Nonpharmacologic Therapy

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Nonpharmacologic therapy includes psychoeducation, exercise, stress management, and psychotherapy. Psychoeducation should include instructing patients to avoid stimulating agents such as caffeine, decongestants, diet pills, and excessive alcohol use. Regular exercise is also recommended. Cognitive-behavioral therapy (CBT), the most effective psychological therapy for GAD patients, helps patients to recognize and alter patterns of distorted thinking and dysfunctional behavior. Some trials suggest that treatment gains with CBT may be maintained for up to 1 year.21 The combination of CBT and an antidepressant may be more effective than either treatment alone. In a recent study, 80.7% of children were much improved on the combination of CBT and an

antidepressant, versus 54.9% with sertraline and 59.7% with CBT alone. Pharmacologic Therapy

Antidepressants, benzodiazepines, buspirone, hydroxyzine, pregabalin, and the second-generation antipsychotics (SGAs), olanzapine and risperidone, have controlled clinical trial data supporting their use in GAD. Antidepressants have replaced benzodiazepines as the drugs of choice for chronic GAD owing to a tolerable side-effect profile, no risk for dependency, and efficacy in common comorbid conditions including depression, panic, obsessive-compulsive disorder (OCD), and SAD. Benzodiazepines remain the most effective and commonly used treatment for short-term management of anxiety where immediate relief of symptoms is desired. They are also recommended for intermittent or adjunctive use during GAD exacerbation or for sleep disturb-

ance during the initiation of antidepressant treatment. Buspirone and pregabalin are alternative agents for patients with GAD without depression. Hydroxyzine is usually adjunctive and is less desirable for long-term treatment owing to side effects including sedation and anticholinergic effects.

Patients with GAD should be treated to remission of symptoms. Most guidelines

recommend continuing treatment for an additional 3 to 10 months. ' An algorithm for the pharmacologic management of GAD is shown in Figure 40-2.


Antidepressants (Table 40—3) are consideredfirst-line agents in the management of chronic GAD. These agents reduce the psychic symptoms (e.g., worry and apprehension) of anxiety with a modest effect on autonomic or somatic symptoms (e.g., tremor, rapid heart rate, and/or sweating). All antidepressants evaluated provide a similar degree of anxiety reduction. The onset of antianxiety effect is delayed 2 to 4 weeks. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepineph-rine reuptake inhibitors (SNRIs) are usually preferred over tricyclic antidepressants (TCAs) such as imipramine owing to improved safety and tolerability. Selection of a particular antidepressant agent generally is based on history of prior response, side-effect profile, drug interaction profile (discussed in Chap. 38), cost, or formulary availability.

I No

Add atypical antisychotic s\r R"7 fr\r crvmotir»

FIGURE 40-2. Treatment algorithm for GAD. (BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor); SNRI, serotonin-norepinephrine reuptake inhibitor. (Adapted, from Kirkwood CK, Melton ST. Anxiety disorders: I. Generalized anxiety, panic and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1163-1178.)

Table 40-3 Antidepressants Used in the Treatment of GAD

FlfrtDmmenrfed Starting

IKujI Thcrjpi'ulir Dasdgp


Medication tlass

Düse (mp/day)

fiance (mg/day)

Hepatic. Insufficiency







EicilalDprjirr" (Li'xafmo)



Max 10 mg Mjy

Fkicnetine (PrWKl



tltriwwtth caution

Fluvo<amine i.l uvo>)



Titrate with caution




lltatewfth cjullort

Paraaeline CR (f aniL



Max 50mg/day

Max SOmgrtiay

fad en)

Serlratne (Zoloft



Oeduce dose


Yentafaxine Kfl°



Reduce dose Si}*

Deduce dose

lEfüewor KR)


Dulcwctinc (CymbaHu)



Use not rocommtKlnJ

Use is not






1 irrste wirh camion

SNHIi ie^faake inhilmors; JSftli. Wt« (ive serotonin leUfaiJoe inhihiKH j; 1(. Aj, T*i<\ik aniideiiiejsants.

"f OA amoved for use In GAD.

•OuliMieiine ui^ not recommended In i eivil impairment (00 lev. than .to nH/tnim. rnom RefcXt ¡6.

SNHIi ie^faake inhilmors; JSftli. Wt« (ive serotonin leUfaiJoe inhihiKH j; 1(. Aj, T*i<\ik aniideiiiejsants.

"f OA amoved for use In GAD.

•OuliMieiine ui^ not recommended In i eivil impairment (00 lev. than .to nH/tnim. rnom RefcXt ¡6.

Antidepressants modulate synaptic 5-HT, NE, and/or dopamine (DA) reuptake and receptor-activated neuronal signal transduction. These intracellular changes ultimately modify the expression of genes and proteins important in stress response (e.g., increase messenger RNA [mRNA] for glucocorticoid receptors and brain-derived neurotrophic factor and decrease mRNA expression for corticotropin-releasing factor).26 Activation of these "stress-adapting" pathways is thought to improve both

somatic and psychic symptoms of anxiety. Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine and duloxetine alleviate anxiety in GAD patients with and without depression. Venlafaxine was shown to reduce anxiety effectively at doses 75 to 225 mg/ day, and response was maintained over an additional 6 months of treatment.28 Venlafaxine has more favorable safety and side-effect profiles than TCAs. The most com-

mon venlafaxine side effects reported by GAD patients are nausea, somnolence, dry

mouth, dizziness, sweating, constipation, and anorexia.

Duloxetine is effective for the treatment of GAD as well, but long-term efficacy has not yet been established. At 60 to 120 mg/day, its efficacy is noninferior to venlafaxine, and tolerability is similar.29 For patients with concurrent pain syndromes, duloxetine has been found to improve anxiety, pain, and functional impairment when compared to placebo.30

Selective Serotonin Reuptake Inhibitors

The SSRIs paroxetine, escitalopram, and sertraline have been shown to be significantly more effective than placebo in reducing anxiety symptoms. Paroxetine at doses of 20 and 40 mg/day achieved response in 62% and 68% of patients, respectively, over 8 weeks of treatment.31 Remission occurred in 30% and 36%, respectively. In a 24-week relapse-prevention study, paroxetine was more effective than placebo at maintaining response, and patients were more likely to achieve remission with contin-

ued treatment (42.5% at 8 weeks versus 73% at 24 weeks). In GAD trials, paroxetine was associated with a high rate of somnolence, nausea, abnormal ejaculation, dry mouth, decreased libido, and asthenia compared with placebo.31

Escitalopram, in a dose range of 10 to 20 mg/day, was more effective than placebo in patients with GAD without depression. Fifty-eight percent of patients on es-

citalopram achieved response versus 38% on placebo over the 8 weeks of treatment.

Side effects included headache, nausea, somnolence, upper respiratory tract infection,

decreased libido, ejaculation disorder, and anorgasmia.

Sertraline was more efficacious than placebo in patients with GAD being treated for 12 weeks. Sertraline treatment resulted in 56% of patients achieving response, whereas 31% achieved remission.34 Side effects included increased rates of nausea, insomnia, sweating, decreased libido, diarrhea, fatigue, and ejaculation disorder.34

Citalopram has been shown to be efficacious in the treatment of GAD in the elderly. Limited comparative trial data suggest comparable outcomes between these SSRIs.36,37 SSRI therapy is better tolerated than TCAs, and tolerability is similar to that with venlafaxine.

Tricyclic Antidepressants

Imipramine provided a higher rate of remission of anxiety symptoms than trazodone, diazepam, or placebo (e.g., 73% versus 69% versus 66% versus 47%) in an 8-week

controlled trial of GAD patients. Antidepressants were more effective than diazepam or placebo in reducing psychic symptoms of anxiety. The use of TCAs generally is limited by bothersome adverse effects (e.g., sedation, orthostatic hypotension, anticholinergic effects, and weight gain). TCAs have a narrow therapeutic index and are lethal in overdose due to atrioventricular (AV) heart block.

Novel Antidepressants

Mirtazapine, an a-2 adrenergic antagonist and postsynaptic serotonin (5-HT2, 5-HT3) receptor antagonist, is an effective antidepressant but has not been extensively evaluated in anxiety disorders. One open-label study found treatment of GAD for 12 weeks

with mirtazapine 30 mg to be efficacious and well tolerated. Mirtazapine is not associated with sexual dysfunction, a common antidepressant side effect, but does have a greater propensity to cause sedation and weight gain. Bupropion, a dopamine and norepinephrine reuptake inhibitor, lacks the common antidepressant side effects of weight gain and sexual dysfunction. Bupropion has not been studied or used extensively in anxiety disorders owing to its stimulating effects that would be expected to worsen anxiety symptoms. However, a pilot-controlled trial comparing bupropion XL to escitalopram found buproprion to have comparable anxiolytic efficacy and tolerab-ility 40


Benzodiazepines are recommended for acute treatment of GAD when short-term relief is needed, as an adjunct during initiation of antidepressant therapy, or to im-21 23

prove sleep. ' Benzodiazepine treatment results in a significant improvement in 65% to 75% of GAD patients, with most of the improvement occurring in the initial 2

weeks of therapy. They are more effective in reducing somatic symptoms of anxiety than psychic symptoms. The major disadvantages of benzodiazepines are their lack of effectiveness in treating depression, the risk for dependency and abuse, and potential interdose rebound anxiety especially with short-acting formulations. Benzodiazepines should be avoided in patients with chemical dependency.

Benzodiazepines exert their effects by enhancing transmission of the inhibitory neurotransmitter GABA through interaction with the GABAa receptor complex.41 Although all benzodiazepines possess anxiolytic properties, only 7 of the 13 currently marketed agents are approved by the FDA for the treatment of anxiety disorders (Table 40-4). All benzodiazepines are expected to provide equivalent benefit when given in comparable doses. Benzodiazpines differ substantially in their pharmacokin-etic properties and potency for the GABAa receptor site.

Benzodiazepines are metabolized by hepatic oxidation (cytochrome P450 3A4) and glucuronide conjugation. Because lorazepam and oxazepam bypass hepatic oxidation and are conjugated only, they are preferred agents for patients with reduced hepatic function secondary to aging or disease (e.g., cirrhosis commonly seen in patients abusing alcohol or with Hepatitis B/C from IV drug use). Many benzodiazepines are metabolized to long-acting metabolites (Table 40_4) that provide long-lasting anxiety relief. Drugs that either inhibit or induce CYP450 isozymes or glucuronidation are the major source of drug interactions (Table 40-5).

The most common side effects associated with benzodiazepine therapy include

CNS depressive effects (e.g., drowsiness, sedation, psychomotor impairment, and ataxia) and cognitive effects (e.g., poor recall and anterograde amnesia). Antero-

grade amnesia is more likely to occur with high-potency benzodiazepines, such as

lorazepam or alprazolam. Some patients also may be disinhibited with benzo-

diazepine treatment and experience confusion, irritability, aggression, and excite-42

ment. Discontinuation of benzodiazepines may be associated with withdrawal, rebound anxiety, and a high rate of relapse. Higher doses of benzodiazepines and longer duration of therapy increase the severity of withdrawal and risk of seizures after abrupt or rapid discontinuation. Patients should be tapered rather than discontinued abruptly from benzodiazepine therapy to avoid withdrawal symptoms. The duration of

the taper should increase with extended duration of benzodiazepine therapy. For example, patients on benzodiazepine therapy over 2 to 6 months should be tapered over 2 to 8 weeks, whereas patients receiving 12 months of treatment should be tapered over 2 to 4 months. A general approach to the taper is to reduce the dose by 25% every 5 to 7 days until reaching half the original dose and then decreasing by 10% to 12% per week until discontinued. Patients should expect minor withdrawal symptoms and discomfort even when tapering. Rebound symptoms (e.g., return of original symptoms at increased intensity) are transient. The patient should be counseled so that rebound anxiety is not interpreted as a relapse. Relapse or recurrence of anxiety may occur in as many as 50% of patients discontinuing benzodiazepine treatment. 8 It is unclear if this relapse rate represents an inferiority of benzodiazepines or supports the chronic nature of GAD.


Buspirone, a 5-HT1A partial agonist, is thought to exert its anxiolytic effects by reducing presynaptic 5-HT firing.4 Unlike benzodiazepines, it does not have abuse potential, cause withdrawal reactions, or potentiate alcohol and sedative-hypnotic effects.

However, it has a gradual onset of action (i.e., 2 weeks) and does not provide immediate anxiety relief. Buspirone is considered a second-line agent for GAD owing to inconsistent data regarding its efficacy in chronic GAD or GAD with comorbid de-


pression. ' Some research suggests that buspirone is less effective in patients who have been treated previously (4 weeks to 5 years) with benzodiazepines. 4

Table 40-4 Benzodiazepine Comparison

Table 40-4 Benzodiazepine Comparison

GAD, generalised anniety d torder, fO, panic disorder. "FDA approved 1ar use in GAD. [FDA approved far ose in CO.

tVPSGi genetic polynvoiphlsnu resulting n hnle or no enzyme activity aie present in lift to Jl'ti of Aslani ard ito do 9H of Slacks and Caucasian; resulting in reduced clearance of desmethylduiepam."

From Reis.24,26.

ChlordiarPrMside* (I ilvium) Des met hykhkïtfrari pcwide [ierttcaeosrri U^rTKM hiyldi.i/eparn QKMepam C lonazepam6 iKlonopiri) □ofarapaK»1 tTianrefw) Des met hyldia/epem fhAWfjam Dwi'punv' (Viliurn)

TfTlWfpill OfMx.'pJm tcrarepanni3 CAiivanf Qxa/epairTtJeri/l

GAD, generalised anniety d torder, fO, panic disorder. "FDA approved 1ar use in GAD. [FDA approved far ose in CO.

tVPSGi genetic polynvoiphlsnu resulting n hnle or no enzyme activity aie present in lift to Jl'ti of Aslani ard ito do 9H of Slacks and Caucasian; resulting in reduced clearance of desmethylduiepam."

From Reis.24,26.

Buspirone should be initiated at a dose of 7.5 mg twice daily and titrated in 5 mg/

The day increments (every 2-3 days) to a usual target dose of 20 to 30 mg/day. maximum daily dose is considered to be 60 mg/day.

Buspirone generally is well tolerated and does not cause sedation. The most common side effects include dizziness, nausea, and headaches. Drugs that inhibit CYP3A4 (e.g., verapamil, diltiazem, itraconazole, fluvoxamine, nefazodone, and erythromycin) can increase buspirone levels. Likewise, enzyme inducers such as rifampin can reduce buspirone levels significantly. Bupirone may increase blood pressure when coadministered with a monoamine oxidase inhibitor (MAOI).

Alternative Agents

Hydroxyzine, pregabalin, and adjunctive SGAs are alternative agents. Hydroxyzine

may be effective for acute reduction of somatic symptoms of anxiety. It does not improve psychic features of anxiety and does not treat depression or other common comorbid anxiety disorders.

Pregabalin is mechanistically unique for an anxiolytic. It is a presynaptic modulator of excessive excitatory neurotransmitter release. It accomplishes this by selectively binding to the ai-S subunit of voltage-gated calcium channels. In a 4-week controlled trial versus alprazolam and placebo, pregabalin was effective for both somatic and psychic symptoms of anxiety with an onset of effect similar to that of alprazolam.45 Compared to venlafaxine and placebo, pregabalin was found to be safe, well-tolerated, and efficacious in GAD, and results were seen 1 week sooner than with venlafaxine.46 Pregabalin has an elimination half-life of approximately 6 hours and must be dosed two to three times daily. It is excreted renally and has a low risk of drug-drug interactions. Pregabalin is a schedule V controlled substance owing to a propensity to cause euphoria and risk of withdrawal symptoms when discontinued abruptly. Pregabalin should be used with caution in patients with a current or past history of substance abuse. It is not beneficial for depression or other anxiety disorders, and long-term effectiveness in GAD is not established.

Table 40-5 Pharmacokinetic Drug Interactions With Benzodiazepines



AlcnhtJ (Ciifonit)

Incm'iml CL uiBZi


Incrflased CL of alnraiolairi


Dtiiwi«) CL <ji ifcnizula.^ (fcapirtiKd dertHpme ¿nd inciiMi*!


Decianed CL of ¿^xazolHn and diasepam


Deaeawd CL of abyaiolarfi


pecnertied Cl nf Afnamlav and tfca wpam


Deceased CL of alprainläm. and pnolonged


tei'nmlly rt^.reji.pd Cl. of alpiamlam and diaMpann


PWenLiallydcaaascd CL of alpNaaolaro


Deenei-i^d CL ol ¿^üa.'ül.i-n, AUC doubltand r, piolonged


DeciPiwd CL of dkUKpam

Qui (omiaMficii'is

Iii lue , .Ii. •■iilMl::m u4 irAmlkMfmxhlc .11*1 tliqhrly dKre.)Srcl ( 1 jdtCCWedCL>nd»CMWed

r,. .i'idia i-cpcm and alprdiolam

fcnowHin« PhenotiartHtal

PtvHnytoin PVühäfVMid PWpriilOk)! Ranitidine

1 heoptylline Vitwoate

Dvíríilíd ÍL <JÍ JlfjitJOirri Increase £L oídcmaícpamand reduced í, , Incieawd-Cl-of ckjauirepam LP"d reducá i. Decreased tL of lorarpíism and prolonged r Deo«s«i tL of íJiiseTMír» ind C"titoiig^i í. Decreased absorben of diazepam InciL'jvttl mtUlx)liimoídii«v:pjiii Decreased (IpfíigiiiTi t onotntiittsrij Decreased CL of lofazEpani

WC. area undw lhe plasma ™™mraiioiicuvi7 BJ. bt™odiaH!pine; CL. ckHrjno^ . i-lim.-yirtin lyill lift-

Fíiom Kítvjcoci CK Melosn 5T. Am*>«v iifcoKtofi; I. Ceneriiisfd inaiity. psnit. anid social írmíery dísonJerí. in: DíPim ir. fafoei r RL. vee G£ « al, eík. Pharmacotherapy: A Parhoph^lologk" Appicurh, /I h ftl NpiV Voík. McIiími H'H VDOftlIW.

Atypical antipsychotics have recently been evaluated for anxiety. Both quetiapine and aripiprazole were effective in reducing anxiety symptoms when added to an an-

47 48

tidepressant. ' However, several other studies of SGAs have failed to demonstrate a significant improvement in anxiety symptoms in poorly responsive patients. Given their risk for metabolic side effects including weight gain, increased triglycerides, and diabetes, compelling effectiveness data are needed to consider these agents as first- or second-line treatment options.

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