Challenges in the Treatment of Major Depressive Disorder With Psychotic Features

Anthony J. Rothschild


Schizophr Bull. 2013;39(4):787-796. 

In This Article

Abstract and Introduction


Psychotic depression is associated with significant morbidity and mortality but is underdiagnosed and undertreated. In recent years, there have been several studies that have increased our knowledge regarding the optimal treatment of patients with psychotic depression. The combination of an antidepressant and antipsychotic is significantly more effective than either antidepressant monotherapy or antipsychotic monotherapy for the acute treatment of psychotic depression. Most treatment guidelines recommend either the combination of an antidepressant with an antipsychotic or ECT for the treatment of an acute episode of unipolar psychotic depression. The optimal maintenance treatment after a person responds to either the antidepressant/antipsychotic combination or the ECT is unclear particularly as it pertains to length of time the patient needs to take the antipsychotic medication. Little is known regarding the optimal treatment of a patient with bipolar disorder who has an episode of psychotic depression or the clinical characteristics of responders to medication treatments vs ECT treatments.


Psychotic depression or major depressive disorder with psychotic features is a serious illness during which a person suffers from the combination of depressed mood and psychosis, with the psychosis commonly manifesting itself as nihilistic type delusions, with the belief that bad things are about to happen. Unfortunately, until recently, the treatment of psychotic depression has not been studied to the same extent as other psychiatric disorders with similar prevalence[1] and remains an underdiagnosed[2] and undertreated[3] psychiatric disorder.

There has been a long-standing discussion as to whether psychotic depression is a distinct syndrome or simply represents a severe form of depression. Much of the debate stems from the fact that in DSM-II, published in 1968, "psychosis" meant severe and did not mean being out of touch with reality or having delusions or hallucinations. In 1970, Gerald Klerman and Eugene Paykel published an influential article that stated that in depression, there was a smooth continuum from mild outpatient depression to severe depression requiring inpatient hospitalization without any demarcation points.[4] Observations that psychotic depressed patients differed from nonpsychotic patients in their response to pharmacological treatments[5] led investigators to focus on more clearly defining this distinct clinical entity.

In 1992, as Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV was being planned, a strong argument was made in the American Journal of Psychiatry that there was sufficient evidence at that time from studies of clinical characteristics and symptoms, biology, family history, course and outcome, and treatment that psychotic depression should be a distinct illness in DSM-IV, separate from major depression.[6]The American Journal of Psychiatry article led to a position paper submitted to the DSM-IV Work Group on mood disorders.[7] The DSM-IV Work Group on mood disorders agreed[7] that the clinical relevance of specifically designating patients with psychotic depression was high and considered 2 options: (1) to continue the classification as in DSM-IIIR designating psychosis as decimal point under the severity code and (2) to designate psychotic depression as a separate syndrome "major depression with psychotic features." After much deliberation, the work group recommended the first option although it recognized it was less than optimal.[7] Thus, in DSM-IV[8] and DSM-IV text revision,[9] psychotic depression remained as a subclassification of major depressive dsorder.

Similarly, in the International Classification of Diseases, 10th revision (ICD-10), psychotic depression is classified as a subtype of severe depression.[10] Arguments that psychotic depression meets the criteria for a valid psychiatric syndrome due to its distinct clinical presentation, neurobiology, heritability, prognosis, and treatment response continue to be made with the hope that this will change in ICD-11.[11]

In DSM-V, psychotic depression will remain as a subclassification of major depressive disorder. However, in DSM-V, psychotic features will be separated from the severity rating, and major depressive disorder with psychotic features will not necessarily need to be classified as "severe." This is a change from DSM-IV. Moreover, in DSM-V, a hierarchy giving precedence to mood-incongruent features is being introduced to allow classification of cases in which mood-congruent and mood-incongruent psychotic features coexist. After reviewing the epidemiology of psychotic depression and its distinction from schizophrenia and relationship to bipolar disorder, I will discuss the acute and long-term treatment of psychotic depression including several key questions such as should antidepressants and antipsychotics be combined for the treatment of psychotic depression? If combination therapy is used, what are the risks of side effects? What are the recommendations for maintenance treatment and relapse prevention?