Oliver Freudenreich

Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations

Objective:  To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials.

Haloperidol increases smoking in patients with schizophrenia

Ten patients with schizophrenia participated in 120-min free-smoking sessions when actively psychotic and free of antipsychotic medications, and again after the initiation of haloperidol treatment. During these free-smoking sessions they had access to cigarettes ad libitum. Their expired air carbon monoxide (CO) and plasma nicotine and cotinine levels were measured at the end of the 120-min free-smoking sessions. These patients smoked more after starting haloperidol treatment, relative to their baseline rate of smoking when free of antipsychotic medications, as evidenced by significantly higher expired CO and plasma nicotine levels.

Clozapine decreases smoking in patients with chronic schizophrenia

The puzzle of why patients with schizophrenia show an extremely high prevalence of cigarette smoking has intrigued researchers for many years. Approximately 80% of patients with schizophrenia smoke (Hughes et al 1986). This is more than twice the prevalence of smoking in the general population. We have reported (McEvoy et al 1991) that heavy smoking was associated with a lack of therapeutic response to the classical antipsychotic haloperidol. Clozapine may be therapeutically effective in patients who are nonresponsive to haloperidol (Kane et al 1988). We report here the changes that occurred in smoking among a group of treatment-refractory patients with schizophrenia when they were switched from haloperidol to clozapine in an ongoing double-blind trial examining treatment response at three distinct clozapine plasma level ranges.

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n=28) and healthy controls (n=32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo-controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia.

Smoking and therapeutic response to clozapine in patients with schizophrenia

BACKGROUND Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.

A double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia.

Abstract: The objective of this study was to examine the efficacy of bupropion for smoking cessation in patients with schizophrenia. Adults with schizophrenia who smoked more than 10 cigarettes per day and wished to try to quit smoking were recruited from community mental health centers, enrolled in a 12-week group cognitive behavioral therapy intervention, and randomly assigned to receive either bupropion sustained-release 300 mg/d or identical placebo. Fifty-three adults, 25 on bupropion and 28 on placebo, were randomized, completed at least 1 postbaseline assessment and were included in the analysis. The primary outcome measures were 7-day point prevalence abstinence in the week after the quit date (week 4) and at the end of the intervention (week 12). Subjects in the bupropion group were significantly more likely to be abstinent for the week after the quit date (36% [9/25] vs. 7% [2/28], P = 0.016) and at end of the intervention (16% [4/25] vs. 0%, P = 0.043). Subjects in the bupropion group also had a higher rate of 4-week continuous abstinence (weeks 8-12) (16% [4/25] vs. 0%, P = 0.043) and a longer duration of abstinence (4.2 [3.2] weeks vs. 1.8 [0.96] weeks, t = 2.30, P = 0.037). The effect of bupropion did not persist after discontinuation of treatment. Subjects in the bupropion group had no worsening of clinical symptoms and had a trend toward improvement in depressive and negative symptoms. We conclude that bupropion does not worsen clinical symptoms of schizophrenia and is modestly effective for smoking cessation in patients with schizophrenia. The relapse rate is high after treatment discontinuation.

A Placebo-Controlled Add-On Trial of the Ampakine, CX516, for Cognitive Deficits in Schizophrenia

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was −0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

A 12-week double-blind, placebo-controlled study of bupropion SR added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% to 100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P = 0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F = 13.8; P < 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P = 0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention.

Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia

The present study examined the hypothesis that elevated serum levels of C-reactive protein (CRP) would be associated with more severe clinical symptoms in patients with schizophrenia. Twenty-six inpatients with schizophrenia or schizoaffective disorder were enrolled. Serum levels of CRP were measured, and each patient was assessed with the Positive and Negative Syndrome Scale (PANSS). Subjects with CRP levels above the normal range (CRP>0.50 mg/dl, elevated CRP group, N=5) scored significantly higher than those with CRP levels in the normal range (CRP<or=0.50 mg/dl, normal CRP group, N=21) on the PANSS total score, negative symptom subscale score and general psychopathology subscale score. There was no significant difference between the two groups on the PANSS positive symptom subscale score. An inflammatory process, as reflected by elevated serum levels of CRP, might be associated with more severe psychopathology in a subgroup of patients with schizophrenia.

An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia

Objective:  We conducted this 6‐week open‐label trial to examine the effects of adjunctive aripiprazole in clozapine‐treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia.