neurobiología

66

CURRENT AND EMERGINGTHERAPEUTICS OF ANXIETY AND

STRESS DISORDERS

JACK M. GORMANJUSTINE M. KENT

JEREMY D. COPLAN

During the 1960s and 1970s the concept of pharmacologicdissection became popular as a putative method for differ-entiating among different categories of psychiatric illness.At the time, it was widely held that anxiety disorders, butnot depression, respond to benzodiazepines, whereasdepression, but not anxiety disorders, responds to anti-depressants. Panic disorder was held to be the one exception,responding only to antidepressants. Alprazolam, selectiveserotonin reuptake inhibitors (SSRIs), and buspirone hadnot yet been tested. On the basis of these observations, itwas asserted that anxiety and depression are clearly distinctcategories of illness.

Thirty years later we find that the situation has changeddramatically. The first inconsistency with the notion ofpharmacologic dissection was the clear finding that panicdisorder does indeed respond to benzodiazepines. For awhile, alprazolam and then clonazepam were regarded bysome authorities and clinicians as first-line therapies forpanic disorder, replacing tricyclics and monoamine oxidaseinhibitors.

An even more potent challenge, however, has come fromthe evidence not only that anxiety disorders respond to anti-depressants but also that antidepressants work better thanbenzodiazepines for most of them. As this chapter discusses,antidepressants are now considered the appropriate pharma-cologic intervention for panic disorder, social anxiety disor-der, posttraumatic stress disorder (PTSD), and generalizedanxiety disorder (GAD). The latter case is particularly inter-esting. Once considered the sole domain of benzodiaze-pines, GAD was then shown to be responsive to a drug inan entirely new category, with no relationship whatsoeverto the benzodiazepine receptor or -aminobutyric acid(GABA)buspirone. At about the same time evidence

Jack M. Gorman, Justine M. Kent, and Jeremy D. Coplan: ColumbiaUniversity, New York State Psychiatric Institute, New York, New York.

began to accumulate from just a few studies that GADmight also respond to antidepressants. This evidence waslargely ignored, and pharmaceutical companies were advisedto stay away from GAD, a condition supposedly so placebo-responsive that no drug would ever be shown effective inlarge clinical trials. To the contrary, venlafaxine is now ap-proved by the Food and Drug Administration (FDA) forthe treatment of GAD, and there is also evidence for theefficacy of paroxetine.

At this point, rather than dissecting among the anxietydisorders or between anxiety disorders and depression, phar-macologic grounds might lead one to assume that theseconditions are variants of each other. This also would proba-bly be an oversimplification. Anxiety and depression aredifferent and we can make distinctions among the anxietydisorders. Nevertheless, the finding that antidepressants areso ubiquitously effective across categories raises interestingquestions and challenges. We review here the evidence forresponsiveness of four anxiety disorders to medication.

PANIC DISORDER

Panic disorder (PD) has a reported lifetime prevalence ofbetween 1.5% and 3.5% (1,2), is highly comorbid withmajor depression, and is associated in its own right withsignificant impairment in psychosocial functioning inde-pendent of depressive symptomatology. In the Epidemio-logic Catchment Area study, subjective reports of patientswith PD indicate that approximately one-third experiencepoor physical and emotional health, rates comparable withmajor depression (2).

Historical Notes

Recognized as a distinct disorder that could be distinguishedfrom the general diagnosis of anxious neurosis, in part

Neuropsychopharmacology: The Fifth Generation of Progress968

through the pharmacologic dissection work of Klein andFink (3,4) in the 1960s, PD was first categorized as a discretediagnostic entity in the Diagnostic and Statistical Manual ofMental Disorders, third edition (DSM-III), in 1980. Despitesome minor changes in diagnostic criteria in the third edi-tion revised (DSM-III-R) and the fourth edition (DSM-IV),primarily involving the number and frequency of attacksrequired, the major criteria remain essentially the same. Thekey triad of symptoms are (a) the occurrence of spontaneouspanic attacks; (b) the presence of anticipatory anxiety; and(c) the presence of phobic avoidance, resulting in some de-gree of functional impairment. The pharmacologic treat-ment of PD has evolved dramatically since the heterocyclicantidepressants were first established as possessing powerfulantipanic properties in the early 1960s (4). Throughout the1970s and 1980s, the heterocyclic antidepressants contin-ued to be the mainstay of pharmacologic treatment of PD,with the monoamine oxidase inhibitors (MAOIs) used pri-marily in patients who failed trials of heterocyclic antide-pressants. The high potency benzodiazepines were increas-ingly prescribed as both primary and adjunct treatmentsthroughout this same time period. With the introductionof the SSRIs in the United States in the late 1980s andearly 1990s for the treatment of depression, this class ofdrug began being used in the treatment of PD with promis-ing results. In the late 1990s, several large-scale, controlledtrials established the SSRIs to be effective and safe treat-ments for PD, thus supplanting the heterocyclic antidepres-sants and benzodiazepines as first-line treatment. Althoughthe serotonin, norepinephrine, and GABA systems remainthe traditional targets for the majority of antipanic medica-tions, widely different classes of drugs targeting an array ofneurochemical systems are now being explored as potentialtreatments for PD.

Heterocyclic Antidepressants

Numerous controlled trials have confirmed the efficacy ofthe heterocyclic antidepressants, since the initial observa-tions of Klein (4), in both the acute and long-term treatmentof PD. In general, heterocyclics with greatest serotoninergicreuptake inhibition effect, such as imipramine and clomi-pramine, appear to be most effective in the treatment ofPD (57). By far the best studied of this class of antidepres-sants is imipramine, which due to its well-established effi-cacy has been generally accepted as the gold standard of PDtreatment (8). In the Cross-National Collaborative PanicStudy, more than 1,000 patients in 14 countries were ran-domized into a study comparing imipramine, alprazolam,and placebo (9). At the studys end, imipramine and alpra-zolam were found to have comparable efficacy, and bothwere significantly superior to placebo on most outcomemeasures. A positive doseresponse relationship betweenimipramine levels and clinical improvement has been re-ported, with plasma levels of 140 mg/mL associated with the

greatest improvement in panic symptoms (10). Althoughseveral other of the heterocyclic antidepressants have beenused in the treatment of PD (amitryptyline, desipramine,nortriptyline, clomipramine), far less controlled data areavailable supporting their efficacy (11,12). Although effec-tive, side effects often limit the use of this class of medicationin the treatment of PD. This is particularly true in the caseof clomipramine, which due to its anticholinergic and anti-histaminergic effects can be difficult for patients to tolerate(13). The use of the heterocyclic antidepressants is oftenlimited by the presence of comorbid medical conditionssuch as cardiac disease and glaucoma. Lethality in overdoseis another concern given the reported high rates of suicidein this population when depression is comorbid (1416).Although the SSRIs are often touted as offering a moretolerable side-effect profile than the heterocyclics, the side-effect burden of imipramine has recently been shown to becomparable to, although different in nature from, that ofthe SSRIs, with most side effects (with the exception of drymouth, sweating, and constipation) not persisting beyondthe first few weeks of treatment (17).

Monoamine Oxidase Inhibitors

Like the heterocyclic antidepressants, the MAOIs, areclearly established to be effective in the treatment of PD, yethave yielded to newer antidepressants with similar antipanicefficacies but less drugdrug and dietary interactions.Among the MAOIs, phenelzine is the best studied in PD,and its efficacy in the acute treatment of PD is supportedby several studies (1820). Dietary restrictions, lethality inoverdose, and drug interaction concerns limit the wide-spread use of the traditional MAOIs. Stemming from theseconcerns, the reversible inhibitors of MAOI (RIMAs) weredeveloped and have demonstrably fewer drugdrug and di-etary interactions. These include moclobemide and brofaro-mine, neither of which is currently marketed in the UnitedStates, but are used extensively throughout Europe andother parts of the world. The efficacy of moclobemide hasbeen shown in the treatment of PD in placebo-controlledstudies (21), and moclobemide has been found to be compa-rable in efficacy to clomipramine (21) and fluoxetine (22).Moclobemide has also been shown to be as effective as fluox-etine in maintenance treatment of PD (23). Brofarominewas shown to be comparable to fluvoxamine (24) and clomi-pramine (25) in small randomized, double-blind studieslacking a placebo. In a placebo-controlled study of the effi-cacy of brofaromine, 30 patients with PD (DSM-III-R defi-nition) were treated for 12 weeks. Although there was nosignificant reduction in the number of panic attacks forthose patients treated with brofaromine, patients demon-strated clinical improvement on several other measures, in-cluding agoraphobic avoidance (26).

Chapter 66: Current and Emerging Therapeutics of Anxiety and Stress Disorders 969

Benzodiazepines

The high-potency benzodiazepines, another mainstay oftreatment for PD, have been shown to be effective, welltolerated, and safe. In the absence of comorbid substanceabuse, concerns about abuse potential have proven largelyunfounded in this population (2730). Among the benzo-diazepines, alprazolam and clonazepam are labeled for thetreatment of panic disorder and have been shown in numer-ous, controlled trials to be effective treatments (3136).Clonazepam, with a long half-life of 20 to 50 hours, allowsfewer doses per day than the short-acting alprazolam, andmay reduce the likelihood of rebound symptoms betweendoses. The benzodiazepines have repeatedly been shown tooffer an early advantage in the treatment of anxiety by pro-viding almost immediate relief of anxiety-related somaticsymptoms such as muscle tension and insomnia (27,37,38).However, in the long term, antidepressants may offer theadvantage of better targeting and relief of psychic symptomsof anxiety (37), and provide the added benefit of treatingassociated depressive symptoms. Discontinuing long-termpharmacotherapy with benzodiazepines can be difficult,with as many as a third of patients with PD being unable todiscontinue use due to dependence/withdrawal (27). Thus,despite their efficacy and safety, many clinicians remain con-cerned about the risk of dependence (39).

Selective Serotonin Reuptake Inhibitors(SSRIs)

Among the antidepressants currently used in the treatmentof PD, the SSRIs have become first-line treatments (40,41).Following in the wake of numerous promising open andcontrolled trials, several large, multicenter, placebo-con-trolled studies involving hundreds of subjects each havedemonstrated the efficacy of the SSRIs in the treatment ofPD (Table 66.1) (4250). Both sertraline and paroxetineare labeled in the United States for the treatment of PD,and citalopram is approved in several European countriesfor this indication. Although fluvoxamine has not beenstudied in clinical trials on the scale of the other SSRIs, ithas been shown to be efficacious in smaller (100 subjects),randomized, placebo-controlled studies (25,44). Despitetheir established efficacy in the treatment of PD, there arecertain problems inherent in prescribing the SSRIs in pa-tients with PD. Of primary concern on the initiation oftreatment is the commonly observed anxiogenic effect,which, despite being dose-dependent, can nonetheless makethe initial several days of treatment a challenge for patients.Initiating treatment with a dose of one-fourth to one-halfthat of the normal starting dose may greatly reduce thepatients feelings of restlessness and increased anxiety. Thedelayed onset of anxiolytic action contributes to making theperiod of SSRI initiation difficult for patients with PD.Other effects such as sexual dysfunction and weight gain

with long-term use can make these drugs as problematic asearlier classes for some patients. Overall, though, the side-effect burden associated with SSRI treatment has beenshown to be more tolerable for most patients than the het-erocyclics and benzodiazepines (51). Because the SSRIs havebeen associated with a discontinuation syndrome character-ized by anxiety, tremor, dizziness, paresthesias, nausea, andother symptoms when abruptly stopped, these medicationsshould be tapered over a few weeks, if possible, to minimizediscontinuation symptoms (38).

Newer Antidepressants

Among the newer antidepressants, several have demon-strated promise in PD. Venlafaxine, a serotonin-norepi-nephrine reuptake inhibitor, has shown efficacy (on somemeasures) in a small, placebo-controlled study (52). Nefazo-done, a weak serotonin-norepinephrine reuptake inhibitorwith serotonin receptor subtype 2C (5-HT2C) antagonistproperties, has been shown to reduce anxiety in depressedpatients with comorbid PD (53). Mirtazapine enhancesboth noradrenergic and serotoninergic neurotransmissionwithout reuptake inhibition. Results of an open study in-volving ten patients suggested that mirtazapine might beeffective in the treatment of PD (54). More recently, in adouble-blind randomized trial comparing mirtazapine andfluoxetine in the treatment of PD, both drugs showed com-parable efficacy on the primary outcome measures and onmost secondary outcome measures (55). Adverse events dif-fered between treatments, with weight gain occurring morefrequently in those patients receiving mirtazapine, whereasnausea and paresthesias occurred more often in those receiv-ing fluoxetine.

Anticonvulsants

Among the anticonvulsants being used in the treatment ofPD are valproate and carbamazepine, and the newest anti-convulsants gabapentin, lamotrigine, pregabalin, and viga-batrin. Valproate has shown promise in several open trials(5658), and one small placebo-controlled study (59). Itmay be particularly effective when mood instability is com-orbid (60). There is far less support for the use of carbamaze-pine in the treatment of PD, with uncontrolled studies inpatients with PD with EEG abnormalities demonstratingsome benefit from carbamazepine treatment (58). However,the only controlled trial of carbamazepine in a small numberof PD patients (N 14) did not report a significant differ-ence for carbamazepine versus placebo in reducing panicattack frequency (61). Gabapentin has shown promise (62)and is recognized as having a benign side-effect profile. La-motrigine, pregabalin, and vigabatrin are currently underinvestigation.


TABLE 66.1. EFFICACY OF THE SSRIs IN THE ACUTE TREATMENT OF PANIC DISORDER BASED ONLARGE-SCALE, PLACEBO-CONTROLLED STUDIES

SSRI Investigators Study Design Dose Range Outcome

Fluoxetine Michelson et al., Multicenter, 10-week Fixed dose: 10 or 20-mg dose was most effective, demonstrating1998 study of 243 patients 20 mg/day significant change versus placebo on panic

attack frequency, CGI improvement scores,Hamilton Anxiety and Depression scores,phobic symptoms, and functional impairmentas measured by the Sheehan Disability Scale(family life and social life); the two fluoxetinegroups did not differ from placebo in thenumber of patients who were panic-free atendpoint

Michelson et al., Multicenter, 12-week Flexible dose: A significantly greater percentage of patients2000 study of 180 patients 2060 mg/day on fluoxetine were panic-free at endpoint

(mean dose = (42%, versus 28% on placebo); significant20 mg) change versus placebo were found for the

CGI Severity, HAM-A, State Anxiety Inventory,and Sheenhan Disability Scale (work andsocial impairment)

Fluvoxamine Black et al., 1993 Multicenter, 8-week Flexible dose: up Fluvoxamine was superior to placebo andstudy of 75 patients to 300 mg/day cognitive therapy at endpoint asrandomized to (mean dose = measured by the Clinical Anxiety Scale andeither fluvoxamine, 230 mg) CGI Severity and Improvement scales;cognitive therapy, fluvoxamine was superior to placebo asor placebo measured by a greater reduction in mean

panic attack severity, and number ofpanic-free patients; fluvoxamine-treatedpatients demonstrated significant reductionsversus placebo on several measures of theSheehan Disability Scale (work, social/leisure)

Paroxetine Oehrberg et al., Multicenter, 12-week Flexible dose: Number of patients with at least 50% reduction1995 study of 120 2060 mg/day in panic attacks was significantly greater in

patientsall the paroxetine-treated than placebo group,received cognitive as was number of patients who had only onetherapy or no panic attacks during the final study

week. The paroxetine group hadsignificantly greater mean reductions inHAM-A and CGI scores versus placebo

Ballenger et al., Multicenter, 10-week Fixed dose: 10, 20, 40-mg group demonstrated the greatest1998 study of 278 patients or 40 mg/day effects, with significant improvement versus

placebo on measures of reduction in numberof panic attacks, intensity of attacks, CGISeverity and Improvement scores, phobicfear score, HAM-A score, and MADRS

Sertraline Pollack et al., Multicenter, 10-week Flexible dose: Significant decreases versus placebo at1998 study of 176 patients 50200 mg endpoint in number of panic attacks, CGI

Improvement and Severity scales, PDSSscores; sertraline also demonstratedsuperiority on improvement in quality oflife scores

Sheikh et al., Pooled data from two Fixed dose: All three doses of sertraline were superior to2000 12-week studies with 50, 100, or placebo on frequency of panic attacks, CGI

a total of 322 200 mg/day Improvement, and change in panic burdenpatients (attack frequency X severity), with no

consistent dose-response effect

(continued)


TABLE 66.1. (continued)

SSRI Investigators Study Design Dose Range Outcome

Citalopram Wade et al., Multicenter, 8-week Fixed dose: Patients treated with citalopram 20/30 or 1997 comparative study citalopram 10 or 40/60 mg/day were comparable to

with clomipramine 15 mg/day, 20 or clomipramine and superior to placebo asand placebo of 30 mg/day, 40 or measured by the number of patients475 patients 60 mg/day; panic-free in the final week of treatment,

clomipramine and by mean reduction in HAM-A total and60 or 90 mg/day psychic subscale, and the MADRS; only the

40/60-mg/day dose demonstratedsuperiority to placebo, along withclomipramine, on the HAM-A somaticsubscale; on the Physicians GlobalImprovement Scale and Patients GlobalImprovement Scale, the 20/30-mg doseexhibited greater effects; however, both the20/30- and 40/60-mg/day doses were superior toplacebo

CGI, Clinical Global Impression; HAM, Hamilton Anxiety Rating Scale; MADRS, Montgomery-Ashberg Depression Rating Scale; SSRI, selective sero-tonin reuptake inhibitor.

Beta-Blockers

Although the beta-blockers are more commonly used in thetreatment of performance anxiety and as adjunctive treat-ment in PTSD, a small number of open studies suggest theymay be effective in the treatment of PD (63), although theyare not considered a first-line treatment.

Future Directions

Several classes of drugs, although initially viewed as promis-ing, have shown limited efficacy in the treatment of PD.These include buspirone, bupropion, ondansetron, and thecholecystokinin (CCK) antagonists (6467). A number ofnew classes of drugs are being studied, including the benzo-diazepine partial agonists such as abecarnil and pagaclone,and the corticotropin-releasing hormone (CRH) inhibitors.Experimental agents showing promise in panic-like modelsin rodents include the group II metabotropic glutamate re-ceptor agonist LY354740 (68) and drugs acting at the neu-ropeptide receptors, including neuropeptide-Y agonists andneurokinin substance P antagonists (69).

In summary, the expansion of the antipanic armamentar-ium suggests that, as with many of the psychiatric disorders,there is no single effective treatment of PD. Among themost commonly prescribed classes of drugs for the treatmentof PD [benzodiazepines, SSRIs, tricyclic antidepressants(TCAs), and MAOIs], there are probably no major differ-ences in treatment efficacy, with most reported differencesin efficacy between classes probably attributable to differ-ences in study design and samples (27). The use of antide-pressants, however, and particularly the SSRIs, has sup-planted the long-term use of benzodiazepines for this

disorder. Antidepressant use has two main advantages overthe benzodiazepines: (a) it provides antidepressant benefitsin a population highly susceptible to depressive symptom-atology and comorbid major depression (70), and (b) iteliminates the difficulties associated with withdrawal symp-toms upon benzodiazepine discontinuation. In the case ofcomparable efficacy, medication choice is based on factorssuch as latency to onset of therapeutic action, safety, andthe individual side-effect profiles of each medication. In thisregard, the SSRIs are currently considered first-line treat-ment for PD, demonstrating comparable efficacy and supe-rior tolerability to other treatment classes. Combinationtherapies are frequently used for treatment resistance, andan approach of prescribing a benzodiazepine at the initiationof treatment with an SSRI, and later tapering it, has provedto be popular with clinicians and has recently been demon-strated to be advantageous in the early stages of treatmentover an SSRI alone (71).

GENERALIZED ANXIETY DISORDER

The diagnostic criteria for generalized anxiety disorder(GAD) have evolved over the past two decades, undergoingsubstantial revision to the current definition emphasizingexcessive, unrealistic worry as the cardinal feature of thisdisorder. Defined in 1980 in DSM-III as a disorder of con-tinuous or persistent worry symptoms of at least 1 monthsduration, the diagnosis of GAD was reframed in DSM-III-R to require symptoms extended for 6 months or longer,and an emphasis on unrealistic worry was stressed. WithDSM-IV, GAD was defined as excessive and persistent


worry, accompanied by three or more physical or psycholog-ical symptoms of anxiety, persisting 6 months or longer.Because of the shift in diagnostic criteria and required dura-tion of symptoms over the years, comparison of pharmaco-logic treatment studies performed prior to the introductionof DSM-III-R is difficult.

In comparison with panic disorder, PTSD, and obses-sive-compulsive disorder (OCD), there are fewer publica-tions devoted to GAD overall, and only a limited numberof published controlled clinical medication trials. Severalreasons have been proposed for this deficiency, includingunderrepresentation in clinical settings and a view of GADas a mild disorder (72). In reality, GAD is one of themost commonly diagnosed anxiety disorders, with a lifetimeprevalence of 4.1% to 6.6% (73,74), which is often chronic(75), and associated with significant compromise in func-tioning (76,77). There remains substantial controversy sur-rounding the validity of GAD as a primary disorder, asopposed to a comorbid condition or a prodromal/residualphase of another disorder (78,79). Findings from epidemio-logic studies of GAD suggest that current comorbidity withother disorders is as high as 58% to 65% (73,76), and life-time comorbidity rates are between 80% and 90% (76,80).Non-comorbid, pure GAD lifetime prevalence was foundto be only 0.5% in the National Comorbidity Survey (76).Overall, the sum of studies examining quality of life issuessupport the idea that non-comorbid GAD is relatively rare,but is associated with significant impairment in its ownright (81,82).

Historical Notes

Prior to the introduction of the benzodiazepines, the mainagents available for the treatment of anxiety were the tri-cyclic antidepressants (doxepin, imipramine, amitrypty-line), antihistamines (diphenhydramine, hydroxyzine), bar-biturates (mephobarbital), and the sedative antianxietyagent meprobamate (Milltown). The development of thebenzodiazepines in the mid-1950s led to the introductionof chlordiazepoxide (Librium) in 1959, and ushered in anera of benzodiazepine use in the treatment of a wide rangeof anxiety symptoms related to anxiety and mood disorders,psychosis, and alcohol withdrawal. Greater tolerability andthe superior safety profiles of the benzodiazepines resultedin a sharp decline in the use of barbiturates for anxietydisorders (83). The benzodiazepines have remained a com-mon treatment choice for GAD throughout the past twodecades. However, concerns about dependence and with-drawal, short-term memory impairment, interactions withalcohol, and psychomotor impairment have resulted in in-creased interest in alternative medications. The introductionof drugs such as buspirone (1986), SSRIs (from 1980 on),and the serotonin and norepinephrine reuptake inhibitor(SNRI) venlafaxine (1994) have broadened the availabletreatment armamentarium for GAD significantly.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) have been in use in thetreatment of GAD for many decades; however, data sup-porting their efficacy from controlled clinical trials are ex-tremely limited. Imipramine is the only TCA shown to beeffective in placebo-controlled trials of GAD patients with-out comorbid depression (84,85). In comparator trials, imi-pramine has been shown to have clinical efficacy comparableto the benzodiazepines (84,86,87).

Benzodiazepines

Five benzodiazepines (alprazolam, chlordiazepoxide, clo-razepate, diazepam, and lorazepam) are currently labeled astreatments for anxiety (GAD) (88). Clonazepam and alpra-zolam are labeled specifically for the treatment of PD. Thereare a limited number of clinical trials demonstrating theefficacy of benzodiazepines in the treatment of GAD in itscurrent (DSM-IV) definition (89,90); however, benzodiaze-pines have been shown effective in controlled studies usingDSM-III criteria for GAD (91).

Buspirone

Buspirone is a serotonin receptor subtype 1A (5-HT1A) par-tial agonist with anxiolytic properties. In a metaanalysis ofplacebo-controlled comparator trials with benzodiazepines,buspirone showed comparable efficacy to the benzodiaze-pines in eight trials in 735 patients meeting DSM-III criteria(1 months duration of illness) for GAD (92). In a metaana-lysis of eight placebo-controlled studies in over 500 GADpatients with coexisting depressive symptoms, buspironedemonstrated significant superiority to placebo (93). Priorrecent treatment with a benzodiazepine (1 month) hasbeen shown to predict poor response to subsequent buspir-one treatment in GAD (92). This may be due to a combina-tion of factors including the presence of benzodiazepinewithdrawal, exacerbation of benzodiazepine discontinua-tion symptoms by buspirone and its metabolite a-(2-pyridi-nyl)-piperazine via enhancement of noradrenergic activity(94), and psychological factors such as patient expectations.

SSRIs

The first published study of a medication with significantserotonin reuptake inhibition properties in GAD involveda small, open-label trial of clomipramine (95). The sugges-tion of efficacy in this study, along with the success of clomi-pramine in treating other anxiety disorders, raised interestin pharmacologic agents for GAD that target the serotonin-ergic system. Following several years later, the first compari-son trial of an SSRI in the treatment of GAD was publishedby Rocca and colleagues (89). Treatment efficacy of paroxe-tine was compared with the tricyclic imipramine and the


benzodiazepine 2-chlordesmethyldiazepam in 81 subjectswith GAD. Of the 63 patients who completed the random-ized, 8-week study, 68% of the paroxetine group, 72% ofthe imipramine group, and 55% of the 2-chlordesmethyl-diazepam group were judged to be responders as measuredby a 50% or more decrease in Hamilton Anxiety RatingScale (HAM-A) scores. The greatest improvement duringthe first 2 weeks occurred in the group receiving the benzo-diazepine, as expected by the early relief of physical anxietysymptoms and insomnia provided by this class of medica-tion. However, from the fourth week forward, the paroxe-tine and imipramine groups demonstrated superior benefits,particularly in the area of psychic symptoms of anxiety.More recently, the efficacy of paroxetine was demonstratedin a large, fixed-dose study of more than 500 patients witha DSM-IV diagnosis of GAD without major depression(96). Patients were randomized to receive paroxetine 20 mg/day, paroxetine 40 mg/day, or placebo for 8 weeks. Patientsreceiving both doses of paroxetine demonstrated significantdifferences in the primary outcome measure, reduction inHAM-A score, versus placebo, with 68% on 20 mg paroxet-ine and 81% on 40 mg paroxetine rated as responders basedon a Clinical Global Impression (CGI-I) score of 1 or 2,versus 52% on placebo.

Venlafaxine

Venlafaxine is an inhibitor of SNRI. Venlafaxine has re-cently been demonstrated in humans, using peripheral mea-sures, to have primarily 5-HT reuptake inhibition propertiesat low doses (75 mg/day), with increasing norepinephrine(NE) reuptake inhibition properties at higher doses (375mg/day) (97). Shown to be effective in the treatment ofanxiety symptoms associated with major depression (98,99),the extended release (XR) form of venlafaxine has beenshown to be effective in the treatment of GAD (DSM-IVcriteria) in several placebo-controlled studies (100,101). Ina placebo-controlled multicenter comparator trial, 405 pa-tients with GAD were randomized to receive venlafaxineXR (75 or 150 mg/day), buspirone (30 mg/day), or placebofor 8 weeks. For the 365 patients for whom efficacy mea-sures were obtained, there was no significant difference be-tween groups in improvement on the primary outcomemeasure, the HAM-A. However, both doses of venlafaxinewere shown to be superior to placebo in improving HAM-A psychic anxiety and anxious mood scores at the endpoint(week 8), and venlafaxine demonstrated superiority to pla-cebo and buspirone on the CGI-S at the same time point.More robust efficacy findings for venlafaxine were reportedin a recent large, multicenter trial, involving 377 outpatientswith GAD without comorbid depression (101). Patientswere randomly assigned to receive either placebo or venla-faxine XR at one of three doses (75, 150, or 225 mg/day)for 8 weeks. Of the 349 patients included in the efficacyanalysis, those receiving 225 mg/day demonstrated signifi-

cant improvement across seven of the eight outcome mea-sures, and the 225-mg/day group was the only group toshow significant improvement in scores on both of the CGIsubscales (severity, global improvement) versus placebo.

Other Agents (Trazodone, Nefazodone,Anticonvulsants, Partial GABA Agonists)

In a randomized, placebo-controlled comparator trial of tra-zodone, diazepam, and imipramine in the treatment of 230patients with GAD, trazodone was found to be superiorto placebo yet somewhat less effective than diazepam andimipramine at the studys endpoint (84). The antidepressantnefazodone, which antagonizes the 5-HT2C receptor andinhibits the reuptake of both serotonin and NE, has shownpromise in the treatment of GAD in an open trial (102).Anticonvulsants such as valproate and carbamazepine havebeen used in the treatment of GAD; however, evidence oftheir efficacy is primarily anecdotal, as there are no con-trolled clinical trials for either of these medications in thetreatment of GAD (103). Other agents such as the partialGABA agonist abecarnil have not demonstrated significantefficacy versus placebo in GAD (101).

In summary, although the benzodiazepines have beenthe mainstay of pharmacotherapy for GAD since their intro-duction, significant concerns regarding their long-term usein GAD have fueled the search for other effective treat-ments. Given the chronic nature of GAD, medications suchas buspirone, and the antidepressants venlafaxine and parox-etine, which have fewer effects on cognitive and psychomo-tor function, now represent first-line therapies for GAD.

SOCIAL PHOBIA

Social phobia (SP) (or social anxiety disorder) is reportedto be the most common anxiety disorder with a 1-year prev-alence of 7% to 8% and a lifetime prevalence of 13% to14% in patients aged 15 to 54 years. Social anxiety disordercan be classified into two subtypesdiscrete and general-ized. Level of disability with SP can be high, and 70% to80% of patients have comorbid psychiatric disorders, partic-ularly depression and substance abuse (104). Given the highdegree of burden of illness in SP, its treatment has becomea major priority.

Historical Notes

Liebowitz et al. (105) noted that SP, like atypical depression(106), had a specific responsivity to the MAOIs, whereasTCAs, although effective for PD and typical majordepression, were not effective for SP (107). The efficacy ofthe MAOIs, which block reuptake of dopamine in additionto NE and serotonin, prompted speculation about a poten-


tial dopaminergic component to the neurobiology of SP.Several open clinical studies have attempted to utilize thedopamine component concept in phamacotherapy withsome success, e.g., seligiline (108) and pergolide (109).However, as data accumulated, other systems were also im-plicated, and the pharmacologic dissection approach seemedless applicable (see above). Positive results with the high-potency benzodiazepine clonazepam (110) suggested aGABAergic component. However, the suitability of benzo-diazepines for long-term treatment of a chronic conditionsuch as social anxiety disorder has been questioned. In addi-tion, the benzodiazepines are ineffective against comorbiddepression.

RIMAs (Reversible Inhibitor ofMonoamine Oxidase A)

Although phenelzine demonstrated efficacy, the need fordietary restrictions severely limited its use. Moclobemide is aRIMA with a much lower propensity to induce hypertensivecrises and has a more favorable side-effect profile. Moclobe-mide had been reported to have efficacy in early studies inthe treatment of social phobia (111). However, conflictingresults have subsequently been reported in placebo-con-trolled trials. Some studies have shown moclobemide to bemore effective than placebo, whereas two recent, large, ran-domized placebo-controlled trials conducted in the UnitedStates have reported less robust results (112,113). Brofaro-mine, another drug in the RIMA class, may still hold prom-ise. The safety and efficacy of brofaromine were examinedin a multicenter trial of 102 outpatients with SP (114).Brofaromine produced a significantly greater change frombaseline in Liebowitz Social Anxiety Scale (LSAS) scorescompared with placebo.

SSRIs

Based on clinical evidence, SSRIs are the first-line treatmentin social anxiety disorder (115). The most extensive databasefor the treatment of social anxiety disorder exists for theSSRI paroxetine. Several large, multicenter, placebo-con-trolled trials have been completed on three different conti-nents (116119). In all cited studies, a significantly greaterproportion of patients responded to paroxetine treatmentcompared with placebo. Paroxetine is currently the onlySSRI licensed for use in this condition in the United States.The SSRIs are particularly attractive agents due to theirfavorable tolerance and safety profile, although typical SSRIside effects may nevertheless be problematic.

Despite promising open studies with fluvoxamine, fluox-etine, and citalopram (120,121) only fluvoxamine has beentested under double-blind, randomized, placebo-controlledtrial conditions (122). Like paroxetine, fluvoxamine yieldedefficacy data superior to placebo. A report on a multicentersertraline trial was pending at the time of this writing.

As is the case with PD, buspirone does not appear effec-tive for SP as monotherapy in placebo-controlled double-blind studies (123). It may, however, have a role in augmen-tation of the SSRIs.

Serotonin/Norepinephrine ReuptakeInhibitors

One open label study (124) aimed to evaluate the clinicalresponse to venlafaxine in SP in 12 patients who were nonre-sponders to SSRIs, and to assess how the response could beinfluenced by Axis II comorbidity with avoidant personalitydisorder (APD). The duration of the study was 15 weeksusing an open flexible-dosing regimen in individuals withor without concomitant APD. Venlafaxine improved SPand/or APD symptomatology, as demonstrated by decreas-ing LSAS total scores. Similar favorable open-labeled resultshave been reported for nefazodone (125,126). Placebo-con-trolled studies are warranted.

Anticonvulsants

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy andsafety of gabapentin in relieving the symptoms of socialphobia. A significant reduction in the symptoms of socialphobia was observed among patients on gabapentin com-pared with those on placebo as evaluated by clinician- andpatient-rated scales (127). Adverse events were consistentwith the known side-effect profile of gabapentin. The effi-cacy of other novel anticonvulsants remains to be investi-gated, although encouraging results have been reported forthe gabapentin-like compound, pregabalin (128).

POSTTRAUMATIC STRESS DISORDER

Despite the high prevalence, chronicity, and associatedcomorbidity of PTSD in the community, relatively few pla-cebo-controlled studies have evaluated the efficacy of phar-macotherapy for this disorder. The symptom overlap be-tween PTSD and other pharmacotherapy-responsivedisorders has suggested that pharmacotherapy might be ef-fective. Nevertheless, in those placebo-controlled trials in-vestigating the pharmacotherapy of PTSD that have beencarried out, statistically significant efficacy for the treatmentbeing studied has traditionally been inconsistent. One ofthe key methodologic limitations has been the fact that moststudies have been conducted with war veterans, who arelikely to constitute a more treatment-refractory population.

SSRIs

More recently, a total of 187 civilian outpatients with DSM-III-R PTSD (73% were women, and 61.5% experienced


physical or sexual assault) were treated with the SSRI sertra-line in a placebo-controlled design (129). Sertraline effec-tively diminished symptoms of PTSD of moderate tomarked severity in comparison to placebo. Using a conserva-tive last-observation-carried-forward analysis, treatmentwith sertraline resulted in a responder rate of 53% at thestudys endpoint compared with 32% for placebo (p .008). Sertraline is the first medication approved by theFDA for the treatment of PTSD. Similar positive resultshave been reported for the SSRI fluoxetine in civilian popu-lations (130,131). In a study by van der Kolk et al. (132),fluoxetine was found to be most effective in the nonveteranversus veteran portion of his study sample. Although pub-lished placebo-controlled data for paroxetine are not avail-able, Marshall et al. (133) have argued that this particularSSRI may have specific advantages because of its relativelylow activating properties. Direct comparative studies arelacking.

Combat Veteran PTSD

Among combat veterans, PTSD is a highly prevalent andoften chronic disorder, persisting in as many as 15% ofVietnam veterans for at least 20 years (134). Treatmentresponse in veterans with combat-related PTSD has beendisappointing. Although anxiolytics, anticonvulsants, anti-psychotics, and antidepressants, including SSRIs, have beentried, none has been consistently associated with improve-ment in all primary symptom domains (i.e., intrusive recol-lections, avoidance/numbing, and hyperarousal). In an openstudy using nefazodone, at mean daily doses of 430 mg(range, 200 to 600 mg/day), 19 treatment-refractory PTSDpatients demonstrated benefit after 12 weeks (134). Double-blind placebo controlled studies would be of interest.

The efficacy of the antidepressant drug bupropion in thetreatment of male combat veterans with chronic PTSD wasinvestigated in an open-label study of 6 weeks duration(135). Improvement was seen in hyperarousal symptomsbut was less significant than the change in depressive symp-toms. Mirtazapine, a novel drug with both noradrenergicand serotoninergic properties, may be effective in individu-als who demonstrate intolerance to side effects of, or a lim-ited response to, SSRIs. Three of six severely refractoryPTSD patients treated with mirtazapine were assessed asresponders in a pilot study (136). Case reports have sug-gested benefit for refractory patients treated with venlafaxine(137) and risperidone (138). Raskind et al. (139) reportedthat the 1-adrenergic antagonist prazosin ameliorated com-bat nightmares in a small sample of veterans with PTSD.

Monoamine Oxidase Inhibitors

Traditional MAOIs have shown efficacy in the treatmentof PTSD, but their use is limited by serious drug and foodinteractions. Moclobemide, a RIMA, is relatively free of

these limitations and is therefore potentially useful in thetreatment of PTSD. Moclobemide was highly effective inan open-labeled design (140). However, in a double-blind,randomized, placebo-controlled, multicenter study, brofar-omine, also a RIMA, failed to surpass efficacy levels seenwith placebo. Thus, the role for RIMAs remains unclear atthis time.

Anticonvulsants

Despite a long-recognized role for anticonvulsants in thetreatment of PTSD (141), few placebo-controlled studieshave been reported. An open study of divalproex reportedfavorable results (142). In a placebo-controlled study, pa-tients treated with lamotrigine showed improvement on re-experiencing and avoidance/numbing symptoms comparedto placebo-treated patients (143). The authors concludedthat lamotrigine may be effective as a primary psychophar-macologic treatment in both combat and civilian PTSDand could also be considered as an adjunct to antidepressanttherapy used in the treatment of PTSD. Further large-sam-ple, double-blind, placebo-controlled trials are warranted.

Summary and Future Directions

Current management of PTSD is well summarized by Da-vidson et al. (144). Clearly, there are many challenges associ-ated with the treatment of PTSD. Different patients withPTSD may not respond to pharmacotherapy in the samemanner, and it is unclear whether this is related to gender,trauma type, or other factors. Antidepressants, particularlythe SSRIs, are currently the form of pharmacotherapy forpatients with PTSD with greatest support in the literature.Psychosocial techniques, such as cognitive-behavioral ther-apy or stress inoculation training, are effective and may beconsidered as adjunctive therapy with medication. Largerplacebo-controlled studies for many different classes ofmedications would be desirable in moving the field forward.In addition, carefully conducted polypharmacy in whichdrug interactions are well understood may well be necessaryfor more difficult cases.

In a review by Shalev and colleagues (145), a synthesisof findings in PTSD studies is provided. Most studies ex-plored a single treatment modality (e.g., pharmacologic, be-havioral). The cumulated evidence from these studies sug-gests that several treatment protocols reduce PTSDsymptoms and improve the patients quality of life. Themagnitude of the results, however, was often limited, andremission was rarely achieved. Given the shortcoming ofunidimensional treatment of PTSD, it was suggested bythe authors that combining biological, psychological, andpsychosocial treatment yields the best results.

A host of novel compounds show promise for the treat-ment of PTSD (146). Such classes of compounds includecorticotropin-releasing factor antagonists, neuropeptide-Y


enhancers, antiadrenergic compounds, drugs that down-regulate glucocorticoid receptors, more specific serotoniner-gic agents, agents that normalize opioid function, substanceP antagonists, N-methyl-D-aspartate facilitators, gluta-matergic antagonists, and antikindling/antisensitization an-ticonvulsants.

CONCLUSION

Antidepressants are the logical first choice for most patientswith anxiety disorders, based on their efficacy and tolerabil-ity. Although maintaining a role, the use of benzodiazepinesfor first-line or long-term therapy is now less likely. Doesthis mean that anxiety disorders are a variant of depression?Certainly, anxiety disorders and depression are highly com-orbid. Untreated, the majority of patients with anxiety dis-orders eventually develop depression, whereas a large frac-tion of depressed patients suffer from clinically significantcomorbid anxiety, if not an overt syndromal anxiety dis-order.

Pharmacologic dissection is clearly perilous, leaving usprone to inferences based on limited knowledge. Most ofthe antidepressants that successfully treat anxiety disordersmanipulate the reuptake of serotonin, norepinephrine, orboth. Altering the brain circuits through these modulatoryneurotransmitters in turn has wide-ranging effects on manyother systems in the brain. The release of CRH from extra-hypothalamic sites like the amygdala is only one such sys-tem. Hence, there may be a common denominator amonganxiety disorders and between anxiety disorders and depres-sion at one or more points in these complex circuits.

The observation, then, that antidepressants work for thefour anxiety disorders discussed in this chapter warrants, inour opinion, only the following inference: it is highly likelythat some substrate of the serotonin and norepinephrinesystems is malfunctioning in several anxiety disorders anddepression. This could be the locus of a common geneticor environmental vulnerability to both categories of illness.Although it will not likely tell us that anxiety and depressionare fundamentally the same thing, the search for such com-mon substrates and vulnerabilities, suggested but not guar-anteed by the psychopharmacologic findings, is likely to bevery illuminating.

ACKNOWLEDGMENTS

Dr. Gorman has received research support from Pfizer,Eli Lilly, the National Institute of Mental Health, andNARSAD. In addition, he has been a consultant and re-ceived honoraria from a number of pharmaceutical compa-nies, including Pfizer, Eli Lilly, Bristol-Myers Squibb,Wyeth-Ayerst, SmithKline Beecham, Astra Zeneca, Janssen,Organon, Forrest, Parke-Davis, Lundbeck, Solvay, Merck,

Sanofi-Synthelabo, and Aventis. Dr. Kent has served as aconsultant for Bristol-Myers Squibb and SmithKline Bee-cham. Dr. Coplan has received research support fromSmithKline Beecham, Eli Lilly, and Janssen. In addition,he has served on a speakers bureau and/or an advisory boardfor the following companies: SmithKline Beecham, Wyeth-Ayerst, and Bristol-Myers Squibb.

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