Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. METHODS: This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. FINDINGS: Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2-24·4] in the metyrapone group vs 22·6 points [20·1-24·8] in the placebo group; adjusted mean difference of -0·51 points [95% CI -3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. INTERPRETATION: Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities. FUNDING: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).

BACKGROUND: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. METHODS/DESIGN: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. DISCUSSION: Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Anticonvulsants in bipolar disorder.

Anticonvulsant drugs are widely used in psychiatric indications. This includes alcohol and benzodiazepine withdrawal symptoms, panic and anxiety disorders, dementia, schizophrenia, and to some extent personality disorders. Besides pain syndromes, their main domain outside epilepsy, however, is bipolar disorder. Carbamazepine, valproate, and lamotrigine are meanwhile recognized mood stabilizers, but several other antiepileptic drugs have also been tried out with diverging or inconclusive results. Understanding the mechanisms of action and identifying similarities between anticonvulsants effective in bipolar disorder may also enhance our understanding of the underlying pathophysiology of the disorder.

Switching, induction of rapid cycling, and increased suicidality with antidepressants in bipolar patients: fact or overinterpretation?

Antidepressants constitute a central cornerstone in the treatment of depressive syndromes. In bipolar patients, however, there is an ongoing controversy about their usefulness for at least 3 decades. Early reports, mainly concerning tricyclic antidepressants, have repeatedly pointed toward unfavorable side effects on the course of the disorder, namely switching into (hypo)mania, induction of rapid cycling, and increased risk of suicide. Most evidence for both unfavorable and favorable effects has been deducted, thus far, from small studies with methodological flaws. More substantiated evidence only recently became available. From this it appears that, at least, the switch risk, and perhaps also the risk for rapid cycling and new-onset suicidality have been overinterpreted. At the same time, these new data raise doubt about the efficacy of antidepressants as a primary-treatment choice in bipolar depression.

The effectiveness of anticonvulsants in psychiatric disorders.

Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.