Kristina Melkersson

Adverse metabolic effects associated with atypical antipsychotics: Literature review and clinical implications

Adverse metabolic effects, such as diabetes mellitus, lipid abnormalities and weight gain, have increasingly been recognised with the use of the newer, so-called atypical antipsychotic drugs. This article reviews the current literature in the field and attempts to answer the question of whether the atypical antipsychotics differ in their effects on glucose-insulin homeostasis and lipid metabolism. It also addresses how then to manage the use of the atypical antipsychotics that do interfere with these metabolic systems. Differences in effects of atypical antipsychotics on leptin levels are also summarised and put into context; bodyweight gain associated with atypical antipsychotics is reviewed elsewhere.In summary, there are no large controlled trials published quantifying the prevalence of adverse effects on glucose-insulin homeostasis and lipid metabolism in patients receiving atypical antipsychotics. Nevertheless, the published articles and case reports reviewed in this article give a fairly good view of those adverse effects occurring with clozapine, olanzapine and risperidone, whereas little data are available regarding quetiapine, ziprasidone and zotepine, and no data exist for amisulpride and aripiprazole. Estimated rankings of the atypical agents, based on the available literature, show that the relative risk of glucose intolerance/diabetes mellitus, hyperlipidaemia and hyperleptinaemia is highest for clozapine and olanzapine, moderately high for quetiapine, rather low for risperidone and lowest for ziprasidone. Since adverse metabolic effects of atypical antipsychotics may have a negative influence on both the antipsychotic treatment outcome as well as the physical health of the patient, these effects have to be recognised and adequately managed. In this review, recommendations for prevention and treatment of the adverse metabolic effects are outlined.

Insulin and leptin levels in patients with schizophrenia or related psychoses : a comparison between different antipsychotic agents

Abstract. Rationale: Conventional as well as newer antipsychotics cause weight gain, and, in the regulation of body weight, both insulin and leptin are hormones involved. Objective: The aim of the present study was to compare these hormonal levels in patients on treatment with different antipsychotics. Methods: Nineteen patients receiving conventional antipsychotics, 14 patients receiving clozapine and 14 patients receiving olanzapine, were studied. Fasting blood samples for insulin, leptin, glucose, and drug serum concentrations were analyzed. In addition, body mass index (BMI) was calculated. Results: The median insulin level was significantly higher in the patients receiving olanzapine than in those receiving conventional agents, whereas there was no significant difference in insulin between the clozapine and the other two groups. However, in the clozapine group, insulin levels were positively correlated to the drug serum concentration. BMI was elevated in about half of the patients, with no difference being found between the groups. The leptin level was significantly higher in the women than in the men in the conventional agent group, but not in the olanzapine or clozapine groups. Conclusions: The higher insulin level in the patients receiving olanzapine than in those receiving conventional antipsychotics, despite similar BMI, points to a probable influence of olanzapine on insulin secretion. The correlation between the insulin levels and the clozapine concentration indicates, in addition, an influence of clozapine on insulin secretion. The gender difference in leptin, i.e. females normally having higher leptin levels than males, was found in the conventional agent group, but not in the olanzapine or clozapine groups, suggesting that also leptin regulation is altered during olanzapine or clozapine treatments. Moreover, it was mainly due to an increase of leptin in the males that leptin levels were equalized between sexes in the olanzapine group. We conclude that the influence of olanzapine and clozapine on both insulin and leptin levels might be associated with their weight-gain-inducing ability, while other mechanisms may be involved in the weight gain caused by conventional antipsychotics.

Clozapine and olanzapine, but not conventional antipsychotics, increase insulin release in vitro

This study was undertaken to examine the influence of conventional and atypical antipsychotics on insulin release in vitro, using isolated pancreatic islets and insulin-secreting INS-1 cells. The effect of the conventional antipsychotics haloperidol and zuclopenthixol, and the atypical agents clozapine and olanzapine in the concentration of 10(-6) M was investigated on basal and glucose-stimulated insulin release. Both clozapine and olanzapine increased basal insulin release, whereas zuclopenthixol inhibited glucose-stimulated release and haloperidol had no significant effect. In summary, clozapine and olanzapine, in contrast to conventional antipsychotics, increase basal insulin release. Interestingly, this stimulatory effect on insulin release in vitro may be supported by recent clinical findings, showing elevated insulin levels in patients being treated with clozapine or olanzapine.

Different effects of antipsychotic drugs on insulin release in vitro

The aim of this study was to examine the influence of antipsychotic drugs on insulin release from pancreatic beta cells in vitro. The effect of seven antipsychotics (i.e. chlorpromazine, haloperidol, perphenazine, zuclopenthixol, clozapine, olanzapine and risperidone) in a concentration of 10(-6) M was investigated on basal and glucose-stimulated insulin release. Clozapine increased basal insulin release, whereas haloperidol inhibited glucose-stimulated release and the other five antipsychotics had no significant effects. A possible stimulatory effect of clozapine on insulin release may explain its ability to increase appetite and induce weight gain.

Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose–insulin homeostasis and lipid metabolism

RationaleWith the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated.ObjectiveThe aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose–insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere.MethodThe guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field.ResultsBoth conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes.ConclusionIn this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.

Serum creatine kinase levels in chronic psychosis patients--a comparison between atypical and conventional antipsychotics.

Creatine kinase is an important enzyme in the energy metabolism of many cell types, including muscle cells. Increased serum levels of creatine kinase may serve as a marker of enhanced creatine kinase synthesis in muscle cells or muscle cell membrane damage. The purpose of this study was to compare serum creatine kinase levels in chronic psychosis patients treated with either atypical or conventional antipsychotics. Forty-nine patients, receiving clozapine (n=18), or olanzapine (n=18), or conventional agents (n=13), were studied. Fasting serum samples were analyzed for creatine kinase. A significant difference in median creatine kinase level was found among the treatment groups (p=0.03), in that the creatine kinase level was higher both in the patients receiving clozapine and in the patients receiving olanzapine, compared to that in patients receiving conventional antipsychotics, p=0.001 and p<0.0001, respectively. In addition, elevated creatine kinase levels above the upper limit of normal were found in 6 (17%) of the patients treated with clozapine or olanzapine, but in none of the patients treated with conventional agents. In summary, the present results indicate that therapy with atypical antipsychotics like clozapine and olanzapine, in contrast to conventional agents, may be associated with serum creatine kinase elevation.

Familial and sporadic schizophrenia: a comparison of somatic diseases and abuse in patients and their relatives

Objective: Comparing schizophrenia patients on the basis of familial and non-familial forms of the illness provides a promising approach to the identification of genes involved in schizophrenia. The aim of this study was to search for somatic factors that discriminate between patients with and without a family history of schizophrenia and between their relatives. Methods: Ninety-five schizophrenia patients were structurally interviewed about mental and physical health and alcohol and substance use in themselves and their families. Besides this, complementary information was obtained from the patients’ case records. Patients with (41%) and without (59%) a family history were then compared. Results: The main differences were found in the patients’ relatives. Fewer patients with a family history, compared with patients without a family history, had relatives with cancer (p = 0.002). Conversely, there was a tendency towards that more patients with a family history, compared with patients without a family history, had relatives with cardiac infarction (p = 0.05). Conclusion: The genetic risk associated with schizophrenia seems to cosegregate into a factor(s) that protects against cancer and possibly also increases the risk for cardiac infarction.

2269 – Evidence for a negative association between schizophrenia and a polymorphism in the insulin receptor substrate-3 (IRS-3) gene

OBJECTIVES Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia. METHODS The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms. RESULTS The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05). CONCLUSION Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development.

PM527. Higher serum concentrations of tyrosine and glutamate in schizophrenia patients treated with clozapine, compared to in those treated with conventional antipsychotics

RATIONALE The effect of long-term treatment with the atypical antipsychotic clozapine on the serum amino acid profile in schizophrenia patients has not previously been studied. OBJECTIVES The aim of this study was to compare serum amino acid patterns in patients on long-term clozapine treatment with long-term conventional antipsychotic treatment, and their relationships to insulin resistance and antipsychotic serum concentrations. METHODS Thirty-three patients with schizophrenia or schizoaffective disorder on long-term treatment (mean 8.3 years) with clozapine (n=20) or conventional antipsychotics (n=13) were studied. Amino acids were quantified in fasting serum samples by ion exchange chromatography and markers of insulin resistance and antipsychotic drug concentrations were determined by standard methods. RESULTS Several amino acids, most notably tyrosine and glutamic acid, were elevated above the reference range in several patients receiving clozapine. Additionally, significantly higher mean values of tyrosine (1.5-fold, p=0.001), glutamic acid (2-fold, p=0.0005) and six other amino acids were observed in the clozapine group than in the conventional antipsychotic group. Several amino acids were related to insulin resistance in both treatment groups. CONCLUSIONS In this study, we show that serum tyrosine and glutamic acid concentrations are markedly elevated in patients on long-term clozapine treatment, compared to patients on long-term conventional antipsychotic treatment. These findings are of importance since these two amino acids have been implicated in the pathophysiology of schizophrenia.

Introduction: Clinical findings related to alterations of the intracellular calcium homeostasis in schizophrenia

It is well established that calcium plays an important role in the regulation of neurotransmitters and hormones in the central nervous system (CNS) and peripherally (Rubin, 1970). For some years, clinical findings regarding schizophrenia and calcium dysregulation in the CNS have also been reported. Therefore, this special issue consisting of three sections – this introduction and two review articles – is dedicated to examining present clinical, in vitro and genetic data in the field “Intracellular calcium homeostasis in schizophrenia”. The first main clinical finding regarding schizophrenia and calcium dysregulationwas published by Jimerson et al. (1979), who reported that calcium levels in cerebrospinal fluid (CSF) increased following remission of acute psychotic symptoms in schizophrenia and schizoaffective disorder patients. Since physiological studies indicate that calcium concentration in lumbar CSF may accurately reflect ventricular levels in man (Hunter and Smith, 1960) and that total calciumconcentration in the CSF is relatively stable even in the case of large acute changes in plasma levels (Davson, 1967), this clinical finding suggests a possible connection betweencalciumdysregulation in theCNSand the acute psychotic state of schizophrenia and related psychotic disorders. Another more recent clinical finding, also linking schizophrenia with calcium dysregulation in the CNS, is the elevation of the calcium ion (Ca)-binding S100B protein observed in CSF and serum of both never-medicated and medicated schizophrenia patients, but with the most pronounced elevations found in the acute stage of the psychotic disorder (Rothermundt et al., 2001, 2004a,b; Schroeter et al., 2009; Zhang et al., 2010). The S100B protein is found primarily in the CNS, in astrocytes, but also in other cell types such as oligodendrocytes and