Some widely used psychoactive drugs, such as tricyclic antidepressants and antipsychotic phenothiazines exhibit iatrogenic effects on the thyroid. These side effects may arise from interactions at different steps of thyroid hormone biosynthesis. These drugs can induce a change in iodine capture by thyroid cells or can complex iodine, making it unavailable for thyroid hormone synthesis and thus decreasing thyroid hormone blood levels; they can also inhibit thyroid peroxidase activity and thus T3 and T4 synthesis or enhance deiodination of T4 to T3 or to Rt3 by stimulation of deiodinase activity. Moreover, tricyclic antidepressants interfere with the hypothalamic-pituitary-thyroid axis via the noradrenergic or serotonergic systems and might therefore decrease T4 or T3 blood levels, respectively. Phenothiazines can induce autoimmune hypothyroidism, as shown by an increase in the expression of the major histocompatibility complex antigen and by a production of antithyroglobulin or antithyroperoxidase antibodies. However, all these mechanisms are only speculative in humans, as they have only been demonstrated in vitro or in animal experiments. Clinically, thyroid function and affective disorders are closely linked. On one hand, the therapeutic response to antidepressants could be influenced by the thyroid status; on the other hand, the larger the thyroxin decrease induced by antidepressants, the better the therapeutic effect might be. Moreover, cotreatment with thyroid hormones and antidepressant drugs could allow either a decrease in the rate of treatment failure or a faster recovery from depression. As antipsychotic or antidepressant treatments are administered over long periods in humans, their thyroid toxic effects must be taken seriously.