Metyrapone as Additive Treatment in Major Depression

Jahn, Holger; Schick, Mildred; Kiefer, Falk; Kellner, Michael; Yassouridis, Alexander; Wiedemann, Klaus

doi:10.1001/archpsyc.61.12.1235

Cited by 163 publications

(62 citation statements)

References 78 publications

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“…The study extends research in this area by exploring the translatability of the proof-of-concept study described by Jahn et al 33 to an outpatient, primary and secondary care, UK NHS population. To date, all published studies of the use of antiglucocorticoids in patients with TRD have used short treatment periods of 1-3 weeks, 27 which can appear counterintuitive in such a potentially chronic condition.…”

Section: Objectivesmentioning

confidence: 71%

“…There have been several open -including randomised -studies of metyrapone augmentation of antidepressants, showing efficacy in TRD. [28][29][30][31][32] In addition, a successful proof-of-concept double-blind, placebo-controlled randomised study has been conducted by Jahn et al 33 in a centre in Germany, with 63 depressed inpatients. Patients were all being treated with a serotonergic antidepressant and were randomised to add-on treatment with metyrapone (1 g/day for 3 weeks) or placebo.…”

Section: Scientific Backgroundmentioning

confidence: 99%

“…The MADRS has preferable psychometric properties and higher sensitivity to change than other depression rating scales, 82 and was associated with the largest effect size in the Jahn study. 33 Additional secondary outcome measures of symptomatology [CAS, 83 86 ] were conducted at the same time points as described for the MADRS. QoL was assessed using the self-completed EuroQol EQ-5D instrument (www.euroqol.org/) 87 and tolerability using the Toronto Side Effects Scale (TSES).…”

Section: Follow-upmentioning

confidence: 99%

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Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

et al. 2015

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BackgroundDepressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. TheAntiglucocorticoid augmentation of antiDepressants inDepression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.ObjectiveTo determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.MethodsA total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.ResultsThe estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.DiscussionThe inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.ConclusionsThe results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.Trial registrationCurrent Controlled Trials ISRCTN45338259.Funding detailsThis study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

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Section: Objectivesmentioning

confidence: 71%

Section: Scientific Backgroundmentioning

confidence: 99%

Section: Follow-upmentioning

confidence: 99%

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Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

et al. 2015

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“…In a double-blind, randomized, placebo-controlled trial, metyrapone showed efficacy as adjunctive treatment in major depression, accelerating the onset of antidepressant action. 35 Ketoconazole also showed to reduce cortisol levels in major depression, but these preliminary results need replication.…”

Section: Stress and Glucocorticoids: Potential Targets For Treatment-mentioning

confidence: 96%

Transtornos de humor refratários a tratamento

Machado‐Vieira

Soares²

2007

Rev. Bras. Psiquiatr.

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A b s t r a c t Objective and Method: Mood disorders are the most prevalent psychiatric disorders. Despite new insights and advances on the neurobiological basis and therapeutic approaches for bipolar disorders and recurrent depression, elevated prevalence of recurrence, persistent sub-syndromal symptoms and treatment resistance are challenging aspects and need to be urgently addressed. The objective of this literature review is to evaluate the current concepts of treatment resistance and refractoriness in mood disorders. Results: Genetic factors, misdiagnosis, use of inappropriate pharmacological approaches, non-compliance and biological/psychosocial stressors account for dysfunctions in mood regulation, thus increasing the prevalence of refractory mood disorders. Regarding available treatments, the use of effective doses during an adequate period followed by augmentation with a second and/or third agent, and finally switching to other agent are steps frequently necessary to optimize efficacy. However, in the treatment-resistant paradigm, drugs mimicking standard strategies, which target preferentially the monoaminergic system, can present reduced therapeutic effects. Thus, the search for new effective treatments for mood disorders is critical to decreasing the overall morbidity secondary to treatment resistance. Conclusion: Emerging strategies targeting brain plasticity pathways or 'plasticity enhancers', including antiglutamatergic drugs, glucocorticoid receptor antagonists and neuropeptides, have been considered promising therapeutic options for difficult-to-treat mood disorders.Descriptors: Depressive disorder, major; Bipolar disorder; Mood disorders; Antidepressive agents; Refractory period, psychologicalResumo Objetivos e Método: Os transtornos de humor estão entre os transtornos psiquiátricos mais prevalentes. Apesar de novas descobertas e avanços no estudo das bases neurobiológicas e abordagens terapêuticas no transtorno bipolar e depressão recorrente, elevadas taxas de recorrência, sintomas subsindrômicos persistentes e refratariedade terapêutica são aspectos clínicos desafiadores e precisam ser abordados. O objetivo desta revisão da literatura é avaliar os conceitos e critérios de resistência e refratariedade ao tratamento, e evidenciar as principais alternativas terapêuticas para transtornos do humor resistentes aos tratamentos disponíveis. Resultados: Fatores genéticos, erro diagnóstico e de tratamento, não-aderência, e estressores biológi-cos e psicossociais podem levar à perda de mecanismos regulatórios e a aumento na prevalência de casos de refratariedade nos transtornos de humor. Com relação aos tratamentos disponíveis, o uso de doses apropriadas, seguido por associação com um segundo ou terceiro fármaco, e após, se indicado, a troca de medicação, são etapas necessárias na busca de melhor eficácia. Entretanto, no paradigma de refratariedade terapêutica, tratamentos atuando em sistemas já conhecidos, especialmente monoaminas, frequentemente apresentam limitada eficácia. Assim, a busca por tratame...

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“…3,198,199 Furthermore, they accelerate antidepressant action of SSRIs in patients. 200,201 Glucocorticoid antagonists attenuate the reduction of synaptic plasticity by stress, display antidepressant actions in rodents, and exert a positive influence on mood (and cognition) in association with SSRIs in psychotic depression, which is characterized by a pronounced overactivation of the HPA axis. 3,167,197,[202][203][204] The beneficial effects of GR antagonists and metyrapone involve a sustained induction of mineralocorticoid receptors, as well as serotonergic and dopaminergic mechanisms.…”

Section: Innovative Neuroendocrine Mechanisms: Calming Hpa Axis Overdmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

180

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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Metyrapone as Additive Treatment in Major Depression

Abstract: Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.

Cited by 163 publications

References 78 publications

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

Transtornos de humor refratários a tratamento

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

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