Our findings build on those from other reviews: first it is clear that there is an association between metabolic risk factors and antipsychotic use; second it seems that antipsychotic use alone is not sufficient to explain the increased metabolic risk seen in schizophrenia.
In a thorough systematic review of atypical antipsychotics and weight gain, Taylor and colleagues discussed a total of 74 papers (6 on amisulpride, 27 on clozapine, 8 on olanzapine, 7 on quetiapine, 13 on risperidone, 7 on sertindole, 3 on ziprasidone and 3 on zotepine) [Taylor and McAskill, 2000
]. They concluded that with the exception of ziprasidone, all medications have been associated with weight gain; however aripiprazole was not included in this review.
Jin and colleagues reviewed studies on the effect of atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) on glucose dysregulation [Jin et al. 2004
]. They included four extensive case series and summaries, 13 epidemiological studies from prescription and drug safety monitoring databases and 10 clinical studies on glucose intolerance and atypical antipsychotics. Despite individual differences noted among various antipsychotics, they noted that patients with known risk factors for type II diabetes mellitus, such as ethnicity, first-degree family history of diabetes mellitus and baseline obesity, appear to be at increased risk for the development of glucose dysregulation during treatment.
Meyer and Koro reviewed 48 studies and focused on the effects of FGAs and SGAs on serum lipids [Meyer and Koro, 2004
]. They stated that high-potency conventional antipsychotics (haloperidol) and some atypicals (ziprasidone, risperidone and aripiprazole) are associated with lower risk of dyslipidaemia, whilst low-potency conventional antipsychotics (chlorpromazine, thioridazine) and some other atypicals (quetiapine, olanzapine and clozapine) are related to higher risk of dyslipidaemia.
Newcomer, in a massive and comprehensive literature review, gathered data from more than 200 studies on the metabolic effects of atypical antipsychotics, with special focus on weight gain and glucose and lipid dysregulation [Newcomer, 2005
]. He extensively discussed eight antipsychotic medications, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole, and provided a detailed account of the metabolic profile of each. Clozapine and olanzapine were associated with the highest risk for causing clinically significant weight gain; risperidone, quetiapine, amisulpiride and zotepine a moderate risk; ziprasidone and aripiprazole a lower risk. He also noted that this ranking reflected the relative risk for insulin resistance, dyslipidaemia and hyperglycaemia.
In a systematic review and meta-analysis Smith and colleagues compared FGAs and SGAs with regards to their risk for type II diabetes mellitus [Smith et al. 2008
]. The atypical antipsychotics included in this review (clozapine, olanzapine, risperidone and quetiapine) appeared to have a small increased risk only for development of diabetes compared with typical antipsychotics.
Simon and colleagues attempted to investigate whether weight gain and metabolic side effects of atypical antipsychotics are dose dependent in a systematic review of 45 original articles [Simon et al. 2009
]. Among the medications included (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, sertindole, amisulpiride and aripiprazole) a dose–response relationship between serum concentrations and metabolic outcomes was suggested only for clozapine and olanzapine, although the association between daily dose and metabolic measures was not clear.
Meyer and colleagues summarized the information available about MetS in patients with schizophrenia and proposed mechanisms for the increased prevalence of MetS in this population [Meyer et al. 2005a
]. They suggested that the vulnerability to developing MetS among patients with schizophrenia derives from the concept that the phenotype of MetS resembles that of Cushing’s disease, and thus is related to an inherent dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis.
Meyer and Stahl returned with a second review in which they focused on the prevalence of MetS in schizophrenia, presenting data from the latest studies [Meyer and Stahl, 2009
]. They also attempted to address the great debate about whether the development of MetS is an environmental epiphenomenon related to health habits seen in schizophrenia, or a fundamental part of this disease. Special emphasis was placed on the importance of the fasting serum triglyceride to HDL ratio in predicting insulin resistance better than fasting serum glucose. The authors also discussed the issue of metabolic monitoring in patients with schizophrenia and made appropriate reference to a number of behavioural and pharmacological interventions. They concluded that because of lifestyle, disease and medication effects, patients with schizophrenia have significant risk for cardio-metabolic disease. They also recommended routine monitoring, preferential use of metabolically neutral antipsychotics, antidiabetic medication and lifestyle education as ways to minimize risk.
In a review of MetS and psychiatric illness, Mendelson emphasized the pathophysiological links between the development of MetS and the emergence of psychotic symptoms in schizophrenia by investigating the role of asymmetrical dimethylarginine (ADMA), homocysteine, s-adenosylmethionine (SAMe) and N-methyl-D-aspartate receptors (NMDAR) [Mendelson, 2008
]. He highlighted the presence of increased levels of ADMA as a common feature between MetS and schizophrenia. ADMA is an endogenous inhibitor of nitric oxide, which is a major intracellular mediator of NMDAR activation. Thus ADMA might contribute to decreases in NMDAR activity that, in turn, may increase the psychotic symptoms in schizophrenia.
Lindley and colleagues provided a detailed account of the insulin-resistance syndrome in schizophrenia, referring to a number of endogenous and exogenous factors [Lindley et al. 2008
]. They emphasized the strong links between insulin resistance and lifestyle characteristics (including weight, diet, exercise, energy expenditure) and discussed the role of stress and HPA axis dysregulation in antipsychotic-induced metabolic disturbances. They also noticed that significantly higher fasting glucose levels are observed in drug-naïve patients with schizophrenia, suggesting an integral role of insulin resistance in this disorder. Following this path of thought they introduced the hypothesis that insulin resistance shares genetic risk factors with schizophrenia and mood disorders.
Among the most comprehensive reviews is without doubt that of Leucht and colleagues [Leucht et al. 2007a
]. In their impressive work, the authors performed a pedantic review of 52 original articles since 1919, the majority of which describe individual features of MetS in patients with schizophrenia. This is definitely one of the most systematic attempts to present both the extent and the nature of this condition. The authors provided a detailed account of numerous estimations of the prevalence of MetS in schizophrenia, showing almost unanimously increased rates compared with the general population.
In a review, De Hert and colleagues summarized all estimates of the prevalence and incidence of MetS in schizophrenia from 2003 onwards [De Hert et al. 2009
]. They also provided suggestions for screening and monitoring of MetS in patients with schizophrenia and emphasized the importance of a multidisciplinary assessment of psychiatric and physical conditions. The authors returned in 2012 with two more meta-analyses on metabolic and cardiovascular adverse effects associated with antipsychotic drugs [De Hert et al. 2012a
]. They concluded that the potential of SGAs to induce or trigger metabolic dysregulation, including type II diabetes mellitus and MetS, is firmly established. They ranked SGAs from high to low in terms of cardiovascular adverse effects as follows: clozapine = olanzapine > quetiapine ≥ risperidone = paliperidone > amisulpride > aripiprazole ≥ ziprasidone. They noted that, for the FGAs, the low-potency agents have the highest potential and the high-potency agents the lowest potential to induce metabolic dysfunction. The risk profiles of the FGAs are comparable to those of the high- and low-risk SGAs. They also recommended regular monitoring as part of the management of patients receiving antipsychotic drugs.
The most recent meta-analyses on this topic come from Mitchell and colleagues [Mitchell et al. 2011
]. The authors provided a very comprehensive review of prevalence and predictors of MetS in adults with schizophrenia and related disorders, accounting for subgroup differences. The overall rate of MetS was calculated at 32.5% and they were only minor differences according to different definitions, treatment setting, country of origin and no appreciable differences between men and women. Older age had a modest influence on the rate of MetS, while the duration of illness had the strongest influence. Waist circumference proved to be the most useful measure in predicting high rates of MetS. The highest rates of MetS were seen in those prescribed clozapine (51.9%) and the lowest rates in those who were unmedicated (20.2%).
There was a significantly lower cardiovascular risk in early compared with chronic schizophrenia. Diabetes and prediabetes appeared uncommon in the early stages, especially in unmedicated patients.
Overall all the reviews already published agree that MetS is increasingly present in patients with schizophrenia. Most authors emphasized the importance of extrinsic factors (antipsychotic medication, increased calorie intake, sedentary lifestyle) in its development, however the concept of intrinsic factors being implicated (genetic links between schizophrenia and diabetes) is also supported.