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Pharmacotherapy for generalized anxiety disorder in adults

Author: Alexander Bystritsky, MD, PhD
Section Editor: Murray B Stein, MD, MPH
Deputy Editor: Michael Friedman, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2021. | This topic last updated: Nov 10, 2020.

INTRODUCTION

Generalized anxiety disorder (GAD) is characterized by excessive worry and anxiety that are difficult to control, cause significant
distress and impairment, and occur on more days than not for at least six months [1].

GAD is a relatively common disorder, most often with onset during adulthood and a chronic course [2-5]. GAD can lead to significant
impairments in role functioning, diminished quality of life, and high healthcare costs [6,7]. The disorder can be effectively treated
with medication, psychotherapy, or a combination of the two modalities.

This topic addresses pharmacotherapy for GAD. The epidemiology, pathogenesis, clinical manifestations, course, and diagnosis of
GAD are described separately, as is psychotherapy for GAD. Anxiety disorders in children and adolescents is also described
separately. (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment,
and diagnosis" and "Psychotherapy for generalized anxiety disorder in adults" and "Anxiety disorders in children and adolescents:
Epidemiology, pathogenesis, clinical manifestations, and course" and "Pharmacotherapy for anxiety disorders in children and
adolescents" and "Psychotherapy for anxiety disorders in children and adolescents".)

Complementary and alternative treatments for anxiety symptoms and disorders are also discussed separately. (See "Complementary
and alternative treatments for anxiety symptoms and disorders: Herbs and medications" and "Complementary and alternative
treatments for anxiety symptoms and disorders: Physical, cognitive, and spiritual interventions".)

APPROACH TO TREATMENT

Our approach to selecting among treatments for generalized anxiety disorder, including the use of pharmacotherapy and
psychotherapy, is discussed separately. (See "Approach to treating generalized anxiety disorder in adults".)

SEROTONERGIC REUPTAKE INHIBITORS (SRI)

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are efficacious in the
treatment of generalized anxiety disorder (GAD).

In cases of co-occurring GAD and depression, a common comorbidity, SSRIs can provide effective treatment for both GAD and major
depression. Other medications efficacious for GAD, eg, benzodiazepines or pregabalin, are not effective treatments for depression.

Efficacy and side effects — There is a paucity of data available directly comparing different SRIs (including SSRIs versus SNRIs) for
GAD [8,9]. Trials have generally shown that all SRIs studied have the same degree of effectiveness, ie, response rates of
approximately 60 to 70 percent for the SRI, versus 40 percent for the placebo. The selection among SRIs can be customized to the
patient based on the drug’s side effect profile, drug-drug interactions, and/or patient treatment history/preference.

SSRIs — A network meta-analysis [10] and numerous randomized trials of patients with GAD have found selective SSRIs including
paroxetine [11-13], sertraline [14,15], citalopram, and escitalopram [16-18] to be more effective in anxiety reduction than placebo.
Uncontrolled trials and our clinical experience suggest other SSRIs (eg, fluoxetine and fluvoxamine) are effective for GAD as well. A
systematic review concluded that five patients with GAD would need to be treated with antidepressants (rather than placebo) for one
patient to achieve a clinical response (ie, number needed to treat = 5) [19].

As an example, the largest trial compared paroxetine at two fixed doses (20 and 40 mg/day) with placebo in 566 patients with GAD.
After eight weeks of treatment, both doses of paroxetine resulted in a greater reduction of anxiety symptoms than placebo (62 and
68 percent versus 46 percent, respectively). Rates of remission (defined as ≤7 on the Hamilton Rating Scale for Anxiety) followed the

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same pattern: 30 and 36 percent for patients receiving 20 and 40 mg/day of paroxetine groups, respectively, compared with 20
percent for patients receiving placebo [12]. Randomized trials have shown SSRIs maintain efficacy for at least six months [20]. Our
clinical experience has been that they work for a much longer time in this chronic condition.

SSRIs can produce side effects that interfere with the patient’s quality of life and medication adherence. Thus, side effects need to be
recognized and managed early in treatment. Individual SSRIs vary in their side effect profile, but common side effects include sexual
dysfunction, gastrointestinal abnormalities (nausea and diarrhea), insomnia and withdrawal on discontinuation. SSRIs can cause
drug interactions, weight gain, and agitation and/or hyperactivation. A table compares side effects of antidepressants ( table 1).
Management of SSRI side effects is described separately. (See "Selective serotonin reuptake inhibitors: Pharmacology,
administration, and side effects" and "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)

SNRIs — Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit serotonin and norepinephrine reuptake. Their efficacy and
tolerability is comparable to SSRIs and the use follows the same general guidelines. (See 'SSRIs' above.)

The SNRIs venlafaxine (extended-release [XR]) [21-23] and duloxetine [24,25] have been shown to be efficacious in network meta-
analysis [10] and randomized trials of patients with GAD:

● In a randomized trial of 541 outpatients with GAD, venlafaxine XR at fixed doses of 75 and 150 mg/day) has been found to be
efficacious compared with placebo on all primary outcome measures at 8 and 24 weeks [26].

● In four clinical trials, duloxetine has been shown to be effective in doses of 60 and 120 mg per day (though duloxetine is typically
started at 30 mg per day).

Longer-term trials have demonstrated efficacy for as long as six months [24,27].

Common side effects of SNRIs are nausea, dizziness, insomnia, sedation, constipation, and sweating. Venlafaxine may increase blood
pressure, usually to a small extent. Rates of 3 to 7 percent have been seen at doses of 100 to 300 mg/day, while the incidence of
increased blood pressure was 13 percent at daily doses >300 mg/day [28]. Typically, we ask patients with doses of venlafaxine of 150
mg per day or higher to monitor their blood pressure. If blood pressure is increased in most cases, we either add or modify
antihypertensive treatment. (See "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side
effects".)

Administration — Therapeutic doses of SSRI and SNRIs are approximately the same as for the treatment of depression. Starting
doses from the lower end of the recommended range should be used to avoid initial agitation ( table 2). Time to onset of clinically
meaningful action for an SRI varies by patient, but averages approximately four weeks. The initial therapeutic dose should be
continued for four to six weeks. If the patient does not show a robust response, the SRI should be increased in one- to two-week
increments until sufficient improvement is seen or the maximum recommended or highest tolerated dose is reached ( table 2).
(See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Dose'.)

BUSPIRONE

The azapirone buspirone has been shown in clinical trials to reduce symptoms of anxiety in patients with generalized anxiety
disorder (GAD), offering similar efficacy to benzodiazepines without the risk of dependence. Buspirone is thought to affect the
serotonergic system via blockade of 5HT1A autoreceptors.

A meta-analysis of eight clinical trials in patients with GAD found buspirone to reduce anxiety symptoms compared with placebo [29].
As an example, a clinical trial first treated 44 patients with GAD with lorazepam (a benzodiazepine) for five weeks and then randomly
assigned them to receive 15 mg/day of buspirone or placebo, with a tapering off of the benzodiazepine [30]. After eight weeks,
patients receiving buspirone experienced reduced anxiety symptoms compared with placebo, and comparable to lorazepam.
Buspirone had fewer side effects compared with lorazepam.

Buspirone’s time to onset is longer than benzodiazepines’ and similar to the antidepressants’ average of four weeks. In our
experience, it has a weaker anxiolytic effect than benzodiazepines. These factors have limited its use by psychiatrists largely to
augmentation of selective serotonin reuptake inhibitors for GAD, though it remains a popular treatment for GAD among primary
care practitioners. Buspirone can be used as monotherapy (in the absence of comorbid major depression) or for augmentation at
doses of 10 to 60 mg/day ( table 2). Typical side effects can include insomnia, agitation, and nausea.

PREGABALIN

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Pregabalin has shown efficacy for generalized anxiety disorder (GAD) in comparison with placebo in several randomized trials [31-
36]. Pregabalin inhibits calcium currents via high-voltage-activated channels containing the a2d-1 subunit, though the relationship of
this mechanism to its efficacy in GAD is not known. It was approved in 2006 for the treatment of anxiety in Europe [37,38]. Pregabalin
is not approved for treating GAD by the US Food and Drug Administration. The doses for pregabalin range from 50 to 300 mg,
though many patients may need a total daily dose of greater than 150 mg ( table 2). Side effects include sedation and dizziness.
Tolerance, withdrawal, and dependence are possible, but pregabalin is generally better tolerated than benzodiazepines ( table 2).

BENZODIAZEPINES

Benzodiazepines have been found to be efficacious in the treatment of generalized anxiety disorder (GAD), generally leading to a
reduction of emotional and somatic symptoms within minutes to hours, depending on the specific medication ( table 3) [39,40].
However, concerns about risks of dependence and tolerance have contributed to a decline in their use [11,22]. A large observational
study of treatment of United States patients with GAD (without comorbidity) found that between 1989 to 1991 and 1996
benzodiazepine use declined and antidepressant use increased [41].

While benzodiazepines should be used with caution, and avoided in patients with a history of a substance use disorder, their use
need not be entirely avoided. They may be used for acute, maintenance, or long-term treatment of GAD, either as monotherapy or,
more commonly, as an adjunct to antidepressant treatment. Benzodiazepines are most commonly used in GAD for acute
management of anxiety and worry during the period before selective serotonin reuptake inhibitors (SSRIs) or serotonin-
norepinephrine reuptake inhibitors take effect. They can counteract the initial agitation often caused by the SSRI. Once the patient
responds to the SSRI, the benzodiazepine can be tapered off gradually. Antidepressants are preferred over benzodiazepines when
depression, a common comorbidity of GAD, is also present, because antidepressants are effective treatments for both conditions.
(See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and
diagnosis".)

Patients with chronic GAD, minimal current depressive symptoms, and no history of a substance use disorder are candidates for
long-term, low-dose benzodiazepine treatment if antidepressants are ineffective or poorly tolerated [42]. Some patients respond well
to chronic treatment with benzodiazepines, do not develop tolerance to their anxiolytic effects, which would require dose increase
and experience only mild, tolerable withdrawal symptoms when the medication is tapered off. Patients who develop rapid tolerance,
increase their doses against medical advice, or exhibit withdrawal symptoms between doses are not good candidates for chronic
benzodiazepine treatment. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management".)

Pharmacology — Benzodiazepines exert their principal pharmacodynamic effect via central nervous system GABA receptors,
potentiating the effects of endogenous GABA, the main inhibitory neurotransmitter. GABA receptors are membrane-bound proteins
divided into three subtypes, GABAA, GABAB, and GABAC receptors. The GABAA receptors are composed of five subunits that
together form the chloride channel, which primarily mediates neuronal excitability (seizures), rapid mood changes, clinical anxiety,
and sleep. GABAB receptors mediate memory, mood, and analgesia. The role of the GABAC receptors remains unclear [43].
Flumazenil, a benzodiazepine antagonist, interacts with GABAA receptors [44] and is used clinically to rapidly reverse the effects of
benzodiazepine overdoses [45]. (See "Benzodiazepine poisoning and withdrawal", section on 'Antidote (flumazenil)'.)

Although they share many class effects, unique properties of individual benzodiazepines have clinical significance. These
pharmacologic differences among the benzodiazepines include the rapidity of onset (distributional half-life), persistence of active
drug and/or metabolite in the body (elimination half-life), major metabolic breakdown pathways (conjugation versus oxidation), and
specific molecular structure (eg, alprazolam has a unique triazole ring that may account for some difference in its clinical effects)
[45]. These differences are summarized in a table for the most widely used benzodiazepines, along with clinically important
pharmacologic characteristics related to the use and abuse of the benzodiazepines ( table 3) [46].

Some benzodiazepines (alprazolam, diazepam, midazolam, triazolam) can lead to elevated methadone peak levels and possibly other
drug interactions via common cytochrome P450 3A4 oxidation pathways in the liver. Oxazepam, lorazepam, and temazepam, which
are metabolized primarily via conjugation and cleared largely by the kidneys, have fewer P450 interactions and are better choices for
patients taking multiple medications, on methadone, or with compromised liver function [47].

Efficacy and side effects — A meta-analysis of 23 clinical trials found benzodiazepines to be efficacious in the treatment of GAD
compared with placebo. A meta-analysis of three clinical trials found the efficacy of benzodiazepines to be comparable to the
antidepressants. A limitation of benzodiazepine trials is that they were conducted in patients diagnosed with the DSM-III definition of
GAD, which differs significantly from the contemporary DSM-5 diagnostic criteria. In our clinical experience, however, the efficacy of
benzodiazepines in patients diagnosed with DSM-5 GAD is evident within minutes of taking a more-rapid onset benzodiazepine.

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Side effects of benzodiazepines include impairment of psychomotor performance, amnesia, dependence and withdrawal symptoms
after long-term treatment, and rebound anxiety after short-term treatment [48]. Withdrawal and cognitive or learning impairment
are more likely for persons taking higher doses.

Persistence of a benzodiazepine (or an active metabolite) in the body governs the timing of withdrawal onset in patients who have
used benzodiazepines every day for prolonged periods. Benzodiazepines with shorter elimination half-lives (eg, alprazolam,
lorazepam, and oxazepam) are more likely to produce acute withdrawal on abrupt cessation after prolonged use. Benzodiazepines
with longer elimination half-lives (eg, clorazepate, diazepam, flurazepam, prazepam, and clonazepam) usually produce more delayed
and somewhat attenuated withdrawal symptoms.

Administration — Benzodiazepines are generally started at a low dose and titrated up as needed based on response. As examples:

● Clonazepam can be started at 0.25 to 0.5 mg orally once or twice daily and titrated up to 1 mg two or three times daily as
needed.

● Diazepam can be started at 2.5 to 5 mg orally once or twice daily and titrated up to 10 mg two or four times daily as needed.

● Lorazepam, a benzodiazepine with an intermediate onset of action and shorter half-life, can be started at 0.5 to 1 mg orally three
times daily and titrated up to 1.5 mg four times daily as needed.

A table provides information on benzodiazepines’ dosing, comparative potency, onset, metabolism, and elimination half-life (
table 3).

Tapering off benzodiazepines is usually done very slowly, at approximately a 10 percent dose reduction per one to two weeks, if
circumstances allow. The prescriber should monitor the patient for symptoms of benzodiazepine withdrawal or relapse of GAD and
slow the rate of dose reduction accordingly. Early signs of withdrawal include anxiety, dysphoria, and tremor; advanced
manifestations include perceptual disturbances, psychosis, and seizures. (See "Benzodiazepine poisoning and withdrawal".)

OTHER MEDICATIONS

A significant proportion of generalized anxiety disorder (GAD) patients fail to improve or have residual symptoms in response to
multiple trials of the medications above [11,22]. Other medications have been used as monotherapy or augmenting agents for
treatment-resistant GAD despite variable levels of supporting evidence [49]. These include other antidepressants, atypical
antipsychotics, anticonvulsants, and hydroxyzine. Dosing and characteristics of medications for GAD are provided in a table (
table 2). (See "Approach to treating generalized anxiety disorder in adults".)

Other antidepressants — Imipramine, a tricyclic antidepressant (TCA), has been shown to be efficacious in treatment of patients
with generalized anxiety disorder, including those without comorbid depression or panic disorder ( table 2) [19]. Selective
serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally preferred over TCAs
because the latter have an increased risk of cardiotoxicity in overdose and less acceptable tolerability profiles [50]. (See "Tricyclic and
tetracyclic drugs: Pharmacology, administration, and side effects".)

In our clinical experience, mirtazapine, a sedating antidepressant, may be useful in the treatment of refractory anxiety with
insomnia. Sedation and weight gain are two prominent side effects of this agent. Clinical trials on the use of mirtazapine in GAD are
insufficient to determine efficacy; the US Food and Drug Administration has not approved mirtazapine for GAD [51].

Clinical trials have found vilazodone, a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist, to be as
efficacious as other SRIs in GAD [52,53]; in our clinical experience vilazodone has no unique advantages compared with other SSRIs.
Vortioxetine has shown mixed results compared with placebo in clinical trials for GAD [53,54].

Antipsychotic medications — Another potential pharmacologic treatment strategy for treatment resistant GAD involves the use of
second-generation antipsychotic medication. Several randomized clinical trials support the use of atypical neuroleptics in GAD, either
as part of an augmentation strategy or as single agents [55]. Quetiapine has been used for GAD, but has not been approved for the
disorder by the US Food and Drug Administration.

Adverse side effects associated with second generation antipsychotics include sedation, extrapyramidal symptoms, and tardive
dyskinesia (TD) ( table 1). Other side effects associated mainly with second-generation antipsychotics include weight gain and
elevation of glucose and lipid levels. Because of the likelihood of these types of adverse effects, atypical antipsychotics should be
considered (usually adjunctively to an SSRI or SNRI) for treatment resistant GAD after safer alternatives have been exhausted. (See
"First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation

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antipsychotic medications: Pharmacology, administration, and side effects" and "Tardive dyskinesia: Etiology, risk factors, clinical
features, and diagnosis".)

Anticonvulsants — Tiagabine has not been found to be superior to placebo for GAD in three randomized trials [56]. There have
been no clinical trials of gabapentin for GAD, which has been tested in other anxiety disorders. (See "Pharmacotherapy for social
anxiety disorder in adults" and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)

Hydroxyzine — Hydroxyzine may be used for short-term or immediate control of anxiety symptoms until maintenance therapy is
effective. We suggest 25 to 50 mg orally up to four times daily. In a meta-analysis of five trials with 884 patients, hydroxyzine
appeared efficacious for GAD, though the analysis suggested a high risk of bias [57]. Hydroxyzine was found to be more sedating
than benzodiazepines and buspirone, and thus potentially useful for treating insomnia associated with GAD.

DURATION OF PHARMACOTHERAPY

If effective, antidepressant treatment for generalized anxiety disorder (GAD) should be continued for at least 12 months rather than
the 6 months supported by previous research [58]. In a randomized trial, 136 patients with GAD who experienced reduced anxiety
during six months of treatment with venlafaxine extended-release (XR) were assigned to continue the medication or to placebo for
an additional six months [59]. Patients continuing venlafaxine XR had a much lower rate of relapse during the second six months
than patients receiving placebo (9.8 versus 53.7 percent). Incidence rates of side effects during the second six months compared with
the first six months were lower, did not differ statistically between drug and placebo patients, and included no new side effects.

If the patient experiences a relapse following termination of an effective medication, the length of treatment can be extended. After
two relapses when tapering off the medication, ongoing maintenance treatment should be considered.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Anxiety and anxiety disorders in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at
the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical
jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your
patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of
interest.)

● Basics topics (see "Patient education: Generalized anxiety disorder (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Our approach to selecting among treatments for generalized anxiety disorder, including the use of pharmacotherapy and
psychotherapy, is discussed separately. (See "Approach to treating generalized anxiety disorder in adults".)

● This topic describes the efficacy, side effects, and administration of medications in the treatment of generalized anxiety disorder
(GAD). Cognitive behavioral therapy (CBT) for GAD is described separately. (See "Psychotherapy for generalized anxiety disorder
in adults", section on 'Cognitive-behavioral therapy'.)

● Serotonergic reuptake inhibitors (SRIs), which include selective serotonin reuptake inhibitors (SSRIs) and serotonin-
norepinephrine reuptake inhibitors (SNRIs), are efficacious in the treatment of GAD. No one SRI (or subclass) has been found to
be more efficacious than another; selection of a specific SRI is typically customized to the patient based on the drug’s side effect
profile, drug-drug interactions, and/or patient treatment history/preference. (See 'Serotonergic reuptake inhibitors (SRI)' above.)

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• As examples, treatment with paroxetine can be initiated at 20 mg per day. The dose can be titrated up in increments of 10
mg, to a maximum of 50 mg/day.

• Extended-release venlafaxine has been shown to be effective at 75 and 150 mg/day and duloxetine in doses of 60 and 120
mg per day (though duloxetine is typically started at 30 mg per day).

• Further dosing, side effects and other characteristic that differ across SRIs are described in tables ( table 1 and table 2).

● Patients who experience a good clinical response to an antidepressant for GAD should continue the medication for at least 12
months to prevent relapse or recurrence. (See 'Duration of pharmacotherapy' above.)

● Buspirone has been shown in clinical trials to reduce symptoms of anxiety in patients with GAD, offering similar efficacy to
benzodiazepines without the risk of physiologic dependence. Typical side effects can include insomnia, agitation, and nausea.
(See 'Buspirone' above.)

● Pregabalin has shown efficacy for GAD in several randomized trials in doses from 50 to 300 mg per day ( table 2). Side effects
include sedation and dizziness. Tolerance, withdrawal, and dependence are possible, but pregabalin is generally better tolerated
than benzodiazepines. (See 'Pregabalin' above.)

● Benzodiazepines are efficacious for acute and long-term treatment of GAD, but should generally be reserved for patients
without a history of a substance use disorder. They may also be useful for acute symptoms during the period before an SSRI
takes effect, or as an adjunct for partial responders to SSRIs or SNRIs ( table 3). (See 'Benzodiazepines' above.)

As an example, clonazepam can be started at 0.25 to 0.5 mg orally one or two times daily and titrated up to 1 mg two or three
times daily based on response.

● For GAD patients with a co-occurring SUD, hydroxyzine (50 to 100 mg) or pregabalin are non-addictive drugs with efficacy in GAD
that can be used for insomnia. (See 'Pregabalin' above and 'Hydroxyzine' above and "Approach to treating generalized anxiety
disorder in adults".)

● Other medication with efficacy in GAD include tricyclic antidepressants, benzodiazepines, mirtazapine, and quetiapine. These
drugs may have comparable efficacy to the SRIs, but are typically more poorly tolerated due to adverse effects. (See 'Other
medications' above.)

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56. Pollack MH, Tiller J, Xie F, Trivedi MH. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized,
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GRAPHICS

Side effects of antidepressant medications [1-6]

Orthostatic QTc Gastrointestinal Weight Sexual

Drug Anticholinergic Drowsiness Insomnia/agitation
hypotension prolongation* toxicity gain dysfunction

Selective serotonin reuptake inhibitors (SSRIs) ¶

Citalopram 0 0 1+ 1+ 3+ Δ 1+ ¶ 1+ 3+

Escitalopram 0 0 1+ 1+ 2+ 1+ ¶ 1+ 3+

Fluoxetine 0 0 2+ 1+ 1+ 1+ ¶ 0 3+

Fluvoxamine 0 1+ 1+ 1+ 1+ 1+ ¶ 1+ 3+

Paroxetine 1+ 1+ 1+ 2+ 0 to 1+ 1+ ¶ 2+ 4+

Sertraline 0 0 2+ 1+ 1 to 2+ 2+ ¶ ◊ 1+ 3+

Atypical agents

Agomelatine § 0 1+ 1+ 0 0 1+ 0 0 to 1+
(not available in
United States)

Bupropion 0 0 2+ (immediate release) 0 1+ 1+ 0 0

1+ (sustained release)

Mirtazapine 1+ 4+ 0 0 1+ 0 4+ 1+

Serotonin-norepinephrine reuptake inhibitors (SNRIs) ¶ , ¥

Desvenlafaxine ‡ 0 0 1+ 0 0 2+ Unknown 1+

Duloxetine 0 0 1+ 0 0 2+ ¶ 0 to 1+ 1+

Levomilnacipran ‡ 0† 0 0 to 1+ 0 to 1+ 0 2+ ¶ 0 1+

Milnacipran ‡ 0 1+ 0 0 0 2+ ¶ 0 1+

Venlafaxine ‡ 0 1+ 1+ 0 1 to 2+ 2+ 0 to 1+ 3+

Serotonin modulators

Nefazodone** 1+ 2+ 0 1+ 0 2+ 0 0

Trazodone 0 4+ 0 1+ (hypnotic 1 to 2+ 1+ (hypnotic dose) 0 (hypnotic 1+ ¶¶

dose) 3+ (antidepressant dose)
3+ dose) 1+
(antidepressant (antidepressant
dose) dose)

Vilazodone 0 0 2+ 0 0 4+ ΔΔ 0 2+

Vortioxetine 0 0 0 0 0 3+ 0 1+

Tricyclic and tetracyclic antidepressants (TCAs)

Amitriptyline 4+ 4+ 0 3+ 1 to 2+ 1+ ◊◊ 4+ 3 to 4+

Amoxapine 2+ 2+ 2+ 2+ 1+ 0 ◊◊ 2+ ND

Clomipramine 4+ 4+ 1+ 2+ 3+ 1+ ◊◊ 4+ 4+

Desipramine 1+ 2+ 1+ 2+ 1 to 2+ 0 ◊◊ 1+ ND

Doxepin 3+ 3+ 0 2+ 3+ 0 ◊◊ 4+ 3+

Imipramine 3+ 3+ 1+ 4+ 3+ 1+ ◊◊ 4+ 3+

Maprotiline 2+ 3+ 0 2+ 1+ 0 ◊◊ 2+ ND

Nortriptyline 2+ 2+ 0 1+ 1 to 2+ 0 ◊◊ 1+ ND

Protriptyline 2+ 1+ 1+ 2+ 1+ 1+ ◊◊ 1+ 3 to 4+

Trimipramine 4+ 4+ 1+ 3+ 1+ 0 ◊◊ 4+ ND

Monoamine oxidase inhibitors

Isocarboxazid 1+ 1+ 2+ 2+ 0 1+ 1+ 4+

Phenelzine 1+ 2+ 1+ 3+ 0 1+ 2+ 4+

Selegiline 1+ 0 1+ 1+ 0 0 0 0

Tranylcypromine 1+ 1+ 2+ 2+ 0 1+ 1+ 4+

Scale: 0 = none; 1+ = slight; 2+ = low; 3+ = moderate; 4+ = high; ND = inadequate data.

* Relative mean QTc prolongation at therapeutic doses; arrhythmogenic potential can be significantly increased in overdose (eg, for cyclic antidepressants, bupropion, citalopram, duloxetine,
venlafaxine, and some others). QTc prolongation classifications are based upon US Food & Drug Administration guidance. [8] The use of other classification criteria may lead to some agents
being classified differently by other sources. Refer to UpToDate topics on acquired long QT syndrome and acute antidepressant poisonings.
¶ All SSRIs and SNRIs can cause transient nausea and gastrointestinal discomfort when starting therapy or increasing dose.
Δ Based upon reports of dose related QTc prolongation and arrhythmia, the maximum recommended dose of citalopram is 40 mg/day in most patients; for patients at increased risk of
elevated serum concentrations (eg, age >60 years, significant hepatic impairment, receiving interacting medications) the maximum daily dose is 20 mg.
◊ Sertraline is associated with higher rates of diarrhea.
§ Agomelatine may be hepatotoxic and is contraindicated in any degree of liver impairment. Transaminase monitoring is required.
¥ SNRIs do not have significant anticholinergic effects. However, SNRIs can produce anticholinergic-like effects (which appear to be mediated by noradrenergic stimulation) such as dry mouth
and constipation, and should be used with caution in narrow angle glaucoma. Levomilnacipran is associated with urinary hesitancy.
‡ May cause persistent dose-related increases in blood pressure (primarily diastolic) and heart rate. Monitor blood pressure regularly.
† Levomilnacipran can cause dose-dependent urinary hesitancy.
** Caution: can cause liver failure; transaminase monitoring is required. Withdrawn from market due to hepatotoxicity in many countries.
¶¶ Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to UpToDate topic on Serotonin modulators.
ΔΔ Gastrointestinal effects include nausea, vomiting, and diarrhea.
◊◊ Gastrointestinal forms of anticholinergic side effects include: dry mouth, constipation, epigastric distress, decreased esophagogastric tone. Refer to "Anticholinergic" data column for
frequency rankings.

References:
1. Wenzel-Seifert K, Wittmann M, Haen E: QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int 2011; 108:687.

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2. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction associated with second generation antidepressants in patients with major depressive disorder: Results from a systematic
review with network meta-analysis. Drug Saf 2014; 37:19.
3. Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf 2011; 34:709.
4. Lexicomp Online. Copyright © 1978-2021 Lexicomp, Inc. All Rights Reserved.
5. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol
2016; 30:242.
6. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug Administration,
June 2017; available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf.
7. The American Psychiatric Association Publishing Textbook of Psychopharmacology, 5th ed, Schatzberg AF, Nemeroff CB (Eds), American Psychiatric Association Publishing 2017.

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Pharmacology of medicines for treatment of adults with generalized anxiety disorder (GAD)

Initial daily Effect on

Daily oral dose Primary Selected characteristics relevant to treatment of adults
Drug oral dose metabolism of
range (mg)* metabolism Δ with GAD
(mg)* other drugs Δ

Selective serotonin reuptake inhibitor (SSRI) antidepressants

Applies to all SSRIs: Onset of effect may be delayed 2 to 4 weeks or more. Adverse effects among the SSRIs include: Nausea, diarrhea, insomnia/agitation, somnolence, impaired sexual
function, and hyponatremia. Adverse effects of individual agents are presented in a separate table in UpToDate.

Citalopram 10 10 to 40 CYP3A4, 2C19 None Lower risk of insomnia/agitation

Few drug interactions
Can prolong QT interval with increasing blood levels

Escitalopram 5 to 10 10 to 20 CYP3A4, 2C19 None Lower risk of insomnia/agitation

Few drug interactions

Sertraline 25 to 50 50 to 200 Limited (minor None Greater risk of insomnia/agitation

CYP2C9, 2D6, and More frequent diarrhea and other gastrointestinal complaints
3A4)

Paroxetine 10 to 20 20 to 50 CYP2D6 Inhibits 2D6 Mildly sedating

Weakly anticholinergic
Lower risk of insomnia/agitation
Withdrawal symptoms if not tapered

Fluoxetine 10 to 20 20 to 60 CYP2D6, 2C9, and Inhibits CYP2D6, Greater risk of insomnia/agitation

several minor 2C19 No withdrawal symptoms if not tapered
Takes weeks to reach steady blood levels due to long half-life

Fluvoxamine 50 100 to 300 CYP1A2, 2D6 Inhibits CYP1A2, Lower risk of insomnia/agitation
2C19 Withdrawal symptoms if not tapered
Significant drug interactions

Serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants

Onset of effect and adverse effects of the SNRIs are similar to the SSRIs (see above). Adverse effects of individual agents are presented in a separate table in UpToDate.

Duloxetine 30 60 to 120 CYP1A2, 2D6 Inhibits CYP2D6 Greater risk of insomnia/agitation

Useful for treatment of comorbid painful conditions
Withdrawal symptoms if not tapered

Venlafaxine 75 75 to 225 CYP2D6, 3A4 None Greater risk of insomnia/agitation

(extended- Increased blood pressure (primarily diastolic) and heart rate with
release) increasing doses
Useful for treatment of comorbid painful conditions
Few drug interactions
Withdrawal symptoms if not tapered

Other

Buspirone 10 mg in divided 10 to 60 mg in CYP3A4 None A nonbenzodiazepine anxiolytic

doses divided doses Augmentation choice for partial response to antidepressant
Slow onset and modest efficacy
Lacks tolerance, dependence, and withdrawal
Ineffective for comorbid major depression

Pregabalin 50 mg in divided 50 to 300 mg in Dependent on None A GABA analog calcium-channel modulator anticonvulsant
doses divided doses renal function for Onset within days of starting treatment
clearance Approved for treatment of anxiety in some countries (not United
States)
Sedation and dizziness
Tolerance, dependence, and withdrawal possible
Schedule V controlled substance in United States
Many patients require >150 mg/day, up to 300 mg/day

Mirtazapine 15 15 to 60 CYP1A2, 2D6, 3A4 None An atypical antidepressant

Alternate or augmentation choice for anxiety with insomnia
Sedating; notably increases appetite

Quetiapine 25 to 50 50 to 300 CYP3A4 None A second generation antipsychotic (SGA)

Potential augmentation choice for partial response to antidepressant
or alternate as monotherapy
Sedation, extrapyramidal effects, weight gain, and metabolic side
effects (see separate table on SGA adverse effects)
Rarely tardive dyskinesia

Hydroxyzine 50 mg at bedtime 25 to 50 mg three None None A sedating antihistamine with anxiolytic properties
to four times per Augmentation option for treatment of insomnia
day as needed Anticholinergic side-effects with increasing doses

Imipramine 75 mg in divided 75 to 200 mg in CYP2C19, 2D6 None A tricyclic antidepressant

doses divided doses Anticholinergic side effects
Cardiotoxic in overdose
May be poorly tolerated relative to SSRI and SNRI antidepressants

The pharmacology of benzodiazepines used for treatment of adults with generalized anxiety disorder is presented in a separate table in UpToDate.

CYP: cytochrome P450; GABA: gamma aminobutyric acid.

* A 50% dose reduction and gradual titration is suggested for older adults and individuals sensitive to adverse effects such as nausea, dizziness, headache, and initial insomnia/activation due
to antidepressants.
Δ Data provided on drug metabolism are included to assess the potential for drug interactions. Only strong or moderate effects on other drugs are listed. These classifications are based upon

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US Food and Drug Administration (FDA) guidance. Other sources may use a different classification system resulting in some agents being classified differently. Specific drug interactions and
management suggestions may be determined by use of Lexi-Interact, the drug interactions program included with UpToDate.

Prepared with data from:

1. World Federation of Societies of Biological Psychiatry (WFSBP), "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First
Revision," World J Biol Psychiatry. 2008; 9(4):248-312.
2. Bandelow B, Sher L, Bunevicius R, et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J
Psychiat Clin, 2012; 16:77.

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Pharmacology of benzodiazepines used to treat anxiety symptoms/disorders

Adult oral total daily Comparative potency Onset after oral dose Elimination half-life
Drug Metabolism
dose (mg)* (mg) ¶ (hours) (hours) Δ

Alprazolam 0.5 to 6 0.5 1 CYP3A4 to minimally active 11 to 15

metabolites. 16 (older adults)
Alprazolam extended 0.5 to 6 once daily 0.5 1
release 20 (hepatic impairment)
22 (obesity)

Bromazepam פ 6 to 30 7.5 1 CYP1A2. No active 8 to 20

metabolite.

Chlordiazepoxide § 5 to 100 10 1 CYP3A4 to active 30 to 100

metabolites. Prolonged in older adults
and hepatic impairment

Clonazepam 0.5 to 4 0.25 to 0.5 0.5 to 1 CYP3A4. No active 18 to 50

metabolite.

Clorazepate 15 to 60 7.5 0.5 to 1 CYP3A4 to active metabolite. 36 to 200

Diazepam 4 to 40 5 0.25 to 0.5 CYP2C19 and 3A4 to active 50 to 100

metabolites. Prolonged in older adults
and renal or hepatic
impairment

Lorazepam 0.5 to 6 1 0.5 to 1 Non-CYP glucuronidation in 10 to 14

0.5 to 4 (hypnotic) liver. No active metabolite.

Oxazepam 30 to 120 15 to 30 1 to 2 Non-CYP glucuronidation in 5 to 15

15 to 30 (hypnotic) liver. No active metabolite.

Prazepam פ 15 to 60 15 2 to 3 CYP3A4 to active 30 to 200

metabolites. Prolonged in older adults

Data on drug metabolism and activity of metabolite(s) are for assessment of potential for CYP drug interactions and risk of accumulation. Risk of accumulation is greater, and dose
reduction necessary, for older or debilitated adults and for patients with renal or hepatic insufficiency.

* Range of usual total daily dose for treatment of adults with anxiety or panic disorder typically given in divided doses two to four times daily.
¶ Important: Data shown are approximate equal potencies relative to lorazepam 1 mg orally and are NOT recommendations for initiation of therapy or for conversion between agents.
Δ Half-life of parent drug and pharmacologically active metabolite, if any.
◊ Not available in US.
§ Use only when other preferred agents are unavailable or not tolerated.

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Contributor Disclosures
Alexander Bystritsky, MD, PhD Nothing to disclose Murray B Stein, MD, MPH Equity Ownership/Stock Options: Oxeia Biopharmaceuticals
[Traumatic Brain Injury]; Epivaro [Substance use disorders and PTSD]. Consultant/Advisory Boards: Acadia Pharmaceuticals [Anxiety and traumatic
stress-related disorders]; Aptinyx [Anxiety and traumatic stress-related disorders]; Bionomics [Anxiety and traumatic stress-related disorders];
BioXcel Therapeutics [Anxiety and traumatic stress-related disorders]; Clexio [Anxiety and traumatic stress-related disorders]; EmpowerPharm
[Anxiety and traumatic stress-related disorders]; GW Pharma [Anxiety and traumatic stress-related disorders]; GABA Therapeutics [Anxiety and
traumatic stress-related disorders]; Janssen [Anxiety and traumatic stress-related disorders]; Jazz Pharmaceuticals [Anxiety and traumatic stress-
related disorders]; Oxeia Biopharmaceuticals [Traumatic brain injury]. Michael Friedman, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-
level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required
of all authors and must conform to UpToDate standards of evidence.

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