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Diagnosis and Management of Generalized Anxiety Disorder and Panic Disorder in Adults AMY B. LOCKE, MD, FAAFP; NELL KIRST, MD; and CAMERON G. SHULTZ, PhD, MSW, University of Michigan Medical School, Ann Arbor, Michigan

G eneralized anxiety disorder (GAD) and panic disorder (PD) are among the most common mental disorders in the United

States and are often encountered by primary care physicians. The hallmark of GAD is excessive, out-of-control worry, and PD is characterized by recurrent and unexpected panic attacks. Both conditions can negatively impact a patient’s quality of life and disrupt important activities of daily living. The rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms often ascribed to physical causes.

This article reviews the diagnosis and management of GAD and PD in adults. Diagnosis and care of children and adoles- cents with these conditions require special considerations that are beyond the scope of this review.

Epidemiology, Etiology, and Pathophysiology The 12-month prevalence for GAD and PD among U.S. adults 18 to 64 years of age is 2.9% and 3.1%, respectively. In this popu- lation, the lifetime prevalence is 7.7% in women and 4.6% in men for GAD, and is 7.0% in women and 3.3% in men for PD.1

The etiology of GAD is not well under- stood. There are several theoretical models, each with varying degrees of empirical sup- port. An underlying theme to several mod- els is the dysregulation of worry. Emerging evidence suggests that patients with GAD may experience persistent activation of areas of the brain associated with mental activity and introspective thinking following worry- inducing stimuli.2 Twin studies suggest that environmental and genetic factors are likely involved.3

Generalized anxiety disorder (GAD) and panic disorder (PD) are among the most common mental disorders in the United States, and they can negatively impact a patient’s quality of life and disrupt important activities of daily living. Evidence suggests that the rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms often ascribed to physical causes. Diagnosing GAD and PD requires a broad differential and caution to identify confound- ing variables and comorbid conditions. Screening and monitoring tools can be used to help make the diagnosis and monitor response to therapy. The GAD-7 and the Severity Measure for Panic Disorder are free diagnostic tools. Suc- cessful outcomes may require a combination of treatment modalities tailored to the individual patient. Treatment often includes medica- tions such as selective serotonin reuptake inhibitors and/or psycho- therapy, both of which are highly effective. Among psychotherapeutic treatments, cognitive behavior therapy has been studied widely and has an extensive evidence base. Benzodiazepines are effective in reducing anxiety symptoms, but their use is limited by risk of abuse and adverse effect profiles. Physical activity can reduce symptoms of GAD and PD. A number of complementary and alternative treat- ments are often used; however, evidence is limited for most. Several common botanicals and supplements can potentiate serotonin syn- drome when used in combination with antidepressants. Medication should be continued for 12 months before tapering to prevent relapse. (Am Fam Physician. 2015;91(9):617-624. Copyright © 2015 American Academy of Family Physicians.)

CME This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions on page 606.

Author disclosure: No rel- evant financial affiliations.

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Patient information: http://www.aafp.org/afp/ 2015/0501/p617-s1.html.

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The etiology of PD is also not well under- stood. The neuroanatomical hypothesis sug- gests that a genetic-environment interaction is likely responsible. Patients with PD may exhibit irregularities in specific brain struc- tures, altered neuronal processes, and dys- functional corticolimbic interaction during emotional processing.4

Typical Presentation and Diagnostic Criteria GENERALIZED ANXIETY DISORDER

Patients with GAD typically present with excessive anxiety about ordinary, day-to- day situations. The anxiety is intrusive, causes distress or functional impairment, and often encompasses multiple domains (e.g., finances, work, health). The anxiety is often associated with physical symptoms, such as sleep disturbance, restlessness, mus- cle tension, gastrointestinal symptoms, and chronic headaches.5 Diagnostic and Statistical Manual of Mental Disorders, 5th ed, (DSM-5) diagnostic criteria for GAD are listed in Table 1.5 Some factors associated with GAD include female sex, unmarried status, lower education level, poor health, and presence of life stressors.6 The age of onset is variable, with a median age of 30 years.1

A number of scales are available to estab- lish diagnosis and assess severity. The GAD-7 (Table 27) has been validated as a diagnostic tool and a severity assessment scale, with a

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Physical activity is a cost-effective treatment for GAD and PD. B 16, 17

Selective serotonin reuptake inhibitors are considered first-line therapy for GAD and PD. B 19, 20, 22

To avoid relapse, medication should be continued for 12 months after symptoms improve before tapering. C 11

When used in combination with antidepressants, benzodiazepines may speed recovery from anxiety-related symptoms but do not improve longer-term outcomes. Because benzodiazepines are associated with tolerance, they should be used only short term during crises.

B 11, 28-30

Psychotherapy can be as effective as medication for GAD and PD. Cognitive behavior therapy has the best level of evidence.

A 11, 37

Successful treatment requires tailoring options to individuals and may often include a combination of modalities. C 11, 37, 42

GAD = generalized anxiety disorder; PD = panic disorder.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Table 1. Diagnostic Criteria for Generalized Anxiety Disorder

The rights holder did not grant the American Academy of Family Physicians the right to sublicense this material to a third party. For the missing item, see the original print version of this publication.

Reprinted with permission from the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:222.

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score of 10 or more having good diagnostic sensitivity and specificity.8 Greater GAD-7 scores correlate with more functional impairment.8 The scale was developed and validated based on DSM-IV criteria, but it remains clinically useful after publication of the DSM-5 because the differences in GAD diagnostic criteria are minimal. The PRO- MIS Emotional Distress–Anxiety–Short Form for adults and the Severity Measure for Generalized Anxiety Disorder–Adult, avail- able from the American Psychiatric Associa- tion at http://www.psychiatry.org/practice/ dsm/dsm5/online-assessment-measures, are intended to aid clinical evaluation of GAD and monitor treatment effectiveness.

PANIC DISORDER

PD is characterized by episodic, unexpected panic attacks that occur without a clear trig- ger.5 Panic attacks are defined by the rapid onset of intense fear (typically peaking within about 10 minutes) with at least four of the physical and psychological symptoms in the DSM-5 diagnostic criteria (Table 3).5 Another requirement for the diagnosis of PD is that the patient worries about further attacks or modifies his or her behavior in maladaptive ways to avoid them. The most common physical symptom accompany- ing panic attacks is palpitations.9 Although unexpected panic attacks are required for the diagnosis, many patients with PD also have expected panic attacks, occurring in response to a known trigger.9 The Sever- ity Measure for Panic Disorder–Adult (http://www. psychiatry.org/File%20Library/Practice/DSM/DSM-5/ Severity Measure For Panic Disorder Adult.pdf) is an assessment scale that can complement the clinical assess- ment of patients with PD.

Differential Diagnosis and Comorbidity When evaluating a patient for a suspected anxiety disor- der, it is important to exclude medical conditions with similar presentations (e.g., endocrine conditions such as hyperthyroidism, pheochromocytoma, or hyper- parathyroidism; cardiopulmonary conditions such as arrhythmia or obstructive pulmonary diseases; neu- rologic diseases such as temporal lobe epilepsy or tran- sient ischemic attacks). Other psychiatric disorders (e.g., other anxiety disorders, major depressive disorder, bipolar disorder); use of substances such as caffeine,

albuterol, levothyroxine, or decongestants; or substance withdrawal may also present with similar symptoms and should be ruled out.5

Complicating the diagnosis of GAD and PD is that many conditions in the differential diagnosis are also common comorbidities. Additionally, many patients with GAD or PD meet criteria for other psychiatric disorders, including major depressive disorder and social phobia. Evidence suggests that GAD and PD usually occur with at least one other psychiatric disorder, such as mood, anxi- ety, or substance use disorders.10 When anxiety disor- ders occur with other conditions, historic, physical, and laboratory findings may be helpful in distinguishing each diagnosis and developing appropriate treatment plans.

Treatment Some studies evaluating anxiety treatments assess non- specific anxiety-related symptoms rather than the set of symptoms that characterize GAD or PD. When possible, the treatments described in this section will differentiate

Table 2. GAD-7 Screening Tool

Over the last 2 weeks, how often have you been bothered by the following problems?

Not at all

Several days

More than half the days

Nearly every day

(Use “✓” to indicate your answer)

1. Feeling nervous, anxious, or on edge

0 1 2 3

2. Not being able to stop or control worrying

0 1 2 3

3. Worrying too much about different things

0 1 2 3

4. Trouble relaxing 0 1 2 3

5. Being so restless that it is hard to sit still

0 1 2 3

6. Becoming easily annoyed or irritable

0 1 2 3

7. Feeling afraid as if something awful might happen

0 1 2 3

Total score = + + +

NOTE: Total score for the 7 items ranges from 0 to 21. Scores of 5, 10, and 15 repre- sent cutoffs for mild, moderate, and severe anxiety, respectively. Although designed primarily as a screening and severity measure for GAD, the GAD-7 also has moderately good operating characteristics for panic disorder, social anxiety disorder, and posttrau- matic stress disorder. When screening for anxiety disorders, a recommended cutoff for further evaluation is a score of 10 or greater.

GAD = generalized anxiety disorder.

Reprinted from Spitzer RL, Williams JB, Kroenke K, et al., with an educational grant from Pfizer Inc. Patient health questionnaire (PHQ) screeners. http://www. phqscreeners.com/overview.aspx?Screener= 03_GAD-7. Accessed July 22, 2014.

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between GAD and PD; otherwise, treatments refer to anxiety-related symptoms in general.

Medication or psychotherapy is a reasonable initial treatment option for GAD and PD.11 Some studies sug- gest that combining medication and psychotherapy may be more effective for patients with moderate to severe symptoms.12 The National Institute for Health and Care Excellence (NICE) guidelines on GAD and PD in adults are a useful review of available evidence; however,

information about self-help and group therapies may have less utility in the United States because of their relative lack of availability.11

EDUCATION

Compassionate listening and education are an impor- tant foundation in the treatment of anxiety disorders.11 Patient education itself can help reduce anxiety, particu- larly in PD.13 The establishment of a therapeutic alliance

between the patient and physician is impor- tant to allay fears of interventions and to progress toward treatment.

Common lifestyle recommendations that may reduce anxiety-related symptoms include identifying and removing possible triggers (e.g., caffeine, stimulants, nicotine, dietary triggers, stress), and improving sleep quality/quantity and physical activity.

Caffeine can trigger PD and other types of anxiety. Those with PD may be more sensi- tive to caffeine than the general population because of genetic polymorphisms in adenos- ine receptors.14 Smoking cessation leads to improved anxiety scores, with relapse lead- ing to increased anxiety. Many studies show an association between disordered sleep and anxiety, but causality is unclear.15 In addition to decreased depression and anxiety, physical activity is associated with improved physical health, life satisfaction, cognitive function- ing, and psychological well-being. Physical activity is a cost-effective approach in the treatment of GAD and PD.16,17 Exercising at 60% to 90% of maximal heart rate for 20 minutes three times weekly has been shown to decrease anxiety16; yoga is also effective.18

MEDICATION

First-Line Therapies. A number of medi- cations are available for treating anxiety (Table 4). Selective serotonin reuptake inhibitors (SSRIs) are generally consid- ered first-line therapy for GAD and PD.19-22 Tricyclic antidepressants (TCAs) are bet- ter studied for PD, but are thought to be effective for both GAD and PD.19,20 In the treatment of PD, TCAs are as effective as SSRIs, but adverse effects may limit the use of TCAs in some patients.23 Venlafaxine, extended release, is effective and well toler- ated for GAD and PD, whereas duloxetine

Table 3. Diagnostic Criteria for Panic Disorder

The rights holder did not grant the American Academy of Family Physicians the right to sublicense this material to a third party. For the missing item, see the original print version of this publication.

Reprinted with permission from the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:208-209.

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(Cymbalta) has been adequately evaluated only for GAD.24 Azapirones, such as buspi- rone (Buspar), are better than placebo for GAD25 but do not appear to be effective for PD.26 Mixed evidence suggests bupropion (Wellbutrin) may have anxiogenic effects for some patients, thus warranting close monitoring if used for treatment of comor- bid depression, seasonal affective disorder, or smoking cessation.27 Bupropion is not approved for the treatment of GAD or PD.

Medications should be titrated slowly to decrease the initial activation. Because of the typical delay in onset of action, medications should not be considered ineffective until they are titrated to the high end of the dose range and continued for at least four weeks. Once symptoms have improved, medica- tions should be used for 12 months before tapering to limit relapse.11 Some patients will require longer treatment.

Benzodiazepines are effective in reduc- ing anxiety, but there is a dose-response relationship associated with tolerance, seda- tion, confusion, and increased mortality.28 When used in combination with antidepres- sants, benzodiazepines may speed recovery from anxiety-related symptoms but do not improve longer-term outcomes. The higher risk of dependence and adverse outcomes complicates the use of benzodiazepines.29 NICE guidelines recommend only short-term use during crises.11 Benzodiazepines with an intermediate to long onset of action (such as clonazepam [Klonopin]) may have less potential for abuse and less risk of rebound.30

Second-Line Therapies. Second-line thera- pies for GAD include pregabalin (Lyrica) and quetiapine (Seroquel), although neither has been evaluated for PD. Pregabalin is more effective than placebo but not as effec- tive as lorazepam (Ativan) for GAD. Weight gain is a common adverse effect of prega- balin. There is limited evidence for the use of antipsychotics to treat anxiety disorders. Although quetiapine seems to be effective for GAD, the adverse effect profile is significant, including weight gain, diabetes mellitus, and hyperlipidemia.31 Hydroxyzine is considered a second-line treatment for GAD,32 but there are minimal data for its use in PD. Its rapid

Table 4. Medications for the Treatment of Generalized Anxiety Disorder and Panic Disorder

Medication Estimated cost*

First line

Selective serotonin reuptake inhibitors

Escitalopram (Lexapro) $25 ($190)

Fluoxetine (Prozac) $5 ($250)

Fluvoxamine for PD $15 (NA)

Paroxetine (Paxil) $5 ($150)

Sertraline (Zoloft) $10 ($200)

Serotonin-norepinephrine reuptake inhibitors

Duloxetine (Cymbalta) for GAD $50 ($210)

Venlafaxine, extended release (Effexor XR) $15 ($230)

Azapirone

Buspirone (Buspar) for GAD $5 ($87)

Second line

Tricyclic antidepressants

Amitriptyline† $5 (NA) Imipramine (Tofranil)‡ $10 ($265) Nortriptyline (Pamelor)† $10 ($725)

Antiepileptics

Pregabalin (Lyrica)† for GAD NA ($145) Antipsychotics

Quetiapine (Seroquel)† for GAD $15 ($130) Hydroxyzine (Vistaril) $12 ($200)

Third line

Monoamine oxidase inhibitors§

Isocarboxazid (Marplan)† NA ($130) Phenelzine (Nardil)† $20 ($50) Tranylcypromine (Parnate)† $50 ($185)

Augmentation

Benzodiazepines||

Alprazolam (Xanax) ¶ $10 ($70)

Clonazepam (Klonopin)** $10 ($70)

Diazepam (Valium) for GAD $10 ($90)

Lorazepam (Ativan)‡ $10 ($300)

NOTE: Medications are used for GAD and PD unless otherwise noted. They are listed from most to least commonly used.

FDA = U.S. Food and Drug Administration; GAD = generalized anxiety disorder; NA = not available; PD = panic disorder.

*—Estimated retail price for one month’s treatment based on information obtained at http://www.goodrx.com (accessed January 19, 2015). Generic price listed first; brand price listed in parentheses.

†—Not FDA approved for this use, although there is some evidence to support its use. ‡—Not FDA approved for PD, although there is some evidence to support its use; approved for GAD.

§—Consideration of monoamine oxidase inhibitors should prompt referral to psychiatry.

||—Benzodiazepines may be used for augmentation during acute treatment. Depen- dence, tolerance, and escalating doses to get the same effect over the long term can be problematic with use of benzodiazepines. Short-term prescribing with emphasis on acute management of uncontrolled anxiety is preferred. Slowly tapered dosing can prevent rebound symptoms.

¶—Short-acting benzodiazepines, such as alprazolam, are not preferred because they have a higher risk of addiction and adverse effects.

**—Not FDA approved for GAD, although there is some evidence to support its use; approved for PD.

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onset can be appealing for patients needing immediate relief, and it may be a more appropriate alternative if ben- zodiazepines are contraindicated (e.g., in patients with a history of substance abuse). Based on clinical experi- ence, gabapentin (Neurontin) is sometimes prescribed by psychiatrists to treat anxiety on an as-needed basis when benzodiazepines are contraindicated. Of note, the placebo response for medications used to treat GAD and PD is high.13

PSYCHOTHERAPY AND RELAXATION THERAPIES

Psychotherapy includes many different approaches, such as cognitive behavior therapy (CBT) and applied relax- ation (Table 5).33,34 CBT may use applied relaxation, exposure therapy, breathing, cognitive restructuring, or education. Psychotherapy is as effective as medication for GAD and PD.11 Although existing evidence is insuf- ficient to draw conclusions about many psychothera- peutic interventions, structured CBT interventions have

consistently proven effective for the treatment of anxiety in the primary care setting.34-36 Psy- chotherapy may be used alone or combined with medication as first-line treatment for PD37 and GAD,11 based on patient preference. Psychotherapy should be performed weekly for at least eight weeks to assess its effect.

Mindfulness has similar effectiveness to traditional CBT or other behavior therapies,38 particularly mindfulness-based stress reduc- tion.39 A meta-analysis of 36 randomized controlled trials on meditation showed that meditative therapies reduce anxiety symp- toms, but most studies looked at anxiety symptoms rather than anxiety disorders.40 Transcendental meditation has similar effec- tiveness to other relaxation therapies.41

After a treatment course, rebound symp- toms may occur less often with psycho- therapy than with medications. Successful treatment requires tailoring options to indi- viduals and may often include a combina- tion of modalities.11,37,42 Combined treatment with medications and psychotherapy reduces relapse even at two years.43

COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPIES

Although a number of complementary and alternative products have evidence for treat- ing depression, most lack sufficient evidence for the treatment of anxiety. Botanicals and

supplements sometimes used to treat GAD and PD are listed in Table 6. Kava extract is an effective treatment for anxiety 44; however, case reports of hepatotoxicity have decreased its use.45 St. John’s wort, tryptophan, 5-Hydroxy tryptophan, and S-adenosyl-L-methionine should be used with caution in combination with SSRIs because of the increased risk of serotonin syndrome.46

Evidence indicates that music therapy, aromatherapy, acupuncture, and massage are helpful for anxiety asso- ciated with specific disease states, but none have been evaluated specifically for GAD or PD.

Referral and Prevention For patients with GAD or PD, psychiatric referral may be indicated if there is poor response to treatment, atypical presentation, or concern for significant comorbid psy- chiatric illness. There is insufficient evidence to support a concise recommendation on the prevention of PD and GAD in adults.

Table 5. Possible Behavior Interventions for the Treatment of Generalized Anxiety Disorder, Panic Disorder, and Anxiety-Related Symptoms

Intervention Comments

Cognitive behavior therapy*

This intervention is useful in treating anxiety disorders. The cognitive portion assists change in thinking patterns that support fears, whereas the behavior portion often involves training patients to relax deeply and helps desensitize patients to anxiety-provoking triggers.

To be effective, therapy must be directed at the patient’s specific anxieties and tailored to his or her needs. There are minimal adverse effects, except that behavior desensitization is typically associated with temporary mild increases in anxiety.33

Mindfulness- based stress reduction†

This intervention promotes focused attention on the present, acknowledgment of one’s emotional state, and meditation for further stress reduction and relaxation.

Key features include moment to moment awareness cultivated with a nonjudgmental attitude, formal meditation techniques, and daily practice.34

NOTE: Formal use of these interventions requires specialized training. In patients whose anxiety and impairment are severe, referral to a trained behavior health specialist should be considered.

*—For more information, see DiTomasso RA, Golden BA, Morris HJ, eds. Handbook of Cognitive-Behavioral Approaches in Primary Care. New York, NY: Springer; 2010, and Craske MG. Cognitive-Behavioral Therapy. Washington, DC: American Psycho- logical Association; 2010. †—For more information, see Brantley J. Mindfulness-based stress reduction. In: Orsillo SM, Roemer L, eds. Acceptance and Mindfulness-Based Approaches to Anxiety: Concep- tualization and Treatment. New York, NY: Springer; 2005:131-145.

Information from references 33 and 34.

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Data Sources: We searched Essential Evidence Plus, PubMed, and Ovid Medline using the keywords generalized anxiety disorder, panic disorder, diagnosis, treatment, medication, epidemiology, etiology, pathophysiology, differential diagnosis, and complementary and alternative medicine. We searched professional and authoritative organizations on the topic of anxiety disorders, including the American Psychological Association, the National Institute of Mental Health, the National Institute for Health and Care Excel- lence, and the Cochrane Collaboration. Search dates: May to July 2014.

The Authors

AMY B. LOCKE, MD, FAAFP, is director of the Integrative Medicine Fellow- ship and an assistant professor in the Department of Family Medicine at the University of Michigan Medical School in Ann Arbor.

NELL KIRST, MD, is assistant residency director of the Family Medicine Residency Program at the University of Michigan Medical School.

CAMERON G. SHULTZ, PhD, MSW, is director of scholarly projects in the Department of Family Medicine at the University of Michigan Medical School.

Address correspondence to Amy B. Locke, MD, University of Michigan Med- ical School, 1801 Briarwood Circle, Bldg. 10, Ann Arbor, MI 48109 (e-mail: [email protected]). Reprints are not available from the authors.

REFERENCES

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2. Paulesu E, Sambugaro E, Torti T, et al. Neural correlates of worry in gen- eralized anxiety disorder and in normal controls: a functional MRI study. Psychol Med. 2010; 40 (1): 117-124.

3. Mackintosh MA, Gatz M, Wetherell JL, Pedersen NL. A twin study of lifetime generalized anxiety disorder (GAD) in older adults: genetic and environmental influences shared by neuroticism and GAD. Twin Res Hum Genet. 2006; 9(1): 30-37.

4. Dresler T, Guhn A, Tupak SV, et al. Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. J Neural Transm. 2013; 120 (1): 3-29.

5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Asso- ciation; 2013.

6. Wolitzky-Taylor KB, Castriotta N, Lenze EJ, Stanley MA, Craske MG. Anxiety disorders in older adults: a comprehensive review. Depress Anxiety. 2010; 27(2): 190-211.

7. Spitzer RL, Williams JB, Kroenke K, et al. Pfizer Inc. Patient health ques- tionnaire (PHQ) screeners. http://www.phqscreeners.com/overview. aspx?Screener= 03_GAD-7. Accessed July 22, 2014.

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9. Craske MG, Kircanski K, Epstein A, et al.; DSM V Anxiety; OC Spectrum; Posttraumatic and Dissociative Disorder Work Group. Panic disorder: a review of DSM-IV panic disorder and proposals for DSM-V. Depress Anxiety. 2010; 27(2): 93-112.

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Table 6. Botanicals and Supplements Sometimes Used to Treat Generalized Anxiety Disorder and Panic Disorder

Therapy Potential significant adverse effects*

Botanicals

Kava (Piper methysticum)

Possible hepatotoxicity, sedation, interference with P450 substrates

Lavender oil (Lavandula angustifolia)

Minimal

Passionflower (Passiflora incarnata)

Dizziness, sedation, decreased blood pressure

St. John’s wort (Hypericum perforatum)†

Similar to serotonin reuptake inhibitors, interference with P450 substrates

Valerian (Valeriana officinalis)

Headache, gastrointestinal upset

Supplements

5-Hydroxytryptophan† Gastrointestinal upset, possible eosinophilia-myalgia syndrome

Inositol Nausea, headache

L-theanine May lower blood pressure; may lower effect of stimulant medication

L-tryptophan† Gastrointestinal upset, possible eosinophilia-myalgia syndrome

S-adenosyl-L- methionine†

Gastrointestinal upset, mania in patients with bipolar disorder

Vitamin B complex Yellow urine

*—This list includes important adverse effects but is not exhaustive. †—Can potentiate serotonin syndrome when used in combination with antidepressants.

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20. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for general- ized anxiety disorder. Cochrane Database Syst Rev. 2003; (2): CD003592.

21. Zohar J, Westenberg HG. Anxiety disorders: a review of tricyclic anti- depressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 2000; 403: 39-49.

22. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ. 2011; 342: d1199.

23. Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disor- ders: a review of progress. J Clin Psychiatry. 2010; 71(7): 839-854.

24. Carter NJ, McCormack PL. Duloxetine: a review of its use in the treat- ment of generalized anxiety disorder. CNS Drugs. 2009; 23(6): 523-541.

25. Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxi- ety disorder. Cochrane Database Syst Rev. 2006; (3): CD006115.

26. Imai H, Tajika A, Chen P, et al. Azapirones versus placebo for panic disorder in adults. Cochrane Database Syst Rev. 2014; (9): CD010828.

27. Wiseman CN, Gören JL. Does bupropion exacerbate anxiety? Curr Psy- chiatry Rep. 2012; 11(6): E3-E4.

28. Weich S, Pearce HL, Croft P, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ. 2014; 348: g1996.

29. Furukawa TA, Streiner DL, Young LT. Antidepressant plus benzodiaz- epine for major depression. Cochrane Database Syst Rev. 2001; (2): CD001026.

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