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Br J Psychiatry. 2002 Oct;181:284-94.

Randomised controlled trials investigating pharmacological and psychological interventions for treatment-refractory depression. Systematic review.

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  • 1University of Wales College of Medicine, Department of Psychological Medicine, Cardiff, Wales, UK.



About 30% of people with depression do not respond to an antidepressant at the recommended dose and can be described as having treatment-refractory depression.


To summarise the findings from all randomised controlled trials (RCTs) that have assessed the efficacy of a pharmacological or psychological intervention for treatment-refractory depression.


We used a systematic search strategy to identify RCTs that included adults aged 18-75 years with a diagnosis of unipolar depression that had not responded to a 4-week course of a recommended dose of an antidepressant.


We identified 16 RCTs. None of the included trials assessed the efficacy of psychotherapy. All the trials were too small to detect an important clinical response. We found only two trials on lithium augmentation, which randomised 50 subjects in total.


There is little evidence to guide the management of depression that has not responded to a course of antidepressants. Treatment-refractory depression is an important public health problem and large pragmatic trials are needed to inform clinical practice.

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