Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia.

Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg b.i.d.) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO <5 p.p.m.) and smoking reduction (CO <8), as well as cigarettes/day (in Study 1), were assessed daily (Monday-Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.

Subtle changes in thyroid indices during a placebo-controlled study of an extract of Withania somnifera in persons with bipolar disorder.

Laboratory indices of thyroid function (TSH, Free T4, and T3) were measured in a randomized clinical trial in which Ashwagandha (ASW) was used to improve cognitive function in patients with bipolar disorder. This was done in light of a case-report of ASW-associated thyrotoxicosis, and data from mice administered ASW that showed significant increases in thyroxine levels. Ten (of the original 60) patients showed abnormal results in one of the thyroid measures either at the beginning or end of the 8-week study. One ASW- treated patient had subclinical hypothyroidism (TSH - 5.7 mIU/L) at baseline that normalized, and all three ASW treated patients experienced T4 increases from baseline (7%, 12%, and 24%). Six of 7 placebo-assigned patients showed decreases in T4 from baseline (4% to 23%), and one patient's TSH moved from the normal to subclinical hypothyroid range (6.96 mIU/L). As thyroid indices were done for safety, and not the primary goal of the original study, only 16.7% had abnormal thyroid indices, and as there was no sub-stratification for treatment assignment by thyroid status, unequal numbers of subjects received ASW (n = 3) or placebo (n = 7). In spite of these limitations, the subtle laboratory changes noted in thyroid indices in an 8-week study suggest that ASW may increase thyroxine levels, and therefore vigilance regarding hyperthyroidism may be warranted. Nonetheless, the thyroid enhancing properties of ASW may also represent a clinical opportunity for the treatment of subclinical hypothyroidism, and these results suggest the need for further study of the effects of ASW on thyroid indices, especially in those with bipolar and unipolar mood disorders.

Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial.

OBJECTIVE: To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder. METHOD: In this 12-week, randomized, double-blind, placebo-controlled trial, adults with bipolar I disorder (DSM-IV criteria) experiencing a manic or mixed episode with a Young Mania Rating Scale (YMRS) score of >or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo. Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks. The study was conducted from October 2001 through October 2003. The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase. RESULTS: The mean +/- SD change in YMRS score from baseline was -10.1 +/- 8.7 (-40.1%) in the topiramate group (N = 143) and -9.6 +/- 8.2 (-40.2%) in the placebo group (N = 144, p = .797). Greater than 50% reduction in YMRS was achieved by 39% of the topiramate group and 38% of the placebo group (p = .914). No significant treatment differences were observed for secondary efficacy measures. Compared with adjunctive placebo, adjunctive topiramate did not worsen mania or induce depression. Paresthesia, diarrhea, and anorexia were more common in the topiramate group. The topiramate group achieved greater reductions than the placebo group in body weight (-2.5 vs. 0.2 kg, p < .001) and body mass index (-0.84 vs. 0.07 kg/m(2), p < .001). CONCLUSION: In patients treated with lithium or valproate, there was no difference in the reduction of YMRS score in the topiramate and placebo groups. Both groups showed declines of 40%. Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms.

Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series.

Topiramate is an antiepileptic agent, which is being investigated as a mood-stabilizer. Three obese individuals with DSM-IV bipolar I disorder and type II diabetes mellitus received topiramate treatment in combination with antipsychotics and valproate or carbamazepine. In addition to improved mood stability, these individuals lost between 16 to 20.5% of their pre-topiramate body weight and also achieved significant glycemic control.