The psychedelic renaissance: the next trip for psychiatry?

The psychedelic research renaissance is gaining traction. Preliminary clinical studies of the hallucinogenic fungi, psilocybin, with psychological support, have indicated improvements in mood, anxiety and quality of life. A seminal, open-label study demonstrated marked reductions in depression symptoms in participants with treatment-resistant depression (TRD). The associated neurobiological processes involve alterations in brain connectivity, together with altered amygdala and default mode network activity. At the cellular level, psychedelics promote synaptogenesis and neural plasticity. Prompted by the promising preliminary studies, a randomized, double-blind trial has recently been launched across Europe and North America to investigate the efficacy of psilocybin in TRD. One of these centres is based in Ireland - CHO Area 7 and Tallaght University Hospital. The outcome of this trial will determine whether psilocybin with psychological support will successfully translate into the psychiatric clinic for the benefit of patients.

Psychedelic science in post-COVID-19 psychiatry.

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Assessing the needs of pregnant women and mothers with severe mental illness: the psychometric properties of the Camberwell Assessment of Need - Mothers (CAN-M).

There is an absence of standardized validated instruments to assess the complex needs of pregnant women and mothers with severe mental illness. We aimed to develop a standardized assessment of need for pregnant women and mothers with severe mental illness. Staff and service users were asked to identify relevant domains of need. Professional experts and service users were then surveyed and asked to rate the importance of the domains of the Camberwell Assessment of Need - Mothers version (CAN-M). Reliability was established using 36 service user-staff pairs. Concurrent validity was assessed with the Global Assessment of Functioning. Inter-rater reliability (concordance) coefficients for unmet needs were 0.93 (95% confidence interval 0.89 to 0.98) (service users) and 0.83 (95% confidence interval 0.73 to 0.94) (staff); test-retest reliability coefficients were 0.91 (95% confidence interval 0.86 to 0.97) and 0.85 (95% confidence interval 0.73 to 0.96), respectively. Relevant CAN-M domains correlated with the Global Assessment of Functioning-symptom (Spearman's r correlation coefficient = -0.36, 95% confidence interval = -0.62 to -0.04, p = 0.05) and Global Assessment of Functioning-disability subscales (Spearman's r correlation coefficient = -0.52, confidence interval = -0.73 to -0.23, p < 0.01). We conclude that the CAN-M is a reliable and valid instrument for assessing the needs of pregnant women and mothers with severe mental illness.

Bone mineral density changes over a year in young females with schizophrenia: relationship to medication and endocrine variables.

INTRODUCTION: Hyperprolactinaemia is associated with the use of potent dopamine-2 receptor blocking anti-psychotic agents in schizophrenia and with bone loss in the general population. Significantly higher rates of reduced bone mineral density (BMD) have been identified in young pre-menopausal females with schizophrenia receiving prolactin-raising anti-psychotics compared to those receiving prolactin-sparing anti-psychotics. This prospective study compared BMD alterations over a period of 1 year in patients maintained on either prolactin-raising (e.g. risperidone, amisulpride or depot anti-psychotics) or prolactin-sparing (olanzapine) anti-psychotics. The effects of specific interventions to improve BMD were also examined in the context of whether patients were receiving either prolactin-raising or anti-psychotics or Olanzapine. METHODS: Pre-menopausal females (n=38) with a diagnosis of schizophrenia, who had received exclusively either prolactin-raising (n=25) or prolactin-sparing (n=13) anti-psychotics during their treatment history, had clinical, endocrine and bone marker assessments performed at baseline and every 3 months for a period of 1 year. BMD was measured by DEXA scan at baseline and at 1-year follow-up. Patients from both groups either received specific interventions (n=16) or no interventions (n=16) to improve bone density. RESULTS: There was an overall gain in lumbar BMD values in the prolactin-sparing subgroup, compared to an overall loss in the prolactin-raising subgroup (p=0.02), for the groups that received no specific interventions to improve BMD. Within the group that received specific interventions, the subgroup receiving prolactin-sparing anti-psychotics had a significant increase in lumbar (p=0.01) and hip (p=0.01) BMD over time, whereas alterations in the prolactin-raising subgroup were not significant. DISCUSSION: Women taking prolactin-raising anti-psychotics and not receiving specific interventions to improve bone density had evidence of ongoing bone demineralisation over a year; whereas women taking prolactin-sparing anti-psychotics had a modest overall increase in BMD. Most clinical interventions appeared to be helpful, but were significantly more effective in those taking prolactin-sparing anti-psychotics.

Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.

BACKGROUND: Lithium is the mainstay of treatment for bipolar disorder, mania and an augmentation therapy in patients with treatment resistant depression. It has a narrow therapeutic index, with recognized adverse multi-system and endocrine side effects. AIM: To assess the impact of lithium therapy, in particular lithium toxicity, on the development of endocrine and renal disorders in a cohort of patients in a single tertiary referral centre in Ireland. STUDY DESIGN: A retrospective analysis was performed of the prevalence of lithium toxicity and renal, thyroid and parathyroid dysfunction in our study population. METHODS: We collected laboratory data from the Clinical Chemistry department of the Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland. Our study population included all patients who had at least one serum lithium measurement from January 1st 2000 to December 31st 2014 inclusive. RESULTS: A total of 580 patients were included in the study. Among our study group, 70 patients (12.1%) had 1 toxic lithium measurement (lithium level >1.2 mmol/l). 27.8% (n > 161) of patients developed stage 3 Chronic kidney Disease (CKD) or higher, which was commoner in those patients who developed toxic lithium levels (P < 0.0001) and in those who developed hypernatraemia (P > 0.0001). 16.2% of patients (n > 94) had one serum sodium >145 mmol/l during follow up. 60 patients(10.3%) had a TSH >10 mU/l, while complete suppression of TSH (<0.05 mU/l) was observed in 22 patients (3.8%) during follow-up. 4% (n > 37) of the study population had ≥1 serum corrected calcium level > 2.55 mmol/l, and 4 patients had biochemical confirmation of primary hyperparathyroidism but PTH levels were only performed in 2.8% (n > 16) of the studypopulation. CONCLUSION: Stage 3 CKD is common in patients receiving lithium therapy. Lithium toxicity is associated with CKD and hypernatraemia. Thyroid dysfunction and hypercalcaemia are common in patients receiving lithium therapy. Patients receiving lithium therapy require surveillance of renal, thyroid and bone biochemistry.

How social context impacts on the development, identification and treatment of mental and substance use disorders among young people - a qualitative study of health care workers.

Introduction Social context has a major influence on the detection and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas, particularly where gang culture, community violence, normalisation of drug use and repetitive maladaptive family structures prevail. This paper aims to examine how social context influences the development, identification and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas from the perspectives of health care workers. METHOD: Semi-structured interviews were conducted with health care workers (n=37) from clinical settings including: primary care, secondary care and community agencies and analysed thematically using Bronfenbrenner's Ecological Theory to guide analysis. RESULTS: Health care workers' engagement with young people was influenced by the multilevel ecological systems within the individual's social context which included: the young person's immediate environment/'microsystem' (e.g., family relationships), personal relationships in the 'mesosystem' (e.g., peer and school relationships), external factors in the young person's local area context/'exosystem' (e.g., drug culture and criminality) and wider societal aspects in the 'macrosystem' (e.g., mental health policy, health care inequalities and stigma). CONCLUSIONS: In socioeconomically disadvantaged urban areas, social context, specifically the micro-, meso-, exo-, and macro-system impact both on the young person's experience of mental health or substance use problems and services, which endeavour to address these problems. Interventions that effectively identify and treat these problems should reflect the additional challenges posed by such settings.

Sex steroid priming effects on growth hormone response to pyridostigmine throughout the menstrual cycle.

To explore the effect of estradiol and progesterone on the GH response to the indirect cholinergic agonist pyridostigmine nine healthy women were challenged with both active drug and placebo at three time points in two consecutive menstrual cycles: a total of six neuroendocrine tests. A randomized, double-blind, counterbalanced design was used. Subjects were tested in the early follicular, mid-cycle, and luteal phases of the cycle. A cannula was inserted in a forearm vein after an overnight fast and baseline GH, estradiol, and progesterone samples were drawn. After 120 mg oral pyridostigmine or placebo tablets further blood samples for GH analysis were drawn at intervals over 3 h. When expressed as maximum change from baseline (delta GH) mean GH responses to pyridostigmine increased incrementally from early (8.4 +/- 2.7 micrograms/L) through mid (18 +/- 1.3 micrograms/L) to late (22.2 +/- 1.9 micrograms/L) cycle. This represents a significant effect of cycle phase on the GH response to pyridostigmine (P less than 0.001, as assessed by analysis of variance). Responses to placebo did not vary. Plasma estradiol values were significantly correlated with GH responsivity to active drug throughout the cycle (P less than 0.02). Multiple regression analysis also revealed a significant positive correlation between progesterone levels and GH response to pyridostigmine (P less than 0.02). Estrogens augment GH responses to other challenges but a priming effect of progesterone on GH responsivity has not previously been demonstrated. Various mechanisms are discussed including a possible sex steroid priming effect on acetylcholine neurotransmission.

Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome.

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS. This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin. There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls. CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.

These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.

Growth hormone responses to pyridostigmine in schizophrenia: evidence for cholinergic dysfunction.

The hypothesis that increased central cholinergic neurotransmitter function may be present in schizophrenic illness and may underlie negative symptoms was tested using a neuroendocrine challenge approach. The cholinergic challenge used was the anticholinesterase pyridostigmine, thought to cause the release of growth hormone (GH) from the anterior pituitary by diminishing inhibitory somatostatin tone. Eleven patients, six neuroleptic-naive and five neuroleptic-free, satisfying DSM-III-R criteria for schizophrenia and 11 matched controls took part. Subjects received pyridostigmine (120 mg orally) and blood was sampled at 0, 60, 90, 120, and 180 min for GH estimation. Peak GH responses were significantly increased in the schizophrenic group compared to controls. There was no relationship between individual peak GH values and negative symptom ratings (Scale for the Assessment of Negative Symptoms). Neither could a relationship be established between other aspects of psychopathology or dyskinesias and GH responses. An increased pyridostigmine/GH response is also found in affective disorders and could be related to nonspecific symptoms common to all these diagnostic groups. This study suggests that schizophrenia may be associated with increased cholinergic neurotransmitter function but the relationship between this cholinergic dysfunction and schizophrenia may involve psychopathology not specific to schizophrenia.

Assessment of serotonergic function in major depression using d-fenfluramine: relation to clinical variables and antidepressant response.

BACKGROUND: d-Fenfluramine, a specific serotonin (5-HT)-releasing agent without the catecholamine effects of d,l-fenfluramine, was used as a serotonergic neuroendocrine challenge in subjects with unipolar major depression. METHODS: Patients were given 30 mg of d-fenfluramine orally, and prolactin and cortisol responses were measured over the following 5 hours. Endocrine responses were examined in relation to clinical variables and subsequent response to antidepressant treatment. RESULTS: 5-HT-mediated cortisol responses at baseline were inversely correlated with depression severity on the Montgomery Asberg Depression Rating Scale, Bech Melancholia Scale, and Clinical Global Impression scale. Prolactin responses were inversely correlated with anxiety on the Brief Symptom Inventory. A higher initial cortisol response to d-fenfluramine predicted a subsequent good antidepressant response. CONCLUSIONS: We conclude that: a) the severity and symptom profile in major depression may be closely related to 5-HT dysfunction; and b) higher cortisol responses to d-fenfluramine predict a preferential response to treatment.

Effect of fluoxetine on noradrenergic mediated growth hormone release: a double blind, placebo-controlled study.

Twelve patients with DSM-III-R major depressive illness were tested for growth hormone (GH) response to desipramine (DMI), a noradrenergic (NA) reuptake inhibitor. The response is mediated by NA alpha 2 receptors. They were then randomly assigned to treatment under double-blind conditions with either fluoxetine, the highly selective serotonin reuptake inhibitor or placebo. After 4 weeks they were retested. Fluoxetine but not placebo was effective in promoting recovery in four of the six patients treated. Patients treated with fluoxetine showed a significant decrease in DMI-mediated GH release irrespective of therapeutic outcome. This is consistent with marked alteration of NA function and raises questions as to the selectivity of fluoxetine.

Specificity of the pyridostigmine/growth hormone challenge in the diagnosis of depression.

Acetylcholine is a neurotransmitter that has been implicated in the pathophysiology of major depression. This is supported by the enhanced growth hormone (GH) release in response to pyridostigmine (PYD) challenge in depressed subjects relative to healthy comparison subjects. The aim of this study is to examine the specificity of the PYD/GH challenge in the diagnosis of depression. Pyridostigmine 120 mg orally, was administered to a total of 116 physically healthy subjects. Growth hormone responses were studied in 38 patients with (DSM-III-R) major depression, 13 subjects with panic disorder, 9 subjects with schizophrenia, 10 recently detoxified alcoholics, and a comparison group of 46 healthy volunteers. Mean delta GH (the difference between basal and maximal GH following PYD) was significantly greater than comparison subjects in patients with major depression. Responses observed in patients with schizophrenia and alcohol dependence syndrome did not differ from the comparison group. Those patients with panic disorder and a high Hamilton depression score had an enhanced delta GH. The sensitivity of the PYD/GH test was 63% for major depression. These results indicate that the PYD/GH test may help distinguish depression from schizophrenia, alcohol-dependence syndrome, or panic disorder with a low Hamilton depression score.

Plasma homovanillic acid profile at different phases of the ovulatory cycle in healthy women.

Variation in some central monoamine levels has been shown to be influenced by cyclical changes in gonadal hormones in women; however, there is less consensus about how the human menstrual cycle affects turnover of dopamine. Fluctuations in plasma homovanillic acid (HVA) are thought to represent changes in central dopamine turnover and activity and, some suggest, may be used to monitor the response to neuroleptic medication or to predict those more likely to respond to antipsychotic treatment. We have measured the effect of fluctuations in gonadal hormones on the level of plasma HVA at four consecutive points across the menstrual cycles of 30 healthy volunteers. We found no significant change in plasma HVA over the cycle and there was no correlation with either estradiol or progesterone levels. This study suggests that peripheral markers of central dopamine function do not change significantly with physiological changes in gonadal hormones levels.

Prolactin and cortisol responses to d-fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function.

OBJECTIVE: Theoretically, d-fenfluramine should be a more selective serotonin (5-HT) challenge agent and has much greater clinical tolerance than the racemic compound that has previously been used. The authors' goal, therefore, was to look at 5-HT function in depression using the d isomer of fenfluramine as a probe. METHOD: They evaluated central 5-HT function in 23 patients with DSM-III-R-diagnosed major depression and 16 healthy control subjects. The depressed group included 10 men and 13 women; four were outpatients, two attended a day hospital facility, and 17 were inpatients. Subjects were cannulated at 8:30 a.m. after an overnight fast. After baseline samples were drawn, 30 mg of d-fenfluramine was administered orally and blood samples were drawn over the following 5-hour period for prolactin and cortisol estimation. RESULTS: The plasma prolactin responses of the depressed patients were significantly lower than those of the control subjects. This blunting was not related to the severity of the depression but was significantly related to the patients' levels of state anxiety. Cortisol responses as well as prolactin responses were impaired in depression. High baseline cortisol levels were correlated with the severity of depression and the presence of weight loss. CONCLUSIONS: Overall, these findings indicate that there is diminished 5-HT responsivity in the depressed state.

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.

Blunting of noradrenergic-stimulated growth hormone release in mania.

Seven drug-free patients with bipolar affective disorder, currently in a manic phase, underwent desipramine-induced growth hormone (GH) stimulation, as did seven healthy age- and sex-matched subjects. There was significant blunting of GH release in the manic patients, suggesting a down-regulation of alpha 2-noradrenergic responses. Blunting of GH release was not related to severity of symptoms, duration of illness, or age. Similar blunting has previously been described in depressed patients.

Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred.

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder linked to chromosome 19q13 that is characterized by sudden onset of primarily bulbar and upper limb dystonia with parkinsonism. METHODS: The authors evaluated 12 individuals from three generations of an Irish family and obtained detailed medical records on a deceased member. The authors describe the clinical, psychiatric, and genetic features of the affected individuals. RESULTS: Five of eight affected members developed sudden-onset (several hours to days) dystonia with postural instability. Four of the five also had bulbar symptoms. Two have stable focal or segmental limb dystonia. One has intermittent hemidystonia with dysarthria that comes on abruptly in times of stress or anxiety. Three had a history of profound difficulty socializing, and at presentation two developed depression. Three patients had a trial of dopamine agonists without benefit. Genetic analysis suggests linkage to chromosome 19 with lod score of 2.1 at zero recombination. CONCLUSION: This is the third reported family with chromosome 19q13 rapid-onset dystonia-parkinsonism. Psychiatric morbidity appeared common in affected members of this family and may be part of the RDP phenotype.

Reduced prolactin and cortisol responses to d-fenfluramine in depressed compared to healthy matched control subjects.

d-Fenfluramine, a specific 5-HT releasing agent without the catecholamine effects of d,l-fenfluramine, was used as a neuroendocrine challenge in 19 subjects with major depression and 19 healthy controls. Patients and controls were matched for age, sex, weight, and menstrual status. 5-HT-mediated prolactin and cortisol responses were both significantly attenuated in the depressed group. Patients with a history of a suicide attempt had lower cortisol responses than those without. Peak cortisol responses were inversely related to baseline cortisol levels. There were also significant relationships between hormone responses and both age and weight. These findings replicate those of a previous study using this challenge and reiterate the role of reduced 5-HT activity in suicide. They also reinforce the need for careful matching in neuroendocrine studies.

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome.

BACKGROUND: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone. METHODS: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol. RESULTS: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029). CONCLUSIONS: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.