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Objective: The best currently available treatments for obsessive-compulsive disorder (OCD) are serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy (CBT). It is generally recommended that patients who have been unsuccessfully treated with SRIs should receive supplementary CBT, although few studies have yet to investigate the proposal's validity. The purpose of the present study is to examine the effectiveness of CBT on a sample of nonselected, pharmacologically treatment-resistant OCD patients., Method: Thirty-six OCD patients (based on DSM-IV criteria) who had not responded to at least 1 adequate SRI trial conducted in our outpatient clinic were treated from January 2000 through April 2004 with CBT, incorporating exposure and ritual prevention. The therapy was conducted in a naturalistic setting and manualized guidelines were adapted to each patient. Pharmacologic treatment underwent no changes during the trial period. Outcome measures included the Yale-Brown Obsessive Compulsive Scale, the Clinical Global Impressions-Severity of Illness scale, and the Global Assessment of Functioning scale. The primary outcome measure was a rating of "much improved" or "very much improved" on the Clinical Global Impressions-Improvement scale (CGI-I)., Results: Two patients (5%) refused CBT after 1 session, and 10 patients (28%) dropped out of the study. Three of the 24 remaining patients completed the trial at 6 months (T1) but did not follow through up to 12 months (T2). The 21 patients completing CBT showed statistically significant improvement (p < .0001) during follow-up on all outcome measures. At T2, 15 (42%) of 36 patients were rated as being "much improved" or "very much improved," as measured by the CGI-I. Symptom reduction was clinically modest but important, with nearly all patients presenting residual symptoms., Conclusion: CBT could be usefully added to pharmacologic treatments for severe, real-world, medication-resistant OCD patients.

Objective: To critically review the antiobsessional properties of serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and clomipramine) in the treatment of obsessive-compulsive disorder (OCD) as an alternative to selective serotonin reuptake inhibitors (SSRIs), which are currently considered the first-line treatment of OCD., Data Sources: A MEDLINE search was performed to identify clinical trials with the SNRIs venlafaxine and clomipramine published from 1996 to 2004 (keywords: SNRIs, venlafaxine, duloxetine, and clomipramine, each matched individually with the term OCD), focusing on the best-designed studies for inclusion., Data Synthesis: Much of the literature about SNRIs in OCD supports the efficacy of these compounds in the treatment of OCD. However, double-blind, placebo-controlled studies with venlafaxine are lacking, and the most relevant studies consist of active comparison trials between SNRIs and SSRIs. In these studies, SNRIs seem to be as effective as SSRIs in OCD; SNRIs might be preferred for patients with certain types of treatment-resistant OCD or those with particular comorbid conditions. A large number of placebo-controlled and active comparison trials with clomipramine document efficacy in OCD, and meta-analytic studies suggest a small superiority over SSRIs. Compared with clomipramine, the SNRI venlafaxine showed fewer side effects and better tolerability., Conclusion: The SNRIs may represent a valid alternative to the SSRIs, particularly in specific cases. Double-blind, placebo-controlled studies are, however, needed to confirm the positive findings reported by several studies with venlafaxine.

Objective: To investigate rates of response and remission in adults with obsessive-compulsive disorder (OCD) after 12 weeks of evidence-based treatment., Method: Post hoc analyses of response and remission were conducted using data from a multisite, randomized, controlled trial comparing the effects of 12 weeks of exposure and ritual prevention (EX/RP), clomipramine (CMI), their combination (EX/RP+CMI), or pill placebo (PBO) in 122 adults with OCD (DSM-III-R or DSM-IV criteria). Response was defined as a decrease in symptoms; remission was defined as minimal symptoms after treatment. Different response and remission definitions were constructed based on criteria used in prior studies. For each definition, the proportion of responders or remitters in each treatment group was then compared., Results: There were significant differences (p<.05) among the 4 treatment groups in the proportion of responders and remitters. In pairwise comparisons, EX/RP+CMI and EX/RP each produced significantly more responders and remitters than PBO; CMI produced significantly more responders and remitters than PBO for some definitions but not for others. When remission was defined as a Yale-Brown Obsessive Compulsive Scale (YBOCS) score of 12 or less, significantly more EX/RP+CMI (18/31 [58%]) and EX/RP (15/29 [52%]) patients entering treatment achieved remission than either CMI (9/36 [25%]) or PBO (0/26 [0%]) patients. However, even in treatment completers, many CMI and some EX/RP+CMI and EX/RP patients did not achieve remission (remission rates for YBOCS

Background: The effect of extended anti-depressant treatment on weight has been poorly investigated. Also unknown is whether different compounds have differential effects. The aim of the present study was to assess changes in weight in obsessive-compulsive disorder (OCD) patients treated for 2.5 years with clomipramine or selective serotonin reuptake inhibitors., Method: 138 DSM-IV OCD patients who responded to 6-month acute treatment at the Mood and Anxiety Disorders Unit, Department of Neuroscience, University of Turin, Italy, were followed-up for 2 years while receiving open-label clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. Patients were consecutively recruited and followed from May 1998 to March 2003. The mean percentage change in weight was compared for each group, as was the proportion of patients who had a > or = 7% weight increase from baseline., Results: At the end of the 2.5-year study period, patients had gained a mean of 2.5% of their body weight with respect to baseline (1.58 kg); 14.5% of the total sample experienced a significant (> or = 7%) weight increase. Within each but the fluoxetine treatment group, paired t tests showed a significant increase in weight from baseline to final visit. Analysis of variance showed a significant difference between treatment groups (p = .009), with clomipramine being associated with the highest weight increase and fluoxetine and sertraline with the lowest. A higher proportion of clomipramine-treated patients (34.8%) gained > or = 7% in weight as compared with sertraline and fluoxetine, which accounted for the lowest percentage of patients with a significant weight gain (4.5% and 8.7%, respectively), although this difference was not statistically significant., Conclusion: Risk of weight gain during extended serotonin reuptake inhibitor treatment for OCD differs depending on which compound is used. The differences among antiobsessive drugs may affect compliance with medication and health risks.

Serotonin reuptake inhibitors (SRIs), especially potent ones given at high doses over long periods of time, are often effective in the treatment of obsessive-compulsive disorder (OCD). However, a large percentage of patients do not respond to treatment with SRIs, and those who do respond often do not fully remit, which should be the standard goal of treatment in OCD. If a patient has been treated for several months and has not yet responded to treatment with several SRIs, the physician should perform a careful assessment of resistant and/or residual clinical symptoms and any comorbid conditions to determine which next-step treatment would be the most appropriate. One strategy for patients who have not responded to treatment with an SRI is to switch them to a serotonin-norepinephrine reuptake inhibitor, because some patients may respond better to agents that target multiple systems. Another promising approach is the augmentation of SRIs with neuroleptics. In addition, open trials have shown that intravenous (IV) clomipramine and IV citalopram may be effective in the treatment of resistant OCD. Novel pharmacotherapeutic treatments and electroconvulsive therapy have been attempted, with mixed success. Recently, researchers have been studying repetitive transcranial magnetic stimulation, vagal nerve stimulation, and neurosurgical approaches such as gamma knife capsulotomy and deep brain stimulation to learn if these procedures are effective in treating treatment-resistant OCD. Repetitive transcranial magnetic stimulation has possibilities not only as a therapy but also as an instrument that can help researchers describe the neurocircuitries involved in OCD. More results are needed before the effectiveness of the nonpharmacologic treatments for OCD can be determined.

Background: Notwithstanding the emerging literature on comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorder, relatively few systematic data exist on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice., Method: The sample comprised 68 patients with comorbid DSM-IV diagnoses of OCD and major depressive episode admitted and treated at the day-hospital in the Department of Psychiatry at the University of Pisa (Pisa, Italy) during a 3-year period (January 1995-December 1998). Thirty-eight patients (55.8%) showed lifetime comorbid bipolar disorder (12 [31.6%] bipolar I and 26 [68.4%] bipolar II). Diagnoses and clinical features were collected by means of structured (Structured Clinical Interview for DSM-IV) and semistructured interviews (OCD-Interview). Assessments of drug treatments, clinical outcome, and adverse effects were made prospectively as part of routine clinical care throughout the course of their day-hospitalization., Results: In contrast with non-bipolar OCD patients, OCD-bipolar patients showed a more episodic course with a greater number of concurrent major depressive episodes. They reported a significantly higher rate of sexual obsessions and significantly lower rate of ordering rituals. Furthermore, they reported more frequent current comorbidity with panic disorder-agoraphobia and abuse of different substances (alcohol, sedatives, nicotine, and coffee). Drug treatment with clomipramine and, to a lesser extent, with selective serotonin reuptake inhibitors was associated with hypomanic switches in OCD-bipolar patients, especially in those not concomitantly treated with mood stabilizers. A combination of multiple mood stabilizers was necessary in 16 OCD-bipolar patients (42.1%) and a combination of mood stabilizers with atypical antipsychotics was required in 4 cases (10.5%). OCD-bipolar patients tended to show a less positive outcome for mood symptomatology and general functioning. Three patients required hospitalization for severe mixed episode., Conclusion: In a tertiary care center, comorbidity between OCD and bipolar disorder is a significant clinical problem affecting a large number of patients and has a substantial impact on the clinical characteristics and treatment outcome of both disorders.

Background: The objective of this study was to investigate, in a single-blind manner over a period of 12 weeks, the efficacy and tolerability of venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder (OCD)., Method: Patients with a DSM-IV diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (YBOCS) score >/= 16 were randomly assigned to receive venlafaxine, 225 to 350 mg/day (26 patients), or clomipramine, 150 to 225 mg/day (47 patients), for 12 weeks, with dosage adjustments according to tolerability and response to treatment. All patients were medication-free from at least 2 months prior to study enrollment. Efficacy measures were the YBOCS and the Clinical Global Impressions scale (CGI), which were completed at baseline and every 4 weeks. We defined responders as patients who had an improvement from baseline in YBOCS score of >/= 35% and a CGI score

Background: The objective of this study was to examine the long-term course of obsessive-compulsive disorder (OCD) in patients treated with serotonin reuptake inhibitors (SRIs) and behavioral therapy and to identify predictors of clinical outcome., Method: Sixty outpatients meeting DSM-II-R or DSM-IV criteria for OCD were followed up for 1 to 5 years (mean = 2.5 years). All of them received prolonged pharmacologic therapy with an SRI., Results: Thirty-seven patients (61.7%) completed an adequate behavioral treatment. At long-term assessment, 22 patients (36.7%) exhibited a global Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score greater than 16 or a final reduction in Y-BOCS global score of less than 35% and were considered nonresponders. Patients who completed behavioral therapy showed a significant decrease in Y-BOCS compulsions subscale score (p = .01), whereas no significant differences in either Y-BOCS global or obsessions subscale scores between those who did and those who did not undergo behavioral therapy were detected. Obsessions of sexual/religious content were the unique factor related to a poorer long-term outcome., Conclusion: A substantial number of OCD patients showed persistent disabling symptoms at the long-term follow-up in spite of combined pharmacologic and behavioral treatment. Major benefits from behavioral therapy appeared to be the improvement of ritualistic behaviors. Sexual/religious obsessions predicted poorer long-term outcome, whereas short-term response to SRI treatment failed to achieve predictive value in the long-term course of OCD.

Background: We report, after 3 years of work, a case series showing our initial results (efficacy, tolerability, and safety) with the addition of venlafaxine immediate release (IR) to either clomipramine or imipramine in depressed patients who had shown only partial response to maximal doses of one of those tricyclic antidepressants (TCAs) and no further improvement after addition of usual augmentation drugs., Method: Eleven patients were treated, 10 of them having a recurrent depressive disorder (DSM-IV) and all of them having current major depression (DSM-IV) that in 9 patients was moderate or severe despite intense TCA treatment as well as usual augmentations. Under open and outpatient conditions, we maintained TCA doses, discontinued previous augmentations, and then added venlafaxine IR to a maximum dosage, if necessary, of 150 mg every 12 hours. There was no control group. Response was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D), DSM-IV criteria, the Clinical Global Impressions-Severity of Illness scale, and persistence of improvements after 6 months. We measured clinical tolerance (using the UKU Side Effect Rating Scale), blood pressure and heart rate, electrocardiogram (ECG), and blood TCA levels after adding venlafaxine IR., Results: A sustained improvement (> 50% decrease in HAM-D score plus decrease in DSM-IV severity level) appeared in 9 patients, and sustained full remission (DSM-IV criteria plus HAM-D score < 5) in 7. Panic-agoraphobic symptoms improved in the 2 patients suffering from them. There were no dropouts, and tolerability was good. No significant changes in blood pressure and heart rate, ECG, or blood tricyclic levels were found., Conclusion: Addition of venlafaxine to clomipramine or imipramine could be an effective and safe augmentation strategy in depressive patients with partial response to maximum-dose monotherapy. A consistent replication of these initial findings is strongly needed.

Background: The major treatments reported to be effective in the treatment of trichotillomania are cognitive-behavioral therapy (CBT) with habit reversal and serotonin-norepinephrine reuptake inhibitors such as clomipramine. However, the 2 treatments have not been previously compared with each other. This study examines the efficacy of CBT and clomipramine compared with placebo in the treatment of trichotillomania., Method: Twenty-three patients with trichotillomania as determined by the Structured Clinical Interview for DSM-III-R entered and 16 completed a 9-week, placebo-controlled, randomized, parallel-treatment study of CBT and clomipramine. Efficacy was evaluated by the Trichotillomania Severity Scale, the Trichotillomania Impairment Scale, and the Clinical Global Impressions-Improvement scale, which were conducted by an independent assessor blinded to the treatment condition., Results: CBT had a dramatic effect in reducing symptoms of trichotillomania and was significantly more effective than clomipramine (p = .016) or placebo (p = .026). Clomipramine resulted in symptom reduction greater than that with placebo, but the difference fell short of statistical significance. Placebo response was minimal., Conclusion: Clinicians should be aware of the potential treatments available for trichotillomania. A larger and more definitive study comparing CBT and a serotonin-norepinephrine reuptake inhibitor is indicated.

Background: This 12-week, placebo-controlled study was carried out to compare the relative efficacy of paroxetine, clomipramine, and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia., Method: After a 3-week single-blind, placebo run-in period, 131 patients were randomly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression scale, the Patient Global Evaluation, the Hamilton Rating Scale for Anxiety, the Marks-Sheehan Phobia Scale, the Montgomery-Asberg Depression Rating Scale, and the Sheehan Disability Scale., Results: Comparisons with placebo revealed significant superiority of paroxetine (20-60 mg/day) and clomipramine (50-150 mg/day) on nearly all outcome measures. On most measures, paroxetine also showed higher efficacy than cognitive therapy. With few exceptions, cognitive therapy did not differ significantly from placebo. The number of subjects becoming panic-free (66%) was higher and the onset of action was faster in the paroxetine-treated group. Treatment with cognitive therapy yielded the highest drop-out rate (26%)., Conclusion: In this short-term study assessing treatment of panic disorder and agoraphobia, paroxetine and clomipramine were consistently superior to pill placebo, whereas cognitive therapy was superior on only a few measures.

Background: Obsessive-compulsive disorder (OCD) is a chronic illness associated with substantial morbidity; it often requires long-term medication. The best-studied therapeutic agent in the treatment of this disorder is the tricyclic antidepressant clomipramine. Since other tricyclic antidepressants appear to lack efficacy in OCD, that of clomipramine has been linked to its potent effects on serotonin. Consequently, agents that selectively inhibit serotonin reuptake have been the focus of several large-scale, placebo-controlled studies of OCD. Their efficacy in OCD is the focus of our review., Data Sources: MEDLINE search (1966 to present) of OCD treatment with clomipramine or SSRI antidepressant medication using the key words obsessive-compulsive disorder, serotonin reuptake inhibitors, clomipramine, and pharmacology., Study Findings: The selective serotonin reuptake inhibitors fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD. In contrast, clomipramine, though efficacious, is often associated with substantial adverse events, particularly anticholinergic side effects. While 2 recent meta-analyses support the superior efficacy of clomipramine over selective serotonin reuptake inhibitors in the treatment of OCD, 5 of 6 head-to-head comparisons of either fluoxetine or fluvoxamine versus clomipramine have found similar efficacy but a lower incidence of side effects with the selective serotonin reuptake inhibitor. A recently completed multicenter, 12-week, double-blind trial of paroxetine versus clomipramine versus placebo showed paroxetine to be as effective as clomipramine. With significantly fewer dropouts due to adverse effects than clomipramine, paroxetine was also associated with superior tolerability., Conclusion: The suggestion that selective serotonin reuptake inhibitors possess efficacy similar to that of clomipramine, but have a superior side effect profile, may have important implications for patients with OCD who require long-term treatment.

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.

Epidemiologic and clinical data support the goal of treating depressed patients to wellness or full remission. Many patients improve but fail to achieve full remission with antidepressant treatment and continue to have residual symptoms, which cause distress and dysfunction. These residual symptoms may meet criteria for subsyndromal and minor depression. Patients who have these milder syndromes after treatment have a greater risk of relapse and recurrence than do those who remain symptom-free. Clinical trials of antidepressants have shown lower rates of remission than of responses that fall short of remission, although some dual-acting antidepressants (e.g., serotonin-norepinephrine reuptake inhibitors) may have higher remission rates than other agents. Treatment with such robust dual-acting antidepressants may result in higher rates of remission and fewer residual symptoms than treatment with selective serotonin reuptake inhibitors.

There is currently available evidence that suggests that drugs combining 2 synergistic mechanisms of action (e.g., enhancement of both noradrenergic and serotonergic neurotransmission) may yield superior therapeutic efficacy compared with a single therapeutic mechanism of highly selective agents such as selective serotonin reuptake inhibitors (SSRIs). The differences in antidepressant efficacy favoring dual-acting drugs may exist in particular for 3 difficult-to-treat groups of patients: those with endogenous depression, those with severe depression, or hospitalized depressed patients. Mirtazapine differs from other new dual-acting antidepressants by not being a reuptake inhibitor. Its antidepressant activity may be related to a direct enhancement of noradrenergic neurotransmission by blockade of alpha2-autoreceptors. The rapid increase in serotonin (5-HT) synaptic levels by blockade of alpha2-heteroreceptors indirectly enhances 5-HT1A-mediated neurotransmission since 5-HT2 and 5-HT3 are blocked by mirtazapine. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. Currently available evidence suggests that mirtazapine is effective in all levels of severity of depressive illness, as well as is in a broad range of symptoms associated with depression.

Aggressive behaviors are frequently observed in patients with attention-deficit/hyperactivity disorder, conduct disorder, and pervasive developmental disorders. Several theories have been postulated to explain the etiology of aggression in these disorders, but no one theory can account for all the different types of aggressive behaviors observed. Numerous uncontrolled studies with small sample sizes have produced mixed results of pharmacologic agents now being used to treat aggression. This article discusses the phenomenology, etiology, assessment, and pharmacologic treatment of aggressive behavior in patients who have attention-deficit/hyperactivity disorder, conduct disorder, and pervasive developmental disorders.

Panic disorder is a chronic and recurring condition, and there is therefore a need for long-term therapy. This paper reviews data from long-term studies of drug treatment for panic disorder to address issues of whether medication benefits persist, whether improvement can continue over several months or years, the tolerability of long-term treatment, patient selection for long-term treatment, and when and how to stop medication. The main conclusion is that long-term drug treatment of panic disorder is necessary, effective, and safe. Serotonin selective reuptake inhibitors offer benefits of ease of dosing, good tolerability, and no safety or dependence problems; TCAs are often poorly tolerated, and benzodiazepines are associated with dependence problems. Withdrawal from all types of medication should be considered, slow, planned, and individualized; some patients require an indefinite duration of treatment.

Advances have been made in understanding the biology of panic disorder and the role of the underlying serotonergic dysfunction. This review summarizes the biological evidence for the involvement of serotonin in the pathogenesis of panic disorder and considers the 2 opposing theories that are currently prevalent (5-HT excess and 5-HT deficit). The serotonin selective reuptake inhibitors are increasingly considered as first-line treatment for panic disorder, and the interaction of these agents with the serotonergic system is considered.

Background: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance., Method: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day., Results: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment., Conclusion: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.

Background: 60%-90% of patients with a primary diagnosis of depression also experience symptoms of anxiety, and such patients have a poorer prognosis than those with uncomplicated depression. The serotonin selective reuptake inhibitors have demonstrated efficacy in the treatment of both depression and certain anxiety states. Furthermore, in a metaanalysis of the paroxetine clinical trial database of 2963 patients in whom depression predominated, there was a concomitant reduction in the Hamilton Rating Scale for Depression anxiety factor. The purpose of the present study was to prospectively compare the efficacy of paroxetine and clomipramine in patients specifically selected for coexisting depression and anxiety., Method: This was a 12-week, double-blind, parallel-group trial comparing paroxetine 20-40 mg/day with clomipramine 75-150 mg/day in 1002 patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Clinical Anxiety Score (CAS) > or = 11 after a 3-7 day placebo run-in period., Results: Both paroxetine and clomipramine reduced the MADRS and CAS ratings at 2, 6, and 12 weeks and at endpoint, with no significant differences between treatment groups at any time point. CGI severity of illness and global improvement ratings were also similar throughout the trial; however, there was a statistically significant difference in the CGI efficacy index at 6 weeks and at endpoint, favoring paroxetine (p = .015 and p = .015, respectively). Paroxetine resulted in fewer treatment-emergent adverse experiences and related withdrawals than clomipramine (p = .025 and p = .008, respectively). The number of serious adverse experiences was not significantly different in the paroxetine group compared with the clomipramine group (14 [2.8%] vs. 27 [5.4%]), but did approach statistical significance (p = .056). Anticholinergic-emergent adverse experiences were reported twice as frequently by patients in the clomipramine group as in the paroxetine group (36.1% vs. 18.6%)., Conclusion: There was no evidence of any significant difference in efficacy between paroxetine and clomipramine in patients with coexisting depression and anxiety. However, paroxetine was better tolerated as shown by total treatment-emergent adverse experiences, anticholinergic adverse experiences, and withdrawals due to adverse experiences.

The treatment of obsessive-compulsive disorder (OCD) has changed dramatically in the last 10 years. Currently, the serotonin reuptake inhibitors (SRIs) and the serotonin selective reuptake inhibitors (SSRIs) are considered the "first choice" agents for pharmacologic treatment of OCD, although few head-to-head comparisons exist between any two specific agents. Strategies for nonresponders and partial responders to the SRI/SSRIs are reviewed. The only agents that have shown significant improvement as augmenting agents to an SRI/SSRI in systematic trials have been clonazepam and haloperidol. Predictors of response to pharmacotherapy have been limited, but several reports have found that an early age at onset of OCD has been associated with a poorer response to medications. Long-term maintenance medication may be necessary for some, although behavioral therapy may improve the need for extended pharmacotherapy. Cognitive behavioral therapy, specifically exposure with response prevention, still remains an effective and important component of treatment for many. One of the newest developments is the identification of a pediatric subtype of OCD characterized by prepubertal acute onset after group A beta-hemolytic streptococcal pharyngitis. Investigation trials with these children include immunomodulatory therapies and penicillin treatment and prophylaxis. If a unique subgroup of children with OCD can be identified, then novel treatments may prove effective and have a role in long-term prophylaxis.

The mainstay of the pharmacologic treatment of obsessive-compulsive disorder (OCD) is a 10- to 12-week trial of a potent serotonin reuptake inhibitor (SRI) at an adequate dose. Double-blind, placebo-controlled trials have established the anti-obsessive-compulsive (OC) efficacy of five different SRIs. One of the most thoroughly studied of these SRIs is fluvoxamine, the focus of this article. Fluvoxamine's pharmacologic and pharmacokinetic properties, its efficacy, and guidelines for its clinical use in OCD and related disorders are briefly reviewed. Potential drug-drug interactions are discussed and placed in clinical perspective. The management of common SRI-induced side effects is also addressed. Recent comparative studies suggest that fluvoxamine may be equivalent in efficacy to clomipramine, yet better tolerated. Fluvoxamine shows promise in the treatment of several so-called OC-spectrum disorders, but additional controlled trials are needed.

The predominant hypothesis about obsessive-compulsive disorder (OCD) pathophysiology implicates abnormal serotonergic function regulation. Pharmacologic agents with potent serotonin reuptake-inhibiting properties have demonstrated effectiveness in treating OCD. In short-term clinical trials compared by meta-analysis, clomipramine and serotonin selective reuptake inhibitors (SSRIs) were found superior to placebo in improving symptoms of OCD. In one-to-one comparative studies, clomipramine has been found as efficacious as fluoxetine and fluvoxamine, and in a comparative trial of clomipramine with sertraline, there was a statistically superior response to sertraline after 16 weeks of treatment; moreover, discontinuation rate in patients taking clomipramine was more than twice that in patients taking sertraline (26% vs. 11%). In contrast to patients receiving clomipramine who showed poor tolerance in long-term use, patients maintained on fluoxetine for 24 weeks after an acute phase well tolerated the medication. In another study, patients responding to 12 weeks of sertraline treatment also showed improved tolerance during an additional 40-week period, with 75% completing the continuation phase. With long-term or even lifelong treatment appearing necessary for people with OCD, those agents that result in better tolerance will prove preferable.

Premenstrual dysphoric disorder describes a subset of women who have severe premenstrual symptoms, including at least one mood symptom. It is included in DSM-IV under "Depressive Disorders Not Otherwise Specified." Criteria differentiating premenstrual dysphoric disorder from premenstrual syndrome are the requirements that patients have at least five symptoms, including one mood symptom; have impairment associated with the illness; and prospectively confirm the symptoms. After decades of treatment research on premenstrual dysphoria, the most consistent positive results have been found for selective antidepressants, primarily those that are active at serotonin receptors. Most studies have used continuous daily treatment for acute phase therapy. Further studies should define the role of intermittent and long-term maintenance therapies with these agents.

Background: Combination treatment with tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed strategy especially in depressed patients unresponsive to monotherapy. Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic interactions that can result in elevated serum TCA levels. For the combinations, safety and tolerability data are lacking., Method: We report tolerability and safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22 patients. Most patients suffered from depression and obsessive-compulsive symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were determined. EEG, ECG, and laboratory parameters and adverse effects reported by the patients, as well as global clinical improvement, were assessed., Results: Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI levels reached 500 to 1200 ng/mL in half of the patients, while corresponding levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in serum were markedly lower under comedication than under CMI monotherapy. Alterations in EEG, ECG, and laboratory parameters that had clinical relevance were rarely observed and were reversible after dose reduction of CMI. However, 2 patients developed myoclonic jerks. A majority of patients improved clinically during combination treatment. Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3., Conclusion: Our results suggest that comedication of fluvoxamine and clomipramine will result in markedly elevated serum clomipramine levels. Therefore, combination treatment with fluvoxamine and clomipramine should be carefully monitored by determination of serum levels of the TCA. Clinically, the pharmacokinetic interactions between fluvoxamine and clomipramine may be well tolerated in a majority of patients. However, in a few patients, higher serum levels may be associated with an increased risk of EEG changes and changes of intracardiac conductance. EEG and ECG should be used regularly to monitor comedicated patients.

Since concomitant anxiety is frequent and prominent, obsessive-compulsive disorder (OCD) is classified as an anxiety disorder. However, effective antidepressant and anxiolytic agents that are nonserotonin-selective are generally ineffective in significantly reducing OCD symptoms, while the potent serotonin reuptake inhibitor, the tricyclic clomipramine, and several serotonin selective reuptake inhibitors (SSRIs) are efficacious. These results suggest that serotonergic transmission may be important in achieving significant antiobsessive efficacy. Although no significant differences in efficacy between SRIs and SSRIs have been demonstrated in the treatment of OCD, there are important differences in side effect profiles and pharmacokinetic factors. Further research in the treatment of OCD is required on comparative efficacy of SRIs, the choice of SRI agents following initial nonresponse, and effects resulting from the long-term use of SRIs.

Body dysmorphic disorder (BDD), a preoccupation with an imagined or slight defect in appearance, has been described for more than a century and reported around the world. However, this distressing and impairing disorder often goes undiagnosed, even though available data suggest that it is relatively common. Virtually any body part can be the focus of concern, with preoccupations most often involving the hair, nose, or skin. Most patients engage in excessive and repetitive behaviors such as mirror checking, skin picking, and reassurance seeking. Insight is generally poor, and many patients are frankly delusional. Most patients experience significant impairment in functioning, and suicide attempts are relatively common. Although the majority of patients with BDD seek often costly nonpsychiatric treatment-most often, surgical or dermatologic-such treatment usually appears to be unsuccessful. In contrast, preliminary data from open studies suggest that the serotonin reuptake inhibitors are often, and perhaps preferentially, effective for BDD. Augmentation, combination, and switching strategies may be useful in treatment-resistant cases. Preliminary data suggest that cognitive-behavioral strategies using exposure and response prevention may also be effective. Investigation of all aspects of this understudied disorder, including controlled treatment trials, is greatly needed.

This article reviews all available studies reported in the literature or presented at national or international meetings on the efficacy of serotonin selective reuptake inhibitors and less selective serotonin uptake inhibitors in panic disorder. The research data lags behind-rather than leads-experience in everyday clinical practice. The emerging data suggest that serotonin uptake inhibitors are superior to placebo and better tolerated than most of the older alternatives. As a result they are now becoming first-choice treatments in panic disorder.

Background: Clinicians and researchers who work with mentally retarded subjects have reported on the frequent exhibition of mental disorders and behavioral problems in this population. Rituals are often among the disturbances described. We decided to treat disabling cleaning and collecting compulsions in mentally retarded adults with clomipramine 75 mg/day, sustained release (SR) preparation., Method: The 8-week trial included 11 subjects, mean age of 24.1 years (range, 21-27) with a mean +/- SD I.Q. of 65.0 +/- 11.0. The majority of subjects (N = 9) were occupied with washing rituals that took hours to complete. Subjects were started on a schedule of 32.5 mg of clomipramine SR once daily for 1 week, then received 75 mg SR once daily for an additional 7 weeks., Results: Improvement was assessed by using the National Institute of Mental Health Global Obsessive Compulsive Scale and the Global Improvement score of the Yale-Brown Obsessive Compulsive Scale. Statistically significant reduction in severity of rituals (p < .05) was found at the trial's completion., Conclusion: Once-daily clomipramine SR 75 mg is effective in treating adults with mental retardation and disabling rituals.

Background: The purpose of this study was to assess the sexual and psychosocial efficacy of clomipramine for rapid ejaculation., Methods: Fifteen physically healthy, self-selected couples (men had a mean age of 38 years) who met six eligibility criteria and did not meet five exclusion criteria participated in a variable-length, repeated measures, randomized, double-blind, placebo-controlled crossover study with a 2-month follow-up period. Sexual and psychosocial assessments were conducted at baseline, after placebo, after 25 mg/day of clomipramine, after 50 mg/day of clomipramine, and at the 2-month follow-up point. The major outcome measures included stopwatch timing of ejaculation latencies, modified Case Western Reserve University Sexual Function Questionnaire, Symptom Checklist-90-R, Dyadic Adjustment Scale, State-Trait Anxiety Inventory, and the Harder Self-Esteem Inventory., Results: Baseline mean ejaculatory latency was 81 seconds; 25 mg/day of clomipramine increased it to 202 seconds and 50 mg/day of clomipramine to 419 seconds. This resulted in significantly greater sexual satisfaction scores for men and their partners (men, p < .001; women, p < .05), improvements in partner coital orgasmic attainment, and greater relationship and emotional satisfaction for the men. Withdrawal of the drug caused ejaculatory latencies to return to baseline., Conclusion: Clomipramine appears to be effective in significantly lengthening ejaculatory latencies and increasing sexual and relationship satisfaction. It can be a cost-effective chronic therapy for selected patients. These impressive results should not be expected in a less carefully screened population of men concerned about the timing of their orgasm during intercourse.

Background: Although a large body of evidence indicates the efficacy of pharmacotherapy in the treatment of obsessive-compulsive disorder (OCD), a considerable percentage of these patients do not respond. Very few studies focus on factors related to treatment response of OCD. The purpose of this study was to investigate which clinical factors are related to drug treatment response in OCD., Method: We examined 53 OCD patients treated with either clomipramine or fluoxetine for a period of 6 months, dividing the sample into "responders" and "nonresponders" to treatment. At admission, patients were evaluated using a semistructured clinical interview, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety. We then compared acute-phase patient characteristics and response to drug treatment. Response was defined as a decrease of at least 40% in the Y-BOCS total score and a rating of "improved" or "very improved" on the Clinical Global Impressions scale within 16 weeks of treatment and maintained over three consecutive evaluations., Results: By the sixth month of treatment, 31 patients (58.5%) responded to either clomipramine or fluoxetine. Nonresponders had lower age at onset and longer duration of the disorder; in addition, they showed higher frequency of compulsions, washing rituals, chronic course, concomitant schizotypal personality disorder, and previous hospitalizations. A worse response to drug treatment was predicted in a stepwise multiple regression by (1) concomitant schizotypal personality disorder, (2) presence of compulsions, and (3) longer illness length., Conclusion: Our findings suggest that there are distinct types of OCD with respect to drug treatment response. They provide indirect evidence of treatment specificity by identifying characteristics responsive to different modalities, which may be of value in the selection of patients for alternative treatments.

Background: Trichotillomania, characterized by an irresistible urge to pull one's hair, may be more prevalent than previously believed. Despite increasing attention devoted to this topic in the recent literature, there are few studies based on large samples that are potentially generalizable to a community population., Method: Surveys addressing clinical profile, comorbidity, and treatment history were mailed to all responders to a nationally distributed magazine article on trichotillomania. Out of 772 surveys sent, 123 completed surveys were returned., Results: While there was a predominance of females in the whole sample, female-to-male prevalence was lower in children than adults. Onset was predominantly in childhood (mean age = 11 years), most frequently in middle childhood and least frequently before age 6. Subjects pulled hair from a variety of sites, including scalp, eyelashes, eyebrows, pubic region, face, and body, but the highest incidence and severity involved scalp hair. Children under 6 were more likely than other age groups to pull scalp hair and possibly less likely to pull other hair. In adults, symptom profile was not associated with age at onset. While subjects reported high rates of comorbid conditions in both self and family, trichotillomania was reportedly formally diagnosed in only 40% of the subjects. Although subjects reported a range of treatments, the majority (58%) reported no treatment history. Finally, only minimal improvement was reported for all modalities, with no significant difference in response to psychotherapy, behavior therapy, clomipramine, or fluoxetine., Conclusion: Trichotillomania is a chronic illness that may be difficult to treat. Controlled studies on comorbidity, epidemiology, treatment-seeking patterns, and long-term treatment response are needed.

Background: Clomipramine, a serotonin reuptake blocker that has been shown to be effective in treating obsessive-compulsive disorder and other unwanted repetitive, ritualized behaviors, was hypothesized to be superior to desipramine, a tricyclic antidepressant with selective noradrenergic effects, for developmental stuttering., Method: Seventeen psychiatrically normal subjects, aged 14-61 years, with developmental stuttering completed a 10-week double-blind crossover trial of clomipramine and desipramine after a 2-week single-blind placebo phase., Results: Clomipramine was superior to desipramine (two-tailed, p < .05) for 5 of 10 self-report ratings including stuttering severity on two scales, degree of preoccupation with stuttering and resistance to stuttering on a visual analog scale, and "expectancy" of stuttering on the Perceptions of Stuttering Inventory., Conclusion: Clomipramine may be clinically useful for some patients with developmental stuttering. Biological links between developmental stuttering and other repetitive motor patterns that are selectively responsive to serotonergic agents should be explored.

Background: Women with postpartum-onset obsessive compulsive disorder may elect treatment with clomipramine. There is minimal information to guide the clinician who must advise breastfeeding women about clomipramine therapy., Method: Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites., Results: Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed., Conclusion: This report adds to the growing literature that suggests that tricyclic use during breastfeeding rarely results in measurable drug levels in infant sera.

In the last 7 years, positron emission tomography (PET) scanning studies of obsessive compulsive disorder have given us new insights into misfunctionings of brain systems that may mediate the symptomatic expression of this classical "neurosis." Work by several PET groups indicates that a prefrontal cortex-basal ganglia-thalamic circuit may be the brain pathway leading to the broken record patterns of obsessions and compulsions.

Exposure in vivo and ritual or response prevention are the essential elements of behavior therapy for obsessive compulsive disorder. Naturalistic behavior therapy helped a fortunate few before the effective elements of behavior therapy were identified and systematically applied. Homework exposure and response prevention are essential and therapist accompaniment is seldom necessary. Homework sessions are planned by patient and clinician and written records facilitate treatment modifications during homework sessions. About a quarter of patients refuse behavior therapy, but 90% of the remainder achieve worthwhile gains with exposure and response prevention. Limited availability of behavior therapy is a substantial public health problem.

Often obsessive compulsive disorder (OCD) patients are labeled as treatment refractory when some first-line options have not been fully explored. Most patients should be encouraged to participate in behavior therapy, even when pharmacotherapy alone has been partially successful. Antiobsessional agents such as clomipramine, fluoxetine, and fluvoxamine should be considered first-line drugs. Their prescription for a sufficient time and at therapeutic doses is imperative. Enhancement strategies for a selected group of OCD patients include low-dose high-potency neuroleptics. In addition, clonazepam can be helpful in augmenting the response to a first-line drug. Results from controlled studies with lithium and buspirone have been disappointing. If most of these pharmacologic alternatives fail, MAOIs appear to be the next best choice. Since in the future most referrals for treatment-refractory OCD patients will emanate from nonpsychiatrists, following a systemic strategy in their evaluation and pharmacologic management is most important.