Steroids and depressionBMJ 1998; 316 doi: https://doi.org/10.1136/bmj.316.7127.244 (Published 24 January 1998) Cite this as: BMJ 1998;316:244
Glucocorticoid steroids affect behaviour and mood
Adrenal steroids are commonly prescribed drugs, the central effects of which are rarely alluded to in routine clinical practice or systematically investigated in medical research. Glucocorticoids are important in the pathogenesis of depression, but this potentially serious psychological side effect is often overlooked in clinical practice.
The unwanted behavioural effects of anabolic steroids are widely known, but those of glucocorticoid therapy, though recognised for over 45 years, receive less attention. Placebo controlled studies have reported that a third of patients taking glucocorticoids experience significant mood disturbance and sleep disruption.1 More importantly, up to 20% of patients on high dose glucocorticoids report psychiatric disorders including depression, mania, psychosis, or a mixed affective state.2 A recent double blind placebo controlled trial of corticosteroid administration in healthy individuals showed that 75% of subjects developed disturbances in mood and cognition, which reversed when steroids were stopped.3 We do not know the characteristics of those who are vulnerable to adverse effects, but those with higher cumulative dosages appear to be most at risk.
Dysregulation of the hypothalamo-pituitary adrenal axis in depression is one of the oldest and most consistent findings in biological psychiatry. A large scale meta-analysis of over 140 studies using the low dose dexamethasone suppression test illustrated that persistent adrenocortical hyperactivity is a robust indicator of poor prognosis and a weaker predictor of suicide in depression.4 From the physicians' view point, medical disorders which feature sustained overdrive of the hypothalamo-pituitary axis carry an unexpectedly high risk of mood disorders. Patients with Cushing's disease, stroke, or chronic alcoholism, and those taking long term steroid treatment have a reported prevalence of depression above 50%.5 The precipitation of dysregulation of the hypothalamo-pituitary axis by environmental stressors may be important in the onset of both Cushing's disease and depression.6 However, not all increases in adrenocortical activity are associated with pathological consequences, and, as the core mediator of the neuroendocrine stress response, an acute failure of activation of the hypothalamo-pituitary axis is equally hazardous in animal and man. In fact, underactivity of the axis may be associated with a range of psychiatric disorders, the most extensively investigated being post-traumatic stress disorder.7
Overall, data from conditions of both exogenous and endogenous steroid excess provide support for a glucocorticoid theory of depression.8 But, if glucocorticoids contribute to the syndrome of major depression, several vexing questions remain. If patients with primary depression have long term cortisol hypersecretion, albeit at a low grade, why don't they have the peripheral stigmata seen in Cushingoid patients? One explanation, which is mooted by some authors to be central to the pathophysiology of depression, is that of partial glucocorticoid resistance at the receptor level. This receives some support from in-vitro studies of type II glucocorticoid receptors.9 However, many depressed patients do show some of the peripheral and central manifestations of Cushing's disease including immunosuppression, osteoporosis, central obesity, menstrual irregularities, and muscle weakness, as well as sleep disturbances and cognitive impairment.
In an attempt to examine central control of the hypothalamo-pituitary axis, some 14 studies have measured levels of corticotrophin releasing factor in the cerebrospinal fluid of depressed patients versus controls (references available from the authors). Five studies found significantly higher concentrations in depressed patients. More conclusively, immunocytochemical analysis of postmortem hypothalami from patients with depression have shown a fourfold increase in corticotrophin releasing factor expressing neurons relative to age matched controls.10 Blocking adrenal steroid synthesis using metyrapone results in augmented levels of adrenocorticotrophic hormone in depressed individuals compared with controls. This, together with blunting of responses to pituitary challenge tests, suggests that peripheral hypercortisolaemia masks central overdrive of the hypothalamo-pituitary axis in depression, via feedback inhibition by glucocorticoids.11 This pathological overdrive may be maintained by the neurotoxic actions of glucocorticoids on the hippocampus, since the hippocampus is the principal locus for feedback inhibition of the hypothalamo-pituitary axis and also the site most vulnerable to damage mediated by glucocorticoids. Of note, in vivo hippocampal atrophy has been documented via magnetic resonance imaging in both depression and Cushing's disease, and preliminary evidence suggests that hippocampal atrophy correlates with plasma cortisol levels.12 Ultimately, the risk factors which govern the development and maintenance of dysregulation of the hypothalamo-pituitary axis in adults may also be those which are relevant in depression: for example, genetic predisposition, early life events, aging, comorbidity, and psychosocial stressors.
The therapeutic potential of antiglucocorticoid drugs has recently been explored in patients with mood disorders. Encouraging results with steroid synthesis inhibitors used in the treatment of depression in patients with Cushing's disease led to several successful controlled trials in primary depressive disorder.8 Furthermore, a re-examination of the actions of conventional antidepressants hints at a mechanism which involves reduction in activity of the hypothalamo-pituitary axis, a previously overlooked possibility.
Overall, chronically raised concentrations of glucocorticoids from endogenous or exogenous sources can produce severe disturbances in mood, and clinicians need to be aware of the potential consequences.