder 3.9 5.0
consideration of both the potential risks of any treatment Panic disorder 1.9 2.3
option as well as risks of an untreated anxiety disorder. Generalized anxiety disorder 1.1 2.2
Antidepressants are generally associated with low terato- Adapted from references [1155,1156]. NCS-A = National Comorbidity Survey-
genic risk and adverse delivery outcomes. Patients should Adolescent supplement
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MDD, other anxiety disorders, and SUD in adulthood anxious symptoms) [1183,1184] demonstrate benefits,
[11,12]. Anxiety and related disorders among younger but indicated programs are associated with larger effect
patients are associated with high rates of comorbid psy- sizes than universal programs [1181].
chiatric conditions [1162-1165], SUD [1166-1169], sleep Both psychological and pharmacological strategies
problems [1170-1173], somatic symptoms [1174], and have been assessed for the prevention of PTSD. An
suicidality [1175], as well as problems with cognition/ early psychological intervention with children involved
attention [1164,1176,1177], academic performance in road traffic accidents failed to result in any significant
[1178,1179], and peer relationships [1180]. benefits over a control group [1185].
Diagnostic issues In a RCT in burn victims, sertraline was more effec-
Diagnostic evaluation of pediatric patients should be tive in preventing PTSD symptoms than placebo accord-
based on DSM-5 criteria, but use developmentally ing to parent report but not child report [890]. Data do
appropriate language, and consider collateral informa- not support the use of propranolol in preventing PTSD
tion from parents and teachers. Children may express [1186] or ASD [886] in pediatric injury patients.
anxiety through crying, tantrums, freezing, or clinging, Treatment issues
as well as through play. The DSM-5 provides some Psychological treatment Psychological therapies for
modifications to adult criteria to assist in the diagnosis children often need to be adapted to suit the chronologi-
of anxiety and related disorders in children (Table 32) cal and developmental ages of young patients and to
[26]. In particular, a separate subtype for patients 6 include parental involvement. Meta-analyses support the
years of age has been added to the criteria for PTSD to efficacy of CBT for the treatment of anxiety and related
make it more developmentally sensitive to young chil- disorders in children and adolescents [1187-1191]. A
dren [26]. meta-analysis of 24 clinical trials showed that almost 70%
Prevention strategies of youths who received CBT no longer met diagnostic
Psychoeducational programs for children and adolescents criteria for their anxiety disorder compared to only 13%
aimed at preventing the development of an anxiety or of wait-list controls [1189]. Meta-analyses and RCTs
related disorder have shown small, but significant effects have confirmed the efficacy of CBT in children with SAD
[1181]. Both universal (administered to all children [1192-1197], panic disorder [1198], OCD [1199-1204],
within target population) [1182] and indicated prevention PTSD [946,1205-1211], school refusal [1212-1215], and
programs (administered to children demonstrating highly separation anxiety disorder [1216].

Table 32 DSM-5 diagnostic criteria for anxiety and related disorders specific to children
Anxiety or related DSM-5 diagnoses specific to children
disorder
Separation anxiety Developmentally inappropriate and excessive fear or anxiety concerning separation from those to whom the individual is
disorder attached, as evidenced by 3 of the following:
Distress when separation occurs, worry about loss or separation, reluctance to leave home, be alone, or go to sleep
because of fear of separation, nightmares involving separation, or complaints of physical symptoms (e.g., headaches, upset
stomach) when separation occurs
Duration of at least 4 weeks
Onset before 18 years of age
The disturbance causes clinically significant distress or impairment in social, academic (occupational), or other important
areas of functioning
Selective mutism Consistent failure to speak in specific social situations in which there is an expectation for speaking (e.g., at school)
despite speaking in other situations
Anxiety or related Changes to adult DSM-5 diagnostic criteria specific to children
disorder
Specific phobia The fear or anxiety may be expressed by crying, tantrums, freezing, or clinging
Other specifiers: loud sounds or costumed characters
SAD (social phobia) The anxiety must occur in peer settings, not just during interactions with adults
The fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failure to speak in social
situations
OCD, panic disorder No pediatric specific criteria
PTSD Qualifiers in children
Intrusion symptoms: repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed;
there may be frightening dreams without recognizable content; trauma-specific re-enactment may occur in play
Specific subtype for children 6 years of age
GAD Less stringent criteria for symptoms than in adults
Adapted from DSM-5 [26].
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CBT has demonstrated efficacy in both group and who are unlikely to respond to CBT due to cognitive
individual formats [1189,1190,1194,1217,1218], as well or other issues. A start low and go slow approach
as in computer- or internet-based formats [1219,1220]. is advised when using medications in this patient
One commonly used pediatric CBT protocol is the population.
Coping Cat program [1221,1222], which has demon- The strength of evidence for pharmacotherapeutic
strated efficacy in RCTs [1221,1223,1224] and in long- agents in the treatment of pediatric patients is shown in
term follow-up studies [1222,1225]. In a RCT, Coping Cat Table 33. When pharmacotherapy is felt to be war-
CBT was as effective as pharmacotherapy with an SSRI, ranted, SSRIs are generally preferred for children and
but less effective than combination therapy [1223,1224]. adolescents with anxiety and related disorders.
Additional specific psychological approaches that have Antidepressants: SSRIs and TCAs have been well studied
demonstrated efficacy in treating anxiety in children and in pediatric patients with anxiety and related disorders
adolescents include: attention bias modification (ABM) (Table 33) [1260-1262], although these agents should be
[1226], MBCT [1195], and social effectiveness therapy used with caution in youths as discussed in the section on
(SET) [1227,1228] for SAD; ERP [1229,1230], family-based safety issues below. Most of the data in pediatric patients
CBT [1231,1232], and meta-cognitive therapy [1229] for are in those with OCD [1204,1261,1263] or SAD [1197].
OCD; cognitive behavioral writing therapy (CBWT) There is good evidence for the efficacy of SSRIs in chil-
[1233], spiritual-hypnosis assisted therapy (SHAT) [1234], dren and adolescents with OCD, including fluoxetine
emotion regulation therapy [1235], exposure therapy (Level 1) [1264-1269], citalopram (Level 2) [1264,1270],
[1236], and EMDR [905,1237,1238] for PTSD; and expo- fluvoxamine (Level 2) [1271], paroxetine (Level 2) [1272],
sure therapy for specific phobias [313]. and sertraline (Level 2) [1273], as well as for the TCA
Approaches that include parental or family involvement clomipramine (Level 1) [1274-1276].
may have some additional benefit over strategies that Similarly, there is good evidence for the efficacy of SSRIs
include children only [1239-1245], especially when parents in SAD, including fluoxetine (Level 1) [1227,1277], fluvox-
suffer from an anxiety or related disorder themselves amine (Level 2) [1278], paroxetine (Level 2) [1279], escita-
[1246]. Parental training only has also demonstrated benefi- lopram (Level 3) [1280], and sertraline (Level 3) [1281], as
cial effects on children with an anxiety disorder [1247,1248]. well as for the SNRI venlafaxine XR (Level 2) [1282], and
The presence of comorbidities may have a negative some evidence for mirtazapine (Level 3) [1283].
impact on the efficacy of CBT in pediatric patients [1249]. There is level 2 evidence for the efficacy of fluoxetine
However, integrated CBT protocols designed to target [1277] and fluvoxamine [1278] in separation anxiety dis-
both conditions have demonstrated efficacy in youths with order, and for fluoxetine [1277], fluvoxamine [1278], and
anxiety and related disorders and comorbid ADHD sertraline [1284] in GAD. In school-refusing children and
[1250], aggression [1251], or comorbid SUD [1252]. adolescents, a small case-series suggested benefit with
Long-term follow-up studies have shown sustained citalopram (Level 4) [1285], and a RCT demonstrated
benefits of CBT over two to seven years posttreatment that imipramine as an adjunct to CBT was more effective
[1218,1225,1228,1253,1254]. than CBT alone (Level 2) [1259].
Pharmacological treatment Complete treatment recom- In pediatric PTSD, sertraline alone [1286] or as an
mendations for the management of anxiety and related adjunct to CBT [946] was not more effective than pla-
disorders in youths are beyond the scope of these guide- cebo or CBT (both Level 2, negative) and cannot be
lines and the reader is referred to specific guidelines for recommended at this time.
the assessment and treatment of children and adolescents Benzodiazepines: There are little data demonstrating
with anxiety disorders, such as those developed by the the efficacy of benzodiazepines in children and adoles-
American Academy of Child and Adolescent Psychiatry cents with anxiety and related disorders (Table 33)
(AACAP) [1255-1258]. [1287-1292]. In fact, the few RCTs have demonstrated
For children and adolescents, psychological treatments no significant improvements in anxiety symptoms with
are generally preferred over pharmacotherapy, or if war- alprazolam over placebo in overanxious or avoidant
ranted combination therapy may be an option. RCTs disorders (Level 2, negative) [1290] or school-refusal
comparing combined pharmacological and psychological (Level 2, negative) [1291], or with clonazepam in
treatments in younger patients with anxiety have demon- separation anxiety disorder (Level 2, negative) [1292].
strated efficacy equal or superior to either treatment Benzodiazepines have limited utility in youths,
alone [1199,1223,1224,1259]. In the pediatric population, although they may be useful for short-term therapy in
safety concerns associated with antidepressants (see specific situations where there is a need to achieve
Safety Issues) should be weighed against the potential rapid reduction in severe anxiety symptoms to allow
benefits of therapy. Medication may be warranted in chil- exposure-related psychotherapy (e.g., panic disorder,
dren and adolescents with severe impairment or those school refusal behavior).
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Table 33 Strength of evidence of treatments for anxiety and related disorders in children and adolescents
Disorder Antidepressants Benzodiazepines and other treatments
OCD Fluoxetine (Level 1) [1264-1269] Antipsychotics
Clomipramine (Level 1) [1274-1276] Adjunctive aripiprazole (Level 3) [1293]
Citalopram (Level 2) [1264,1270] Other
Fluvoxamine (Level 2) [1271] Riluzole (Level 4) [1294]
Paroxetine (Level 2) [1272]
Sertraline (Level 2) [1273]
Panic disorder Anxiolytics
Clonazepam (Level 4) [1287,1288]
Alprazolam (Level 4) [1289]
SAD Fluoxetine (Level 1) [1227,1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Alprazolam (Level 2, -ve) [1290]
Paroxetine (Level 2) [1279]
Venlafaxine XR (Level 2) [1282]
Escitalopram (Level 3) [1280]
Sertraline (Level 3) [1281]
Mirtazapine (Level 3) [1283]
Separation anxiety disorder Fluoxetine (Level 2) [1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Clonazepam (Level 2, -ve) [1292]
GAD Fluoxetine (Level 2) [1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Alprazolam (Level 2, -ve) [1290]
Sertraline (Level 2) [1284]
School-refusal Citalopram (Level 4) [1285] Anxiolytics
Adjunctive imipramine (Level 2) [1259] Alprazolam (Level 2, -ve) [1291]
PTSD Sertraline (Level 2, -ve) [1286]
Adjunctive sertraline (Level 2, -ve) [946]
XR = extended release; (-ve) = negative.

Other treatments: In open trials in pediatric patients in young children [1299-1301]. Regulatory bodies in many
with treatment-resistant OCD, the atypical antipsychotic countries have issued black-box warnings about suicidal
aripiprazole (Level 3) [1293] and the glutamate antago- ideation/suicide attempts with the use of antidepressants
nist riluzole (Level 4) [1294] have demonstrated some in patients younger than 19 years. However, in a compre-
efficacy. hensive analysis, the pooled absolute risk difference for
Combination psychological and pharmacological suicidal thinking or behavior between SSRI- and placebo-
therapies The combination of sertraline and CBT was sig- treated youth with anxiety and related disorders was non-
nificantly superior to both monotherapies in a large RCT significant (0.5-0.7%), and lower than the risk for youth
in pediatric patients with separation anxiety disorder, treated for MDD (0.9%) [1302]. Anxiety and related disor-
GAD, or SAD [1223]. In pediatric patients with OCD, the ders also increase the risk of suicidality nearly eight
addition of CBT in those with a partial response to SSRIs times for suicidal ideation and six times for suicide
resulted in significantly greater response rates compared attempts compared with not having an anxiety disorder
with the SSRI alone [1199], while the addition of d-cyclo- [1175]. Therefore, risks and benefits of treatment should
serine to CBT was not superior to placebo [1295]. be discussed with both children and their parents.
Alternative therapies There is currently little evidence The most common antidepressant adverse events are
supporting the efficacy of exercise in reducing anxiety generally activation and vomiting in children, and som-
symptoms in pediatric populations [1296], although nolence in adolescents [1303]. More conservative dosing
some open data suggest it may have a small beneficial strategies may be needed especially in younger children
effect in pediatric PTSD [1297,1298]. or those with low body weight [1301].
Safety issues An important consideration when using Summary
antidepressant medications in children and adolescents is The management of anxiety and related disorders in chil-
the potential for an increased risk of suicidality. Clinicians dren and adolescents can be challenging. Diagnostic eva-
should be aware of the potential activating side effects of luation of pediatric patients should use developmentally
SSRIs (insomnia, agitation, tremor, and anxiety), especially appropriate language and consider collateral information
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from parents and teachers. Children may express anxiety [1330,1331]. Furthermore, the relationship between anxi-
through crying, tantrums, freezing, or clinging, as well as ety and related disorders in the elderly and cognitive
through play. For children and adolescents, psychological impairment remains largely neglected [1332].
therapies are generally preferred over pharmacotherapy, Diagnostic issues
or if warranted combination therapy may be an option. The recognition and accurate diagnosis of anxiety and
Psychological therapies often need to be adapted to suit related disorders in older patients can be challenging
the chronological and developmental ages of young [1333]. Modifications to the DSM-5 diagnostic criteria
patients and to include parental involvement. When may assist clinicians in more accurately recognizing and
pharmacotherapy is warranted, SSRIs are generally pre- diagnosing anxiety and related disorders in the elderly
ferred, although antidepressants should be used with cau- [1333].
tion in pediatric patients. Older patients with anxiety often present differently
than younger patients [1327,1334]. Avoidance and
Elderly excessive anxiety may be difficult to detect in older
Epidemiology patients [1333]. Older adults may describe symptoms
The lifetime and 12-month prevalence of any anxiety or differently; for example, they may discuss concerns
related disorder among those age 65 or older is estimated rather than worries [1327,1333]. They are less likely to
to be 13.6% and 7.0%, respectively, compared with 27.8% attribute symptoms to anxiety and related disorders, but
and 17.8% in the overall adult population [1304]. Including rather may attribute them to physical illness and they
subthreshold anxiety increases the 12-month prevalence may have difficulty remembering symptoms [1327,1335].
from about 6% to over 26% in older adults [1305]. The Obtaining information from collateral sources may be
prevalence rates of anxiety and related disorders have gen- useful. Assessing impact on work or social functioning
erally been shown to decline with age, and as in younger may also be complicated by changes in responsibilities
age groups, the prevalence is higher in women than in associated with aging (e.g., retirement) [1333]. It may be
men [509,1304,1306,1307]. The decline in prevalence may helpful to ask about activities relevant to older adults,
be related to age biases in the assessment of anxiety and such as visiting grandchildren. Similarly, avoidance may
the masking effect of other risk factors that increase with be harder to detect because of limitations in physical
aging [1308]. Under-diagnosis is common, with one study mobility or visual problems, leading to a decline in
finding that only 34% of older patients with GAD had pre- activities outside the home [1336].
viously had anxiety symptoms documented [1309]. Chronic medical illness or the use of medications can
Among older adults (55 years) with mood or anxiety also complicate the diagnosis of anxiety and related dis-
and related disorders, 60-70% do not use mental health orders [1333]. Determining which came first, the physical
care services [1310,1311], although use is higher among illness or the anxiety symptoms can be helpful. However,
those with comorbid disorders [1312]. Older adults with when a medical illness is chronic, this precludes the like-
anxiety and related disorders have higher rates of sleep lihood that the anxiety would resolve when the medical
disturbances [1313-1315] and greater impairment in cog- condition resolves.
nitive functioning [1316-1319] compared to those with- Late-onset anxiety and related disorders are relatively
out anxiety disorder. In addition, anxiety negatively unusual [2], therefore older patients with new onset anxi-
impacts physical functioning and mobility [1320,1321], ety should be investigated for potential causative factors
and health related QoL [1321,1322]. (e.g., physical illness, medication side effects).
Comorbidities Depression is among the most common Psychological treatment
comorbid disorders among older adults with anxiety and Relaxation training, CBT, supportive therapy, and CT
related disorders [1323-1325], and is associated with poorer have support for the treatment of anxiety symptoms and
outcomes of both disorders [1326]. Approximately 80% of disorders in older patients [1337]. Meta-analyses suggest
adults 65 years of age have at least one chronic medical the efficacy of psychological treatment is similar to that
condition, and this may be even higher among those with of pharmacotherapy for the treatment of anxiety and
anxiety disorders [1327]. Older patients with anxiety and related disorders in older patients [1338,1339].
related disorders report higher rates of diabetes, gastroin- In meta-analyses, CBT was an effective option in redu-
testinal conditions, and dementia [1325,1327,1328]. cing anxiety symptoms among older patients compared to
Chronic urinary incontinence, hearing impairment, wait-list or active controls [1340-1342]. Some data suggest
hypertension, respiratory disease, and poor sleep were that CBT may be less effective for anxiety and related dis-
associated with elevated rates of anxiety symptoms or orders in older patients than in working-age adults
disorders [1315,1329]. Comorbid anxiety in patients with [1337,1342]. Older patients may benefit from the inclusion
medical illnesses, particularly cardiovascular disease, has of learning- and memory-aids with standard CBT
been associated with an increased risk of mortality [1343,1344]. In RCTs in older patients, CBT demonstrated
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efficacy for the treatment of GAD [1337,1343,1345-1347] many medications [1368,1369]. Factors which may alter
and panic disorder [1348,1349]. Exposure therapy, with or drug metabolism and plasma concentrations among
without CBT, demonstrated efficacy in case-controlled elderly patients include frailty, reduced homoeostatic
studies in patients with PTSD [1350] or specific phobias mechanisms, and psychosocial issues [1368]. Age-related
[1351]. CBT may also be effectively delivered via changes in body composition can result in increases or
telephone, although improvements may not be long lasting decreases of drug volume distribution, and hepatic or
[1352]. renal dysfunction can impair drug metabolism and drug
In a case-control study, regular physical exercise clearance [1369,1370]. All of these changes are highly
reduced the risk of developing anxiety disorders among variable in elderly patients, further complicating use of
older adults [1353]. medications in this population [1368,1369]. A review of
Pharmacological treatment the literature found that almost half of available antide-
Data suggest that pharmacotherapy including antidepres- pressants are associated with age-related clearance
sants or anticonvulsants is likely as effective in older adults changes and identified at least 45 medications that could
as it is in younger patients [575]. Most of the studies in interact with specific antidepressants [1371].
older patients include those 60 or 65 years and have been DDIs may be more common in older adults because of
conducted in patients with GAD or panic disorder. the greater number of concomitant medication they may
The most robust data in elderly patients with GAD are be taking to treat multiple comorbid conditions. In one
from a large RCT (n=273), which demonstrated signifi- study of US community-dwelling older adults, almost
cant improvements and good tolerability with pregabalin 30% used at least five prescription medications, 80% used
compared with placebo [1354]. Pregabalin was also effec- at least one prescription medication, and almost half
tive as adjunctive therapy in an open trial in older used over-the-counter and dietary supplements [1372].
patients with comorbid GAD and depression [1355]. Psychotropic medications have been associated with an
Pooled analyses of subsets of older patients from mul- increased risk of fractures [1369,1373,1374]. In a meta-
tiple RCTs demonstrate that duloxetine [1356] and ven- analysis, the RR of fractures was 1.34 for benzodiaze-
lafaxine [575] were effective for the treatment of GAD. pines, 1.60 for antidepressants, 1.54 for anticonvulsants,
Citalopram was effective in an eight-week RCT [1357] and 1.59 for antipsychotics [1373]. In a prospective
and in an open study over six months of treatment cohort study (The Rotterdam Study) of subjects over 55
[1358]. Some data suggest that escitalopram may be use- years of age, the risk of non-vertebral fractures was 2.35
ful in older patients with GAD [550,1359]; although in for current SSRI use versus non-use [1375]. The
one RCT, response rates were not significantly different increased risk for hip fracture associated with benzodia-
than placebo in the intention-to-treat analysis [550]. zepines was further increased with increasing dose and
Sertraline was more effective than CBT [1349], particu- the use of concomitant interacting drugs [1369,1374].
larly at a one-year follow-up assessment [1360], and was There does not appear to be any difference between aty-
as effective as buspirone [561] in older adults with GAD. pical antipsychotic agents in the increased risk of falls or
In older patients with panic disorder, paroxetine was as fractures [1376].
effective as CBT and more effective than a wait-list con- An increased mortality risk has been associated with
trol, and results were sustained at a six-month follow-up the use antipsychotics in older patients with dementia
[1348]. Escitalopram [1361] and citalopram [1361] were [1377-1379], which appears to be greater with conven-
equally effective in a small, open trial. A small, open trial tional compared to atypical antipsychotics [1378-1380].
also showed fluvoxamine to be effective in older patients Antidepressants are frequently used to treat symptoms
with GAD, panic disorder, or OCD [1362]. Data in of anxiety in older adults who suffer from comorbid medi-
patients with MDD, suggest that mirtazapine may have cal conditions such as heart disease. In a meta-analysis of
beneficial anxiolytic effects in the elderly [1363,1364]. SSRIs versus placebo or no antidepressant therapy in
Data show that 45-60% of older patients (>55 years) patients with coronary heart disease (CHD) and depres-
with anxiety and related disorders are prescribed a ben- sion, SSRIs were associated with lower rates of all-cause
zodiazepine, which is higher than the rate of antidepres- mortality and readmissions for CHD, indicating that treat-
sant use [1365-1367]. The very high use of these agents is ment may improve CHD prognosis [1381]. Clinicians
a cause for concern since they are not a preferred long- should weigh the risks associated with antidepressants
term treatment strategy and elderly patients may be against the potential benefits when making prescribing
more sensitive to their negative effects [1365,1366]. decisions.
Safety issues The elderly maybe more susceptible to Summary
adverse drug events and drug-drug interactions (DDIs) While onset of anxiety and related disorders in late-life
due to gradual age-related physiologic changes that affect is uncommon, they do persist into older age and can
the pharmacokinetic and pharmacodynamic properties of have substantial impact on QoL and functionality. Older
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patients can present differently compared to younger Major depressive disorder (MDD)
patients, and diagnosis can be complicated by communi- Q. What is the prevalence and impact of comorbid MDD
cation barriers, changes in role functioning, memory dif- and anxiety/related disorders?
ficulties, and comorbid medical conditions. MDD is very common in patients with anxiety, being
Few treatment studies are conducted in older reported in 20-36% of patients [121,310,360,1382]; and
patients; however, data suggest that psychological conversely, about 60% of patients with MDD will have a
treatment and pharmacotherapy appear to be similarly comorbid anxiety or related disorder [44]. In patients
effective in older patients. Using pharmacotherapy in with anxiety, comorbid depression has been associated
elderly patients can be challenging, and should con- with more severe symptoms [46,1384], lower likelihood
sider patient factors such as body mass, hepatic and of remission [47], greater functional impairment
renal function, comorbid conditions, and use of conco- [46,871,1384], an increased risk of suicide [652], and a
mitant medications. greater risk of having another comorbid anxiety disorder
[360]. Similarly, in patients with MDD, comorbid anxi-
Anxiety with comorbid conditions ety and related disorders were associated with poorer
Overview treatment outcomes including higher recurrence rates
Anxiety and related disorders often present together with [1385-1387], poorer QoL [1391], and an increased risk
other psychiatric or medical conditions [3,16,43, of suicide [24,1387,1392,1393].
1382,1383]. About 60-80% of patients with an anxiety Q. What pharmacological treatment may be useful for
disorder have at least one other comorbid psychiatric patients with an anxiety/related disorder and comorbid MDD?
condition, which most commonly include another anxi- Guidelines generally recommend antidepressants (most
ety or related disorder, MDD, bipolar disorder, ADHD, commonly SSRIs and SNRIs) as first-line treatments in
and SUD [3]. The presence of comorbid disorders has patients with both anxiety and depressive symptoms
a negative impact on most aspects of care. Patients [32,1394]. SSRIs and SNRIs in patients with anxiety and
with psychiatric comorbidities have more severe symp- related disorders, including panic disorder, GAD, OCD, or
toms [46,1384], poorer treatment outcomes for both dis- PTSD, with comorbid MDD have been shown to be effec-
orders [47,1385-1387], greater functional impairment tive in improving both disorders [224,723,1359,1395].
[46,871,1384], poorer QoL [1388,1389], and an increased Among the atypical antipsychotics, quetiapine has been
risk of suicide [652]. found to have efficacy as monotherapy in both MDD
Medical conditions and pain disorders are also common [1396] and GAD [1397], as well as MDD with anxiety
comorbidities in patients with anxiety and related disor- [1398], while case series suggest that aripiprazole augmen-
ders. Medical conditions frequently reported in patients tation of antidepressants [496], and risperidone monother-
with anxiety and related disorders include cardiovascular apy [267] may also reduce comorbid depressive and
disease, gastrointestinal disease, arthritis, respiratory dis- anxiety symptoms.
ease, thyroid disease, migraine, and allergic conditions
[16,52]. Patients with both anxiety disorders and medical Bipolar disorder or psychoses
conditions experience elevated disability, including more Q. What is the prevalence and impact of comorbid bipolar
psychiatric comorbidity and depressive symptoms, as well disorder or psychoses with anxiety/related disorders?
as poorer interpersonal and physical functioning [52,142]. Among patients with anxiety and related disorders, almost
Patients with chronically painful conditions such as arthri- 14% also met criteria for bipolar I or II disorder [121].
tis, back pain, or migraine are at a two- to four-fold higher However, among patients with bipolar disorder the rates
risk of having an anxiety or related disorder, particularly of comorbid anxiety disorders are very high compared to
panic disorder or PTSD [1390]. the general population, and the DSM-5 notes anxiety dis-
The high probability of comorbid disorders should orders as the most common comorbidities in patients with
be considered when diagnosing and treating patients bipolar disorder [26]. In epidemiological surveys, the life-
with anxiety and related disorders. In patients with time comorbidity rates for any anxiety or related disorder
comorbid psychiatric conditions, such as another anxi- among patients with bipolar disorder was 52% in Canada
ety disorder or mood disorder, consider therapies that [43] and 60-75% in the US [1389,1399]. In a clinic popula-
are effective for both disorders [32]. Benzodiazepines tion, the rate of anxiety and related disorders was 22% in
should be prescribed with additional caution in patients with bipolar disorder, compared to 17% in
patients with comorbid SUDs. In patients with comor- patients with schizophrenia, and 30% in those with schi-
bid medical conditions, the clinician must weigh the zoaffective disorder [1400]. A meta-analysis of prevalence
benefits and risks of medication for the anxiety or studies found that the rates of various anxiety disorders in
related disorder, but should also consider the impact patients with schizophrenia and related psychotic disor-
of untreated anxiety [32]. ders ranged from 10-15% [1401].
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Comorbid anxiety and related disorders in patients with 50-60% into adulthood [45,1417,1418]. In a community-
bipolar disorder were associated with a greater risk of MDD based survey, the estimated prevalence of current self-
and drug use disorders, a poorer bipolar course, lower QoL, reported adult ADHD was 4.4% [45]. While ADHD has
and lower psychosocial functioning [1388,1389]. Data are long been known to persist into adulthood [1419,1420],
conflicting on the impact of anxiety and related disorders it has only recently become the focus of widespread
on suicidal tendencies in patients with bipolar disorder, clinical attention [1421-1423].
with some analyses finding an increased risk [1389,1402], Of adults identified with ADHD in the National
but not all [1403]. Similar findings have been reported in Comorbidity Survey-Replication (NCS-R), only one in
patients with schizophrenia, where comorbid anxiety and 10 had received treatment within the previous year [45].
related disorders have been associated with more past Of these individuals, it is estimated that approximately
SUDs, lower social adjustment and overall QoL, and greater 47% meet criteria for an anxiety or related disorder
suicidality [1404,1405]. within 12 months of assessment, with the most common
Q. What pharmacological treatment may be useful for being SAD (29.3%), followed by specific phobia (22.7%),
patients with an anxiety/related disorder and comorbid PTSD (11.9%), panic disorder (8.9%), and GAD (8.0%)
bipolar disorder or psychoses? [45]. Patients with an anxiety or related disorder were
The management of patients with anxiety and related dis- reportedly four times more likely to meet criteria
orders and comorbid bipolar disorder, schizophrenia, or for ADHD than the general population [45]. Similar
other psychosis should consider therapies that are effective results were found in a Canadian survey of patients in an
for both disorders [32]. Atypical antipsychotics are recom- anxiety disorders clinic, where the rate of adult ADHD
mended treatments for bipolar disorder and schizophrenia was 28% [378].
[111,1406], while the long-term use of antidepressants Q. What factors should be considered when treating patients
may destabilize patients with bipolar I disorder [111,1394]. with an anxiety/related disorder and comorbid ADHD?
Data in patients with a diagnosed anxiety or related dis- When managing a patient with ADHD, it may be
order and comorbid bipolar disorder or psychosis are important to differentiate ADHD with anxious symp-
limited. In a RCT, risperidone monotherapy was shown toms from comorbid ADHD and anxiety/related disor-
to be no more effective than placebo for patients with ders. This can be challenging, as anxiety symptoms are
bipolar and comorbid panic disorder or GAD [1407]. frequently related to a sense of being overwhelmed or to
However, in a single-blind trial, olanzapine or lamotri- compensatory skills in patients with ADHD. Stimulants
gine when added to lithium demonstrated improvements may play a larger role in managing ADHD in patients
in anxiety disorder symptoms in patients with remitted with anxiety symptoms [1424,1425]; however, in an
bipolar disorder [1408]; and in an open trial, switching to open trial, atomoxetine improved ADHD and comorbid
aripiprazole significantly improved social anxiety and symptoms of depression and anxiety [1426].
psychosis in patients with SAD and schizophrenia [379]. Treatment of patients with comorbid ADHD and an
In addition, atypical antipsychotics have demonstrated anxiety or related disorder may be more complicated.
efficacy in RCTs in patients with anxiety and related dis- Generally, in patients with comorbid anxiety disorders
orders (see specific disorder sections for evidence), and and ADHD the diagnostic and treatment priority should
data show that these agents can significantly reduce anxi- be determined by the relative severity of symptoms and
ety symptoms in patients with bipolar disorder risks of each disorder [1427]. There are limited data on
[1409-1413]. Taken together, these data suggest these the role of stimulants in patients with ADHD and an
agents may be useful in comorbid patients. anxiety disorder. In a RCT, atomoxetine significantly
Anticonvulsants have also demonstrated efficacy in the improved ADHD and SAD symptoms compared with
treatment of some anxiety and related disorders (see spe- placebo [487]. In separate open trials, adjunctive atomox-
cific disorder sections for evidence) and are often used etine [1428] and adjunctive extended release mixed
for the treatment of bipolar disorder [111]. In patients amphetamine salts [1429] significantly improved anxiety
with bipolar disorder, adjunctive valproate and gabapen- symptoms in patients with ADHD and GAD refractory to
tin have demonstrated efficacy for the treatment of panic antidepressants alone.
disorder [281,1414] and resulted in reductions in anxiety
symptoms [1415,1416]. Medical comorbidities
Q. What is the prevalence and impact of comorbid medical
ADHD conditions and anxiety/related disorders?
Q. What is the prevalence of comorbid ADHD and anxiety/ Medical conditions are also common comorbidities that
related disorders? must be considered when prescribing medication for
It is estimated that the lifetime rate of ADHD in chil- patients with anxiety and related disorders. Medical con-
dren is 6-9%, with 70% persistence into adolescence and ditions are reported in over 60% of patients with anxiety
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and related disorders including cardiovascular diseases, gain [109-116,1443]. Some antidepressants, including
gastrointestinal diseases, arthritis, respiratory diseases amitriptyline, mirtazapine, and paroxetine have also been
such as asthma, thyroid disease, migraine headaches, associated with weight gain [1448].
back pain, and allergic conditions [16,52,1430-1432].
Comorbidities are particularly common among patients Canadian Anxiety Guidelines Initiative Group
with GAD, panic disorder, and PTSD [16,140,515, Additional authors
517,1390,1433]. Martin M. Antony1, Stphane Bouchard2, Alain Brunet3,
Patients with anxiety and related disorders and medi- Martine Flament4, Sophie Grigoriadis5, Sandra Mendlo-
cal conditions experience more psychiatric comorbidity, witz6, Kieron OConnor7, Kiran Rabheru4, Peggy M.A.
depressive symptoms, and more severe anxiety disorder Richter5, Melisa Robichaud8, John R. Walker9
1
symptoms, as well as poorer interpersonal and physical Department of Psychology, Ryerson University,
functioning [52,140,142,515]. Toronto, M5B 2K3, Canada; 2Department of Psychoe-
Q. What factors should be considered when treating ducation and Psychology, University of Qubec in Out-
patients with an anxiety/related disorder and comorbid aouais, Gatineau, J9A 1L8, Canada; 3 Department of
chronic pain? Psychiatry, McGill University, Montreal, H3A 1A1,
Chronically painful conditions (i.e., arthritis, back pain, Canada; 4 Department of Psychiatry, University of
and migraine) are commonly associated with anxiety Ottawa, Ottawa, K1Z 7K4, Canada; 5 Department of
[515,1390,1430,1434]. Patients with anxiety and related Psychiatry, University of Toronto, Toronto, M5S 1A1,
disorders are twice as likely to have painful physical Canada; 6Department of Child Psychiatry, University of
symptoms compared to of those without, 45-60% versus Toronto, Toronto, M5S 1A1, Canada; 7Department of
28% [515,1433]. About 60-70% of patients with anxiety Psychiatry, University of Montreal, Montreal, H3C 3J7,
disorders report migraine headaches [140,141]. Canada; 8 Departments of Psychiatry and Psychology,
For the management of anxiety and related disorders in University of British Columbia, Vancouver, V6T 2A1,
patients with pain it may be helpful to consider treat- Canada; 9 Department of Clinical Health Psychology,
ments that have demonstrated efficacy in both anxiety University of Manitoba, Winnipeg, R3E 3N4, Canada
disorders as well as pain. While there are few data avail- Email: Martin M. Antony - mantony@psych.ryerson.ca;
able, duloxetine has demonstrated efficacy for both GAD Stphane Bouchard - stephane.bouchard@uqo.ca; Alain
and pain symptoms in RCTs [1435-1437]. TCAs, and to Brunet - alain.brunet@mcgill.ca; Martine Flament - mar-
a lesser extent SSRIs, have been shown to reduce head- tine.flament@theroyal.ca; Sophie Grigoriadis - sophie.gri-
ache attacks in patients with migraine [1438], and pro- goriaidis@sunnybrook.ca; Sandra Mendlowitz - sandra.
vide moderate relief of neuropathic pain [1439]. mendlowitz@sickkids.on.ca; Kieron OConnor - kieron.
Q. What factors should be considered when treating oconnor@umontreal.ca; Kiran Rabheru - kiranrabheru@-
patients with an anxiety/related disorder and comorbid hotmail.com; Peggy M.A. Richter - peggy.richter@sunny-
cardiovascular disease? brook.ca; Melisa Robichaud - robichau@mail.ubc.ca; John
Although panic attacks can sometimes be mistaken for R. Walker - jwalker@cc.umanitoba.ca
cardiovascular symptoms, it is important to be aware that
patients with anxiety and related disorders do have a two- Additional contributors to the comorbidity section
to three-times greater risk of cardiovascular disease com- Gordon Asmundson10, Larry J. Klassen11, Raymond W.
pared to the general population [1431,1432]. In addition, Lam12, Roger S. McIntyre13, Isaac Szpindel14
10
anxiety disorders have been associated with increased risk Department of Psychology, University of Regina,
of cardiovascular hospitalization rates and mortality risk Regina, S4S 0A2, Canada; 11Department of Psychiatry,
[1440-1442]. In patients with cardiovascular or cerebrovas- Faculty of Medicine, University of Manitoba, Winnipeg,
cular comorbidity, it is important to consider the impact R3T 2N2, Canada; 12Department of Psychiatry, Univer-
of treatments used for anxiety on heart rate, blood pres- sity of British Columbia, Vancouver, V6T 2A1, Canada;
13
sure, and lipid measures [1443-1445]. Departments of Psychiatry and Pharmacology, Univer-
Q. What factors should be considered when treating sity of Toronto, Toronto, M5S 1A1, Canada; 14Attention
patients with an anxiety/related disorder and comorbid and Learning Related Disorders, START Clinic, Tor-
diabetes and metabolic syndrome? onto, M4W 2N4, Canada
Patients with anxiety symptoms have an elevated risk of Email: Gordon Asmundson - gordon.asmundson@ur-
type 2 diabetes [1446]. While glycemic measures do not egina.ca; Larry J. Klassen - larryjklassen@hotmail.com;
appear to be affected by anxiety symptoms [1447], some Raymond W. Lam - r.lam@ubc.ca; Roger S. McIntyre -
treatments, particularly some atypical antipsychotics, roger.mcintyre@uhn.ca; Isaac Szpindel - iszpindel@start-
alter glucose parameters, lipid levels, and cause weight clinic.ca
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Additional material GlaxoSmithKline (MK, SG), Janssen Ortho (MK), Lundbeck (MK, PR, SG),
Organon (MK), Pfizer (SG), Servier (SG), Shire (MK), Solvay (MK), Wyeth (MK,
SG)
Additional file 1: Suggested dosing ranges Dosing ranges of various Educational support: Astra Zeneca (RSM), BMS (RSM), CME Outfitters (RSM),
psychiatric medications Eli Lilly Canada (RSM, IS), France Foundation (RSM), I3CME (RSM), Merck
(RSM), Optum Health (RSM), Pfizer (RSM), Physicians Postgraduate Press
(RSM), Shire (IS)
Research grants/clinical trial funding: AstraZeneca (KK, MK, P. Bleau, RSM,
List of abbreviations used RWL), Biovail (RWL), BMS (KK, P. Bleau, RWL), Canadian Foundation for
AACAP: American Academy of Child and Adolescent Psychiatry; ABM: Innovation (MK), Canadian Institutes of Health Research (CIHR) (MK, RWL, SG),
attention bias modification; ACOG: American Congress of Obstetricians and Canadian Network for Mood and Anxiety Treatments (CANMAT) (RWL),
Gynecologists; ADHD: attention-deficit/hyperactivity disorder; APA: American Canadian Psychiatric Association (CPA) Foundation (MK, RWL), Centre for
Psychiatric Association; ASD: acute stress disorder; B-I-I: blood-injection-injury; Addiction and Mental Health Foundation (MK), CR Younger Foundation (SG),
BPD: borderline personality disorder; CBT: cognitive behavioral therapy; Eli Lilly Canada (MK, P. Bleau, PR, RSM, RWL), Genuine Health (MK),
CBWT: cognitive behavioral writing therapy; CCHS: Canadian Community GlaxoSmithKline (MK), Janssen Ortho (MK, RSM), Litebook Company (RWL),
Health Survey; CHD: coronary heart disease; CPT: cognitive processing Lundbeck (KK, MK, P. Bleau, RSM, RWL), Lundbeck Institute (RWL), Mochida
therapy; CR: controlled release; DBT: dialectical behavioral therapy; DDI: drug- (RWL), National Alliance for Research on Schizophrenia and Depression
drug interactions; DIRT: danger ideation reduction therapy; DSM-5: (NARSAD) (RSM), National Institutes of Mental Health (NIMH) (RSM), Ontario
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; EMDR: eye Ministry of Health (SG), Ontario Mental Health Foundation (SG), Organon
movement desensitization and reprocessing; ERP: exposure with response (MK), Pfizer (P. Bleau, RSM, RWL), Roche (PR), Servier (RWL), Sick Kids
prevention; FDA: Food and Drug Administration; GAD: generalized anxiety Foundation (MK), Solvay (MK), St. Judes Medical (RWL), Shire (MK, RSM),
disorder; HARS: Hamilton Anxiety Rating Scale; HDL: high-density lipoprotein; Stanley Medical Research Institute (RSM), Takeda (RWL), UBC Institute of
ICBT: internet-based CBT; IPT: interpersonal therapy; IV: intravenous; LDL: low- Mental Health/Coast Capital Savings (RWL), Wyeth (MK, P. Bleau)
density lipoprotein; MAOI: monoamine oxidase inhibitor; MBCT: mindfulness- Unrestricted grants: Astra Zeneca Canada (MK), Eli Lilly Canada (MK),
based cognitive therapy; MBT: mindfulness-based therapy; MDD: major Janssen Inc. (MK), Lundbeck Canada (MK), Pfizer (MK), Purdue Pharma (MK),
depressive disorder; Mini-SPIN: Mini-Social Phobia Inventory; MRI: magnetic Servier Canada (MK), Shire Canada (MK), Valeant Canada (MK)
resonance imaging; N/A: not available; NaSSA: noradrenergic and specific Reimbursements, fees, funding, or salary: In the past five years, MVA
serotonergic antidepressant; NCS-A: National Comorbidity Survey received reimbursements, fees, funding, or salary from: Astra Zeneca, Biovail,
Adolescent supplement; NCS-R: National Comorbidity Survey Replication; Canadian Foundation for Innovation (CFI), Cephalon, Eli Lilly, Forest
NMDA: N-methyl-D-aspartate; NNT: number needed to treat; NPPO-REAC: Laboratories, GlaxoSmithKline, Hamilton Academic Health Sciences
neuro psycho physical optimization-radio electric asymmetric conveyor; Organization (HAHSO) Innovation Grant (AFP Innovation Grant), Janssen
NSAID: nonsteroidal anti-inflammatory drug; OCD: obsessive-compulsive Ortho, Labo Pharm, Lundbeck, National Institutes of Health (NIH), Novartis,
disorder; ODT: orally disintegrating tablet; PNAS: poor neonatal adaptation Pfizer Inc., Servier, Shire, Sunovion, Valeant, Wyeth-Ayerst
syndrome; PTSD: posttraumatic stress disorder; QoL: quality of life; RCT: Stock/share ownership: Clinique et Dveloppement In Virtuo Inc. (SB)
randomized controlled trial; REAC: radioelectric asymmetric conveyor; RIMA:
reversible inhibitors of monoamine oxidase A; RR: relative risk; rTMS: Authors contributions
repetitive transcranial magnetic stimulation; SAD: social anxiety disorder; SET: We thank all co-authors for their considerable expertise in generating these
social effectiveness therapy; SHAT: spiritual-hypnosis assisted therapy; SNRI: guidelines. Authors who were members of the executive committee (MK, PB,
serotoninnorepinephrine reuptake inhibitor; SR: sustained release; SSRI: PB, PC, KK, MVA) took part in teleconferences and a meeting in December
selective serotonin reuptake inhibitor; SUD: substance use disorder; TC: total 2012 to reach consensus on the strength of evidence and treatment
cholesterol; TCA: tricyclic antidepressant; TF-CBT: trauma-focused-CBT; TG: recommendations. Draft guidelines were then developed by the core
triglycerides; vLDL: very-low-density lipoprotein; VRE: virtual reality exposure; committee and revised by all co-authors. The entire content was
XL: extended release; XR: extended release; Y-BOCS: Yale-Brown Obsessive subsequently circulated to all members of the Canadian Anxiety Guidelines
Compulsive Scale. Initiative Group for additional comments and approval during 2013. GA, LJK,
RWL, RSM, and IS provided additional reviews of the comorbidity section.
Competing interests The final manuscript was then circulated to external reviewers (MP, DS, LDM)
Unrestricted educational grants for the development of these guidelines and revisions were made based on input from the core committee.
were provided by Astra Zeneca Canada, Eli-Lilly Canada, Janssen Inc.,
Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier Canada Inc., Shire Acknowledgements
Canada, and Valeant Canada. None of the members received payment for The consensus group would like to thank Astra Zeneca Canada, Eli-Lilly
participating in the development of these guidelines. Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada,
The following authors do not have any competing interests to declare: Servier Canada Inc., Shire Canada, and Valeant Canada for their generous
AB, GA, JRW, KO, MMA, MF, LK, MR, SM. support of the guideline process with unrestricted educational grants. Funds
Advisory board/speakers bureau: Astra Zeneca (KK, KR, MK, P. Bleau, P. were used for editorial assistance and meeting logistics; none of the
Blier, RWL, RSM), Biovail (RWL), Boehringer Ingelheim (MK), BMS (KK, KR, MK, members received payment for participating in the guideline development
P. Bleau, P. Blier, PC, RWL, RSM), Canadian Institutes of Health Research process. The consensus group would also like to thank Pauline Lavigne and
(CIHR) (RWL), Canadian Network for Mood and Anxiety Treatments Steven Portelance who provided medical writing services on their behalf.
(CANMAT) (RWL), Canadian Psychiatric Association (CPA) Foundation (RWL),
Eli Lilly Canada (MK, P. Bleau, P. Blier, PC, SG, RWL, RSM, IS), France Declarations
Foundation (RSM), GlaxoSmithKline (MK, P. Blier, RSM, SG), Janssen Ortho (KK, The development and publication of these guidelines was supported by
MK, P. Blier, PC, RSM), Labopharm (P. Blier), Litebook Company (RWL), unrestricted educational grants provided by Astra Zeneca Canada, Eli-Lilly
Lundbeck (KK, KR, MK, P. Bleau, P. Blier, PC, RWL, RSM, SG), Lundbeck Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier
Institute (RWL), Organon (MK, RSM), Merck (P. Blier, RSM), Mochida (RWL), Canada Inc., Shire Canada, and Valeant Canada. None of the members
Otsuka (KK), Pfizer (P. Bleau, P. Blier, PC, RWL, RSM, SG), Pierre Fabre (P. Blier), received payment for participating in the development of these guidelines.
Purdue (IS), Servier (P. Blier, RWL, SG), Shire (MK, RSM, IS), Solvay (MK), St. This article has been published as part of BMC Psychiatry Volume 14
Judes Medical (RWL), Sunovion (KK, P. Blier), Takeda (P. Blier, RWL), UBC Supplement 1, 2014: Canadian Anxiety Disorders Guidelines Initiative: Clinical
Institute of Mental Health/Coast Capital Savings (RWL), Valeant (P. Blier, IS), practice guidelines for the management of anxiety, posttraumatic stress and
Wyeth (P. Bleau, MK, SG) obsessive-compulsive disorders. The full contents of the supplement are
Consultation fees: AstraZeneca (MK), BMS (MK), Boehringer Ingelheim (MK), available online at http://www.biomedcentral.com/bmcpsychiatry/
Clinique et Dveloppement In Virtuo Inc. (SB), Eli Lilly Canada (MK, SG), supplements/14/S1.
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 Page 49 of 83
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Authors details 18. Wittchen HU: Generalized anxiety disorder: prevalence, burden, and
1
Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1, cost to society. Depress Anxiety 2002, 16:162-171.
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Psychiatry, University of Alberta, Edmonton, AB, T6G 2R7, Canada. 20. Nepon J, Belik SL, Bolton J, Sareen J: The relationship between anxiety
5
Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T disorders and suicide attempts: findings from the National
2A1, Canada. 6Department of Psychiatry and Behavioural Neuroscience, Epidemiologic Survey on Alcohol and Related Conditions. Depress
McMaster University, Hamilton, ON, L8N 3K7, Canada. Anxiety 2010, 27:791-798.
21. Bolton JM, Cox BJ, Afifi TO, Enns MW, Bienvenu OJ, Sareen J: Anxiety
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DOI: 10.1177/0269881114525674
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David S Baldwin1,2, Ian M Anderson3, David J Nutt4, Christer


Allgulander5, Borwin Bandelow6, Johan A den Boer7,8, David M
Christmas9, Simon Davies10, Naomi Fineberg11, Nicky Lidbetter12,
Andrea Malizia13, Paul McCrone14, Daniel Nabarro15, Catherine ONeill12,
Jan Scott16, Nic van der Wee17 and Hans-Ulrich Wittchen18

Abstract
This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders
provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination
treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts
in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines
are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical
decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines
management and formulary committees.

Keywords
Anticonvulsants, antidepressants, antipsychotics, anxiety disorders, anxiolytics, benzodiazepines, cognitive behaviour therapy, evidence-based
guidelines, generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, pregabalin, separation anxiety
disorder, serotonin-noradrenaline reuptake inhibitor, social anxiety disorder, specific phobia, selective serotonin reuptake inhibitor, treatment.

1. Introduction
The British Association for Psychopharmacology (BAP; www. meetings, fostering research and teaching, encouraging publica-
bap.org.uk) aims to advance education and research in the sci- tion of research results, and providing guidance and information
ence and practice of psychopharmacology by arranging scientific on matters relevant to psychopharmacology. As part of this

1Faculty of Medicine, University of Southampton, Southampton, UK 11Postgraduate Medical School, University of Hertfordshire, Hatfield, UK
2Department of Psychiatry and Mental Health, University of Cape Town, 12Anxiety UK, Manchester, UK
Cape Town, South Africa 13North Bristol NHS Trust, Bristol, UK
3Neuroscience and Psychiatry Unit, University of Manchester, 14Institute of Psychiatry, Kings College London, London, UK

Manchester, UK 15OCD Action, London, UK


4Division of Experimental Medicine, Imperial College London, 16Newcastle University, Newcastle, UK

London, UK 17Department of Psychiatry, Leiden University Medical Center, Leiden,


5Karolinska Institutet, Stockholm, Sweden The Netherlands
6Department of Psychiatry and Psychotherapy, University of 18Institute of Clinical Psychology and Psychotherapy, Technical

Goettingen, Goettingen, Germany University Dresden, Dresden, Germany


7Department of Nuclear Medicine and Molecular Imaging, University

Medical Centre Groningen (UMCG), Groningen, The Netherlands Corresponding author:


8PRA International Zuidlaren,The Netherlands David Baldwin, University Department of Psychiatry, University of
9Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK Southampton, College Keep, 4-12 Terminus Terrace, Southampton,
10Centre for Addiction and Mental Health, University of Toronto, SO14 3DT, UK.
Toronto, ON, Canada Email: dsb1@soton.ac.uk
2 Journal of Psychopharmacology

process the BAP has developed and periodically revised a series 3. Process for achieving consensus
of consensus statements on the use of psychotropic drugs in
patients with psychiatric and other disorders, with an emphasis The revision of the original BAP guidelines started in February
on making concise and realistic recommendations based on a 2011, with a consensus meeting attended by experts in the field
review of the evidence [IV] (Anderson etal., 2000, 2008; Barnes and representatives of patient groups (all who attended are named
and Schizophrenia Consensus Group of British Association for in the acknowledgments). Brief presentations were made on key
Psychopharmacology, 2011; Burns and OBrien., 2006; Goodwin, areas, with an emphasis on systematic reviews and randomised
2003, 2005; Goodwin etal., 2008; Lingford-Hughes etal., 2004, controlled trials. Each presentation was followed by discussion,
2012; National Institute for Health and Clinical Excellence, to identify areas of consensus or uncertainty.
2011; OBrien and Burns, 2010; Nutt etal., 2006; Wilson etal., A literature review was then performed to ascertain the valid-
2010). ity of the consensus points. Logistical factors made it impossible
Anxiety symptoms and disorders are common in community to perform a systematic review of all possible data from primary
settings, and in primary and secondary medical care. The per- sources. Existing systematic reviews and randomised controlled
sonal and societal burden associated with anxiety disorders is trials were identified from MEDLINE and EMBASE searches
considerable, but many people who might benefit from treatment and from the Cochrane Database, as well as from recent previous
are not recognised or treated. Likely factors in this sub-optimal guidelines and reviews [IV] (Baldwin etal., 2011b; Bandelow
management include the range of different anxiety disorders, etal., 2008a; Batelaan etal., 2012; Blanco etal., 2013; Fineberg
their co-morbidity with other disorders (particularly mood disor- etal., 2012; Ipser and Stein, 2012), through cross-referencing,
ders), a widespread lack of awareness of anxiety disorders by and through discussion with experts in the field. We also drew on
affected individuals and health practitioners, and the low confi- recent guidelines for generalised anxiety disorder, panic disorder,
dence of many practitioners in their management. Conversely, social anxiety disorder, post-traumatic stress disorder and obses-
some patients with only mild or transient anxiety symptoms sive-compulsive disorder developed by the National Institute for
receive unnecessary or inappropriate treatment. Given the con- Health and Clinical Excellence (2005, 2011a, 2011b, 2013).
siderable room for improvement, the BAP previously produced Particular attention was paid to research findings which had
evidence-based guidelines for the pharmacological treatment of appeared since 2005, the year of publication of the original
anxiety disorders [IV] (Baldwin etal., 2005): this revision of guidelines. Draft versions of the consensus statement, with rec-
those guidelines provides an update on key steps in diagnosis and ommendations based on the level of supporting evidence, were
treatment. circulated repeatedly to the presenters and other participants and
their comments were incorporated into the final version of the
guidelines. Given the range and depth of the subject area it was
2. Caveats not possible for all participants in the wider group to achieve full
consensus on all points.
Clinical guidelines are systematically derived statements that aim
to inform treatment decisions in clinical care. Recommendations
are graded according to the strength of evidence, and whenever 4. Levels of evidence and strength of
possible are derived from the findings of systematic reviews and
randomised controlled trials. Principal recommendations apply
recommendations
to the management of typical patients and hence apply much of The categories of evidence for causal relationships and the grad-
the time: we therefore use expressions such as clinicians should ing of recommendations have their origin in the methodology of
consider in the summary boxes. But there are many patients the North of England Evidence-Based Guideline Development
and many clinical decision points where slavish adherence to Project undertaken by the Centre for Health Services Research,
guideline recommendations may be unhelpful and possibly University of Newcastle upon Tyne and the Centre for Health
harmful. In situations where the evidence is weaker we summa- Economics, University of York [IV] (Shekelle etal., 1999).
rise potential management options, recognising that their imple- Given current debates about their competing merits, we have
mentation depends upon clinician experience, patient clinical accorded a similar level (I) in the hierarchy of evidence to the
features and preference, and local circumstance [IV] (Haynes findings of systematic reviews and to the results of randomised
etal., 2002). Some of our recommendations may be regarded as controlled trials, noting the evidence source which is available
standards of clinical care that are largely driven by custom and for each statement and recommendation (Table 1). Weaker levels
practice: these are standards which are intended to be applied of recommendations do not necessarily imply a reduced level of
routinely. clinical importance. As in some previous guidelines we have
There is often a tension between existing established clinical included a category denoted as S (representing a standard of
practice and the possible implications of new research findings care), for a recommendation that reflects important consensus on
for changing practice. Existing practice may be accepted on the good clinical practice rather than on empirical evidence.
basis of prolonged clinical experience but limited good quality
evidence: new treatments may have proven superiority to pla-
cebo in methodologically robust randomised controlled trials, but 5. Aim and scope of the guidelines
lack comparator data against established treatments. We attempt
We hope the guidelines will prove relevant to most doctors treat-
to strike a balance between the risks of advocating specific novel
ing patients with anxiety and related disorders, in primary, sec-
treatment recommendations that may prove premature and adher-
ondary and tertiary medical care settings. Each of the principal
ing to established routines when the evidence supporting them is
disorders generalised anxiety disorder, panic disorder, specific
questionable.
Baldwin et al. 3

Table 1. Levels of evidence and strength of recommendations.

Categories of evidence relevant to treatment


I [M] Evidence from meta-analysis of randomised double-blind placebo-controlled trials
I [PCT] Evidence from at least one randomised double-blind placebo-controlled trial
II Evidence from at least one randomised double-blind comparator-controlled trial (without placebo)
III Evidence from non-experimental descriptive studies
IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Categories of evidence relevant to observational findings and associations
I Evidence from large representative population samples
II Evidence from small, well designed but not necessarily representative samples
III Evidence from non-representative surveys, case reports
IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Strength of recommendations
A Directly based on category I evidence (either I [M] or I [PCT])
B Directly based on category II evidence or an extrapolated recommendation from category I evidence
C Directly based on category III evidence or an extrapolated recommendation from category I or II evidence
D Directly based on category IV evidence or an extrapolated recommendation from other categories
S Standard of clinical care

(or simple) phobia, social anxiety disorder (also known as social mild, transient and without associated impairment in social and
phobia), post-traumatic stress disorder, and obsessive-compulsive occupational function, but many patients are troubled by severe
disorder is considered in turn, following key steps in manage- and persistent symptoms that cause significant personal dis-
ment (acute treatment; longer-term treatment; combination with tress, impair function and reduce quality of life. To meet the
psychological approaches; treatment resistance). The continued diagnosis of an anxiety disorder, patients have to experience a
inclusion or otherwise of obsessive-compulsive disorder within certain number of symptoms for more than a minimum speci-
the broad category of anxiety disorders is the subject of continu- fied period, the symptoms causing significant personal dis-
ing debate, given evidence of its dissimilarity from other anxiety tress, with an associated impairment in everyday function.
disorders and its resemblance to other conditions characterised by Most research in the field has been based on the diagnostic
compulsivity and impulsivity: but the principles of pharmacologi- categories for anxiety disorders in the fourth edition of the
cal treatment of anxiety disorders and obsessive-compulsive dis- Diagnostic and Statistical Manual (DSM-IV) [IV] (American
order share many common features, and so we have chosen to Psychiatric Association, 1994) which are broadly similar to
retain obsessive-compulsive disorder within these guidelines. We those in the tenth edition of the International Classification of
also include separation anxiety disorder, given its inclusion within Diseases (ICD-10) [IV] (World Health Organisation, 1992).
anxiety disorders in the Diagnostic and Statistical Manual (DSM- The DSM system has recently been revised, and it is uncertain
5) (American Psychiatric Association, 2013), though evidence whether the approach to anxiety disorders within ICD-11 will
relating to its treatment in adults is at present very sparse. We also differ substantially from ICD-10 or DSM-5.
summarise the evidence for treatment of patients with health anxi- We give simplified versions of the principal clinical features
ety (illness anxiety disorder), partly because of the overlap in of the anxiety disorders, post-traumatic stress disorder and obses-
clinical features with those of generalised anxiety disorder. sive-compulsive disorder in Table 2: a simple algorithm for ini-
We expect the guidelines will be most useful in informing tial delineation of anxiety and depressive symptoms into disorders
decisions in primary and secondary care, regarding pharmaco- is suggested in Figure 1.
logical treatment in patients aged between 1865 years. The Epidemiological studies in the general population indicate
nature and prevalence of anxiety disorders changes during child- that when taken together anxiety disorders have a 12-month
hood and adolescence and the mean age of onset in adult patients period prevalence of approximately 14% [I] (Wittchen etal.,
varies between anxiety disorders. Most adults with anxiety disor- 2011) (see Table 3), and a lifetime prevalence of approximately
ders report an onset of symptoms in childhood or adolescence 21% [I] (Wittchen and Jacobi, 2005). Individual disorders are
(Jones, 2013; Kessler etal., 2005), and some recommendations less frequent, with estimated 12-month prevalence rates rang-
(for example those pertaining to obsessive-compulsive disorder ing between 0.7% (obsessive-compulsive disorder) and 6.4%
and social phobia) will therefore be potentially applicable to ado- (specific phobia), and estimated lifetime prevalence rates
lescent patients. Similarly the recommendations are also likely to between 0.8% (obsessive-compulsive disorder) and 13.2%
be pertinent to elderly patients although we did not specifically (specific phobia). The age and sex distribution of individual
review evidence in those aged over 65 years. disorders varies: for example, specific phobias are markedly
more common in women than men across all age bands, whereas
6. Epidemiology of anxiety symptoms panic disorder is almost as frequent in men and women in mid-
dle age. Despite this variation within individual anxiety disor-
and disorders ders, the pattern for all disorders taken together is fairly constant
Anxiety symptoms are common in the general population and with an overall female: male ratio of approximately 2:1 across
in primary and secondary medical care. Symptoms may be the age range.
4 Journal of Psychopharmacology

Table 2. Principal clinical features of the anxiety disorders, post-traumatic stress disorder, and obsessive-compulsive disorder.

Generalised anxiety disorder


Generalised anxiety disorder is characterised by excessive and inappropriate worrying that is persistent (lasting more than a few months) and not
restricted to particular circumstances. Patients have physical anxiety symptoms and key psychological symptoms (restlessness, fatigue, difficulty
concentrating, irritability, muscle tension and disturbed sleep). Generalised anxiety disorder is often co-morbid with major depression, panic disor-
der, phobic anxiety disorders, health anxiety and obsessive-compulsive disorder.
Panic disorder (with or without agoraphobia)
Panic disorder is characterised by recurrent unexpected surges of severe anxiety (panic attacks), with varying degrees of anticipatory anxi-
ety between attacks. Panic attacks are discrete periods of intense fear or discomfort, accompanied by multiple physical or psychological anxiety
symptoms. Panic attacks typically reach their peak within 10 min and last around 3045 min. Most patients develop a fear of having further panic
attacks. Around two-thirds of patients with panic disorder develop agoraphobia, defined as fear in places or situations from which escape might be
difficult or in which help might not be available, in the event of having a panic attack. These situations include being in a crowd, being outside
the home, or using public transport: they are either avoided or endured with significant personal distress.
Social phobia (social anxiety disorder)
Social phobia is characterised by a marked, persistent and unreasonable fear of being observed or evaluated negatively by other people, in social
or performance situations, which is associated with physical and psychological anxiety symptoms. Feared situations (such as speaking to unfamiliar
people or eating in public) are either avoided or are endured with significant distress.
Specific phobia
Specific, simple or isolated phobia is characterised by excessive or unreasonable fear of (and restricted to) single people, animals, objects, or situa-
tions (for example, dentists, spiders, lifts, flying, seeing blood) which are either avoided or are endured with significant personal distress.
Separation anxiety disorder
Separation anxiety disorder is characterised by fear or anxiety concerning separation from those to whom an individual is attached: common
features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential
harms to attachment figures or untoward events that might result in separation.
Post-traumatic stress disorder
Post-traumatic stress disorder is characterised by a history of exposure to trauma (actual or threatened death, serious injury, or threats to the
physical integrity of the self or others) with a response of intense fear, helplessness or horror; with the later development of intrusive symptoms
(such as recollections, flashbacks or dreams), avoidance symptoms (for example efforts to avoid activities or thoughts associated with the trauma),
negative alterations in cognitions and mood, and hyper-arousal symptoms (including disturbed sleep, hypervigilance and an exaggerated startle
response).
Obsessive-compulsive disorder
Obsessive-compulsive disorder is characterised by recurrent obsessive ruminations, images or impulses, and/or recurrent physical or mental rituals;
which are distressing, time-consuming and cause interference with social and occupational function. Common obsessions relate to contamination,
accidents, and religious or sexual matters; common rituals include washing, checking, cleaning, counting and touching.
Illness anxiety disorder
A somatic symptom related disorder characterised by excessive or disproportionate preoccupations with having or acquiring a serious illness, with
excessive health-related behaviours and high levels of alarm about personal health status.

6.1. Course of anxiety symptoms and


Significant anxiety-
related symptoms and
impaired function,
disorders
Longitudinal studies in community samples indicate that many
Also
moderate/ Yes individuals with anxiety symptoms that are below the threshold
Treat
severe depression for an anxiety disorder diagnosis experience an episodic condi-
depression?
tion with prolonged periods of remission: reappearance or wors-
No
Predominant symptom focus
ening of symptoms being associated with adverse life events and
Trauma
Obsessions +
Uncontrollable intermittent panic/anxiety other psychosocial stressors. By contrast, follow-up studies in
history and worry about
flashbacks? compulsions
several areas
attacks and avoidance
patient groups demonstrate that anxiety disorders tend to run a
chronic course, often over many years, with symptoms fluctuat-
Fear of Discrete Some ing in severity between periods of remission and relapse, the
social
scrutiny
object/ uncued/
situation spontaneous
course of illness varying between disorders [II] (Bruce etal.,
2005).
Generalised anxiety disorder tends to run a waxing and wan-
Check for Check for Check for Check for Check for Check for
PTSD OCD GAD social specific panic ing course in non-clinical samples [I] (Angst etal., 2009), and a
phobia phobia disorder
prolonged course in primary care [I] (Rodriguez etal., 2006): but
may also switch to other diagnoses particularly depression and
Figure 1. Suggested scheme for exploring a suspected anxiety disorder. somatoform disorders [II] (Rubio and Lopez-Ibor, 2007a). Social
GAD: generalised anxiety disorder; OCD: obsessive-compulsive disorder; anxiety disorder tends to run a chronic course in primary [I]
PTSD: post-traumatic stress disorder. (Beard etal., 2010) and secondary medical care settings [II]
Baldwin et al. 5

Table 3. Twelve-month prevalence of anxiety disorders within the European Union.

Diagnosis (DSM-IV) Inter-quartile range (%) Best estimate (%) Number affected (millions)a

Anxiety disorders Not applicableb 14.0 61.5


Panic disorder 0.42.0 1.8 7.9
Agoraphobia 0.42.0 2.0 8.8
Social anxiety disorder 1.14.4 2.3 10.1
Specific phobias 3.47.1 6.4 22.7
Generalised anxiety disorder 0.62.2 1.73.4c 8.9
Obsessive-compulsive disorder 0.51.1 0.7 2.9
Post-traumatic stress disorder 0.72.5 1.12.9d 7.7

aAccording to Eurostat Directorate General of European Commission (Eurostat 2010) for the age groups used.
bAggregate data from single study. 95% confidence interval, 13.415.6%.
cAge range 1465 years, 1.7%; age 65+ years, 3.4%.
dAge range 1434 years, 2.9%; age range 3565 years, 1.3%; age 66+ years, 1.1%.

Best estimates represent consensus view of experts on most probable estimate from identified range. Full data available in Wittchen etal. (2011). DSM-IV refers to the
Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association (1994).

(Bruce etal., 2005; Ramsawh etal., 2009). For panic disorder, frequent among those individuals with more severe anxiety
prospective studies reveal high degrees of symptom chronicity symptoms. Cross-sectional studies in European community and
[I] (Batelaan etal., 2010b), relapse after remission [I] (Batelaan clinical settings [I] (Fehm etal., 2005; Goodwin, 2005; Lieb etal.,
etal., 2010a), and switching to other diagnoses [II] (Rubio and 2005) and in UK primary medical care [I] (Nease and Aikens,
Lopez-Ibor, 2007b). Childhood separation anxiety disorder often 2003) reveal a significant correlation between measures of anxi-
resolves with entry into adolescence [I] (Copeland etal., 2014). ety and depressive symptom severity. Many patients with anxiety
Retrospective longitudinal studies in obsessive-compulsive dis- disorders also simultaneously fulfil diagnostic criteria for another
order suggest a very poor outcome, though prospective studies in disorder, this pattern typically being named co-morbidity. High
non-clinical [I] (Fineberg etal., 2013) and clinical samples [II] levels of co-morbidity are seen between the anxiety disorders,
(Eisen etal., 2010; Kempe etal., 2007) indicate a more favoura- and with major depression [I] (Wittchen and Jacobi, 2005), bipo-
ble prognosis. Cohort studies which have examined the course of lar disorder [II] (Gaudiano and Miller, 2005; Henry etal., 2003),
symptoms following traumatic experiences suggest that post- schizophrenia (IV) (Buckley etal., 2009) substance misuse
traumatic stress disorder emerges in only a minority of affected (Castle, 2008; Crippa etal., 2009; Robinson etal., 2009;
individuals (for example, [II] Mayou etal., 2001) the course of Ziedonis etal., 2008) and physical illness [IV] (Davies etal.,
established post-traumatic stress disorder is not established, 2007; Roy-Byrne etal., 2008).
though a chronic course was seen in almost one-half of adoles- The presence of a comorbid anxiety disorder is associated
cents and young adults [I] (Perkonigg etal., 2005). with both a longer time to recovery and with a greater risk of end-
ing treatment prematurely in patients with major depression [II]
(Brown etal., 1996). An early systematic review found that
Recommendations: increased awareness of anxiety patients with comorbid conditions generally had worse outcomes
disorders than those with anxiety disorder or depressive disorder alone [I]
(Emmanuel etal., 1998). This is supported by the findings of the
Become familiar with the main features of the anxiety US National Comorbidity Survey which demonstrated that indi-
disorders, post-traumatic stress disorder and obsessive- viduals with comorbid generalised anxiety disorder and major
compulsive disorder: and with the main symptoms depression were significantly more likely to remain symptomatic
which distinguish between them [S] than individuals with depression or generalised anxiety disorder
Develop systematic questions to ask about the nature, alone [I] (Kessler etal., 2008).
severity, duration, distress and associated impairment Detection of co-morbid depression can sometimes lead to
in patients with anxiety symptoms, to decide whether simultaneous recognition of an underlying primary anxiety disor-
an anxiety disorder, post-traumatic stress disorder or der. For example, a French primary care study of the prevalence,
obsessive-compulsive disorder is present [S] recognition and treatment of social phobia found that detection
Become familiar with the fluctuating nature of symp- rates were increased in the presence of comorbid depression
toms in patients with anxiety disorders, and with the ten- (66%, compared with 53% in those without depression) [I]
dency for symptoms to change in nature over time [S] (Weiller etal., 1996). However the presence of a seemingly more
pressing comorbid condition can result in sub-optimal treatment
for the anxiety disorder. Data from a United Kingdom general
6.2. Co-existing psychological symptoms and practice cluster randomised controlled trial of the impact of men-
tal health guidelines, which found that only 54% of patients with
co-morbid mental disorders a common mental disorder (depression or anxiety) were offered
Anxiety symptoms often co-exist with other psychological symp- active treatment, revealed that patients with anxiety or mixed
toms, especially depressive symptoms, which are particularly anxiety-depression were significantly less likely to be offered
6 Journal of Psychopharmacology

treatment than patients with depression alone [I] (Hyde etal., from among the wider group, in many of whom intervention
2005). Analysis of a Dutch primary care database involving may be unnecessary.
patients with a newly diagnosed anxiety disorder found that ben- The limited detection of anxiety disorders in primary care has
zodiazepines were significantly more frequently prescribed in been observed in multiple countries over many years. A Dutch
patients with psychiatric comorbid conditions, and antidepres- study found a low (47%) rate of detection of anxiety and depres-
sants significantly more frequently prescribed in patients with sion, recognition being more likely in anxiety disorders of shorter
comorbid physical illness: in both forms of comorbidity, the pre- duration [I] (Ormel etal., 1991). A German study, in which 5.3%
scription pattern of benzodiazepines was inconsistent with cur- of patients fulfilled diagnostic criteria for generalised anxiety
rent guideline recommendations [I] (Smolders etal., 2007). disorder, and 1.6% for comorbid major depressive episode and
The presence of marked co-existing depressive symptoms is generalised anxiety disorder, found that whilst the majority (over
an important consideration in treatment decisions. Where anxiety 70%) of affected individuals were recognised as having clinically
symptoms are present within the context of a depressive disorder, significant emotional problems, accurate diagnosis was less com-
antidepressant drug treatment is often effective in reducing anxi- mon (34.4% for generalised anxiety disorder) [I] (Wittchen etal.,
ety (IV) (Anderson etal., 2008). Where depression follows or is 2002). A United States investigation of older patients with gener-
comorbid with an anxiety disorder it is generally indicative of alised anxiety disorder found low rates of recording of anxiety
greater severity and associated with poorer prognosis (II) (Albus symptoms (34%) or anxiety disorder (9%) despite much use of
and Scheibe, 1993; Brown etal., 1995; Cowley etal., 1996; health services [I] (Calleo etal., 2009). A Canadian study found
Erwin etal., 2002; Martinsen etal., 1998; Rief etal., 2000; the majority of cases of anxiety disorder diagnosed through a
Shalev etal., 1998). Clinical practice has usually been to direct structured clinical interview did not have a recorded diagnosis
treatment towards the depressive disorder in the first instance, (generalised anxiety disorder, 71.0%; panic disorder, 85.8%;
choosing treatments that also have action against the symptoms social anxiety disorder, 97.8%) [I] (Vermani etal., 2011).
of the anxiety disorder: though some guidance notes that when a Limited recognition is partly related to difficulty in discussing
patient has an anxiety disorder and comorbid depression or emotional difficulties: many patients do not express emotional
depressive symptoms, treating the anxiety disorder first should symptoms and many doctors find it hard to raise concerns about
also be considered, as effective treatment of the anxiety disorder potential psychological distress. A United Kingdom general prac-
will often improve the depression or depressive symptoms tice survey involving patients whose questionnaire scores indi-
(National Institute for Health and Clinical Excellence, 2011). cated likely psychiatric caseness found the vast majority had
not mentioned emotional problems in the consultation, mainly
through fears of either being unable to cope with the ensuing dis-
Recommendations: enquiring about coexisting symp- tress or of embarrassment, or through not wishing to trouble their
toms and comorbid disorders doctor: but many also felt there would be either insufficient time,
or the doctors could do nothing to help [II] (Cape and McCulloch,
Check for anxiety symptoms in patients presenting 1999). A United States primary care study found that doctors who
with symptoms of other mental disorders, including were more sensitive to non-verbal communications were more
depression, bipolar disorder, psychosis and substance likely to make diagnoses; but those who tended to blame
misuse [A] patients made fewer psychological assessments, and were less
Remember that coexisting depressive symptoms in accurate in detecting distress [II] (Robbins etal., 1994).
patients with anxiety disorders are associated with Fortunately general practice is structured in such a way that
greater functional impairment and a longer duration of many patients present repeatedly, which provides an opportunity
illness [B] for recognition of symptoms at subsequent consultations, if an
Assess for comorbid depression and treat if depressive anxiety disorder is not detected at the first visit. In a United
symptoms are of more than mild intensity [S] Kingdom longitudinal study of the detection of depression and
anxiety which found that many cases were not detected at the
initial appointment, the vast majority of undetected cases of
depression or anxiety were recognised at follow-up [I] (Kessler
7. Detection of anxiety symptoms in etal., 2002). A Dutch primary care practice survey found that
primary medical care settings patients with an anxiety disorder were less likely to be diagnosed
than patients with a depressive episode, but the likelihood of
Within the setting of primary medical care (general practice), diagnosis in both conditions increased with the number of con-
most patients with anxiety or depression have relatively mild sultations, and the expression of more severe psychological
and transient symptoms, which tend to resolve without the need symptoms [I] (Verhaak etal., 2006).
for intervention: but many have severe, persistent and disabling
symptoms, which are likely to benefit from psychological or
pharmacological treatment. However, many patients with anxi- Recommendations: increasing skills in detecting anxi-
ety and depressive symptoms do not present to primary medical ety symptoms
care services [I] (Andrews and Carter, 2001; Roness etal.,
2005). Even when patients do consult their general practitioner, Remember that many patients are either reluctant to
anxiety symptoms are usually not their presenting complaints. present with psychological symptoms or find it hard
The general practitioner therefore faces a significant challenge, discuss emotional problems [A]
in detecting the sample of patients most in need of treatment,
Baldwin et al. 7

investigation, which included a nested case-control study of care


Be sensitive to non-verbal expression of psychological received by patients with or without psychosocial problems,
distress [B] found that individuals with associated problems were signifi-
Use the opportunity provided by repeated consulta- cantly more likely to receive benzodiazepines and less likely
tions in primary care to ask follow-up questions about to receive antidepressants: which may have contributed to
possible anxiety symptoms when these were suspected their poorer outcomes [I] (Van Rijswijk etal., 2006). A cross-
but not established at earlier appointments [A] sectional study of anxiety and depressive symptoms in Australian
Routine screening of all patients for the presence of family practices found that unemployed patients, when com-
anxiety symptoms is not recommended [A] pared to employed patients, were significantly more likely to
report affective symptoms, to have greater symptom severity, to
have previously undergone treatment and to be prescribed psy-
8. Screening for anxiety disorders in chotropic medication: but were no more likely to be referred to
primary care settings mental health services than were employed patients [I] (Comino
etal., 2000).
In theory, patients and health professionals might benefit from Data from the United States indicate that black and Hispanic
the use of screening tools for detecting anxiety disorders, which patients were less likely than white patients to receive care for
can lead to discussion of psychological symptoms at both the depression and anxiety, or to receive antidepressant prescriptions
index and subsequent appointments. A Danish primary care study (and for Hispanic patients, to undergo counselling) in primary
of the potential value of screening for common mental disorders care; and black patients were less likely than white patients to
found that disclosure of scores on screening questionnaires receive antidepressant prescriptions from a psychiatrist [II]
increased the recognition of mental disorders by doctors with (Lagomasino etal., 2011). Similar discrepancies were seen in a
moderate or low recognition rates; and also resulted in increased treatment review among United States primary care patients with
discussion of psychological concerns and planned follow-up con- anxiety disorders, where non-white individuals were signifi-
sultations in patients who had screened positive [I] (Christensen cantly less likely to receive treatment [II] (Weisberg etal., 2007).
etal., 2005). However, use of screening questionnaires needs to This situation may not necessarily apply in all countries, as a
be accompanied by other changes in practice structure, and it is Dutch general practice study of the quality of care for anxiety and
uncertain whether routine screening and disclosure of screened depression across ethnic minority groups found that all groups
positive patients with anxiety disorders leads to improved clini- (with the exception of individuals originating from Surinam and
cal outcomes. An educational intervention involving this design, the Antilles) were as likely to receive guideline-concordant medi-
among United States primary care patients found no evidence for cal care [I] (Fassaert etal., 2010).
an improvement in patient outcomes [I] (Mathias etal., 1994).
The criteria for diagnosing psychiatric disorders are mainly
from clinical observations in psychiatric outpatients and inpa-
Recommendations: paying particular attention to
tients and so may not be appropriate for routine use in screening
certain patient groups
for common mental disorders, among the more mildly ill
patients in primary care. Primary care doctors often have reser- Remember that anxiety symptoms tend to persist
vations about the usefulness of DSM-IV criteria for diagnosis in longer in patients who are experiencing long-standing
primary care, and many of their patients are reluctant to accept socioeconomic difficulties [B]
any offered diagnoses or undergo psychotropic drug treatment Ensure that the presence of socioeconomic disadvan-
[II] (Van Rijswijk etal., 2009). Although general practitioners tage or membership of a minority ethnic group among
sometimes find using screening questionnaires to be trouble- patients in your practice is not associated with a
some within a standard consultation, patients do not object to reduced chance of their undergoing evidence-based
completing them [II] (Leydon etal., 2011). The use of question- pharmacological or psychological treatment [S]
naires for detecting and following up patients with depressive
symptoms has become part of routine primary care practice in
the United Kingdom, suggesting that use of a similar question- 10. Identifying which patients with
naire for detecting anxiety disorders is feasible in practice [IV]
(Buszewicz and Chew-Graham, 2011).
anxiety disorders should undergo
treatment
Many anxious individuals have mild symptoms of recent onset
9. Increasing awareness of anxiety that are associated with stressful life events or troublesome situ-
disorders in particular patient ations, which will often improve without needing specific treat-
ment. However, the chronic nature and significant associated
populations disability of anxiety disorders means that most patients who fulfil
When compared with the general population, anxiety disorders the diagnostic criteria for an anxiety disorder in terms of sever-
are more common among patients with other mental disorders, ity, duration, distress and impairment are likely to benefit from
with chronic physical illness, and in certain demographic groups. some form of treatment, whether this is psychological or pharma-
Patients with long-standing socioeconomic problems, and those cological. The need for treatment is influenced by the intensity
from certain ethnic populations, may be at greater risk of receiv- and duration of illness, the impact of symptoms on everyday life,
ing sub-optimal care and treatment. A Dutch primary care the presence of co-existing depressive symptoms and comorbid
8 Journal of Psychopharmacology

disorders, and the presence of concomitant medication; together


with other features such as a good response to, or poor tolerabil- Record the diagnosis and review this at subsequent
ity of, previous treatments. The choice of a particular treatment appointments [A]
should be influenced by the supporting evidence base, by patient The choice of a particular treatment should be influ-
characteristics (such as co-morbid physical illness, previous enced by the supporting evidence base, by clinical
response, or treatment contraindications), the preferences of characteristics (such as treatment contraindications and
patients and experience of doctors, and the local availability of expected impact of potential side effects), the prefer-
any proposed intervention [IV] (Haynes etal., 2002). ences of patients, personal experience, and the local
However, many patients with anxiety disorders who might availability of any proposed intervention[S]
benefit from treatment do not receive it. A United States longitu-
dinal primary care study of the use of health services by patients
with panic disorder found that 64% had undergone some form of 11. Anticipating common concerns
intervention over 410 months, but only 22% had been given
appropriate pharmacological treatment, and only 12% had about potential adverse effects of
received appropriate psychological treatment [II] (Roy-Byrne psychotropic drugs
etal., 1999). The quality of treatment in those who do receive it
Many patients experience unwanted and distressing adverse
may be enhanced through making an accurate diagnosis and by
effects of psychotropic drug treatment, such as sexual dysfunc-
regular monitoring of progress. Another United States primary
tion with selective serotonin reuptake inhibitors (SSRIs), exces-
care study of the treatment of patients with panic disorder found
sive perspiration with serotonin-noradrenaline reuptake inhibitors
that inadequate dosage and insufficient duration of treatment
(SNRIs), drowsiness with pregabalin and the benzodiazepines, or
were both common, and suggested that enhanced patient educa-
weight gain with antipsychotic drugs. Others fear developing a
tion and an increased frequency of appointments would be more
tolerance or becoming dependent on medication, and so are
likely to facilitate adequate treatment than would physician edu-
reluctant to start, letalone continue, pharmacological treatment.
cation [II] (Roy-Byrne etal., 2002). A study of adherence to evi-
In addition, many patients and health professionals and some
dence-based guidelines for depression and anxiety disorders
commentators consider pharmacological intervention to be a
within the setting of Dutch primary medical care found that only
merely symptomatic and not a definitive treatment. For these rea-
27% of patients with anxiety disorders received guideline-
sons, many of those who might benefit from treatment do not
consistent care: symptom severity had no influence on adher-
receive it, and many of those who do undergo treatment stop it
ence, but documentation of a diagnosis by the general practitioner
early because of the emergence of unwanted effects.
significantly increased the likelihood of receiving guideline-
Opinions about the potential value and drawbacks of psy-
consistent care [I] (Smolders etal., 2009).
chotropic drug treatment vary widely. A United States cross-
Media reports in many countries have raised concerns about
sectional study of patients with panic disorder attending primary
the medicalisation of anxiety, shyness, worrying and adjust-
care found high levels of willingness to see a psychiatrist or psy-
ment to trauma, and about the inappropriate prescribing of psy-
chotherapist, or to undergo pharmacological treatment [III]
chotropic drugs to patients who are experiencing life stresses or
(Johnson etal., 2000). However a United Kingdom primary care
situational problems. This may be a factor in some settings,
qualitative study of patients views on anxiety and depression
though most studies find a low level of inappropriate prescribing
found marked preferences regarding their perceived health
and a high level of unmet need. For example, a Norwegian pri-
needs, and much scepticism about the value of pharmacological
mary care study involving over 1300 patients found some of evi-
treatments [II] (Kadam etal., 2001). Certain patient groups may
dence of overtreatment (including inappropriate counselling,
be particularly reticent about starting or continuing psychotropic
prescription of psychotropic medication, or specialist referral) in
drug treatment. For example, in a United States study of beliefs
11% of individuals without a formal psychiatric diagnosis, but
about psychotherapy and psychotropic drug treatment for an
also found substantial rates of under-treatment for individuals
anxiety disorder which found few differences between diagnos-
with the diagnoses of major depressive episode (49%) or gener-
tic groups, coexisting depression was associated with more
alised anxiety disorder (64%) [I] (Olsson etal., 2006).
favourable views regarding drug treatment, whereas individuals
from black and minority ethnic groups were less favourably
inclined towards pharmacological or psychological treatments
Recommendations: deciding when and which treat- [II] (Wagner etal., 2005).
ment is required Adherence to prescribed treatment may be enhanced by pro-
Assess the severity and duration of anxiety symptoms, viding relevant information about treatment and minimising
and the associated distress and impairment, when administrative challenges. A qualitative study of experiences of
deciding which patients should be offered pharmaco- care among groups of treatment-adherent and non-adherent eco-
logical or psychological treatment [S] nomically disadvantaged patients with panic disorder found that
Remember to ask about coexisting depressive symp- providing information was empowering and reduced a sense of
toms and other potential comorbid disorders [S] isolation; that patients used a continuing process to evaluate the
Consider other factors such as the presence of physical benefits and risks of treatment; and that barriers to treatment
illness, current concomitant medication, and a history were primarily logistical [II] (Craske etal., 2005). Another inves-
of good response to, or poor tolerability of, previous tigation of perceived barriers to care suggested that difficulties in
treatments [S] the continuing treatment of panic disorder were primarily admin-
istrative, such as being uncertain where to seek help, worrying
Baldwin et al. 9

about potential costs, a lack of health insurance cover, and a Fluoxetine and paroxetine are inhibitors of some cytochrome
delay in receiving appointments [II] (Mukherjee etal., 2006). P450 enzymes and hence may interact with some other psycho-
tropic drugs and treatments for physical illness [IV] (Muscatello
etal., 2012). When stopped abruptly, and even when tapered
Recommendations: ascertaining attitudes to care and slowly, SSRIs can produce a discontinuation syndrome charac-
treatment terised by dizziness, insomnia and flu-like symptoms [I (M)]
(Baldwin etal., 2007; Schatzberg etal., 2006): this seems more likely
Explore attitudes and expectations about pharmaco- with paroxetine and least likely with fluoxetine [II] (Tint etal., 2008).
logical and psychological treatment and correct any The SNRIs duloxetine and venlafaxine have proven efficacy
misconceptions with patients prior to making a specific in short-term and long-term treatment of generalised anxiety dis-
treatment recommendation [S] order [IV] (Baldwin etal., 2011b), and placebo-controlled trials
Review patient attitudes and experiences periodically indicate that venlafaxine is also efficacious in the acute treatment
during the course of treatment [B] and prevention of relapse in panic disorder [IV] (Batelaan etal.,
Consider the administrative aspects of practice organi- 2012). Although the tolerability profiles of SSRIs and SNRIs in
sation to see whether these facilitate the care and treat- patients with anxiety disorders are not established fully, system-
ment of patients with anxiety disorders [S] atic reviews of studies in depressed patients suggest that duloxe-
tine and venlafaxine may be less well tolerated than the SSRIs [I
(M)] (Cipriani etal., 2012; Schueler etal., 2011). Both duloxe-
12. Pharmacological treatments in tine and venlafaxine have been associated with discontinuation
patients with anxiety disorders symptoms after abrupt withdrawal [I(M)] (Baldwin etal., 2007;
Perahia etal., 2005) in adult patients, data being limited in chil-
It has often proved difficult to demonstrate the benefit of antide- dren and adolescents [IV] (Hosenbocus and Chahal, 2011).
pressant drug treatment in patients with mild depressive symp- Although evidence is mixed (Harrison etal., 2004; Mbaya etal.,
toms and the same difficulty is likely to be seen in patients with 2007; Thase, 1998) venlafaxine is sometimes associated with an
milder forms of anxiety disorders. Randomised controlled trials increase in blood pressure, and monitoring is recommended with
across a range of anxiety disorders also often demonstrate a high higher daily doses [IV] (Joint Formulary Committee, 2012). A
placebo response [IV] (Baldwin etal., 2011b; Batelaan etal., systematic review [I (M)] (McIntyre etal., 2008) and the findings
2012; Blanco etal., 2013; Fineberg etal., 2013, 2012; Ipser and of pharmacoepidemiological studies [I (M)] (Strombom etal.,
Stein, 2012) which suggests that non-specific effects of assess- 2008; Wernicke etal., 2008a, 2008b) provide no consistent evi-
ment and monitoring can play a large part in overall improvement. dence of an increased risk of hepatotoxicity with duloxetine, but
It should be emphasised that treatment response is not immediate; it is recommended that duloxetine is avoided in patients with
that a transient worsening of symptoms can sometimes occur; that known liver disease and patients considered to be at risk of
prolonged courses are needed to maintain an initial treatment hepatic dysfunction [IV] (Joint Formulary Committee, 2012).
response; and that psychotropic medications and psychological
treatments can have additive effects in some disorders.
The selection of a particular drug class (and of a specific drug 12.2. Other antidepressant drugs
within that class) should be determined principally by the evi-
Certain tricyclic antidepressants (TCAs) [IV] (Baldwin etal.,
dence base supporting its use, and also by whether the patient has
2011b; Bandelow etal., 2008a; Batelaan etal., 2012; Blanco
previous experience of treatment with that compound. The
etal., 2013; Fineberg etal., 2012; Ipser and Stein, 2012) are effi-
absence of a licensed indication does not necessarily mean an
cacious in some anxiety disorders, but TCAs are associated with
absence of evidence for the proposed treatment intervention:
a greater burden of adverse effects than either SSRIs or SNRIs
conversely it should not be assumed that all drugs within a class
[IV] (Anderson etal., 2008), and for this reason should be gener-
are likely to be efficacious in the treatment of a particular anxiety
ally be reserved for use after a non-response to or poor tolerance
disorder, when one member of that class has proven efficacy [IV]
of initial treatment with an SSRI or SNRI. TCAs should be
(Aquilina etal., 2007; Baldwin and Kosky, 2007; Royal College
avoided in patients considered to be at risk of suicide, due to their
of Psychiatrists, 2007). The presence of coexisting depressive
potential fatal toxicity after overdose [IV] (Thanacoody and
symptoms of moderate or greater severity should guide treatment
Thomas, 2005; Woolf etal., 2007). As with some SSRIs, many
choice towards the prescription of antidepressant drugs rather
possible pharmacokinetic interactions limit their use in patients
than benzodiazepines.
taking concomitant medication (listed in Appendix 1 of the
British National Formulary, Joint Formulary Committee, 2012).
12.1. SSRIs and SNRIs As with other antidepressants, stopping TCAs abruptly can cause
a discontinuation syndrome [IV] (Schatzberg etal., 2006).
SSRIs have broad spectrum efficacy in both short-term and The traditional irreversible monoamine oxidase inhibitor
long-term treatment, and are generally well tolerated; and for (MAOI) phenelzine has proven efficacy in panic disorder and
these reasons are widely considered to be the first-line pharmaco- social phobia: but side effects and the need to follow dietary
logical approach in patients with anxiety disorders or obsessive- restrictions limit its use, so it should generally be reserved for
compulsive disorder. However SSRIs have potentially when patients have not responded to, or proved intolerant of,
troublesome adverse effects, including initial increased nervous- other treatment approaches. Phenelzine overdose is potentially
ness, insomnia, nausea and sexual dysfunction [I (M)] (Gartlehner fatal [III] (White etal., 2008), and it should usually be avoided in
etal., 2011; Serretti and Chiesa, 2009; Sinclair etal., 2009). patients considered to be at risk of suicide. Interactions involving
10 Journal of Psychopharmacology

traditional MAOIs and serotonergic antidepressants such as and Prieto, 2013). Common adverse effects include drowsiness
SSRIs and clomipramine can be hazardous (Lane and Baldwin, and dizziness though it may be better tolerated than other medi-
1997). Moclobemide, a reversible inhibitor of mono-amine oxi- cations in the acute treatment of generalised anxiety disorder [I
dase A (RIMA) has proven efficacy in social phobia [IV] (Blanco (M)] (Baldwin etal., 2011a). Long-term treatment is accom-
etal., 2013) and some evidence of benefit in panic disorder [I panied by weight gain in approximately 20% of patients
(PCT)] (Ross etal., 2010): the reversibility of its action reduces [III] (Montgomery etal., 2013). It is not subject to hepatic metab-
the need for dietary restrictions at lower daily doses though olism and is excreted unchanged in the urine, which is a potential
avoidance of tyramine-containing foods is advisable at higher advantage in patients with hepatic impairment and in patients
dosage [I (PCT)] (Dingemanse etal., 1998). taking other drugs metabolised by the liver, but potentially disad-
Agomelatine has proven efficacy in acute treatment (Stein vantageous in patients with renal disease. There is no known
etal., 2008a) and prevention of relapse (Stein etal., 2012) in untoward interaction with lithium. Spontaneous reports of
generalised anxiety disorder: sexual dysfunction is less likely adverse sexual side effects are uncommon but the incidence of
than with SSRI or SNRI antidepressants [I (M)] (Serretti and treatment-emergent sexual dysfunction with pregabalin is uncer-
Chiesa, 2009), as are discontinuation symptoms [I (PCT)] tain [IV] (Baldwin etal., 2013). Discontinuation symptoms after
(Goodwin etal., 2009; Montgomery etal., 2004): elevations of abrupt withdrawal of pregabalin have been reported, as has the
hepatic enzymes occur in more than 1% of treated patients and abuse of pregabalin generally in individuals with a history of
regular monitoring of liver function tests is required in the early other substance abuse: but the relative potential for developing
months of treatment [IV] (McAllister-Williams etal., 2010). The tolerance and abuse, when compared to with medications, is not
evidence for the efficacy of mirtazapine in patients with anxiety established [IV] (Baldwin etal., 2013).
disorders is limited and inconsistent (Andrisano etal., 2013;
Muehlbacher etal., 2005; Schutters etal., 2010), but in depressed
patients treatment-emergent sexual dysfunction is probably less 12. 5. Other agents
frequent than with SSRIs [I (M)] (Watanabe etal., 2011). Antipsychotic drugs are often prescribed to patients with anxiety
disorders, but the strongest evidence for benefit is restricted to
acute treatment and prevention of relapse with quetiapine in gen-
12. 3. Benzodiazepines
eralised anxiety disorder [IV] (Baldwin etal., 2011b), and the
Some benzodiazepines have proven efficacy in the treatment of augmentation of SSRI antidepressants in patients with obsessive-
patients with panic disorder, generalised anxiety disorder and compulsive disorder [IV] (Fineberg etal., 2012). The tolerability
social anxiety disorder [IV] (Baldwin etal., 2011b; Bandelow profile of antipsychotic drugs is such that they should generally
etal., 2008b; Batelaan etal., 2012; Blanco etal., 2013). However be reserved for treatment after a non-response to other interven-
benzodiazepines can cause troublesome sedation and cognitive tions [IV] (National Institute for Health and Clinical Excellence,
impairment in both short-term and long-term treatment, and tol- 2011). The azapirone drug buspirone is efficacious in the acute
erance and dependence can occur (especially in predisposed treatment of generalised anxiety disorder [I (M)] (Chessick etal.,
patients) with prolonged use: and it is hard to identify those 2006), as is the anti-histamine drug hydroxyzine [I (M)] (Guaiana
patients at risk of developing long-term problems [IV] (DellOsso etal., 2010), though neither has published evidence of efficacy in
and Lader, 2012). It is uncertain whether benzodiazepines are the prevention of relapse.
efficacious in relieving depressive symptoms in patients with
anxiety disorders but there is no evidence of efficacy for benzo-
diazepines in the acute treatment of patients with minor depres- Recommendations: general aspects of pharmacologi-
sion [I (M)] (Barbui etal., 2011) and antidepressants should cal treatment
therefore be preferred in patients with significant coexisting
depressive symptoms. Benzodiazepines will usually be reserved Discuss the anticipated balance of potential benefits
for the further treatment of patients who have not responded to at and potential risks of specific psychotropic medica-
least three previous treatments (such as after non-response to tions with patients before starting treatment [S]
both an SSRI and an SNRI and a psychological intervention); but Consider a SSRI for first-line treatment, as SSRIs are
it has been argued that concerns about potential problems in effective across the anxiety and related disorders, in
long-term use should not prevent their use in patients with persis- both the short-term and long-term, and are generally
tent, severe, distressing, and impairing anxiety symptoms, when well tolerated [A]
other treatments have proved ineffective [IV] (Baldwin and Talat, Remain familiar with the evidence base for other
2012; Nutt, 2005). classes of medication, as many patients do not respond
to or are intolerant of SSRI treatment, but may respond
to other classes of psychotropic drug [S]
12. 4. Pregabalin Discuss potential adverse effects early in treatment,
including increased nervousness, worsened agitation,
Pregabalin has proven efficacy in both acute treatment and pre- and review patient progress carefully over the first few
vention of relapse in generalised anxiety disorder [IV] (Baldwin weeks of treatment [A]
etal., 2011b) and social anxiety disorder. In generalised anxiety Remember that benzodiazepines can be effective in
disorder, it is efficacious in relieving depressive symptoms of many patients with anxiety disorders [A], but recog-
mild to moderate intensity [I (M)] (Stein etal., 2008a), and in nise that their use should generally only be short-term:
reducing the severity of sleep disturbance (Holsboer-Trachsler
Baldwin et al. 11

occur; that prolonged courses are often needed to maintain an


and only considered bey