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Schizophrenia and diabetes R. I. G. Holt et al. Schizophrenia, the metabolic syndrome and diabetes
R. I. G. Holt*, R. C. Peveler† and C. D. Byrne* Abstract
*Endocrinology & Metabolism Sub-division, Fetal The prevalence of diabetes is increased in patients with schizophrenia. Although Origins of Adult Disease Division and †Community many reasons, including hereditary and lifestyle factors, contribute to this Clinical Sciences Division, School of Medicine, association, recently there has been heightened interest in the subject because of University of Southampton, Southampton, UK the link between the use of the newer atypical anti-psychotic drugs and the development of diabetes. These drugs cause significant weight gain and this maybe one of the mechanisms by which they increase incident diabetes. The in-creased prevalence of diabetes among people with schizophrenia has implica-tions for the delivery of care by psychiatrists, diabetologists and primary care.
Keywords
atypical anti-psychotic drugs, delivery of care, diabetes, insulin names. This search yielded 289 abstracts which were read and Introduction
relevant papers obtained. Further articles were found through Schizophrenia is a neurodevelopmental disorder, which affects hand searches of the reference lists contained within these 1.4 – 4.6 per 1000 of the general population, has an incidence rate of 0.16 – 0.42 per 1000 population and is associated withexcess mortality [1]. Although the rate of suicide and accidents The prevalence of diabetes in schizophrenia
in schizophrenia is increased, the shortened life expectancycannot be fully attributed to social and behavioural causes.
The association between diabetes and schizophrenia has been Epidemiological studies show an association between schizo- recognized for over a century. In 1879, Sir Henry Maudsley in phrenia and an increased prevalence of Type 2 diabetes and ‘The Pathology of Mind’ commented that, ‘Diabetes is a disease cardiovascular vascular disease (CVD). The newer atypical which often shows itself in families in which insanity pre- anti-psychotic drugs are associated with significant weight vails’. More recent studies have shown that the prevalence of gain that may increase further the incidence of diabetes impaired glucose tolerance and diabetes is increased 2–3-fold in individuals with schizophrenia (Table 2) [3–11].
This review article will discuss the evidence for an increased prevalence of Type 2 diabetes in patients with schizophrenia The metabolic syndrome in schizophrenia
and will discuss the putative underlying mechanisms. We willalso discuss the clinical implications of these findings for those The metabolic syndrome is a cluster of cardiovascular risk fac- specializing in psychiatry and diabetes. The data for this tors including insulin resistance, hypertension, central obesity, review reflect our own clinical and academic interests and dyslipidaemia and glucose intolerance [12]. A few recent stud- experience. We have also undertaken an electronic search of ies indicate that the prevalence of the metabolic syndrome the PubMed and MEDLINE databases using the key words is increased in people with schizophrenia (Table 2) and this ‘diabetes’ or ‘metabolic syndrome’ with ‘schizophrenia’, ‘anti- may provide an explanation for the increased prevalence of psychotic drug’ and each of the individual anti-psychotic drug diabetes and CVD in schizophrenia [13,14]. Furthermore,there is an increase in the prevalence of some of the individualfeatures of the metabolic syndrome but not others. For Correspondence to: Dr R I G Holt, Level F, Centre Block, MP 113, Southampton example, there is little evidence to suggest that the prevalence General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail: righ@soton.ac.uk of hypertension is increased in schizophrenia [15].
2004 Diabetes UK. Diabetic Medicine, 21, 515– 523
Schizophrenia and diabetes • R. I. G. Holt et al. Table 1 Characteristics of ‘atypical’ anti-psychotic drugs in common use
Table 2 Studies examining the prevalence of diabetes (a) and the metabolic syndrome (b) in patients with schizophrenia
(a)
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Table 2 Continued
OGTT, oral glucose tolerance test; DM, diabetes mellitus; IGT, impaired glucose tolerance; IFG, impaired fasting glycaemia; FBG, fasting blood glucose; WHO, World Health Organization; NCEP, National Education Cholesterol Programme; OP, out-patient; IP, in-patient.
effect because HDL-cholesterol fell by 24% within 1 week of Insulin resistance
starting drug therapy. Drug therapy did not affect serum total Although it has been known since 1922 that schizophrenia is cholesterol or triglyceride concentrations [27].
associated with impaired insulin action [16], there have beenfew detailed studies examining insulin resistance in schiz- Platelet function
ophrenia using gold standard methodology. Most of these stud-ies have been uncontrolled, have involved few subjects and Several but not all studies point to an abnormality in platelet have not taken into account confounding factors such as dis- aggregation in subjects with schizophrenia [28 –31]. Platelet ease severity and drug therapy [17,18]. More recently, a small aggregation in response to collagen and arachidonic acid is cross-sectional study of first-episode, drug-naïve patients with enhanced while there is a diminished inhibitory effect of schizophrenia has shown that 15% of the patients with schiz- prostaglandin E1. There is also up-regulation of the integrin ophrenia had impaired fasting glycaemia and were more insu- α(IIb)β(IIIa) receptor, which may contribute to increased platelet lin resistant than healthy controls [8]. Furthermore, a study of 39 non-diabetic patients with acute psychosis demonstratedan inverse correlation between the clinical global impression The mechanisms underlying the increased
score, a measure of psychological stress, and insulin sensitivity prevalence of diabetes
and β-cell function. Both insulin sensitivity and β-cell functionimproved following treatment of the mental state [19].
The mechanisms that underlie the increased prevalence ofdiabetes in schizophrenia include hereditary and environmen-tal factors, such as less healthy lifestyles and poorer health Body composition
care, as well as side-effects of anti-psychotic medication Individuals with schizophrenia are more likely to have obese parents [20], but obesity is not more common in schizophrenia[21–24]; at least one study has shown that elderly patientsweigh less than healthy controls [25]. However, there are dif-ferences in body composition between patients with schizo-phrenia and healthy controls. When assessed by CT scanningand anthropometry, drug-naïve and drug-free schizophrenicpatients were found to have significantly higher waist to hipratios, and over three times as much visceral fat [26].
Lipid profile
The lipid profile in first-episode, drug-naïve patients withschizophrenia was found to be more favourable than in healthycontrols [8], but in contrast high density lipoprotein (HDL)cholesterol levels are decreased and triglycerides are increasedin chronic schizophrenic patients treated with phenothiazines[27]. Some of this difference may be explained by a treatment Figure 1 Mechanisms linking diabetes with schizophrenia.
2004 Diabetes UK. Diabetic Medicine, 21, 515– 523
Schizophrenia and diabetes • R. I. G. Holt et al. from 4.2% in 1956 to 17.2% in 1968 and the term ‘phenothia- Hereditary factors
zine diabetes’ appeared in the literature [46]. Several more Up to 30% of people with schizophrenia have a family history recent studies have confirmed that the use of any anti-psychotic of Type 2 diabetes [33]. Genetic factors appear at least as drug is associated with an increase in newly diagnosed diabetes important in the aetiology of schizophrenia as diabetes and hypertension [34] and studies to map diabetes and schizophrenia Interest in the link between atypical anti-psychotic drugs genes are on-going. There is strong evidence that gene regions and glucose metabolism began with case reports of clozapine- and on 6p and 8p contain schizophrenia susceptibility genes, while olanzapine-treated patients who developed diabetic ketoaci- regions on 6q, 13q and 22q are also being studied [35]. As dosis. Although these patients may represent a different popu- there is some overlap with the chromosomal regions that have lation from those at increased risk of Type 2 diabetes, they been linked to Type 2 diabetes [36], it is possible that there are form an important group because of the mortality associated areas of linkage disequilibrium that may predispose to both with diabetic ketoacidosis and because the diabetes may resolve after the discontinuation of the drugs [52,53].
A further intriguing possible mechanism linking diabetes Drug safety studies then detected a signal that abnormal and schizophrenia is the effect of the intrauterine environment glucose regulation and Type 2 diabetes is associated with creating a ‘common soil’ effect. There are now over 38 reports clozapine, olanzapine and risperidone [54] but the absolute linking poor fetal growth with impaired glucose metabolism in rate was low [55]. In the latter study of 8858 patients receiving later life [37]. Most of these studies report an inverse relation- olanzapine via their general practitioners, only eight new cases ship between birth weight and plasma glucose and insulin con- of diabetes, possibly related to treatment, were found during centrations, the prevalence of Type 2 diabetes and measures of Three recent analyses [47,48,56] examined the risk of new In the general population, low birth weight, resulting from diabetes between users of atypical and conventional anti- either poor intrauterine growth or prematurity, is associated with psychotic medications (Table 3). The results from these studies neurological and psychological problems during childhood and have been conflicting, with two studies showing an increased adolescence, including schizophrenia [38,39]. The mechanisms risk with some atypical anti-psychotic drugs [47,48] and one underlying these associations are unknown, but acute maternal finding no difference. In a further study, Sernyak found food deprivation in the first trimester of pregnancy during the that the prevalence of diabetes was higher in current users Dutch Hunger Winter of 1944 is associated with a twofold of atypical drugs compared with those using conventional increase in the prevalence of schizophrenia in the offspring [40].
anti-psychotics, with the difference being most marked inthe younger age group [9]. In a case-control study of 7227psychiatric patients with newly treated diabetes and 6780 Lifestyle
psychiatric controls, the risk of developing diabetes was Poverty and poor access to good nutrition may also contribute 13–34% higher in those receiving non-clozapine treatment, to the increased prevalence of Type 2 diabetes. In one study of patients with schizophrenia in Scotland, although patients There is considerable debate about the relative risk of devel- consumed fewer calories, the percentage of energy obtained oping diabetes with the different atypical anti-psychotic drugs.
from fat was increased and the amount of fibre, fruit and veg- Some studies have shown an increased risk with olanzapine etables in the diet was decreased [41]. Furthermore, their diet [47,51,58], while in others the risk appears similar regardless was deficient in multiple vitamins and anti-oxidants. In a fur- of the choice of atypical anti-psychotic drug [59].
ther study in Southampton, patients with schizophrenia were These and other studies are difficult to interpret for a found to consume a diet higher in fat and lower in fibre than number of reasons [60]. Too often there have been few cases the general population [21]. In the same study, patients with of diabetes. Most of the studies are retrospective, have used schizophrenia were found to take little exercise. Inactivity and variable diagnostic criteria for diabetes and have not controlled apathy are characteristic of schizophrenia, but may be wors- for age, race, diet, physical activity, polypharmacy or changes ened by hospitalization where there is little opportunity for in medications. It is possible that those prescribed typical neu- exercise [42]. The physical inactivity may reflect developmen- roleptics were less likely to take their medications because of tal delays [43] as well as social factors, such as high levels of their side-effects, as compliance was not assessed. The pre- perceived criticism from other family members [44]. Smoking, scription of an atypical anti-psychotic drug and the diagnosis another risk factor for the metabolic syndrome, is increased in of diabetes may be associated with more severe forms of schiz- ophrenia. This is supported by the observation that more ofthose treated with atypical drugs in the Sernyak study hadmajor depression, alcoholism and admission to a psychiatric Anti-psychotic medication
hospital in the previous year [9]. Finally, the use of atypical After the introduction of phenothiazines, the prevalence of neuroleptics may be linked to better health care in an environ- Type 2 diabetes in schizophrenic female in-patients increased ment where a diagnosis of diabetes is more likely to be made.
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Table 3 Effect of conventional and atypical anti-psychotic drugs on the risk of developing diabetes
Olanzapine vs. conventional 4.2 (1.5 –12.2) 5.8 (2.0 –16.7) Risperidone vs. conventional 1.6 (0.7– 3.8) & managed health Conventional 2.1 (1.1– 4.1) To address some of these concerns, Lindenmayer and with diabetes within 3 months of exposure, 87% were male and colleagues have examined the role of atypical neuroleptics in 49% were Afro-Caribbean or Latino. Most were overweight prior increasing the risk of developing diabetes in a small double to treatment and nearly a half had a family history of diabetes [62].
blind randomised controlled study of 157 patients with schiz- The mechanism by which anti-psychotic drugs increase the ophrenia who received clozapine, olanzapine, risperidone, or risk of diabetes may be mediated primarily through weight haloperidol for a period of 14 weeks. Of these, seven subjects gain rather than a direct effect on insulin resistance or β-cell had previously undiagnosed diabetes at baseline and 14 patients function. In healthy volunteers, treatment with olanzapine or developed diabetes during the trial (6/27 with clozapine, risperidone for 2 weeks led to an 18% reduction in insulin sen- 4/22 with olanzapine, 3/23 with risperidone, and 1/25 with sitivity and a 25% increase in insulin secretion in response to haloperidol). Clozapine, olanzapine, and haloperidol were hyperglycaemia. The change in the insulin response correlated associated with increased glucose concentrations, while cloza- with changes in body mass index and when the analysis was pine and olanzapine were also associated with an increase in adjusted for changes in weight, no significant effect on insulin cholesterol [61]. This suggests that while schizophrenia is asso- response or insulin sensitivity was detected after treatment ciated with a high risk of developing diabetes, there are no sig- with either drug [63]. Furthermore, insulin secretion was not nificant differences in risk attributable to the different drugs.
impaired after prolonged hyperglycaemia after treatment with A review of the characteristics of those developing diabetes on either drug, implying that there was no direct toxic effect on β atypical anti-psychotic medication showed that 45% presented 2004 Diabetes UK. Diabetic Medicine, 21, 515– 523
Schizophrenia and diabetes • R. I. G. Holt et al. In a further study of subjects with schizophrenia, there was anti-psychotic drug that most consistently elevates serum no difference in glucose disposal rates during a hyperinsulinae- prolactin concentrations, is not associated with diabetes more mic clamp between different anti-psychotic drugs, although frequently than the other atypical drugs.
subjects with schizophrenia were significantly more insulin It is unlikely that weight gain and a central effect on glucose homeostasis are sufficient to induce diabetic ketoacidosis The different atypical anti-psychotic drugs have different and additional mechanisms are likely to be involved. Auto- propensities for weight gain, with clozapine and olanzapine antibodies are negative but it has been hypothesized that producing the most weight gain and quetiapine and ziprasi- ketoacidosis occurs in individuals with a pre-existing latent done producing the least weight gain [65]. Some populations, defect in insulin secretion [18]. These individuals fail to mount such as children and adolescents, mentally retarded adults and a compensatory response to the increase in insulin resistance.
patients with bipolar disorders may be more vulnerable to As a consequence, hyperglycemia develops and results in weight gain with atypical anti-psychotic drugs [2]. The factors glucose toxicity, further suppressing beta-cell insulin secretion.
that predict weight gain are similar across a range of typicaland atypical anti-psychotic drugs and include better clinical Implications for psychiatric care and
outcome and low baseline body mass index. There is no evi- screening for diabetes
dence that lower drug doses are associated with lesser weightgain [66]. Men treated with atypical drugs are at greater risk Although physical illness occurs in nearly 50% of patients of weight gain and diabetes than women [67].
with schizophrenia, much of this morbidity is misdiagnosed or The potential mechanisms by which atypical anti-psychotic undiagnosed. A fragmented health care system, lack of access drugs induce weight gain are unknown but include effects on to care, patient inability to appreciate clearly or describe a the hypothalamus, an anti-histamine effect, sedation, decreased medical problem, and patient reluctance to discuss such prob- physical activity and an effect on leptin concentrations. The lems, all contribute to the lack of attention to these medical lateral hypothalamus is a critical anatomical site for weight regulation. Dopamine activity within this structure reduces The National Institute for Clinical Excellence has recom- food intake and the effect is blocked by local and systemic mended that atypical anti-psychotic drugs should be con- infusion of various anti-psychotic drugs [68,69]. Dopamine sidered as first-line therapy for patients with schizophrenia agonists may reduce weight gain and amantadine counteracts because of their improved efficacy and the minimization of the weight gain induced by olanzapine [70]. The lateral dystonia and extra-pyramidal side-effects. There is therefore hypothalamic neurones release orexins that are involved in a need for a strategy to identify those schizophrenic patients body weight regulation and arousal. Anti-psychotic drugs acti- with diabetes and those at high risk of diabetes in the future.
vate these orexin neurones, in a way that correlates with their There is uncertainty regarding the best method to identify propensity for weight gain [71]. Other neurotransmitters, people from the general population with undiagnosed asym- such as GABA, have been implicated in the regulation of ptomatic Type 2 diabetes and, as a result, arrangements are body weight and some atypical anti-psychotic drugs have been often haphazard and inconsistent. It is therefore unsurprising shown to alter the balance between GABA and glutamate [72].
that it is unclear which psychiatric patients should be screened, Histamine signalling in the hypothalamus may produce an and when and by what test. Although risk prediction tables anti-obesity effect. There is a strong correlation between the can improve the diagnostic rate for diabetes, these scores do affinity of the atypical anti-psychotic drugs for the histamine-1 receptors and the induction of weight gain [73]. There is a Despite the lack of published evidence about this topic, we case report of nizatidine, a histamine antagonist, reversing the believe that it is logical to monitor all patients with schizophre- weight gain induced by olanzapine [74].
nia for the presence of diabetes, given the high overall preva- Treatment with clozapine as well as with conventional lence and frequent asymptomatic presentation of diabetes.
anti-psychotics is associated with increased levels of circulating Opportunistic screening with either a fasting or random blood leptin and this is reversed after discontinuation of treatment sugar is probably the most appropriate method, given the dif- [75,76]. Although this may reflect the increase in adipose ficulties of performing an oral glucose tolerance test in this tissue, it has been speculated that there may also be desensiti- zation of the hypothalamus to leptin [77].
Hypothalamic dopamine antagonism by anti-psychotic Implications for the diabetologist: the
drugs may be a further contributing factor leading to glucose challenges of treating diabetes in people
intolerance. It has been postulated that dopamine plays a role with schizophrenia
in the central regulation of blood glucose and dopamineagonists such as bromocriptine can decrease elevated blood It is likely that the number of patients with schizophrenia glucose concentrations [78]. While the influence of hypotha- attending for diabetic care in either primary or secondary care lamic dopamine activity may be one contributing factor, it is will increase through an increased awareness of the problem by probably not the most important as risperidone, the atypical psychiatrists and increased usage of the atypical anti-psychotic 2004 Diabetes UK. Diabetic Medicine, 21, 515– 523
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