Faculty Bibliography

d-Cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3-5 times per week for 8weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions=26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score >/=20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks.

IMPORTANCE: It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy. OBJECTIVE: To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention. INTERVENTIONS: Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76. MAIN OUTCOMES AND MEASURES: Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior. RESULTS: Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64, 45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events. CONCLUSIONS AND RELEVANCE: Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621777.

OBJECTIVE: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine-treated patients with schizophrenia. METHOD: In an 8-week randomized, double-blind, placebo-controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole-body dual-energy X-ray absorptiometry (DXA). RESULTS: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 +/- 0.006 vs. -0.005 +/- 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low-density lipoprotein (LDL) levels (-15.1 +/- 19.8 vs. 4.4 +/- 22.5 mg/dl, P = 0.019) and LDL particle numbers (-376 +/- 632 vs. -36 +/- 301 nm, P = 0.035). Further, there was a significant reduction in the lean mass (-1125 +/- 1620 vs. 607 +/- 1578 g, P = 0.011) measured by whole-body DXA scan in the aripiprazole group. All values were expressed as mean +/- standard deviation, aripiprazole vs. placebo. CONCLUSION: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine-treated patients with schizophrenia.

STUDY OBJECTIVES: In schizophrenia there is a dramatic reduction of sleep spindles that predicts deficient sleep-dependent memory consolidation. Eszopiclone (Lunesta), a non-benzodiazepine hypnotic, acts on gamma-aminobutyric acid (GABA) neurons in the thalamic reticular nucleus where spindles are generated. We investigated whether eszopiclone could increase spindles and thereby improve memory consolidation in schizophrenia. DESIGN: In a double-blind design, patients were randomly assigned to receive either placebo or 3 mg of eszopiclone. Patients completed Baseline and Treatment visits, each consisting of two consecutive nights of polysomnography. On the second night of each visit, patients were trained on the motor sequence task (MST) at bedtime and tested the following morning. SETTING: Academic research center. PARTICIPANTS: Twenty-one chronic, medicated schizophrenia outpatients. MEASUREMENTS AND RESULTS: We compared the effects of two nights of eszopiclone vs. placebo on stage 2 sleep spindles and overnight changes in MST performance. Eszopiclone increased the number and density of spindles over baseline levels significantly more than placebo, but did not significantly enhance overnight MST improvement. In the combined eszopiclone and placebo groups, spindle number and density predicted overnight MST improvement. CONCLUSION: Eszopiclone significantly increased sleep spindles, which correlated with overnight motor sequence task improvement. These findings provide partial support for the hypothesis that the spindle deficit in schizophrenia impairs sleep-dependent memory consolidation and may be ameliorated by eszopiclone. Larger samples may be needed to detect a significant effect on memory. Given the general role of sleep spindles in cognition, they offer a promising novel potential target for treating cognitive deficits in schizophrenia.

Patients with schizophrenia may have altered pain perception, as suggested by clinical reports of pain insensitivity, and recent neuroimaging findings. Here, we examined neural responses to an aversive electrical stimulus and the immediate anticipation of such a stimulus using fMRI and a classical conditioning paradigm, which involved pairing an electrical shock with a neutral photograph. Fifteen men with schizophrenia and 13 healthy men, matched for demographic characteristics, electrical stimulation level and scan movement, were studied. The shock induced robust responses in midbrain, thalamus, cingulate gyrus, insula and somatosensory cortex in both groups. However, compared to controls, the schizophrenic patients displayed significantly lower activation of the middle insula (p(FWE)=0.002, T=5.72, cluster size=24 voxels). Moreover, the lack of insula reactivity in the schizophrenia group was predicted by the magnitude of positive symptoms (r=-0.46, p=0.04). In contrast, there were no significant differences between the two groups in the magnitude of neural responses during anticipation of the shock. These findings provide support for the existence of a basic deficit in interoceptive perception in schizophrenia, which could play a role in the generation and/or maintenance of psychotic states.

Following successful smoking cessation, smokers with schizophrenia are vulnerable to relapse shortly after treatment discontinuation. Our objective was to assess the feasibility and effectiveness of a 12-month relapse prevention intervention in recently abstinent smokers with schizophrenia. Adult outpatient smokers with schizophrenia received weekly cognitive behavioral therapy groups, bupropion slow release, transdermal nicotine patch, and nicotine gum or lozenge for three months. Subjects with seven-day point prevalence abstinence at month 3 received an additional 12 months (months 4-15) of therapy with bupropion, transdermal nicotine patch, and nicotine gum/lozenge in conjunction with relapse prevention-based cognitive behavioral therapy groups that were held weekly in month 4, biweekly in months 5-6, and monthly in months 7-15. Seventeen of 41 participants (41.5%) attained biochemically verified self-report of seven-day point prevalence abstinence at the end of three months of treatment and entered relapse prevention treatment. There was an 81% attendance rate at relapse prevention groups. At the end of the 12-month relapse prevention phase (month 15 overall), 11 of 17 (64.7%) demonstrated biochemically verified seven-day point prevalence abstinence, and 10 of 17 (58.8%) reported four-week continuous abstinence. Almost one quarter of the sample (23.5%) demonstrated long-term prolonged abstinence through the end of the trial. There were no clinically detected cases of psychiatric symptom exacerbation. One participant, who was managed as an outpatient, self-reported psychiatric symptom exacerbation in the interim period between study visits. Extended duration smoking cessation treatment is well-tolerated and may improve smoking outcomes for recently abstinent smokers with schizophrenia. Controlled trials are warranted.

OBJECTIVE: This study examined the effect of adjunctive intranasal insulin therapy on psychopathology and cognition in patients with schizophrenia. METHODS: Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder and been on stable antipsychotics for at least 1 month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale and the Scale for Assessment of Negative Symptoms. A neuropsychological battery was used to assess cognitive performance. The assessment for psychopathology and cognition was conducted at baseline, week 4, and week 8. RESULTS: A total of 45 subjects were enrolled in the study (21 in the insulin group and 24 in the placebo group). The mixed model analysis showed that there were no significant differences between the 2 groups at week 8 on various psychopathology and cognitive measures (P > 0.1). CONCLUSIONS: Adjunctive therapy with intranasal insulin did not seem to be beneficial in improving schizophrenia symptoms or cognition in the present study. The implications for future studies were discussed.

Uncontrolled studies have suggested that increasing the dose of ziprasidone above the standard maximum daily dose of 160 mg may be more effective for some patients with schizophrenia. To test this hypothesis, we conducted an 8-week, placebo-controlled, fixed-dose escalation trial comparing ziprasidone 160 versus 320 mg/d in individuals with schizophrenia or schizoaffective disorder who remained symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks. Of 75 randomized patients, 42 completed the study. Serum ziprasidone concentrations increased significantly in the high-dose group compared with the standard-dose group at week 4 but did not differ between groups at week 8. Both treatment groups exhibited significant symptomatic improvement. Response did not differ between treatment groups; however, in the high-dose group, higher ziprasidone serum concentrations were associated with better response at a trend level. Higher ziprasidone concentrations were also associated with reductions in diastolic blood pressure and, at a trend level, with more prominent negative symptoms and greater QTc prolongation. In summary, increasing the ziprasidone dose to 320 mg/d did not produce a sustained elevation in serum concentrations or symptomatic improvement compared with a standard ziprasidone dose of 160 mg/d.