Between 10 and 30% of depressed patients, mostly bipolar, develop a therapy-resistant illness. The known causes of such chronic evolutions are discussed: misdiagnosis (underlying schizophrenia, personality disorder or dementia), drug-induced depression (neuroleptics), systemic disease (hypothyroidism, multiple sclerosis, cardiovascular or neoplastic disease etc.), or lack of efficacy (drug compliance, insufficient dosage). Remedies are suggested: adequate dosage, drug combination (Newcastle cocktail. tricyclic antidepressant + MAOI, imipramine + T3), carbamazepine in lithium-resistant cases, alprazolam, reduction in vanadium intake, sleep deprivation, psychosurgery.