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Intervention Review

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Pharmacological treatment for psychotic depression

  1. Jaap Wijkstra1,*,
  2. Jeroen Lijmer2,
  3. Huibert Burger3,4,
  4. John Geddes5,
  5. Willem A Nolen4

Editorial Group: Cochrane Depression, Anxiety and Neurosis Group

Published Online: 26 NOV 2013

Assessed as up-to-date: 12 APR 2013

DOI: 10.1002/14651858.CD004044.pub3


How to Cite

Wijkstra J, Lijmer J, Burger H, Geddes J, Nolen WA. Pharmacological treatment for psychotic depression. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD004044. DOI: 10.1002/14651858.CD004044.pub3.

Author Information

  1. 1

    UMCU, Department of Psychiatry, Utrecht, Netherlands

  2. 2

    UMCU, Psychiatry, Utrecht, Netherlands

  3. 3

    University Medical Center Groningen, University of Groningen, Department of Epidemiology, Groningen, Netherlands

  4. 4

    University Hospital Groningen, Department of Psychiatry, Groningen, Netherlands

  5. 5

    University of Oxford/Warneford Hospital, Department of Psychiatry, Oxford, UK

*Jaap Wijkstra, Department of Psychiatry, UMCU, B.01.206, Postbox 85500, 3508 GA, Utrecht, Netherlands. J.Wijkstra@umcutrecht.nl.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 26 NOV 2013

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This is not the most recent version of the article. View current version (30 JUL 2015)

 
Characteristics of included studies [ordered by study ID]
Anton 1990

MethodsRandomised, double-blind comparison


ParticipantsNo explicit use of structured interview
DSM-III criteria; psychotic depressive episode
HRSD 17 > 18
Inpatients.
No data about prior treatment of current episode


InterventionsAmoxapine versus amitriptyline + perphenazine.
300 to 500 mg versus 150 to 250 mg + 24 to 40 mg
No blood levels
Five days placebo period. Additional medication in these five days: lorazepam or oxazepam in 'low dose'
Treatment period: four weeks. Additional medication is not mentioned in these four weeks


OutcomesDichotomous data: author defined: Response is reduction of HRSD-17 > 50%. No remission data
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: yes (two in ami + per)
Mortality rate: 0


Notes56 participants provided informed consent. 10 dropped out in washout before receiving active medication (four refused and six improved substantially); 46 participants were randomly assigned

46 participants: four dropouts in both groups (total eight). Unclear how many bipolar participants among these eight dropouts; 38 participants were analysed, including six bipolar participants
6/38 bipolar = 15.8%
ITT responders: amoxapine 12/21 and ami + per 17/25 (instead of 12/17 and 17/21)
Dropouts after random assignment: 9/21 and 7/25
Author had no additional data available
See also 1993 J Aff Disorders 28:125-131 (same data set)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'Patients were randomly assigned in a double blind fashion'

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Double blind treatment with identical capsules'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'Double blind treatment with identical capsules'

Blinding (performance bias and detection bias)
of outcome assessors
Unclear riskProbably yes. No explicit data

Incomplete outcome data (attrition bias)
All outcomes
High risk46 participants were randomly assigned. In the publication, only those participants who completed at least two weeks of active medication were analysed. Four dropouts in both groups (total eight)

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasHigh riskUnclear how many bipolar participants were present among these eight dropouts; 38 participants were analysed, including six bipolar participants. 6/38 bipolar = 15.8%. No additional data available to exclude bipolar participants from reanalysis
We reanalyzed the data with ITT responders (intention-to-treat; dropouts included): amoxapine 12/21 and ami + per 17/25 (instead of 12/17 and 17/21). ITT dropouts after random assignment: 9/21 and 7/25

Bruijn 1996

MethodsRandomised, double-blind comparison


ParticipantsUse of checklist with DSM-III-R criteria
SADS depression portion was performed in the presence of a second psychiatrist
DSM-III-R depressive episode; excluded psychotic depression with hallucinations
HRSD-17 > 17
Inpatients. Subgroup psychotic depression. Probably only with delusions
51% of included participants were adequately pretreated during the current episode: adequate dose of an antidepressant during at least four weeks


InterventionsImipramine versus mirtazapine; 37.5 to 450 mg imipramine (blood level: 199 to 400 ng/mL) versus 40 to 100 mg mirtazapine (blood level 49 to 93 ng/mL)
Washout: three days medication free and four days placebo
Additional medication: one to six tablets a day containing 45 mg of an extract of valerian, lorazepam 1 to 5 mg a day or haloperidol 1 to 15 mg a day
Treatment period: four weeks after predefined blood levels reached (mirtazapine group: five to 21 days; imipramine group: seven to 25 days)


OutcomesDichotomous data: author defined: Response is reduction of HRSD-17 ≥ 50%. No remission data
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: no ITT data in subgroup
Mortality rate: 0


NotesWorse responding in a group leads to more participants given haloperidol
107 participants included; six bipolar; 10 dropouts
Subgroup: MDD psychotic; 30 (15 mirtazapine and 15 imipramine)
Mirtazapine group: seven haloperidol treatment (six non-responders, one responder) Imipramine group: two haloperidol treatment (two non-responders)
Participants treated with haloperidol by us counted as dropouts
Mirtazapine group: one dropout + seven haloperidol treatment = 8/18; imipramine group: two dropouts + two haloperidol treatment = 4/15
Additional information from author included


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'Patients were randomly allocated to a double blind treatment'

Allocation concealment (selection bias)Unclear riskNo explicit information

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Identical capsules. Dose adjustment by an independent psychiatrist on the basis of blood levels'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'Identical capsules. Dose adjustment by an independent psychiatrist'

Blinding (performance bias and detection bias)
of outcome assessors
Low riskSide effects were not systematically rated to prevent bias towards unblinding. After completion of the study, the research psychiatrist guessed the medication: 46 correct and 37 incorrect

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasHigh riskParticipants with psychotic depression with hallucinations were excluded. So only participants with psychotic depression with delusions were included in the reanalyzed subgroup

We reanalyzed the data in the subgroup with psychotic depression. We counted as dropout: one participant with bipolar disorder, nine participants with haloperidol treatment (seven in mirtazapine group and two in imipramine group)

Worse responding in psychotic depression leads in this study to more open co-treatment with haloperidol 1 to 15 mg, especially in the mirtazapine group. Only one of these nine participants (mirtazapine group) was a responder. So haloperidol probably was not instrumental in the recovery of those participants

Meyers 2009

MethodsRandomised double-blind study


Participants259 participants; DSM-IV-TR psychotic depression; 18 years of age or older; HAM-D ≧ 21 and SADS delusional severity rating ≧ 3

Inpatients


Interventions12 weeks treatment with olanzapine + placebo and olanzapine + sertraline


OutcomesRemission rates (HAM-D 17 ≦ 10 and SADS delusional item score = 1)


Notes53% dropout in olanzapine arm and 37% dropout in olanzapine + sertraline arm


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs reported: 'Computer generated randomisation list'

Allocation concealment (selection bias)Unclear riskNo further data

Blinding (performance bias and detection bias)
of participants
Low riskStudy was double blind (reported as: 'sertraline and placebo under double-blind conditions')

Blinding (performance bias and detection bias)
of personnel
Low riskWell described double blinding. 'Sertraline and placebo under double-blind conditions'. As reported: 'Investigators and raters were blind to treatment assignment'

Blinding (performance bias and detection bias)
of outcome assessors
Low riskWell described double blinding. 'Sertraline and placebo under double-blind conditions'. As reported: 'Investigators and raters were blind to treatment assignment'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Low riskProtocol available. Generally accepted outcomes have been used

Other biasUnclear riskRelatively high dropout rate with significant difference between treatment groups.(53% olanzapine and 37% olanzapine + sertraline)

Patients with only hallucinations excluded

Mulsant 2001

MethodsRandomised, double-blind comparison


ParticipantsClinical interview, Brief Psychiatric Rating Scale, Global Assessment Scale and a consensus conference were used for diagnosis
DSM-III-R; psychotic major depressive episode (manic episode in history excluded). HAM-D-17 > 17
Age > 50 years
Inpatients
No data about prior treatment of current episode


InterventionsNortriptyline versus nortriptyline + perphenazine
Open nortriptyline until therapeutic plasma level (target 100 ng/mL); once between 50 and 150 ng/mL, random assignment followed
Mean doses: nortriptyline 76 mg versus nortriptyline 63 mg + perphenazine 19 mg
Mean blood levels: 101 ng/mL versus 120 + 4 ng/mL
Additional medication: lorazepam as needed
Treatment period: after random assignment 2 to 16 weeks (total treatment at least four weeks)
''After a washout of other psychotropic medication except lorazepam ....'' It is unclear how long this washout has been


OutcomesDichotomous data: author defined: Response is HAMD-17 < 11 and BPRS (11, 12, 15) 1 or 2. No remission data
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: nortriptyline + perphenazine 1/17; nortriptyline + placebo 2/19
Mortality rate: 0


Notes54 participants included; 16 dropouts: three improved on nortriptyline, three adverse effects and nine administrative reasons; 36 participants randomly assigned. This is by procedure a selected group: responders on nortriptyline and participants with adverse effects and with other reasons are excluded (28%)
Open nortriptyline (eight to 21 days; median two weeks); once between 50 and 150 ng/mL, random assignment followed
Responder somewhere between two and 16 weeks after randomisation (median nine weeks); three dropouts in both groups after random assignment. These are excluded by the author and included by us for ITT analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information. As reported: 'Patient[s] were randomly allocated to a double blind treatment'

Allocation concealment (selection bias)Unclear riskNo information. As reported: 'Patient[s] were randomly allocated to a double blind treatment'

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Double blind treatment. No further data'

Blinding (performance bias and detection bias)
of personnel
Low risk'Dose adjustments by non blinded psychiatrist who were not involved in the care'

Blinding (performance bias and detection bias)
of outcome assessors
Low riskAs reported: 'Double blind treatment'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes has been used

Other biasHigh riskNo outcome data about prescription of 'lorazepam as needed'

EPS rating could have led to blinding bias

Participants treated with only nortriptyline (+ placebo) were excluded after four weeks without improvement, and participants treated with nortriptyline + perphenazine after four + two weeks

Rothschild 2004a

MethodsRandomised, double-blind comparison
Random assignment was 2:2:1 for olanzapine, placebo and olanzapine fluoxetine combination, respectively


Participants124 participants; DSM-IV diagnosis (unclear how)
Major depression with psychotic features
Inpatients for at least one week.
No data about prior treatment of current episode


Interventions2004a: olanzapine (5 to 20 mg, clinically titrated; mean 11.9 mg) versus olanzapine (5 to 20 mg, clinically titrated; mean 12.4 mg) plus fluoxetine (20 to 80 mg, clinically titrated; mean 23.5 mg) versus placebo

2004b: same procedure: olanzapine (mean 14.0 mg) versus olanzapine (mean 13.9 mg) plus fluoxetine (mean 22.6 mg)
Three to nine days screening; probably no washout period

Treatment period: eight weeks
Additional medication: 30 mg a day diazepam equivalent for no more than five consecutive days or 10 cumulative days


OutcomesDichotomous data: author defined: Response is reduction of HAMD-24 ≥ 50% at endpoint. Remission is HAMD-24 ≤ 8 for two consecutive visits
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: no ITT data
Mortality rate: probably 0


NotesWashout unclear
23 investigators randomly assigned at least one participant. Excluded patient characteristics not described
Dropouts in study a: 28%; lost before baseline + one visit: 7% (were excluded from results; included in our data); 24% in study a are LOCF (last observation carried forward; in our data not counted as dropouts); some of these LOCFs are counted as responders; total non-completers (LOCF included) 28 + 7 + 24 = 59%

Dropouts in study b: 38%; lost before baseline + one visit: 9% (were excluded from results; included in our data); LOCF in study b: 6%; total non-completers 28 + 9 + 6 = 53%

Completers in study a: 41%; in study b: 47%


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'Patients were randomly allocated'; no further information

Allocation concealment (selection bias)Unclear riskAs reported: 'Patients were randomly allocated'; no further information

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Double blind therapy. Dose adjustments in all study arms with 'capsules' (assuming identical capsules because the study is double blind)'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'Double blind therapy'

Blinding (performance bias and detection bias)
of outcome assessors
Unclear riskNo explicit information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts described in general terms. Very high dropout rate

Selective reporting (reporting bias)Unclear riskNo protocol available. According to the authors, the olanzapine-fluoxetine group was designed as a exploratory pilot arm. However, in the conclusions, it is stated that an olanzapine/fluoxetine combination was a well-tolerated treatment associated with significant and quick reduction in depressive (and psychotic) symptoms in one trial. With ITT data, this difference is seen in one study to be not statistically significant, and in the other study barely significant. Pooling of these two studies would result in no significance.

The authors discuss as a limitation the absence of a fluoxetine arm. They state that they cannot rule out that the effect of fluoxetine/olanzapine was due to fluoxetine. So this should have been mentioned in the conclusion

Other biasHigh riskHigh dropout rate of 34.7% reduces the internal validity of the study

High placebo response is contradictory to the literature

Rothschild 2004b

MethodsRandomised, double-blind comparison
Random assignment was 2:2:1 for olanzapine, placebo and olanzapine fluoxetine combination, respectively


Participants124 participants. DSM-IV diagnosis (unclear how)
Major depression with psychotic features
Inpatients for at least one week.
No data about prior treatment of current episode


Interventions2004a: olanzapine (5 to 20 mg, clinically titrated; mean 11.9 mg) versus olanzapine (5 to 20 mg, clinically titrated; mean 12.4 mg) plus fluoxetine (20 to 80 mg, clinically titrated; mean 23.5 mg) versus placebo

2004b: same procedure: olanzapine (mean 14.0 mg) versus olanzapine (mean 13.9 mg) plus fluoxetine (mean 22.6 mg)
Three to nine days screening; probably no washout period

Treatment period: eight weeks
Additional medication: 30 mg a day diazepam equivalent for no more than five consecutive days or 10 cumulative days


OutcomesDichotomous data: author defined: Response is reduction of HAMD-24 ≥ 50% at endpoint. Remission is HAMD-24 ≤ 8 for two consecutive visits
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: no ITT data
Mortality rate: probably 0


NotesWashout unclear
23 investigators randomly assigned at least one participant. Excluded patient characteristics not described
Dropouts in study a: 28%; lost before baseline + one visit: 7% (were excluded from results; included in our data); 24% in study a are LOCF (last observation carried forward; in our data not counted as dropouts). Some of these LOCFs are counted as responders; total non-completers (LOCF included) 28 + 7 + 24 = 59%

Dropouts in study b: 38%; lost before baseline + one visit: 9% (were excluded from results; included in our data); LOCF in study b: 6%; total non-completers 28 + 9 + 6 = 53%

Completers in study a: 41%; in study b: 47%


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'Patients were randomly allocated'; no further information

Allocation concealment (selection bias)Unclear riskAs reported: 'Patients were randomly allocated'; no further information

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Double blind therapy. Dose adjustments in all study arms with 'capsules' (assuming identical capsules because the study is double blind)'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'Double blind therapy'

Blinding (performance bias and detection bias)
of outcome assessors
Unclear riskNo explicit information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts described in general terms. Very high dropout rate

Selective reporting (reporting bias)Unclear riskNo protocol available. According to the authors, the olanzapine-fluoxetine group was designed as a exploratory pilot arm. However, in the conclusions, it is stated that an olanzapine/fluoxetine combination was a well-tolerated treatment associated with significant and quick reduction in depressive (and psychotic) symptoms in one trial. With ITT data, this difference is seen in one study to be not statistically significant, and in the other study to be barely significant. Pooling of these two studies would result in no significance. The authors discuss as a limitation the absence of a fluoxetine arm. They state that they cannot rule out that the effect of fluoxetine/olanzapine was due to fluoxetine. So this should have been mentioned in the conclusion

Other biasHigh riskHigh dropout rate of 47.2% reduces the internal validity of the study

High placebo response is contradictory to the literature

Spiker 1985

MethodsRandomised, double-blind comparison
Random assignment procedure described in part
Blinding adequately described


ParticipantsSADS and RDC criteria for major depressive disorder, primary subtype and psychotic subtype (only with delusions); bipolar participants included
Severity rating 4 or greater on 6-point scale in the SADS that rates severity of delusion
HRSD-17 > 14
Inpatients
No data about prior treatment of current episode


InterventionsThree groups: perphenazine versus amitriptyline versus amitriptyline + perphenazine
Doses: perphenazine mean 50 mg versus amitriptyline mean 218 mg versus amitriptyline mean 170 mg + perphenazine mean 54 mg
Blood levels: perphenazine 19 to 113 ng/mL versus amitriptyline (+ nortriptyline) 130 to 500 ng/mL versus amitriptyline 157 to 690 ng/mL + perphenazine 18 to 128 ng/mL
Seven days drug free
Treatment period: four weeks
Additional medication: benztropine mesylate 4 mg


OutcomesDichotomous data: author defined: Response is HRSD-17 < 7 and delusional rating score = 1 (6-point scale in the SADS). No remission data (definition of response is definition of remission)
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: amitriptyline + perphenazine 2/22, perphenazine 1/17
Mortality rate: 0


NotesOnly participants with delusions
Seven drop out in ITT (in the original data, dropouts are excluded from the analysis); response data ITT 3/17 (original 3/16); 7/19 (7/17); 14/22 (14/18)
9/58 = 15.5% bipolar participants in analysis. Because of lack of data, we were not able to exclude these bipolar participants from the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'The hospital pharmacist assigned patients randomly'

Allocation concealment (selection bias)Low riskProbably yes: 'The hospital pharmacist assigned patients randomly'

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'The hospital pharmacist assigned patients randomly. All tablets looked identical'

'All raters and floor staff and the patient were blind to the patient's drug treatment and the plasma-level data'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'The hospital pharmacist assigned patients randomly. All tablets looked identical'

'All raters and floor staff and the patient were blind to the patient's drug treatment and the plasma-level data'

Blinding (performance bias and detection bias)
of outcome assessors
Low riskAs reported: 'The hospital pharmacist assigned patients randomly. All tablets looked identical'

'All raters and floor staff and the patient were blind to the patient's drug treatment and the plasma-level data'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasUnclear riskOnly participants with delusions are included

9/58 = 15.5% bipolar participants in analysis. Because of lack of data, we were not able to exclude these bipolar participants from the analysis

We reanalyzed the data to ITT

Spiker 1988

MethodsReanalyzing two studies (not including the data of the Spiker 1985 study)
Randomised, double-blind, placebo-controlled
Randomisation procedure not explicitly described
Blinding adequately described in original studies


ParticipantsRe-diagnosing by using DSM-III criteria
Major depressive disorder DSM-III
HRSD-17 > 14 (30 or more based on the sum of two raters)
Inpatients. Subgroup psychotic participants
No data about prior treatment of current episode


InterventionsAmitriptyline versus placebo
Three days 50; four days 100; seven days 150, 14 days 200 mg amitriptyline (at least three weeks ≥ 150 mg)
Blood levels: unknown
Extra medication: none
Two weeks drug-free washout period
One week placebo (single-blind); total period of three weeks drug free
Treatment period: four weeks


OutcomesDichotomous data: author defined: Response is HRSD-17 < 7 (< 14/2) + not psychotic or HRSD-17 = 6.5 to 9.5 (13/2 to 19 /2) + not psychotic + 1/3 or less of entering score. Remission data not specified
Continuous data: symptom reduction: no data; global response: no data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: no data
Mortality rate: 0 (no data)


Notes20% response in two-week drug-free period (psychotic + non-psychotic); no data about psychotic versus non-psychotic in these two weeks
Four weeks treatment; only two weeks 200 mg; no blood levels
Subgroup of 27 participants with psychotic depression. Amitriptyline 14; placebo 13
Dropouts four (amitriptyline) and three (placebo) are excluded from analysis by the authors. Responders amitriptyline 4/10 and placebo 0/10. ITT responders: amitriptyline 4/14 and placebo 0/13


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs reported: 'Patients were randomly assigned'

Allocation concealment (selection bias)Unclear riskNo data

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'All patients received 4 identical capsules daily: patients and staff were blind'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'All patients received 4 identical capsules daily: patients and staff were blind'

Blinding (performance bias and detection bias)
of outcome assessors
Unclear riskNo data

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasHigh riskParticipants were retrospectively re-diagnosed. Psychotic depression and non-psychotic depression were included and randomly assigned. We used the data about psychotic participants

14 days drug-free period (20% remission with no further data) + one week placebo before random assignment could be due to low placebo response

van den Broek 2004

MethodsRandomised, double-blind comparison


ParticipantsDSM-IV diagnosis major depressive disorder; assessed with the depression part of the SADS
HRSD-17 > 16
Inpatients; subgroup of psychotic depression
39% of all included participants were pretreated with an SSRI and 22.7% with a TCA, but none as inpatients with adequate plasma level for at least four weeks during the present episode


InterventionsImipramine versus fluvoxamine
Four days placebo washout
Predefined blood levels. Imipramine 150 to 450 mg (blood level imipramine + desimipramine 192 to 521). Fluvoxamine 150 to 1800 mg (blood level 109 to 325 ng/mL). Treatment period: four weeks after reaching predefined blood levels. Additional medication: one to six tablets a day containing 45 mg of an extract of valerian, lorazepam 1 to 3 mg a day or haloperidol 1 to 10 mg a day


OutcomesDichotomous data: author defined: Response is reduction of HRSD-17 ≥ 50%. Remission is HRSD-17 < 8


NotesSubgroup with psychotic features. Some participants in this subgroup had been treated with haloperidol (by us counted as dropouts). Worse responding in a group leads to more participants who were given haloperidol
We used additional psychotic subgroup data from the author


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs reported: 'A computer generated randomisation list was used'

Allocation concealment (selection bias)Unclear riskNo specific data

Blinding (performance bias and detection bias)
of participants
Low riskAs reported: 'Tablets identical in appearance, weight and taste were administered. Preparation of the tablets was done by the pharmacist. The treating physician received blood level data in percentages'

Blinding (performance bias and detection bias)
of personnel
Low riskAs reported: 'Tablets identical in appearance, weight and taste were administered. Preparation of the tablets was done by the pharmacist. The treating physician received blood level data in percentage'

Blinding (performance bias and detection bias)
of outcome assessors
Low riskAs reported: 'The treating physicians were not involved in the ratings'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasHigh riskWorse responding in a group leads to more participants who were given haloperidol

We reanalyzed the data: Participants treated with haloperidol were counted as dropouts

Wijkstra 2010

MethodsRandomised double-blind study


ParticipantsDSM-IV-defined psychotic depression

Inpatients


InterventionsSeven weeks of treatment with imipramine (plasma levels 200 to 300 μg/L), venlafaxine (375 mg/d), venlafaxine + quetiapine (375 mg/d + 600 mg/d)


OutcomesDichotomous data: author defined (response). Response is ≧ 50% decrease in HAM-D 17 scores from baseline to study endpoint, and a final HAM-D score ≦ 14. Remission is HAMD ≦ 7 (not predefined)


NotesNo quetiapine arm. Inclusion did not reach planned number (122 i.s.o. 155)

Relatively low dropout rate (22/122 = 18%)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs reported: 'Randomisation was executed centrally using a computer-generated randomisation list: randomly permuted blocks of size six'

Allocation concealment (selection bias)Low riskAs reported: 'Randomisation was executed centrally'

Blinding (performance bias and detection bias)
of participants
Low riskThe study was double-blind. Blood was collected from each participant (only imipramine blood level was assessed). Treatment guesses were analysed and indicated high preservation of blindness

Blinding (performance bias and detection bias)
of personnel
Low riskDouble-blind study. Blood was collected from each participant (only imipramine blood level was assessed). Treatment guesses were analysed and indicated high preservation of blindness

Blinding (performance bias and detection bias)
of outcome assessors
Low riskAs reported: 'Blindness was checked and high. All dose adjustments were done centrally by an independent psychiatrist'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Low riskProtocol available. Generally accepted outcomes have been used

Other biasUnclear risk122 participants included i.s.o. with the planned 155 resulting in loss of power

Post hoc remission as secondary outcome measure

Zanardi 1996

MethodsRandomised, double-blind comparison


ParticipantsThe SCID patient version was used for some participants but not for all (reply of author to letter to editor)
DSM-III-R criteria; psychotic depressive episode
No HRSD criteria described at inclusion
Inpatients
No data about prior treatment of current episode


InterventionsSertraline versus paroxetine
Dose: 150 mg versus 50 mg from day 8
Blood levels: unknown
Additional medication: flurazepam < 30 mg (bipolar participants additional medication lithium; bipolar participants are excluded from our data)
One week medication free (single-blind placebo period)
Treatment period: five weeks


OutcomesDichotomous data: author defined: Response is HRSD-21 < 8 + DDERS (Dimensions of Delusional Experience RS) = 0. Remission data not specified
Continuous data: symptom reduction: no data; global response: no data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: same as overall dropout
Mortality rate: 0


Notes5/14 dropouts in paroxetine group and 0/18 in sertraline group
Bipolar participants could be excluded from our analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAs reported: 'Patients were randomly assigned to two therapy groups'

Allocation concealment (selection bias)Unclear riskNo data

Blinding (performance bias and detection bias)
of participants
Unclear riskAs reported: 'Patients were randomly assigned'. In title and abstract: 'Double-blind controlled trial. No information about methods of blinding'

Blinding (performance bias and detection bias)
of personnel
Unclear riskAs reported: 'Double-blind controlled trial'

Blinding (performance bias and detection bias)
of outcome assessors
Unclear riskNo data

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasUnclear riskWe reanalyzed the data by excluding bipolar participants

Difference in dropout is high: 5/14 versus 0/18

Zanardi 2000

MethodsRandomised, double-blind comparison


ParticipantsUnclear diagnosing procedure
DSM-IV criteria; psychotic depressive episode
No HRSD criteria described at inclusion
Inpatients
No data about prior treatment of current episode


InterventionsVenlafaxine versus fluvoxamine
Dose: 300 mg versus 300 mg from day 8
Blood levels: unknown
Additional medication: flurazepam < 30 mg
One week medication free (single-blind placebo period)
Treatment period: five weeks


OutcomesDichotomous data: author defined: Response is HRSD-21 < 9 + DDERS (Dimensions of Delusional Experience RS) = 0. Remission data not specified
Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data
Overall dropout rate: yes
Dropout due to adverse effects: same as overall dropout rate
Mortality rate: 0


NotesWe used additional data from the author to exclude the bipolar participants from the analysis
Included 22 participants with major depressive disorder (MDD) with psychotic features. Responders in venlafaxine group 6/11 MDD. Responders fluvoxamine group 9/11 MDD. No dropouts in fluvoxamine group. Two dropouts in venlafaxine group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs reported: 'Randomization was performed by a computer-generated schedule'

Allocation concealment (selection bias)Unclear riskRandomisation method not described
Blinding not explicitly described. No data

Blinding (performance bias and detection bias)
of participants
Unclear riskAs reported: 'Patients were randomly assigned'

'Double-blind controlled study'

Blinding (performance bias and detection bias)
of personnel
Unclear risk'Double-blind controlled study', but unclear whether double-blind includes personnel

Blinding (performance bias and detection bias)
of outcome assessors
Low riskAs reported: 'Raters were blind to treatment'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone

Selective reporting (reporting bias)Unclear riskNo protocol available. Generally accepted outcomes have been used

Other biasUnclear riskWe reanalyzed the data by excluding bipolar participants with additional data from the author

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Belanoff 2001Only four days of treatment

Bellini 199425% bipolar participants (in each group three bipolar participants)
The author did not respond to our request for additional information

Blasey 2009Impossible to compare two defined pharmacological treatments

Blasey 2011Impossible to compare two defined pharmacological treatments

Cassacchia 1984'Unipolar psychotic depression' is probably 'manic depressive psychosis, depressive type' (ICD9). This is not the same as 'psychotic depression'
Number of bipolar participants is not clear
Dropouts not in results. It is not possible to extract ITT response data
Reason for exclusion: unclear diagnosis, number of bipolar participants unclear, ITT data not available

Davidson 1981Reason for exclusion: unclear diagnosis and short treatment period

DeBattista 2006Impossible to compare two defined pharmacological treatments. 48.3% + 12.9% = 61.2% HAMD response with placebo after one week

Ebert 1997Randomisation not adequate, open study

Flores 2006Impossible to compare two defined pharmacological treatments and treatment only seven days

Friedman 1966No comparable diagnostic procedure. No data about MDD subgroup
Dropouts have been excluded

Künzel 2008No ITT data; bipolar participants 17.5% in per-protocol data; continued treatment with lithium, valproic acid

Malison 1999Only three psychotic participants

McLaughlin 1969Diagnosis unclear

Müller 1998In this subgroup, no data are given about responders, bipolar participants and dropouts
The author did not respond to our request for additional information

Navarro 2001Citalopram versus nortriptyline
Subgroup with nine psychotic depressive episodes
Reason for exclusion: This subgroup was also treated with haloperidol. No data available about this subgroup
The author did not respond to our request for additional information

Nelson 1984Unknown from data in which group the responders are located (imipramine or ami). So comparison is impossible

Spiker 1982Pre-published data from the 1985 study

Zanardi 199830.5 % bipolar participants

 
Comparison 1. Antidepressant versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Amitriptyline versus placebo
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Dropouts1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Amitriptyline versus placebo
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Antipsychotic versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Olanzapine versus placebo
2201Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.74, 1.73]

 2 Dropouts2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Olanzapine versus placebo
2201Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.57, 1.08]

 
Comparison 3. Antidepressant versus antidepressant

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response5Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Imipramine versus venlafaxine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Imipramine versus mirtazapine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Imipramine versus fluvoxamine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Fluvoxamine versus venlafaxine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Sertraline versus paroxetine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Dropouts5Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Imipramine versus venlafaxine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Imipramine versus mirtazapine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Imipramine versus fluvoxamine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.4 Fluvoxamine versus venlafaxine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.5 Sertraline versus paroxetine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. Antidepressant versus antipsychotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Amitriptyline versus perphenazine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Dropouts1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Amitriptyline versus perphenazine
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 5. Antidepressant plus antipsychotic versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Fluoxetine + olanzapine versus placebo
2148Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.23, 2.82]

 2 Dropouts2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Fluoxetine + olanzapine versus placebo
2148Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.48, 1.18]

 
Comparison 6. Antidepressant plus antipsychotic versus placebo plus antipsychotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response4447Risk Ratio (M-H, Fixed, 95% CI)1.83 [1.40, 2.38]

    1.1 amitriptyline + perphenazine versus perphenazine
139Risk Ratio (M-H, Fixed, 95% CI)3.61 [1.23, 10.56]

    1.2 Fluoxetine + olanzapine versus olanzapine
2149Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.10, 2.44]

    1.3 Olanzapine + sertraline versus olanzapine
1259Risk Ratio (M-H, Fixed, 95% CI)1.76 [1.21, 2.54]

 2 Dropouts4447Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.63, 1.01]

    2.1 Amitriptyline + perphenazine versus perphenazine
139Risk Ratio (M-H, Fixed, 95% CI)3.09 [0.38, 25.19]

    2.2 Fluoxetine + olanzapine versus olanzapine
2149Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.59, 1.53]

    2.3 Olanzapine + sertraline versus olanzapine
1259Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.53, 0.92]

 
Comparison 7. Antidepressant plus antipsychotic versus placebo plus antidepressant

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response4286Risk Ratio (M-H, Fixed, 95% CI)1.44 [1.15, 1.80]

    1.1 Nortriptyline + perphenazine versus nortriptyline
136Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.49, 2.53]

    1.2 Venlafaxine + quetiapine versus venlafaxine
180Risk Ratio (M-H, Fixed, 95% CI)1.98 [1.20, 3.24]

    1.3 Amitriptyline + perphenazine versus amitriptyline
141Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.89, 3.37]

    1.4 Amitriptyline + perphenazine versus amoxapine
146Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.75, 1.88]

    1.5 Venlafaxine + quetiapine versus imipramine
183Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.87, 1.81]

 2 Dropouts4286Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.58, 1.44]

    2.1 Nortriptyline + perphenazine versus nortriptyline
136Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.26, 4.81]

    2.2 Venlafaxine + quetiapine versus venlafaxine
180Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.33, 2.08]

    2.3 Amitriptyline + perphenazine versus amitriptyline
141Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.35, 8.41]

    2.4 Amitriptyline + perphenazine versus amoxapine
146Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.29, 1.45]

    2.5 Venlafaxine + quetiapine versus imipramine
183Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.39, 2.66]

 
Comparison 8. Antidepressant plus antipsychotic versus placebo plus the same antidepressant

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical response3157Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.19, 2.43]

    1.1 Nortriptyline + perphenazine versus nortriptyline
136Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.49, 2.53]

    1.2 Venlafaxine + quetiapine versus venlafaxine
180Risk Ratio (M-H, Fixed, 95% CI)1.98 [1.20, 3.24]

    1.3 Amitriptyline + perphenazine versus amitriptyline
141Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.89, 3.37]

 2 Dropouts3157Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.52, 2.07]

    2.1 Nortriptyline + perphenazine versus nortriptyline
136Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.26, 4.81]

    2.2 Venlafaxine + quetiapine versus venlafaxine
180Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.33, 2.08]

    2.3 Amitriptyline + perphenazine versus amitriptyline
141Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.35, 8.41]