Sunday, September 24, 2023
Anxiety disorders are the most common psychiatric disorders. Approximately 1 in 4 individuals in the United States reports a lifetime history of at least 1 anxiety disorder. According to the Epidemiologic Catchment Area (ECA) data, in a 6-month period, 6% of men and 13% of women in the United States have an anxiety disorder.[1] Comorbidity is also a significant problem, with approximately 75% of individuals with an anxiety disorder meeting criteria for at least 1 comorbid psychiatric condition. The lifetime prevalence of panic disorder ranges from 1.5% to 3.5%, social phobia from 2.4% to 13.3%, and generalized anxiety disorder (GAD) from 4.1% to 6.6%.[2-4] Despite these high prevalence rates, fewer than 30% of individuals who suffer from anxiety disorders seek treatment. Moreover, anxiety disorders are not culture-bound; they are prevalent worldwide, and their individual, societal, and economic impact is considerable. Currently, patients with anxiety disorders seldom receive appropriate treatment in primary care, most often due to underrecognition, misdiagnosis, and the complications of comorbidity. Several symposia at the International Congress of Biological Psychiatry in Sydney, Australia, addressed advances in the treatment of anxiety disorders. Speakers reviewed current and novel pharmacologic and combined treatment strategies for panic disorder, GAD, and social anxiety disorder (SAD) and discussed cross-cultural societal and cultural effects on anxiety disorders.
Panic disorder is a commonly occurring, chronic, often unremitting anxiety disorder that can be associated with extreme impairment and disability. The core symptoms of panic disorder are recurrent and often unexpected; panic attacks are often coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors (SSRIs) have emerged as the most favorable treatment due to their safe and tolerable side-effect profile. High-potency benzodiazepines, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and cognitive-behavioral therapy (CBT) are efficacious in the acute and long-term treatment of panic disorder.[5,6]
Vladen Starcevic, MD,[7] from the Nepean Hospital and University of Sydney, Australia, reviewed recent advances in the treatment of panic disorder, hoping to strike a balance between psychological and psychopharmacologic treatment options. According to Starcevic, our expectations for the treatment of panic disorder are manifold and demanding: fast response, disappearance of panic attacks, alleviation of general and anticipatory anxiety, decrease or disappearance of phobic avoidance, increased coping skills, improved quality of life, decreased vulnerability to relapse, long-term treatment efficacy, maintenance of treatment gains after treatment cessation, minimal propensity to induce dependence, good tolerability, few side effects, low cost, ease of administration, and ease of compliance. In the 1980s and 1990s, panic disorder received a preponderance of research focus. In recent years, however, there has been a "certain neglect" of pharmacologic advances for panic disorder, perhaps due to a perceived, or misperceived, notion that the current pharmacologic agents are effective. Long-term efficacy data suggest that acute treatment benefits often fail to endure over time, and relapse rates are high. Starcevic stated that there is "significant room for improvement" in the management of panic disorder. Both pharmacologic and cognitive-behavioral treatments suggest clinical efficacy in panic disorder,[5,6] yet the relative advantages and disadvantages of each are debated between the two camps. Dr. Starcevic outlined some of the primary areas of perceived advantage and disadvantage from a pharmacologic perspective.
"Perceived" advantages of pharmacologic interventions vs CBT:
"Perceived" disadvantages of pharmacologic interventions vs CBT:
To date, there has been equivocal evidence of increased treatment efficacy, long-term outcome, treatment compliance, and faster response with add-on medications. There is, however, good evidence that dependence-related problems have decreased, particularly since treatment no longer relies on short-acting benzodiazepines for longer-term treatment.[8,9]
Antidepressants (TCAs, SSRIs) and benzodiazepines were the first effective treatments for panic disorder and remain valuable tools in the management of panic and other anxiety disorders. There are publications supporting the efficacy of all SSRIs in the treatment of panic disorder,[10] and the US Food and Drug Administration (FDA) has approved paroxetine and sertraline for panic treatment. Meta-analyses suggest that both high-potency benzodiazepines and antidepressants are effective in reducing panic attacks, achieving a panic-free state, and improving anxiety, agoraphobic avoidance, and overall functional impairment.[11-13] Antidepressants may hold a distinct advantage over benzodiazepines in their ability to reduce depressive symptoms. Drawbacks exist for each drug class. Benzodiazepines are associated with sedation, interdose anxiety, and rebound symptoms upon discontinuation; TCAs provoke undesirable anticholinergic effects, which may be particularly troublesome for panic patients; and SSRIs have a slow therapeutic onset and may cause sexual side effects or hyperstimulation. Maximizing the strengths and minimizing the weaknesses of these agents can result in a successful combination treatment.
Combined pharmacotherapy may accelerate response and improve tolerability. Starcevic recommended beginning acute treatment with a benzodiazepine plus an SSRI, in order to reduce early treatment somatic side effects (eg, "jitteriness"), and continuing maintenance treatment with SSRI monotherapy. A slow benzodiazepine taper reduces the potential for abuse and/or rebound symptoms. Panic patients tend to fear the physiological sensations of fear and arousal (similar to those produced by many psychotropic agents), and these concerns may play a role in maintaining the disorder. It is therefore particularly important to minimize medication side effects early in treatment. Several studies offer evidence that a benzodiazepine plus an antidepressant has a faster onset of action than antidepressant monotherapy.[14-16]
In sum, benzodiazepines are indicated in moderate to severe panic disorder to accelerate therapeutic onset and reduce initial side effects that may be associated with other medications. The addition of a benzodiazepine does not appear to effect long-term efficacy, nor does it appear to benefit the patient beyond the initial few weeks of treatment. Though the risks are fewer with longer-acting benzodiazepines, abuse potential and discontinuation difficulties should be considered when using benzodiazepines for the treatment of panic.[6,8,9]
New pharmacologic approaches for panic have been examined in pursuit of enhanced efficacy, response, and tolerability. Results thus far have provided neither consistent nor convincing evidence that the new medications are more effective; however, some agents may have an earlier onset of efficacy (eg, escitalopram, mirtazapine) and better tolerability (eg, escitalopram, nefazodone, mirtazapine).[17-22]
In a recent study, Stahl and colleagues[18] completed a 10-week, randomized, double-blind, placebo-controlled trial of escitalopram and citalopram in panic disorder. The authors found that both escitalopram and citalopram decreased panic symptoms and severity more than placebo. Moreover, escitalopram was associated with greater panic- free rates at end point vs placebo, though this difference was significant only at the tend-level. Escitalopram was associated with lower rates of discontinuation due to adverse events (6.3%) when compared with citalopram (8.4%) and placebo (7.6%). Escitalopram may offer earlier onset of efficacy than citalopram (ie, week 4 vs week 8) as well as better tolerability and decreased side effects.
A new enteric-coated formula of paroxetine has also shown good efficacy and tolerability in panic patients.[23] Little efficacy exists for nefazodone[19,20] or reboxetine[24] in panic disorder samples. Several studies of the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine suggest promising results.[25-28] An extended-release formulation of venlafaxine (venlafaxine-XR) has demonstrated statistically superior response and remission rates vs placebo,[27,28] good tolerability, and equivalent efficacy to other SSRIs.[28] GABAergic agents such as gabapentin have been minimally effective,[29] and controlled trials with vigabatrin and tiagabine are needed to better assess their anxiolytic properties in a panic disorder population.[30,31]
CBT has demonstrated efficacy as a treatment for panic disorder.[32] Pharmacologic agents have also been successfully combined with CBT and may offer distinct treatment advantages. Evidence suggests that pharmacotherapies may be most effective against unexpected panic attacks, and therefore more so in the treatment of panic disorder without agoraphobia. Furthermore, cognitive-behavioral tools and exposure-based practice may enhance pharmacotherapeutic outcomes in the long-term and facilitate relapse prevention efforts.
In one study, Barlow and colleagues[33] conducted a methodologically rigorous randomized, double-blind, placebo-controlled study examining the efficacies of CBT, imipramine, or their combination in the acute (3-month) and maintenance (6-month) treatment of 312 patients with panic disorder. Both imipramine and CBT were significantly superior to placebo in the acute treatment phase, as measured by improvement on the Panic Disorder Severity Scale (PDSS); however, this advantage did not hold up on the Clinical Global Impressions Scale (CGI). After 6 months of maintenance treatment, imipramine and CBT were more effective than placebo on both primary outcome measures. The acute response rate for the combined treatment was 60.3% for the PDSS and 64.1% for the CGI. CBT plus imipramine did not differ significantly from the other treatment groups. The 6-month response rates for CBT plus imipramine were greater than CBT alone and imipramine alone on the PDSS, and greater than imipramine alone on the CGI. Of note, CBT plus imipramine did not confer a unique advantage over CBT plus placebo. At 6-month follow-up, patients receiving CBT plus imipramine were more likely to relapse than those receiving CBT plus placebo or CBT alone. Though the implications of this finding are somewhat unclear, the authors concluded that the combination of CBT plus imipramine may confer limited advantage in the acute management of panic disorder and more substantial advantage by the end of maintenance therapy. Each treatment worked well immediately following treatment and during maintenance, and CBT appeared particularly robust at follow-up.
In a second study, Biondi and Picardi[34] conducted a 4- to 12-month investigation of pharmacotherapy and CBT in 53 panic disorder patients. Medications and dosages were uncontrolled. Follow-up results indicated that 78% of patients relapsed in the medication-only group vs 14.3% in the medication plus CBT group. However, these findings must be viewed in light of significant methodologic limitations.
Starcevic also discussed the discrepancy between research and practice. Despite good evidence that the combination of pharmacotherapy and CBT may enhance the efficacy of either treatment alone, questions about state-dependent learning effects and the attribution of treatment gains to medication rather than self-mastery are viable concerns that have yet to be examined empirically. Furthermore, gaps in the literature leave questions such as, "when is the combination of pharmacotherapy and CBT most useful?" and "how are medications and CBT best combined in order to maximize treatment gains?" insufficiently answered. Starcevic and colleagues[35] attempted to address some of these queries in an interesting study of 102 patients with panic disorder and agoraphobia. The authors examined the factors that influenced psychiatrists' treatment decisions to use CBT alone, CBT plus a high-potency benzodiazepine, or CBT combined with a benzodiazepine and an SSRI. The authors conducted a series of logistic regressions predicting treatment modality from pretreatment patient characteristics. Combination treatments were employed most often in the most severe cases. Patients whose panic-related cognitions were prevalent and dominant received CBT alone. Patients with more frequent panic attacks and somatic symptoms received CBT plus a benzodiazepine, and patients with concomitant depressive symptomatology, comorbidity, and pronounced disability received CBT plus a benzodiazepine and an SSRI. Patients in each treatment condition experienced significant symptom improvement.
To conclude, Dr. Starcevic emphasized the importance of efficacy and maintenance of treatment gains as the goal for all aspects of panic disorder. Accelerated efficacy not only provides rapid symptom relief but also promotes treatment compliance and treatment satisfaction. Novel agents may offer distinct advantages, but until their efficacy profiles are better established, their status should still be considered experimental. Treatments combining pharmacologic and/or cognitive-behavioral techniques may be useful in increasing long-term outcome and decreasing risk of relapse upon treatment cessation.
Sigfried Kasper, MD,[36] from the University of Vienna, Austria, described GAD as a "poorly understood disorder," and highlighted the recent upsurge in attention to its diagnosis and treatment. The diagnostic criteria of GAD have continuously evolved over the past 2 decades, making consistent research efforts difficult. Despite these changes, clinicians and researchers generally agree that the principal targets of intervention in GAD are persistent and uncontrollable worry, psychological anxiety, and somatic symptoms (eg, physical tension, difficulty concentrating). The symptoms of GAD are excessive and endure for most of the day nearly every day for a minimum of 6 months. Prevalence rates of GAD range from 1.5% to 3% for current GAD, 3% to 5% for GAD in the past 12 months, and 4% to 8% for lifetime GAD.[37] Many more individuals experience subsyndromal forms of GAD. GAD is highly comorbid; lifetime and current comorbidity estimates are 89.9% and 65%, respectively.[38-40] Studies suggest that approximately 38.6% patients with GAD also meet criteria for major depressive disorder,[40] the latter of which often drives professional help-seeking. According to Dr. Kasper, GAD patients frequently attend treatment, though treatment is often inadequate. Effective treatment of GAD should strive to attain a strong therapeutic alliance, reduce acute symptoms, resolve persistent and chronic anxiety, and prevent relapse. Optimal treatments may incorporate pharmacotherapy and psychotherapy for long-term symptom management.
Treatment options for GAD are many and include empathic listening, applied relaxation, CBT, benzodiazepines, serotonin-1A (5-HT1a) partial agonists, antidepressants (ie, SSRIs, SNRIs), and newer compounds such as pregabalin. Historically, GAD was treated with benzodiazepines, which offer a good low-cost anxiolytic effect in the short-term. Several randomized, controlled trials of benzodiazepines have demonstrated acute clinical efficacy in reducing GAD symptom severity. The long-term efficacy of benzodiazepines is less robust.[41-43] The primary anxiolytic effect of the benzodiazepines addresses the somatic symptoms of GAD but leaves the cognitive features of GAD such as worry and psychological distress somewhat unresolved. Furthermore, benzodiazepines do not appear to be efficacious in reducing the depressive symptoms common in GAD. Because of the risk for physical dependence, rebound anxiety upon discontinuation, and side effects, benzodiazepines are now a secondary treatment option or an acute adjunct to long-term treatment with other agents.
In general, 5-HT1a partial agonists have proven substandard in the treatment of GAD, with the exception of the azapirone buspirone. Early trials of buspirone suggested it was an efficacious alternative to benzodiazepines for treating anxiety, with some specificity for the psychological symptoms of GAD.[44-46] However, recent studies are more equivocal about buspirone's efficacy in GAD[47,48] and the symptoms of its common comorbid conditions.[41]
More recently, antidepressants have secured a primary role in the pharmacopoeia of GAD. Data suggest that TCAs are equally as effective, if not more effective, as benzodiazepines in treating GAD, and imiprimane consistently produces higher improvement rates than placebo.[41] The anticholinergic effect of TCAs may exacerbate anxiety in patients who are already disposed to somatic symptoms. Rickels and colleagues[49] conducted a randomized, double-blind, 8-week comparative trial of imipramine (mean maximum daily dose, 143 mg), trazodone (255 mg), and diazepam (26 mg) in 230 patients with GAD. Patients with comorbid panic disorder or depression were excluded. All active treatments were more effective than placebo at reducing GAD symptoms. The greatest number of patients responded to imipramine (73%), followed by trazodone (69%), diazepam (66%), and placebo (47%). Patients treated with diazepam showed the most improvement in anxiety ratings during the initial weeks of treatment, with enhanced efficacy for somatic symptoms. However, imipramine achieved better anxiolytic efficacy in the latter weeks of treatment. Trazodone was comparable with diazepam. Imipramine was most effective for psychic symptoms of tension, apprehension, and worry, and all 3 treatments reduced somatic symptoms. Overall, patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients, but discontinuation rates did not differ by treatment group.
There is a growing body of literature demonstrating the efficacy of SSRIs in placebo-controlled studies of GAD.[50-53] While the majority of these reports have studied paroxetine,[52] which is now approved by the FDA for the treatment of GAD, positive findings with fluvoxamine and sertraline are also published.[41-43] A pooled analysis of 3 positive, double-blind, placebo-controlled studies in 856 patients with GAD found that escitalopram has effective anxiolytic properties in this population.[53]
The SNRIs such as venlafaxine have also demonstrated efficacy in reducing GAD symptoms; venlafaxine is the first agent indicated for the long-term treatment of GAD. Several placebo-controlled studies have indicated that venlafaxine-XR is effective in reducing the somatic and psychic symptoms of anxiety specific to GAD both in acute[54-56] and long-term treatment.[57-59] For example, Davidson and colleagues[55] found that venlafaxine-XR was associated with a greater reduction in Hamilton Anxiety Rating Scale scores than both buspirone and placebo. Taken as a whole, these studies suggest a rapid onset of action, greater tolerability than TCAs, and relapse prevention efficacy for at least 6 months with venlafaxine-XR administration.
New therapeutic options include the not-yet-marketed agent pregabalin, which has shown early onset of action and short-term and long-term efficacy in GAD patients.[60-62] In a controlled trial, Pollack and colleagues[62] found that pregabalin was more effective than placebo at 300, 450, and 600 mg, and more effective than alprazolam at 300 and 600 mg/day. A 10-week, randomized, open-label trial of tiagabine,[63] a GABA reuptake inhibitor, and paroxetine found that both agents significantly reduced anxiety and depressive symptoms and improved sleep quality and overall functioning. Both tiagabine and paroxetine were well tolerated.
Psychotherapeutic tools that help patients develop coping and cognitive-restructuring strategies to manage their symptoms of anxiety are also efficacious in the integrated treatment of GAD. The most extensively studied psychotherapy for GAD is CBT, which targets the intolerance of uncertainty and the perceived uncontrollability or danger associated with worry. CBT has demonstrated efficacy as a short-term and long-term treatment option in GAD and is associated with low relapse rates.[42]
In an interesting study, Fisher and Durham[64] conducted a reanalysis of 6 randomized, controlled trials of psychological therapy with GAD. Individual CBT and applied relaxation, focusing on excessive worry and physiological arousal, performed well, with overall recovery rates of 50% to 60% at 6-month follow-up. In general, GAD patients are responsive to treatment; however, they are also sensitive to medication side effects. Combined pharmacotherapy (eg, benzodiazepines plus SSRIs) or pharmacotherapy plus CBT may be appropriate for treatment-resistant patients.
SAD has been the subject of increased research scrutiny in recent years. SAD is an early onset, chronic, frequently disabling disorder with lifetime reported prevalence rates around 13%.[2] SAD is characterized by a persistent fear of negative evaluation or scrutiny by others in social situations, resulting in excessive fear of humiliation or embarrassment, decrease in adaptive functioning, and clinical distress.[65] Patients with SAD are at high risk for comorbid disorders including other anxiety disorders, depression, and substance abuse problems. Both pharmacologic and cognitive-behavioral approaches to SAD are effective and offer complementary strengths. David Baldwin, MD,[66] from the University of Southampton, United Kingdom, reviewed acute and long-term treatment studies in SAD as well as predictors of treatment response and intervention strategies for treatment-resistant patients.
The efficacy of irreversible MAOIs in the treatment of SAD is well established with several randomized, placebo-controlled trials.[67,68] For example, in a study of 65 severe and chronic SAD patients, Gelernter and colleagues[69] found that phenelzine, cognitive-behavioral group therapy (CBGT), and alprazolam were superior to placebo (self-instructed exposure) in reducing SAD symptoms. Phenelzine conferred some advantage over alprazolam on measures of work and social disability. At week 12, 69% of the phenelzine group had responded compared with 38% of the alprazolam group, 24% of the CBGT group, and 20% of the placebo group. At the 2-month follow-up, following medication discontinuation, only the phenelzine and CBGT treatment groups maintained their treatment gains. These results are somewhat difficult to interpret since the study included one of the principal components of CBT, exposure, as a control group.
In a 12-week treatment study, Heimberg and colleagues[70] examined phenelzine and CBGT vs a pill-placebo and psychotherapy control (educational supportive group therapy) in SAD patients. At end point, both phenelzine therapy and CBGT were associated with a significant positive response. Although phenelzine therapy was superior to CBGT on some measures, both treatment conditions were superior to the pill-placebo and psychotherapy control conditions. Responders to the acute trial entered a 6-month maintenance phase, and patients who continued to respond through the maintenance phase entered a 6-month treatment-free phase. In general, phenelzine patients entered the maintenance phase with greater improvements than did CBGT patients, and groups did not differ on relapse rates. Of note, phenelzine patients showed a trend toward greater relapse during the treatment-free follow-up. In a separate study, Liebowitz and colleagues[67] found that 64% of generalized SAD patients responded to phenelzine compared with 30% and 23% of patients treated with atenolol and placebo, respectively.
Despite phenelzine's efficacy in SAD, the dietary restrictions and risk of hypertensive crisis have reduced its acceptability as the favored first-line treatment for chronic SAD. The reversible MAOIs, such as moclobemide and brofaromine, have lower risk potential and fewer side effects than traditional MAOIs. Controlled trials of moclobemide have yielded inconsistent findings over the past several years.[71-75] For example, in a double-blind, placebo-controlled comparison of phenelzine and moclobemide, both active treatments demonstrated clinical efficacy beyond placebo, and phenelzine was associated with significantly more adverse side effects than moclobemide. Relapse rates for both agents were quite high after discontinuation.[72] Large, multicenter, placebo-controlled studies of moclobemide have found minimal[73] to no efficacy.[71]
Some benzodiazepines and newer anticonvulsant agents have demonstrated efficacy in the short-term treatment of SAD.[76] Studies with benzodiazepines suggest relative efficacy similar to the SSRIs; notwithstanding problems of unwanted side effects, abuse potential, and high relapse rates on discontinuation.[77,78] Gabapentin yielded better, albeit low, response rates when compared with placebo (32% vs 14% respectively), and was associated with high rates of adverse side effects (ie, somnolence, nausea, and dry mouth).[79] Feltner and colleagues[80] found that pregabalin (600 mg/day) was more efficacious than both pregabalin (150 mg/day) and placebo at week 11, and was associated with symptom relief as early as week 1. Post-hoc analysis suggested that patients with psychiatric comorbidity benefited less from pregabalin 600 mg/day treatment than patients without comorbidity diagnoses.
Based on their efficacy for SAD and common comorbid disorders, tolerability, and safety, SSRIs are considered the first-line pharmacologic treatment option for most patients. Controlled studies of fluvoxamine,[81,82] paroxetine,[83-87] sertraline,[88-90] citalopram,[91-93] and escitalopram[94] have yielded statistically significant response rates for SSRIs vs placebo. Efficacy data with fluoxetine is less robust.[95,96] Paroxetine has been the most well-studied SSRI in SAD. In a randomized, double-blind, placebo-controlled study, Stein and colleagues[87] compared paroxetine with placebo in a double-blind, randomized study in 187 SAD patients. A total of 55% of the paroxetine group vs 23% of the placebo group were considered treatment responders at week 12. Moreover, patients in the active treatment group experienced greater mean reductions in Liebowitz Social Anxiety Scale (LSAS) scores than those in the placebo control group (39% vs 17.4%, respectively). Baldwin and colleagues[97] reported similar efficacy rates to those noted above in a large, multicenter, randomized, placebo-controlled study of paroxetine. Specifically, 66% of the paroxetine group vs 32% of the placebo group responded to treatment.
Meta-analyses have compared the efficacy of medications currently used in SAD.[98,99] Blanco and colleagues[98] reviewed empirical articles published between January 1980 and June 2001 and references in published manuscripts. Trials were included if they reported outcome data on the LSAS, or if they used a categorical measure of response status. The authors found the largest effect sizes (ESs) for phenelzine (ES, 1.0; confidence interval (CI), 0.49-1.45), clonazepam (ES, 0.97; CI, 0.49-1.45), gabapentin (ES, 0.78; CI, 0.29-1.27), brofaromine (ES, 0.66; CI, 0.38-0.94), and the SSRIs (ES, 0.65; CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups; however, the authors conducted further analysis using sophisticated meta-analytic techniques, which revealed the greatest evidence of efficacy for the SSRIs and brofaromine.[98] Van der Linden and colleagues[99] conducted a separate meta-analysis of SSRIs. The authors calculated odds ratios for treatment response to SSRIs vs placebo. Patients receiving SSRIs had a 2.1- to 26.2-fold increase in treatment response compared with patients on placebo. SSRIs had moderate to large ESs in randomized, controlled trials.
The SNRI venlafaxine has recently proven efficacious in a number of studies.[100-102] For example, Baldwin presented pooled data from a large 5-site multicenter, randomized, double-blind, placebo-controlled (plus 2 paroxetine-controlled) studies of flexible-dose venlafaxine-XR in the treatment of SAD.[100] There was a significant treatment effect on symptom-related disability on social, work, and family life scales of the Sheehan Disability Scales. Venlafaxine-XR and paroxetine were similarly efficacious.
Though the majority of efficacy studies for SAD have been acute trials, long-term studies also indicate that patients remaining on SSRIs maintain superior treatment gains over time than those remaining on placebo.[103-109] In a Canadian multicenter study, Walker and colleagues[103] assessed 50 adult outpatients with generalized SAD who responded to a 20-week placebo-controlled trial of sertraline (50-200 mg/day). Patients were randomized to sertraline or placebo for another 24 weeks. Placebo responders were included in the continuation phase and were maintained on placebo. More than twice as many patients in the sertraline-continuation group completed the study than those in the placebo-switch and placebo-responder group. In the intent-to-treat end point analysis, 1of 25 (4%) patients in the sertraline group, and 9 of 25 (36%) patients in the placebo-switch group had relapsed. The authors reported a 10.2 relative risk for relapse associated with a placebo-switch relative to sertraline maintenance treatment. According to Dr. Baldwin, it is important to note that despite statistically significant decreases in measures of social anxiety or global severity, the majority of SAD patients remain symptomatic and experience functional impairment, even in light of therapeutic intervention.[94,100] Individuals who discontinue after acute treatment (ie, 12-20 weeks) appear more likely to relapse than do those who continue on active medications. These results strongly suggest the importance of tolerable longer-term treatments.
There is empirical evidence for the efficacy of exposure-based CBT in the treatment of SAD, and controlled studies suggest that the effects are generally maintained at long-term follow-up. According to Dr. Baldwin, patients may benefit from initial treatment with an SSRI and a subsequent referral for CBT. Specifically, cognitive restructuring and exposure to feared situations may enhance patient response to antidepressant treatment.[110,111]
In conclusion, SSRIs and CBT are considered first-line treatment for SAD. SSRIs are recommended in severe cases of SAD, in the presence of significant psychiatric comorbidity, when a rapid onset of action is warranted, and when a skilled provider of CBT is unavailable. Clinical experience suggests that SSRI nonresponders may benefit from trials with additional SSRI agents or a switch to a different class of medications.[101,112] Partial responders may benefit from SSRI augmentation with CBT,[90,95] buspirone,[110] benzodiazepines, gabapentin,[74] or venlafaxine.[113] There are evidence-based treatments are available to treat SAD; however, more research is needed to better guide the management of treatment-resistant patients and to prevent relapse in the long-term.
Borwin Bandelow, MD,[114] at the University of Goettingen, Germany, discussed the many steps involved in the life of a developing drug, including synthesis, animal testing, safety and tolerability testing, efficacy and tolerability testing (100-200 patients), efficacy and tolerability testing (greater than 2500 patients), new drug application, and postmarketing studies. Despite the thousands of agents entering phase 1 of development, only a small percentage of newly developed agents emerge in the latter stages, and of these, fewer yet demonstrate efficacy greater than placebo. According to Dr. Bandelow, the current pharmacopoeia for anxiety disorders includes SSRIs, SNRIs, TCAs, benzodiazepines, some anticonvulsants, and some miscellaneous agents. Despite the development of newer and safer antidepressants, undesirable side effects and delayed therapeutic onset remain a problem. Furthermore, more than 25% of patients do not respond to available therapies.[115]
Studies of emotional processing in animals and humans implicate the amygdala's essential role in the acquisition of conditioned fear, and the expression of innate and learned fear responses. Efferents from the amygdala activate the systems, which are responsible for anxiety symptoms and the fight-flight response (eg, respiratory symptoms, increased heart rate, pupilary dilation). Along with other limbic structures, the septohippocampal areas, the prefrontal cortex, and the locus coeruleus (LC) are implicated in anxiety disorders. The LC is the major site of norepinephrine in the mammalian brain and receives information directly from the sensory cortex. The projections from the amygdala to the LC create an intersection of many different neurochemicals, which form the basis of the current psychopharmacology for anxiety disorders. There are many neurotransmitters and neuropeptides thought to play a role in anxiety disorders, most of which directly or indirectly affect the amygdala. These include serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor (CRF), sigma receptors, neurokinin (NK) receptors (specifically, NK1, NK2, NK3), CRH1 receptors, NMDA/glutamate receptors, neuropeptides, natriuretic peptides, melanocortin-Y receptors, and cholecystokinin (CCK), and they have become the target of new pharmacologic interventions for the treatment of anxiety disorders.
For example, one etiologic hypothesis of anxiety disorders involves the interaction between the serotonergic and noradrenergic system. Serotonergic neurons, projecting from the raphe nucleus to the LC, have an inhibitory effect on noradrenergic activity. Pharmacologic agents that downregulate or stabilize the LC (eg, SSRIs, SNRIs) have anxiolytic properties. New serotonergic agents currently in development include gepirone, sunepitrone, lesopitrone, flesinoxan, and deramciclane. The latter 2 agents have been withdrawn.
GABA has an inhibitory effect on the LC. GABAergic agents such as benzodiazepines potentiate these inhibitory effects, causing their anxiolytic effect. On the other hand, glutamate, an excitatory amino acid that is thought to be anxiogenic, stimulates the LC. GABA agonists and antagonists have long been used as hypnotics, sedatives, tranquilizers, and anticonvulsants, and include agents such as gabapentin, pregabalin, levetiracetam, vigabatrin, tiagabine, Ro-19-8022, and gaboxadol. Pregabalin is an analogue of the GABA neurotransmitter that does not bind to GABA receptors and serves to decrease calcium influx. Pregabalin is currently indicated as an anticonvulsant, and for SAD, GAD, panic disorder, and mood disorders. Early trials suggest that Pregabalin is efficacious in alleviating symptoms of GAD, panic disorder, and SAD.[61,62,80] Vigabatrin and tiagabine have also shown some efficacy in open studies of anxiety disorders and as an adjunct to anticonvulsant treatment.[116,117]
CRF is a hypothalamic hormone that coordinates neuroendocrine, autonomic, and behavioral responses to stress by stimulating the release of adrenocorticotropic hormone. CRF is likely involved in the expression of stress, anxiety, and mood disorders. CRF injections in animals have led to a range of behaviors that are analogous to anxiety and mood disorders, and mice lacking CRF have shown a decrease in anxiety-related behaviors. Humans with major depressive disorder and various anxiety disorders have shown hypersecretion of CRF in the central nervous system.[118] The CRF1 receptor antagonists have shown some efficacy in reducing anxiety and depression symptoms;[119] however, the agent has since been withdrawn due to liver toxicity.
Sigma receptor sites are a type of nonopiate receptor with high concentrations in the spinal cord, pons and medulla, and cerebellum. The role of sigma receptors has been associated with several behaviors, including anxiety, depression, analgesia, learning processes, and psychosis.[120] Siramesine is a selective opioid receptor currently in phase 2 study for anxiety.
NKs are a family of 3 related peptides. NK receptors are located in brain regions including the amygdala and periaquaductal gray, and are associated with smooth muscle contractile activities. NKs appear to play a role in the regulation of emotions and have produced antidepressant and anxiolytic activity in animal models.[121] Antagonists of NK receptors are a target of new psychotropic drugs. Two agents currently in development are aprepitant and onasetant. They have been indicated in chemotherapy-induced nausea, depression, and anxiety. Preliminary trials on depression and anxiety symptoms have thus far been disappointing.[122]
CCK is one of the first discovered gastrointestinal hormones and one of the most abundant neuropeptides in the brain. CCK activity is associated with the reduction of food intake and the induction of anxiety-related behavior. Highly specific, CCK-B receptor antagonists have reached clinical trials and have potential clinical utility as anxiolytics, antipsychotics, antianorexics, or analgesics.[123,124]
With some skepticism and an air of humor, Dr. Bandelow offered pheromones as a final target for new anxiolytic treatments. Pheromones are chemicals produced by an organism that signals its presence to other members of the same species. Pheromones puff off the skin in the form of vapor and are detected in the vemeronasal organ. Some researchers suggest that these chemicals can induce calmness in the opposite sex and may be powerful mediators of sexual, anxiety, and hormone-related disorders. One agent, vomeropherin, available as a nasal spray, has been associated with decreased respiration and cardiac frequency.[125] Its indications are for major depressive disorder, anxiety disorders, premenstrual syndrome, kleptomaniac, overeating, and aggression. Potential benefits of pheromones are their immediate onset and very low side effect profile.
Robert Golden, MD,[126] Chair of the Department of Psychiatry, UNC School of Medicine, discussed the impact of drug-related side effects on patient compliance. SSRIs are safe and effective and have become the most widely prescribed antidepressants worldwide; however, several issues limit SSRI treatment outcomes. SSRIs have a favorable side effect profile when compared with earlier antidepressant agents, but even "minor" side effects can significantly affect treatment outcome by interfering with patient compliance. Approximately 33% of patients stop taking their prescribed medication within the first month; nonadherence increases to 56% after 4 months of treatment.[127] Adherence may be increased with increased patient and family education, careful and sensitive inquiry and monitoring over the cause of treatment-related side effects, and selection of medications based on expected side effects (including an understanding of pharmacodynamic and pharmacokinetic profile).
Nausea is one of the most common and early-occurring SSRI side effects. Nausea is reported in 20% to 25% of patients on SSRIs.[128] Over time, gastrointestinal (GI) side effects typically wane; however, this time-lag carries a burden in terms of treatment outcome. For example, GI effects are associated with medication noncompliance, which is associated with delaying the time to attain a full therapeutic dose, or resulting in the failure to reach that desired dose due to early treatment discontinuation. SSRIs are initially absorbed in the upper small intestine. The drug stimulates serotonin receptors in the submucosal plexus, which is associated with orchestrated peristalsis. When the SSRI is present, serotonin floods the receptors and causes overstimulated contractions. Recent delivery advances (eg, a controlled-release formulation of paroxetine) can diminish these effects. Specifically, the active SSRI is an enteric-coated formula that is absorbed in a more distal region of the small intestine, thus avoiding the stimulation of gastrointestinal 5-HT receptors that mediate nausea. Recent studies have demonstrated that Paxil-CR is associated with fewer dropout rates due to side effects than the original formulation of Paxil.[129]
Sexual side effects are also associated with decreased compliance in SSRI maintenance treatment. Approximately 15% to 50% of individuals will report some sexual side effect with SSRI therapy. According to Dr. Golden, several strategies may be employed to decrease these undesired effects.
According to Dr. Golden, future research should focus on making advances where it matters; specifically, using medical knowledge to decrease side effects that may sabotage patient treatment compliance.
Mark Radford, MD,[130] Professor of Behavioural Science, Hokkaido University, Sapporo, Japan, discussed epidemiologic trends, comorbidity, and implications of pharmacologic interventions within different cultural contexts. Dr. Radford focused his talk on mental health changes in Japan. Recent epidemiologic surveys suggest that anxiety and affective disorders are prevalent in all countries and cultures. In one study,[131] Greece and Germany had the highest rates of GAD (14.9% and 9.0%, respectively), and the United Kingdom and the United States revealed the highest rates of panic disorder (3.5% and 1.9%, respectively). Despite cultural differences in nomenclature, symptomatology (eg, anxiety, tension, decreased concentration) typically overlaps. There are important regional variations in prevalence rates. For example, Dr. Radford indicated that the difference in prevalence rates of anxiety and depression between Tokyo and Nagasaki (within Japan) might be greater than differences between Japan and other Western countries. Comorbidity of anxiety and depression is also high cross-culturally. Reports suggest that more than 10% of individuals with major depression also meet criteria for an anxiety disorder, and close to 12% of individuals with an anxiety disorder also meet criteria for major depression.[132]
According to Dr. Radford, both depression and anxiety, in their milder forms, have adaptive functions in traditional Japanese culture. For example, anxiety and depression may prevent individuals from making rash decisions when they are sick. In addition, melancholy, mild depression, humility, and inhibition are socially acceptable. Furthermore, anxiety can promote group cohesion. There is a Japanese emphasis on interpersonal dependency, or amae. Colloquially, amae translates into acting in a childish or dependent fashion. Amae is considered normal behavior in Japanese individuals, regardless of gender, age, or social position. In excess, however, the behavior can become dysfunctional. Jibyo is characterized by somatic symptoms of pain or fatigue. Individuals are expected to care for and manage their own symptoms. By western standards, jibyo would likely be diagnosed as mild depression. However, in Japan, this state may have a positive value as it draws people together and enhances social support.[133] Cultural differences can also mediate the negative impact of certain symptoms. For example, according to Dr. Radford, decision-making difficulty is not considered a problem in Japanese patients. The focus on community (interdependency) and the role of family and immediate support networks is considered appropriate and helpful in coping with anxiety and depression.
When traditional support mechanisms break down, there are negative consequences. Over the past 20 years, the prevalence of mental illness, especially major depression and anxiety disorders, has increased in Japan.[134] Dr. Radford stated that this transformation reflects changes in Japanese society. For example, the population is aging rapidly and the birth rate is declining. Furthermore, extended families are becoming nuclear; with this transition, traditional social support mechanisms and methods are lost. On a sociopolitical and economic level, unemployment rates have increased and workplace environments have changed from a seniority system to a performance and output-based environment. The stability and predictability of the Japanese workplace has become uncertain and subject to change. The stress associated with these changes is likely a large contributing factor to the increased prevalence of mental illness in Japan.
Dr. Radford presented figures showing that work-related fatigue, accompanied by stress, anxiety, and depression symptoms, has risen from 5% up to 15% to 30% in the past decade. In light of the Japanese culture, which tends to repress stressed feelings, these figures are likely an underestimation. The increased rates of adult-onset diseases such as obesity, diabetes II, and cardiovascular disease reflect the relationship between declining mental and physical health. Koroshi (suicide) has also increased. In 2000, 71% of completed suicides were men; economic reasons were the most commonly cited reason for completed suicide.[135,136]
Because mild anxiety and depression are socially accepted in Japan, the rates of disorder are likely both underestimated and underreported. The cultural implications are profound. The changes in society and economy in Japan have contributed to increases in mental illness, individual dysfunction, and disability. The cultural response in Japan does not facilitate adaptive help-seeking behavior. Mental illness remains a taboo topic, and psychopathology is associated with stigmatization. Mental illness is seen as a weakness, and health providers will often misdiagnose and/or undertreat psychopathology out of concern for their own and their patients' reputation. Terms of "diagnosis" are rarely used in clinical practice. Therefore, underrecognized, underdiagnosed, and undertreated remains the status quo. According to Dr. Radford, approximately 60% of patients with major depression and 74% of patients with an anxiety disorder do not seek treatment. The small numbers of individuals who present with "culturally acceptable" somatic symptoms typically do not receive antidepressants or anxiolytics. Dr. Radford stated that the economic burden of affective and anxiety disorders in Japan is growing at a rate such that by 2020, major depression will be second only to ischemic heart disease in terms of economic burden.
The solution may lie in the development of safe, reliable, and effective treatments and proactive prevention measures. Until recently, affective disorders and anxiety disorders in Japan were treated solely with TCAs and benzodiazepines. More recently, SSRIs have been integrated into the pharmacopoeia and are now recommended as first-line interventions. There has been recent efficacy data for paroxetine in the treatment of panic disorder, GAD, and SAD in a Japanese sample. Results suggest similar efficacy as Western societies.[137] It is important to enhance assessment, increase recognition, and advance treatment cross-culturally to minimize the individual, social, and economic burden associated with these disorders.
