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Psychotic depression
Evidence review G
NICE Guideline, No. 222
Psychotic depression
Review question
For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Introduction
Psychosis in depression commonly manifests as nihilistic delusions, delusions of guilt, inadequacy and disease, or derogatory auditory hallucinations. People with psychotic depression also demonstrate more severe psychomotor disturbance and greater psychosocial impairment than those without psychosis. Psychotic symptoms are more common in samples of older patients than in younger patients and people with psychotic depression are more likely to require inpatient treatment and to die from suicide or medical causes in the years following their admission. There is also some evidence that people with major depression with psychotic features exhibit more frequent relapses or recurrences than patients with non-psychotic depression. Psychotic depression is often not diagnosed accurately, even in specialist settings, because the psychosis may be subtle, intermittent or concealed, and consequently, it is often inadequately treated.
The majority of international treatment guidelines on pharmacological approaches to psychotic depression advocate the combination of an antidepressant and antipsychotic medication. However, antipsychotic use is associated with weight gain and metabolic effects and the use of antidepressant-antipsychotic combinations increases the risks of arrhythmia and cardiac arrest.
In reviewing the evidence for further-line treatment (see Evidence rereview D), the committee agreed that it was not meaningful to separate out subgroups with psychotic depression, coexisting personality disorders, and chronic depression. Therefore, a single category was formed ‘further-line treatment’ which combined all these groups where participants are randomised at the point of non-response and treatment strategies include increasing dose, augmenting or switching. However, the committee were also aware that there are people with psychotic depression who have not received treatment for the current episode, or who have recovered following initial treatment, and that it was not appropriate to combine these groups with those who have shown an inadequate response to initial treatment. The committee therefore agreed to review the evidence for first-line treatment and relapse prevention of psychotic depression in the current evidence report, and the evidence for further-line treatment of psychotic depression is considered in the context of a broader evidence base in Evidence review D.
The aim of this review is to identify the most effective first-line treatment or relapse prevention strategy for adults with psychotic depression.
Summary of the protocol
See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
For further details, see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A.
Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy. Those interests declared until April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see Register of Interests).
Clinical evidence
Included studies
Eight randomised controlled trials (RCTs) were included in this review.
Four RCTs (Kunzel 2009, Mulsant 2001, Spiker 1985and Wijkstra 2010) compared antipsychotic augmentation of antidepressants versus antidepressants alone (or with placebo) for the treatment of depression.
Two RCTs (Flint 2019, Meyers 2001) compared antipsychotic augmentation of antidepressants versus antidepressants (plus placebo) for the prevention of relapse.
Two RCTS (Meyers 2009, Spiker 1985) compared antidepressant augmentation of antipsychotics versus antipsychotics (plus placebo) for the treatment of depression.
One RCT (Spiker 1985) compared perphenazine (plus placebo) versus amitriptyline (plus placebo) for the treatment of depression.
One RCT (Wijkstra 2010) compared venlafaxine versus imipramine for the treatment of depression.
One RCT (Navarro 2008) compared continuation electroconvulsive therapy (ECT) plus nortriptyline versus nortriptyline plus treatment as usual for the prevention of relapse.
The included studies are summarised in Table 2.
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
Studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.
Summary of studies included in the evidence review
Summaries of the studies that were included in this review are presented in Table 2 to Table 7.
Table 2
Summary of included studies for Comparison 1. Antipsychotic plus antidepressant versus antidepressant (alone or plus placebo) for the treatment of depression.
Table 3
Summary of included studies for Comparison 2. Antipsychotic plus antidepressant versus antidepressant plus placebo, for relapse prevention.
Table 4
Summary of included studies for Comparison 3. Antidepressant plus antipsychotic versus antipsychotic plus placebo for the treatment of depression.
Table 5
Summary of included studies for Comparison 4. Perphenazine (plus placebo) versus amitriptyline (plus placebo) for the treatment of depression.
Table 6
Summary of included studies for Comparison 5. Venlafaxine versus imipramine for the treatment of depression.
Table 7
Summary of included studies for Comparison 6. Continuation ECT plus nortriptyline versus nortriptyline plus treatment as usual, for relapse prevention.
See the full evidence tables in appendix D and the forest plots in appendix E.
Quality assessment of studies included in the evidence review
See the evidence profiles in appendix F.
Economic evidence
Included studies
A single economic search was undertaken for all topics included in the scope of this guideline but no economic studies were identified which were applicable to this review question. See the literature search strategy in appendix B and economic study selection flow chart in appendix G.
Excluded studies
A list of excluded economic and utility studies, with reasons for exclusion, is provided in supplement 3 - Economic evidence included & excluded studies.
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.
Evidence statements
Clinical evidence statements
Comparison 1. Antipsychotic plus antidepressant versus antidepressant (alone or plus placebo) for the treatment of depression
Critical outcomes
Depression symptomatology
- Very low quality evidence from 3 RCTs (N=167) shows neither a clinically important nor statistically significant difference between combined antipsychotic and antidepressant treatment and antidepressant treatment only on depression symptomatology change from baseline to endpoint, for adults with psychotic depression.
Response
- Very low quality evidence from 2 RCTs (N=174) shows neither a clinically important nor statistically significant difference between combined antipsychotic and antidepressant treatment and antidepressant treatment only on the rate of response, for adults with psychotic depression.
Remission (of depression)
- Very low quality evidence from 3 RCTs (N=210) shows neither a clinically important nor statistically significant difference between combined antipsychotic and antidepressant treatment and antidepressant treatment only on the rate of remission (of depression), for adults with psychotic depression.
Remission (of depression and psychotic symptoms)
- Very low quality evidence from 2 RCTs (N=77) shows a clinically important but not statistically significant benefit of combined antipsychotic and antidepressant treatment, relative to antidepressant treatment only, on the rate of remission of depression and psychotic symptoms, for adults with psychotic depression.
Discontinuation due to any reason
- Very low quality evidence from 4 RCTs (N=251) shows a higher rate of discontinuation due to any reason associated with combined antipsychotic and antidepressant treatment, relative to antidepressant treatment only for adults with psychotic depression, however this effect is not statistically significant.
Discontinuation due to side effects
- Very low quality evidence from 4 RCTs (N=251) shows a higher rate of discontinuation due to side effects associated with combined antipsychotic and antidepressant treatment relative to antidepressant treatment only for adults with psychotic depression, however this effect is not statistically significant.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Comparison 2. Antipsychotic plus antidepressant versus antidepressant plus placebo, for relapse prevention
Critical outcomes
Relapse
- Very low quality evidence from 2 RCTs (N=155) shows neither a clinically important nor statistically significant difference between combined antipsychotic and antidepressant treatment and antidepressant treatment (with placebo) on the rate of relapse of depression or psychotic symptoms, for adults with remitted psychotic depression.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Comparison 3. Antidepressant plus antipsychotic versus antipsychotic plus placebo for the treatment of depression
Critical outcomes
Depression symptomatology
- Very low quality evidence from 1 RCT (N=34) shows a clinically important and statistically significant benefit of combined antidepressant and antipsychotic treatment, relative to antipsychotic treatment (with placebo), on depression symptomatology for adults with psychotic depression.
Remission (of depression and psychotic symptoms)
- Very low quality evidence from 2 RCTs (N=298) shows a clinically important and statistically significant benefit of combined antidepressant and antipsychotic treatment, relative to antipsychotic treatment (with placebo), on the rate of remission of depression and psychotic symptoms for adults with psychotic depression.
Discontinuation due to any reason
- Very low quality evidence from 2 RCTs (N=298) shows neither a clinically important nor statistically significant difference between combined antidepressant and antipsychotic treatment and antipsychotic treatment (with placebo), on discontinuation due to any reason for adults with psychotic depression.
Discontinuation due to side effects
- Very low quality evidence from 2 RCTs (N=298) shows a lower rate of discontinuation due to side effects associated with combined antidepressant and antipsychotic treatment relative to antipsychotic treatment (with placebo) for adults with psychotic depression, however this effect is not statistically significant.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Comparison 4. Perphenazine (plus placebo) versus amitriptyline (plus placebo) for the treatment of depression
Critical outcomes
Depression symptomatology
- Very low quality evidence from 1 RCT (N=33) shows neither a clinically important nor statistically significant difference between perphenazine and amitriptyline on depression symptomatology for adults with psychotic depression.
Remission (of depression and psychotic symptoms)
- Very low quality evidence from 1 RCT (N=36) shows a higher rate of remission of depression and psychotic symptoms associated with amitriptyline relative to perphenazine for adults with psychotic depression, however this effect is not statistically significant.
Discontinuation due to any reason
- Very low quality evidence from 1 RCT (N=36) shows a higher rate of discontinuation due to any reason associated with amitriptyline relative to perphenazine for adults with psychotic depression, however this effect is not statistically significant.
Discontinuation due to side effects
- Very low quality evidence from 1 RCT (N=36) shows a higher rate of discontinuation due to side effects associated with perphenazine relative to amitriptyline for adults with psychotic depression, however this effect is not statistically significant.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Comparison 5. Venlafaxine versus imipramine for the treatment of depression
Critical outcomes
Depression symptomatology
- Very low quality evidence from 1 RCT (N=81) shows neither a clinically important nor statistically significant difference between venlafaxine and imipramine on depression symptomatology change from baseline to endpoint, for adults with psychotic depression.
Response
- Very low quality evidence from 1 RCT (N=81) shows a higher rate of response associated with imipramine relative to venlafaxine for adults with psychotic depression, however this effect is not statistically significant.
Remission (of depression)
- Very low quality evidence from 1 RCT (N=81) shows a higher rate of remission of depression associated with venlafaxine relative to imipramine for adults with psychotic depression, however this effect is not statistically significant.
Discontinuation due to any reason
- Very low quality evidence from 1 RCT (N=81) shows neither a clinically important nor statistically significant difference between venlafaxine and imipramine on discontinuation due to any reason for adults with psychotic depression.
Discontinuation due to side effects
- Very low quality evidence from 1 RCT (N=81) shows a higher rate of discontinuation due to side effects associated with imipramine relative to venlafaxine for adults with psychotic depression, however this effect is not statistically significant.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Comparison 6. Continuation ECT plus nortriptyline versus nortriptyline plus treatment as usual, for relapse prevention
Critical outcomes
Relapse
- Very low quality evidence from 1 RCT (N=33) shows a clinically important and statistically significant benefit of continuation ECT plus nortriptyline compared to nortriptyline plus treatment as usual, on preventing relapse for adults with psychotic depression.
Important outcomes
No evidence was identified for quality of life or functioning outcomes for this comparison.
Economic evidence statements
No economic evidence was identified which was applicable to this review question.
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most
The aim of this review was to determine which treatments are effective at treating psychotic depression so the committee identified depression symptomatology, response and remission as critical outcomes that would measure whether and to what extent symptoms had improved. An episode of psychotic depression can be frightening and leave people anxious about recurrence, so it is important to people that it does not recur, and therefore relapse was also prioritised by the committee as a critical outcome for comparisons that included a population of people who had remitted from depression. Discontinuation for any reason was used by the committee as a marker of acceptability of the treatment and for pharmacological treatments discontinuation due to side effects was prioritised as an indicator of the tolerability of the treatment. As discontinuation can lead to a poor treatment response these outcomes were both prioritised as critical outcomes.
Quality of life and functioning were prioritised as important outcomes. The committee were aware that these outcomes are very important to people with depression, but that there was likely to be less evidence for these outcomes so they would not be as useful to the committee’s decision-making process.
The quality of the evidence
The quality of evidence for outcomes was assessed using GRADE and ranged from moderate to very low.
The evidence identified covered a range of pharmacological interventions, but was generally from single RCTs with a small sample size, and was of very low quality. The quality of the evidence was most frequently downgraded due to a high or unclear risk of bias or due to imprecision.
Benefits and harms
As with other treatment recommendations in the guideline, the committee agreed that treatment options should be discussed with people who have psychotic depression in order to involve them in making shared treatment decisions. However, they recognised that people with psychotic depression may lack capacity to make treatment decisions.
The committee also discussed whether people with psychotic depression could be safely and effectively cared for within primary care services and agreed, based on their expertise and experience, that due to their complex symptoms their needs could be better met by specialist mental health services, and so recommended referral to specialist mental health services. The committee specifically discussed whether GPs would be confident commencing prescriptions for antipsychotics to augment antidepressant treatment. The committee agreed, based on their knowledge and experience, that this would often not be the case. Consequently, they recommended that the treatment in specialist mental health services should include a risk assessment, and an assessment of needs, a programme of coordinated multi-professional care and access to psychological interventions after improvement of psychotic symptoms, so that the complex needs of those with psychotic depression could be treated effectively.
The committee considered the evidence for combined treatment with antipsychotics and antidepressants. Evidence from the comparison of an antipsychotic plus antidepressant compared to an antidepressant alone was inconsistent. However, there was some evidence for clinical benefits (on the rate of response) associated with quetiapine for acute treatment and olanzapine for relapse prevention. The committee therefore recommended that combination treatment with both an antidepressant and an antipsychotic should be considered for people with psychotic depression, and the specific antipsychotics that showed clearer benefits were given as examples. The committee also knew that quetiapine has antidepressant effects as well as antipsychotic effects so it was theoretically a good choice, and is often used for psychotic depression. However, the committee discussed that not everyone with psychotic depression may want to take antipsychotic medication. They also considered the evidence from the comparison of an antidepressant plus antipsychotic relative to an antipsychotic (plus placebo) that showed clinical benefits associated with the antidepressant treatment (on depression symptomatology, and remission of depression and psychotic symptoms), and therefore recommended that in such cases antidepressant treatment alone should be offered.
The committee agreed that the combination of an antidepressant and an antipsychotic may lead to increased side effects and that it was therefore important to monitor the combination for side effects and discontinue the antipsychotic as soon as possible. The committee discussed the cessation of the antipsychotic and agreed, based on their expertise and experience, that GPs may not be confident to make the decision to discontinue the prescription, and that the decision would be better made in conjunction with or by specialist mental health services and so they made this recommendation.
There was evidence from single studies comparing an antipsychotic to an antidepressant or different types of antidepressants. However, based on the absence of any clinically important and statistically significant differences between individual drugs, the committee agreed not to recommend any specific class or individual antidepressant over another.
The committee thought that it was important to emphasise that there was more information on how to prescribe and monitor antipsychotics available in the NICE guideline on psychosis and schizophrenia in adults, and therefore signposted the recommendations on prescribing and monitoring antipsychotics in that guideline.
The committee discussed the evidence for ECT in the treatment of psychotic depression. There was no evidence for ECT in the acute treatment of psychotic depression, although the committee were aware of data that suggests a higher remission rate in psychotic depression compared with non-psychotic depression. There was evidence from a small single study of the benefit of ECT in relapse prevention that was considered too limited to form the basis of a treatment recommendation.
The committee discussed that no evidence on psychological interventions for people with psychotic depression had been identified. Based on their knowledge and experience of the use of psychological interventions in the treatment of psychosis, the committee agreed that psychological interventions delivered by practitioners with experience and specialist training in working with people with psychosis and depression may also be effective for psychotic depression. As there was no evidence for psychological or psychosocial interventions and such limited evidence for pharmacological treatment and ECT the committee made a research recommendation.
Longer-term follow-up
The committee noted that none of the studies on psychotic depression reported any followup data. The committee agreed that this created uncertainty about the sustainability of clinical benefits. This was consistent with broader uncertainty associated with the limited evidence base and contributed to the committee agreement that they were only able to recommend that combination antidepressant and antipsychotic medication be ‘considered’.
Quality of life and functioning outcomes
The committee also noted that none of the studies on psychotic depression reported any quality of life or functioning outcomes. As with the absence of follow-up data, the committee agreed that the lack of quality of life and functioning outcomes contributed to the limitations of the evidence base, and consequently the committee could only recommend that combination antidepressant and antipsychotic medication be ‘considered’.
Cost effectiveness and resource use
No evidence on the cost-effectiveness of interventions for adults with depression with psychotic symptoms was identified and no further economic analysis was undertaken. The committee considered the costs associated with the treatment of people with depression with psychotic symptoms, including costs of inpatient care in psychiatric wards and, potentially, of Accident and Emergency visits. The committee acknowledged that referring people with depression with psychotic symptoms to specialist mental health services was likely to incur additional costs compared with no referral; however, they agreed that specialist services can deal more effectively with the complex needs of this population, including conducting a risk assessment, providing coordinated multi-professional care, and having expertise in initiation of antipsychotics to augment antidepressant treatment so as to deal with psychotic symptoms prior to initiation of psychological therapy. They agreed that specialist care is likely to lead to better outcomes (improvement in both psychotic and depressive symptoms) and also cost-savings resulting from better treatment effects and thus a reduction in the need to change treatments (which comes at a cost) as well as in the need for costly inpatient psychiatric care. Therefore, they expressed the opinion that referral costs were likely to be at least partially offset by cost-savings and improved outcomes in this population. The committee discussed the costs of antipsychotics, and given that a wide range of antipsychotics are currently available in a generic form, they estimated that augmentation of the current treatment plan with antipsychotic medicine was likely to lead to small resource implications.
Recommendations supported by this evidence review
This evidence review supports recommendations 1.12.1 to 1.12.6 and research recommendations in the NICE guideline.
References
Flint 2019
Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Alexopoulos GS, Rudorfer MV et al Stop-Pd Ii Study Grp. Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission The STOP-PD II Randomized Clinical Trial. Jama-Journal of the American Medical Association. 2019. 322(7): 622–631. [PMC free article: PMC6704758] [PubMed: 31429896]Kunzel 2009
Künzel HE, Ackl N, Hatzinger M, Held K, Holsboer-Trachsler E, Ising M, Kaschka W, Kasper S, Konstantinidis A, Sonntag A, Uhr M. Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol–a double-blind multicenter trial. Journal of Psychiatric Research. 2009 Apr 1;43(7):702–10. [PubMed: 19038406]Meyers 2001
Meyers BS, Klimstra SA, Gabriele M, Hamilton M, Kakuma T, Tirumalasetti F, Alexopoulos GS. Continuation treatment of delusional depression in older adults. The American Journal of Geriatric Psychiatry. 2001 Sep 1;9(4):415–22. [PubMed: 11739068]Meyers 2009
Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, Papademetriou E, Leon AC, Heo M. 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). Archives of General Psychiatry. 2009 Aug 1;66(8):838–47. [PMC free article: PMC2840400] [PubMed: 19652123]Mulsant 2001
Mulsant BH, Sweet RA, Rosen J, Pollock BG, Zubenko GS, Flynn T, Begley AE, Mazumdar S. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. The Journal of Clinical Psychiatry. 2001 Aug;62(8):597–604. [PubMed: 11561930]Navarro 2008
Navarro V, Gastó C, Torres X, Masana G, Penadés R, Guarch J, Vazquez M, Serra M, Pujol N, Pintor L, Catalan R. Continuation/maintenance treatment with nortriptyline versus combined nortriptyline and ECT in late-life psychotic depression: a two-year randomized study. The American Journal of Geriatric Psychiatry. 2008 Jun 1;16(6):498–505. [PubMed: 18515694]Spiker 1985
Spiker DG, Weiss JC, Dealy RS, Griffin SJ, Hanin I, Neil JF, Perel JM, Rossi AJ, Soloff PH. The pharmacological treatment of delusional depression. Am J Psychiatry. 1985 Apr 4;142(4):430–6. [PubMed: 3883815]Wijkstra 2010
Wijkstra J, Burger H, Van den Broek WW, Birkenhäger TK, Janzing JG, Boks MP, Bruijn JA, Van Der Loos ML, Breteler LM, Ramaekers GM, Verkes RJ. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatrica Scandinavica. 2010 Mar;121(3):190–200. [PubMed: 19694628]
Appendices
Appendix A. Review protocol
Review protocol for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Table 8. Review protocol for psychotic depression (PDF, 252K)
Appendix B. Literature search strategies
Literature search strategies for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Clinical search
Database(s): Embase 1974 to 2019 Week 12, Emcare 1995 to present, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to March 26, 2019, PsycINFO 1806 to March Week 3 2019
Date of Search: 27/03/2019
Search updated: 04/03/2021
Download PDF (198K)
The Cochrane Library: Cochrane Database of Systematic Reviews, Issue 3 of 12, March 2019; Cochrane Central Register of Controlled Trials, Issue 3 of 12, March 2019
Date of search: 27/03/2019
Search updated: 04/03/2021
Download PDF (146K)
Health Economics search
Database(s): Embase 1974 to 2019 Week 08, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to February 26, 2019, PsycINFO 1806 to February Week 1 2019
Date of search: 27/02/12019
Search updated: 02/03/2021
Download PDF (160K)
Database(s): NIHR Centre for Reviews and Dissemination: Health Technology Assessment Database (HTA)
Date of search: 26/02/2019
Download PDF (129K)
Database(s): CINAHL Plus (Cumulative Index to Nursing and Allied Health Literature) 1937-current, EBSCO Host
Date of search: 26/02/2019
Search updated: 02/03/2021
Download PDF (141K)
Appendix C. Clinical evidence study selection
Study selection for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Figure 1. Study selection flow chart (PDF, 160K)
Appendix D. Clinical evidence tables
Evidence tables for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Please refer to the clinical evidence tables in supplement G – Clinical evidence tables for Evidence Review G Psychotic depression
Appendix E. Forest plots
Forest plots for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Comparison 1. Antipsychotic plus antidepressant versus antidepressant (alone or plus placebo) for acute treatment of psychotic depression in adults
Figure 2. Depression symptomatology (HAMD change score) (PDF, 187K)
Figure 3. Response (number of participants improving by at least 50% from baseline on HAMD) (PDF, 187K)
Figure 4. Remission of depression (number of participants scoring HAMD<8/9/11) (PDF, 186K)
Figure 6. Discontinuation due to any reason (PDF, 199K)
Figure 7. Discontinuation due to side effects (PDF, 238K)
Comparison 2. Antipsychotic plus antidepressant versus antidepressant plus placebo for relapse prevention in adults with psychotic depression
Figure 8. Relapse of depression or psychotic symptoms (PDF, 190K)
Comparison 3. Antidepressant plus antipsychotic versus antipsychotic plus placebo for the treatment of psychotic depression in adults
Figure 9. Depression symptomatology (HAMD) (PDF, 190K)
Figure 11. Discontinuation due to any reason (PDF, 117K)
Figure 12. Discontinuation due to side effects (PDF, 117K)
Comparison 4. Perphenazine (plus placebo) versus amitriptyline (plus placebo) for the treatment of psychotic depression in adults
Figure 13. Depression symptomatology (HAMD) (PDF, 157K)
Figure 15. Discontinuation due to any reason (PDF, 179K)
Figure 16. Discontinuation due to side effects (PDF, 179K)
Comparison 5. Venlafaxine versus imipramine for the treatment of psychotic depression in adults
Figure 17. Depression symptomatology (HAMD change score) (PDF, 157K)
Figure 18. Response (at least 50% improvement from baseline on HAMD and a final HAMD score <15) (PDF, 108K)
Figure 19. Remission (HAMD<8) (PDF, 108K)
Figure 20. Discontinuation due to any reason (PDF, 188K)
Figure 21. Discontinuation due to side effects (PDF, 188K)
Comparison 6. Continuation ECT plus nortriptyline versus nortriptyline plus treatment as usual for relapse prevention
Figure 22. Relapse (met DSM-IV criteria for major depression and HAMD score≥16 in 2 consecutive visits) (PDF, 109K)
Appendix F. GRADE tables
GRADE tables for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Appendix G. Economic evidence study selection
Economic evidence study selection for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
A global health economics search was undertaken for all areas covered in the guideline. Figure 23 shows the flow diagram of the selection process for economic evaluations of interventions and strategies for adults with depression and studies reporting depression-related health state utility data.
Appendix H. Economic evidence tables
Economic evidence tables for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
No economic evidence was identified which was applicable to this review question.
Appendix I. Economic evidence profiles
Economic evidence profiles for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
No economic evidence was identified which was applicable to this review question.
Appendix J. Economic analysis
Economic evidence analysis for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
No economic analysis was conducted for this review question.
Appendix K. Excluded studies
Excluded studies for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Clinical studies
Please refer to the excluded studies in supplement G – Clinical evidence tables for Evidence Review G Psychotic depression
Economic studies
Please refer to supplement 3 - Economic evidence included & excluded studies.
Appendix L. Research recommendations
Research recommendations for review question: For adults with psychotic depression what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination (as first-line treatment or relapse prevention)?
Research question
What are the most effective and cost effective interventions for the treatment and management of psychotic depression (including consideration of pharmacological, psychological, psychosocial interventions and ECT)?
Why this is important
There is limited evidence on the most effective interventions for the treatment of psychotic depression. All identified evidence examined different pharmacological strategies, with no evidence identified for psychological or psychosocial interventions. Additionally, the current evidence for pharmacological interventions consisted primarily of small, low quality RCTs. The lack of evidence for psychological or psychosocial interventions alone or in combination with pharmacological is a further limitation. There is also very little data on the long-term outcomes for people with psychotic depression.
Table 15. Research recommendation rationale (PDF, 131K)
Table 16. Research recommendation modified PICO table (PDF, 135K)
Supplemental Data
g1: clinical evidence tables for review question 2.8 (excel)
Final version
Evidence review underpinning recommendations 1.12.1 to 1.12.6 and research recommendations in the NICE guideline
Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
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- Psychotic depressionPsychotic depression
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