Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To determine if adjunctive treatment with a standardized extract of Withania somnifera (WSE), with known anti-inflammatory and immunomodulating properties, improves psychopathology and stress in patients with schizophrenia or schizoaffective disorder (DSM-IV-TR). METHODS: Patients experiencing an exacerbation of symptoms were assigned to WSE (1,000 mg/d) or placebo for 12 weeks, added to their antipsychotic medication, in a random-assignment, double-blind, placebo-controlled study conducted from April 2013 to July 2016. Primary outcomes were change from baseline to end of treatment on the Positive and Negative Syndrome Scale (PANSS total, positive, negative, and general symptoms) between treatment groups. Secondary outcomes evaluated stress and inflammatory indices using the Perceived Stress Scale (PSS), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP). RESULTS: Sixty-six randomized patients (n = 33 per group) provided efficacy data. Beginning at 4 weeks and continuing to the end of treatment, WSE produced significantly greater reductions in PANSS negative, general, and total symptoms (Cohen d: 0.83, 0.76, 0.83), but not positive symptoms, when compared to placebo. PSS scores improved significantly with WSE treatment compared to placebo (Cohen d: 0.58). CRP and S100B declined more in the WSE group but were not significantly different from placebo. Adverse events were mild to moderate and transient; somnolence, epigastric discomfort, and loose stools were more common with WSE. No significant between-treatment differences were noted in body weight, vital signs, or laboratory measures, which remained stable. CONCLUSIONS: This early study suggests that adjunctive treatment with a standardized extract of Withania somnifera provides significant benefits, with minimal side effects, for negative, general, and total symptoms and stress in patients with recent exacerbation of schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01793935.

Varenicline for smoking cessation in bipolar disorder: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Virtually no clinical trials for smoking cessation have been undertaken in bipolar disorder. Varenicline has shown efficacy for smoking cessation, but warnings about neuropsychiatric adverse events have been issued. We assessed the efficacy and safety of varenicline in euthymic bipolar subjects motivated to quit smoking. METHOD: Clinically stable adult patients with DSM-IV bipolar disorder (n = 60) who smoked ≥ 10 cigarettes per day were randomized to a 3-month, double-blind, placebo-controlled varenicline trial and a 3-month follow-up. Study enrollment was completed from February 2010 through March 2013. Varenicline was dosed using standard titration, and smoking cessation counseling was provided to all patients. The primary outcome was defined as a 7-day point prevalence of self-reported no smoking verified by expired carbon monoxide level < 10 ppm at 12 weeks. Psychopathology and side-effects were assessed at each visit. RESULTS: At 3 months (end of treatment), significantly more subjects quit smoking with varenicline (n/n = 15/31, 48.4%) than with placebo (n/n = 3/29, 10.3%) (OR = 8.1; 95% CI, 2.03-32.5; P < .002). At 6 months, 6 of 31 varenicline-treated subjects (19.4%) remained abstinent compared to 2 of 29 (6.90%) assigned to placebo (OR = 3.2; 95% CI, 0.60-17.6; P = .17). Psychopathology scores remained stable. Ten serious adverse events occurred (n = 6, varenicline; n = 4, placebo). Abnormal dreams occurred significantly more often in varenicline-treated subjects (n/n = 18/31, 61.3%) than in those receiving placebo (n/n = 9/29, 31%; Fisher exact test, P = .04). Eight varenicline-treated and 5 placebo-assigned subjects expressed fleeting suicidal ideation, a nonsignificant difference. CONCLUSIONS: Varenicline shows efficacy for initiating smoking cessation in bipolar patients, but medication trials of longer duration are warranted for maintaining abstinence. Vigilance for neuropsychiatric adverse events is prudent when initiating varenicline for smoking cessation in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01010204.

Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder.

OBJECTIVE: Cognitive impairments contribute significantly to inadequate functional recovery following illness episodes in bipolar disorder, yet data on treatment interventions are sparse. We assessed the cognitive effects of a standardized extract of the medicinal herb Withania somnifera (WSE) in bipolar disorder. METHOD: Sixty euthymic subjects with DSM-IV bipolar disorder were enrolled in an 8-week, double-blind, placebo-controlled, randomized study of WSE (500 mg/d) as a procognitive agent added adjunctively to the medications being used as maintenance treatment for bipolar disorder. Study enrollment and data analyses were completed between December 2008 and September 2012. Cognitive testing at baseline and 8 weeks assessed primary efficacy outcomes. Psychopathology and adverse events were monitored at scheduled visits. RESULTS: Fifty-three patients completed the study (WSE, n = 24; placebo, n = 29), and the 2 groups were matched in terms of demographic, illness, and treatment characteristics. Compared to placebo, WSE provided significant benefits for 3 cognitive tasks: digit span backward (P = .035), Flanker neutral response time (P = .033), and the social cognition response rating of the Penn Emotional Acuity Test (P = .045). The size of the WSE treatment effect for digit span backward was in the medium range (Cohen d = 0.51; 95% CI, 0.25-0.77). None of the other cognitive tasks showed significant between-group differences. Mood and anxiety scale scores remained stable, and adverse events were minor. CONCLUSIONS: Although results are preliminary, WSE appears to improve auditory-verbal working memory (digit span backward), a measure of reaction time, and a measure of social cognition in bipolar disorder. Given the paucity of data for improving cognitive capacity in bipolar disorder, WSE offers promise, appears to have a benign side-effects profile, and merits further study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00761761.

A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia.

BACKGROUND: Targeting glutamatergic dysfunction provides an exciting opportunity to improve cognitive impairment in schizophrenia. One treatment approach has targeted inadequate antioxidant defenses at glutamatergic synapses. Animal and human data suggest NMDA antagonists worsen executive cognitive controls--e.g. increase perseverative responses and impair set-shifting. We conducted a preliminary study to test the hypothesis that L-carnosine, an antioxidant and anti-glycation agent which is co-localized and released with glutamate would improve executive dysfunction, a cognitive domain associated with glutamate. METHODS: Seventy-five symptomatically stable adults with chronic schizophrenia were randomly assigned to L-carnosine as adjunctive treatment (2 g/day) or a matched placebo in a double-blind manner for 3 months. Cognitive domains (executive dysfunction, memory, attention and motor speed) were assessed using a computerized battery at baseline, 4 and 12 weeks, along with psychopathology ratings and safety parameters. RESULTS: The L-carnosine group performed significantly faster on non-reversal condition trials of the set-shifting test compared with placebo but reversal reaction times and errors were not significantly different between treatments. On the strategic target detection test, the L-carnosine group displayed significantly improved strategic efficiency and made fewer perseverative errors compared with placebo. Other cognitive tests showed no significant differences between treatments. Psychopathology scores remained stable. The carnosine group reported more adverse events (30%) compared with the placebo group (14%). Laboratory indices remained within acceptable ranges. CONCLUSIONS: These preliminary findings suggest that L-carnosine merits further consideration as adjunctive treatment to improve executive dysfunction in persons with schizophrenia.

A Pilot, 15-month, randomised effectiveness trial of Risperidone long-acting injection (RLAI) versus oral atypical antipsychotic agents (AAP) in persons with bipolar disorder.

UNLABELLED: Chengappa KNR, Turkin SR, Schlicht PJ, Murphy SL, Brar JS, Fagiolini A, Houck PR, Garbutt RG, Fredrick N. A Pilot, 15-month, randomised effectiveness trial of Risperidone long acting injection (RLAI) versus oral atypical antipsychotic agents (AAP) in persons with bipolar disorder. OBJECTIVE: Long-acting injectible antipsychotic agents are rarely considered in the treatment of bipolar patients [bipolar disorder (BPD)]. We posited that BPD patients receiving risperidone long-acting injections [Risperidone long-acting injections (RLAIs)] would experience fewer negative clinical events than those receiving oral atypical antipsychotic agents (AAP). METHODS: Adult BPD patients in a hypomanic, manic or mixed episode were randomised to either oral risperdone followed by RLAI (n = 23) or an AAP (n = 25) for 15 months. Any mood stabilizers were continued. An independent clinician board declared any clinical events that occurred but the treatment assignment was concealed. RESULTS: Nine of the 48 patients who participated in this study did not improve, leaving 39 patients in 1-year extension. RLAI patients received the following bi-weekly dosages: 25 mg (n = 9), 37.5 mg (n = 8), and 50 mg (n = 6). The AAP group included aripiprazole (n = 11, 15-30 mg/day), quetiapine (n = 8, 300-700 mg/day), olanzapine (n = 5, 15-25 mg/day), and ziprasidone, (n = 1, 160 mg/day). In total, 47 clinical events were declared. The RLAI-treated group experienced significantly fewer clinical events (mean: 0.86 ± 0.73) compared with the AAP group (1.61 ± 1.29), t = 2.29, d.f. = 37, p = 0.028 (95% CI = 0.087-1.421). Of all, 50% of the AAP subjects gained ≥ 7% of their baseline body weight as did 38% of the RLAI-treated patients. CONCLUSIONS: RLAI-treated patients experienced significantly fewer negative clinical events. Further exploration should focus on which subtypes of BPD patients might benefit from RLAI treatment. Weight gain in BPD subjects requires clinical attention. Limitations include an open design, small sample size and the inability to conclude on whether this strategy is useful for depressive episodes.