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Metabolic syndrome and schizophrenia

  • Jogin H. Thakore (a1)

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Metabolic syndrome – a cluster of disorders comprising obesity (central and abdominal), dyslipidaemias, glucose intolerance, insulin resistance (or hyperinsulinaemia) and hypertension – is highly predictive of type 2 diabetes mellitus and cardiovascular disease. In order to improve detection of this syndrome and estimate its prevalence, both the World Health Organization (Alberti & Zimmet, 1998) and the National Cholesterol Education Program Adult Treatment Panel (National Cholesterol Education Program, 2001) have provided working criteria for its diagnosis (the World Health Organization criteria are reproduced in an appendix to this paper; copyright restrictions prevent the inclusion here of the National Cholesterol Education Program criteria). Using the latter criteria, Heiskanen et al (2003) found that the frequency of metabolic syndrome was 2–4 times higher in a group of people with schizophrenia, treated with both atypical and typical neuroleptics, than in an appropriate reference population.

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References

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Alberti, K. G. & Zimmet, P. Z. (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus, provisional report of a WHO commission. Diabetic Medicine, 15, 539553.
American Diabetic Association (2004) Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care, 27, 596601.
Heiskanen, T., Niskanen, L., Lyytikainen, R., et al (2003) Metabolic syndrome in patients with schizophrenia. Journal of Clinical Psychiatry, 64, 575579.
Hellewell, J. S. (1999) Treatment-resistant schizophrenia: reviewing the options and identifying the way forward. Journal of Clinical Psychiatry, 60 (suppl. 23), 1419.
Holsboer, F. (1998) The endocrinology of mental disease. In Clinical Endocrinology (ed. Grossman, A.), pp. 10961116. Oxford: Blackwell Science.
Lieberman, J., Phillips, M., Gu, H., et al (2003) Atypical and conventional antipsychotic drugs in treatment-naive first episode schizophrenia: a 52 week randomized trial of clozapine vs. chlorpromazine. Neuropsychopharmacology, 28, 991003.
Mukherjee, S., Schnur, D. B. & Reddy, R. (1989) Family history of type 2 diabetes in schizophrenic patients (letter). Lancet, i, 495.
National Cholesterol Education Program (2001) Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 258, 24862497.
Ryan, M. C. M., Collins, P. & Thakore, J. H. (2003) Impaired fasting glucose and elevation of cortisol in drug-naive first-episode schizophrenia. American Journal of Psychiatry, 160, 284289.
Ryan, M. C. M., Flanagan, S., Kinsella, U., et al (2004a) Atypical antipsychotics and visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sciences, 74, 19992008.
Ryan, M. C. M., Sharifi, N., Condi en, R., et al (2004b) Evidence of basal pituitary–adrenal overactivity in first episode, drug naive patients with schizophrenia. Psychoneuroendocrinology, 29, 10651070.
Thakore, J. H. (ed.) (2001) Physical Consequences of Depression. Cambridge: Wrightson.
Thakore, J. H., Vlahoos, J., Martin, A., et al (2002) Increased visceral fat distribution in drug-naïve and drug-free patients with schizophrenia. International Journal of Obesity Related Metabolic Disorders, 26, 137141.
Zhang, Z.-J., Yao, Z.-J., Liu, W., et al (2004) Effects of antipsychotics on fat deposition and changes in leptin and insulin levels: magnetic resonance imaging study of previously untreated people with schizophrenia. British Journal of Psychiatry, 184, 5862.

Metabolic syndrome and schizophrenia

  • Jogin H. Thakore (a1)

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Metabolic syndrome and schizophrenia

  • Jogin H. Thakore (a1)
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eLetters

Re: Antipsychotics and diabetes

Jogin H Thakore, Psychiatrist
25 August 2005

I am grateful to Valeria Frighi for suporting the notion of improvingclinical care of the seriously mentally ill (SMI). However, her assertion that I have wrongly quoted 2 papers in the editorial deserve comment. Firstly, the study by Zhang et al (2004) showed increases in 'non-fasting glucose', this is not a standardized measure and therefore reporting it is meaningless. It is certainly not a 2 hr post-prandial glucose that one might measure as part of an oral

glucose tolerance test. Furthermore, Lieberman et al (2003) did not find a

statistically significant increase in glucose at either 12 or 52 weeks post randomization though plasma levels of glucose did increase.

The discrepancy between our findings and those of study by Arranz et al (2004) clearly show that using fasting glucose as a sole means of diagnosing type 2 diabetes may lead to high false negative rates.

Lastly, I am not suggesting that antipsychotics do not play a part inthe evolution of type 2 diabetes in schizophrenia. I am trying to determine what the magnitude of their effects might be so as to restore balance to this critical issue and ensure that all patients with SMI have a full physical screen soas to reduce and perhaps, prevent the onset of diabetes and cardiovascular disease.

1) Ryan, M.C.M., Collins, P. & Thakore, J.H. (2003). Impaired fasting glucose and elevation of cortisol in drug-naïve first-episode schizophrenia. American Journal of Psychiatry, 160, 284-289.

2) Arranz, B., Rosel, P., Ramirez, N., et al (2004) Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but

not in antipsychotic-naive first-episode schizophrenia patients. Journal of Clinical Psychiatry 65, 1335-1342.

3) Zhang, Z.J., Yao, Z.J., Liu, W., et al (2004) Assessment of fat distribution by MRI and changes in leptin and insulin following antipsychotic treatment of

drug-naïve schizophrenic patients. British Journal of Psychiatry 184, 58-62.

4) Lieberman, J., Phillips, M., Gu, H. et al. (2003). Atypical and conventional antipsychotic drugs in treatment-naïve first-episode schizophrenia: a 52 week randomized trial of clozapine vs. chlorpromazine. Neuropsychopharmacology 28, 999-1003
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Conflict of interest: None Declared

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Metabolic syndrome and schizophrenia

Gavin P. Reynolds, Professor of Neuroscience
25 August 2005

In his recent editorial, Thakore (2005) rightly draws attention to the importance of the association of the metabolic syndrome and one of itsconsequences, type 2 diabetes, with schizophrenia. Despite acknowledging that antipsychotic drugs can induce substantial weight gain, he avoids ascribing the metabolic disturbances in schizophrenia to drug-induced obesity. His suggestion that untreated schizophrenia is itself associatedwith metabolic disturbance is based on a study of 19 subjects who had substantially greater deposits of intra-abdominal fat than a control group(Ryan et al, 2004). This contrasts with other studies investigating antipsychotic-naive subjects with schizophrenia in which 40 patients showed no elevation over controls in intra-abdominal fat (Zhang et al, 2004), and 50 patients who did not differ from a control group in terms ofbody-mass index, fasting plasma glucose or insulin (Arranz et al, 2004). In attempting to explain discrepancies in terms of methodological differences, Thakore is wrong to state that our control group consisted of“elderly men”; controls were “well matched for age and gender with the patient group” (Zhang et al, 2004).

These larger studies also show antipsychotic drug treatment is associated with increased intra-abdominal fat (Zhang et al, 2004) and insulin resistance (Arranz et al, 2004), despite negative findings from Ryan et al (2004). The risk of diabetes in schizophrenia is higher in patients receiving olanzapine than conventional antipsychotics (Koro et al, 2002); olanzapine is particularly liable to induce weight gain. Theseand other studies indicate that antipsychotic drug treatment can result inmetabolic morbidity. It would thus be misleading, if not dangerous, to imply that obesity resulting from treatment with some antipsychotic drugs is unusually free of an association with the development of the metabolic syndrome and type 2 diabetes.

Thakore listed criteria for the metabolic syndrome; these have now been superseded by a more clinically accessible and less stringent definition. The core criterion is central (abdominal) obesity defined on the basis of waist circumference, plus two of four risk factors based on elevated triglycerides, reduced HDL cholesterol, raised blood pressure andraised fasting plasma glucose (International Diabetes Federation, 2005).

Arranz, B., Rosel, P., Ramirez, N., et al (2004) Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patientsbut not in antipsychotic-naive first-episode schizophrenia patients. Journal of Clinical Psychiatry 65, 1335-1342.

International Diabetes Federation (IDF) (2005) The IDF consensus worldwide definition of the metabolic syndrome. Brussels,Belgium: IDF http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf

Koro, C.E., Fedder, D.O., L’Italien, G.J. et al (2002) Assessment of independent effect of olanzapine and risperidone on risk of diabetes amongpatients with schizophrenia: population based nested case-control study. British Medical Journal 325, 243-247.

Ryan, M.C.M., Flanagan, S., Kinsella, U., et al (2004) Atypical antipsychotics and visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sciences, 74, 1999-2008.

Thakore, J.H. (2005) Metabolic syndrome and schizophrenia. British Journal of Psychiatry 186, 435-436.

Zhang, Z.J., Yao, Z.J., Liu, W., et al (2004) Assessment of fat distribution by MRI and changes in leptin and insulin following antipsychotic treatment of drug-naïve schizophrenic patients. British Journal of Psychiatry 184, 58-62.

Declaration of interest:

GPR has received research support and honoraria from Bristol-Myers Squibb and Janssen-Cilag.
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Conflict of interest: None Declared

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Antipsychotics and diabetes

Valeria Frighi, MD
19 August 2005

The benefits of drawing clinicians’ attention to the metabolic syndrome could be lost to the editorial’s premature conclusion that the higher rates of type 2 diabetes found in schizophrenia might be a function of the illness itself (1).

This view is inadequately supported as hyperglycaemia in severe mental illness was documented in the pre-antipsychotic era by methods which would be generally considered insufficiently robust according to today’s standards. Furthermore, the conclusions of the cited study on 26 first episode, drug-naïve patients with schizophrenia (2) were not confirmed by the only other published study of the kind, which showed no difference in fasting plasma glucose between 50 drug-naive first episode schizophrenic patients, 50 long term non compliant schizophrenic patients and 50 control subjects (3).

The editorial mentions two studies on previously untreated schizophrenic patients to cast doubts on the causal association between antipsychotics and diabetes in schizophrenia. However, the first study (4) showed a clinically and statistically significant increase in post-prandial glucose after 10 weeks treatment with chlorpromazine or risperidone, although the editorial only mentions the lack of change in fasting glucose. The second (5) was wrongly quoted as not showing a significant change after 52 weeks treatment with either clozapine or chlorpromazine. What the study actually showed was a gradual, sustained, clinically important increase in mean fasting glucose from randomization, when it was normal, to 12 and 52 weeks and that glucose levels were similar in the clozapine and the chlorpromazine treated patients.

Given the contradictions of available data, a link between diabetes and schizophrenia independently of drug exposure needs to be confirmed by further studies.

On the other hand, hyperglycaemia, in adults and children, has been proven beyond reasonable doubt to be a side effect of both atypical and conventional antipsychotics by a large body of evidence accumulated since the introduction of chlorpromazine over 50 years ago.

Attributing the metabolic abnormalities of schizophrenia to attractive but yet unproven causes rather than to the well known albeit poorly understood actions of antipsychotics could delay instead of promoting the long overdue improvements in clinical care that Jogin Thakore rightly wishes to foster.

1)Thakore, J.H. (2005) Metabolic syndrome and schizophrenia. British Journal of Psychiatry 186, 455-456.

2) Ryan, M.C.M., Collins, P. & Thakore, J.H. (2003). Impaired fasting glucose tolerance in first-episode,drug-naïve patients with schizophrenia. American Journal of Psychiatry, 160, 284-289.

3) Arranz, B., Rosel, P., Ramirez, N., et al (2004) Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patients. Journal of Clinical Psychiatry, 65, 1335-1342.

4) Zhang, Z.J., Yao, Z.J., Liu, W., et al (2004) Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia. British Journal of Psychiatry, 184, 58-62.

5) Lieberman, J., Phillips, M., Gu, H. et al. (2003). Atypical and conventional antipsychotic drugs in treatment-naïve first-episode schizophrenia: a 52 week randomized trial of clozapine vs. chlorpromazine. Neuropsychopharmacology, 28, 995-1003.

Declaration of interest: none
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Conflict of interest: None Declared

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