Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia.

AIMS: To determine whether there is an association between Type 2 diabetes mellitus and schizophrenia, independent of medication. METHODS: In this cross-sectional study we performed an oral glucose tolerance test on 38 non-obese white Caucasians who fulfilled the criteria for first-episode drug-naïve schizophrenia, 38 control subjects (matched for age, gender, smoking status, alcohol intake and ethnicity) and 44 first-degree relatives of the patients. RESULTS: The frequency of impaired glucose tolerance (IGT), defined by World Health Organization criteria, was 10.5% (n = 4) in patients with schizophrenia, 18.2% (n = 8) in unaffected relatives and 0.0% in healthy control subjects (chi(2) = 4.22, d.f. = 2, P < 0.05). CONCLUSIONS: The high point prevalence of IGT in never-treated patients and relatives supports either shared environmental or genetic predisposition to IGT. Both patients and their relatives present an ideal cost-effective opportunity to screen for Type 2 diabetes mellitus, as they are both easily identifiable.

HPA axis response to a psychological stressor in generalised social phobia.

Social phobia may be associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In this study we determined HPA axis responsivity to a psychological stressor in patients with social phobia and compared them to healthy controls. Fifteen patients with DSM IV social phobia with a mean score of 77.7 on the Liebowitz Social Anxiety Scale and 15 age and sex matched controls underwent the stressor consisting of mental arithmetic and a short term memory test performed in front of an audience. Plasma levels of cortisol and corticotropin were measured at various intervals throughout the test. Although baseline measures of cortisol did not differ between patients (319.8+/-34.6 nmol/l) and controls (279.5+/-42.7 nmol/l)(t=0.7, df=28, P<0.5) nor did baseline corticotropin values (8.6+/-2.1 pg/ml vs 13.7+/-2.0 pg/ml respectively) (t=-1.8, df=28, P<0.08) this stressor resulted in a significantly greater delta max cortisol response (the difference between baseline values and the maximum increase during the stressor) in patients (167.1+/-23.7 nmol/l) than in controls (106.7+/-16 nmol/l) (t=2.1, df=28, P<0.04). There was no significant difference in delta max corticotropin between groups (patients 8.8+/-2.1 pg/ml vs controls 9.1+/-1.9 pg/ml) (t=-0.08, df=28, P<0.9). This preliminary study indicates that patients with social phobia appear to have a hyper-responsive adrenocortical response to psychological stress.

Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia.

OBJECTIVE: To investigate visceral fat distribution in patients with schizophrenia. DESIGN: Cross sectional study using CT scanning in patients with drug-naive and drug-free schizophrenia. SUBJECTS: Fifteen (13 men and two women) subjects with schizophrenia (mean age 33.7 y; mean body mass index (BMI)=26.7 kg/m(2)), and 15 age- and sex-matched controls (mean age 30.5 y; mean BMI=22.8 kg/(2)). MEASUREMENTS: Various fatness and fat distribution parameters (by CT scanning and anthropometry) and 16:00 h plasma cortisol. RESULTS: In comparison to controls, patients with schizophrenia had central obesity and had significantly higher levels of plasma cortisol. Furthermore, previous neuroleptic exposure did not appear to influence these findings as both drug-naive and drug-free patients had equally high levels of visceral fat deposition. CONCLUSION: Central obesity is a well recognized risk factor in developing certain general medical conditions. This study shows that patients with schizophrenia have increased intra-abdominal fat which may provide one explanation for why they die prematurely.

Cushing's disease and melancholia.

Striking similarities exist in the endocrinology of Cushing's disease and melancholic depression.Laboratory abnormalities, which have been found in both, include raised urinary,plasma and salivary cortisol, non-suppression of cortisol in the dexamethasone suppression test and adrenocorticotrophin (ACTH) hypersecretion. The hypercortisolism can be so severe in melancholic depression that it is difficult to distinguish from Cushing's disease and has been described as a "pseudo-Cushing's" state. Cerebrospinal fluid corticotrophin-releasing hormone (CRH) levels have been found to be lower in patients with Cushing's disease than in depressed subjects. Dynamic endocrine tests may help to distinguish between the two disorders.An exaggerated response to synacthen has been found in both but a reduced ACTH response to CRH occurs in depression, unlike those with Cushing's disease who show ACTH hyper-responsiveness. Other tests, which may help to distinguish between the two disorders,include the dexamethasone-CRH test, the naloxone test, the insulin-induced hypoglycemia test and the desmopressin stimulation test. Similarities in psychiatric symptoms have been recognised for many years. More recently, the physical complications of melancholic depression have been noted. These include osteoporosis, an increased risk of death from cardiovascular disease, hypertension, a redistribution of fat to intra abdominal sites and insulin resistance. Cushing's disease shares these physical complications and we propose that the common underlying factor is excessive plasma glucocorticoids. The increasing recognition of the physical complications and the increased morbidity and mortality in those who suffer from depression underscores the necessity for early detection and treatment of this illness and screening for undetected physical complications.

Melancholic depression and abdominal fat distribution: a mini-review.

Fat is stored around the abdomen in both subcutaneous and intra abdominal (visceral) sites. Visceral fat is associated in its own right with a set of metabolic abnormalities, including non insulin dependent diabetes, hypertension and dyslipidaemias. States of marked hypercortisolaemia, for example Cushing's syndrome, lead to the preferential accumulation of visceral fat. Since melancholic depression is known to be associated with elevated plasma Cortisol levels, this review explores whether depressed patients are prone to excess visceral fat storage, with the subsequent risk of developing the associated metabolic disturbances. Though the literature is limited, there is evidence that intra abdominal fat is increased in major depression. There is also evidence that depression is associated with increased risk of death from cardiovascular disease. Is visceral fat and its association with metabolic abnormalities the link between depression and physical illness?

Effects of antidepressant treatment on corticotropin-induced cortisol responses in patients with melancholic depression.

To date, there appears to be no consensus of opinion as to whether the adrenal glands are hyperresponsive during depression and, if so, whether this a state-dependent phenomenon. We aimed to determine the effects of antidepressant treatment on ACTH-induced cortisol responses in patients with melancholic depression. Seven female patients with DSM-III-R major depressive disorder, non-psychotic, melancholic subtype, were evaluated using the following rating scales: the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale and the Newcastle Endogenicity Scale. All subjects were then given an intravenous bolus dose (250 micrograms) of tetracosactrin, a potent stimulus of adrenocortical hormone secretion. Plasma levels of cortisol were measured at times 0, + 30, + 60, + 90, + 120 and + 180 min. Patients were then randomised to receive either 50 mg of sertraline or 20 mg of paroxetine (both of which are selective serotonin re-uptake inhibitors) and were re-tested while medication-free. Treatment resulted in a significant decrease in delta (the difference between the baseline values and the maximum increase post-ACTH administration) cortisol values of 1633.3 +/- 378.5 nmol/l vs. 595.1 +/- 207.7 nmol/l. Successful pharmacological treatment of major depressive disorder appears to be associated with a reduction in ACTH-induced cortisol release in drug-free patients.

d-fenfluramine-induced prolactin responses in mania: evidence for serotonergic subsensitivity.

OBJECTIVE: The authors examined serotonergic-mediated prolactin release in bipolar mania, using d-fenfluramine as a probe. METHOD: Hospitalized patients with bipolar disorder, currently manic, were matched for age and sex to healthy comparison subjects. Each group consisted of nine subjects (seven men and two women). After an overnight fast, all subjects had an intravenous cannula inserted into a forearm at 8:30 a.m., and baseline blood samples for determination of prolactin and cortisol levels were drawn. d-Fenfluramine (30 mg p.o.) was then administered; plasma prolactin levels were measured 15 minutes before d-fenfluramine was given, immediately before, and 60, 120, 180, 240, and 300 minutes afterward. RESULTS: Baseline serum cortisol levels were higher in the bipolar manic subjects than in the comparison subjects, although baseline prolactin levels were similar in the two groups. The plasma prolactin responses to d-fenfluramine of the bipolar manic subjects were significantly lower than those of the comparison subjects. CONCLUSIONS: Bipolar mania appears to be associated with a state of decreased serotonergic responsivity similar to that found in unipolar depression.

Blunted dexamethasone-induced growth hormone responses in acute mania.

Dynamic endocrine testing using a variety of probes has revealed abnormalities of the somatotropic axis in bipolar mania. In health, acute administration of dexamethasone (DEX) results in the secretion of growth hormone (GH) by possibly inhibiting somatostatin tone. We elected to determine DEX/GH responses in acute mania. Eight male bipolar manics were compared with eight age-matched healthy volunteers. Four milligrams of oral DEX was administered at 0900 h (time 0 min) and plasma samples for GH were taken at +60, +180, +240 and +300 min. Baseline samples for GH and cortisol were taken at -15 min and 0 min. Patients had higher basal cortisol levels (391.6 +/- 89.4 nmol/l) as opposed to controls (138.0 +/- 13.2 nmol/l) (paired t-test, t = 4.68, df = 6, p < .0004). The mean (+/- SD) delta GH (calculated as the maximum GH level relative to baseline) in the manic patients was 0.7 +/- 0.8 ng/ml and in the healthy controls was 9.2 +/- 4.3 ng/ml (paired t-test, t = -0.589, df = 6, p < .0001). In conclusion, patients with bipolar mania had lower DEX-induced GH responses in comparison to controls.

Are blunted dexamethasone-induced growth hormone responses unique to depression?

In health, acute administration of glucocorticoids, such as dexamethasone (DEX), leads to growth hormone (GH) secretion. Depression is characterized by blunted DEX/GH responses. In order to determine the specificity of this test for depression we administered 4 mg of oral DEX, to patients with a DSM-III-R diagnosis of depression, schizophrenia, mania and alcohol dependency syndrome. Samples for GH estimation were taken at -15 min, 0 min, +60 min, +180 min, +240 min and +300 min. GH responses were attenuated to a similar degree in depression and mania. Less marked attenuation was seen in schizophrenia while those with alcohol dependency syndrome had GH responses indistinguishable from normal volunteers. Overall, we conclude that subnormal DEX/GH secretion is not specific to depression.

An open trial of adjunctive sertraline in the treatment of chronic schizophrenia.

While the positive symptoms of schizophrenia are amenable to treatment with standard neuroleptics, negative symptoms are often difficult to treat. Co-prescribing antidepressants, such as sertraline, for patients on stable neuroleptic depot preparations is one pharmacological method of overcoming this problem. A total of 20 patients with chronic schizophrenia were enrolled in an open trial over a 12-week period during which sertraline was added to their usual antipsychotic medication. Prior to this, baseline scores for positive and negative symptoms, and extrapyramidal side-effects, were measured. The addition of sertraline resulted in global improvement, with a significant reduction in positive and negative symptom scores and no increase in undesirable neuroleptic side-effects. Sertraline may act by indirectly reducing dopaminergic activity.

Prescription of antidepressants by general practitioners: recommendations by FHSAs and health boards.

BACKGROUND: In order to cut costs of prescribing by general practitioners family health service authorities (FHSAs) and health boards in the UK have been instructed to improve the quality and cost-effectiveness of prescribing by general practitioners in their area by tailoring advice to individual general practices. AIM: As over 95% of patients suffering from depression are treated by their general practitioner, a study was set up to investigate the effectiveness of the advice given by FHSAs and health boards to general practitioners on treatment of depression and prescription of antidepressant drugs. METHOD: The recommendations on prescription of antidepressants of professional advisors from all 117.FHSAs and health boards in the UK were elicited by telephone. Those who had produced written information for the general practitioners in their area regarding depression and antidepressants prescribing during the study period were asked to send a copy to the researchers. RESULTS: An excellent response rate (100%) was obtained to the telephone survey, and all of the bodies that provided their general practitioners with written information on depression and prescription of antidepressants sent in copies. Most of the documents received were informative and accurate; however, others provided information that was incorrect. CONCLUSION: Bulletins and newsletters from FHSAs and health boards are capable of influencing the prescribing patterns of general practitioners in their area, and must contain accurate and up-to-date information if they are to improve the management of depressed patients in the community.

Loss of the diurnal variation of pyridostigmine-induced growth hormone responses in depression: the effect of cortisol.

Growth hormone (GH) plasma concentrations reflect a balance between stimulation via GH-releasing hormone and inhibition by somatostatin. Cholinergic agonists enhance GH release by inhibiting somatostatin secretion and in health, stimulated GH release undergoes diurnal variation. We investigated the influence of cortisol on pyridostigmine-induced GH responses by testing six patients with DSM-III-R major depression at 09.00 and 14.00 h. There were no differences in GH responses to pyridostigmine between 09.00 and 14.00 h despite a preservation of the circadian variation of cortisol levels. If cortisol plays an important role in regulating cholinergic activity one would expect the diurnal variation of pyridostigmine-induced GH release to be preserved. As it is not, a reasonable assumption to make is that the muscarinic supersensitivity observed in depression may be independent of the prevailing steroid milieu.

Effect of fluoxetine on dexamethasone-induced growth hormone release in depression: a double-blind, placebo-controlled study.

OBJECTIVE: The authors' objective was to characterize the effects of fluoxetine treatment on dexamethasone-induced growth hormone (GH) responses in depressed patients. METHOD: Twelve patients (six women and six men) with major depression diagnosed according to DSM-III-R underwent dexamethasone-induced GH stimulation before and after random assignment to 4 weeks of treatment with either placebo (N = 6) or fluoxetine (N = 6). RESULTS: All six patients treated with fluoxetine and two of the six patients given placebo demonstrated an increase in their dexamethasone-induced GH responses. CONCLUSIONS: Clinical recovery was associated with an increase in GH release in response to dexamethasone.

Cortisol synthesis inhibition: a new treatment strategy for the clinical and endocrine manifestations of depression.

Evidence exists that oversecretion of cortisol may be responsible for the clinical manifestations and serotonergic abnormality in depressive illness. Using the cortisol synthesis inhibitor ketoconazole, we investigated the effects of directly lowering cortisol on the symptoms and the response of prolactin (PRL) to d-fenfluramine in eight patients suffering from major depression. Prolactin responses to d-fenfluramine were measured, and patients were treated with 400-600 mg of ketoconazole for 4 weeks, after which they were retested. Five patients treated with ketoconazole recovered from their depression, while the other three had decreases in their Hamilton Depression Rating Scale (HAMD) scores of < or = 50% and were deemed partial responders. Posttreatment prolactin responses to d-fenfluramine were higher than pretreatment values. Ketoconazole normalizes the blunted prolactin responses to d-fenfluramine and may be an effective method by which to treat depression. This implies that hypercortisolemia may be responsible for the clinical features and serotonergic subsensitivity observed in depression.

Growth hormone responses to dexamethasone in healthy females throughout the menstrual cycle.

OBJECTIVE: In health, acute administration of dexamethasone (DEX) leads to growth hormone release. As sex steroids have a profound influence on the somatotrophic axis, we decided to investigate the effects of DEX on GH release throughout the menstrual cycle. DESIGN: A within subjects, randomized double-blind counter-balanced design was employed. METHODOLOGY: Baseline levels of GH, oestradiol and progesterone were taken at three time points in two consecutive menstrual cycles, after which 4 mg of oral DEX or placebo was administered. Plasma samples for GH estimation were taken at 60, 180, 240 and 300 minutes. Each woman was tested 6 times, 3 times with placebo and 3 times with DEX. SUBJECTS: Six women with regular menstrual cycles were studied. MEASUREMENTS: Plasma GH, oestradiol and progesterone were measured by radioimmunoassay. RESULTS: When expressed as maximum change from base line (delta GH) mean GH responses to DEX increased incrementally from early (12.2 +/- 2.5 mU/l), through mid (25.6 +/- 3.3 mU/l) to late (37.2 +/- 3.5 mU/l) cycle. This represents a significant effect of cycle phase on GH responses to DEX (P < 0.05). GH responses at both the mid-cycle and the luteal time points are different from those during the follicular phase (P < 0.05) and difference between mid-cycle and luteal phases just fail to reach significance (P < 0.15). Responses to placebo did not vary from baseline. Plasma oestradiol values were significantly correlated with GH responsivity to active drug throughout the cycle (P < 0.05); the same was not true of progesterone. CONCLUSION: Our study has demonstrated that dexamethasone-mediated GH release shows a stepwise increase throughout the menstrual cycle.