1. Evidence-based Treatment of Psychotic Depression Gregory W. Dalack, MD June 22, 2006

2. The Practice of EBM Step 1: Asking an answerable question Step 2: Tracking down the best evidence to answer that question Step 3: Critically appraise the evidence for validity, size of the effect, and utility of the findings Step 4: Incorporate the clinical appraisal into our clinical expertise and patient’s individual issues Step 5: Evaluate and improve steps 1-4 with each new opportunity to apply these principles

3. Brief case history 77 year old man with recurrent unipolar depression. Currently in episode, BDI and HAM-D in severe range. + psychotic, mood congruent ideation. History of excellent response to ECT, but his medical comorbidities make this less favorable now.

4. Asking answerable clinical questions (CEBM- Oxford)

5. An answerable clinical question For patients with psychotic depression......is antidepressant treatment alone......when compared to antidepressant plus antipsychotic treatment…...result in greater improvement of depressive/psychotic symptoms? patient patient intervention intervention comparison comparison outcome outcome

6. www.lib.umich.edu/taubman

7. Search Treatment of Psychotic Depression Electronic Books ACP Medicine (2006): “Depression with associated psychotic features must be treated with an antidepressant and an antipsychotic medication.”70 ACP Medicine (2006): “Depression with associated psychotic features must be treated with an antidepressant and an antipsychotic medication.”7070 Treatment of Psychiatric Disorders (2001): “The relative refractoriness of psychotic depression to antidepressant treatment alone suggests that psychotic symptoms require additional specific treatments. In a prospective study, Spiker et al. (1985) demonstrated superior efficacy for treatment of psychotic depression using a combination of an antidepressant and an antipsychotic drug compared with monotherapy with an antidepressant.” Treatment of Psychiatric Disorders (2001): “The relative refractoriness of psychotic depression to antidepressant treatment alone suggests that psychotic symptoms require additional specific treatments. In a prospective study, Spiker et al. (1985) demonstrated superior efficacy for treatment of psychotic depression using a combination of an antidepressant and an antipsychotic drug compared with monotherapy with an antidepressant.”Spiker et al. (1985Spiker et al. (1985

8. Classic Study The pharmacological treatment of delusional depression DG Spiker, JC Weiss, RS Dealy, SJ Griffin, I Hanin, JF Neil, JM Perel, AJ Rossi and PH Soloff Am J Psychiatry, 1985 The authors investigated the pharmacological treatment of delusional depression by assigning patients on a random double- blind basis to amitriptyline alone, perphenazine alone, or a combination of the two. Fourteen (78%) of the 18 patients assigned to amitriptyline plus perphenazine were responders, compared with seven (41%) of 17 patients treated with amitriptyline alone and three (19%) of the 16 patients treated with perphenazine alone. The combination of amitriptyline and perphenazine was clearly superior (p less than.01).

9. Search Treatment of Psychotic Depression Review Article (J Clin Psychiatry, suppl. 2003) Abstr: “Data support the use of antipsychotics in combination with antidepressants for major depression with psychotic features, but other treatments may have great or greater efficacy for the disorder” Abstr: “Data support the use of antipsychotics in combination with antidepressants for major depression with psychotic features, but other treatments may have great or greater efficacy for the disorder” “atypical antipsychotics alone may be effective for psychotic depression….Olanzapine has also been found successful monotherapy in psychotic depression…substantial improvement in symptoms of psychotic depression in a patient…and a case report in Germany….” “atypical antipsychotics alone may be effective for psychotic depression….Olanzapine has also been found successful monotherapy in psychotic depression…substantial improvement in symptoms of psychotic depression in a patient…and a case report in Germany….” “The drug treatments that have been typically been effective for psychotic depression include combination of antidepressants with antipsychotics” “The drug treatments that have been typically been effective for psychotic depression include combination of antidepressants with antipsychotics” Supplement supported by Eli Lilly and company Supplement supported by Eli Lilly and company

12. Search Treatment of Psychotic Depression Cochrane Review: Wijkstra et al, (16-Nov-2005) Plain language summary: The combination of an antidepressant with an antipsychotic may not be more effective than an antidepressant alone, however, combination therapy may be more effective than an antipsychotic alone. Starting with the combination of an antidepressant and an antipsychotic, as well as starting with an antidepressant alone and adding an antipsychotic if the patient does not respond, both appear to be appropriate options for patients with psychotic depression. Clinically, the balance between risks and benefits suggests that initial antidepressant monotherapy should be the preferred option for many patients. Antipsychotic monotherapy is not an appropriate treatment strategy. The general lack of available data limits confidence in the conclusions drawn. Plain language summary: The combination of an antidepressant with an antipsychotic may not be more effective than an antidepressant alone, however, combination therapy may be more effective than an antipsychotic alone. Starting with the combination of an antidepressant and an antipsychotic, as well as starting with an antidepressant alone and adding an antipsychotic if the patient does not respond, both appear to be appropriate options for patients with psychotic depression. Clinically, the balance between risks and benefits suggests that initial antidepressant monotherapy should be the preferred option for many patients. Antipsychotic monotherapy is not an appropriate treatment strategy. The general lack of available data limits confidence in the conclusions drawn.

13. Cochrane review: Pharmacological treatment for psychotic depression Objectives: examine effectiveness of antidepressant vs antipsychotic vs combination therapy for psychotic depression examine effectiveness of antidepressant vs antipsychotic vs combination therapy for psychotic depressionMethods: meta-analysis of randomized controlled trials of psychotic depression meta-analysis of randomized controlled trials of psychotic depressionResults: 10 trials (548 patients) were identified 10 trials (548 patients) were identified both antidepressant alone and antidepressant + antipsychotic were superior to antipsychotic alone both antidepressant alone and antidepressant + antipsychotic were superior to antipsychotic alone antidepressant + antipsychotic was no more effective than antidepressant alone antidepressant + antipsychotic was no more effective than antidepressant alone 2 trials compared TCA to non-TCA (fluvoxamine, mirtazapine): TCA more effective 2 trials compared TCA to non-TCA (fluvoxamine, mirtazapine): TCA more effective

14. Cochrane review: Pharmacological treatment for psychotic depression In this meta-analysis, data were re-analyzed using “intention to treat”: “a method of analysis for randomized trials in which all patients randomly assigned to one of the treatments are analyzed together, regardless of whether or not they completed or received that treatment” (Sackett et al.,2000) In eight of the 10 studies we recalculated intention-to- treat response rates using all randomised patients as the denominator… In both studies of Spiker (Spiker 1985; Spiker 1988) seven dropouts were excluded from the analysis but we included these dropouts. Spiker 1985 Spiker 1988Spiker 1985 Spiker 1988

15. In Spiker et al. 1985 report: In Antidepressant plus Antipsychotic arm (AD+AP): 14 responders, 4 non-responders, 4 drop-outs In Antidepressant plus Antipsychotic arm (AD+AP): 14 responders, 4 non-responders, 4 drop-outs In Antidepressant arm (AD): 7 responders, 10 non-responders, 2 drop-outs In Antidepressant arm (AD): 7 responders, 10 non-responders, 2 drop-outs In Antipsychotic arm (AP): 3 responders, 13 non-responders, 1 drop-out In Antipsychotic arm (AP): 3 responders, 13 non-responders, 1 drop-out

16. Relative Risk: the ratio in the treated group to the risk in the control group (TG/CG) Spiker’s analysis (AD+AP vs AD): TG: 14/18=0.78 TG: 14/18=0.78 CG: 7/17=0.41 CG: 7/17=0.41 RR: 0.78/0.41=1.90- statistically significant RR: 0.78/0.41=1.90- statistically significant In Cochrane re-analysis TG: 14/22=0.64 TG: 14/22=0.64 CG: 7/19=0.37 CG: 7/19=0.37 RR: 0.64/0.37=1.73 ns RR: 0.64/0.37=1.73 ns

18. Conclusions “Only 10 RCTs were identified in psychotic depression, which illustrates that this most severe form of depression is very under investigated.” “As a result of the paucity of RCTs, few clinically relevant conclusions can be drawn… “the data indicate that an antidepressant alone can be effective.” “the data indicate that an antidepressant alone can be effective.” Pooled results AD vs. PBO: (four RCTs; RR 2.06, 95% CI 1.41 to 3.00). Antipsychotic alone is ineffective: (four RCTs; RR 1.23, 95% CI 0.89 to 1.71) Antipsychotic alone is ineffective: (four RCTs; RR 1.23, 95% CI 0.89 to 1.71)

19. Conclusions “Second, there is no evidence that the combination of an antidepressant plus an antipsychotic is more effective than an antidepressant alone. Therefore, it can be concluded that the recommendation in the APA guidelines (APA 2000) that in psychotic depression the combination should be preferred over an antidepressant alone is not reliably evidence based, if not necessarily incorrect. APA 2000APA 2000 “The recommendation in the APA Guideline is based on the trial of Spiker 1985, …the difference between the combination and amitriptyline alone was only statistically significant in the completers analysis and not in the ITT analysis reported here. (RR 1.73, 95% CI 0.89 to 3.37, P=0.11). “The recommendation in the APA Guideline is based on the trial of Spiker 1985, …the difference between the combination and amitriptyline alone was only statistically significant in the completers analysis and not in the ITT analysis reported here. (RR 1.73, 95% CI 0.89 to 3.37, P=0.11).Spiker 1985Spiker 1985 Combination of an AD plus AP vs. AD monotherapy: 2 RCTs, total n=77 patients (RR 1.44, 95% CI 0.88 to 2.41, p=0.16) Combination of an AD plus AP vs. AD monotherapy: 2 RCTs, total n=77 patients (RR 1.44, 95% CI 0.88 to 2.41, p=0.16)

20. Conclusions “Third, there is evidence that the combination of an antidepressants plus an antipsychotic is more effective than an antipsychotic alone. This was the major result of the study comparing amitriptyline plus perphenazine versus perphenazine alone (Spiker 1985) and was also found in one of the studies comparing fluoxetine plus olanzapine versus olanzapine alone (Rothschild 2004a; Rothschild 2004b). Moreover, it was confirmed in the pooled analysis of these studies.” Spiker 1985Rothschild 2004a Rothschild 2004bSpiker 1985Rothschild 2004a Rothschild 2004b We note again small number of studies, small n’s and need for more research.