L. Poon

Neural response to pleasant stimuli in anhedonia: an fMRI study

The aim of this study was to investigate the neural correlates of affect processing in depressed anhedonic patients and healthy controls. Whole brain functional magnetic resonance imaging scans were obtained from seven females with a diagnosis of chronic unipolar major depression and high levels of anhedonia, and seven healthy females, while they were presented with positive valence and neutral images. Patients, compared to controls, showed decreased activation in medial frontal cortex, and increased activation in inferior frontal cortex, anterior cingulate, thalamus, putamen and insula. Reduced activation in medial frontal cortex may underlie abnormal positive affect processing in patients. Increases in neural activation in putamen and thalamus, previously found in transient sadness, and anterior cingulate could point to an involvement of these structures in anhedonia.

Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance

BACKGROUND People with severe depressive illness have raised levels of cortisol and reduced glucocorticoid receptor function. AIMS To obtain a physiological assessment of hypothalamic-pituitary-adrenal (HPA) axis feedback status in an in-patient sample with depression and to relate this to prospectively determined severe treatment resistance. METHOD The prednisolone suppression test was administered to 45 in-patients with depression assessed as resistant to two or more antidepressants and to 46 controls, prior to intensive multimodal in-patient treatment. RESULTS The patient group had higher cortisol levels than controls, although the percentage suppression of cortisol output after prednisolone in comparison with placebo did not differ. Non-response to in-patient treatment was predicted by a more dysfunctional HPA axis (higher cortisol levels post-prednisolone and lower percentage suppression). CONCLUSIONS In patients with severe depression, HPA axis activity is reset at a higher level, although feedback remains intact. However, prospectively determined severe treatment resistance is associated with an impaired feedback response to combined glucocorticoid and mineralocorticoid receptor activation by prednisolone.

Salivary Cortisol Profiles in Chronic Fatigue Syndrome

Salivary cortisol profiles (hourly sampling over a 16-hour period) of 10 patients with chronic fatigue syndrome (CFS) but without concurrent depressive disorder were compared with those of 10 healthy volunteers matched for age, sex and menstrual cycle. The mean saliva cortisol concentration over the 16-hour period was slightly but significantly greater in the patients than the controls (p < 0.05). These findings are at variance with earlier reports that CFS is a hypocortisolaemic state and suggest that in CFS the symptom of fatigue is not caused by hypocortisolaemia.

Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers

The effects of acute administration of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers on habituation and prepulse inhibition (PPI) of the acoustic startle reflex in two experiments. In Experiment 1, 40 male non–smoker volunteers were tested for habituation and PPI (defined as percentage reduction of the pulse-alone amplitude; prepulses 9 dB above background) before and after double–blind administration of either 2mg haloperidol or placebo. No influence of haloperidol was observed on either habituation or PPI of the startle reflex in this experiment. In Experiment 2, 60 male volunteers underwent startle testing before and after double-blind administration of a single oral dose of 5 mg haloperidol, 5 mg damphetamine or placebo. Habituation and PPI (prepulses 15 dB above background) for the placebo group did not differ significantly from that observed for the rf-amphetamine or for the haloperidol group. However, in a subgroup of smoking subjects, both d-amphetamine and haloperidol reduced PPI as compared to that observed prior to drug administration. The implications of these findings in relation to animal pharmacological studies and observed sensorimotor gating deficits in schizophrenia are discussed. Behav Pharmacol 1998; 9:567— 576

The ratio of cortisol/DHEA in treatment resistant depression

OBJECTIVE Hypercortisolaemia has been well described in depression and may be a factor associated with treatment resistance. The role of the more abundant adrenal steroid dehydroepiandrosterone (DHEA) has been recently investigated, with some evidence that it may have an antiglucocorticoid effect. This study measured cortisol, DHEA and their ratio in treatment resistant depression (TRD) and healthy controls and also related these measures to treatment outcome. METHOD Plasma cortisol, DHEA and cortisol/DHEA ratio were determined at 0900h in 28 patients with TRD and 40 healthy controls. The measures were repeated following inpatient treatment in a subgroup of 21 patients and related to the outcome of such treatment. The stability of cortisol/DHEA ratios was assessed with 2 hourly samples from 0900 to 1700h in a subgroup of 15 controls. RESULTS Basal levels of cortisol and the cortisol/DHEA ratio were higher in patients compared to controls. Whilst cortisol levels were lower after treatment, there was no relationship between cortisol levels and treatment outcome. In contrast, treatment responders had significantly lower DHEA on admission and a higher cortisol/DHEA ratio both on admission and on discharge. Cortisol/DHEA ratios were stable between 9 a.m. and 5 p.m. CONCLUSIONS In addition to cortisol, the cortisol/DHEA ratio is raised in TRD; thus, there is no evidence that DHEA levels could negate the increased glucocorticoid activity in TRD. Patients with a more abnormal cortisol/DHEA ratio, possibly indicating greater biological dysfunction, responded preferentially to inpatient therapy, though the raised cortisol/DHEA ratio persisted after response. The cortisol/DHEA ratio is stable throughout the day and may be a more practical biological marker of TRD.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression

BACKGROUND Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

Salivary cortisol measurements during a medically assisted alcohol withdrawal

Previous studies using plasma cortisol estimations have suggested that hypothalmo‐pituitary‐axis (HPA) activation occurs in alcohol‐dependent patients during alcohol withdrawal. The present study set out to confirm this finding using salivary cortisol assays, which are a better indicator of plasma free cortisol, the fraction which exerts its physiological effects. Nine alcohol dependent patients provided four saliva samples (at 10 a.m., 2 p.m., 6 p.m. and 10 p.m.) on days 1, 3 and 7 of a medically assisted alcohol withdrawal (corresponding to 1, 3 and 7 days following the last drink, respectively).Withdrawal symptom severity, craving and mood disturbance were also measured. A group of non‐alcohol‐dependent individuals, without psychiatric or medical disorder, gave four samples at the same times on one day only. Mean daily cortisol levels in our alcohol‐dependent population, as calculated by the area under the curve (AUC), decreased significantly over time (mean AUC (nmol/l/hour) on day 1 = 149, on day 7 = 85.7, p = 0.009) and were significantly higher than controls on each day (mean AUC in controls = 28.3, p = 0.001). The cortisol response showed a similar temporal trend to withdrawal symptom severity and mood disturbance. This is consistent with previous studies measuring plasma cortisol in alcohol withdrawal. However, the magnitude of the effect in our study was greater, and in contrast to some previous studies, levels were far from normal by day 7. The comparatively low cortisol response in our one mildly dependent patient suggests that there may be a relationship between dependence severity and the size of the cortisol response to withdrawal. Salivary cortisol sampling could prove to be a useful prognostic tool, with implications for subsequent withdrawal symptom severity, mood disturbances, risk of relapse and alcohol‐related cognitive decline. There are implications for developing new treatments for alcohol withdrawal but more studies are needed.

Clomipramine In Vitro Reduces Glucocorticoid Receptor Function in Healthy Subjects but not in Patients with Major Depression

Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 μM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.

Effects of social support during weekend leave on cortisol and depression ratings: a pilot study

BACKGROUND The biological mechanism by which social support influences the course of a depressive episode may involve the stress response which is reflected and/or mediated by cortisol. The study took advantage of the weekend leave that inpatients receive towards the end of an admission to investigate the inter-relationship between social support, cortisol secretion, and the severity of depression. METHOD For 23 inpatients with a major depressive episode (DSM IV) differences between ward and home in social support, depression ratings, and cortisol secretion were compared. The effect of hassles on cortisol secretion was also assessed. RESULTS An inverse linear relationship was found between changes in social support and depression ratings across the two settings. No relationship was found between changes in the other two sets of variables. Hassles resulted in increased cortisol secretion. LIMITATIONS The small sample limits the analysis of hypotheses of interest. Findings are restricted to an inpatient tertiary referral sample. CONCLUSIONS Weekend leave is an appropriate paradigm to study the effect of social influences on cortisol secretion, and the severity of depression. It is feasible for depressed inpatients to accurately collect timed saliva samples both on the ward and when at home, and for research workers to measure social support provided by a ward. The relationship between social support and depression has clinical implications in terms of interpreting mood changes following weekend leave. Hassles are associated with increased secretion of cortisol in depressed patients, which extends similar previous findings in normal subjects.

A Comparison of Prepulse Inhibition in Pre-and Postmenopausal Women and Age-Matched Men

Prepulse inhibition (PPI) of the startle response is sensitive to sex with women showing less PPI compared with age-matched men and varies according to the menstrual cycle in women. Relatively less is known about sex differences in prepulse facilitation (PPF). To examine further the roles of sex and circulating sex hormones, pre- (n=20) and postmenopausal women (n=20) were compared with men of similar ages (n=17, 18–40 years; n=18, 55–69 years). All participants were assessed on PPI and PPF, and provided saliva samples for measurement of 17β-estradiol (estrogen) and testosterone. Premenopausal women showed less PPI compared with age-matched men, with no significant difference in PPF. Postmenopausal women did not differ in PPI but showed more PPF than age-matched men. There was less PPI and PPF in older, relative to young, men; pre- and postmenopausal women did not differ significantly. PPI showed no association with the levels of sex hormones. PPF showed small positive associations with both the levels of estrogen and testosterone, especially in young men. The present findings extend recent observations in mice showing less PPI in premenopausal, but not postmenopausal, female compared with male mice of similar ages (Ison and Allen, Behav Brain Res, 2007) to humans. There appear to be no substantial relationships between individual differences in endogenous levels of sex hormones and PPI; fluctuations within an individual may have a stronger role.