Clinical and Social Psychiatry Research Unit, Department of Psychiatry, University Hospital Marqués de Valdecilla, Santander, Spain
Department of Endocrinology, University Hospital Marqués de Valdecilla, Santander, Spain
Department of Biochemistry, University Hospital Marqués de Valdecilla, Santander, Spain
Clinical and Social Psychiatry Research Unit, Department of Psychiatry, University Hospital Marqués de Valdecilla, Santander, Spain
Correspondence: Andrés Herrán, Clinical and Social Psychiatry Research Unit, Department of Psychiatry, University Hospital Marqués de Valdecilla, Avda. de Valdecilla s/n, 39008 Santander, Spain. Tel: 34 942 202545; Fax: 34 942 203447; e-mail: herran{at}humv.es
Declaration of interest This study was supported by a grant from the Fundación Marqués de Valdecilla, 1996.
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ABSTRACT |
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Aims To study the effects of long-term antipsychotic treatment on leptin levels in patients with schizophrenia.
Method Serum leptin levels were determined in 59 out-patients with chronic schizophrenia and in the same number of healthy subjects controlled by gender, age and body mass index.
Results Leptin levels did not differ between patients and controls. Leptin levels in patients with schizophrenia correlated with weight gain, even after controlling for current weight, but did not show any association with clinical variables. Antipsychotic class tended to exert different effects over leptin levels (among atypicals, olanzapine induced a greater increase).
Conclusions Elevation of leptin levels induced by chronic antipsychotic treatment can be attributed to weight gain, but other mechanisms could be involved.
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INTRODUCTION |
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METHOD |
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Fifty-nine healthy subjects without current or past psychiatric disorder and controlled by gender and age were selected as controls. In addition, they were matched by the current body mass index (BMI) of the patients. Exclusionary criteria were the same as for patients. Neither patients nor controls had alimentary restriction or evidence of clinical malnutrition. After a complete description of the study, all patients and healthy controls gave informed consent to participate in the investigation.
Clinical data were obtained from the patients and blood samples were obtained from patients and controls.
Clinical measures
Demographic, social and medical antecedent variables were assessed using a
specifically created questionnaire. Clinical information included DSM-IV
schizophrenia subtype and the Spanish version of the Positive and Negative
Syndrome Scale (PANSS; Peralta &
Cuesta, 1994; for English version see
Kay et al, 1987).
Additional data regarding clinical evolution and treatment were derived from
the clinical records.
Chlorpromazine equivalents were calculated according to commonly used equivalent doses (American Psychiatric Association, 1997). All patients had been on treatment with their current antipsychotic for at least 6 months. Patients (n=5) on treatment with fluphenazine depot and another antipsychotic drug were considered as taking only phenothiazines. Four patients were treated exclusively with behavioural psychotherapy and were not taking antipsychotic medication.
Height and weight were assessed immediately before blood sample extraction. For patients, weight at the onset of the illness was derived from clinical records. The BMI was expressed in kg/m2.
Serum measures
Fasting blood samples were withdrawn from an antecubital vein between 08.00
and 09.00 h. Samples were centrifuged immediately and serum was stored at
-40°C until assayed. Samples were obtained simultaneously for patients and
controls within a 6-month period to avoid seasonality.
Serum leptin levels were determined by radioimmunoassay (RIA) from Linco (Linco Research Inc., St Charles, MO, USA). Precisions within and between assay variation were 4.9 and 4.5%, respectively. Normal values are: < 10 ng/ml for males and < 20 ng/ml for females, with BMI <25 kg/m2.
Analysis
Data were analysed with the Statistical Package for the Social Sciences
(SPSS) version 8.0. Given the skewed distribution of leptin levels, a base-10
logarithm transformation was used for analysis. Comparisons between
schizophrenia and control groups were made by t-test. Group mean
differences among schizophrenia subtypes (clinical, treatment) were checked by
means of t-test or analysis of variance (ANOVA). The General Linear
Model (Factorial) command of the SPSS was used when controlling for
covariates. For the relationship between leptin levels, weight and BMI,
Pearson's correlation was used (and partial correlation when controlling for
the effects of other additional variables). For the relationship with clinical
(ordinal) variables, Spearman's correlation was used.
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RESULTS |
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Sample description
The sample consisted of patients with chronic schizophrenia, with a mean of
13.7 years of evolution of the illness (s.d.=11.1). There was a predominance
of patients with residual schizophrenia. Clinical subtypes were as follows:
paranoid, 19 (32.3%); disorganised, 7 (11.9%); undifferentiated, 9 (15.5%);
and residual schizophrenia, 24 (40.7%). Mean scores on the PANSS scale reflect
a moderate severity of the illness and a predominance of negative symptoms.
Mean scores were: positive sub-scale, 10.9 (s.d.=4.9); negative sub-scale,
17.6 (s.d.=7.3); general sub-scale, 27.4 (s.d.=9.9); and total PANSS score,
55.8 (s.d.=18.3). Mean weight gain in patients since the onset of the illness
was 10.6 kg (s.d.=9.3) and mean BMI gain was 3.8 kg/m2
(s.d.=3.3).
Mean antipsychotic dose (as chlorpromazine equivalents) was 317.8 mg/day (s.d.=206.8). Seventeen patients (30.9% of those taking antipsychotic treatment) were taking long-acting depot neuroleptics and the same number of patients were on atypical antipsychotics. Twenty-six patients were on treatment with phenothiazines (perphenazine, fluphenazine, trifluoperazine), eight with haloperidol, two with zuclopenthixol, one with loxapine, one with pimozide, five with risperidone, five with clozapine and seven with olanzapine. Some of the patients also received benzodiazepines and/or anticholinergic drugs, but none received antidepressants or mood stabilisers.
Serum leptin levels
Serum leptin levels did not differ significantly between patients and
controls, either in the total sample (t=0.150; d.f.=116;
P=0.8) or when they were compared by gender. Levels were higher in
females than in males, both in patients (t=-5.602; d.f.=57;
P=0.000) and control groups (t=-5.968; d.f.=57;
P=0.000) (Table 1). The BMI did not differ significantly between male and female groups. Age did
not correlate with leptin levels.
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Relationships between leptin levels and weight, BMI, gain in weight and gain in BMI are shown in Table 2. In both patients and controls, leptin showed a strong correlation with BMI, and in the case of patients leptin also correlated with weight gain and BMI gain. Because weight gain correlated strongly with current weight (r=0.740; P=0.000) and BMI gain correlated with current BMI (r=0.767; P=0.000), the effects of weight and BMI gain were controlled for current weight and BMI. Leptin levels in patients with schizophrenia correlated significantly with weight gain and showed a trend for an association with BMI gain.
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Neither clinical variables (age at the onset of the illness, years of evolution, PANSS scores) nor schizophrenia subtype (F=0.048; d.f.=3; P=0.9) exerted any effect over leptin levels. Also, antipsychotic dosage and method of treatment (oral v. depot) did not show any association with leptin levels. Patients on typical antipsychotic treatment did not differ from those on atypical drugs (clozapine, olanzapine, risperidone) (t=-0.572; d.f.=53; P=0.5). Serum leptin levels, weight and BMI according to antipsychotic class are shown in Table 3. Patients taking clozapine and olanzapine tended to show a higher BMI than patients taking other antipsychotic drugs.
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Serum leptin levels did not differ among patients taking different antipsychotics when controlling for current BMI. When comparing patients taking atypical drugs (clozapine, olanzapine, risperidone) the differences in leptin levels were significant (F=4.442; d.f.=2; P=0.03). Patients on treatment with olanzapine had the highest leptin levels, patients on risperidone had the lowest and patients taking clozapine had intermediate values. The difference in leptin levels between patients taking olanzapine and risperidone remained at the limit of statistical significance, even after controlling for BMI (F=4.877; d.f.=1; P=0.05).
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DISCUSSION |
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The present study focused on the relationship between leptin levels and psychopathology, the effects of chronic treatment with antipsychotic drugs on weight and serum leptin levels and the differential effects of antipsychotic subgroups (particularly the newer atypical ones) over this hormone. The main findings were: serum leptin levels do not differ between patients with schizophrenia taking chronic antipsychotic medication and healthy subjects controlled by gender, age and BMI; leptin levels in patients with schizophrenia correlated with weight gain; leptin levels did not show any association with clinical variables; and among atypical antipsychotics olanzapine appeared to induce a greater increase in leptin independently of weight gain.
There are a number of limitations to the present study. First, given the transverse design of the study, we must be cautious with the conclusions: correlation does not imply causal association. In addition, we cannot exclude a number of confounding factors, such as other pharmacological treatments (anticholinergic drugs, etc.), and we did not assess the patients' eating behaviour. Additionally, there was a limited number of patients in each group (clinical and treatment groups).
Weight gain
As has been stated (Wirshing et
al, 1999), the antipsychotics clozapine and olanzapine caused
the most weight gain. In our sample, patients taking these drugs tended to
show higher BMI. Weight gain and BMI gain were also higher for patients on
these drugs, but without statistical significance, probably owing to the small
size of the sample. It is atypical in this sample that the group of patients
on risperidone had gained less weight than those on haloperidol and
phenothiazines, because previous trials have shown the opposite findings
(Allison et al, 1999;
Wirshing et al,
1999). This could be attributed to the low number of patients in
each group, or it could be that the patients have not been on risperidone long
enough for their weight to have increased.
Although there are reports suggesting a link between body weight gain and clinical efficacy of antipsychotics (Jalenques et al, 1996), some authors do not agree with this hypothesis (Baptista, 1999). On the other hand, it has been suggested that leptin could exert central nervous system effects involved in the beneficial effect of antipsychotics (Kraus et al, 1999). This particular issue has not been analysed, but our results suggest that it is unlikely. Leptin levels were not associated with any clinical variable included in the present study, and given the chronic nature of the sample it would be expected that, if leptin were associated with the beneficial effect of antipsychotics, it would be correlated with clinical measures.
Leptin and antipsychotic treatment
Leptin levels did not differ between patients and healthy subjects matched
by BMI. At least two studies have analysed the behaviour of leptin over
short-term antipsychotic treatment. Brömel
et al (1998) found
that leptin increased in a 10-week period of treatment with clozapine. Kraus
et al (1999) found an
increase in leptin levels in patients taking clozapine or olanzapine over 4
weeks, but not in patients taking haloperidol. Both groups suggested that the
most probable reasons for these increases in leptin levels were overeating and
weight gain, which induce increased leptin secretion. Our results of unchanged
levels in a sample of long-term treated patients compared with BMI-matched
controls support this hypothesis. However, the difference in leptin levels
between patients on olanzapine and those on risperidone is intriguing. Perhaps
most of the effect of antipsychotics on leptin levels could be attributed to
weight gain, but other mechanisms could be involved. Leptin is known to be
affected by several neurotransmitters, such as histamine
(Morimoto et al,
1999) and serotonin (Yamada
et al, 1999). The serotonin reuptake inhibitor fluoxetine
decreased plasma leptin levels in rats
(Dryden et al, 1999).
It is possible that, given the different pharmacological profile of
antipsychotics (including the atypical ones) over these receptors
(Moore, 1999), diverse drugs
could exert differential effects over leptin levels irrespective of induced
weight gain. This could support the hypothesis of Baptista
(1999) regarding different ways
in which antipsychotics induce weight gain: olanzapine, for example, could
exert some direct effect over leptin. None the less, given that the main
finding of the present study is that the leptin levels are raised in
association with body weight, we must keep in mind the limitations discussed
about the weight gain of patients on risperidone (low number of patients, not
sufficiently long taking this drug). Prospective studies with larger samples
are necessary to elucidate these issues.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA.
American Psychiatric Association (1997) Practice guideline for the treatment of patients with schizophrenia. American Journal of Psychiatry, 154, 10.
Baptista, T. (1999) Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatrica Scandinavica, 100, 3-16.[Medline]
Brömel, T., Blum, W. F., Ziegler, A., et al (1998) Serum leptin levels increase rapidly after initiation of clozapine therapy. Molecular Psychiatry, 3, 76-80.[CrossRef][Medline]
Dryden, S., Brown, M., King, P., et al (1999) Decreased plasma leptin levels in lean and obese Zucker rats after treatment with the serotonin reuptake inhibitor fluoxetine. Hormone Metabolism and Research, 31, 363-366.
Friedman, J. M. & Halaas, J. L. (1998) Leptin and the regulation of body weight in mammals. Nature, 395, 763-770.[CrossRef][Medline]
Ganguli, R. (1999) Weight gain associated with antipsychotic drugs. Journal of Clinical Psychiatry, 60 (suppl. 21), 20-24.
Herrán, A., García-Unzueta, M. T., Amado, J. A., et al (1999) Folate levels in psychiatric outpatients. Psychiatry and Clinical Neurosciences, 53, 531-534.[CrossRef][Medline]
Herrán, A., de Santiago, A., Sandoya, M., et al (2000a) Determinants of smoking behaviour in outpatients with schizophrenia. Schizophrenia Research, 41, 373-381.[CrossRef][Medline]
Herrán, A., García-Unzueta, M. T., Fernández-González, M. D. et al (2000b) Higher levels of serum copper in schizophrenic patients treated with depot neuroleptics. Psychiatry Research, 94, 51-58.[CrossRef][Medline]
Jalenques, Y., Tauveron, Y., Albuisson, E., et al (1996) Weight gain as a predictor of long-term clozapine efficacy. CNS Drugs, 12, 16-25.
Kay, S. R., Fiszbein, A. & Opler, L. A. (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261-276.[Medline]
Kraus, T., Haack, M., Schuld, A., et al
(1999) Body weight and leptin plasma levels during treatment
with antipsychotic drugs. American Journal of
Psychiatry, 156,
312-314.
Moore, N. A. (1999) Behavioural pharmacology of the new generation of antipsychotic agents. British Journal of Psychiatry, 174 (suppl. 38), 5-11.
Morimoto, T., Yamamoto, Y., Mobarakeh, J. I., et al (1999) Involvement of the histaminergic system in leptin-induced suppression of food intake. Physiology and Behavior, 67, 679-683.[Medline]
Peralta, V. & Cuesta, M. J. (1994) Validación de la Escala de los Síndromes Positivo y Negativo (PANSS) en una muestra de esquizofrénicos españoles. Actas Luso-Españolas de Neurología, Psiquiatría y Ciencias Afines, 22, 171-177.[Medline]
Vázquez-Barquero, J. L., Gaite, L., Artal, J., et al (1994) Desarrollo y Verificación de la Versión Española de la Entrevista Psiquiátrica "Sistema SCAN" (Cuestionarios para la Evaluación Clínica en Neuropsiquiatría). Actas Luso-Españolas de Neurología, Psiquiatría y Ciencias Afines, 22, 109-120.[Medline]
Wing, J. K., Babor, T., Brugha, T., et al (1990) SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Archives of General Psychiatry, 47, 589-593.[Abstract]
Wirshing, D. A., Wirshing, W. C., Kysar, L., et al (1999) Novel antipsychotics: comparison of weight gain liabilities. Journal of Clinical Psychiatry, 60, 358-363.[Medline]
Yamada, J., Sugimoto, Y. & Ujikawa, M. (1999) The serotonin precursor 5-hydroxytryptophan elevates serum leptin levels in mice. European Journal of Pharmacology, 383, 49-51.[CrossRef][Medline]
Yanovski, J. A. & Yanovski, S. Z. (1999)
Recent advances in basic obesity research. Journal of the American
Medical Association, 282,
1504-1506.
Zhang, Y., Proenca, R., Maffei, M., et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature, 372, 425-432.[CrossRef][Medline]
Received for publication May 9, 2000. Revision received January 29, 2001. Accepted for publication January 31, 2001.