Side effects and time course of response in a placebo-controlled trial of fluoxetine for the treatment of geriatric depression.

A high rate of improvement among patients who receive placebo in controlled trials of antidepressants can complicate the evaluation of true drug effect. Placebo response may be a reaction to the psychosocial factors of study participation or a function of changes in the natural course of depression. Drug side effects may also influence patients' expectations, and they should be distinguished from the somatic symptoms associated with major depression. The authors reanalyzed data from a large, multicenter, placebo-controlled clinical trial of fluoxetine treatment of geriatric depression to evaluate similarities and differences between responders and nonresponders in both treatment groups. Specifically, the authors examined weekly somatic complaints as possible predictors of response and of dropout, as well as the time course and onset of response. Fluoxetine was superior to placebo on all outcome measures. Among somatic complaints associated with fluoxetine response, headache before and after randomization was associated with a good response and anxiety after randomization was associated with a poor response. Somnolence before and after randomization was associated with a good placebo response. Early and persistent improvement occurred among similar proportions of responders in both groups. The difference between fluoxetine and placebo seemed to be a persistent response beginning during the 4th week. Pretreatment somnolence was associated with early, persistent improvement in both groups and may serve as a marker for placebo response.

Side effects as predictors of drug response in obsessive-compulsive disorder.

Differences between the side effect profiles of clomipramine (CMI) and the selective serotonin reuptake inhibitors may be important factors in both treatment outcome and patient selection in obsessive-compulsive disorder (OCD). Safety and efficacy data from an industry-sponsored, multicenter clinical trial of CMI were analyzed previously using tabular and multiple regression methods. Good response, defined as at least a 35% drop in final scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), was associated with a later age of OCD onset and certain early side effects that may reflect a sensitivity of responders to CMI's serotonergic actions. The authors conducted a similar analysis of data from an industry-sponsored clinical trial of fluoxetine in OCD. Fluoxetine response did not seem to be associated with age of OCD onset. Good response to both drugs was associated with initial nervousness and sexual complaints. The common side effects of fluoxetine (headache, nausea, and gastrointestinal complaints) did not seem to be associated with treatment response. Slight differences in the protocols of the two clinical trials yielded patient populations that were different in factors found to be associated with treatment outcome: subjects in the fluoxetine study had lower scores on the Y-BOCS, higher scores on the Hamilton Rating Scale for Depression, and an earlier age of OCD onset.

Clinical characteristics of response to fluoxetine treatment of obsessive-compulsive disorder.

Fluoxetine is effective in treating obsessive-compulsive disorder (OCD). Nonetheless, a substantial number of patients do not respond or have only partial improvement. Data generated by a multicenter, placebo-controlled, fixed-dose trial of fluoxetine were reanalyzed to identify characteristics of responders. Multiple regression methods were used to evaluate the relationship between therapeutic response and baseline measures such as severity of symptoms, type of symptoms (obsessions, compulsions, depression), course of illness, previous treatment, age of onset, and other demographic factors (age, race, and sex). Fluoxetine was more effective than placebo on all outcome measures. A 60-mg dosage was associated with a greater drop in Yale-Brown Obsessive-Compulsive Scale total score and a greater drop in Compulsion items than a 20-mg dosage. Response rates and overall improvement were greatest for patients with a history of remissions, with no previous drug treatment or with only prior behavior therapy, with more severe OCD (especially with greater interference and distress from obsessions), or with either low or high Hamilton Rating Scale for Depression scores. This study did not detect any associations between response and current age, age of OCD onset, gender, and race. None of the demographic or clinical factors evaluated was found to be related to improvement in the placebo group.

Characteristics of fluoxetine versus placebo responders in a randomized trial of geriatric depression.

Results from placebo-controlled trials of antidepressants can be used to identify patients most likely to benefit from medication. Using data from a randomized clinical trial of fluoxetine versus placebo for 671 elderly outpatients with major depression, we evaluated characteristics of those who improved with and without active medication. We found that the choice of outcome measure made a difference when evaluating the effectiveness of fluoxetine relative to placebo and determining the accuracy of predictive variables in both treatment groups. Generally, less severe depression predicted favorable response (greater than 50% improvement on the 21-item Hamilton Rating Scale for Depression [HAM-D-21], less than 3 on the Clinical Global Impressions [CGI] and Patient Global Impressions [PGI] improvement scales) and remission (less than 9 on 6-week HAM-D-21) with both fluoxetine and placebo. Less anxiety/somatization was associated with favorable fluoxetine response, and lower levels of cognitive and sleep disturbance were associated with remission in the placebo group. By contrast, higher levels of psychomotor retardation in the placebo group were associated with clinician and patient ratings of much or very much improved. The similarities among responders in both groups may indicate that some in the fluoxetine group would have improved with placebo.

Relationship between early side effects and therapeutic effects of clomipramine therapy in obsessive-compulsive disorder.

Early adverse effects of a drug may be a manifestation of individual differences in drug metabolism or of different pathologic processes. These differences may influence therapeutic responsiveness. Using data from Ciba-Geigy's multicenter 10-week clinical trial, we studied the relationship between early side effects and subsequent therapeutic response to clomipramine (CMI) in obsessive-compulsive disorder. We used tabular analyses and multiple regression to evaluate associations between early complaints and change in score on the Yale-Brown Obsessive-Compulsive Scale. We also evaluated whether early complaints were drug related (i.e., true side effects). It appeared that dry mouth, constipation, dizziness, insomnia, male impotence, nervousness, palpitation, and tremor reported during the first 4 weeks were predictive of good response to CMI. Myoclonus and tinnitus appeared weakly associated with treatment success. Most of these complaints were reported more by the CMI group than the placebo group, and more during CMI treatment than before. The more common complaints may reflect an individual's ability to metabolize CMI appropriately so that adequate therapeutic blood levels are attained. The less common complaints may reflect a sensitivity to CMI's serotonergic actions.

Use of receiver-operator characteristic (ROC) curve analysis to evaluate predictors of response to clomipramine therapy.

We used receiver-operator characteristic (ROC) curve analysis to evaluate predictors of response to clomipramine in obsessive-compulsive disorder (OCD). Previously, we identified response predictors among 230 OCD patients who received clomipramine in a placebo-controlled, multicenter clinical trail. We found that at baseline a later age of OCD onset, low scores on the Hamilton Depression scale, and high scores on items 3 and 8 of the Yale-Brown Obsessive Compulsive Scale predicted good response. Certain early side effects also predicted outcome. We fitted a logistic regression model containing baseline information and then calculated each patient's estimated response probability by substituting individuals' values in the regression equation. Next we compared the estimated response risks with each patient's known outcome. Finally, we produced a ROC curve by plotting the true positive and false positive rates for various cutoff points of the risk scores. The same steps were followed for Weeks 1 through 4, adding information about early side effects and weekly response. We found that baseline information predicted outcome better than chance, and predictive ability increased with data on side effects and early response.

Clomiphene citrate and neural tube defects: a pooled analysis of controlled epidemiologic studies and recommendations for future studies.

OBJECTIVE: To estimate the degree to which neural tube defects (NTDs) are associated with periconceptional clomiphene citrate (CC) exposure in controlled epidemiologic studies, to investigate the consistency of study findings with respect to this association, and to identify key problems that future studies should address. DESIGN: Pooled analysis of 10 epidemiologic studies. SETTINGS: Hospitals and clinics. PATIENTS: Women undergoing treatment for infertility. INTERVENTIONS: Oral administration of CC. MAIN OUTCOME MEASURE: Prevalence ratio for NTDs. RESULTS: Ten controlled epidemiologic studies were identified that supplied sufficient data on CC and NTDs for inclusion. The estimated ratio of NTD prevalence among CC-exposed versus unexposed pregnancies ranged from 0.55 to 5.73 among the studies, but the variation was compatible with random fluctuation. The estimated summary prevalence ratio was 1.08, with 95% confidence limits of 0.76 and 1.51. CONCLUSION: This analysis indicates that an elevation in NTD risk due to CC cannot be ruled out, but any such elevation seems likely to be less than twofold, and there may be no elevation at all. Future studies should be designed to avoid several methodological problems not addressed in studies to date.

Predictors of treatment response in obsessive-compulsive disorder: multivariate analyses from a multicenter trial of clomipramine.

There have been many attempts to find predictors of the therapeutic response to the clomipramine treatment of obsessive-compulsive disorder. The majority of studies have failed to identify such predictors. Possible reasons for this failure include the small sample size of most studies, samples homogeneous with respect to the study factors of interest, and the use of statistical procedures that are insensitive to individual differences or that inadequately control for confounding. We have reanalyzed data from Ciba-Geigy's large, multicenter clinical trial of clomipramine for obsessive-compulsive disorder, using stratification and regression techniques to identify multiple prognostic factors and control for confounders. We assessed the relationship between therapeutic response and baseline measures such as severity of symptoms, type of symptoms (obsessions, compulsions, depression), length of illness, age of onset, and other demographic factors (age, race, and sex). We found age of onset to be a strong predictor of response to clomipramine: people who develop obsessive-compulsive disorder later in life have a better chance of responding than do those who become ill earlier, independent of length of illness. We also found that baseline depression is associated with response, but the association appears to be nonlinear.

Low dose desipramine treatment of cocaine-related panic attacks.

Thirteen patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia that started during or shortly after cocaine exposure were treated in the UCLA Anxiety Disorders Program (Los Angeles, CA). Low starting doses (ranging from 2.5 to 10 mg/day) of desipramine were used. Doses were then slowly increased to an average daily dose of 25 mg. Eleven patients who were able to tolerate an initial increase in panic anxiety responded to this treatment strategy with almost full resolution of panic attacks. The authors discuss the possible value and mechanisms of low dose treatment of cocaine-related panic attacks.

Lithium Information Center. One model of a computer-based psychiatric information service.

The Lithium Information Center has been functioning as a specialized psychiatric information service for nearly ten years. Over the years, the center has disseminated information about the medical uses of lithium to psychiatrists and other physicians, to patients, to the family and friends of patients, and to a host of other individuals and organizations including pharmacists, lawyers, nurses, social workers, mental health centers, clinics, and support groups. To encourage the development of similar psychiatric information services, we outline the center's methods of acquiring, organizing, and disseminating lithium information.

Lithium Information Center: The Lithium Library revisited.

The Lithium Information Center's experience over the past 7 years is discussed. The center is a computer-based reference service which specializes in dissemination of information about the medical uses of lithium. At the heart of the center is the Lithium Library, a bibliographic retrieval system containing references to the lithium literature. More than 5,000 requests for literature searches and patient information have been answered by Lithium Library staff members since 1977. The center has recently expanded its services, creating the Lithium Index and Lithium Consultation, computerized programs that provide immediate answers to specific questions about lithium. The center's services are directed to patient care, lithium research, and medical and patient education. Because of topical specialization and use of computers, the Lithium Information Center has been able to provide more immediate, comprehensive, relevant, integrated, and up-to-date information than other bibliographic services.

The Lithium Index: an innovative approach to consultation by computer.

The Lithium Index, a computer consultation program, was developed at the Lithium Information Center to quickly provide up-to-date information about lithium and its side effects. Information is contained in brief summaries that are compiled from the literature, organized by clinical topic, and written and retrieved by means of an interactive computer program. Computer-stored texts are easily updated to incorporate new information. The authors present an example that deals with the use of lithium during pregnancy, the most frequently requested topic.