James W. Jefferson

Treatment of social phobia with gabapentin: A placebo-controlled study

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.

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

Abstract 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.

Efficacy of the Novel Anxiolytic Pregabalin in Social Anxiety Disorder: A Placebo-Controlled, Multicenter Study

Abstract: Pregabalin is a novel compound in the development for the treatment of anxiety disorders. The safety and efficacy of pregabalin for the treatment of social anxiety disorder was evaluated in a double-blind, multicenter clinical trial in which 135 patients were randomized to 10 weeks of double-blind treatment with either pregabalin 150 mg/d, pregabalin 600 mg/d, or placebo. The primary efficacy parameter was change from baseline to end point in the Liebowitz Social Anxiety Scale (LSAS) total score. Safety was assessed through clinical and laboratory monitoring, and recording spontaneously reported adverse events. Ninety-four patients (70%) completed the 11-week double-blind treatment phase. LSAS total score was significantly decreased by pregabalin 600 mg/d treatment compared with placebo (P = 0.024, analysis of covariance). Significant differences (P ≤ 0.05) between pregabalin 600 mg/d and placebo were seen on several secondary measures including the LSAS subscales of total fear, total avoidance, social fear, and social avoidance, and the Brief Social Phobia Scale fear subscale. Pregabalin 150 mg/d was not significantly better than placebo on any measures. Somnolence and dizziness were the most frequently occurring adverse events among patients receiving pregabalin 600 mg/d. In conclusion, pregabalin 600 mg/d was an effective and well-tolerated treatment of social anxiety disorder.

Brofaromine for social phobia: a multicenter, placebo-controlled, double-blind study.

The safety and efficacy of brofaromine, a reversible and selective monoamine oxidase inhibitor, were examined in a multicenter trial of 102 outpatients with social phobia. After a 1-week placebo washout, subjects were randomly assigned to 10 weeks of treatment with either brofaromine (N = 52) or placebo (N = 50). Brofaromine dosage began at 50 mg/day and was titrated to a maximum of 150 mg/day, depending on treatment response. Brofaromine produced a significantly greater change from baseline in Liebowitz Social Anxiety Scale (LSAS) scores compared with placebo, F(1) = 6.01, p < 0.016. Mean LSAS scores decreased from 81.8 at baseline to 62.6 at endpoint for brofaromine, t = 5.41,p < 0.001, and from 79.8 to 70.7 for placebo, t = 3.66, p < 0.001. Eleven of the 14 brofaromine early terminators discontinued because of adverse experiences, as did 4 of the 17 placebo early terminators. Side effects more common with brofaromine than placebo included insomnia, dizziness, dry mouth, anorexia, tinnitus, and tremor. No clinically significant variations in vital signs or laboratory values were found. The findings are consistent with the clinical efficacy for the treatment of social phobia.

Computer-administered clinical rating scales A review

Abstract 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.

Fluoxetine in social phobia: a double-blind, placebo-controlled pilot study.

The objective of the study was to examine the efficacy of fluoxetine in social phobia. Sixty subjects were randomly assigned to 14 weeks of double-blind therapy with either fluoxetine or placebo. Dose was fixed at 20 mg for fluoxetine during the first 8 weeks of double-blind treatment; during the final 6 weeks, the dose could be increased every two weeks by 20 mg to a maximum of 60 mg/day. An intentto-treat analysis was used. A significant change from baseline to endpoint was found for both fluoxetine and placebo on the Liebowitz Social Anxiety Scale. However, no significant difference was found between fluoxetine and placebo. The change for fluoxetine was somewhat lower than that found with other selective serotonin reuptake inhibitors, whereas the placebo response was greater. Fluoxetine failed to separate from placebo in this trial. It is unknown whether a larger dose for longer duration would have yielded separation from placebo. A higher than usual placebo response rate was found.

Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale

OBJECTIVE To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation. METHOD Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior). RESULTS 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively. CONCLUSIONS Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation.

Computer-administered clinical rating scales

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.

Is baseline agitation a relative contraindication for a selective serotonin reuptake inhibitor: a comparative trial of fluoxetine versus imipramine.

A common presentation for major depression includes psychomotor agitation. However, this subtype has been the infrequent subject of controlled investigation during depression trials. Yet, the subcategorization of agitated depression has historically been associated with the belief that older, sedating compounds have a superior risk:benefit profile. In the 8-week, double-blind, randomized, parallel trial, 124 subjects with Research Diagnostic Criteria-compatible agitated depression were randomized to either imipramine (IMI) or fluoxetine (FLU). Both compounds proved to be similarly effective as measured by change in HAM-D17, HAM-D17 response, and HAM-D17 remission rates. Similar comparability was seen in secondary measures of agitation, anxiety, suicidality, and global impressions. However, of note, a statistically significant difference in early discontinuations because of intolerable adverse events emerged. Whereas 43.5% of IMI subjects discontinued early, only 9.7% of FLU subjects (p < 0.001) did. Significantly more central nervous system events characterized the IMI than the FLU subgroup (IMI, 24.2%, vs. FLU, 6.5%; p = 0.006). In conclusion, among subjects with major depression, subtype agitated, the risk:benefit profile favored FLU over IMI. This was driven by the superior tolerance of FLU. No evidence emerged in support of the clinical hypothesis that a “sedating” agent is the treatment of choice for this group. The results are important when striving to maximize compliance with pharmacotherapy in order to minimize recidivism and associated psychological and economic morbidity. (J Clin Psychopharmacol 1994;14:385–391)

Thyroid disease, behavior, and psychopharmacology

Abstract The authors review psychiatric complications of thyroid disease and the use of psychotropic agents in hyper- and hypothyroid patients. Neuropsychiatric symptoms of hyperthyroidism tend to resolve with treatment of excessive thyroid production; those of hypothyroidism respond in a variable manner to thyroid replacement, but most patients improve substantially after becoming euthyroid. The judicious use of most psychotropics has its place even in the presence of overt thyroid disease. The important antithyroid effects of lithium should be noted when treating patients with thyroid disease. Routine monitoring of thyroid function in otherwise healthy patients taking antipsychotic agents, tricyclic antidepressants, or monoamine oxidase inhibitors (MAOIs) is not believed necessary.