Department of Psychiatry, University College Cork
Correspondence: GF Unit, Cork University Hospital, Wilton, Cork, Ireland. E-mail: t.dinan{at}ucc.ie
Declaration of interest T.G.D. has lectured at meetings and served on advisory boards organised by companies promoting antipsychotic medications, including Eli Lilly, Janssen-Cilag, Pfizer and AstraZeneca.
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ABSTRACT |
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Aim To examine the role of stress in the emergence of diabetes mellitus in patients with schizophrenia.
Method Selective literature review.
Results A model is developed suggesting that patients with schizophrenia show overactivation of both the hypothalamicpituitaryadrenal and sympathoadrenal medullary axes, manifested by increased production of cortisol and adrenaline. Both of these hormones are known to be diabetogenic and are proposed as playing a part in the onset of diabetes mellitus in schizophrenia.
Conclusions Stress has an important role in the onset of schizophrenia and may also play a part in relapse. Further research is needed to clarify the extent to which stress accounts for the genesis of diabetes in such patients.
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INTRODUCTION |
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Pseudostressors, originating in subjective space, are represented by the core symptoms of schizophrenia, namely delusions and hallucinations. These stressors can have profound emotional intensity, which can render them both qualitatively and quantitatively different from the stresses experienced by the rest of the population. The biological impact of such stressors has been only superficially explored, but given the behavioural disturbance they can produce, it is reasonable to assume that they also lead to major endocrinological changes.
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METHOD |
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RESULTS |
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Adrenaline and noradrenaline exert their impact through - and
ß-adrenoceptors (Ahlquist,
1974). Adrenaline is most potent at ß1- and
ß2-receptors, with far less effect on
-receptors,
whereas noradrenaline is more potent at
-receptors. The hyperglycaemic
impact of the adrenomedullary hormone is mediated by adrenaline, which is a
profoundly diabetogenic hormone. Adrenaline produces a hyperglycaemic effect
in that it both stimulates hepatic glucose production and also limits glucose
utilisation. The hepatic effect is mediated largely through ß-adrenergic
stimulation, although
-adrenergic stimulation may have a part to play
(Macdonald, 1999). The impact
of adrenaline on glucose production is transient and takes place within
minutes. The ability to limit glucose utilisation occurs predominantly through
the ß-receptor. As a result of this impact on glucose utilisation,
sustained hyperadrenalism produces sustained hyperglycaemia.
Noradrenaline exerts hyperglycaemic actions when released from axon
terminals of sympathetic post-ganglionic neurons. The liver has an important
sympathetic innervation, and in animals when these sympathetic nerves are
electrically stimulated a decrease in glycogen content is reported, together
with increased hepatic glucose release, resulting in hyperglycaemia
(Lautt, 1980). There is no
evidence that this system is involved in the regulation of carbohydrate
metabolism under normal circumstances, but it comes into play in situations of
significant stress. Interestingly, Kjaer et al
(1995) reported that the liver
denervation that occurs with transplantation does not cause a gross alteration
in carbohydrate metabolism. The primary metabolic impact of the SAM axis is
control of fat metabolism (Niijima,
1989). Prolonged starvation and other significant stressors
increase lipolysis through the SAM response mediated by ß-adrenoceptors.
In marked contrast, stimulation of -adrenoceptors inhibits lipolysis in
adipose tissue. Although the sympathetic innervation of white adipose tissue
mainly supplies the vasculature, in some areas there is direct innervation of
the adipose cells. Overall, brown adipose tissue has a greater vascular supply
and innervation than white tissue and a greater percentage of these cells are
sympathetically innervated, with the metabolic effects again mediated through
ß-adrenoceptors. Stimulation of the sympathetic innervation of the
pancreatic ß-cells produces an inhibition of insulin release mediated by
-adrenoceptors, probably of the a2 subtype. When the SAM
system remains activated there is a reduction in the effectiveness of insulin
to stimulate glucose uptake and utilisation. Such an impact is produced
through the ß2-adrenoceptors and is mimicked by drugs such as
salbutamol and terbutaline. High doses of ß2 agonists
stimulate adipose tissue lipolysis and induce pancreatic glucagon secretion,
which can lead to increased ketone production.
Function of the SAM axis in schizophrenia
No comprehensive study has used contemporary assays to examine SAM function
in schizophrenia. Kemali et al
(1985) examined catecholamine
release over 24 h in patients with schizophrenia and a matched comparison
group; the patients had been drug-free for a minimum of 2 weeks. Plasma
noradrenaline levels were consistently elevated in the patients during the
waking period but not during sleep. In a similar study, Barbeito et
al (1984) found an
elevation in catecholamine levels in both plasma and urine, and their data
support the view that urinary catecholamine measurement could be used as a
reliable assessment of SAM activity in schizophrenia. The finding is
consistent with a report that unmedicated patients with schizophrenia have
elevated levels of noradrenaline as well as heightened responsivity on
measures of electromyographic activity, skin conductance and heart rate
(Albus et al, 1982);
the patients showed an attenuated response to the cold pressor test, noise and
mental arithmetic stressors. A more recent study by Fleischhaker et
al (1998) reported that
response to clozapine in patients with treatment-resistant schizophrenia was
associated with increases in adrenaline levels, a finding that might help to
explain the pro-diabetic effect of this drug.
Hypothalamicpituitaryadrenal axis
The ability to sustain a stress response is dependent on chronic activation
of the HPA axis. Its major hormones are well defined and are easily assayed.
The prohormone pro-opiomelanocortin is produced in the corticotrophs of the
anterior pituitary and has a pivotal role in the axis. Its cleavage results in
the production of adrenocorticotrophic hormone (ACTH), ß-endorphin and
several other biologically active peptides. The release from the adrenal
cortex of cortisol, dehydroepiandrosterone (DHEA) and other steroids is
stimulated by ACTH. Corticotrophin-releasing hormone (CRH) and arginine
vasopressin are the major secretagogues of the HPA stress system.
Corticotrophin-releasing hormone, a 41 amino acid peptide originally
discovered and sequenced by Vale et al
(1981), is produced in the
medial parvicellular neurons of the paraventricular nucleus of the
hypothalamus. These neurons project to the external zone of the median
eminence, where CRH is released into the portal vasculature to act on CRH type
1 receptors of the anterior pituitary. The hormone acts synergistically with
arginine vasopressin in bringing about ACTH release from the corticotrophs.
Following its identification in 1954, vasopressin, a nonapeptide, was
considered to be the principal factor in the regulation of ACTH release, but
with the subsequent elucidation of the structure of CRH and the domination of
the one neuron one transmitter principle, the role of
CRH came to supersede that of arginine vasopressin. It is now apparent that in
stress-free situations CRH is the dominant regulator of the HPA axis, but with
chronic stress many paraventricular neurons that normally produce CRH begin to
co-express arginine vasopressin (Scott
& Dinan, 2002). In these circumstances arginine vasopressin
plays an important part in sustaining HPA activation. The CRH1
receptor downregulates with increased production of CRH, while increased
production of arginine vasopressin upregulates the V1b receptor.
This latter effect is important in maintaining high cortisol output in the
presence of a chronic stressor. In the absence of such a mechanism,
adrenocortical activity will decrease over time and prevent an adequate
biological response to the chronic stress.
The HPA axis is well characterised and has been investigated in a variety of central and peripheral disorders. In depression, HPA dysregulation has been extensively investigated, but in schizophrenia HPA function has received far less attention.
Function of the HPA axis in schizophrenia
Given that the onset of schizophrenia is frequently precipitated by stress
and that relapse often takes place in a similar setting, it is surprising that
the investigation of stress at a biological level has received so little
attention in schizophrenia research. Walder et al
(2000) assayed cortisol levels
in multiple salivary samples from people with schizophrenia. This technique
has the advantage of being stress-free, and as the cortisol in saliva is
unbound to protein, the assay provides a measure of biological activity. They
found that cortisol levels were significantly elevated, and that the greater
the severity of symptoms the greater the elevation. The results support the
view that the psychotic features of schizophrenia generate considerable
biological stress. In a study of 53 patients taking medication, Kaneda et
al (2002) found elevated
levels of ACTH but failed to find abnormalities in plasma cortisol.
Demonstrating differences in the latter usually requires multiple sampling,
even in patients with overt Cushings disease. The dexamethasone
suppression test is a test of delayed feedback mechanisms in the HPA axis. In
patients with predominantly positive symptoms a non-suppression rate of 56%
was reported; patients with negative symptoms had a non-suppression rate of
53% (Pivac et al,
1997). These results are similar to those observed in major
depression and are clearly different from those observed in healthy
individuals. In a similar study Muck-Seler et al
(1999) reported high baseline
cortisol levels in schizophrenia with a non-suppression rate of 50%, and
Plocka-Lewandowska et al
(2001) reported data
suggesting that patients with schizophrenia who are suicidal are most likely
to be non-suppressors. These studies support the view that defective HPA
feedback mechanisms, possibly due to insensitive glucocorticoid receptors, may
have a causative role. Levels of CRH in the cerebrospinal fluid have been
investigated by Banki et al
(1987): in patients with
schizophrenia they found levels that were above normal, but not as high as
those observed in patients with melancholic depression. The
dexamethasoneCRH test has been applied to patients with schizophrenia
(Heuser et al, 1994). This test involves the administration of dexamethasone at 23.00 h and the
administration of CRH on the following day at 15.00 h. Paradoxically, the
dexamethasone pretreatment enhances the response to CRH in healthy
individuals, and this enhancement is augmented in patients with major
depression. Heuser et al
(1994) found that patients
with schizophrenia release more cortisol and ACTH after the
dexamethasoneCRH test than do age-matched healthy controls.
Few investigators have employed non-pharmacological strategies to activate the HPA axis in schizophrenia. Jansen et al (2000) used public speaking as a psychological stressor in patients with schizophrenia, and measured their salivary cortisol response to this stress. The patients showed a blunted response, in contrast to their response to the physical stress of cycling.
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Clinical Implications and Limitations |
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LIMITATIONS
Stress and glucose regulation
There has been no systematic research to date exploring the endocrine
response in people with schizophrenia exposed to a high-EE environment. This
is surprising given the large number of studies published, especially in the
UK, on high expressed emotion and schizophrenia. However, Shiloah et
al (2003) examined
ß-cell function and insulin sensitivity using the homoeostasis model in
non-diabetic patients with schizophrenia who had acute psychosis. A total of
39 individuals were assessed and the homoeostasis model assessment was based
on two samples of glucose and insulin. Stress was assessed using the Clinical
Global Impression (CGI) scale, which rates psychological stress as a score of
07 (Guy, 1976). On
admission the mean CGI score of the patients was 5.3 (s.d.=0.8) and on
discharge it was 1.6 (s.d.=0.7). Patients with the highest CGI scores on
admission had the highest glucose and insulin levels. Mean ß-cell
function was lowest on admission (96.8%, s.d.=33.2%) and highest at discharge
(134.4%, s.d.=60.0%). In marked contrast, mean insulin sensitivity was highest
on admission (101.7%, s.d.=36%) and had decreased significantly by discharge
(77.1%, s.d.=34.8%). However, insulin sensitivity inversely correlated with
CGI score: a high CGI score was associated with low insulin sensitivity, and a
low score was associated with high insulin sensitivity. The data support the
view that psychotic stress produces a transient suppression of ß-cell
function and alters insulin sensitivity.
The impact of psychosis on glucose tolerance in drug-naïve patients with first-episode schizophrenia has been reported by Ryan et al (2003), who compared 26 patients with schizophrenia and a similar number of control participants matched for age and gender. Four of the patients and none of the comparison group had an impaired fasting blood glucose concentration as defined by the American Diabetes Association (1997): >6.1 mmol/l (>110 mg/dl) and <7.0 mmol/l (<126 mg/dl). Patients had higher mean fasting levels of glucose and insulin. Furthermore, they had elevated cortisol levels, raising the possibility that the dysregulation in glucose homoeostasis is secondary to overactivation of the HPA.
Effect of glucocorticoids
Glucocorticoids inhibit insulin function in a variety of ways. Cortisol has
a pronounced antagonistic impact on insulin-mediated inhibition of hepatic
glucose release while simultaneously decreasing glucose utilisation in muscle
and reducing the binding affinity of insulin receptors
(Meyer & Badenhoop, 2003).
When patients are treated with glucocorticoids over long periods almost half
of them develop deranged glucose metabolism, and in half of these patients
this dysregulation persists even after reduction or withdrawal of the
glucocorticoid. This situation is analogous to that occurring in
schizophrenia, where glucose homoeostasis may be altered during acute episodes
of illness and where the overall emergence of type 2 diabetes mellitus is
higher than that seen in the general population.
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DISCUSSION |
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