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.

Changes in metabolic syndrome parameters in patients with schizoaffective disorder who participated in a randomized, placebo-controlled trial of topiramate.

This study evaluated changes in the metabolic syndrome (MetS) parameters among patients with schizoaffective disorder-bipolar type who had previously participated in a randomized, placebo-controlled study of topiramate (Chengappa et al., 2007). Topiramate (or placebo) was added to pre-existing mood-stabilizer and/or antipsychotic treatment. Nearly 41% of the 46 participants with fully available data met criteria for MetS at the pre-study baseline, and six (13%) additional subjects met criteria for MetS during the 16-week study. Several subjects (mostly topiramate treated) showed the hypothesized and expected loss in body weight and this correlated with improved glycosylated hemoglobin or systolic and diastolic blood pressure measurements or improvements in lipid levels, whereas a few patients had inconsistent results. Limitations of the study include the lack of targeted treatments for specific components of the metabolic syndrome, and no controls for exercise, diet or concomitant medications. Nevertheless, screening, monitoring and targeted treatment for the metabolic syndrome in psychiatric patients is increasingly becoming the standard of practice. Moreover and especially pertinent to the readership of this journal is that as the prevalence of overweight and MetS have increased worldwide, the World Health Organization has proposed lower cut-off thresholds for obesity in Asia. Furthermore, lower thresholds for waist circumference have also been recommended for Asians.

A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type.

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.

The prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar subtype.

OBJECTIVES: To evaluate the point prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar type. METHODS: Consenting patients who were participants in an ongoing clinical trial of adjunctive topiramate treatment for schizoaffective disorder, bipolar type were evaluated at baseline for the point prevalence of the metabolic syndrome. The criteria for the metabolic syndrome included: (a) waist circumference > 102 cm (40 inches) in males, or > 88 cm (35 inches) in females; (b) fasting serum triglyceride levels > or = 150 mg/dL; (c) fasting high density lipoproteins (HDL) cholesterol <40 mg/dL in men or <50 mg/dL in women; (d) blood pressure > or = 130/85 mmHg; and (e) fasting glucose > or = 110 mg/dL. Subjects who had at least three of these five criteria were defined as meeting criteria for the metabolic syndrome. RESULTS: Thirty-six subjects (males = 15, females = 21) were evaluated, and three were excluded for missing data. Among those 33 subjects with complete data, 14 subjects (42.4%, males = 7, females = 7, African Americans = 6, Caucasians = 8) met criteria for the metabolic syndrome. Not unexpectedly, those with the metabolic syndrome were significantly more likely to be obese, and have significantly higher mean systolic and diastolic blood pressure, mean fasting triglyceride levels and larger mean waist circumferences, and significantly lower HDL cholesterol levels; and a trend toward higher fasting blood glucose levels. Furthermore, the fasting mean total cholesterol in those with the metabolic syndrome was 217 mg/dL (+/-46). CONCLUSIONS: This preliminary report suggests that the point prevalence of the metabolic syndrome in patients with schizoaffective disorder appears to be higher than that reported in the general population of the USA. Targeted weight reduction and life style change strategies (increased exercise, smoking cessation, stress reduction) may provide useful interventions to decrease the morbidity and mortality that accompanies the presence of the metabolic syndrome in patients with psychiatric illnesses.