Psychotic Depression: Underrecognized, Undertreated-and Dangerous

July 31, 2014

Here: the history of psychotic depression for the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a summary its epidemiology, significance, diagnostic complexity, and treatment, as well as case vignettes.

This article describes the history of this diagnostic construct for the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) and summarizes research on the epidemiology, significance, diagnostic complexity, and treatment of psychotic depression. Case vignettes are provided to highlight diagnostic and therapeutic issues. (Additional information on the STOP-PD project is available from Meyers and Avari.1)

A brief overview

Conceptualization of psychotic depression as a distinct variant of major depression is a recent development in psychiatric nosology that largely results from advances in psychopharmacology. Although the occurrence of delusions in a subset of patients with a severe depressive illness was described by Kraepelin in the early 20th century, the impact of associated psychotic phenomena on treatment response and prognosis was not recognized until the introduction of antidepressants more than a half century later.

Early placebo-controlled studies using TCAs demonstrated that patients with major depression associated with delusions had very poor treatment responses. These findings focused attention on whether delusional depression is a distinct subtype of major depression. In 1977, Glassman and colleagues2 reported that 95% of 25 hospitalized patients with melancholic nondelusional depression treated with higher than median imipramine dosages achieved remission. Only one-third of the subgroup of control patients with delusions achieved remission.

These results stimulated research into the clinical characteristics, treatment response, and prognosis of psychotic major depression (PMD). These studies led to a shift from DSM-II conceptualization of affective psychosis as largely a function of severity to the inclusion in DSM-III of major depression with psychotic features as a diagnostic subtype that requires delusions and/or hallucinations in association with major depression. In DSM-5, the presence of psychotic features is a specifier and not indicative of a subtype, because the presence of psychotic features does not preclude the presence of other specifiers, such as melancholia.

The overall community prevalence of PMD is 0.4%; it occurs in 14% to 20% of individuals with MDD.3,4 The prevalence of PMD is markedly higher among hospitalized patients; it exceeds 25% in mixed-age adults and occurs in up to 45% of depressed geriatric inpatients.4,5

PMD is associated with severe health consequences. Relapse and recurrence rates approximating 50% have been reported.6,7 Compared with patients who have MDD, patients with PMD have poorer outcomes; they have more residual symptoms, greater functional impairment, and more frequent suicide attempts as well as more malignant health outcomes.

An index episode of PMD predicts a greater than 2-fold higher 15-year mortality rate and 3-fold greater risk of suicide after an initial suicide attempt.8,9 The longitudinal risk for suicide is substantial because approximately 20% of patients with PMD make a suicide attempt during an episode.10 The association between suicidal outcomes and PMD presumably results from the behavioral impact of PMD: conviction about highly pessimistic and/or paranoid beliefs that occur in association with the pain of depression may make the choice of suicide appear as rational. Therefore, depressed patients must be assessed for both suicidal and delusional ideas, and depressive and psychotic domains of illness must be treated.


PMD is often considered interchangeable with delusional depression because the vast majority of patients with psychosis have delusional ideation, whereas hallucinations without delusions are less common. Delusions are fixed beliefs that are resistant to the laws of logic and evidence to the contrary. Psychiatrists expect their depressed patients to have pessimistic and fearful concerns; unfortunately, extra diagnostic rigor is required to differentiate depressive ruminations from the fixed beliefs of PMD.

In STOP-PD, 27% of patients who had delusions did not receive a diagnosis of PMD.11 Because depressive ruminations that focus on themes of somatic, financial, and guilty concerns are expected concomitants of MDD, clinicians may ignore the question of whether these concerns are held fixedly and are influencing the patient’s behavior. Paranoid concerns are more likely to focus attention on the possible presence of delusions, particularly if the fears are not congruent with a depressive theme.

In light of diagnostic inaccuracy, it is not surprising that nearly 20% of research participants who met criteria for PMD had not received antidepressants before study entry, 25% had not received an antipsychotic medication, and only 10% had received intensive pharmacotherapy with both an antipsychotic and an antidepressant.12

An association between an index episode of unipolar PMD and the subsequent development of bipolar disorder has been established. Conversion rates from an index PMD to bipolar disorder as high as 20% and 37% have been reported in clinical samples, particularly if the initial episode occurs in young adulthood or adolescence.13-15 In contrast, 10-year longitudinal studies have demonstrated that bipolar disorder developed in only 10.2% to 13.8% of patients who initially had uni-polar PMD.16,17

A recent population registry-based study demonstrated that earlier age of onset and recurrent depressive episodes of unipolar PMD significantly increased the likelihood of conversion to a bipolar diagnosis.18 Although specific clinical features, such as greater psychomotor disturbance and reverse vegetative signs, are often considered indicative of a bipolar diagnosis, systematic investigations of whether clinical features reliably distinguish unipolar from bipolar depression are lacking.

The following case vignettes highlight the importance of early recognition and effective management.


Mrs Burns is a recently widowed 72-year-old. She is admitted to a psychiatric hospital after referral from her internist because of symptoms of sadness, anhedonia, diminished energy, and poor appetite. She acknowledges feeling sad and hopeless but attributes these feelings to her poor appetite, lack of energy, and weight loss. She expresses concern that she is suffering from an undiagnosed cancer, stating that she has no other reason to be depressed.

In the past few weeks, Mrs Burns has seen 3 gastroenterologists and received multiple imaging studies that she felt had missed the malignancy. She does not believe her physicians had deceived her but expresses a lack of confidence in the diagnostic procedures, citing news reports of cases of missed diagnoses. She denies suicidal thoughts or wishes.

The diagnosis is major depression with somatic anxiety and ruminations. Mrs Burns’s physical examination and laboratory workup do not show an active medical illness. She is informed that she is suffering from depression and that loss of appetite and weight loss occur commonly with depression. She is treated with sertraline, 100 mg/d, and her mood brightens. She becomes more engaged in activities during the 2 weeks of treatment while she is hospitalized, and she acknowledges that her depression is “50% better.”

Although her appetite improves with a small increase in weight, she continues to doubt her psychiatrist’s view that her physical symptoms were a result of the depression, and she requests additional GI consultations. In addition, she complains of mild symptoms of nausea and constipation that are considered adverse effects of the medication.

Mrs Burns is discharged as moderately improved, and she agrees to continue the sertraline despite the mild GI symptoms. She is referred to a psychiatrist in her community, and her daughters agree to monitor her adherence to further treatment. Shortly after discharge, Mrs Burns makes a consultation appointment with a new gastroenterologist, specifically requesting a workup for an occult malignancy. After a physical examination and record review, the gastroenterologist informs her that further testing is not necessary and suggests that she discuss her concerns with her psychiatrist. Soon after returning home from this visit, Mrs Burns writes a note expressing her hopelessness, frustration with doctors, and fear of dying in pain. She states that she prefers suicide to a slow, painful death from cancer and takes an overdose of over-the-counter medications.

It is likely that Mrs Burns suffered from an undiagnosed PMD. Neither her somatic preoccupation nor her suicidal risk had been sufficiently assessed during the hospitalization. The chart did not document whether somatic concern had been considered as possibly irrational or whether adding an antipsychotic medication to her treatment had been considered. Although improvement in her depressive syndrome had been easily achieved, reassurance by her psychiatrist had been only transiently and mildly effective.

Mrs Burns had been discharged though her pessimistic preoccupation persisted. The question of whether Mrs Burns required additional treatment for a delusion component of her depression was not addressed and a comprehensive as-sessment of her risk for suicide had not been discussed with her or her daughters. The treatment team expected that Mrs Burns would fully recover from her depression.


Mr Harris, a 65-year-old married accountant, is referred for psychiatric treatment before submitting his annual tax return because of depressed mood, anhedonia, anorexia, weight loss, and guilty ruminations about having submitted inaccurate tax returns in previous years. Mr Harris shamefully acknowledges that he had exaggerated a tax deduction by $500 on his last return, and he now believes that he will be audited and arrested for tax evasion. He voices concerns that the FBI is investigating him and that both his and his family’s reputations would be ruined as a result. He denies having suicidal ideation or intent.

His family reports that he has been scrupulous in his business affairs and in preparing his tax returns. They are convinced that his worry about an excessive deduction is irrational. Despite the family’s reassurance, Mr Harris has retained an attorney.

Mr Harris’s psychiatric diagnosis is major depression, and he receives an antidepressant and a low-dose antipsychotic. His family agrees to monitor and otherwise support Mr Harris’s treatment. After 3 weeks of treatment, Mr Harris’s mood, appetite, and interest in social activities improve. At the psychiatrist’s recommendation and with Mr Harris’s consent, an accountant is retained to prepare his new tax return and communicate with the IRS about paying any fine due for his past exaggeration of a deduction. Nevertheless, Mr Harris continues to express concern that he is being investigated and that he will be sent to prison for his past tax report error.

The day after his new tax return is submitted, Mr Harris reads a news article about the arrest of a public figure for tax fraud. He writes a letter to his family apologizing for his past behavior and stating that he wishes to spare them humiliating consequences of his behavior. He hangs himself.

Mr Harris’s major depression was associated with a distressing irrational idea that led him to retain an attorney. Despite being an accountant, he had grievously exaggerated the impact his alleged past error would have on his and his family’s future. Although Mr Harris’s overall mood improved with an antidepressant and a low dose of an antipsychotic, his preoccupation with a mood-congruent delusion of deserved punishment persisted. The dose of antipsychotic or the specific medication may have been inadequate, or Mr Harris may have been resistant to pharmacotherapy.

His psychiatrist had recognized the seriousness of Mr Harris’s delusion and implemented interventions designed to reassure him. However, Mr Harris’s delusion was irrational and was impervious to both reassurance and the realistic step of having his accountant submit a new tax return. Most important, Mr Harris’s suicidal risk was not systematically assessed and the option of treating his acute episode in a hospital was not explored.

In retrospect, the intensity of Mr Harris’s preoccupation with his delusion and the expected consequences to him and his family if the belief were valid should have led to a deliberate consideration of hospitalization. An imminent risk of suicide should guide the decision about outpatient versus hospital treatment of PMD. More aggressive combination pharmacotherapy or electroconvulsive therapy (ECT) would have been more easily rendered on an inpatient basis, and the tragic outcome may have been avoidable.

Acute and postremission treatment of PMD

Consensus guidelines consider 2 treatments as effective for PMD: ECT and pharmacotherapy that combines an antidepressant with an antipsychotic. Results from a STOP-PD randomized controlled trial (RCT) demonstrated the efficacy of combined olanzapine (average dosage, 14.7 mg/d) and sertraline (average dosage, 170 mg/d) compared with olanzapine plus placebo.10 The 12-week remission rate of 41.2% was comparable to remission rates reported in RCTs of less depressed outpatients.

A recent RCT using quetiapine (average dosage, 600 mg/d) combined with venlafaxine (average dosage, 375 mg/d) demonstrated efficacy comparable to that found in STOP–PD, with a 41.5% remission rate.19 The STOP-PD results underscore the importance of deciding on postremission treatment: STOP-PD participants experienced significant weight gain and increases in their plasma lipid levels during the trial. Therefore, the risk to benefit ratio of continuing combined treatment versus discontinuing the antipsychotic following a sustained remission of PMD has great clinical importance. The ongoing STOP-PD II trial, Sustaining Remission of Psychotic Depression, investigates this question by randomizing patients with symptom remission to continue sertraline plus olanzapine or to continue sertraline plus placebo for 36 weeks.20

Future directions

Knowledge about the diagnosis and treatment of PMD has increased markedly over the past 35 years. Nevertheless, advances in the understanding of underlying pathophysiology of one of the few spontaneously occurring and fully reversible psychotic conditions have emerged slowly. The cortisol dysregulation hypothesis continues to gain support, with an increasing focus on genes that regulate central glucocorticoid receptors. From the perspective of phenomenology, conceptualization of psychosis and delusional thinking as domains of interest would facilitate research into irrational thinking within and across psychiatric disorders.

Psychotic thinking would be a more focused domain than positive symptoms for inclusion in the NIMH Research Domain Criteria (RDoC) project. Irrational thought processing meets the RDoC project criteria of both being a dimensional pathology and occurring across multiple psychiatric diagnoses. Including irrational thinking as a specific domain would facilitate research into the underlying neuro-biological and neuropsychological mechanisms of delusional thinking and further our ability to characterize and treat this important area of psychopathology.

Acknowledgment-STOP-PD researchers include Alastair Flint at the University of Toronto, Anthony Rothschild at the University of Massachusetts Medical School, Ellen Whyte at the University of Pittsburgh School of Medicine, Benoit Mulsant at the Centre for Addiction and Mental Health in Toronto, and Barnett Meyers at Weill Cornell Medical College. The NIMH has supported the STOP-PD studies of unipolar major psychotic depression for more than a decade (MH 62446, MH 62518, MH 62565, and MH62624).


Dr Meyers is Professor of Psychiatry at Weill Cornell Medical Center in White Plains, NY. He reports that he has received grant support from Pfizer for an NIMH research study.


1. Meyers BS, Avari JN. Psychotic depression. In: Mann JJ, McGrath PJ, Roose SP, eds. Clinical Handbook for the Management of Mood Disorders. Cambridge, UK: Cambridge University Press; 2013:75-85.

2. Glassman AH, Perel JM, Shostak M, et al. Clinical implications of imipramine plasma levels for depressive illness. Arch Gen Psychiatry. 1977;34:197-204.

3. Johnson J, Horwath E, Weissman MM. The validity of major depression with psychotic features based on a community study. Arch Gen Psychiatry. 1991;48:1075-1081.

4. Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry. 2002;159:1855-1861.

5. Guze SB, Woodruff RA Jr, Clayton PJ. The significance of psychotic affective disorders. Arch Gen Psychiatry. 1975;32:1147-1150.

6. Meyers BS, Greenberg R. Late-life delusional depression. J Affect Disord. 1986;11:133-137.

7. Spiker DG, Stein J, Rich CL. Delusional depression and electroconvulsive therapy: one year later. Convuls Ther. 1985;1:167-172.

8. Vythilingam M, Chen J, Bremner JD, et al. Psychotic depression and mortality. Am J Psychiatry. 2003;160:574-576.

9. Suominen K, Haukka J, Valtonen HM, Lönnqvist J. Outcome of patients with major depressive disorder after serious suicide attempt. J Clin Psychiatry. 2009;70:1372-1378.

10. Meyers BS, Flint AJ, Rothschild AJ, et al; STOP-PD Group. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the Study of Pharmacotherapy of Psychotic Depression (STOP-PD) [published correction appears in Arch Gen Psychiatry. 2011;68:626]. Arch Gen Psychiatry. 2009;66:838-847.

11. Rothschild AJ, Winer J, Flint AJ, et al; Study of Pharmacotherapy of Psychotic Depression (STOP-PD) Collaborative Study Group. Missed diagnosis of psychotic depression at 4 academic medical centers. J Clin Psychiatry. 2008;69:1293-1296.

12. Andreescu C, Mulsant BH, Peasley-Miklus C, et al; STOP-PD Study Group. Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. J Clin Psychiatry. 2007;68:194-200.

13. Akiskal HS, Walker P, Puzantian VR, et al. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J Affect Disord. 1983;5:115-128.

14. Goes FS, Sadler B, Toolan J, et al; Bipolar Disorder Phenome Group. Psychotic features in bipo-lar and unipolar depression. Bipolar Disord. 2007;9:901-906.

15. Strober M, Carlson G. Bipolar illness in adolescents with major depression: clinical, genetic, and psychopharmacologic predictors in a three- to four-year prospective follow-up investigation. Arch Gen Psychiatry. 1982;39:549-555.

16. Coryell W, Endicott J, Maser, JD, et al. Long-term stability of bipolarity distinctions in the affective disorders. Am J Psychiatry. 1995;152:385-390.

17. Ruggero CJ, Kotov R, Carlson GA, et al. Diagnostic consistency of major depression with psychosis across 10 years. J Clin Psychiatry. 2011;72:1207-1213.

18. Østergaard SD, Straszek S, Petrides G, et al. Risk factors for conversion of unipolar psychotic depression to bipolar disorder. Bipolar Disord. 2014;16:180-189.

19. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121:190-200.

20. Flint AJ, Meyers BS, Rothschild AJ, et al; STOP-PD II Study Group. Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II. BMC Psychiatry. 2013;13:38.