Senior Lecturer in Psychiatry, Royal College of Surgeons in Ireland; Neuroscience Centre, St Vincents Hospital, Richmond Road, Fairview, Dublin 3, Ireland.
Correspondence: Tel: +353 1 884 2400; fax: +353 1 884 2450; E-mail: jthakore{at}rcsi.ie
Declaration of interest J.H.T. is supported by a grant from Eli Lilly & Co.
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ABSTRACT |
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Aims To determine whether schizophrenia is associated (independently of medication) with the development of certain metabolic disturbances and whether these might be explained by stress axis dysfunction.
Method Literature review.
Results Most studies did not control for confounding factors such as previous usage of medication, lifestyle, age and ethnicity. A few conducted in drug-naïve patients with first-episode schizophrenia appear to indicate that these patients have higher than expected rates of visceral obesity and impaired fasting glucose concentrations, which may be related to a subtle disturbance of the hypothalamicpituitaryadrenal axis.
Conclusions Schizophrenia is independently associated with physical illnesses that have a metabolic signature. Therefore, patients need to have a thorough physical assessment at diagnosis and at regular intervals thereafter. Metabolic disturbances have been found in drug-naïve patients with first-episode illness and may be an inherent part of the illness.
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INTRODUCTION |
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METHOD |
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RESULTS |
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In order to control for the confounding effects of medication, we measured visceral fat distribution using computed tomography in 15 patients with schizophrenia and matched them with healthy controls in terms of age, exercise, diet, smoking habits and alcohol intake (Thakore et al, 2002). Seven patients were drug-naïve and the rest had not taken any oral neuroleptic preparation for at least 6 weeks and had had no intramuscular preparation for 6 months; none of the patients had been taking any form of atypical neuroleptic agent prior to entering the study. Patients with schizophrenia had a higher mean BMI than the control group: 26.7 (s.d.=1.1) kg/m2 v. 22.8 (s.d.=0.5) kg/m2. Patients and controls had similar amounts of total body fat and subcutaneous fat, but the patients had over 3.4 times more intra-abdominal fat than the normal controls: 13 232.0 (s.d.=2666.5) mm2 v. 3879.9 (s.d.=571.9) mm2 However, there was no difference in intra-abdominal fat distribution between patients who were drug-naïve and those who were drug-free: 12 442.4 (s.d.=9762.6) mm2 v. 14 133.9 (s.d.=11 656.8) mm2.
An increase in visceral fat is not merely a mass effect of a
raised BMI; Enzi et al
(1986) found that healthy
volunteers with BMI values 26 had less intra-abdominal fat (4650
mm2) than the patients in our study (13 232 mm2).
Chronically elevated levels of cortisol, also seen in our study, may provide
an explanation for the increase in intra-abdominal fat, as the density of
glucocorticoid receptors (cytosolic signal transducers for steroids such as
cortisol) and the concentrations of the lipogenic enzyme lipoprotein lipase (a
key enzyme in fat deposition) are higher in visceral fat than in subcutaneous
fat (Ottoson et al,
1994; Pedersen et al,
1994).
Hyperglycaemia, insulin resistance and schizophrenia: an illness effect?
Even though the higher rates of type 2 diabetes mellitus observed in people
with schizophrenia have been attributed to the use of antipsychotic
medications in particular, atypical agents this is by no means
a universally accepted finding. For instance, Mukherjee et al
(1996) studied a cohort of
patients with schizophrenia (n=95), and observed that the prevalence
of diabetes was age-dependent and greater in those taking conventional
neuroleptic medications. Subramaniam et al
(2003) reported a rate of
undiagnosed diabetes mellitus of 16% and a rate of impaired glucose tolerance
of just over 30% in a cohort of residential patients with schizophrenia, none
of whom had ever received an atypical neuroleptic drug; yet the rate of type 2
diabetes mellitus in the general population of a similar age was over 22%,
indicating that patients with schizophrenia are less likely to have their
diabetes diagnosed than their counterparts without mental illness.
The introduction of atypical neuroleptics has added to this debate, although most of the evidence implicating these compounds is based on case reports and various cross-sectional epidemiological studies (Liebzeit et al, 2001; Sernyak et al, 2002). In contrast to these findings, Lieberman et al (2003) conducted a prospective study in a Chinese population, comparing chlorpromazine with clozapine in drug-naïve patients with first-episode schizophrenia over a 52-week period, and showed that despite significant increases in weight (which were equal between the two compounds in question), there was no significant increase in fasting plasma glucose levels at the end of the study period. However, the study did not have a normal control group as a reference population. This is important, because the rates of obesity and type 2 diabetes mellitus in this population are lower than those found in North America, or indeed in Europe. Furthermore, lifestyle issues such as diet and exercise were not discussed either before or during the treatment period.
Is it possible that a mechanism other than medication might be responsible for such findings? A number of papers from the era before the use of antipsychotic drugs add credence to this hypothesis, although problems with diagnosis, small size of study group and other methodological issues make it difficult to interpret the significance of these valuable earlier studies (Lorenz, 1922; Braceland et al, 1945; Freeman, 1946; Langfeldt, 1952). It is notable that a family study found that up to 19% of first-degree relatives of patients with schizophrenia had type 2 diabetes mellitus, which indicates that this endocrine condition and schizophrenia might have a genetic association (Mukherjee et al, 1989).
In an attempt to determine whether schizophrenia is associated with abnormal glucose metabolism, we compared fasting levels of plasma glucose, insulin, lipids and cortisol measures in a group of hospitalised, drug-naïve patients with first-episode schizophrenia (n=26) with those of a healthy volunteer group matched in terms of age, ethnicity, exercise, diet, smoking habits and alcohol intake (Ryan et al, 2003). Anthropometric and lifestyle data indicated that the only significant difference between the two groups was that patients had a higher saturated fat intake than did controls. Over 15% of patients with schizophrenia had impaired fasting glucose levels compared with none in the control group as defined by the American Diabetes Association (1997) criteria. Patients with schizophrenia, compared with the control group, had significantly higher plasma levels of fasting glucose (5.3 (s.d.=0.9) mmol/l v. 4.8 (s.d.=0.3) mmo/l), insulin (68.2 (s.d.= 64.6) pmol/l v. 55.2 (s.d.=26.5) pmol/l) and cortisol (499.4 (s.d.=161.4) nmol/l v. 303.2 (s.d.=10.5) nmol/l), and were more insulin-resistant: 2.3 (s.d.=1.0) v. 1.7 (s.d.=0.7). Both the control and the patient groups had similar levels of lipids. Finally, there was no significant association between severity of symptoms and plasma levels of glucose, indicating that the stress of hospitalisation was an unlikely cause of the hyperglycaemia.
The rate of impaired fasting glucose concentration observed in our group of patients (>15%) is greater than that found in a recent European study (8.5%, Gourdy et al, 2001). Type 2 diabetes mellitus and vascular complications occur in a third of those with impaired fasting glucose levels (Alberti, 1996). Medication, age, ethnicity, physical inactivity and smoking are unlikely to explain our findings (King & WHO Ad Hoc Reporting Group, 1993; Shaten et al, 1993). Although our patients consumed more saturated fat, studies do not indicate a positive association between a high intake of saturated fat and hyperglycaemia (Colditz et al, 1992; Salmeron et al, 1997, 2001), however, patients with schizophrenia did have higher levels of cortisol than did normal controls.
Are patients with schizophrenia biologically stressed?
A common endocrine reaction to stress involves activation of the
hypothalamicpituitaryadrenal (HPA) axis
(Axelrod & Reisine, 1984). As in Cushings syndrome and melancholic depression
(Wajchenberg et al,
1995; Condren & Thakore,
2001; Thakore et al,
2002), a dysregulated HPA axis can lead to abnormal glucose
metabolism and visceral obesity (Rosmond
& Bjorntorp, 2002). Schizophrenia is associated with
abnormalities of this axis (Altamura et
al, 1989; Coryell &
Tsuang, 1992; Kaneko et
al, 1992; Lammers et
al, 1995), and we have confirmed this using a rather crude
indicator of HPA axis activity in two studies
(Thakore et al, 2002;
Ryan et al,
2003).
To date, HPA axis disturbance has been less consistently reported in schizophrenia than in depression (Holsboer, 1998; Cotter & Pariante, 2002). With respect to schizophrenia, adrenocorticotrophic hormone (ACTH) and cortisol responses to corticotrophin-releasing hormone (CRH) are indistinguishable from controls, although pre-treatment with dexamethasone results in an exaggerated CRH-induced pituitaryadrenal response in patients (Roy et al, 1986; Lammers et al, 1995). Most (but not all) studies have shown that dexamethasone suppresses plasma levels of cortisol in patients with schizophrenia (Dewan et al, 1982; Tandon et al, 1991). Equally discordant findings have been reported in terms of basal activity of the HPA axis as measured by serum cortisol levels (Gil-Ad et al, 1986; Roy et al, 1986; Whalley et al, 1989; Van Cauter et al, 1991; Breier & Buchanan, 1992; Rao et al, 1995; Elman et al, 1998; Kaneda et al, 2002). Methodological problems may partly explain the differences observed between the studies quoted. For instance, the effects of medication on HPA axis activity are unclear (Hellewell, 1999), and often a single sample of cortisol has been used to determine HPA activity although it is not clear whether this accurately represents an estimate of mean 24 h activity (Muller & von Werder, 1989).
As mean or integrated measures, such as area under the curve (AUC), of plasma cortisol between 13.00 h and 16.00 h can be used to detect hypercortisolism (Halbreich et al, 1982), we decided to determine cortisol, ACTH and arginine vasopressin (AVP) levels in drug-naïve patients with first-episode schizophrenia and compare them with a group of volunteers matched for age and gender (Ryan et al, 2004). Baseline levels of cortisol and AVP were indistinguishable between patients and controls, although patients had higher ACTH levels. Patients with schizophrenia had a higher mean AUC of ACTH (26.3 (s.d.=6.2) nmol/l v. 13.9 (s.d.=3.0) nmol/l) and cortisol (279.4 (s.d.=26.0) nmol/l v. 213.1 (s.d.=18.4) nmol/l) but had a lower mean AUC of AVP (0.87 (s.d.=0.24) pmol/l v. 1.42 (s.d.=0.34) pmol/l) than controls. A positive correlation between plasma levels of AVP and cortisol, and higher levels of plasma ACTH during the test period, indicate that the pituitaryadrenal axis was more sensitive to vasopressin-mediated stimulation in our patients with schizophrenia. This may be due first to the fact that vasopressin can directly stimulate the release of cortisol from the adrenal cortex (Guillon et al, 1995), and second, to the fact that glucocorticoid-induced inhibition of AVP gene transcription may be overcome, thereby allowing this hypothalamic neuropeptide to stimulate the pituitaryadrenal axis (Rivier & Vale, 1983; Kovacs & Sawchenko, 1996; Aguilera & Rabadan-Diehl, 2000; Aguilera et al, 2000), leading to a relative hypercortisolaemia with all its consequent effects.
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DISCUSSION |
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Clinical Implications and Limitations |
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LIMITATIONS
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