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Objective: A subset of patients undergoing initial antidepressant treatment experience worsening of symptoms, including thoughts of suicide or suicidal behavior. The present study explores whether this subset of patients is also more likely to experience recurrence or worsening of these symptoms during a second treatment trial with a different antidepressant., Method: We examined data collected between July 2001 and September 2006 from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter effectiveness study of outpatients with major depressive disorder diagnosed by a DSM-IV checklist. In that study, subjects who did not remit with citalopram treatment were randomized among next-step treatment options. The main outcome measure for this post hoc analysis, presence of suicidal thoughts and behaviors, was assessed using the suicide item on the 16-item Quick Inventory of Depressive Symptomatology--Self-Rated. Logistic regression was used to examine association between emergence or worsening of these symptoms with the first-step (level 1) citalopram treatment and emergence or worsening with next-step (level 2) pharmacologic or psychosocial treatment, including augmentation with bupropion or buspirone; switch to sertraline, venlafaxine, or bupropion; or addition of or switch to cognitive therapy., Results: Of 1,240 subjects entering level 2 with a score less than 3 on the suicide item, 102 (8.2%) experienced emergence or worsening of suicidal thoughts or behaviors. Emergence or worsening at level 1 was strongly associated with reemergence or worsening at level 2 (crude OR = 4.00 [95% CI, 2.45-6.51], adjusted OR = 2.95 [95% CI, 1.76-4.96]). Overall magnitude of risk was similar among next-step pharmacologic augmentation versus switching., Conclusions: These results suggest that individuals who experience emergence or worsening of suicidal thoughts or behaviors with one antidepressant treatment may warrant closer follow-up during the next-step treatment, as these symptoms may recur regardless of which modality is selected., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: To examine the efficacy and safety of atomoxetine combined with buspirone versus atomoxetine monotherapy and placebo in adult attention-deficit/hyperactivity disorder (ADHD)., Method: In this randomized, 8-week, 3-arm, double-blind, placebo-controlled trial conducted from November 2004 through December 2005, 241 adults with ADHD were randomly assigned in a 2:2:1 ratio to receive up to twice-daily atomoxetine and thrice-daily buspirone (n = 97), twice-daily atomoxetine (n = 97), or placebo (n = 47). Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD. The primary efficacy measure was the adult ADHD Investigator Symptom Rating Scale (AISRS)., Results: Decrease in the AISRS total score was significantly greater for atomoxetine-buspirone than placebo at all time points from weeks 1 to 7, with an estimated mean difference of -4.80 (P = .001). Reduction in the mean AISRS total score was numerically greater for atomoxetine-buspirone than for atomoxetine at all time points, but statistically significant at week 4 only (estimated difference = -2.04, P < .10). The effect size for atomoxetine plus buspirone was 0.51, and for atomoxetine alone, it was 0.40. Insomnia, nausea, dry mouth, headache, and asthenia were frequently reported adverse events for both active treatment groups, and dizziness was also frequently reported for the atomoxetine-buspirone group. Discontinuations due to treatment-related adverse effects were 15.5% for atomoxetine-buspirone, 11.3% for atomoxetine, and 14.9% for placebo., Conclusions: There was little indication of improvement for atomoxetine plus buspirone versus atomoxetine monotherapy, as most efficacy measures showed only slightly greater quantitative improvement for the combination, generally without statistical significance. It is of note, however, that the quantitative differences between these 2 groups were virtually all in the direction of greater efficacy for the atomoxetine plus buspirone group., Trial Registration: clinicaltrials.gov Identifier: NCT00174226., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Anxiety disorders, as a group, are among the most common mental health conditions and frequently cause significant functional impairment. Both psychotherapeutic and pharmacologic techniques are recognized to be effective management strategies. This review provides a discussion of the major classes of psychotropic medications investigated in clinical trials of the following anxiety disorders: panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Findings suggest that both selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are useful first-line agents for most of the anxiety disorders, particularly given the frequent comorbidity with mood disorders. Highly serotonergic agents are preferred for obsessive-compulsive disorder. Other antidepressants, such as tricyclic antidepressants or monoamine oxidase inhibitors, are generally reserved as second- and third-line strategies due to tolerability issues. Evidence for other agents, including anticonvulsants and atypical antipsychotics, suggests that they may have an adjunctive role to antidepressants in cases of treatment resistance, while azapirones have been used effectively for generalized anxiety disorder, and a substantial body of evidence supports benzodiazepine use in panic disorder and generalized anxiety disorder. Despite notable advances, many patients with anxiety disorders fail to adequately respond to existing pharmacologic treatments. Increased research attention should be focused on systematizing pharmacologic and combined pharmacologic-psychosocial strategies to address treatment resistance and developing novel treatments for anxiety disorders., ((c) Copyright 2010 Physicians Postgraduate Press, Inc.)

Generalized anxiety disorder (GAD) has a lifetime prevalence in the US population of about 5.7%. Typically, GAD begins in early adulthood and tends to have a chronic and persistent course. The disorder frequently presents comorbidly with other conditions, and about 90% of patients with GAD have at least 1 comorbid lifetime psychiatric disorder. Patients with GAD tend to be high users of medical services; the disorder is associated with significant physical as well as psychological symptomatology and impacts health, family relationships, and employment. Pharmacologic and psychosocial treatments are available for GAD. Different side effect profiles, speed of onset of action, and discontinuation requirements of individual drugs need to be taken into account when selecting treatment. Treatment selection should include consideration of comorbidity, psychological function, social impairment, and refractoriness, as well as the need for ongoing intervention for many individuals. Innovative treatments, including anticonvulsants, atypical antipsychotics, and others, as well as treatment targeting concomitant insomnia, may help improve outcomes for affected individuals., (Copyright 2009 Physicians Postgraduate Press, Inc.)

Augmentation strategies for the treatment of major depressive disorder (MDD) are needed when patients with MDD have not tolerated or responded to antidepressant monotherapies. Clinicians can employ sequenced treatment steps, preferably coupled with the use of a treatment algorithm, to utilize augmentation strategies that will enable patients to achieve remission. The focus of augmentation therapy has been combining an antidepressant medication with another antidepressant; however, atypical antipsychotics are becoming commonly used to augment antidepressants. Beyond antidepressants and antipsychotics, alternative augmentation strategies include emerging pharmacologic treatments and nonpharmacologic strategies.

Objective: The incidence of sexual dysfunction due to antidepressant drugs reported in pre-marketing clinical efficacy trials is often several times lower than in subsequent clinical experiences and independent reports. Although it is commonly believed that the reason for this discrepancy is that the nonleading questions employed in conventional clinical trials underestimate sexual dysfunction while the direct questioning used in independent trials provides more accurate data, few studies have actually compared these 2 methods., Method: In this study, 119 patients with a DSM-IV-defined major depressive episode (82 women and 37 men) who had been treated with but not responded to a selective serotonin reuptake inhibitor (SSRI; either citalopram or paroxetine) were assessed regarding sexual functioning by means of open-ended questions and direct questioning at baseline (after SSRI treatment only) and after 4 weeks of SSRI treatment plus buspirone or placebo., Results: More patients reported sexual dysfunction in response to direct questioning (41%) as compared with spontaneous report (6%) (p < .001). Sexual dysfunction correlated with the duration of the depressive episode, but not with age, dose of SSRI, plasma level of SSRI, duration of SSRI treatment, or any measurement of depression. No statistically significant differences regarding the incidence of sexual dysfunction were found between the citalopram and the paroxetine groups., Conclusion: Open-ended questions are an insufficient tool to estimate sexual dysfunction, and premarketing clinical trials should therefore include basic explicit assessments. The failure to find a correlation between treatment duration and sexual dysfunction adds to the notion that sexual side effects due to SSRIs do not abate over time.

Selection of appropriate treatment for generalized anxiety disorder (GAD) is influenced by several considerations, including psychiatric comorbidity. Emerging data suggest that GAD has a chronic course and a high comorbidity with depression. Successful treatment can be facilitated by first establishing treatment goals, which include managing acute anxiety and following through to remission. Prevention of GAD recurrence should be the ultimate objective. Many treatments exist to aid in the realization of treatment goals, including benzodiazepines, hydroxyzine, buspirone, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). Some SSRIs and an SNRI have been demonstrated effective in both acute and long-term trials, establishing them as first-line therapies. Benzodiazepines are helpful because of their rapid onset of action and efficacy in somatic and autonomic symptoms of GAD. Other medications in the pipeline include gamma-aminobutyric acid (GABA) modulators, which may have lower abuse potential than currently available agents that act at the GABA receptor; corticotropin-releasing hormone (CRH) antagonists; and pregabalin. The recent realization of the chronic nature of GAD and the recognition of its frequent comorbidity with depression, coupled with data from randomized clinical trials of newer generation agents, should help physicians better diagnose GAD and achieve the goal of bringing patients to full remission.

Generalized anxiety disorder (GAD) is characterized by chronically persistent worry and therefore requires effective long-term treatment. This article reviews the benefits and risks associated with various pharmacologic and psychological therapies to assess their ability to achieve the elimination of GAD symptomatology and restoration of normal function. Psychotherapeutic approaches such as applied relaxation, cognitive therapy, and cognitive-behavioral therapy have all been shown to be effective when used as monotherapies and may be beneficial when used adjunctively. Current effective pharmacotherapies for patients with GAD include anxiolytic benzodiazepines, buspirone, and antidepressants including venlafaxine and paroxetine. Benzodiazepines have long been used to treat anxiety and are particularly appropriate in short-term treatment situations; however, their adverse side-effect profile and their inability to treat depression commonly comorbid with GAD renders them less than ideal in many situations. Buspirone has demonstrated anxiolytic benefits but, like benzodiazepines, shows negligible antidepressant action. Antidepressants like paroxetine and venlafaxine are not only effective antidepressants but also effective anxiolytics, thus implying their special ability to treat GAD and concurrent depression, even over the long-term.

Generalized anxiety disorder (GAD) is characterized by chronic worry that may persist for many years. It is a debilitating disorder, and effective long-term treatment is required. Psychotherapy, particularly relaxation, cognitive therapy, and cognitive-behavioral therapy, has shown long-term benefit in GAD and may be a useful approach alone and as an adjunct to pharmacotherapeutic options. Available medications for GAD include benzodiazepine anxiolytics, buspirone, and antidepressants. Although benzodiazepines are effective as short-term anxiolytics, their use is compromised by a poor adverse event profile and, like buspirone, they lack the antidepressant efficacy important for addressing the comorbid depression experienced by many patients with GAD. Antidepressants, including paroxetine and the serotonin-norepinephrine reuptake inhibitor venlafaxine, are effective anxiolytics and resolve symptoms of depression in patients with GAD. The benefit of venlafaxine is sustained long term, enabling increased numbers of patients to attain remission from symptoms and experience restoration of normal functioning. Although further clinical studies are required to establish the use of psychosocial therapy in the treatment of GAD. preliminary results are encouraging. At present, the use of psychosocial therapy and second-generation antidepressants, such as some selective serotonin reuptake inhibitors and venlafaxine, offer the best approach to attaining long-term benefit for patients with GAD.

Less than one third of people afflicted with generalized anxiety disorder (GAD) experience spontaneous remission, and the symptoms of GAD wax and wane throughout a person's life. The burden of GAD may be reduced with psychopharmacologic therapy. The medications with the most evidence of efficacy in GAD are the benzodiazepines, including a new long-acting formulation of alprazolam. These drugs have a low incidence of side effects but may cause physical dependence, withdrawal, and sedation. Antidepressants are also efficacious in GAD but act less quickly than benzodiazepines. Tricyclic antidepressants such as imipramine may substantially reduce symptoms of anxiety but are not considered a first-line therapy because of their side effects spectrum. The extended-release formulation of venlafaxine and selective serotonin reuptake inhibitors such as paroxetine and sertraline are also efficacious in GAD. While their association with sexual dysfunction may be intolerable for some adults, these drugs may be more appropriate than the benzodiazepines because their chronic use does not lead to dependence. Buspirone also significantly reduces symptoms of GAD and is associated with less sexual dysfunction than SSRIs and less sedation than benzodiazepines. Combining antidepressant and benzodiazepine therapy or medication treatment and psychotherapy may lead to an increase in improvement in patients not responding to 1 treatment approach alone. The most effective treatment for managing the recurrent symptoms of this chronic disorder will remain unknown until more long-term studies using both drug and nondrug therapies are conducted. Remission rates are still only about 40%, signifying the need for improved treatment interventions.

Background: The efficacy of anxiolytic drugs in generalized anxiety disorder (GAD) is conventionally assessed by evaluating changes in the total score of psychometric scales such as the Hamilton Rating Scale for Anxiety (HAM-A). The purpose of this pooled analysis of data was to evaluate the efficacy of venlafaxine extended release (XR) on individual items of the HAM-A and the Brief Scale for Anxiety (BSA)., Method: Data were pooled from 5 studies of patients with GAD who were treated with either venlafaxine XR or placebo for 8 weeks (N = 2,021) and up to 6 months (N = 767). Individual items of the HAM-A and the BSA were examined. and, using the mean changes from baseline to endpoint, an effect size for each item was calculated by dividing the difference between baseline and endpoint values for each item by the standard deviation of this difference. The effect sizes determined for the venlafaxine group were compared with those for the placebo group. Items from each scale that are concordant with the DSM-IV diagnostic criteria for GAD were selected for further examination, and the specific effect sizes of each item were expressed after controlling for placebo effects., Results: The effect size of the majority of the 14 items of the HAM-A scale and the 10 items of the BSA scale associated with treatment with venlafaxine XR was greater than with placebo at both 8 weeks and 6 months. Furthermore, the effect sizes at 6 months were generally greater than at 8 weeks in venlafaxine XR-treated patients. Effect sizes associated with venlafaxine XR were greatest for the HAM-A items that were most closely related to diagnostic symptoms of GAD, namely anxious mood, tension, intellectual functioning, and behavior at interview at both 8 weeks and 6 months. Similarly, GAD-related BSA items of inner tension, worrying over trifles, hostile feelings, and muscular tension were associated with the greatest improvements with venlafaxine XR at both time-points., Conclusion: The HAM-A and BSA items that most closely corresponded to DSM-IV diagnostic criteria for GAD showed the largest improvement during treatment with venlafaxine XR. This indicates that the specific symptoms of GAD can be treated effectively with venlafaxine XR, both in the short and longer term.

Background: Research on the pharmacotherapy of body dysmorphic disorder (BDD) is limited. No placebo-controlled, continuation, maintenance, or discontinuation studies have been published. Only one augmentation study has been published., Method: In this chart-review study of 90 patients with DSM-IV BDD treated for up to 8 years by the first 2 authors (K.A.P., R.S.A.) in their clinical practice, response to a variety of medications, including augmentation strategies, was assessed. The relapse rate with medication discontinuation was also determined., Results: All subjects received a serotonin reuptake inhibitor (SRI), with 63.2% (55/87) of adequate SRI trials resulting in improvement in BDD symptoms; similar response rates were obtained for each type of SRI. Discontinuation of an effective SRI resulted in relapse in 83.8% (31/37) of cases. Response rates to selective SRI augmentation were clomipramine, 44.4% (4/9) of trials; buspirone, 33.3% (12/36) of trials; lithium, 20.0% (1/5); methylphenidate, 16.7% (1/6); and antipsychotics, 15.4% (2/13) of trials., Conclusion: These findings from a clinical setting suggest that a majority of BDD patients improve with an SRI and that all SRIs appear effective. Certain SRI augmentation strategies may be beneficial. The high relapse rate with SRI discontinuation suggests that long-term treatment is often necessary. These preliminary findings require confirmation in placebo-controlled efficacy studies and effectiveness studies.

Background: Autism spectrum disorders are characterized by core deficits in social interaction and speech/communication skills, repetitive behaviors, and restricted interests. Other abnormalities include seizures, electroencephalographic (EEG) abnormalities, affective instability, impulsivity, and aggression. Divalproex sodium is indicated as both an anticonvulsant in epilepsy and a mood stabilizer in bipolar illness and thus might be useful for these complicating symptoms in autism., Method: A retrospective pilot study was conducted to determine whether divalproex sodium was effective in treating core dimensions and associated features of autism. Fourteen patients who met DSM-IV criteria for autism, Asperger's disorder, or pervasive developmental disorder not otherwise specified, both with and without a history of seizure disorders or EEG abnormalities, were openly treated with divalproex sodium. Improvement was assessed via the Clinical Global Impressions-Improvement scale., Results: Of 14 patients who completed a trial of divalproex sodium, 10 (71%) were rated as having sustained response to treatment. The mean dose of divalproex sodium was 768 mg/day (range, 125-2500 mg/day), and it was generally well tolerated. Improvement was noted in core symptoms of autism and associated features of affective instability, impulsivity, and aggression., Conclusion: Divalproex sodium may be beneficial to patients with autism spectrum disorders, particularly those with associated features of affective instability, impulsivity, and aggression as well as those with a history of EEG abnormalities or seizures. Of note, all patients with an abnormal EEG and/or seizure history were rated as responders. However, these findings must be interpreted with caution, given the open retrospective nature of the study. Controlled trials are needed to replicate these preliminary findings.

Background: Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect., Method: One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales., Results: After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo., Conclusion: Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.

Benzodiazepines have traditionally been used to treat acute anxiety disorders, but they are not ideal in the treatment of chronic generalized anxiety disorder (GAD). Following long-term therapy, benzodiazepines have the potential to produce dependency and withdrawal symptoms. In addition, although agents such as the benzodiazepines and buspirone alleviate anxiety, they have little effect on depression, which is a common comorbidity of GAD. Antidepressants have long been viewed as promising alternatives to benzodiazepines for the treatment of some types of anxiety. Although they have been shown to be useful in the treatment of panic disorder, social anxiety disorder/social phobia, and obsessive-compulsive disorder, they have not until recently been regarded as potential therapies for GAD. Treatment with antidepressants has opened up a new area of investigation into the pharmacotherapy of GAD, with a growing body of evidence supporting the role of therapies such as paroxetine and venlafaxine extended release.

Anxiety and depression in elderly people are major public health problems in the United States. Recognition and treatment of these conditions will likely gain more attention in the next 30 to 50 years because of the projected growth of the geriatric population. As in many younger patients, the most common presentation of anxiety in elderly patients is comorbid anxiety and depression. Although age is not a risk factor for either anxiety or depression, factors associated with aging--such as increased medical burdens and loss of independence--are substantial risk factors for development of these conditions. Moreover, there is a close association in older people between untreated mental illness and exacerbation of physical illness. Some of the newer antidepressants are more appropriate long-term options for the treatment of comorbid anxiety and depression than either benzodiazepines or tricyclic antidepressants. The newer antidepressants can decrease symptoms, improve quality of life, and potentially promote healthier outcomes in geriatric patients who have comorbid anxiety and depression and/or comorbid mental and physical illness.

gamma-Aminobutyric acid (GABA), serotonin (5-HT), and norepinephrine (NE) have each been implicated in the putative pathophysiology of anxiety, and patients with generalized anxiety disorder (GAD) demonstrate dysregulation of these neurotransmitters. In addition, neurobiological studies have demonstrated that these neurotransmitter systems are extensively interrelated. As a result, drugs that affect serotonergic systems may also, directly or indirectly, affect other neurotransmitter systems including GABA and NE. In recent years, clinical pharmacology studies have demonstrated that pharmacotherapeutic agents that target more than one neurotransmitter system are more effective than agents that target a single system, presumably due to synergistic mechanisms. Agents that modulate more than one neurochemical have a broader spectrum of action and may facilitate the attainment of remission among patients with moderate to severe GAD, who are likely to have comorbid psychiatric illnesses such as depression. Preclinical and clinical data supporting the role of GABA, 5-HT, and NE in the pathophysiology of GAD are reviewed here. The pharmacotherapeutic agents that modulate these neurotransmitter systems and have been proved efficacious in reducing the symptoms associated with GAD are also summarized.

Sexual dysfunction and dissatisfaction are common symptoms associated with depression. Optimal antidepressant treatment should result in remission of the symptoms of the underlying illness and minimize the potential for short- and long-term adverse effects, including sexual dysfunction. Sexual dysfunction and dissatisfaction are frequently persistent or worsen with the use of some antidepressant medications; this sexual dysfunction and dissatisfaction can have negative impact on adherence to treatment, quality of life, and the possibility of relapse. Successful management of sexual complaints during antidepressant treatment should begin with a systematic approach to determine the type of sexual dysfunction, potential contributing factors, and finally management strategies that should be tailored to the individual patient. The basic physiologic mechanisms of the normal sexual phases of libido, arousal, and orgasm and how these mechanisms may be interrupted by some antidepressants provide a framework for the clinician to utilize in order to minimize sexual complaints when initiating and continuing antidepressant treatment. This article provides guidelines, based upon this type of model, for the assessment, management, and prevention of sexual side effects associated with antidepressant treatment.

Background: An earlier preliminary report suggested that prior treatment with benzodiazepines might predict a reduced response to buspirone in patients diagnosed with generalized anxiety disorder (GAD). To confirm or refute this hypothesis, the present data analysis was conducted., Method: One large data set (N = 735) of GAD patients (DSM-III) treated with buspirone, a benzodiazepine, and a placebo was analyzed by dividing all patients into 3 prior benzodiazepine (BZ) treatment groups: no prior BZ treatment, recent (< 1 month) BZ treatment, and remote (> or = 1 month) BZ treatment. Using an intent-to-treat last-observation-carried-forward (LOCF) data set, acute 4-week treatment response was assessed in terms of clinical improvement, attrition, and adverse events as a function of these 3 prior benzodiazepine treatment groups., Results: Patient attrition was significantly higher (p < .05) in the recent BZ treatment group than in the remote and no prior BZ treatment groups with lack of efficacy given as the primary reason by patients receiving buspirone but not benzodiazepine or placebo. In the buspirone group, adverse events occurred more frequently in the recent BZ treatment group than in the remote BZ treatment and no prior BZ treatment groups. Finally, clinical improvement with buspirone was similar to benzodiazepine improvement in the no prior BZ treatment and remote BZ treatment groups, but less than benzodiazepine improvement in the recent BZ treatment group, leading to the smallest buspirone/placebo differences in improvement in the recent BZ treatment group., Conclusion: These data suggest that the initiation of buspirone therapy in GAD patients who have only recently terminated benzodiazepine treatment should be undertaken cautiously and combined with appropriate patient education.

Although the majority of patients with depression respond well to their initial pharmacologic treatment, as many as 30% to 45% fail to achieve an adequate response. In addition to the more traditional lithium and thyroid hormone augmentation strategies, a number of new pharmacotherapeutic approaches are currently being used to help manage refractory depression, including the addition of another agent or a switch to another antidepressant. Augmentation and switching strategies are often selected in order to obtain a different neurochemical effect (e.g., adding a relatively noradrenergic agent to a relatively serotonergic antidepressant). In particular, several studies have suggested that depressed patients refractory to treatment with selective serotonin reuptake inhibitors (SSRIs) may show a good response to newer agents that have a pharmacologic profile distinct from the SSRIs. Furthermore, preliminary studies have shown that the addition of SSRIs to either noradrenergic drugs such as the tricyclic antidepressants (TCAs) or dopaminergic agents may be efficacious, even though concerns about drug-drug interactions and tricyclic cardiac toxicity have limited the use of TCA-SSRI combinations. The introduction of reboxetine, a relatively selective norepinephrine reuptake inhibitor, may increase the use of the latter therapeutic approach because of its improved safety profile compared with the TCAs. The review of treatment options for refractory depression that follows will outline the advantages, disadvantages, and level of support for a number of new treatment strategies.

Augmentation strategies and combination treatments have become a popular method of treating refractory depression, enhancing therapeutic response in partial responders and increasing the likelihood of more rapid response. The evidence supporting these strategies will be reviewed, their methods of administration discussed, and the relative advantages and disadvantages considered.

Background: One hypothesis to explain selective serotonin reuptake inhibitor (SSRI)-induced bruxism states that SSRIs increase extrapyramidal serotonin levels, thereby inhibiting dopaminergic pathways controlling movement. Previous reports have emphasized buspirone's postsynaptic dopaminergic effect as a partial antidote to the suppressed dopamine levels., Case Reports: Four patients, recently started on treatment with the SSRI sertraline, presented with new-onset complaints attributable to SSRI-induced bruxism. All 4 responded to adjunctive buspirone, a serotonin-1A (5-HT1A) receptor agonist, with relief of bruxism and associated symptoms., Discussion: We expand the hypothesis put forth in previous reports by proposing that buspirone is not only acting postsynaptically in the extrapyramidal system, but also presynaptically on serotonergic neurons that influence masticatory modulation in the mesocortical tract. Our 4 cases support the concept of buspirone acting as a full agonist at the presynaptic 5-HT1A somatodendritic receptors located on the cell bodies of raphe serotonergic neurons that project to the ventral tegmental area (VTA) of the midbrain. These serotonergic neurons modulate the firing of the mesocortical tract, which itself projects from the VTA to the prefrontal cortex and acts on masticatory muscle activity through inhibiting spontaneous movements such as bruxism. While the literature is confusing and contradictory on definitions of bruxism and etiologies of incompletely understood movement disorders, we believe SSRI-induced bruxism is best conceptualized as a form of akathisia.

Background: The objective of this randomized, double-blind study was to compare the efficacy and safety of venlafaxine extended release (XR) and buspirone in outpatients with generalized anxiety disorder (GAD) but without concomitant major depressive disorder., Method: Male and female outpatients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with either venlafaxine XR (75 or 150 mg/day), buspirone (30 mg/day in 3 divided doses), or placebo for 8 weeks. The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale (CGI) scores. Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale (HAD)., Results: The efficacy analysis included 365 patients and the safety analysis, 405. At week 8, adjusted mean HAM-A psychic anxiety, anxious mood, and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients. On the HAD anxiety subscale, venlafaxine XR, 75 or 150 mg/day, was significantly more efficacious than placebo at all time points except weeks 1 (both dosages) and 2 (150-mg/day dosage only) and significantly more efficacious than buspirone at all time points except week 1. On the CGI-Improvement scale, scores for venlafaxine XR (both dosages) and buspirone were numerically superior to those for placebo at all time points, and statistical significance was observed at weeks 3, 4, 6, and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone. The adverse events were not essentially different between treatment groups., Conclusion: Venlafaxine XR is an effective, safe, and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder. This agent was significantly superior to buspirone on the HAD anxiety subscale. Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response.

The functional anatomy of anxiety involves amygdala-based neurocircuits with critical reciprocal connections to the medial prefrontal cortex. Traumatic experiences leave emotional imprints involving the amygdala, with facilitated fear-conditioned associations involving declarative memory traces. Avoidance conditioning is an additional component. An understanding of the functional anatomy of anxiety allows for a new perspective on the various anxiety disorders. The neurotransmitters involved in these circuits are reviewed for their relevance to the pharmacologic choices in the treatment of anxiety. Potent serotonin reuptake inhibitors appear to have superior efficacy in many of the anxiety disorders, with indications that norepinephrine reuptake inhibitors have an advantage in severe forms of major depression. Medications with dual effects--blocking reuptake of both serotonin and norepinephrine (e.g., clomipramine and venlafaxine XR)--have superior benefits in achieving remission in major depression and GAD. These medications may also offer a faster onset of action and theoretically superior benefits in patients with comorbid anxiety disorder and major depression.

This article reviews results of reports suggesting that venlafaxine extended release (XR) may play an important role in the treatment of anxiety disorders, particularly generalized anxiety disorder (GAD). Statistically significant improvements in GAD for venlafaxine XR compared with placebo on the basis of the Hamilton Rating Scale for Anxiety were seen in the acute treatment studies up to 8 weeks and were maintained for 6 months. One comparative study found venlafaxine XR to be as effective as, or on some measures more effective than, buspirone at relieving GAD. Venlafaxine XR was safe and well tolerated in the GAD studies, with discontinuation rates due to adverse effects similar to the rates seen with placebo or buspirone.

Background: Case reports and open studies have reported beneficial therapeutic effects of adding buspirone to a selective serotonin reuptake inhibitor (SSRI) in the management of treatment-refractory depression. This is the first placebo-controlled study to evaluate the efficacy and safety of this combination., Method: One hundred nineteen patients (82 women, 37 men) who fulfilled criteria for a major depressive episode according to DSM-IV and who had failed to respond to a minimum of 4 weeks (mean = 211 days) of treatment with citalopram or paroxetine were randomly assigned to 4 weeks of treatment with an SSRI plus buspirone (N = 58) or an SSRI plus placebo (N = 61). In addition, 97 patients participated in an optional open-label poststudy treatment phase with the SSRI plus buspirone for 2 weeks. The primary outcome measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale., Results: A total of 50.9% of patients in the buspirone group and 46.7% in the placebo group responded after 4 weeks of treatment. The difference in response rate was not statistically significant. No statistically significant differences were found in the frequency of adverse events. At the follow-up of the open SSRI plus buspirone treatment, 69.4% of patients had responded., Conclusion: Adding buspirone to an SSRI is a safe and well-tolerated drug regimen. This study failed to demonstrate any difference in efficacy between buspirone or placebo augmentation of an SSRI. It could be argued, however, that the study was inconclusive due to the unusually high placebo response.

Background: The current study was designed to assess the safety and efficacy of imipramine and buspirone in the treatment of major depression in elderly depressed attendees of primary care practices., Method: 177 patients aged 65 and over (mean age = 72 years; range, 65-89) who met DSM-III-R criteria of unipolar major depression with a minimum Hamilton Rating Scale for Depression score of 18 were randomly assigned to 8 weeks of double-blind, placebo-controlled treatment with flexible doses of either imipramine or buspirone., Results: Moderate to marked global improvement after 8 weeks of treatment (LOCF analysis) occurred in 70% of patients treated with imipramine, 61% of patients treated with buspirone, and 42% of patients treated with placebo (chi2 = 9.1, df = 2, p < .02). Drug treatment was well tolerated, with 77% of imipramine- and 61% of buspirone-treated patients completing 8 weeks of therapy. Imipramine/placebo differences were present from week 2 on, but buspirone/placebo differences occurred only at week 8. The presence of comorbid medical illness or concomitant use of nonpsychiatric prescription medications was not associated with poorer antidepressant response, increased adverse effects, or study attrition., Conclusion: Imipramine and to a lesser extent buspirone were found to be effective and well tolerated in the treatment of elderly depressed outpatients.

Background: We evaluated the efficacy and safety of buspirone in the management of anxiety and irritability in children with pervasive developmental disorders (PDD)., Method: Twenty-two subjects, 6 to 17 years old, with DSM-III-R diagnosed PDD-NOS (N = 20) or autistic disorder (N = 2), were included. They were treated with buspirone in dosages ranging from 15 to 45 mg/day in an open-label trial lasting 6 to 8 weeks. Responders continued buspirone treatment and were followed up for up to 12 months., Results: Nine subjects had a marked therapeutic response and 7 subjects a moderate response on the Clinical Global Impressions (CGI) scale after 6 to 8 weeks of treatment. Side effects were minimal, except for 1 patient who developed abnormal involuntary movements., Conclusion: These results suggest that buspirone may be useful for treating symptoms of anxiety and irritability in children with PDD.

This paper provides an overview of antidepressant nonresponse and the role of augmentation strategies in the management of treatment-resistant depression. When effective, the more widely used augmentation strategies, including lithium salts, thyroid hormones, pindolol, buspirone, and psychostimulants, share two important advantages when compared with "switching" strategies: avoidance of ill effects associated with discontinuing the initial antidepressant and rapidity of onset of action. Ideally, advances in the understanding of the neurobiology of mood disorders and mechanisms of antidepressant response will permit a more efficient and specific matching between patient, initial antidepressant, and subsequent strategy for enhancing response to treatment.

Treatment-resistant depression is commonly encountered by mental health professionals. Strategies for the treatment of resistant depression, including augmentation strategies and switching antidepressants, are reviewed. The potential advantages and disadvantages of each of these strategies are discussed.

The administration of anxiolytic drugs often accompanies treatment with antidepressant medications. Although benzodiazepines help alleviate the secondary depressive symptoms of anxiety and sleep disturbance, they do not actually enhance antidepressant response. On the other hand, the anxiolytic agent buspirone does facilitate direct antidepressant response, largely through its ability to activate both presynaptic and postsynaptic 5-HT1A receptors and thus modulate serotonin release. Several case studies and open-label trials have demonstrated the effectiveness of buspirone as an augmentation agent. Because buspirone is also associated with few adverse effects, it appears to be both effective and safe in the augmentation of antidepressant pharmacotherapy.

Background: The results of open pilot studies suggest that the serotonin-1A (5-HT1A) receptor agonist buspirone might be effective in social phobia., Method: In the present study, the efficacy of buspirone was investigated in patients with social phobia using a 12-week double-blind placebo-controlled design. Thirty social phobic patients (DSM-IV) were treated with either buspirone 30 mg daily or placebo. Efficacy of treatment was measured using the Social Phobia Scale (subscores anxiety and avoidance) and the Hamilton Rating Scale for Anxiety., Results: Taking a reduction of 50% or more on the Social Phobia Scale as a criterion for clinically relevant improvement, only 1 patient on buspirone and 1 on placebo were classified as responder to treatment. A subjective and clinically relevant improvement was reported by 4 patients (27%) on buspirone and 2 patients (13%) on placebo. There were no statistically significant differences between buspirone and placebo on any of the outcome measures. Generally speaking, buspirone was well tolerated., Conclusion: The results of the study do not support the results of open studies, in which a reduction of social anxiety and social avoidance was reported in patients with social phobia treated with buspirone.

Generalized Anxiety Disorder (GAD) is a highly prevalent condition whose course of illness is often chronic in nature and fluctuating in severity. Pharmacotherapy options include the benzodiazepines, the azapirones, of which only buspirone is marketed at the present time, and the antidepressant imipramine. Buspirone is probably the treatment of choice when prolonged therapy is indicated because it does not produce physical dependence, dose not interact with alcohol, and does not cause psychomotor impairment. Dosing instructions for buspirone and guidelines for switching patients from benzodiazepines to buspirone are offered. Non-drug therapies such as interpersonal and cognitive therapies are often also found helpful in treating patients with GAD.

Anxiety in the elderly is often unrecognized and inadequately treated. Several factors complicate recognition and treatment, including concomitant medical illness, overlap with cognitive disorders, cohort effects, ageism, and cormorbid depression. Although available data from controlled clinical trials are limited for anxiety patients in the geriatric age group, data from young adult studies and clinical experience indicate that pharmacologic treatments are safe and effective for anxious elderly patients. Age-related physiologic changes warrant modifications in dosing, including initial low doses increased in gradual increments. Education and psychotherapy are often recommended whether or not pharmacologic treatment is indicated.

Background: The development of effective and well-tolerated anxiolytic agents is an area of critical clinical importance. Abecarnil, a beta carboline, is a partial benzodiazepine-receptor agonist that has demonstrated promise as an anxiolytic agent. In this study, we examine the efficacy, safety, and discontinuation-related effects of abecarnil, buspirone, and placebo in the acute and long-term treatment of patients who have generalized anxiety disorder., Method: This is a double-blind, placebo-controlled study of two dosages of abecarnil and buspirone. In total, 464 patients were randomized. After a placebo run-in week, patients entered a 6-week double-blind treatment period, followed by an optional 18-week maintenance period for treatment responders. After abrupt discontinuation of the acute or maintenance treatment, patients entered a 3-week placebo-substitution follow-up period. Treatment response was assessed with the Hamilton Rating Scale for Anxiety and the Clinical Global Impressions (CGI) Scale., Results: Compared with placebo, abecarnil showed significant anxiolytic activity early in the treatment period, particularly in the high-dosage group, though these differences did not maintain statistical significance at the end of the trial. Buspirone was associated with a slower onset of action and better symptom relief than placebo after 6 weeks of therapy. Withdrawal symptoms emerged in patients who abruptly discontinued abecarnil (particularly at the higher dosage) only in those receiving a longer duration of treatment., Conclusion: The results of this study need to be understood in the context of a high placebo-response rate, which hampers the ability to demonstrate significant drug-placebo differences. This study suggests that abecarnil may be an effective anxiolytic agent; further attention is warranted to assess its spectrum of clinical effectiveness.

Social phobia is a common anxiety disorder that is underdiagnosed and undertreated. To date, three classes of serotonin drugs have been used to treat patients suffering from social phobia. These include the serotonin selective reuptake inhibitors (SSRIs), the partial 5-HT1A agonist buspirone, and the 5-HT3 antagonist ondansetron. Although none of the serotonin agents have yet been directly compared with the gold standard monoamine oxidase inhibitor phenelzine or the high potency triazolobenzo-diazepines alprazolam or clonazepam, the SSRIs, as a class, appear to be clinically useful agents. Further studies using larger sample sizes and double-blind methodology are needed to clarify the role of serotonin drugs in the treatment of social phobia.

Premenstrual symptoms are common among young menstruating women, but the psychiatric disorder premenstrual dysphoric disorder (PMDD) is seen only in approximately 3% of this group. The symptom profile of PMDD has been empirically derived from a number of investigations including a large data base from five university centers. The most commonly reported symptoms are depression and mood swings, but a substantial number of women report tension and anxiety. Lifetime psychiatric illness is also common in women with PMDD, and although mood disorders predominate, past histories of anxiety disorders are also common, further suggesting an association between PMDD and anxiety disorders. The strongest data supporting such an association lie with challenge studies that have been used to provoke panic in panic patients and are effective in precipitating panic attacks in women with PMDD. Finally, treatments that are effective for anxiety disorders are also useful in the treatment of PMDD. In this paper, the above outlined relationship between anxiety disorders and PMDD is reviewed.

Patients frequently present to primary care physicians with somatic symptoms that mask an underlying anxiety disorder. As a result, unnecessary diagnostic tests are ordered, and inappropriate medications are prescribed. Psychiatrists may help improve their primary care colleagues' ability to identify and treat these anxiety disorders. This paper reviews the adverse effects of untreated anxiety in managed care settings and outlines a treatment algorithm that psychiatrists may wish to use to assist primary care physicians in the cost-efficient, pharmacologic treatment of anxiety disorders in their patients.

Background: This study was designed to evaluate the anxiolytic efficacy of buspirone in patients with a diagnosis of generalized anxiety disorder (GAD) with coexisting mild depressive symptoms., Method: Patients who participated in this multicenter study scored >/= 18 on the Hamilton Rating Scale for Anxiety (HAM-A) and between 12 and 17 on the Hamilton Rating Scale for Depression (HAM-D). Following a 7- to 10-day placebo lead-in phase, patients who continued to qualify were randomly assigned to receive either buspirone titrated from 15 to 45 mg/day (N = 80) or placebo (N = 82) for the next 6 weeks. 121 patients completed 6 weeks of treatment. The primary efficacy measure was the HAM-A, taken weekly during the study., Results: Buspirone-treated patients averaged a 12.4-point reduction from their baseline total HAM-A score of 24.9, while their counterparts on placebo averaged a 9.5-point reduction from their mean baseline total HAM-A score of 25.6. This 2.9-point difference in HAM-A reductions between treatment groups was significantly different (p < .03). Buspirone patients decreased their HAM-D scores by an average 5.7 points from their mean baseline total HAM-D score of 15.8, while placebo patients decreased their HAM-D scores by an average 3.5 points from their mean baseline score of 16.3 (p < .05). Overall, the incidence of adverse events was similar for both treatment groups, but buspirone-treated patients reported significantly more nausea, dizziness, somnolence, and sweating than placebo patients., Conclusion: Buspirone is superior to placebo in improving anxiety and depressive symptoms in GAD patients who have coexisting depressive symptoms.

Symptoms of generalized anxiety disorder are commonly observed in elderly persons and especially in those suffering from dementia. In the demented elderly, these symptoms are often defined as agitation. Approximately 60% of demented persons will present with symptoms of agitation at some point during the course of their illness. The presence of agitation has devastating consequences for the patient and the caregiver. This paper reviews some of the existing literature with regard to the etiology and treatment of agitation in the demented elderly. Agitated behaviors are generally divided in three categories (verbal agitation physically nonaggressive agitation, and aggressive agitation). It is suggested that each category may have a different etiology and treatment; verbal agitation is often related to underlying medical conditions, physically nonaggressive behavior responds to behavioral treatment, and aggressive agitation is more likely to respond to a combination of behavioral and pharmacologic treatment.

Accumulating evidence suggests that a large proportion of patients diagnosed with generalized anxiety disorder suffer from a chronic or recurrent condition that is associated with a moderate amount of disability and impairment in quality of life. Acute drug therapy is well studied and appears to be highly effective in providing symptom relief, but relapse/recurrence is high. Little research has been reported that identifies predictors of recurrence or studies the clinical parameters of maintenance drug therapy, including benefit-risk assessments or optimal doses or durations of treatment.

The demonstrated efficacy in anxiety disorders of drugs such as buspirone or fluoxetine has emphasized the importance of 5-hydroxytryptamine (5-HT or serotonin). Buspirone is a selective agonist at a subtype of serotonin receptor termed 5-HT1A, whereas fluoxetine is a selective inhibitor of the reuptake of 5-HT. At least 14 types of mammalian serotonin receptors have been isolated and classified into seven major families, using pharmacologic, transductional, and structural criteria. The subtypes of serotonin receptors are localized in different regions of the brain. Selective compounds for particular subtypes of serotonin receptors may yield selective pharmacologic effects. Since the latency between the initiation of treatment with an SSRI and the appearance of clinical effects may be due to the desensitization of presynaptic autoreceptors, the development of drugs to decrease latency is an active area of investigation. This article provides a brief overview of the physiology and pharmacology of serotonin systems so that the relationship between serotonin compounds and anxiety can be better understood.

Approximately 20% to 40% of patients will fail to respond to the first antidepressant used for their current major depressive episode. Furthermore, it has been suggested that a further 20% to 30% of patients will have only a partial response. There are four main options to consider in the treatment of these patients: optimization, substitution, augmentation, and combination therapy. Several combination antidepressant treatments have been used in treatment-refractory depression. Moreover, various augmentation strategies have also proved to be successful. Although the empirical data to support these treatment options are limited, augmentation treatment has several potential advantages over the other clinical options available, particularly substitution. These data are reviewed and clinical applications discussed. Particular attention is paid to the role of anxiolytics as augmentation agents in the treatment of major depression.

Anxiety symptoms are common among alcoholics. Despite evidence suggesting that anxiety symptoms eventually resolve in most alcoholics during persistent abstinence, clinical care often requires rapid evaluation and intervention. This article provides guidelines to differentiate transient from persistent anxiety states, a distinction that has important treatment implications. Psychosocial support and coping skills training to maintain abstinence are recommended for treatment of transient anxiety states. The use of medication should be reserved for persistent anxiety states. Recent placebo-controlled trials of buspirone, a non-benzodiazepine anxiolytic, suggest that this medication may help to retain anxious alcoholics in treatment and to reduce anxiety symptoms and heavy drinking. Guidelines are provided for the appropriate use of buspirone in alcoholics with persistent anxiety symptoms.