Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naïve population

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Abstract

Objective

This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment.

Methods

A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol).

Results

144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated.

Conclusions

Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Introduction

A growing number of studies suggest a causative relationship between antipsychotic treatment and metabolic disturbances. The most frequent problems linked to antipsychotic drugs have been abnormalities of glucose metabolism like insulin resistance, hyperglycemia or new onset diabetes mellitus and dyslipidemia, including increased levels of total cholesterol, LDL-cholesterol and triglycerides.

Compared with the general population it has been consistently found that patients with schizophrenia have a higher risk of diabetes (Holt et al., 2005). But it is unclear if it is the schizophrenia per se, the associated less healthy lifestyle or the antipsychotic treatment which is the factor that confers a higher risk of diabetes on these patients. The attribution mainly to antipsychotic drugs is based on the recent studies reporting higher rates of metabolic abnormalities coinciding with the introduction of the second generation agents. But we have to take into account that in the last years the incidence of diabetes in the general population has notably increased as well (Engelgau et al., 2004). In addition, the quality of health care of the psychiatric population has improved and therefore these subjects are more likely to have glucose testing.

There are conflicting results in the published literature (Holt and Peveler, 2006). Most epidemiological studies have shown that diabetes is more frequent in patients having antipsychotics than in non-treated patients (Gianfrancesco et al., 2006, Ramaswamy et al., 2006)—especially in those treated with second generation drugs. On the contrary, prospective randomized clinical trials with placebo control groups have not found significant differences at short (Marder et al., 2003) or medium term (Beasley et al., 2003). The causal mechanism has not been established. There is no clear evidence to support that antipsychotics cause a direct toxic effect on peripheral tissues. The weight gain induced by antipsychotics has been proposed as a potential mechanism by which these drugs may increase the risk for insulin resistance, hyperglycemia and dyslipidemia. However, it seems that not all the cases of glucose dysregulation can be explained by weight increase (Jin et al., 2002). Several recent studies have focused on the receptor-binding profiles of antipsychotics to explain their differences in side effects but still the mechanisms are not well understood (Nasrallah, 2008).

Prospective long-term studies in drug-naïve first episode psychosis patients could contribute towards clarifying of the link between antipsychotic therapy and metabolic side effects. There are some advantages in this study population. Firstly, there is no carry-over effect of previous treatments. Secondly, the effect of the illness on lifestyle is expected to be minimal in these early stages. Thirdly, to detect an impairment in glucose or lipid metabolism a long term follow-up is required.

In this study we examined several parameters of glucose and lipid metabolism in fasting conditions before and after the first year of exposure to antipsychotic treatment in a population of drug-naïve patients with first episode of psychosis. Secondarily, we compared the effect of three randomly assigned antipsychotic drugs (haloperidol, olanzapine and risperidone) on metabolic parameters. Finally we studied the relationship between weight gain and changes in metabolic parameters.

Section snippets

Method

This study was conducted in the outpatient and inpatient psychiatric units of Marques de Valdecilla University Hospital, located in the province of Cantabria, in the north of Spain. The hospital is a reference centre of a catchment area population of 555,000 people and provides the only psychiatric acute inpatient unit and 24 h emergency care service for the whole province. To guarantee the inclusion of all first episodes of psychosis regular meetings with all Mental Health Care services of

Enrolment and characteristics of study population

From February 2001, 225 subjects were screened. Of these, 59 were excluded for not meeting the inclusion criteria and two refused to participate in the study. A total of 164 patients were included and randomized to receive: haloperidol (52), olanzapine (54) and risperidone (58). We had a 12% dropout rate at 1 year (18 patients were lost to follow up and two patients refused to be evaluated). Finally 144 patients were included in the analysis to assess weight gain [for more details see (

Discussion

After the first year of exposure to antipsychotic treatment a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol, triglycerides and weight was found. These changes resulted clinically in a significantly higher proportion of subjects with obesity (4.3% to 22.6%) and a higher proportion of subjects with hypertriglyceridemia (4.9% to 18.3%). None of the patients developed diabetes.

The values observed in fasting

Role of funding source

The present study was performed at the Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de Salud Carlos III, FIS 00/3095 and SENY Foundation Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07.

No pharmaceutical company supplied financial support.

Contributors

All the authors have participated and have made substantial contributions to this paper:

Rocio Perez-Iglesias: design, analysis and interpretations of data and, drafting the article.

Benedicto Crespo-Facorro and Jose Luis Vazquez-Barquero: conception, design and revising.

Ignacio Mata, Obdulia Martinez-Garcia, Ana Berja, Jose Maria Pelayo-Teran: collection and interpretation of data.

Jose Antonio Amado and Maria Teresa Garcia-Unzueta: interpretation of data and revising.

They have read and approved

Conflict of interest

All authors declare they have NO conflicts of interest.

Financial disclosure

We have no affiliation or financial or other relationships with any organization or entity with a financial interest in or in financial competition with the subject matter or materials discussed in the manuscript.

Acknowledgements

We wish to thank the PAFIP researchers who helped with data collection and assistance during the investigations. In addition, we acknowledge the study participants and their families for enrolling in this study.

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