Schizophrenia and Impaired Cardiovascular Fitness

Schizophrenia and Impaired Cardiovascular Fitness

We’re pleased to announce Randall’s work has been released in a recent publication in the journal Psychiatric Research:

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1– and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non-clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug’s greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality.

Kim DD, Lang DJ, Procyshyn RM, Woodward ML, Kaufman K, White RF, Honer WG and Warburton DER. Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia. Psychiat Res. 2018;262:28-33.

12-month trial of clozapine augmentation with aripiprazole or haloperidol

The latest trial for clozapine-resistant patients comes from Italy (1). The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a multicentre, randomized, 12-month trial of patients with schizophrenia and persistent positive symptoms despite at least six months of clozapine therapy at a minimum dose of 400 mg. Outcome measures included the Brief Psychiatric Rating Scale and, for subjective rating of adverse effects, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The primary outcome was treatment discontinuation, “a pragmatic and reliable estimate of treatment efficacy and tolerability” according to the authors.

Based on a power calculation, the investigators intended to recruit 194 participants but randomized 106 patients, about 65% men and with a mean age of 41 years. In addition to clozapine, patients received either haloperidol or aripirpazole for 12-months. Baseline demographics and BPRS scores did not significantly differ between the groups. The dose of adjunctive antipsychotic was adjusted according to clinical response, and the patients could receive any necessary additional medications including mood stabilizers and antidepressants. Although the investigators did not report the mean dose of adjunctive antipsychotics in this publication, they reported in 2011 that at month 3, the mean aripiprazole dose was 11.8 mg and the mean haloperidol dose was 2.8 mg (2).

During the study, 19 aripirpazole and 15 haloperidol patients withdrew, which was not significantly different. At 6 months, the mean BPRS score in the aripirpazole group had decreased by 8.8, and in the haloperidol group, by 8.1; the improvement persisted at 12 months. By 3 months the mean LUNERS score decreased significantly in the aripirpazole group but not in the haloperidol group, which indicated that patients taking aripirpazole reported a decrease in adverse effects whereas those taking haloperidol did not.
Both aripirpazole and haloperidol showed effectiveness in augmenting clozapine, but aripirpazole was better tolerated by self-report. Despite this apparent preference for aripirpazole, the groups had a comparable rate of treatment discontinuation: about a third of patients dropped out, most during the first 6 months of augmentation. The findings of the study are limited by lack of statistical power and of a placebo arm. The researchers claim, however, that CHAT is the longest non-industry-sponsored RCT of treatment-resistant schizophrenia.


1. Cipriani A, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33: 533-537. Abstract

2. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011;31: 266-273. Abstract