The Psychopharmacology of Anxiety

by Julie Dopheide, Pharm.D., BCPP, and Susie Park, Pharm.D.

Psychiatric Times March 2002 Vol. XIX Issue 3
The range of medicinal compounds useful for anxiety disorders
has expanded from:
antidepressants,
1. SSRIs.. Fluoxetine (Prozac),

2. Fluvoxamine (Luvox)

3. citalopram (Celexa),

4. paroxetine (Paxil)

5. sertraline (Zoloft)

6. clomipramine (Anafranil)

7. clonazepam (Klonopin) 0.5 mg

8. Venlafaxine. (Effexor XR)

9. Mirtazapine. (Remeron)

10. Nefazodone.
11.imipramine (Tofranil)
benzodiazepines
1. lorazepam (Ativan)

2. Alprazolam (Xanax)

3. Clonazepam
4. diazepam (Valium)

5.Buspirone
anticonvulsants,
1. valproate (Depakene) and gabapentin (Neurontin)
Valproate,
2. carbamazepine (Tegretol)
3. and lamotrigine (Lamictal)

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 some antipsychotics
1. Haloperidol (Haldol)
2. and risperidone (Risperdal),

3. olanzapine (Zyprexa) and

4. clozapine (Clozaril).
and herbal/alternative compounds.
1. Kava Kava (Piper methysticum).

2. Valerian (Valeriana officinalis).

Frequently, combination therapy is needed (e.g.,

antidepressant and benzodiazepine) to achieve maximum
efficacy and tolerability.
Epidemiologic studies (e.g., Kessler et al., 1994; Lecrubier,
1998) show that between 30% and 60% of patients with
anxiety disorders have comorbid illnesses such as depression
or a substance abuse disorder. The presence of comorbid
psychiatric and medical conditions guides drug therapy
selection. For example, antidepressants are preferred if
comorbid depression exists, and benzodiazepines may be
problematic in those with active substance abuse disorders. A
World Health Organization study found that recognition of
comorbidity in anxiety disorders was a key reason for
preferentially prescribing antidepressants rather than
benzodiazepines in most primary care practices worldwide
(Lecrubier, 2001).
When symptoms of anxiety persist and cause functional
impairment, a thorough diagnostic assessment is needed to
determine if one or more of the following distinct DSM-IV-TR
anxiety disorders are present: generalized anxiety disorder
(GAD), social anxiety disorder (SAD, also known as generalized
social phobia), obsessive-compulsive disorder (OCD), panic
disorder (PD) or posttraumatic stress disorder (PTSD). An
individualized, evidence-based approach that utilizes
established dosing and appropriate duration of therapeutic trial
(typically six to 12 weeks) for each anxiety disorder is needed
for treatment success. Typically, medication is needed to
decrease symptoms sufficiently for patients to participate in
psychotherapeutic and behavioral interventions. Establishing
rapport with the patient through counseling about the illness
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and medication management can improve treatment success
(Gorman, 2001).
Antidepressants
SSRIs. Selective serotonin reuptake inhibitors are broad-
spectrum anti-anxiety agents considered first-line therapy for
all major anxiety disorders. (There are, however, differences in
current approved U.S. Food and Drug Administration
indications, dosing and pharmacokinetic/drug interaction
profiles). According to several reviews (Ballenger, 2001;
Brunello et al., 2000; Pigott and Seay, 1999), 50% to 75% of
patients with anxiety disorders experience significant benefit
after adequate dose and duration of therapy with an SSRI.
Fluoxetine (Prozac) is perhaps the most activating SSRI, with
once-daily dosing in the morning recommended for most
patients. Fluvoxamine (Luvox) is better tolerated with
bedtime dosing, and citalopram (Celexa), paroxetine
(Paxil) and sertraline (Zoloft) should be initiated in the
morning with a change to bedtime dosing if drowsiness occurs.
The SSRIs can cause dose-related nausea, restlessness,
insomnia and sexual dysfunction, although they are generally
better tolerated with less toxicity in overdose compared to
tricyclic antidepressants and monoamine oxidase inhibitors.
Several investigators (Fava et al., 2000; Lake et al., 2000; Mace
and Taylor, 2000) described less common but potentially
serious adverse effects, including hyponatremia,
extrapyramidal side effects, weight gain and increased
bleeding. As described by Black et al. (2000), SSRI withdrawal
reactions, such as anxiety, diarrhea, fatigue, gait instability,
headache, emesis, tremor, paresthesias and visual
disturbances, can occur upon abrupt discontinuation of an SSRI
after one month of therapy. Symptoms resolve within 72 hours
of restarting SSRI therapy.
In considering SSRIs for specific anxiety disorders, SSRIs and
clomipramine (Anafranil) are significantly more effective
than other less serotonergic antidepressants in alleviating
symptoms of OCD, according to several well-controlled trials
(Pigott and Seay, 1999). Significant efficacy may take 10 to 12
weeks at maximally tolerated doses. The time to onset of effect
is longer when treating OCD compared to SAD, GAD and even
PD, in which symptoms lessen within one month of treatment
at antidepressant doses. Key distinguishing features of OCD

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pharmacotherapy include a negligible placebo response and
high relapse (>90%) upon drug discontinuation.
Compared to those with depression and other anxiety
disorders, individuals with PD and PTSD are frequently more
sensitive to the activating side effects of SSRIs (Ballenger et
al., 1998; Brunello et al., 2001; Davidson, 2000). Lower initial
doses are needed to improve tolerability. In 1998, an
International Consensus Group on PD, led by Ballenger,
recommended initiating SSRI therapy at lower doses (e.g.,
paroxetine at 10 mg, sertraline at 25 mg) with titration based
on tolerability to usual antidepressant doses. In 2001, Goddard
and colleagues reported that clonazepam (Klonopin) 0.5 mg
tid added to sertraline therapy 100 mg/day for PD resulted in
more rapid onset of anti-panic effect (one week versus three
weeks) and good tolerability. The clonazepam was tapered off
over three weeks and discontinued without incident. Clearly,
combination therapy is preferred when rapid relief of symptoms
is needed.
Therapy with SSRIs significantly decreases the frequency of or
extinguishes panic attacks, lessens anticipatory anxiety, and
can even improve phobic symptoms (Ballenger et al., 1998;
Leinonen et al., 2000). Hyperarousal and psychological
numbing or avoidant symptoms of PTSD are more responsive to
SSRI therapy than re-experiencing the trauma (Brady et al.,
2000; Davidson, 2000). It may take eight to 12 weeks for full
therapeutic response for PD and PTSD. Maintenance therapy
for six months to one year has demonstrated efficacy in
preventing symptom relapse in PTSD and PD, respectively.
However, longitudinal studies conducted over a lifetime are
needed.
Generalized anxiety disorder and SAD are the most recent
disorders to demonstrate clear therapeutic benefit from SSRI
therapy (Ballenger, 2001; Brunello et al., 2000). Compared to
benzodiazepines, antidepressants are more effective for
psychic symptoms, like worries. Usual antidepressant doses are
effective after about one month of treatment. Duration of
therapy requires further study.
Venlafaxine. In 2000, Gelenberg et al. and Rickels et al.
published studies establishing venlafaxine extended release
(Effexor XR) as an effective, well-tolerated medication for
GAD. It is likely effective for SAD and PD as well, according to
positive clinical trials (Kelsey, 1995; Papp et al., 1998). Its

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efficacy for PTSD and OCD, however, requires further study. As
do SSRIs, venlafaxine can cause nausea, sexual dysfunction
and hyponatremia. In addition, dizziness, flushing and sweating
are possible side effects -- as is increased blood pressure,
particularly at doses >300 mg/day (Thase, 1998). When
initiating venlafaxine, gradual titration based on tolerability is
best (for example, venlafaxine XR 37.5 mg qam, increased by
37.5 mg to 75 mg weekly to a usual effective dose of between
150 mg/day and 225 mg/day).
Mirtazapine. Several reviews of small, uncontrolled trials and
case studies report efficacy for mirtazapine (Remeron) in
treating PTSD, PD and GAD, either alone or in combination with
SSRI therapy (Brunello et al., 2001; Falkai, 1999; Good and
Petersen, 2001). Mirtazapine increases noradrenergic outflow
pre-synaptically via -2 antagonism, in addition to modulating
serotonin function via post-synaptic 5-HT2 and 5-HT3
antagonism. Compared to SSRIs, it is not associated with
nausea or sexual dysfunction, but it can cause significant
sedation and weight gain. There are rare (0.1% to 1%) reports
of bone marrow suppression; thus, careful monitoring in
immunocompromised patients is required (Hutchison, 2001).
Mirtazapine's place in therapy requires further study.
Nefazodone. Several reviews of open trials and case reports
(Ballenger, 2001; Brunello et al., 2001) describe nefazodone
(Serzone) in antidepressant doses as a useful option in treating
GAD, PTSD and PD (Papp et al., 2000). Nefazodone modulates
serotonin through pre-synaptic reuptake inhibition and post-
synaptic 5-HT2 antagonism. Compared to SSRIs, nefazodone
causes less nausea, sexual dysfunction and restlessness, and it
causes more sedation, dry mouth and constipation. Case
reports describe successful remission of SSRI-associated
akathisia after switching to nefazodone (Chelben et al., 2001).
A controlled trial reported significantly less delayed ejaculation
and anorgasmia associated with nefazodone as compared to
paroxetine and sertraline (Waldinger et al., 2001). Recent
reports of nefazodone hepatotoxicty (Eloubeidi et al., 2000)
necessitate careful monitoring, patient counseling and
avoidance in patients with liver disease.
TCAs. Among the TCAs, imipramine (Tofranil) has the most well-
established efficacy for significantly decreasing symptoms of
PD, GAD and SAD, according to clinical trials (Charney et al.,
1986; Rickels et al., 1993) and several reviews (Ballenger,
2001; Brunello et al., 2000; Gorman, 2001). Other TCAs are
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likely effective for these three disorders as well, although
several researchers, including Goodman et al. (1990),
discovered that TCAs other than clomipramine were ineffective
for OCD.
The TCAs have third-line status in the treatment of anxiety
disorders due to toxicity in overdose and adverse effects that
include orthostasis, dry mouth, constipation, sedation and risk
of heart block that necessitates baseline and follow-up
electrocardiogram monitoring. Low initial dosing is
recommended, particularly in patients with PD, to improve
tolerability, although effective doses are within the
antidepressant dosing range (Ballenger et al., 1998).
MAOIs. The monoamine oxidase inhibitor phenelzine (Nardil)
has well-established efficacy for treating PD and SAD
(Ballenger et al., 1998; Brunello et al., 2000). It may be
effective for some patients with PTSD as well, although efficacy
studies are conflicting. Tranylcypromine (Parnate) is less well-
studied. Adverse effects such as dizziness, insomnia and
weight gain, in addition to drug interactions and dietary
restrictions, limit MAOI usefulness.
Benzodiazepines
Benzodiazepines are effective first-line treatments for PD, SAD
and GAD in select patients when rapid onset is essential and
substance abuse is not an issue. Daily benzodiazepine therapy
provides symptom relief with good tolerability in one to two
weeks for 60% to 70% of patients, according to reviews by
Ballenger (2001), Gorman (2001) and Brunello et al. (2000).
Compared to antidepressants, benzodiazepines are more
effective for physical symptoms of anxiety, particularly in the
first three weeks of treatment. Disadvantages of
benzodiazepines include the risk of memory problems,
decreased coordination and withdrawal symptoms upon abrupt
discontinuation, including nervousness, insomnia, restlessness,
nausea, lethargy and (rarely) seizures. Paradoxical reactions to
benzodiazepines are possible and include emotional lability,
agitation and occasionally rage reactions (Gutierrez et al.,
2001).
Benzodiazepine selection is based on each drug's
pharmacokinetic properties. For example, when qd or bid
dosing is preferred, clonazepam (t½: 20 hours to 50 hours) is a
good option. If drug accumulation is a concern, lorazepam
(Ativan) is preferred due to its intermediate half-life (10 hours
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to 20 hours). Alprazolam (Xanax) is the most-studied
benzodiazepine for PD, and it should be considered if
clonazepam is ineffective. Disadvantages of alprazolam include
a requirement for multiple daily dosing and a difficult and
potentially serious withdrawal (Ballenger et al., 1998; Gorman,
2001).
Inter-individual variability in response exists, meaning if
alprazolam is effective, equipotent doses of clonazepam may
or may not be effective (Rosenbaum, 1990). Clonazepam may
be less likely to produce a reinforcing euphoria, compared to
diazepam (Valium) or alprazolam. Risk of benzodiazepine abuse
must be assessed on a case-by-case basis. Personality
disorders, history of alcohol or substance abuse, and genetic
predisposition contribute to a likelihood of abuse. However,
benefits of benzodiazepine therapy far outweigh risks for many
patients with anxiety disorder who are unable to find relief with
antidepressants (Ballenger, 2001; Gorman, 2001; Shader and
Greenblatt, 1993).
Buspirone
Buspirone is a 5-HT1A receptor partial agonist with well-
documented efficacy for GAD (Ballenger, 2001). Buspirone is
ideal for GAD patients who cannot tolerate antidepressant
therapy and do not want the sedation, cognitive impairment or
adverse interaction with alcohol associated with
benzodiazepine therapy. Buspirone has not been shown to be
effective for other anxiety disorders (Apter and Allen, 1999)
except as an adjunct to SSRIs for some patients with OCD, SAD
and PTSD who are partial responders or who tend to suffer
sexual side effects. Disadvantages of buspirone compared to
benzodiazepines include delayed onset of effect (two to four
weeks) and poor patient satisfaction. Buspirone should be
initiated at 5 mg tid or 7.5 mg bid and titrated as tolerated to a
usual effective dose of between 20 mg/day and 40 mg/day.
Common adverse effects that typically subside with treatment
include jitteriness, dizziness, nausea and headache.
Anticonvulsants
Researchers have investigated GABAergic anticonvulsants like
valproate (Depakene) and gabapentin (Neurontin) for
anxiety disorders (Keck et al., 1993; Pande et al., 2000, 1999).
Three small, uncontrolled studies describe valproate as an
effective anti-panic treatment at doses between 500 mg/day
and 2250 mg/day (Primeau et al., 1990). Onset of therapeutic
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effect occurred between two and four weeks of treatment;
adverse effects were nausea, dizziness, drowsiness, tremor and
diarrhea. Valproate, carbamazepine (Tegretol) and
lamotrigine (Lamictal) were studied in small, uncontrolled
trials and described as effective for hyperarousal, aggression,
impulsivity and explosiveness associated with PTSD (Brunello
et al., 2001).
Gabapentin 600 mg/day to 3600 mg/day was compared to
placebo in separate trials studying PD and SAD. Only the most
severe PD patients responded, while the patients with SAD
improved significantly more than with placebo. Reported
adverse effects included somnolence, dizziness and nausea.
Until anticonvulsants are found comparable to standard
antidepressant or benzodiazepine therapy for anxiety
disorders, they should be considered for treatment-refractory
patients or if a comorbid condition warrants anticonvulsant
therapy.
Antipsychotics
Haloperidol (Haldol) and risperidone (Risperdal), two
antipsychotics with significant dopaminergic blockade, may be
useful adjuncts for patients with tics and OCD who fail SSRI
therapy, (McDougle et al., 1994; Stein et al., 1997). Patients
without tics did not benefit in these reports; however, one open
trial (Pfanner et al., 2000) reported significant benefit when
risperidone was added to SSRIs in 20 patients with OCD
refractory to SSRI therapy. Case reports have noted that
olanzapine (Zyprexa) and clozapine (Clozaril) may worsen
obsessive-compulsive symptoms (Mottard and de la
Sablonniere, 1999), although an open trial described
olanzapine as a useful adjunct to SSRI therapy in refractory
patients (Weiss et al., 1999). Clearly, antipsychotics should be
reserved for patients with psychosis or treatment-refractory
OCD, with careful monitoring to detect worsening of OCD
symptoms.
Herbals
The use of alternative therapies for chronic central nervous
system illnesses such as headaches, depression and anxiety is
increasing every year (Eisenberg et al., 1998). One survey
reported that 54% of psychiatric outpatients tried alternative
therapy to relieve both psychiatric and physical symptoms
(Knaudt et al., 1999). Common attitudes that herbal remedies
are "natural," have fewer side effects and are readily available
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contribute to their appeal to patients. Two herbal products
commonly used to self-medicate symptoms of anxiety are
valerian and kava kava. Clinicians should be aware of realistic
expectations of these remedies in addition to possible adverse
effects ).
Kava Kava (Piper methysticum). A meta-analysis
documented greater efficacy of kava versus placebo for anxiety
symptoms across several studies (Pittler and Ernst, 2000). One
of the most extensive randomized, placebo-controlled studies
evaluated the effects of kava in 100 patients diagnosed with
agoraphobia, specific phobia, GAD and adjustment disorder
with anxiety (Volz and Kieser, 1997). Patients treated with 70
mg kavalactones (the agent responsible for kava's psychotropic
properties) three times daily showed significant improvement
after eight weeks of treatment, with continued benefit at 24
weeks.
The recommended anxiolytic dose of kava is 50 mg to 70 mg
purified kavalactones or 100 mg to 250 mg dried kava root
extract, three times daily. Adverse effects of kava include
morning fatigue and mild gastrointestinal disturbances
(Pepping, 1999). Toxic doses (>300 g) may, however, cause
progressive ataxia, muscle weakness, ascending paralysis and
scaling of skin on the extremities (Singh and Blumenthal,
1997). Reports of hepatotoxicity are currently under
investigation by the FDA. Kava can potentiate the effects of
CNS depressants, including ethanol, barbiturates and
benzodiazepines; therefore, concomitant use should be
avoided. Finally, kava should be avoided during pregnancy due
to the potential for loss of uterine tone (Brinker, 1998). While
kava may be an effective and well-tolerated anxiolytic
compound for many patients, there is no evidence to suggest it
is more effective than antidepressants or benzodiazepines.
Valerian (Valeriana officinalis). Although used more often
for its hypnotic properties, valerian is taken to relieve mild
symptoms of anxiety (Hobbs, 1989). While there are no
controlled studies describing efficacy for any diagnosed anxiety
disorder, one paper (Kohnen and Oswald, 1988) reviewed
valerian's effects in 48 subjects placed under an experimental
social stress situation. These volunteers were randomized to
receive valerian 100 mg, propranolol (Inderal) 20 mg, both
agents or placebo administered 90 minutes before the
situation. Valerian alone had no effect on physiological

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activation or concentration, but it did decrease somatic
arousal.
Adverse effects associated with valerian include sedation and
withdrawal symptoms similar to benzodiazepine withdrawal
following abrupt discontinuation (Garges et al., 1998). Adverse
effects and toxicity have not been adequately studied;
however, four cases of hepatotoxicity associated with valerian
use have been reported (Plushner, 2000). Additional studies are
required to determine if valerian has any significant and
sustained anxiolytic properties.
Summary
Pharmacotherapy for anxiety disorders is shifting away from
benzodiazepines toward serotonergic antidepressants. Newer
antidepressants, particularly SSRIs and venlafaxine, are
increasingly utilized as first-line agents. Research shows that
they are effective, generally well-tolerated and have low risk of
abuse compared to benzodiazepines. Compared to buspirone,
serotonergic antidepressants offer a broader spectrum of
efficacy. They treat symptoms of PD, OCD, PTSD and comorbid
major depression in addition to GAD.
Benzodiazepines are still widely prescribed. They have
established efficacy for PD, GAD and SAD. Benzodiazepines
offer a more rapid onset of benefit without the risk of sexual
dysfunction associated with SSRIs and venlafaxine.
Anticonvulsants and some antipsychotics are useful adjuncts
for appropriate patients. Based on lack of controlled trials and
risk of toxicity, kava-kava and valerian cannot replace
established medicinal compounds.
Dr. Dopheide is associate professor of clinical pharmacy in
psychiatry

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