Stargardt macular dystrophy and therapeutic approaches.

Stargardt macular dystrophy (Stargardt disease; STGD1; OMIM 248200) is the most prevalent inherited macular dystrophy. STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). Major advances in understanding both the clinical and molecular features, as well as the underlying pathophysiology, have culminated in many completed, ongoing and planned human clinical trials of novel therapies.The aims of this concise review are to describe (1) the detailed phenotypic and genotypic characteristics of the disease, multimodal imaging findings, natural history of the disease, and pathogenesis, (2) the multiple avenues of research and therapeutic intervention, including pharmacological, cellular therapies and diverse types of genetic therapies that have either been investigated or are under investigation and (3) the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6.8 kb ABCA4 open reading frame.

VLDL receptor gene therapy for reducing atherogenic lipoproteins.

Over the past 40 years, there has been considerable research into the management and treatment of atherogenic lipid disorders. Although the majority of treatments and management strategies for cardiovascular disease (CVD) center around targeting low-density lipoprotein cholesterol (LDL-C), there is mounting evidence for the residual CVD risk attributed to high triglyceride (TG) and lipoprotein(a) (Lp(a)) levels despite the presence of lowered LDL-C levels. Among the biological mechanisms for clearing TG-rich lipoproteins, the VLDL receptor (VLDLR) plays a key role in the trafficking and metabolism of lipoprotein particles in multiple tissues, but it is not ordinarily expressed in the liver. Since VLDLR is capable of binding and internalizing apoE-containing TG-rich lipoproteins as well as Lp(a), hepatic VLDLR expression has the potential for promoting clearance of these atherogenic particles from the circulation and managing the residual CVD risk not addressed by current lipid lowering therapies. This review provides an overview of VLDLR function and the potential for developing a genetic medicine based on liver-targeted VLDLR gene expression.

Acute worsening of chronic depression during a double-blind, randomized clinical trial of antidepressant efficacy: differences by sex and menopausal status.

OBJECTIVE: Acute worsening of depression can negatively impact the outcomes of clinical trials of antidepressants and patient compliance to treatment. We hypothesized that acute worsenings would be more frequent in premenopausal women, relative to men or postmenopausal women, and in women who had demonstrated premenstrual symptom exacerbations (PMEs) prior to treatment, relative to those who had demonstrated no PMEs. METHOD: Subjects diagnosed with DSM-III-R chronic major depressive disorder or double depression (dysthymia with concurrent major depressive episode) were randomly assigned between February 1993 and December 1994 to 12 weeks of double-blind treatment with flexibly-dosed sertraline or imipramine, with crossover to the alternate drug in the absence of response. A 6-point or more increase in the 17-item Hamilton Rating Scale for Depression relative to the (7-14 day) previous visit defined worsening. PME was assessed through daily diaries prior to treatment. RESULTS: There were 3582 evaluable visits attended by 554 subjects. Premenopausal women had a deteriorating depressive presentation at a greater proportion of their visits (8.6%) than did postmenopausal women (4.5%, p < .01) or men (5.9%, p < .01). The presence of PME at baseline was associated with more worsenings than the absence of PME (12.0% vs. 7.3%, p < .05). Results were similar whether the subject was treated with sertraline or imipramine. Nonresponse at treatment completion was more likely among subjects with worsening (p < .01). Dropouts were more likely than completers to have had an exacerbation at their terminal visit (p < .05). CONCLUSION: Acute worsening of depression was associated with reproductive variables and negatively affected clinical trial outcomes including early treatment discontinuation and nonresponse.

Efficacy of sertraline in posttraumatic stress disorder secondary to interpersonal trauma or childhood abuse.

BACKGROUND: In posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse. METHODS: 395 adult patients with PTSD were randomized to 12-weeks double-blind treatment with flexible dose sertraline (50-200 mg/d) or placebo. Patients with different index traumas were compared in terms of baseline demographic and clinical characteristics, as well as treatment response. Primary efficacy variables included part 2 of the Clinician Administered PTSD Scale (CAPS-2). RESULTS: Interpersonal trauma and childhood abuse were both more common in females than males, and were associated with early age at time of index trauma and longer duration of PTSD, but not with PTSD symptom severity. Sertraline was significantly more effective than placebo on most primary efficacy variables, irrespective of whether patients had experienced interpersonal trauma or childhood abuse. CONCLUSIONS: These data demonstrate that sertraline is valuable for the treatment of PTSD, irrespective of whether the precipitating trauma involves interpersonal trauma in general, or childhood abuse in particular.

Multidimensional effects of sertraline in social anxiety disorder.

Clinical trials of social anxiety disorder (SAD) have largely focused on the effect of treatment on symptoms of fear and avoidance, while neglecting the third clinically relevant dimension, physiological arousal. Data were combined from two previously reported placebo-controlled trials of sertraline in the treatment of moderate-to-severe generalized SAD. Efficacy was evaluated using the Brief Social Phobia Scale (BSPS). Three hundred forty-six subjects were randomized to 12-13 weeks of treatment with sertraline and 273 subjects to placebo. Following treatment, significant improvement was noted in favor of sertraline on the full BSPS (P < .001), as well as on each of the individual BSPS subscales: fear (P = .001); avoidance (P < .0001); and physiological arousal (P < .0001). Of the physiological symptoms assessed, the treatment advantage with sertraline was maintained for blushing (P < .003) and palpitations (P < .03), but not for trembling and sweating. These results confirm the efficacy of treatment with a selective serotonin reuptake inhibitor (SSRI), sertraline, across the spectrum of fear, avoidance, and physiological arousal in generalized SAD (GSAD). Among common physiological symptoms in this population, blushing and palpitations appear more treatment responsive than trembling and sweating to acute treatment with sertraline.

Quality-of-life impairment in depressive and anxiety disorders.

OBJECTIVE: Previous reports demonstrating quality-of-life impairment in anxiety and affective disorders have relied upon epidemiological samples or relatively small clinical studies. Administration of the same quality-of-life scale, the Quality of Life Enjoyment and Satisfaction Questionnaire, to subjects entering multiple large-scale trials for depression and anxiety disorders allowed us to compare the impact of these disorders on quality of life. METHOD: Baseline Quality of Life Enjoyment and Satisfaction Questionnaire, demographic, and clinical data from 11 treatment trials, including studies of major depressive disorder, chronic/double depression, dysthymic disorder, panic disorder, obsessive-compulsive disorder (OCD), social phobia, premenstrual dysphoric disorder, and posttraumatic stress disorder (PTSD) were analyzed. RESULTS: The proportion of patients with clinically severe impairment (two or more standard deviations below the community norm) in quality of life varied with different diagnoses: major depressive disorder (63%), chronic/double depression (85%), dysthymic disorder (56%), panic disorder (20%), OCD (26%), social phobia (21%), premenstrual dysphoric disorder (31%), and PTSD (59%). Regression analyses conducted for each disorder suggested that illness-specific symptom scales were significantly associated with baseline quality of life but explained only a small to modest proportion of the variance in Quality of Life Enjoyment and Satisfaction Questionnaire scores. CONCLUSIONS: Subjects with affective or anxiety disorders who enter clinical trials have significant quality-of-life impairment, although the degree of dysfunction varies. Diagnostic-specific symptom measures explained only a small proportion of the variance in quality of life, suggesting that an individual's perception of quality of life is an additional factor that should be part of a complete assessment.

Symptoms of late-life depression: frequency and change during treatment.

OBJECTIVE: The authors determined the symptoms frequently present in older patients with major depression that showed the greatest change during treatment and that best correlated with an independent measure of improvement (the Clinical Global Impression scale [CGI]). METHODS: Subjects included 728 patients over the age of 60 years with major depression who were selected for entry into a clinical trial. Authors determined the frequency of symptoms on the 17-item Hamilton Rating Scale for Depression (Ham-D) and the effect size of symptom change during treatment. RESULTS: Nine symptoms were identified that were frequent, showed the greatest change during treatment, and best correlated with CGI. The items included depressed mood; loss of interest in work and activities; psychic anxiety; somatic symptoms, general (decreased energy); somatic anxiety; guilt; middle insomnia; late insomnia; and suicidal ideation. These nine items accounted for 92% of the variance in the 17-item Ham-D score, correlated with the CGI at a level similar to the 17-item Ham-D, and were at least as sensitive as the 17-item Ham-D for detecting drug-placebo differences. A comparison with five other similar approaches in non-geriatric samples suggested that the symptoms identified were relatively similar in both age-groups. CONCLUSIONS: Symptoms frequent in patients with late-life depression are similar to those in mixed-aged samples. Nine of the Ham-D items appear most useful for assessment of change during treatment.

Efficacy of sertraline in a 12-week trial for generalized anxiety disorder.

OBJECTIVE: Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated. METHOD: Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25). The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score. A secondary efficacy measure was the Clinical Global Impression (CGI) improvement score; response was defined as a score of 2 or less. RESULTS: Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4. Analysis of covariance of the intent-to-treat group at endpoint (with the last observation carried forward) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline (mean=11.7) and placebo (mean=8.0). Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor (6.7 versus 4.1) and somatic factor (5.0 versus 3.9). The rate of responders, based on CGI improvement and last observation carried forward, was significantly higher for sertraline (63%) than placebo (37%). Sertraline was well tolerated; 8% of patients versus 10% for placebo dropped out because of adverse events. CONCLUSIONS: Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder.

Improvement of anger at one week predicts the effects of sertraline and placebo in PTSD.

In previous work we demonstrated an early, robust and sustained effect for sertraline vs placebo on irritability and anger in subjects with PTSD. In this report, we explore the same dataset to assess whether a clinician might usefully predict ultimate response to sertraline, on the basis of its effect upon anger after one week. Three hundred and eighteen subjects were assessed. Outcome was measured by whether or not the score was reduced by at least 50% from baseline. Ordinary least squares regression was used to estimate the effects of change in anger at one week. Logistic regression was applied to estimate the effects on odds of a 50% drop in score. Cut points were developed for one-week change scores on anger for sertraline and placebo. The best cut point was selected as predictive of non-response, i.e. a cue suggesting that treatment switch would be in order. An increase in anger of 30% at one-week best predicted the likelihood of not responding to treatment in both the drug and placebo groups. Twenty-five percent of all non-responders were incorrectly identified, while only 7% of all improvers were incorrectly categorized as non-responders using this cutoff. Our findings imply that, for patients similar to those in this study, an increase in anger after one week of treatment might be one factor to consider when making a decision about continuation of the medication.

Sertraline versus paroxetine in the treatment of panic disorder: an acute, double-blind noninferiority comparison.

OBJECTIVE: Several classes of medications have demonstrated efficacy in panic disorder, but direct comparison of 2 proven treatments is still uncommon. The purpose of this study was to compare sertraline and paroxetine in the acute treatment of panic disorder. METHOD: Adult outpatients with panic disorder with or without agoraphobia (DSM-IV and ICD-10 criteria) were randomly assigned in double-blind fashion to 12 weeks of treatment with flexible doses of sertraline (titrated up to 50-150 mg/day; N = 112) or paroxetine (titrated up to 40-60 mg/day; N = 113). Patients were then tapered off medication over 3 weeks. The primary analysis was a noninferiority analysis of Panic and Agoraphobia Scale (PAS) scores. Secondary measures included panic attack frequency and the Clinical Global Impressions-Improvement scale (CGI-I) (with responders defined as those with a CGI-I score < or = 2). Data were collected from January 2000 to June 2001. RESULTS: Sertraline and paroxetine were associated with equivalent levels of improvement on the PAS total score, as well as on all secondary outcome measures. Eighty-two percent of patients taking sertraline versus 78% of those taking paroxetine were CGI-I responders at endpoint. Numerically more patients on paroxetine treatment compared with sertraline treatment discontinued due to adverse events (18% vs. 12%; NS), and a significantly higher proportion of paroxetine patients showed > or = 7% weight gain (7% vs. < 1%; p <.05). During the taper period, the proportion of panic-free patients increased by 4% with sertraline but decreased by 11% with paroxetine (p <.05). CONCLUSION: Sertraline and paroxetine had equivalent efficacy in panic disorder, but sertraline was significantly better tolerated and was associated with significantly less clinical worsening during taper than paroxetine.

Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness.

OBJECTIVES: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness. SETTING: Multicenter. DESIGN: Randomized, double-blind, placebo-controlled study. PARTICIPANTS: A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. MEASUREMENTS: Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression-Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey. RESULTS: In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by-comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group (P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group. CONCLUSION: Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness.

The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder.

RATIONALE: A common polymorphism (5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder. We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm. OBJECTIVES: We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele. METHODS: HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week, placebo-controlled study in elderly depressed subjects. Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the sertraline and placebo groups ( n=206). RESULTS: Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2, as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele ( P=0.01 at both weeks). No significant difference was observed in the placebo group. CONCLUSIONS: These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs.

Does antidepressant therapy improve cognition in elderly depressed patients?

OBJECTIVES: To analyze the effects of antidepressants on cognitive functioning in elderly depression. METHODS: Data were pooled for elderly participants with major depression from two double-blind 12-week studies (n = 444) comparing sertraline to fluoxetine and to nortriptyline. A cognitive battery was performed pre-treatment and post-treatment that included the Shopping List Task (SLT), which quantifies short-term and long-term memory storage and retrieval, and the Digit Symbol Substitution Test (DSST), which measures visual tracking, motor performance, and coding. RESULTS: Older age, male gender, higher systolic blood pressure, and higher illness severity were associated with lower performance on specific cognitive measures at baseline. For the entire group, improved depression and a lower anticholinergic side effect (dry mouth and constipation) severity were associated with statistically significant improvement in the SLT and DSST. The correlations between improvements in depression and improvement in tested cognitive function were highest for sertraline followed by nortriptyline and then fluoxetine. CONCLUSIONS: Acute improvement in depression is associated with cognitive improvement as measured by the SLT and DSST. Prospective studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes in geriatric depression.

Affective and anxiety comorbidity in post-traumatic stress disorder treatment trials of sertraline.

Comorbidity of mood and anxiety disorders is common in patients suffering from post-traumatic stress disorder (PTSD). The current study evaluated the efficacy and tolerability of sertraline in a subgroup of PTSD patients suffering from anxiety or depression comorbidity. Two multicenter, 12-week, double-blind, flexible-dose US studies of adult outpatients from the general population with a DSM-III-R diagnosis of PTSD evaluated the safety and efficacy of sertraline (50 to 200 mg/d) compared to placebo in the treatment of PTSD. The total severity score of the Clinician-Administered PTSD Scale (CAPS-2) and the Davidson Trauma Scale (DTS) were used to examine the effect of comorbidity on treatment outcome. Among the combined 395 subjects enrolled in the two trials, 32.9% had a comorbid depressive diagnosis (no anxiety diagnosis), 6.3% had a comorbid anxiety disorder diagnosis (no depression), 11.4% had both a depression and anxiety disorder diagnosis, and 49.4% had no comorbidity. The correlation, at baseline, between Hamilton Depression Rating Scale (HAM-D) total score and the three CAPS-2 clusters was 0.37 for the re-experiencing/intrusion cluster, 0.52 for the avoidance/numbing cluster, and 0.45 for the hyperarousal cluster. Patients suffering from PTSD complicated by a current diagnosis of both depression and an anxiety disorder showed the highest baseline CAPS-2 cluster score severity. Patients treated with sertraline improved significantly (P <.05) compared to placebo on both the CAPS-2 and DTS whether or not they had a comorbid depressive or anxiety disorder. Sertraline was well tolerated. The presence of comorbidity was associated with a modest and mostly nonspecific increase in the side effect burden of approximately 10% to 20% on both study treatments. Patients suffering from dual depression and anxiety disorder comorbidity benefited from somewhat higher doses (147 mg v 125 mg; P =.08). Similarly, the presence of dual comorbidity resulted in a modest but nonsignificant increase in the mean time to response from 4.5 weeks to 5.5 weeks. We conclude that sertraline (50 to 200 mg/d) is effective and well tolerated in the treatment of PTSD for patients suffering from a current, comorbid depressive or anxiety disorders.

Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study.

BACKGROUND: Generalized social anxiety disorder is an early onset, highly chronic, frequently disabling disorder with a lifetime prevalence of approximately 13%. The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults. METHOD: After a 1-week single-blind placebo lead-in period, patients with DSM-IV generalized social phobia were randomly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline (50-200 mg/day) or placebo. Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale (LSAS) total score and the responder rate for the Clinical Global Impressions-Improvement scale (CGI-I), defined as a CGI-I score

An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression.

OBJECTIVE: There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients. This placebo-controlled study of sertraline was designed to confirm the results of non-placebo-controlled trials. METHOD: The subjects were outpatients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher. The patients were randomly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline. The primary outcome variables were the Hamilton scale and Clinical Global Impression (CGI) scales for severity and improvement. RESULTS: A total of 371 patients assigned to sertraline and 376 assigned to placebo took at least one dose. At endpoint, the patients receiving sertraline evidenced significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales. The mean changes from baseline to endpoint in Hamilton score were -7.4 points (SD=6.3) for sertraline and -6.6 points (SD=6.4) for placebo. The rate of CGI-defined response at endpoint was significantly higher for sertraline (45%) than for placebo (35%), and the time to sustained response was significantly shorter for sertraline (median, 57 versus 61 days). There were few discontinuations due to treatment-related adverse events, 8% for sertraline and 2% for placebo. CONCLUSIONS: Sertraline was effective and well tolerated by older adults with major depression, although the drug-placebo difference was not large in this 8-week trial.

Early improvement predicts endpoint remission status in sertraline and placebo treatments of panic disorder.

The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder.

Behavior therapy for obsessive-compulsive disorder guided by a computer or by a clinician compared with relaxation as a control.

BACKGROUND: The demand for effective behavior therapy for obsessive-compulsive disorder (OCD) by exposure and ritual prevention exceeds its supply by trained therapists. A computer-guided behavior therapy self-help system (BT STEPS) was created that patients access by telephone from home via interactive voice response technology. This study compared the value of computer-guided behavior therapy value with that of clinician-guided behavior therapy and systematic relaxation as a control treatment. METHOD: After screening by a clinician, 218 patients with DSM-IV OCD at 8 North American sites were randomly assigned to 10 weeks of behavior therapy treatment guided by (1) a computer accessed by telephone and a user workbook (N = 74) or (2) a behavior therapist (N = 69) or (3) systematic relaxation guided by an audiotape and manual (N = 75). RESULTS: By week 10, in an intent-to-treat analysis, mean change in score on the Yale-Brown Obsessive Compulsive Scale was significantly greater in clinician-guided behavior therapy (8.0) than in computer-guided (5.6), and changes in scores with both clinician-guided and computer-guided behavior therapy were significantly greater than with relaxation (1.7), which was ineffective. Similarly, the percentage of responders on the Clinical Global Impressions scale was significantly (p < .05) greater with clinician-guided (60%) than computer-guided behavior therapy (38%), and both were significantly greater than with relaxation (14%). Clinician-guided was superior to computer-guided behavior therapy overall, but not when patients completed at least 1 self-exposure session (N = 36 [65%]). At endpoint, patients were more satisfied with either behavior therapy group than with relaxation. Patients assigned to computer-guided behavior therapy improved more the longer they spent telephoning the computer (mostly outside usual office hours) and doing self-exposure. They improved slightly further by week 26 follow-up, unlike the other 2 groups. CONCLUSION: For OCD, computer-guided behavior therapy was effective, although clinician-guided behavior therapy was even more effective. Systematic relaxation was ineffective. Computer-guided behavior therapy can be a helpful first step in treating patients with OCD when clinician-guided behavior therapy is unavailable.