Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder.

OBJECTIVES: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients. METHODS: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21. RESULTS: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated. CONCLUSIONS: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.

Efficacy and safety of paliperidone palmitate 6-monthly long-acting injectable in reduction of relapses in patients with schizophrenia: An Asian subgroup analysis of phase 3, randomized study.

BACKGROUND: Evaluate efficacy and safety of paliperidone palmitate 6-monthly (PP6M) for patients with schizophrenia in the Asian subgroup of a global, multicenter, noninferiority phase-3 study (NCT03345342). METHODS: Patients received paliperidone palmitate 1-monthly (PP1M, 100/150 mg eq.) or paliperidone palmitate 3-monthly (PP3M, 350/525 mg eq.) during the maintenance phase and entered a 12-month double-blind (DB) phase, wherein they were randomized (2:1) to PP6M (700/1000 mg. eq.) or PP3M (350/525 mg eq.). Subgroup analysis was performed for 90 (12.7%) patients from Asia region (India, Taiwan, Malaysia, Hong Kong, and Korea). Primary endpoint was time-to-relapse during DB phase (Kaplan-Meier estimates). Secondary endpoints were changes from baseline in Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, Personal and Social Performance (PSP) scale score. RESULTS: In Asian subgroup, 91.9% (82/90) of patients completed DB phase (PP6M: 54/62 [87%]; PP3M: 28/28 [100%]). Median time-to-relapse was "not-estimable" due to low relapse rates in both groups. Estimated difference (95% confidence interval [CI]) between relapse-free patients in PP6M and PP3M groups of Asian subgroup was -0.1% [-8.5%, 8.4%] (global study population: -2.9% [-6.8%, 1.1%]). Mean change from baseline in secondary efficacy parameters was comparable between both groups, similar to the global study population. The incidence of extrapyramidal symptoms was higher in the Asian subgroup than in the global study population. CONCLUSION: Consistent with the global study population, PP6M was noninferior to PP3M in preventing relapse in patients with schizophrenia from the Asia region. Findings suggest the possibility of switching from PP1M/PP3M to twice-yearly PP6M without loss of efficacy and with no unexpected safety concerns.

Utility of repetitive transcranial stimulation as an augmenting treatment method in treatment-resistant depression.

About 30 to 46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. Treatment-resistant depression (TRD) is a severely disabling disorder with no proven treatment options; novel treatment methods like rTMS can be used as augmentation to ongoing pharmacotherapy or as a solitary method of treatment. To evaluate the utility of repetitive transcranial magnetic stimulation as an augmenting method in TRD. In an open-label study, 21 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 2 antidepressants were given rTMS therapy for 4 weeks, keeping the dose of pre-existing antidepressants unchanged. High-frequency (10 Hz) stimulations were delivered over left dorsolateral prefrontal cortex at intensity of 110% of patient's motor threshold. Treatment response was defined as a reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Change and -Severity scales. At the end of 4 weeks, 19 patients completed the 4-week study and were assessed. In ITT analysis, the mean HAM-D17 scores were reduced from 30.80±5.00 to 19.00±6.37 (t=8.27, P<0.001). Only four patients reported headache, but there was no discontinuation due to adverse effects. The study indicates the potential utility of rTMS as an augmenting agent in TRD. Adequately powered, randomized controlled trials are necessary to evaluate the role of rTMS in TRD.

Utility of repetitive transcranial magnetic stimulation as an augmenting treatment method in treatment-resistant depression.

BACKGROUND: About 30-46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. Treatment-resistant depression is a severely disabling disorder with no proven treatment options; novel treatment methods, such as repetitive transcranial magnetic stimulation (rTMS) can be used as augmentation to ongoing pharmacotherapy or as a solitary method of treatment. AIM: To evaluate the utility of rTMS as an augmenting method in treatment-resistant depression. MATERIALS AND METHODS: In an open-label study, 21 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 2 antidepressants were given rTMS therapy for 4 weeks keeping the dose of pre-existing antidepressants unchanged. High-frequency (10 Hz) stimulations were delivered over left dorsolateral prefrontal cortex at an intensity of 110% of the patient's motor threshold. Treatment response was defined as a reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Change and -Severity scales. RESULTS: At the end of 4 weeks, 19 patients completed the 4 weeks study and were assessed. In ITT analysis the mean HAM-D17 scores were reduced from 30.80±5.00 to 19.00±6.37 (t=8.27, P<0.001). Only 4 patients reported headache but there was no discontinuation due to adverse effects. CONCLUSIONS: The study indicates the potential utility of rTMS as an augmenting agent in treatment-resistant depression. Adequately powered, randomized controlled trials are necessary to evaluate the role of rTMS in treatment-resistant depression.

Tolerability of zotepine in Indian patients: Preliminary experience.

Zotepine is an antipsychotic used in Japan and Europe for years and recently being introduced in Indian markets. It is claimed to be particularly effective for negative symptoms, and somnolence and weight gain are the most common side effects. Our aim is to share our clinical experience of use of zotepine with respect to its tolerability. We reviewed the first 10 patients who were prescribed zotepine at our center.

Comprehensibility of translated informed consent documents used in clinical research in psychiatry.

BACKGROUND: Informed consent forms are required in all clinical trials which are approved by an independent Ethics Committee before practical use in the trials. However, how much the average subject actually understands of the information contained in these informed consent forms is uncertain. AIM: In a cross sectional study, the translated informed consent forms used in psychiatric clinical trials were assessed with respect to their ease of readability. MATERIALS AND METHODS: We analyzed 30 informed consent forms translated from English to Hindi used in multinational and multicentre psychiatric clinical trials sponsored by different sponsors. We examined consent forms for readability scores and factors that might relate to readability. RESULTS: The mean readability score for the informed consent forms, determined by the Flesch-Kincaid Grade Level Index (FKGL) was grade levels of 13.66. The ease of readability assessed by the Flesch Reading Ease Score (FRES) was 46.08 suggesting significant complexity of the texts. These values carry even more significance when the average years of schooling for India as a whole are 6.2 years. CONCLUSION: Our results show that the most informed consent forms were too complex to understand by an average adult subject. We suggest reducing this complexity and increasing the ease of readability so those average subjects receive the intended information as exactly as it could be. This can be achieved by few simple measures like improving the deficiencies in translation processes, encouraging the investigators to participate while preparing these forms, and enhanced understanding of the site specific requirements, namely culture, language (dialect), general literacy rate, etc.