Drug Safety 2006; 29 (6): 491-508 REVIEW ARTICLE 0114-5916/06/0006-0491/$39.95/0 2006 Adis Data Information BV. All rights reserved. Psychotic Major Depression A Benefit-Risk Assessment of Treatment Options Audrey R. Tyrka, Lawrence H. Price, Marcelo F. Mello, Andrea F. Mello and Linda L. Carpenter Mood Disorders Research Program, and the Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Providence, Rhode Island, USA Contents Abstract .................................................................................... 491 1. Rationale .............................................................................. 492 2. Historical Perspective .................................................................... 492 3. Differential Diagnosis .................................................................... 493 4. Psychotic Major Depression: Unique Characteristics ........................................ 494 5. Benefit-Risk Assessment: General Considerations ........................................... 494 6. Electroconvulsive Therapy (ECT) .......................................................... 495 6.1 Adverse Effects and Limitations of ECT ................................................. 496 7. Antidepressant Plus Antipsychotic Combinations ........................................... 496 7.1 Combined Treatment with Tricyclic Antidepressants (TCAs) and First-Generation Antipsychotics (FGAs) ................................................................ 496 7.2 Adverse Effects and Risks of Combined Treatment with TCAs and FGAs ................... 497 7.3 Combined Treatment with Selective Serotonin Reuptake Inhibitors (SSRIs)/Newer Antidepressants and Antipsychotic Drugs .............................................. 497 7.4 Adverse Effects of Combined Treatment with SSRIs/Newer Antidepressants and Antipsychotic Drugs .................................................................. 498 8. Antidepressant Monotherapy ............................................................ 499 9. Antipsychotic Monotherapy: Second-Generation Antipsychotic Agents ...................... 501 10. On the Horizon: Antiglucocorticoid Agents ................................................ 501 10.1 Cortisol Synthesis Inhibitors ........................................................... 501 10.2 Adverse Effects and Risks of Cortisol Synthesis Inhibitors ................................. 501 10.3 Glucocorticoid Receptor Antagonists ................................................. 501 10.4 Adverse Effects and Risks of Glucocorticoid Receptor Antagonists ....................... 502 11. Treatment Duration ..................................................................... 502 12. Treatment Costs ........................................................................ 503 13. Conclusions ............................................................................ 504 Numerous studies in the past three decades have characterised ‘psychotic Abstract major depression’, a subtype of major depression which is accompanied by delusions or other psychotic features. Evidence from phenomenological and neurobiological investigations indicates that this is a unique disorder with clinical and biological characteristics that are distinct from those of nonpsychotic depres- sion and from other psychotic disorders. Treatment studies have provided evi- dence of small placebo effects and good responses to electroconvulsive therapy or combination treatment with an antidepressant plus an antipsychotic agent. How-