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.

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.

Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.

Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

Changes in the maternal hypothalamic-pituitary-adrenal axis during the early puerperium may be related to the postpartum 'blues'.

Most women experience time-limited and specific mood changes in the days after birth known as the maternity blues (Blues). The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes gradual changes during pregnancy because of an increasing production of placental corticotrophin-releasing hormone (CRH). The abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery. These changes may be involved in the aetiology of the Blues given the central role of the HPA axis in the aetiology of mood disorders in general, and in perinatal depression in particular. We aimed to test the novel hypothesis that the experience of the Blues may be related to increased secretion of hypothalamic adrenocorticotrophic hormone (ACTH) secretagogue peptides, after the reduction in negative-feedback inhibition on the maternal hypothalamus caused by withdrawal of placental CRH. We therefore examined hormonal changes in the HPA axis in the days after delivery in relation to daily mood changes: our specific prediction was that mood changes would parallel ACTH levels, reflecting increased hypothalamic peptide secretion. Blood concentrations of CRH, ACTH, cortisol, progesterone and oestriol were measured in 70 healthy women during the third trimester of pregnancy, and on days 1-6 post-delivery. Blues scores were evaluated during the postpartum days. Oestriol, progesterone and CRH levels fell rapidly from pregnancy up to day 6, whereas cortisol levels fell modestly. ACTH concentrations declined from pregnancy to day 3 post-delivery and thereafter increased up to day 6. Blues scores increased, peaking on day 5, and were positively correlated with ACTH; and negatively correlated with oestriol levels during the postpartum days, and with the reduction in CRH concentrations from pregnancy. These findings give indirect support to the hypothesis that the 'reactivation' of hypothalamic ACTH secretagogue peptides may be involved in the aetiology of the Blues.

Increased pituitary-adrenal activation and shortened gestation in a sample of depressed pregnant women: a pilot study.

BACKGROUND: Major depression (MD) is frequently accompanied by a relatively increased production of the stress hormone cortisol. During pregnancy corticotrophin releasing hormone (CRH) is secreted from the placenta and critically high levels of CRH are one of the key triggers for parturition. Maternal cortisol promotes the secretion of placental CRH. In this study, we examined the hypothesis that women suffering with MD in pregnancy would have relatively increased cortisol secretion, a time-advanced rise in placental CRH production and an earlier delivery of the baby. METHODS: A group of medication-free pregnant women, free of know obstetric and medical complications, with (n=27) and without (n=38) MD were recruited. Blood concentrations of CRH, adrenocorticotrophic hormone (ACTH) and diurnal salivary cortisol concentrations were measured at fixed time points. RESULTS: Maternal cortisol concentrations were highly correlated with placental CRH secretion for the entire group. Second trimester CRH concentrations and mean evening salivary cortisol concentrations were significantly higher in the depressed women. Although pregnancy length was shorter in the depressed women there were no statistical relationships between the stress hormone measures and pregnancy length. LIMITATIONS: The sample size was small and highly selected. CONCLUSIONS: These findings suggest that depressed pregnant women hypersecrete cortisol in a diurnal pattern similar to that typical of MD, and that this leads to a time-advanced rise in placental CRH secretion. Factors other than this stress-delivery mechanism may be contributing to the shortened pregnancy length in depressed women.

A survey of Cambodian health-care providers' HIV knowledge, attitudes and intentions to take a sexual history.

Cambodia has one of the highest prevalence rates of HIV in Asia and is scaling up HIV testing. We conducted a cross-sectional survey with 358 health care providers in Phnom Penh, Cambodia to assess readiness for voluntary testing and counselling for HIV. We measured HIV knowledge and attitudes, and predictors of intentions to take a sexual history using the Theory of Planned Behaviour. Over 90% of health care providers correctly answered knowledge questions about HIV transmission, but their attitudes were often not positive towards people living with HIV. The Theory of Planned Behaviour constructs explained 56% of the variance in intention to take a sexual history: the control providers perceive they have over taking a sexual history was the strongest contributor (51%), while social pressure explained a further 3%. Attitudes about taking a sexual history did not contribute to intention. Interventions with Cambodian health care providers should focus on improving skills in sexual history-taking.

Vagus nerve stimulation for depression: efficacy and safety in a European study.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

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.

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.

Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia.

BACKGROUND: High rates of osteoporosis in schizophrenia may result from the prolactin-raising effects of some antipsychotic medication. Aims To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics. METHOD: Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for >10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones. RESULTS: Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values. CONCLUSIONS: These results suggest that patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.

Bupropion in the management of apathy.

We report on three males with prominent apathy as part of the symptom complex of depression or organic brain disease. Significant clinical responses were observed following treatment with bupropion, an antidepressant with dopamine (DA) reuptake activity. We present clinical evidence in support of the hypothesis that remission in these patients occurred as a consequence of bupropion-induced increases in central DA neurotransmission.

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.

Central 5-HT receptor hypersensitivity in migraine without aura.

Serotonin has long been implicated as a key neurotransmitter in migraine. There is a dearth of research specifically examining 5-HT1A receptor sensitivity in migraine despite the importance of this receptor in regulating central serotonergic tone. In this study we examined the hypothesis that migraine without aura is associated with hypersensitivity of central 5-HT1A receptors, using a 5-HT1A neuroendocrine challenge drug and comparing serum prolactin responses between a test group with migraine and a matched group of healthy controls. Twelve female subjects fulfilling International Headache Society (IHS) criteria for migraine without aura were evaluated. Following an overnight fast, subjects presented for testing at 9am. An intravenous canula was inserted and serum prolactin was assessed at baseline and every 30 min for 3 h following a single dose of 30 mg oral buspirone, a 5-HT1A-receptor agonist. Subjects were assessed during the first 5 days of the menstrual cycle. No subjects were taking psychotropic medication or migraine prophylactic treatment. Patients with current or previous psychiatric disorder, daily headache or analgesic overuse were excluded. 16 healthy female volunteers matched for age and menstrual status were also evaluated and served as controls. There was no difference in baseline prolactin between groups. There was a significant rise in prolactin following buspirone in both groups. Subjects with migraine had a significantly increased prolactin response to buspirone (delta max) compared to controls (P < 0.001). This study supports the hypothesis that migraine without aura is associated with a relative hypersensitivity of central 5-HT1A receptors. This is of relevance given the role of the 5-HT1A receptor in controlling raphe 5-HT tone and in the possible association between migraine and anxiety and depression.

Sexual dysfunction in patients taking conventional antipsychotic medication.

BACKGROUND: Antipsychotic drugs are associated with sexual dysfunction but the mechanisms are poorly understood. AIMS: To ascertain the frequency of sexual dysfunction in patients taking conventional antipsychotics and to determine the possible underlying mechanisms. METHOD: Sexual dysfunction was assessed in 101 patients receiving conventional antipsychotic medication, 57 normal controls and 55 controls attending a sexual dysfunction clinic. RESULTS: Sexual dysfunction occurred in 45% of patients taking antipsychotic medication, 17% of normal controls and 61% of controls attending a sexual dysfunction clinic. Sexual dysfunction was associated with autonomic side-effects in normoprolactinaemic males, but the presence of hyperprolactinaemia overrode other causes of sexual dysfunction. For women, hyperprolactinaemia was the main cause of sexual dysfunction. CONCLUSIONS: Conventional anti-psychotic medications cause significant levels of sexual dysfunction. Clinicians should routinely enquire about sexual symptoms prior to the prescription of antipsychotics and on follow-up.

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.

Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion.

OBJECTIVE: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS. DESIGN: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS. PATIENTS: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls. MEASUREMENTS: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo. RESULTS: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS. CONCLUSIONS: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.