Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis.

BACKGROUND: Questions have been raised regarding the relative efficacy and tolerability of the different serotonin transport inhibitors in the treatment of obsessive-compulsive disorder. We compared the results from four large multicenter placebo-controlled trials of the serotonin transport inhibitors clomipramine hydrochloride (N = 520), fluoxetine hydrochloride (N = 355), fluvoxamine maleate (N = 320), and sertraline hydrochloride (N = 325) for the treatment of obsessive-compulsive disorder. METHODS: Effect size was calculated by subtracting the end-point drug treatment mean change from the end-point placebo mean change and dividing by the end-point pooled change standard deviation. A test for overall differences between effect sizes was conducted, followed by all possible pairwise comparisons. The Yale-Brown Obsessive Compulsive Scale was the primary outcome measure for all four studies. RESULTS: All four agents were significantly more effective than placebo, with clomipramine significantly more effective than the other three treatments, which did not differ in effect size. A significantly greater percentage of patients treated with clomipramine were rated much or very much improved than were patients treated with fluoxetine, fluvoxamine, or sertraline. CONCLUSION: While the results of this meta-analysis support the superiority of clomipramine, head-to-head, double-blind comparisons of these compounds would be the best test of comparative efficacy and tolerability.

Medical costs attributed to depression among patients with a history of high medical expenses in a health maintenance organization.

BACKGROUND: While previous studies have compared medical utilization between depressed and nondepressed patients, we conducted a study that focused specifically on patients who had a history of high medical expenditures. METHODS: This study was designed to determine whether a positive screen for depression is predictive of continued high medical expenditures. Medical utilization data were obtained on 50,000 patients enrolled in the DeanCare health maintenance organization for 2 consecutive years. Consistent high utilizers were identified based on the medical utilization costs (paid by the health maintenance organization) for those 2 consecutive years, 1992 and 1993. A depression screen based on the Medical Outcomes Survey was mailed to 786 high utilizers. Their costs were determined for 1994. Regression analyses identified 1994 costs associated with depression, adjusting for age, sex, benefits package, and medical comorbidity. RESULTS: Depressed high utilizers were more likely than nondepressed high utilizers to have higher medical costs in 1994. Among high utilizers, depressed patients' 1994 costs were significantly higher ($5764 vs $4227; P < .001), although expenditures for depressed and nondepressed high utilizers were similar for the previous 2 years. The total medical cost associated with depression in 1994, adjusted for age, sex, benefits package, and medical comorbidity, was $1498 per patient. CONCLUSIONS: In the third year (1994), a positive Medical Outcomes Survey screen for depression in high utilizers was associated with $1498 in higher medical costs. The average actual amount spent on depression treatment accounted for only a small portion of total medical costs for depressed high utilizers in the third year.

Sertraline for social phobia: a double-blind, placebo-controlled crossover study.

OBJECTIVE: The authors examined the efficacy of sertraline in the treatment of social phobia. METHOD: In a double-blind crossover study, 12 outpatients were randomly assigned to 10 weeks of sertraline (50-200 mg/day, flexible dosing) and 10 weeks of placebo. RESULTS: A statistically significant improvement in scores on the Liebowitz Social Anxiety Scale was found with sertraline but not with placebo. There was no significant difference between scores obtained with computer- and clinician-administered versions of the Liebowitz Social Anxiety Scale, and the majority of patients preferred to be interviewed by the computer. CONCLUSIONS: Sertraline seems a safe and effective treatment for social phobia, and computer administration may be a preferable mode of assessment with socially phobic patients.

Impact of generalized social anxiety disorder in managed care.

OBJECTIVE: The authors determined the costs associated with generalized social anxiety disorder in a managed care setting. METHOD: A three-phase mail and telephone survey was conducted from July to October 1998 in two outpatient clinics of a large health maintenance organization (HMO). The survey assessed direct costs, indirect costs, health-related quality of life, and clinical severity associated with generalized social anxiety disorder, both alone and with comorbid psychopathology. RESULTS: The weighted prevalence rate of current generalized social anxiety disorder was 8.2%. In the past year, only 0.5% of subjects with generalized social anxiety disorder had been accurately diagnosed. Yet 44.1% had a mental health specialty visit or had been prescribed an antidepressant, and psychiatric comorbidity was found in 43.6%. Noncomorbid generalized social anxiety disorder was associated with significantly lower health-related quality of life, work productivity, and earnings and greater utilization of health services; generalized social anxiety disorder with comorbid psychopathology was even more disabling. Suicide was attempted by 21.9% of subjects with noncomorbid generalized social anxiety disorder. Persons with average-severity generalized social anxiety disorder had probabilities of graduating from college that were 10 percentage points lower, earned wages that were 10% lower, and had probabilities of holding a technical, professional, or managerial job that were 14 percentage points lower than the comparison group. CONCLUSIONS: In a community cohort of HMO members, generalized social anxiety disorder was rarely diagnosed or treated despite being highly prevalent and associated with significant direct and indirect costs, comorbid depression, and impairment.

An open-label trial of St. John's Wort (Hypericum perforatum) in obsessive-compulsive disorder.

BACKGROUND: Recent interest in and evidence for the efficacy of St. John's wort (Hypericum perforatum) for the treatment of mild-to-moderate depression has led to speculation about its efficacy in other disorders. Hypericum's mechanism of action is postulated to be via inhibition of the synaptosomal uptake of serotonin. As such, there is a suggestion that Hypericum may be effective for obsessive-compulsive disorder (OCD). METHOD: Twelve subjects were evaluated with a primary DSM-IV diagnosis of OCD of at least 12 months' duration. Treatment lasted for 12 weeks, with a fixed dose of 450 mg of 0.3% hypericin (a psychoactive compound in Hypericum) twice daily (extended-release formulation). Weekly evaluations were conducted with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Patient Global Impressions of Improvement Scale, and the Clinical Global Impressions of Improvement scale (CGI) and monthly evaluation with the Hamilton Rating Scale for Depression. RESULTS: A significant change from baseline to endpoint was found, with a mean Y-BOCS change of 7.4 points (p = .001). Significant change occurred at 1 week (p = .020) and continued to increase throughout the trial. At endpoint, 5 (42%) of 12 were rated "much" or "very much improved" on the clinician-rated CGI, 6 (50%) were "minimally improved," and 1 (8%) had "no change." The most common side effects reported were diarrhea (N = 3) and restless sleep (N = 2). CONCLUSION: Significant improvement was found with Hypericum, with a drop-in Y-BOCS score similar to that found in clinical trials. The fact that a significant change was found as early as 1 week into treatment suggests a possible initial placebo response, although improvement grew larger over time. Results warrant a placebo-controlled study of Hypericum in OCD.

The effect of enalapril on serum lithium levels in healthy men.

BACKGROUND: Several authors have recently described the development of lithium toxicity after the addition of angiotensin-converting enzyme inhibitors to a stable lithium regimen. This pilot study was designed to systematically investigate the effects of enalapril, an angiotensin-converting enzyme inhibitor, on the serum level of lithium. METHOD: In a 26-day outpatient study, nine healthy men took lithium for 10 days, lithium and enalapril for 10 days, and lithium alone again for 6 days. Serum lithium levels were measured while patients were taking lithium alone and while they were taking the lithium/enalapril combination. RESULTS: There were no statistically significant differences between mean serum lithium level during treatment with lithium alone and during treatment with the lithium/enalapril combination. However, one subject showed a 31% increase in serum lithium level after enalapril was added. CONCLUSION: Although no statistically significant differences between mean serum lithium level during treatment either with lithium alone or with lithium/enalapril were found, it is possible that the low dose of enalapril and low serum lithium levels employed for subject safety may have resulted in a type II statistical error. If enalapril doses or initial serum lithium levels were similar to those described in case reports, a significant difference in mean serum lithium levels may have been observed. While a predictable interaction between lithium and enalapril probably does not occur in all patients, factors such as enalapril dose, serum lithium level before addition of enalapril, or the presence of heart disease may make such an interaction more likely. At the levels of lithium and enalapril used in this study, elevated serum lithium concentration does not appear to be a universal event, but physicians must exercise appropriate caution.

A double-blind, placebo-controlled trial of fluvoxamine versus imipramine in outpatients with major depression.

The authors employed a double-blind, placebo-controlled design to investigate the effectiveness of fluvoxamine versus imipramine in 54 outpatients with moderate major depression. Fluvoxamine proved superior to placebo but not to imipramine on the Hamilton Rating Scale for Depression and the Montgomery and Asberg Depression Rating Scale. Nausea and hyperarousal were the most common side effects in the fluvoxamine-treated patients.

Computer-administered clinical rating scales. A review.

While clinician-administered symptom rating scales are the most commonly used outcome measures in pharmaceutical research, error variance due to poor inter-rater reliability increases the risk of type II errors in multi-center clinical trials. Such error variance could obscure true differences between active drug and placebo, or between two comparator compounds. Computer-administered versions of symptom rating scales originally designed to be administered by trained clinicians offer a solution to this problem. This paper reviews the empirical data on the reliability, validity and equivalence of computer-administered rating scales. Computer-administered versions of clinician-administered scales are now available for the assessment of depression, anxiety, obsessive-compulsive disorder, and social phobia. Validation studies support the reliability, validity and equivalence of these scales. Patient reaction has been positive, with patients generally more honest with and often preferring the computer for assessing sensitive areas such as suicide, alcohol or drug abuse, sexual behavior, or HIV related symptoms. Applications using Interactive Voice Response (IVR) technology facilitate longitudinal monitoring of patients without requiring office visits to collect data, increase the accessibility of information to the clinician, and the quality of patient care through more informed decision making. When used in accordance with established ethical guidelines, computers offer a reliable, inexpensive, accessible, and time-efficient means of assessing psychiatric symptoms.

Behavioral versus pharmacological treatments of obsessive compulsive disorder: a meta-analysis.

The goal of the study was to provide a quantitative analysis of the relative efficacy of all five currently available serotonin reuptake inhibitors (SRIs) and behavior therapy [exposure and response prevention (ERP)] for obsessive compulsive disorder. The relationship between effect size and methodological characteristics was also empirically examined. A search was conducted of several computerized databases covering the dates from 1973 to 1997. Seventy-seven studies were identified, yielding 106 treatment comparisons involving 4641 patients. Effect sizes were analyzed between individual interventions and between intervention class [SRI, ERP or the combined treatment of an SRI with ERP(ERP/SRI)]. Data were analyzed both before and after controlling for methodological variables. The effect size for clomipramine (CMI) was significantly greater than the other SRIs, with the exception of fluoxetine (FLX). CMI was not significantly greater than ERP or ERP/SRI. As a class, ERP was significantly greater than SRIs as a whole. Effect sizes were larger for studies without a control group or random assignment, for self-reported outcome measures, and varied significantly by method of effect size calculation. Year of publication was significantly related to effect size. When controlling for these methodological variables, CMI was not significantly greater than FLX or fluvoxamine (FLV), and ERP was no longer significantly greater than the SRIs as a whole. No significant difference was found between CMI and the other SRIs as a group in head to head trials. No differences in drop-out rates were found. CMI stands out from the other SRIs. This difference is probably not clinically significant enough to warrant first choice treatment, given CMI's greater lethality in overdose. The choice between an SRI or ERP is dominated primarily by the infrequent availability of ERP and to a lesser degree by personal preference. Methodological differences significantly impact effect size.

A 1 year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive-compulsive disorder.

The objective of this study was to evaluate the safety and efficacy, over a 1 year treatment period, of three dose levels of sertraline and placebo in the treatment of non-depressed adult out-patients with obsessive-compulsive disorder (OCD). Following 1 week of single-blind placebo washout, patients (n = 325) from 11 sites following identical protocols were randomly assigned to 12 weeks of double-blind treatment with one of three fixed doses of sertraline (50, 100 or 200 mg) or placebo. At the end of 12 weeks, treatment responders (including placebo patients) were offered an additional 40 weeks of double-blind treatment at their assigned doses. Efficacy measures were the Yale-Brown Obsessive Compulsive Scale, the NIMH Global Obsessive Compulsive Scale, Clinical Global Impressions of Severity of Illness and Global Improvement and the Maudsley Obsessive Compulsive Inventory. Patients in the pooled sertraline group showed greater improvement than placebo-treated patients on all efficacy measures, based on the endpoint analyses. Moreover, pairwise comparisons at endpoint revealed a significant effect on all three investigator-rated scales in patients receiving 50 or 200 mg of sertraline; in the 100 mg group, there was a significant effect on the NIMH Global Obsessive Compulsive Scale only. Patients completing 3 months of sertraline treatment exhibited excellent toleration and sustained improvement during an additional 40 weeks of therapy. Results support the safety, efficacy and tolerability of daily doses of 50-200 mg of sertraline in the long-term treatment of patients with OCD.

Do subtle neurological impairments predict treatment resistance to clomipramine in children and adolescents with obsessive-compulsive disorder?

ABSTRACT A 10-week double-blind, placebo-controlled design was employed to investigate the effectiveness of clomipramine (CMI) versus placebo in 16 outpatients (ages 10-18 years) with obsessive-compulsive disorder (OCD). While a trend favoring clomipramine was observed, the difference in efficacy between clomipramine (N=8) and placebo (N=8) did not reach statistical significance, partly due to small sample size (N = 6,8). Post-hoc exclusion of two clomipramine-resistant subjects with subtle neurological impairments did, however, yield a statistically significant improvement with drug treatment. Neurological impairments are commonly seen in children with OCD, and may be a risk factor for the disorder during childhood. Speculatively, subtle neurological impairments may also predict resistance to CMI therapy in some patients, and influence the outcome of clinical and research medication trials, depending on differences in neurological inclusion and exclusion criteria.

Effect of primary care treatment of depression on service use by patients with high medical expenditures.

OBJECTIVE: The study examined the impact of identifying and treating depression among patients who had a history of high medical expenditures. Effects on service use, disability, and quality of life were measured. METHODS: A total of 786 high users of services from two primary care clinics and an equal number of randomly selected patients who were not high users were screened for depression using the Medical Outcomes Study (MOS) depression screen. High-user patients who screened positive were subsequently seen by their primary care physician for a diagnostic interview. The 20 patients with a confirmed diagnosis of depression were offered open-label antidepressant treatment by their primary care physician for six months. RESULTS: All 20 patients completed the six-month study. Treatment resulted in significant reductions in depression and significant improvements in quality of life in the areas of social functioning, general health, mental health, physical functioning, emotional role functioning, and vitality. Days of missed work per month were reduced, and the percentage of patients who reported not being at all impaired by their depression at work increased. Costs for service use fell from $13.28 to $6.75 per day; when costs for the treatment study were added, the daily service use cost was $12.55. CONCLUSIONS: Identification and treatment of depression among patients with a history of high medical expenditures improved depression and increased work productivity and quality of life. Service use decreased with treatment. A larger sample and control group are needed to determine if treatment is associated with a statistically significant decrease in medical expenditures.

Computerized screening for psychiatric disorders in an outpatient community mental health clinic.

OBJECTIVE: This study examined the validity and utility of two types of computer-administered versions of a screening interview, PRIME-MD (Primary Care Evaluation of Mental Disorders), in a mental health setting: one administered by desktop computer and one by computer using a touch-tone telephone and interactive voice response (IVR) technology. METHODS: Fifty-one outpatients at a community mental health clinic were given both IVR and desktop PRIME-MD and the Structured Clinical Interview for DSM-IV (SCID-IV), which was administered by a clinician, in a counterbalanced order. Diagnoses were also obtained from charts. RESULTS: Prevalence rates found by both computer interviews were similar to those obtained by the SCID-IV for the presence of any diagnosis, any affective disorder, and any anxiety disorder. Prevalence rates for specific diagnoses were also similar to those found by the SCID-IV except for dysthymia, obsessive-compulsive disorder, and panic disorder; the first two conditions were found to be more prevalent by the computer, and panic disorder was more prevalent by the SCID. Compared with the prevalence rates in the charts, the rates found by the computer were higher for anxiety disorders, particularly for obsessive-compulsive disorder and social phobia. Using the SCID-IV as the criterion, both computer-administered versions of PRIME-MD had high sensitivity, specificity, and positive predictive value for most diagnoses. No significant difference was found in how well patients liked each form of interview. CONCLUSIONS: Results support the validity and utility of both desktop and IVR PRIME-MD for gathering information from mental health patients about certain diagnoses.

Decision support for patient care: computerized rating scales.

Cost-effective patient assessment instruments continue to be developed and improved. Computer technology advances enable these instruments to be administered more efficiently, with more rapid feedback to clinical decision makers and patients. This article describes several of these instruments and how they are used in primary care and behavioral healthcare settings for treatment planning and disease management. The authors are eminent research pioneers and leaders in this field.

Inaccuracy in clinical trials: effects and methods to control inaccuracy.

The increasing rate of failed trails found in mood and anxiety disorders is now being seen in Alzheimer's studies. Factors related to the administration of clinician rating scales, such as poor inter-rater reliability, poor interview quality and rater bias may be a contributing factor. Studies have found inter-rater reliability to be problematic in Alzheimer's studies, even with less subjective outcome measures. Lack of standardization of administration and scoring procedures has been identified as a major contributing factor. Remediation through better training procedures has been found to be successful, although ongoing calibration is needed to prevent rater drift. Expectancy bias and baseline score inflation is more difficult to remediate. Inflation of baseline scores increases placebo response, since lower severity has been found to be associated with higher placebo response. The use of centralized raters that are independent from study sites may help ameliorate these issues. Increased methodological research examining new approaches to these problems is warranted. The increased costs associated with this research should offset the time and expense of continuing with 'business as usual'.

Computerized and clinician assessment of depression and anxiety: respondent evaluation and satisfaction.

This investigation examined differences in subjects' satisfaction and reaction to computer- and clinician-administered versions of the Hamilton Depression and Anxiety Rating Scales in outpatients with affective disorders (n = 121), anxiety disorders (n = 52), other psychiatric disorders (n = 7), and adults without psychiatric disorders (n = 76). Subjects' reactions to clinician- and computer-administered interviews were similar in the areas of overall comfort level and ease in answering questions. Clinicians were rated more positively with regard to determining how subjects really felt, sensitivity to their needs, and asking questions specific to their feelings. Subjects felt less embarrassed giving information to the computer. We found psychiatric subjects to prefer the clinician-administered interview, whereas nonpsychiatric subjects indicated no preference.

Mini-SPIN: A brief screening assessment for generalized social anxiety disorder.

The objectives of this study are to develop a brief self-rated screening instrument for generalized social anxiety disorder (GSAD) and to test the efficiency of the instrument. The Social Phobia Inventory (SPIN), a 17-item self-administered scale for GSAD, was given to 263 individuals with GSAD and controls. A subset of three items yielding high sensitivity and specificity for the diagnosis of GSAD was identified. This abbreviated version of the SPIN (Mini-SPIN) was administered to a group of managed care patients in conjunction with an epidemiological study of GSAD. Patients (n = 7,165) were sent a questionnaire comprising the Mini-SPIN and a brief depression screener. Respondents screening positive for GSAD on the Mini-SPIN (n = 344) were interviewed using the social phobia module of the Structured Clinical Interview for DSM-IV (SCID) to verify the diagnosis. A random sample of those who screened negative for GSAD on the Mini-SPIN were administered a similar interview to identify two control groups without GSAD for comparison (n = 673). With this information, the sensitivity, specificity, and positive and negative predictive values for the Mini-SPIN were determined (weighted for sampling). Using a cutoff score of 6 or greater, the Mini-SPIN demonstrated a sensitivity of 88.7%, specificity of 90.0%, positive predictive value of 52.5%, and negative predictive value of 98.5%. The scale possessed 90% accuracy (efficiency) in diagnosing the presence or absence of GSAD in a managed care population. The Mini-SPIN demonstrates good efficiency, supporting its utility as a screening tool for generalized social anxiety disorder.

Computerized assessment of depression and anxiety over the telephone using interactive voice response.

We examined the reliability and validity of computer-administered versions of the Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Rating Scales that were administered over the telephone using Interactive Voice Response (IVR). In two identical studies (HAMD: N = 113, HAMA: N = 74), both the IVR- and clinician-administered versions were administered in a counterbalanced order to a heterogeneous sample of subjects with psychiatric disorders and controls. Both the IVR HAMD and HAMA demonstrated adequate internal-consistency reliability (.90 and .93, respectively) and test-retest reliability (.74 and .97, respectively). The correlation between the IVR and clinician was high (HAMD = .96; HAMA = .65). The mean score difference between the IVR and clinician versions was less than one point for both the HAMD (.69 of a point) and HAMA (.60 of a point). It took subjects 12.23 minutes to complete the IVR HAMD, compared to 15.21 minutes for the clinician version; and 11.27 minutes for the IVR HAMA, compared to 15.33 minutes for the clinician (p < .001 for both comparisons). Subjects rated the clinician better in the areas of how much they liked being interviewed and how well they were able to describe their feelings. However, they were significantly more embarrassed with the clinician than with the IVR. Results support the psychometric properties of the IVR versions of the HAMD and HAMA scales. IVR technology presents new opportunities for expanding the utility of computerized clinical assessment.

Computer-administered rating scales for social anxiety in a clinical drug trial.

Computer-administered versions of two clinician-administered symptom rating scales for social anxiety (the Liebowitz Social Anxiety Scale [LSAS] and the Brief Social Phobia Scale [BSPS]) and one paper-and-pencil scale (the Fear Questionnaire) were developed and utilized in a clinical trial for social phobia. The reliability and validity of the computer versions were examined, as were their equivalence to the traditional versions. Correlations between the computer and original versions were high at baseline, and remained high throughout the study. The internal consistency reliability of the computer scales was also high, and almost identical to the original versions. Mean score differences between computer and original versions were not significant at baseline, and no significant differences were found between computer and traditional versions on the amount of change detected from baseline to endpoint. Seventy-seven percent of subjects felt that the computer did not interfere with their visit at baseline and a plurality (36%) preferred the computer, with 30% preferring the clinician and 34% having no preference. By the end of the study, the plurality (41%) had no preference, with 27% preferring the computer and 32% preferring the clinician. Results support the use of these computer-administered symptom rating scales of social anxiety as a viable alternative to the clinician-administered versions with this subset of patients, which should offer researchers and clinicians a reliable and cost-effective method for evaluating social phobia.