Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699

Depression is a common disorder which causes intense personal suffering and socio-occupational dysfunction. It also imposes a heavy economic burden on society. It has been shown that between 29% and 46% of depressed patients fail to respond adequately to antidepressant medication. Treatment-resistant depression may contribute to the morbidity and mortality associated with affective illness. When treatment resistance is suspected, the patient's history should be reevaluated particularly regarding diagnostic subtypes and comorbidity. An assessment of treatment adequacy in terms of dose, duration and compliance should also be made. Treatment strategies for treatment-resistant depression should be systematic and empirically grounded because of the risk of increased resistance and loss of time in case of a random trial-and-error approach, and the inherent risks in certain novel strategies. A stepped care approach to treatment-resistant depression involves optimization of the current drug under trial, augmentation with drugs such as lithium and triiodothyronine, and switching to other somatic therapies such as electroconvulsive therapy and monoamine inhibitors. Only if these strategies fail, should novel treatments such as the use of venlafaxine, antidepressant combinations and augmentation with sleep deprivation be considered. Experimental strategies such as the use of antiglucocorticoids and sex hormones, which carry considerable risk, should be restricted to research settings. Somatotherapy should be combined in all cases with depression-specific psychotherapy. Psychosurgery should be considered only in truly intractable cases. Rational and energetic treatment can adequately help a large majority of patients with treatment-resistant depression.