Patients with mood disorders frequently present with treatment resistant syndromes or develop tolerance to once effective first line medications. Refractory depressive, manic or mixed episodes challenge psychiatrists to find means of augmenting traditional therapies, despite the paucity of evidence based data that support this practice. The balance between risks and benefits in most cases seems acceptable, provided that the physician and the patients have a clear understanding of the possible adverse and therapeutic interactions and that treatment resistance is not the result of inadequate (dose/time) prescription of a first line monotherapy. The workshop will review the pharmacokinetic and pharmacodynamic interactions among the psychotropic drugs and the strategies to safely and successfully use a rational polypharmacy for the management of treatment resistant mood disorders.