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Continuing Education Article

Journal of Pharmacy Practice


2014, Vol. 27(2) 116-130
Obsessive–Compulsive Disorder ª The Author(s) 2014
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DOI: 10.1177/0897190014521996
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Gyula Bokor, MD1, and Peter D. Anderson, PharmD, BCPP2

Abstract
Obsessive–compulsive disorder (OCD) is a common heterogeneous psychiatric disorder manifesting with obsessions and
compulsions. Obsessions are intrusive, recurrent, and persistent unwanted thoughts. Compulsions are repetitive behaviors or
mental acts that an individual feels driven to perform in response to the obsessions. The heterogeneity of OCD includes themes
of obsessions, types of rituals, presence or absence of tics, etiology, genetics, and response to pharmacotherapy. Complications of
OCD include interpersonal difficulties, unemployment, substance abuse, criminal justice issues, and physical injuries. Areas of the
brain involved in the pathophysiology include the orbitofrontal cortex, anterior cingulate gyrus, and basal ganglia. Overall, OCD
may be due to a malfunction in the cortico–striato–thalamo–cortical circuit in the brain. Neurotransmitters implicated in OCD
include serotonin, dopamine, and glutamate. Numerous drugs such as atypical antipsychotics and dopaminergic agents can cause
or exacerbate OCD symptoms. The etiology includes genetics and neurological insults. Treatment of OCD includes psy-
chotherapy, pharmacotherapy, electroconvulsive therapy, transcranial magnetic simulation, and in extreme cases surgery.
Exposure and response prevention is the most effective form of psychotherapy. Selective serotonin reuptake inhibitors (SSRIs)
are the preferred pharmacotherapy. Higher doses than listed in the package insert and a longer trial are often needed for SSRIs
than compared to other psychiatric disorders. Alternatives to SSRIs include clomipramine and serotonin/norepinephrine reup-
take inhibitors. Treatment of resistant cases includes augmentation with atypical antipsychotics, pindolol, buspirone, and
glutamate-blocking agents.

Keywords
obsessive–compulsive disorder, serotonin reuptake inhibitors, psychopharmacology, psychiatry, exposure and response
prevention

Continuing Education Learning Objectives


1. Describe the clinical presentation and diagnostic criteria of obsessive–compulsive disorder (OCD).
2. Describe the pathophysiology of OCD.
3. Distinguish OCD from related conditions.
4. Name several drugs and medications that can produce or aggravate OCD symptoms.
5. Describe the pharmacology, side effects, and role of SSRIs in the treatment of OCD.
6. Describe the pharmacology of clomipramine.
7. Name several medications used as augmentation therapy with OCD.
8. Describe several types of nonpharmacological therapies for OCD.

Obsessive–compulsive disorder (OCD) is a heterogeneous Diagnostic Criteria


disorder consisting of obsessions and compulsions.1 Obses-
The Diagnostic and Statistical Manual of the Mental Disor-
sions are intrusive, recurrent, and persistent unwanted
ders, Fifth Edition (DSM-5) lists formal criteria for diagnosis
thoughts.2 Compulsions are repetitive behaviors or mental acts
of OCD.2 In order to have a diagnosis of OCD, the presence
that an individual feels driven to perform in response to the
obsessions.2 Examples of obsessions include preoccupation
with germs, preoccupation with order and symmetry, fear of
1
causing harm to others, excessive focus on religious ideas, or Staff Psychiatrist, Taunton State Hospital, Taunton, MA, USA
2
unwarranted fear of losing items. Examples of compulsions are Psychopharmacology Consultant, private practice, Randolph, MA, USA
excessive hand washing and excessive checking of locks, Corresponding Author:
switches, or appliances. The prevalence of OCD in adults in the Peter D. Anderson, 5308 Avalon Drive, Randolph, MA 02368, USA.
United States is approximately 1%.3 Email: pander7291@aol.com
Bokor and Anderson 117

Table 1. Examples of Obsessions. clutters active living areas and impairs functioning. Trichotil-
lomania (hair-pulling disorder) is manifested by recurrent
Germs
Images of violent scenes
pulling out of one’s hair, producing hair loss. Excoriation
Repugnant thoughts (eg, kicking a baby, shooting a coworker, etc) (skin-picking disorder) is recurrent skin picking resulting in skin
Fear of causing harm to oneself or others accidently or intentionally lesions. Substance/medication-induced obsessive–compulsive
Fear of losing items that one may need and related disorder is where obsessions, compulsions, hair-
Order and symmetry pulling, skin-picking, or other body-focused repetitive behaviors
Religious and moral believes result from a medication or drug abuse.2 Amphetamines and
Intrusive sexual thoughts cocaine are known to produce obsessive–compulsive symptoms.
Superstitions
Methylphenidate has been reported to produce obsessive–
compulsive symptoms.6,7 Atypical antipsychotics have also been
reported to produce obsessive–compulsive symptoms.8-10 Dopa-
Table 2. Examples of Compulsions. mine agonists, especially agonists of the D3 receptor (eg, ropinir-
ole, pramipexole, and pergolide), have been reported to produce
Washing hands excessively
Excessive cleaning of household items
obsessive–compulsive-like behaviors.11 Obsessive–compulsive
Washing a particular part of the body first when taking a shower and related disorder due to another medical condition manifests
Repeatedly checking that the doors are locked or that the stove is turned off with obsessions, compulsions, preoccupations with appearance,
Excessive rereading or rewriting hoarding, skin-picking, hair-pulling, and other body-focused
repetitive behaviors, which is the result of a general medical
disorder. Examples of medical illness that may produce
obsessive–compulsive symptoms include Sydenham’s chorea
of obsessions, compulsions, or both is required. See Tables 1 and pediatric autoimmune neuropsychiatric disorders associ-
and 2 for examples of obsessions and compulsions. The obses- ated with streptococcal infections. Obsessive–compulsive
sions and compulsions must be time consuming such as taking symptoms that occur exclusively with delirium are not consid-
more than an hour per day. The obsessions and compulsions ered an obsessive–compulsive-related disorder due to another
must not be due to the pharmacological effects of a medication medical condition.
or a drug of abuse. For example, an obsession with obtaining Obsessive–compulsive personality disorder (OCPD) con-
more cocaine by an addict is not OCD. The disturbance must sists of a pervasive pattern of preoccupation with orderliness,
not be due to another psychiatric disorder such as paraphilic perfectionism, and mental and interpersonal control to the
disorder, body dysmorphic disorder, or hoarding.2 There are degree that flexibility, openness, and efficiency are impaired.11
several changes in the OCD criteria in DSM-5 from Diagnos- In OCPD, the individual is preoccupied with details, rules,
tic and Statistical Manual of the Mental Disorders, Fourth order, lists, organization, or schedules to the extent that the
Edition (DSM-IV). For starters, in DSM-IV OCD was listed major point of the activity is lost. Individuals with OCPD are
in the chapter on anxiety disorders.4,5 In DSM-5, OCD is in overly rigid and stubborn. Unlike OCD, OCPD lacks true
a chapter entitled ‘‘Obsessive-Compulsive and Related Disor- obsessions and compulsions.12 The manifestations of OCPD
ders.’’2 In DSM-IV, the person (unless a child) must have are egosyntonic, the affected individual finds the behavior suit-
recognized that the obsessions or compulsions are unreason- able and correct. The manifestations of OCD are egodystonic,
able or excessive. DSM-5 lacks this requirement. Neverthe- the affected individual finds the behavior inappropriate and
less, DSM-5 does allow for a range of insight with good or stressful. Persons with OCPD usually obtain pleasure with
fair, poor insight, or absent insight/delusional beliefs.5 organizing and controlling.
Tic disorders and Tourette’s syndrome are a frequent
comorbidity with OCD.4,13 Tics are sudden, brief, intermittent,
Similar Conditions involuntary, or semivoluntary movements or vocal sounds.14
Conditions related to OCD include body dysmorphic disorder, Types of tics include simple motor tics, simple vocal tics, com-
hoarding disorder, trichotillomania (hair-pulling disorder), plex motor tics, and complex vocal tics.13,14 Simple motor tics
excoriation (skin-picking) disorder, substance/medication- include eye blinking, nose twitching, and head jerking. In
induced obsessive–compulsive and related disorder, and obses- theory, any skeletal muscle in the body could produce a tic.
sive–compulsive and related disorder due to another medical Complex tics involve several muscles. Examples of complex
condition.2 All of these conditions are listed in the chapter motor tics include head shaking, hair brushing, touching, rude
‘‘Obsessive–Compulsive and Related Disorders’’ in the gestures, and imitating gestures. Complex motor tics are stereo-
DSM-5.2 Body dysmorphic disorder is where the individual typed movements. Complex motor tics can be confused with
is preoccupied with one or more perceived flaws or defects compulsive behaviors.4
in physical appearance that are not observable or minimal in Vocal tics are also known as phonic tics. Examples of
others. Hoarding disorder is persistent difficulty with discard- simple vocal tics include sniffing, throat clearing, grunting,
ing possessions regardless of actual value. This results in humming, screaming, coughing, and blowing. In theory, any
accumulations of materials or items to the degree that it nonword vocal sound can be a vocal tic.15 Normal childhood
118 Journal of Pharmacy Practice 27(2)

behavior often involves making various noises. The feature OCD. However, the association between substance abuse and
distinguishing tics from normal childhood behavior is the OCD is less robust than with anxiety disorders.25 Suicidal
constancy, repetitive, and inappropriateness of the behavior. behavior has been reported with OCD.26,27
Complex vocal tics are linguistically meaningful utterances
and verbalizations. Complex vocal tics include shorting of
obscenities, profanity, repeating one’s own words, or imitating Neurobiology of OCD
others. A diagnosis of Tourette’s disorder is based on the pres-
Areas of the brain implicated in the pathophysiology include
ence of multiple motor tics and at least 1 vocal tic.13 Over 50%
the orbitofrontal cortex, anterior cingulate gyrus, and caudate
of the patients with Tourette’s syndrome will have significant
nucleus.28-30 The basis for this hypothesis is predominately
obsessive–compulsive symptoms and approximately 30% will
structural and functional imaging studies.28,30 The parietal
have a diagnosis of OCD.16
lobe, superior temporal gyrus, and hippocampus may also be
Comorbidity of OCD with psychotic disorders including
involved in OCD.28,30 The basal ganglia may be the most rel-
schizophrenia has been reported. OCD symptoms may occur
evant part of the brain in OCD. The basal ganglia functions
in 8% to 26% of patients with schizophrenia.17 This comorbid-
in complex integrative motor and behavioral functions such
ity could represent a subtype of schizophrenia referred to as
as execution of learned behaviors.31 The basal ganglia is
‘‘obsessive–compulsive schizophrenia.’’18 Some patients with
composed of striatum (caudate nucleus and putamen), globus
schizophrenia may have repetitive behavior in response to psy-
pallidus, substantia nigra, nuclear accumbens, and subthalamic
chotic ideation.17 Repetitive behavior resulting from a paranoid
nucleus. Lesions of the basal ganglia have been reported to
delusion is not a compulsion.
produce acquired OCD.30,32
Other psychiatric disorders that can occur with OCD include
The neurotransmitters implicated in OCD include serotonin,
posttraumatic stress disorder, generalized anxiety disorder,
dopamine, and glutamate.33-35 This is based on neuroimaging
panic disorder, and social phobia. Neurological disorders that
studies as well as pharmacological studies. The effectiveness
can occur with OCD include temporal lobe epilepsy, Hunting-
of selective serotonin reuptake inhibitors (SSRIs) and clomipra-
ton’s disease, multiple sclerosis, and possibly Parkinson’s
mine in treating OCD further suggests a role of serotonin in
disease.17 Strokes affecting the inferior parietal, basal ganglia,
OCD.33,34 The contrasting improvement in or aggravation of
caudate, and/or posterior frontal lobe have been reported to
OCD symptoms from atypical antipsychotics suggests dopamine
produce OCD symptoms acutely.17
and/or serotonin contributes to OCD.8-10 Dopamine agonists and
OCD may manifest with sexual obsessions. Conversely,
reuptake inhibitors can cause or worsen OCD symptoms.6,7,11
OCD needs to be differentiated from paraphilias. A paraphilia
Serotonin is a modulator for dopamine.36 More recent research
is a condition where the person’s sexual arousal and gratifica-
examined glutamate as a cause of OCD.37 Evidence supporting
tion depend on fanaticizing and engaging in sexual behavior
the role of glutamate in OCD include genetic studies, neuro-
that is atypical and extreme.19 Paraphilias may involve objects
chemical studies, animal models, pharmacological experiments,
or individuals. Alternatively, a paraphilia may revolve around a
small clinical studies, and case reports with glutamate-altering
particular act such as exposing oneself or inflicting pain.20
drugs.37 Overall, OCD may be due to a malfunction in the
Examples of paraphilias include voyeurism (peeping on others),
cortico–striato–thalamo–cortical circuit in the brain.38-40 A key
exhibitionism (exposure of genitals), frotteurism (touching a
role for this network is maintaining self-control.
nonconsenting individual), sexual masochism (sexual pleasure
from pain or humiliation), sexual sadism (sexual pleasure from
inflicting pain on others), pedophilia, and severe fetishes. Unlike
patients with OCD, individuals with paraphilias obtain pleasure
Causes of OCD
in the act and the main reason to resist the act is because of OCD appears to be a hereditary condition.41 Due to the hetero-
negative consequences such as criminal prosecution. geneity of the disorder, a single gene is not likely involved in
all cases. Candidate genes for OCD include genes affecting
serotonin, dopamine, and glutamate. Serotonergic genes
Complications of OCD include the 5-HTTLPR serotonin transporter, the 5HT1D beta
The time consuming and oddness of the compulsions regularly receptor gene, 5HT2a serotonin receptor, and the serotonin
strain social relationships with friends and family members.21 5HT2c receptor.42 Some studies suggest a repeat in the dopamine
Quality of life and functional impairment occur.19 OCD can receptor type 4 (DRD4) gene. The D2 receptor gene has been
result in unemployment.22 Physical injuries can occur from found to be associated with OCD with tics but not with OCD
certain rituals such as dermatological conditions from exces- without tics.42 Genes affecting catechol-O-methyltransferase
sive hand washing.23 Criminal justice issues can result from and monoamine oxidase may be involved in OCD. The most
OCD. Case in point, a man with OCD was washing and polish- likely glutaminergic gene associated with OCD is SLC1A1,
ing his neighbors’ automobiles without permission. He was the glutamate transporter gene.37 The SAPAP3 gene, which
arrested but was later released when he explained to the officers encodes for the ionotropic glutamate receptors, has been
that he had OCD. On his way out the station, he started cleaning implicated in OCD.37 Other genes that may be involved with
the police cars.24 Substance abuse is another complication of OCD include BDNF locus, SLITRK1, gamma-aminobutyric
Bokor and Anderson 119

acid type receptor 1 (GABBR1), OLIG2, and myelin oligoden- Rating Scales
drocyte glycoprotein.42,43
The most common rating scale used in OCD clinical trials is the
One hypothesis is that exposure to group A beta hemolytic
Yale-Brown Obsessive Compulsive Scale (Y-BOCS). It is a
Streptococcus bacteria (GABHS) may cause some cases of
10-question semistructured questionnaire. Each item of the
OCD in children. The phrase for this phenomena is Pediatric
Y-BOCS has a 5-point scale, ranging from zero to 4. The zero
Autoimmune Neuropsychiatric Disorder Associated with
is least symptomatic and 4 being the most symptomatic. The
Streptococcus (PANDAS).44 When the body is exposed to
possible total range is from zero to 40. A children’s version of the
Streptococcus, antibodies develop. The antibodies then cross-
Y-BOCS is also available. Many clinical trials define a response
react with nerve tissue including the basal ganglia, a mechan-
to pharmacotherapy as a 25% or a 35% reduction in the Y-BOCS
ism similar to the cardiac effects produced from rheumatic
score. Other studies only examine the total decrease in score. An
fever. The onset of OCD or tics is sudden.44 Other symptoms
individual is still able to have severe symptoms despite a 35%
that appear with PANDAS include personality changes, rage
decrease.
episodes, decline in academic performance, deterioration in
Other rating scales used for OCD include the National Insti-
handwriting, symptoms of attention-deficit hyperactivity
tute of Mental Health General Obsessive-Compulsive Scale,
disorder (ADHD), excessive sensory stimulation (eg, hypersen-
Maudsley Obsessive-Compulsive Inventory, and the Leyton
sitivity to noises, light, etc), and frequent urination which differ
Obsession Inventory. The clinical global impression scale,
from the typical clinical presentation of OCD.44-46 Children
severity of illness, and the clinical global impression and
with OCD and PANDAS are more likely to have separation
improvement are commonly used but are not specific to OCD.
anxiety, urinary urgency, oppositional defiant disorder, and
Rating scales for measuring depression (eg, Hamilton Depres-
mood swings than a child with OCD only. A Streptococcus
sion Rating Scale) and anxiety are also used in OCD clinical
infection occurs prior to or at the time the OCD symptoms ini-
trials.
tially occur or abruptly increase in severity with an existing
case of OCD. An increase in anti-Streptolysin O antibodies
provides clinical evidence of PANDAS in an individual patient.
However, no reliable biomarkers are currently available.45 The Nonpharmacological Treatment of OCD
autoimmunity reaction from the Streptococcus is postulated to The most common nonpharmacological treatment of OCD is
cause the OCD.44,45 The OCD is not a direct result from the cognitive behavioral therapy (CBT).52 CBT is a psychothera-
infection with Streptococcus. peutic approach that addresses dysfunctional emotions,
The main criticism regarding the concept of PANDAS is maladaptive behaviors, and cognitive processes through a vari-
the difficulty with documenting an association of a new ety of goal-orientated, explicit procedures. A key element of
Streptococcus infection with and exacerbations of tics/OCD- CBT is to differentiate rational and irrational thoughts as well
like behavior.45 Another criticism of the PANDAS model is the as change maladaptive thinking. There are many types of CBT,
lack of other features found with rheumatic fever.45 Further- the most effective for OCD is ‘‘Exposure and Response Preven-
more, both GABHS infections and OCD are common conditions tion’’ (ERP).53 The exposure in ERP deals with confronting the
so that co-occurrence may be a random coincidence.47 Strictly images, thoughts, objects, and events that make a person with
speaking, even if PANDAS is proven, it would not technically OCD anxious.52 The ‘‘Response Prevention’’ in ERP refers
be a cause of OCD. Obsessive–compulsive behavior due to a to selecting an option not to do a compulsive act such as
medical condition is classified as obsessive–compulsive and coming into contact with the objects or situations that make a
related disorder due to another medical condition by the person anxious.52 Numerous studies and meta-analyses support
DSM-5.2 the use of ERP for treating OCD.52
PANDAS has many similarities and many differences from Transcranial magnetic stimulation (TMS) is a procedure that
Sydenham Chorea (SC), a neurological disorder of childhood uses magnetic fields to depolarize or hyperpolarize neurons in
resulting from infection with GABHS. SC consists of rapid, the brain. TMS has been studied in OCD.54 Two brain areas
irregular, and aimless involuntary movements of the extremi- show promise for improvement in OCD, the supplementary
ties, trunk, and facial muscles.48 Symptoms of OCD may occur motor area and the orbitofrontal cortex.55 Stimulation of the
with SC.48 Other manifestations of SC include muscle weak- dorsolateral prefrontal cortex appears to be ineffective for treat-
ness, incoordination, poor handwriting, and emotional instabil- ing OCD.55 A rare but potentially serious adverse reaction to
ity.48 The etiology of SC may involve antibodies cross reacting TMS is seizures.56 TMS is not a routine treatment for OCD.53
with cellular material in the basal ganglia.47 The literature for electroconvulsive therapy for OCD is lim-
Certain cases of OCD may be caused by psychological ited to case reports.57-60 Brain surgery is a rarely used treatment
traumatic events.49,50 Fontenelle and colleagues proposed a for refractory OCD.61 Targets for surgical intervention of OCD
posttraumatic subtype of OCD.51 Features of posttraumatic include the anterior limb of internal capsule, the anterior cingu-
subtype of OCD include a higher rate of self-injurious beha- late gyrus, and nucleus accumbens.61 Deep brain stimulation
vior, history of suicide plans, panic disorder with agoraphobia, for treating OCD received the Food and Drug Administration
and compulsive buying.51 (FDA) approval in 2009 under a humanitarian device
120 Journal of Pharmacy Practice 27(2)

exception.62 Deep brain stimulation electrodes are implanted in 6-week interval. Of the 7 partial responders, 5 became full
the anterior limbs of the internal capsule or in the white matter responders by week 8. None of the partial responders in the pla-
projections from the anterior cingulate. The electrodes are cebo group improved from week 6 to week 8. Of the 21 subjects,
attached to a pulse generator implanted either in the abdomen 9 became responders.
or near the clavicle. Extended-release fluvoxamine was found to increase
quality-of-life measures in 12-week, placebo-controlled trial.75
Fluvoxamine was found to be more effective than placebo but
Pharmacotherapy less effective than behavioral therapy in a group of Japanese sub-
jects.76 Fluvoxamine demonstrated similar efficacy but superior
Selective Serotonin Reuptake Inhibitors tolerability over clomipramine in a group of 227 patients.77 A
The SSRIs are the primary drugs for treating OCD.53,63-65 Par- multicenter study also reported comparable effectiveness of
oxetine (Paxil1), sertraline (Zoloft1), fluoxetine (Prozac1), fluvoxamine and clomipramine but better tolerability with
and fluvoxamine (Luvox1) have FDA approval for treating the former.78 Fluvoxamine has demonstrated effectiveness in
OCD. Citalopram (Celexa1) and escitalopram (Lexapro1) children and adolescents with OCD.79 Numerous other studies
do not have FDA approval for treating OCD.66,67 A Cochrane support the use of fluvoxamine for treating OCD.
database analysis confirmed that SSRIs are more effective than The effectiveness of fluoxetine in OCD was first documen-
placebo for treating OCD.68 No convincing evidence was ted in open-label trials reported in 1990.80 Placebo-controlled
found that any particular SSRI is more effective than another studies were later done to confirm its effectiveness.81 Fluoxe-
SSRI with regard to OCD.68 Often, higher doses of SSRIs are tine has FDA approval for treatment of OCD in children over
needed for treating OCD than depression or anxiety disor- 8 years of age. Published studies also support the use of
ders.69 A meta-analysis of dose response found higher doses fluoxetine for younger children with OCD.82,83 Fluoxetine
of SSRI to be more effective in treating OCD than lower demonstrated comparable efficacy to clomipramine.84 Fluoxe-
doses.70 In addition, the response of OCD is slower than tine has an active metabolite, norfluoxetine.85 Fluoxetine is
depression so a longer trial of 10 to 12 weeks in duration is also a potent inhibitor of cytochrome P-450 (CYP) 2D6.85
needed.71 SSRIs are the best choice for pharmacotherapy of Numerous clinical trials support the effectiveness of sertra-
OCD in children and adolescents.72 line for OCD.86-88 Sertraline does not have FDA approval for
The first SSRI to be studied in clinical trials for OCD was children or adolescents. Clinical studies support the use of ser-
fluvoxamine. Perse et al conducted a double-blind, placebo- traline for pediatric OCD.89,90
controlled crossover study that was published in 1987.73 Paroxetine also works for OCD.91,92 Paroxetine has several
Twenty outpatients were studied. All patients received placebo disadvantages over other SSRIs. Paroxetine is more likely to
initially for 2 weeks. The subjects then received either placebo cause birth defects and has category D rating by the FDA.93 Par-
or fluvoxamine for 8 weeks. On weeks 11 and 12, all patients oxetine produces more withdrawal reactions compared to other
received placebo. Patients then received the opposite treatment SSRIs.94 Antimuscarinic activity is greater with paroxetine than
for the next 8 weeks. Of the 16 subjects, 13 showed improve- with other SSRIs.94 Paroxetine is also a strong inhibitor of CYP
ment. Of the 16 patients, 9 showed major improvement. A 2D6.
crossover study may not be the best design for OCD studies for Citalopram lacks a labeled indication for OCD. A number of
a variety of reasons. The 2-week washout period may have studies document the efficacy of citalopram.82,95 Only 1
been adequate for the drug to eliminate from the body but not placebo-controlled study was found with a Medline search.95
enough for changes in receptor downregulation. Clinical trials include the use of citalopram in combination stud-
Two years later, Goodman and colleagues published findings ies with clomipramine and quetiapine. 96,97 Escitalopram also
from a double-blind, placebo-controlled study with fluvoxa- lacks FDA approval for OCD. Studies of escitalopram are in the
mine.74 In all, 21 patients received fluvoxamine and 21 patients literature.98-100 Citalopram and escitalopram have minimal inhi-
received placebo. Fluvoxamine was started at 50 mg every hour bitory activity on the CYP, which is an advantage over other
of sleep. The dose was increased to 50 mg twice daily after 3 SSRIs.101 Citalopram and escitalopram can produce QTc prolon-
days unless severe side effects were present. After 2 weeks of gation, especially in overdose.102 Torsades de pointes is a
treatment, the dose could be increased to 50 mg every 3 to 4 days life-threatening development of a prolonged QTc interval. This
up to a maximum of 300 mg per day. The Y-BOCS and the promoted FDA to issue a warning letter regarding citalopram,
Clinical Global Impression Scale for Improvement evaluated with the key point of not using citalopram in doses above 40
treatment response. At 6 weeks of treatment, the fluvoxamine mg.103 Many clinicians disagree with this recommendation.102
group had a decrease in Y-BOCS scores from 25 at baseline to Sheeler et al suggest obtaining an electrocardiogram if doses
19.4 at week 6. The placebo group had no significant changes about 40 mg are used. Patients should be accessed for other risk
at 6 weeks. A ‘‘responder’’ was defined as ‘‘a score of much factors for QTc prolongation including bradycardia, hypokale-
improved or very improved on the Clinical Global Impression mia, and hypomagnesemia.
Severity of Illness item.’’ Partial responders were defined as Interestingly, the FDA has not issued a warning for escita-
‘‘minimally improved’’ and were considered nonresponders. lopram. QTc prolongation has been reported with escitalo-
Seven partial responders to fluvoxamine were present at the pram.104-106 The Medicines and Healthcare Products
Bokor and Anderson 121

Regulatory Agency of the United Kingdom issued a warning for Clomipramine has many disadvantages over SSRIs.
both citalopram and escitalopram.107 A retrospective review was Clomipramine has the potential for cardiac toxicity including
conducted on 374 citalopram and 421 escitalopram overdose QTc prolongation.120-122 Antimuscarinic side effects are also
cases. The study conclusions are that escitalopram is less toxic common with clomipramine and include dry mouth, constipa-
than citalopram in acute overdose.108 Citalopram overdose does tion, urinary retention, and tachycardia.123,124 Another draw-
have higher seizure potential than escitalopram overdose.108 back with clomipramine is the potential for orthostatic
Side effects of the SSRIs include nausea, nervousness, hypotension.125 Similar to the SSRIs, serotonin syndrome can
dizziness, tiredness, insomnia, reduced sexual drive, erectile result from clomipramine.126,127 Due to its dopamine antago-
dysfunction, weight changes, dry mouth, vomiting, and diar- nist activity, it has been argued that clomipramine can cause
rhea. When starting a patient on an SSRI, the possibility of neuroleptic malignant syndrome.126 Clomipramine has the
starting a manic episode needs to be considered. Activation of potential to activate a manic episode in patients with underly-
a manic episode has been reported with the SSRIs.109 Signs ing bipolar disorder.128 Clomipramine causes greater weight
of a manic episode include delusions of grandeur, a rapid rate gain than SSRIs.129 The main enzyme involved in clomipra-
of speech, unusual and excessive happiness, spending sprees, mine metabolism is CYP 2D6 so dosage reductions are likely
hypersexual behavior, aggression or agitation, and prolonged needed for patients receiving potent inhibitors of CYP 2D6
insomnia without fatigue. such as paroxetine or fluoxetine. Clomipramine is also metabo-
A potential complication of SSRI therapy is serotonin syn- lized by CYP 2C19.130
drome.110 The most common cause of serotonin syndrome is Clomipramine is not commercially available as an intravenous
drug interactions. SSRIs are contraindicated with monoamine formulation in the United States but is available in Europe. Intra-
oxidase inhibitors. Serotonin syndrome can also result from venous clomipramine may have a faster onset than oral clomipra-
combining SSRIs with lithium, psychostimulants (eg, cocaine mine. Onset may be a matter of days rather than weeks.131
and the amphetamines), and dextromorphan.110 Pharmacoki-
netic interactions can cause serotonin syndrome such as admin-
istrating sertraline with erythromycin.111 The serotonin
Serotonin Norepinephrine Reuptake Inhibitors
syndrome is characterized by the triad of altered mental status, Serotonin norepinephrine reuptake inhibitors (SNRIs) include
autonomic dysfunction, and neuromuscular abnormalities.111,112 venlafaxine, duloxetine, milnacipran, and levomilnacipran.
Specific signs and symptoms include agitation, mydriasis, None of the SNRIs have FDA approval for treatment of OCD.
hyperthermia, tachycardia, fluctuating blood pressure, mutism, Numerous case reports, open-label studies, and 3 controlled
tremor, muscle rigidity, hyperreflexia, and seizures.112 Lead- double-blind studies support the efficacy of venlafaxine for
pipe rigidity of the muscles is more likely to be due to neurolep- OCD.132 Albert et al conducted a study comparing clomipra-
tic malignant syndrome than serotonin syndrome.112 mine to venlafaxine.133 The response rate for venlafaxine was
36%, which was less than clomipramine with a response rate of
50%.133 The study only had 13 subjects in each group, there-
Clomipramine fore strong conclusions cannot be made. Venlafaxine produces
Clomipramine (Anafranil1) was the first drug to obtain FDA a withdrawal syndrome greater than the SSRIs.134 Hyperten-
approval for treating OCD. It was developed in the early sion is a common adverse reaction to venlafaxine.135,136
1960s by Geigy which is now Novartis.113 Clomipramine is a Duloxetine has also been used for treating OCD but data are
tricyclic antidepressant with nearly an identical structure to limited to a handful of case reports.137-139 Sansone and Sansone
imipramine. A chlorine atom is substituted for hydrogen at suggest SNRIs may be a reasonable second-line agent after
position 3 on the ring structure.113 This simple change created SSRIs.132 Milnacipran (Savella1) is another SNRI. The only
a potent inhibitor of serotonin reuptake. Imipramine has mini- labeled indication for milnacipran is fibromyalgia. Data for
mal serotonin activity. In contrast to SSRIs, clomipramine also milnacipran are limited to 1 study in laboratory mice and case
inhibits the reuptake of norepinephrine.114 Clomipramine also reports.132 The latest SNRI to enter the US market is levomil-
has dopamine-blocking effects.115 Desmethylclomipramine is nacipran extended release (Fetzima1). Levomilnacipran is the
the primary metabolite and is active on the norepinephrine active enantiomer of the racemic milnacipran and is the most
transporter.116 The first open-label study of clomipramine was selective of the SNRIs for norepinephrine. It has 17 times the
done in the 1960s.117 Clomipramine did not receive FDA selectivity for norepinephrine compared to venlafaxine and
approval for OCD until 1989. 27 times the selectivity compared to duloxetine.140 The FDA
Meta-analyses suggested that clomipramine is more effec- approved levomilnacipran for major depressive disorder. To
tive than SSRIs.118,119 Criticisms of the meta-analyses include the best of our knowledge, no studies have been done for
that clomipramine studies were conducted years earlier than levomilnacipran for OCD.
SSRIs.65 Many of the clomipramine studies consisted of
treatment-naive patients. Many of the SSRIs included patients
with a history of pharmacotherapeutic interventions.65 Head-
Augmentation Therapy
to-head studies of SSRIs and clomipramine have found similar The percentage of responders in placebo-controlled studies is
efficacy.77,84 typically 40% to 60%.141 As discussed earlier, a decrease in
122 Journal of Pharmacy Practice 27(2)

25% to 35% in the Y-BOCS is often used to define a response placebo. The fluoxetine regimen was limited to 40 mg per day,
to treatment. Even with a 35% response rate, the patient may and the olanzapine dose was limited to 10 mg a day. Earlier
have remaining significant symptoms. Treatment resistance open-label studies were conducted with olanzapine. Weiss
can be defined as failed a single trial of a serotonin reuptake et al had a mean dose of 7.3 mg of olanzapine per day.152 Com-
inhibitor and treatment refractory can be defined as having mon complaints with olanzapine include sedation and weight
failed 2 adequate trials of serotonin reuptake inhibitors.141 gain.150,152 Potential long-term effects of olanzapine include
Readers should bear in mind that definitions of treatment metabolic abnormalities such as elevated triglycerides and glu-
resistance and treatment refractory vary from study to study. cose (including type 2 diabetes mellitus). To varying degrees
Treatment options for resistant OCD include combining an metabolic effects occur with other second-generation
SSRI with clomipramine.141 Other options include adding pin- antipsychotics.
dolol, mirtazapine, lithium, buspirone, and antipsychotics to an Korton et al conducted a placebo-controlled study of quetia-
SSRI. pine (Seroquel1) augmentation therapy to serotonin reuptake
Haloperidol was studied in a placebo-controlled study in inhibitors.153 Patients received serotonin reuptake inhibitor for
patients with fluvoxamine-refractory OCD.142 Subjects were at least 12 weeks. Subjects then received up to 400 mg of que-
titrated to a dose of 300 mg/d of fluvoxamine and received this tiapine for 6 weeks. The quetiapine dose could be increased to
dose for 7 weeks. Patients were considered refractory to 600 mg for the next 6 weeks. Quetiapine showed no benefit
fluvoxamine by an improvement of less than 35% in the over placebo. The study was limited to 40 patients. An earlier
Y-BOCS and or a total score of 16. The refractory patients were placebo-controlled study by Fineberg and colleagues did not
entered into either the placebo or the haloperidol arm. Haloper- find a statistically significant difference between quetiapine
idol was started at 2 mg/d for 3 days. The dose was increased by and placebo.154 Furthermore, quetiapine demonstrated no
2 mg every 3 days to a maximum of 10 mg. Benztropine was benefits over placebo in another study.155 Only 1 study with
administered for prophylaxis of extrapyramidal symptoms. A placebo comparison found quetiapine to be effective.156
statistical significant difference was shown after 4 weeks of Quetiapine was found to be more effective than clomipramine
therapy with haloperidol. Tics as a comorbidity was shown to for add-on therapy in patients with inadequate response to
be predictor of positive response to haloperidol. SSRIs.157 This study was limited to 10 patients with clomipra-
More studies have evaluated the use of atypical antipsycho- mine and 11 with quetiapine.
tics (second generation) than typical antipsychotics (first Ziprasidone (Geodon1) was introduced in 2001.158 No
generation). A number of studies have examined risperidone placebo-controlled studies of ziprasidone were found with a
(Risperdal1) for augmentation therapy of OCD.143-145 Risper- Medline search. A retrospective analysis was done comparing
idone was found to be more effective than aripiprazole in a ziprasidone to quetiapine in OCD.159 The review included 15
group of 41 patients resistant to SSRIs.144 Risperidone demon- patients on quetiapine and 9 with ziprasidone. Quetiapine was
strated comparable effectiveness to olanzapine in a group of 91 found more effective than ziprasidone.
patients.145 Positron emission tomography revealed that Two placebo-controlled studies found aripiprazole (Abil-
improvement from risperidone was associated with increased ify1) more effective than placebo.160,161 Risperidone was
metabolic activity in the striatum, cingulated gyrus, and in the found to be more effective than aripiprazole in head-to-head
orbital region of the prefrontal cortex.146 Only 2 placebo- study of 23 patients.144 Other open-label studies support the use
controlled studies support the use of risperidone as an augment- of aripiprazole for OCD.162
ing agent for OCD.147,148 Risperidone was compared to Clozapine (Clozaril1) is not effective for treating OCD.163
exposure and ritual prevention therapy as augmentation therapy Clozapine has been reported to induce obsessive–compulsive
for OCD. Exposure and ritual prevention therapy was found to symptoms.8,164 Interestingly, olanzapine, aripiprazole, paliper-
be more effective than risperidone.149 A pilot trial of paliperi- idone, and quetiapine have also been reported to cause OCD
done, an active metabolite of risperidone, did not show statistical symptoms.9,10,165-167 No literature was found for iloperidone
difference compared to placebo in treatment of resistant (Fanapt1), lurasidone (Latuda1), or asenapine (Saphris1)
OCD.150 either as a treatment of or as a cause of OCD. The apparently
Olanzapine (Zyprexa1) has also been studied as a treatment opposite effects from atypical antipsychotics in different
for OCD. Olanzapine has been compared to placebo conducted patients further document the heterogeneity of OCD.
at the Neuropsychiatric Institute and Hospital.150 Olanzapine Case reports from the 1980s suggested that lithium is
could be dosed up to 20 mg but the average dose was 11.2 effective for refractory OCD.168 However, these reports were
mg. Of the 13 subjects in the olanzapine group, 6 have a 25% before serotonergic drugs became available. A controlled study
reduction in the Y-BOCS score. Limitations include a small on lithium augmentation versus placebo found no benefit of
patient group and a short duration of 6 weeks. lithium.169
A 6-week, placebo-controlled trial of olanzapine add-on ther- Pindolol (Visken1) is a nonselective beta blocker with
apy to fluoxetine was conducted at the University of Florida.151 partial agonist activity at the beta receptors. Pindolol has been
Subjects first received an open-label trial of fluoxetine for 8 used as an augmentation agent for OCD.170 One placebo-
weeks. Partial or nonresponders received olanzapine of up to controlled, double-blind study found pindolol more effective
10 mg per day. Olanzapine demonstrated no benefit over than placebo for patients refractory to paroxetine.170
Bokor and Anderson 123

Table 3. American Psychiatric Association (APA) Practice Guidelines: Obsessive–Compulsive Disorder, Key Points.

First-line treatment of OCD is either a CBT or an SSRI


CBT, consisting of exposure and response prevention, is recommended for a patient who lacks major depression, anxiety, and is not too severely
impaired to cooperate with the treatment actions
If psychotherapy is tried first, then it should involve exposure and response prevention
If pharmacotherapy is tried first then an SSRI should be used before clomipramine
Higher doses of SSRIs than the maximum doses listed in the package insert may be needed for some patients
Patients with a partial response to an SSRI can be considered for augmentation therapy such as combining an SSRI with antipsychotics or combining CBT
with an SSRI
Patients with no response to an SSRI then a trial of different SSRI can be considered
For cases that do not respond to SSRIs with antipsychotics then augmentation of SSRIs with clomipramine, buspirone, pindolol, riluzole, or once weekly
morphine sulfate
Successful medication treatment should be continued for 1 to 2 years before considering a gradual taper. This taper should be 10% to 25% every 1 or 2
months

Abbreviations: CBT, cognitive behavioral therapy; OCD, obsessive–compulsive disorder; SSRIs, selective serotonin reuptake inhibitors.

Preliminary studies suggest 5-HT3 antagonists may be an trial is currently investigating riluzole compared to placebo as
effective augmentation agent for OCD.171 A single blind study add-on therapy for serotonin reuptake inhibitors.182 A small
used ondansetron (Zofran1) as augmentation for patients that placebo-controlled study found that lamotrigine (Lamictal1)
failed a prior regimen of SSRIs and antipsychotics. Of the 14 augmentation of serotonin reuptake inhibitors reduced OCD
patients, 9 experienced a greater than 25% reduction in the symptoms.183 Lamotrigine is an anticonvulsant that inhibits the
Y-BOCS rating scale.171 Granisetron (Kytril1) was investigated release of glutamate. Ketamine (Ketalar1) has been studied as a
as add-on therapy for fluvoxamine.172 A study compared 20 sub- treatment for OCD but should be considered for research interest
jects with placebo to 19 subjects with granisetron for patients not rather than clinical interest at this point.184,185
responding to fluvoxamine. A response (ie, >25% reduction in
Y-BOCS scores) was seen after 6 weeks in 100% of the granise-
tron group and 35% in the placebo group. An open-label study
Practice Guidelines for OCD
consisting of ondansetron as monotherapy for OCD reported that The American Psychiatric Association has a series of practice
3 of the 6 patients received a 35% or greater improvement in the guidelines for treating OCD in adults.186 The highlights of the
Y-BOCS scores.173 guidelines are given in Table 3. The American Academy of
Two studies examined the addition of buspirone (BuSpar1) Child and Adolescent Psychiatry (AACAP) developed practice
to SSRIs in the treatment of OCD.174,175 Both studies had only guidelines for treating OCD in pediatric patients.187 One major
14 patients. Neither study found buspirone effective compared difference between the adult and the pediatric guidelines is that
to placebo. Another small study found buspirone ineffective as CBT is preferred over pharmacotherapy in children and adoles-
adjuvant therapy to clomipramine.176 However, there may be cents with mild to moderate OCD.187 The AACAP has stronger
isolated cases where patients do respond to buspirone.177 Data language to discourage the use of clomipramine over SSRIs for
with mirtazapine (Remeron1) as a treatment for OCD are lim- treating OCD. The AACAP guidelines specifically address
ited. One study found mirtazapine speeds up the time period to comorbid OCD and ADHD. When both OCD and ADHD are
response with citalopram.178 However, this study included present, the OCD should be treated first. Obsessions impair
mirtazapine at the initiation of citalopram rather than studying attention, and treatment of OCD may improve attention.187
treatment nonresponders to citalopram. After 12 weeks, Furthermore, psychostimulants may exacerbate obsessions.187
mirtazapine provided no additional benefit to citalopram. An The AACAP deemphasizes augmentation therapy with the
open-label study showed some efficacy of mirtazapine as exception of combining psychotherapy with SSRIs.
monotherapy for OCD.179
In summary, there is no compelling evidence to support a
drug of choice for refractory OCD. However, there is more evi-
Measurement of Outcomes
dence with certain atypical antipsychotics than other classes. Ideally, outcomes should be measured with a rating scale such
as the Y-BOCS. Other measurements of outcomes include
occupational functioning and a decrease in OCD-related
Glutamate Antagonists physical illness (eg, skin conditions secondarily to excessive
Glutamate may play a role in the pathophysiology of OCD.37 cleaning). Side effects of medications should also be assessed.
This led to research on glutamate antagonists as a potential treat-
ment of OCD including as monotherapy and add-on therapy. An
open-label study found riluzole (Rilutek1), a glutamate antago-
Conclusions
nist, effective for OCD in children.180 Another open-label study The heterogeneity of OCD includes themes of obsessions,
reported riluzole effective as augmentation therapy.181 A clinical types of rituals, presence or absence of tics, etiology, genetics,
124 Journal of Pharmacy Practice 27(2)

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Declaration of Conflicting Interests compulsive disorder. Brain Dev. 2008;30(4):231-237.
The author(s) declared the following potential conflicts of interest 17. Pallanti S, Grassi G, Sarrechia ED. Obsessive-compulsive disor-
with respect to the research, authorship, and/or publication of this der comorbidity: clinical assessment and therapeutic implications.
article: Dr Anderson owns stock in Abbott Laboratories. Front Psychiatry. 2011;70(2):1-11.
18. Berman I. Is there a subtype of obsessive-compulsive schizophre-
Funding nia. Psychiatric Annals. 1999;29(9):506.
The author(s) received no financial support for the research, author- 19. Anonymous. Paraphilias. http://www.psychologytoday.com/con-
ship, and/or publication of this article. ditions/paraphilias. Accessed November 20, 2013.
20. American Psychiatric Association. Paraphilic Disorders. Diag-
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