Changes in serum lipids, independent of weight, are associated with changes in symptoms during long-term clozapine treatment

Changes in serum lipids, independent of weight, are associated with changes in symptoms during long-term clozapine treatment

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J Psychiatry Neurosci 2007;32(5):331-8

Ric M. Procyshyn, PhD; Kishor M. Wasan, PhD; Allen E. Thornton, PhD; Alasdair M. Barr, PhD; Eric Y.H. Chen, MD; Edith Pomarol-Clotet, MD; Emmanuel Stip, MD; Richard Williams, MB; G. William MacEwan, MD; C. Laird Birmingham, MD; William G. Honer, MD; for the Clozapine and Risperidone Enhancement Study Group

Procyshyn, Honer — Department of Research, Riverview Hospital, Port Coquitlam, BC; Procyshyn, Wasan — Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC; Thornton — Department of Psychology, Simon Fraser University, Burnaby, BC; Barr, Williams, MacEwan, Birmingham, Honer — Department of Psychiatry, University of British Columbia, Vancouver, BC; Birmingham — Centre for Health Evaluation and Outcome Sciences, St. Paul’s Hospital, Vancouver, BC; Stip — Department of Psychiatry, University of Montreal, Montréal, Que; Chen — Department of Psychiatry, University of Hong Kong, Hong Kong, China; Pomarol-Clotet — Department of Psychiatry, University of Cambridge, Cambridge, UK

Abstract

Objective: Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine.
Methods: The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight.
Results: The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores.
Conclusion: Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine’s therapeutic activity.

Résumé

Objectif : Les chercheurs ont signalé que le gain de poids attribué à la clozapine est associé à sa réaction clinique. Toutefois, le gain de poids est une variable physiologique non spécifique qui, en soi, n’explique pas le mécanisme sous-tendant cette relation. D’autres variables biologiques qui sont souvent associées au gain de poids, comme les lipides sériques, peuvent aider à expliquer cette observation. Le principal objectif de cette étude consistait à déterminer si une augmentation des lipides sériques est associée à une amélioration des symptômes de la schizophrénie pendant le traitement en état stable à la clozapine.
Méthodes : Les données de cette étude représentent un sous-ensemble de données tirées d’une étude cliniquee randomisée, à double insu, dans le cadre de laquelle on a évalué des sujets atteints de schizophrénie qui démontraient une réaction médiocre au traitement à la clozapine. Les sujets ont été affectés au hasard au groupe recevant 3 mg de rispéridone par jour ou au groupe recevant un placebo pendant huit semaines tout en continuant leur traitement à la clozapine. Ce protocole de traitement a été suivi d’un traitement optionnel (ouvert) de 18 semaines où on augmentait la dose de rispéridone. Dans l’étude actuelle, nous avons inclus tous les sujets de l’étude clinique antérieure qui ont subi des analyses des lipides à jeun et avaient une note sur l’échelle des syndromes positifs et négatifs (Positive and Negative Syndrome Scale – PANSS) pour les jours 7 et 63 (n = 55). Pour les analyses primaires, nous avons eu recours à la régression multiple afin d’examiner le lien entre les concentrations de lipides sériques et les notes PANSS, après un contrôle du poids.
Résultats : Les analyses ont révélé que la variation de la concentration de lipides sériques a prédit un changement des symptômes par rapport à ceux d’un changement de poids. Plus particulièrement, une augmentation de la concentration de triglycéride sérique était associée à une diminution de la note totale PANSS (p = 0,037). De plus, une augmentation de la concentration totale de cholestérol sérique (p = 0,007), de la concentration de triglycéride sérique (p = 0,017) ou de leur effet combiné (p = 0,010) était associée à une diminution des notes PANSS négatives sur la sous-échelle.
Conclusion : L’élévation des lipides sériques est associée à une amélioration des symptômes de la schizophrénie chez les sujets ayant subi un traitement à la clozapine. Bien que le mécanisme ne soit pas clair, les lipides sériques pourraient influencer l’activité thérapeutique de la clozapine.


Medical subject headings: clozapine; triglycerides; cholesterol; lipids.

Competing interests: Dr. Procyshyn has received consulting or advisory board fees and lecture fees from AstraZeneca, GlaxoSmithKline, Janssen and Eil Lilly. Dr. Chen has recieved grant funding from AstraZeneca. Dr. Stip has recieved consulting or advisory board fees from AstraZeneca, Janssen and Eli Lilly; Pfizer lecture fees from AstraZeneca, Janssen and Eli Lilly; and grant funding from AstraZeneca. Dr. Williams has received consulting or advisory board fees from AstraZeneca, Genpharm, Janssen, Eli Lilly and Prestwick Pharmaceuticals; lecture fees from AstraZeneca, Genpharm, Janssen, Eli Lilly, Novartis, Pfizer and Prestwick Pharmaceuticals; and grant funding from AstraZeneca, Janssen and Pfizer. Dr. MacEwan has received consulting or advisory board fees from AstraZeneca, Janssen, Eli Lilly and Novartis; lecture fees from GlaxoSmithKline; and grant support from AstraZeneca. Dr. Honer has received consulting or advisory board fees from In Silico Biosciences, Janssen, and Wyeth and lecture fees from AstraZeneca.

Submitted Dec. 13, 2006; Revised Mar. 9, 2007; Accepted Mar. 13, 2007

Correspondence to: Dr. Ric M. Procyshyn, 128 Administration Building, Riverview Hospital, 2601 Lougheed Highway, Coquitlam BC V3C 4J2; fax 604 524-7800; rprocyshyn@bcmhs.bc.ca