F. Mandel

Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: A pooled analysis of 6 studies

Epidemiological evidence supports comorbidity of generalized anxiety disorder (GAD) and major depressive disorder (MDD) or dysthymia, and its association with significant disability. As pregabalin, a new alpha(2)-delta anxiolytic treatment for GAD, unlike most other licensed treatments for GAD has not undergone investigation in patients with MDD, we examined its efficacy in depressive symptoms associated with GAD, through a post-hoc analysis of the existing clinical trial database. The results provide consistent evidence that in patients with GAD pregabalin reduced associated symptoms of depression. This was seen in the 150 mg/day, 300-450 mg/day and 600 mg/day dosing groups. Even in subjects with more prominent depressive symptoms, pregabalin remained effective for both sub-syndromal depression and GAD symptoms, with pregabalin 300-450 mg/day demonstrating the most beneficial response. In conclusion, pregabalin, an alternative treatment option for GAD with a novel mechanism of action, also demonstrated efficacy in treating depressive symptoms typically encountered in GAD patients.

The efficacy of pregabalin and benzodiazepines in generalized anxiety disorder presenting with high levels of insomnia.

The objective of this study was to assess the impact of high levels of insomnia on response to pregabalin (PGB) in patients with generalized anxiety disorder (GAD). Pooled data were analyzed from six double-blind, placebo-controlled, 4- to 6-week trials of outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria for GAD with a minimum Hamilton Rating Scale for Anxiety (HAM-A) score = 18. Response was evaluated for three fixed-dose PGB groups (150, 300–450, 600 mg/day), and for a benzodiazepine group (alprazolam or lorazepam). A ‘high-insomnia’ subgroup was defined by a baseline HAM for Depression (HAM-D) insomnia factor score greater than 3 (maximum = 6). At baseline, 1002 (54%) patients met the criteria for the high-insomnia subgroup, and 852 (46%) for the low-insomnia subgroup. Mean baseline HAM-A scores were 1–2 points higher in high-insomnia versus low-insomnia patients. In high-insomnia patients, PGB produced significantly greater improvement in HAM-A total scores at last observation carried forward endpoint on 300–450 mg (−13.1±0.6) and 600 mg (−11.2±0.5) dose groups compared with placebo (−8.3±0.5; P<0.0001 for both comparisons); the improvement on PGB 150 mg was not significant (−9.9±0.7; P = 0.051). Improvement was significant in the benzodiazepine group (−11.0±0.6; P<0.0001). In the high-insomnia subgroup, treatment with PGB significantly (P<0.001) improved the HAM-D insomnia factor scores on both the 300–450 mg (−2.73) and 600 mg (−2.35) doses, and on benzodiazepines (−2.52) compared with placebo (−1.51); improvement on PGB 150 mg (−1.69) was not significant. Rates of treatment-emergent insomnia were lower on PGB compared with placebo in both the high- and low-insomnia subgroups. In conclusion, PGB was well tolerated, and improved overall anxiety symptoms, while specifically improving insomnia in patients with GAD presenting with high levels of concurrent insomnia.

Efficacy of ziprasidone in dysphoric mania: Pooled analysis of two double-blind studies

BACKGROUND Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms. OBJECTIVE This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania. METHODS Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring >/=2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance. RESULTS 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n=124; placebo, n=55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p<0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo. LIMITATIONS The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs. CONCLUSION In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings.

Early onset anxiolytic efficacy after a single dose of pregabalin: double-blind, placebo- and active-comparator controlled evaluation using a dental anxiety model.

To evaluate acute onset of anxiolytic activity using a dental anxiety model, 89 patients were randomised to double-blind single dose pregabalin 150 mg, alprazolam 0.5 mg or placebo 4 h before a scheduled dental procedure. A Dental Anxiety Total score >12 (moderate-to-severe) without meeting Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) (DSM-IV) anxiety disorder criteria was required. Efficacy and safety, assessed 2, 2.5, 3, 3.5 and 4 h postdose, included 100 mm Visual Analogue Scale for Anxiety (VAS-Anxiety; primary outcome), 100 mm VAS-Sedation and Time-to-Onset of Action Scale (TOAS), a patient-rated anti-anxiety drug-benefit scale (no [0] to full benefit [10]). Mixed model analysis found significantly greater VAS-A improvement slopes for pregabalin (t = −2.47; P = 0.014) and alprazolam (t = −2.39; P = 0.018). There was a significant improvement versus placebo in the TOAS from 2 h through endpoint in alprazolam patients and from 3 h onward in pregabalin patients. Pregabalin produced significantly greater increases in VAS-Sedation versus placebo from 2.5 h through 4 h (2 h onward for alprazolam). Notably, there was a higher correlation between TOAS and VAS-Sedation (r = +0.58) than VAS-Anxiety (r = −0.50) on Spearman’s analysis. The majority of Adverse Effects (AEs) were mild, and the most frequent for pregabalin, alprazolam, and placebo, respectively, were fatigue (N = 7, 7, 3), dizziness (N = 6, 3, 3), attention disturbance (N = 3, 1, 0), somnolence (N = 3, 0, 0), feeling abnormal (N = 0, 2, 0) and balance disorder (N = 0, 2, 0). These results suggest that onset of clinically meaningful anxiolytic effect after single-dose pregabalin occurs within the first 3—4 h. Additional research is needed to determine whether anxiolytic effect occurs in generalized anxiety disorder populations by day 1 or within 3—4 h post-first dose.

Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial

To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, outpatients (N = 106) with a lifetime diagnosis of generalized anxiety disorder (current diagnosis could be subthreshold) who had been treated with a benzodiazepine for 8–52 weeks were stabilized for 2–4 weeks on alprazolam in the range of 1–4 mg/day. Patients were then randomized to 12 weeks of double-blind treatment with either pregabalin 300–600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25% per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free (primary) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist (PWC). At endpoint, a non-significant higher proportion of patients remained benzodiazepine-free receiving pregabalin compared with placebo (51.4% vs 37.0%). Treatment with pregabalin was associated with significantly greater endpoint reduction in the HAM-A total score versus placebo (−2.5 vs +1.3; p < 0.001), and lower endpoint mean PWC scores (6.5 vs 10.3; p = 0.012). Thirty patients (53%) in the pregabalin group and 19 patients (37%) in the placebo group completed the study, reducing the power to detect a significant difference on the primary outcome. The results on the anxiety and withdrawal severity measures suggest that switching to pregabalin may be a safe and effective method for discontinuing long-term benzodiazepine therapy.

Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials.

BACKGROUND Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. OBJECTIVE We aimed to understand determinants of response to antipsychotic treatment. METHOD Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). RESULTS While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. CONCLUSIONS Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments.

Impact of geographical and cultural factors on clinical trials in acute mania: lessons from a ziprasidone and haloperidol placebo-controlled study

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

A comparison of ziprasidone and risperidone in the long-term treatment of schizophrenia: a 44-week, double-blind, continuation study.

Objective: This randomized, double-blind, multicentre extension study compared the efficacy, tolerability, and safety of ziprasidone and risperidone for schizophrenia or schizoaffective disorder. Methods: Patients who had responded to treatment for an acute exacerbation of illness in an 8–week study received ziprasidone, 80 to 160 mg/day (n = 62), or risperidone, 6 to 10 mg/day (n = 77), for up to 44 additional weeks. Primary efficacy variables included changes in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression Severity (CGI-S) score. Tolerability and safety assessments included movement disorders, adverse events, study discontinuation rates, and weight and metabolic parameters. Results: Both the ziprasidone and risperidone groups showed statistical improvement from baseline in PANSS and CGI-S scores at study end point with no significant differences between treatment groups. More risperidone-treated patients completed the study (41.6%) than ziprasidone-treated patients (33.9%), but the difference was not statistically significant. Ziprasidone-treated patients who completed the study showed greater improvement in depressive symptoms assessed by Montgomery and Asberg Depression Rating Scale than risperidone-treated patients (P < 0.05). Ziprasidone was associated with a more favourable effect on extrapyramidal symptom (EPS) measures and prolactin as well as less weight gain than risperidone. Median dosages were ziprasidone 120 mg/day and risperidone 8 mg/day. Conclusions: Ziprasidone and risperidone demonstrated similar efficacy during long-term treatment of patients with schizophrenia or schizoaffective disorder. While more subjects on risperidone completed the extension study, ziprasidone was associated with fewer adverse effects on weight, EPS measures, and prolactin than risperidone.

Impact of gastrointestinal symptoms on response to pregabalin in generalized anxiety disorder : results of a six-study combined analysis

The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GI) symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4–6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300–450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.5 mg/day; lorazepam, 6 mg/day). A GI-high subgroup (high GI symptomatology) was defined by a baseline HAM-A item-11 (GI) score of 3 or greater (severe/very severe). At baseline, 301 patients (16.2%) met criteria for the GI-high subgroup. Baseline characteristics were approximately similar for the four study treatments in the GI-high subgroup. For the GI-high subgroup, last observation carried forward (LOCF) endpoint reduction in HAM-A was significantly higher on PGB-300/450 −13.8±1.2 and PGB-600 −14.7±1.0 compared with PBO −10.1±0.9 (P<0.01 for both comparisons); but the difference on PGB-150 did not achieve significance (−13.5±1.6; P=0.083). Also in the GI-high subgroup, endpoint reduction in HAM-A item-11 was significantly higher on PGB-300/450 compared with PBO (−1.93±0.16 vs. −1.52±0.13; P=0.04), but did not achieve significance on PGB-600 mg (−1.89±0.14; P=0.06), or PGB-150 mg (−1.90±0.23; P=0.16). In the GI-high subgroup, treatment with a benzodiazepine was not associated with significant endpoint reduction in either the HAM-A total score or the HAM-A item-11 score. Patients in the GI-high subgroup had higher discontinuation rates when treated with benzodiazepines, whereas treatment with PGB 300–600 mg/day was not associated with treatment-emergent worsening in GI symptoms compared with placebo. Treatment with PGB improved overall levels of anxiety, as well as specifically improving GI symptoms.

An Examination of Bias in Volunteer Subject Selection: Findings from an In-Depth Child Abuse Study

Remarkably few reported studies tested the assumption that a research sample can be constructed which is representative of the population of interest. In order to investigate potential volunteer bias in abuse research, we utilized a database assembled for an NIMH funded study investigating the relationship among adolescent physical abuse, suicidal behavior, and psychopathology. Extensive information was available concerning the nonparticipant pool from which this sample was assembled, allowing for a comprehensive assessment of possible sample bias. The volunteer sample of 99 abused families who agreed to participate in our study was compared on a large number of variables with a random sample of 99 abused families who declined to participate. Comparisons of the two groups did not support the hypothesis that the non-participating families represented a more dysfunctional population. The two groups were far more similar to, than disparate from, each other.