Articles
Pharmacological treatments for psychotic depression:
Lancet Psychiatry 2024;
11: 210–20
See Comment page 162
*Contributed equally
Departament de Medicina,
Facultat de Medicina i Ciències
de la Salut, Institut de
Neurociències, Universitat de
Barcelona, Barcelona, Spain
(V Oliva MD, C Possidente MD,
M De Prisco MD, G Fico MD,
G Anmella PhD,
D Hidalgo-Mazzei PhD,
A Murru PhD, J Radua PhD,
Prof E Vieta PhD); Bipolar and
Depressive Disorders Unit,
Hospìtal Clinic de Barcelona,
Barcelona, Spain (V Oliva,
C Possidente, M De Prisco, G Fico,
G Anmella, D Hidalgo-Mazzei,
A Murru, Prof E Vieta); Institut
d’Investigacions Biomèdiques
August Pi i Sunyer, Barcelona,
Spain (V Oliva, C Possidente,
G Fico, G Anmella,
D Hidalgo-Mazzei, A Murru,
J Radua, Prof E Vieta);
Department of Biomedical and
Neuromotor Sciences,
University of Bologna,
Bologna, Italy (V Oliva,
C Possidente, G Fanelli MD,
C Fabbri PhD,
Prof A Serretti PhD); Centro de
Investigación Biomédica en
Red de Salud Mental, Instituto
de Salud Carlos III, Madrid,
Spain (M De Prisco, G Anmella,
J Radua, Prof E Vieta);
Department of Human
Genetics, Radboud University
Medical Center, Nijmegen,
Netherlands (G Fanelli);
Donders Institute for Brain,
Cognition and Behaviour,
Radboud University, Nijmegen,
Netherlands (G Fanelli); Social,
Genetic & Developmental
Psychiatry Centre, Institute of
Psychiatry, Psychology &
Neuroscience, King’s College
London, London, UK (C Fabbri);
Section of Psychiatry,
Department of Neuroscience,
Reproductive Science and
Odontostomatology, Federico
II University of Naples, Naples,
Italy (M Fornaro PhD,
Prof A de Bartolomeis PhD);
Department of Psychiatry and
210
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a systematic review and network meta-analysis
Vincenzo Oliva*, Chiara Possidente*, Michele De Prisco, Giovanna Fico, Gerard Anmella, Diego Hidalgo-Mazzei, Andrea Murru, Giuseppe Fanelli,
Chiara Fabbri, Michele Fornaro, Andrea de Bartolomeis, Marco Solmi, Joaquim Radua, Eduard Vieta, Alessandro Serretti
Summary
Background There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic
depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and
safety of pharmacological treatments for psychotic depression.
Methods In this systematic review and network meta-analysis, we searched ClinicalTrials.gov, CENTRAL, Embase,
PsycINFO, PubMed, Scopus, and Web of Science from inception to Nov 23, 2023 for randomised controlled trials
published in any language that assessed pharmacological treatments for individuals of any age with a diagnosis of
a major depressive episode with psychotic features, in the context of major depressive disorder or bipolar disorder
in any setting. We excluded continuation or maintenance trials. We screened the study titles and abstracts
identified, and we extracted data from relevant studies after full-text review. If full data were not available, we
requested data from study authors twice. We analysed treatments for individual drugs (or drug combinations) and
by grouping them on the basis of mechanisms of action. The primary outcomes were response rate (ie, the
proportion of participants who responded to treatment) and acceptability (ie, the proportion who discontinued
treatment for any reason). We calculated risk ratios and did separate frequentist network meta-analyses by using
random-effects models. The risk of bias of individual studies was assessed with the Cochrane risk-of-bias tool and
the confidence in the evidence with the Confidence-In-Network-Meta-Analysis (CINeMA). This study was
registered with PROSPERO, CRD42023392926.
Findings Of 6313 reports identified, 16 randomised controlled trials were included in the systematic review, and 14 were
included in the network meta-analyses. The 16 trials included 1161 people with psychotic depression (mean age 50·5 years
[SD 11·4]). 516 (44·4%) participants were female and 422 (36·3%) were male; sex data were not available for the
other 223 (19·2%). 489 (42·1%) participants were White, 47 (4·0%) were African American, and 12 (1·0%) were Asian;
race or ethnicity data were not available for the other 613 (52·8%). Only the combination of fluoxetine plus olanzapine
was associated with a higher proportion of participants with a treatment response compared with placebo (risk ratio 1·91
[95% CI 1·27–2·85]), with no differences in terms of safety outcomes compared with placebo. When treatments were
grouped by mechanism of action, the combination of a selective serotonin reuptake inhibitor with a second-generation
antipsychotic was associated with a higher proportion of treatment responses than was placebo (1·89 [1·17–3·04]), with
no differences in terms of safety outcomes. In head-to-head comparisons of active treatments, a significantly higher
proportion of participants had a response to amitriptyline plus perphenazine (3·61 [1·23–10·56]) and
amoxapine (3·14 [1·01–9·80]) than to perphenazine, and to fluoxetine plus olanzapine compared with olanzapine
alone (1·60 [1·09–2·34]). Venlafaxine, venlafaxine plus quetiapine (2·25 [1·09–4·63]), and imipramine (1·95 [1·01–3·79])
were also associated with a higher proportion of treatment responses overall. In head-to-head comparisons grouped by
mechanism of action, antipsychotic plus antidepressant combinations consistently outperformed monotherapies from
either drug class in terms of the proportion of participants with treatment responses. Heterogeneity was low. No high-
risk instances were identified in the bias assessment for our primary outcomes.
Interpretation According to the available evidence, the combination of a selective serotonin reuptake inhibitor and a
second-generation antipsychotic—and particularly of fluoxetine and olanzapine—could be the optimal treatment
choice for psychotic depression. These findings should be taken into account in the development of clinical practice
guidelines. However, these conclusions should be interpreted cautiously in view of the low number of included
studies and the limitations of these studies.
Funding None.
Copyright © 2024 Elsevier Ltd. All rights reserved.
Introduction delusions, or both, in the context of a major depressive
Psychotic depression is a severe form of depression episode, and it can occur in both major depressive
characterised by the presence of hallucinations or disorder and bipolar disorder. The lifetime prevalence of
www.thelancet.com/psychiatry Vol 11 March 2024

Research in context
Evidence before this study
Psychotic depression is a severe and difficult-to-treat form of
depressive disorder. Guidelines recommend combination
therapy with an antipsychotic and an antidepressant, but
they do not provide specific recommendations on the most
efficacious drug options. We comprehensively searched
CENTRAL, Embase, PsycINFO, PubMed, and MEDLINE with
the terms “psychotic depression”, “delusional depression”,
“depression”, “psychotic features”, “treatment*”, and
“intervention*” for systematic reviews and pairwise meta-
analyses or network meta-analyses in any language of the
efficacy and safety of pharmacological interventions for
psychotic depression from database inception to Jan 12, 2023.
Our search identified previous systematic reviews and
pairwise meta-analyses, including Cochrane systematic
reviews, but no network meta-analyses. One systematic
review and meta-analysis showed that combination therapies
were more efficacious than monotherapies. Other systematic
reviews and meta-analyses were limited in their ability to
combine data because the original studies investigated only a
few comparisons between pairs of pharmacotherapies or
between therapies and placebo. Thus, there is no meta-
analytic evidence for the best drug options for psychotic
depression.
Added value of this study
To the best of our knowledge, our study is the first systematic
review and network meta-analysis of pharmacological
psychotic depression can be as high as 1% in community
samples.1 Psychotic depression is associated with greater
illness severity and impairment and longer episode
duration than non-psychotic depression, and there is a
risk of recurrence of psychotic features in subsequent
episodes.2
Despite its clinical importance, psychotic depression
remains widely under-recognised and under-studied.3
Only a few randomised controlled trials have been done
to test the efficacy and safety of pharmacological
interventions for acute psychotic depression; previous
rigorous meta-analyses4–6 of these trials’ data have
consistently suggested that the combination of an
antidepressant plus an antipsychotic is more efficacious
than either class alone. However, these meta-analyses4–6
did not draw conclusions about individual drugs because
of the paucity of available studies and the differing
interventions used in the studies, which prevented meta-
analytic synthesis.
In line with the findings of the previous meta-analyses,
guidelines suggest the combination of an antidepressant
and an antipsychotic as first-line treatment for psychotic
depression, but there are no recommendations for
specific drugs, and no treatments have been granted
regulatory approval specifically for the disorder.7 In view
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Articles
Ottawa Hospital Research
Institute Clinical Epidemiology
Program, University of Ottawa,
interventions for psychotic depression and provides the first Ottawa, ON, Canada
meta-analytic evidence for the optimal choice of treatment. (M Solmi PhD); Regional Centre
Our findings suggest that the combination of a selective for the Treatment of Eating
Disorders and On Track: The
serotonin reuptake inhibitor and a second-generation Champlain First Episode
antipsychotic (and particularly the combination of fluoxetine Psychosis Program,
plus olanzapine) yielded the highest proportion of Department of Mental Health,
participants with a treatment response compared with The Ottawa Hospital, Ottawa,
ON, Canada (M Solmi);
placebo. This combination also had a favourable safety Department of Child and
profile. Adolescent Psychiatry, Charité
Universitätsmedizin, Berlin,
Implications of all the available evidence Germany (M Solmi);
This expansion of evidence for the pharmacological Department of Medicine and
Surgery, Kore University of
treatment of psychotic depression should improve clinical
Enna, Enna, Italy
care, facilitate the development of treatment guidelines, and
(Prof A Serretti)
provide valuable insights for future clinical research, which
Correspondence to:
remains insufficiently developed. In decades of clinical Prof Eduard Vieta, Bipolar and
research, only a few randomised controlled trials have been Depressive Disorders Unit,
done in psychotic depression, and these studies have involved Hospital Clinic, University of
Barcelona, 170 Villarroel St 12-0,
heterogeneous populations and outdated pharmacological
08036 Barcelona, Spain
treatments, and lacked specificity in clinical indications. To evieta@clinic.cat
address this gap, new trials with more homogeneous patient
populations primarily based on the primary diagnosis
(whether major depressive disorder or bipolar disorder) and
that incorporate emerging psychopharmacological
treatments are needed. Such trials are crucial for refining
understanding of the most efficacious and safe interventions
for psychotic depression and could yield substantial data to
inform the development of clinical guidelines.
of the clinical relevance of the topic, the limitations of
previous research, and the paucity of new randomised
controlled trials of treatments for psychotic depression, a
comprehensive approach to synthesise available evidence
on pharmacological treatments is needed. We did a
network meta-analysis (which enables robust inferral
and ranking of the efficacy of any drug—or drug
combination—compared with a placebo) of treatments
for psychotic depression in an attempt to fill this evidence
gap.
Methods
Search strategy and selection criteria
In this systematic review and network meta-analysis,
which followed PRISMA guidelines,8 we searched
ClinicalTrials.gov, CENTRAL, Embase, PsycINFO,
PubMed, Scopus, and Web of Science with terms
including “major depression” or “bipolar depression”
combined with terms related to psychotic symptoms,
such as “psychotic”, “delusion”, or “hallucination”
within randomised controlled trials from inception
until Nov 23, 2023, with no language restrictions. We
also searched the reference lists of previous systematic
reviews and meta-analyses on the topic.4–6 Our complete
search strategy, including a full list of search terms, is
211
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See Online for appendix provided in the appendix (pp 11–13). We included
randomised controlled trials of the efficacy and safety
of any pharmacological treatment for an acute major
depressive episode with psychotic features (according
to any version of the Research Diagnostic Criteria,
the DSM, or the ICD) in participants of any age in any
setting (ie, both inpatients and outpatients) with a
diagnosis of either major depressive disorder or bipolar
disorder. To provide a comprehensive synthesis and
comparison of available treatments, trials of both
monotherapy and combination treatments were
included. We excluded continuation or maintenance
trials.
Study screening and data extraction were done by VO
and CP. Discrepancies were resolved through consensus,
with input from a third senior author (AS or EV). If full
data were not available in the published article, we
contacted study authors twice to request the necessary
data. VO and CP used the Cochrane risk-of-bias
tool (version 2) to assess the risk of bias by comparing
the primary outcome of included studies with the
primary outcomes of our systematic review and network
meta-analysis. The findings of this bias assessment were
confirmed by AS and EV. Two levels of classification
were used to identify nodes:9 on a narrow level, we
assigned each medication or combination of medications
a specific node, whereas on a broader level, we grouped
medications into nodes on the basis of the most
commonly used pharmacological classification (which
considers mechanisms of action).4 The drug classes
considered were noradrenergic and specific serotonergic
antidepressants (NaSSAs), selective serotonin reuptake
inhibitors (SSRIs), serotonin–noradrenaline reuptake
inhibitors (SNRIs), tricyclic antidepressants (TCAs),
first-generation antipsychotics (FGAs), and second-
generation antipsychotics (SGAs). Each medication or
combination of medications was assigned a specific
node matching the molecules at a narrow level. The
study protocol is in the appendix (pp 7–13).
Data analysis
The primary efficacy outcome was the response rate
(ie, the proportion of participants who responded to
treatment, as defined by the authors of the original
studies on the basis of scores on a clinician-rated
symptom-rating scale). The primary safety outcome
was treatment acceptability, which was based on the
overall proportion of participants who dropped out of
studies for any reason during the acute treatment
phase. Secondary outcomes were the mean change
from baseline in scores on depression symptom scales
(to assess efficacy in reducing symptom severity
compared with the initial state), remission rate (ie, the
proportion of participants who went into remission
from psychotic symptoms, as defined by the authors of
the original studies on the basis of scores on a clinician-
rated symptom-rating scale), tolerability (the proportion
212
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of patients who discontinued treatment because of
adverse events), and the frequency of individual adverse
events. During our systematic review, we updated the
primary efficacy outcome from change in depression
symptom scale scores, as had been planned in the
protocol, to the proportion with an overall response. We
made this change to enable incorporation of nearly all
treatments used in randomised controlled trials in
psychotic depression into the network meta-analysis,
which allowed for a more comprehensive comparison
of treatments. The shift also ensured consistency with
previous meta-analyses5,6 and adherence to regulatory
standards for pivotal trial assessments of clinical
relevance (appendix p 10).
We did distinct frequentist network meta-analyses
based on random-effects models. We calculated the
standardised mean difference for continuous outcomes
and risk ratios (RRs) for dichotomous outcomes, along
with corresponding 95% CIs for both. The normality of
the continuous data was preverified by calculating the
mean-to-SD ratio on symptom rating scales. The
presence of statistical heterogeneity in the networks
was assessed using τ² for between-study variance and
I² for global heterogeneity. Transitivity was assumed on
the basis of study design and diagnosis, and by
comparing potential effect modifiers (ie, mean age, sex,
baseline symptom severity) across studies. In case of
identification of outliers in these comparisons,
sensitivity analyses in which outliers were removed
from the main analysis were done. We assessed local
inconsistency with a node-splitting analysis, and we
assessed global inconsistency across the entire network
with the design-by-treatment Q statistic. For each
outcome, a hierarchy of treatments among included
interventions was calculated on the basis of the surface
under the cumulative ranking curve (SUCRA) and its
frequentist analogue, the P-score. Publication bias was
assessed by visually examining funnel plots and with
Egger’s test (when more than ten studies were
available). We used the Confidence-In-Network-Meta-
Analysis (CINeMA) framework to assess the certainty
of evidence for primary outcomes. For the primary
efficacy and safety outcomes, we did sensitivity analyses
of only the studies that did intention-to-treat analyses,
and of the studies including adults only, people with
major depressive disorder only, inpatients only, and
people with severe depression only. All statistical
analyses were done in R (version 4.2.3) with the netmeta
package. This study was registered with PROSPERO,
CRD42023392926.
Role of the funding source
There was no funding source for this study.
Results
Overall, we identified 6313 records. 173 full-text articles
were assessed after title and abstract screening, and
www.thelancet.com/psychiatry Vol 11 March 2024

15 reports,10–24 including 1161 people with psychotic
depression, fulfilled the inclusion criteria (figure 1).
The mean age of participants was 50·5 years (SD 11·4;
range of means 39·3–72·5). 516 (44·4%) participants
were female, 422 (36·3%) were male, and the sex of the
remaining 223 (19·2%) participants was not disclosed.
489 (42·1%) participants were White, 47 (4·0%) were
African American, and 12 (1·0%) were Asian (ethnicity
data were not reported for the other 613 [52·8%]
participants). One report16 provided data from
two randomised controlled trials, and thus 16 trials
were included in the systematic review. Two studies
were not included in the network meta-analysis because
they did not assess treatments similar to those assessed
in the other studies.22,23 13 reports,10–21,24 encompassing
14 randomised controlled trials, were included in our
network meta-analysis (figure 1, appendix p 14). The
appendix details characteristics of the included studies
(pp 15–18) and a list of excluded studies with reasons
for exclusion (pp 19–32).
All included trials were parallel randomised controlled
trials. The mean trial duration was 6 weeks (range 4–16).
Eight trials13–17,20,21 included only people with major
depressive disorder, and one19 included only people
with bipolar disorder; the other seven10–12,18,22–24 included
participants with either disorder. Nine trials10,11,17,18,20–24
included inpatients, two16 included patients treated for
at least a week as inpatients, and the rest included both
inpatients and outpatients. Oral drugs were studied in
all trials. Two trials11,19 adopted the Montgomery-Asberg
Depression Rating Scale as a tool to assess treatment
efficacy, whereas in all other studies the Hamilton
Rating Scale for Depression was used. In nine
trials,11,13,15,16,19,20,23,24 analysis was by intention to treat; in
the others per-protocol analyses were presented.
Overall, the risk of bias at the study level was high for
four trials,10,16,19 but there were no instances of a high
risk of bias for the outcome-level assessments (appendix
pp 33–34). Assessment of transitivity assumption is
reported in the appendix (pp 35–37), as are network
plots, forest plots, SUCRA and P-score rankings, the
number of studies and patients for each intervention,
and league tables for each network meta-analysis
(pp 38–91).
Figures 2A and 2B show the networks of eligible
comparisons for overall response by specific drugs (or
combinations of drugs). Two distinct networks emerged
in our network meta-analysis because of the non-
comparability of some drugs included in the trials
(figure 3; appendix pp 38–41). The first network (k=5;
n=352) comprised six different pharmacotherapies or
combinations of pharmacotherapies (amitriptyline, ami­
triptyline plus perphenazine, amoxapine, fluoxetine plus
olanzapine, olanzapine, and perphenazine) and placebo.
Compared with placebo, the overall proportion of
participants with a treatment response was higher only
for fluoxetine plus olanzapine (RR 1·91 [95% CI
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Articles
6313 potentially eligible studies identified through database
search
2440 duplicates excluded
3873 titles and abstracts screened
3696 excluded
177 studies eligible
4 excluded (full text could not
be accessed)
173 full-text studies assessed for eligibility
158 excluded
32 wrong publication type*
42 wrong study design†
65 wrong population type‡
17 no DSM, ICD, or RDC diagnosis
2 did not use validated
assessment scale
15 studies (encompassing 16 randomised controlled trials)
included in systematic review
2 excluded (assessed different
treatments from other studies)
13 studies (encompassing 14 randomised controlled trials)
Figure 1: Study selection
RDC=Research Diagnostic Criteria. *Wrong publication types were conference
abstracts, posters, comments, errata, corrigendum, letters, reviews, and
protocols. †Wrong study design refers to non-randomised trials and secondary
analyses. ‡Wrong population type refers to studies that included people with
diagnoses other than psychotic depression in the context of major depressive
disorder or bipolar disorder or that did not distinguish between patients with
psychotic depression and those with non-psychotic depression.
1·27–2·85]). In head-to-head comparisons of active
treatments, a significantly higher proportion of
participants had a response to amitriptyline plus
perphenazine (3·61 [1·23–10·56]) and amoxapine
(3·14 [1·01–9·80]) than to perphenazine, and to
fluoxetine plus olanzapine compared with olanzapine
alone (1·60 [1·09–2·34]; figure 3). The second network
(k=4; n=229) comprised five different interventions:
fluvoxamine, imipramine, mirtazapine, venlafaxine, and
venlafaxine plus quetiapine. Compared with venlafaxine,
venlafaxine plus quetiapine (2·25 [1·09–4·63]) and
imipramine (1·95 [1·01–3·79]) were associated with a
higher proportion of treatment responses overall
(figure 3).
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A B C
Amitriptyline plus PLA
perphenazine Fluvoxamine NaSSA
SGA
Amitriptyline
Imipramine
FGA

Venlafaxine plus SNRI

Amoxapine Placebo quetiapine
TCA plus FGA
Fluoxetine plus
olanzapine

SNRI plus
Mirtazapine SGA
Perphenazine TCA plus FGA
Olanzapine Venlafaxine
SSRI

SSRI plus SGA TCA

Figure 2: Networks of eligible comparisons for the network meta-analyses of efficacy for specific treatments in subnetwork one (A) and subnetwork two (B),
and for treatments grouped by mechanism of action (C)
Node size is proportional to the number of participants receiving the treatment in the included randomised controlled trials. The edges between nodes represent the
presence of direct comparisons between two treatments and their width is proportional to the number of randomised controlled trials in which the treatments were
compared. FGA=first-generation antipsychotic. NaSSA=noradrenergic and specific serotonergic antidepressant. SGA=second-generation antipsychotic.
SNRI=serotonin–noradrenaline reuptake inhibitor. SSRI=selective serotonin reuptake inhibitor. TCA=tricyclic antidepressant.

Efficacy Comparison Acceptability

Amitriptyline plus 0·84 1·73 3·09 2·27 2·42 2·14 .. .. .. .. ..

perphenazine (0·24–2·96) (0·35–8·41) (0·38–25·19) (0·29–17·77) (0·31–19·15) (0·28–16·50)

1·15 Amoxapine 2·06 3·68 2·70 2·88 2·55 .. .. .. .. ..

(0·79–1·66) (0·27–15·53) (0·32–42·49) (0·24–30·16) (0·26–32·45) (0·23–28·06)

1·73 1·51 Amitriptyline 1·79 1·31 1·40 1·24 .. .. .. .. ..

(0·89–3·37) (0·70–3·23) (0·18–18·02) (0·35–4·90) (0·37–5·31) (0·34–4·51)

7·60 6·62 4·40 Fluoxetine plus 0·73 0·78 0·69 .. .. .. .. ..

(0·40–142·55) (0·34–127·23) (0·25–76·40) olanzapine (0·05–10·48) (0·05–11·27) (0·05–9·76)

3·61 3·14 2·09 0·47 Perphenazine 1·07 0·94 .. .. .. .. ..

(1·23–10·56) (1·01–9·80) (0·64–6·82) (0·02–10·44) (0·77–1·48) (0·74–1.20)

12·15 10·59 7·03 1·60 3·37 Olanzapine 0·88 .. .. .. .. ..

(0·65–228·41) (0·55–203·86) (0·40–122·43) (1·09–2·34) (0·15–74·21) (0·64–1·22)

14·47 12·62 8·38 1·91 4·01 1·19 Placebo .. .. .. .. ..

(0·79–264·11) (0·68–235·78) (0·50–141·44) (1·27–2·85) (0·19–85·95) (0·79–1·81)

.. .. .. .. .. .. .. Venlafaxine 0·46 0·43 0·41 0·33

plus quetiapine (0·05–4·66) (0·10–1·79) (0·08–2·13) (0·07–1·59)

.. .. .. .. .. .. .. 1·15 Imipramine 0·94 0·89 0·73

(0·59–2·24) (0·15–5·84) (0·11–6·99) (0·10–5·53)

.. .. .. .. .. .. .. 1·82 1·58 Fluvoxamine 0·95 0·77

(0·77–4·33) (0·78–3·21) (0·37–2·45) (0·32–1·87)

.. .. .. .. .. .. .. 2·25 1·95 1·23 Venlafaxine 0·81

(1·09–4·63) (1·01–3·79) (0·62–2·44) (0·33–2·02)

.. .. .. .. .. .. .. 3·68 3·20 2·02 1·64 Mirtazapine

(0·90–15·12) (0·92–11·13) (0·48–8·47) (0·40–6·72)

Figure 3: Head-to-head comparison of efficacy and acceptability of treatments for psychotic depression
Data are RR (95% CI). Treatments are reported according to the surface under the cumulative ranking curve. Efficacy describes the proportion of participants with a treatment response, whereas
acceptability refers to the proportion of participants who discontinued treatment for any reason. For efficacy, RRs higher than 1 favour the column-defining treatment, whereas for acceptability, RRs
less than 1 favour the row-defining treatment. RR=risk ratio.

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 Articles

Efficacy Comparison Acceptability

SNRI plus SGA 0·91 1·0 1·02 2·45 0·81 1·47 2·49 1·12 1·38 1·30 1·03
(0·31–2·69) (0·41–2·71) (0·17–6·27) (0·47–12·76) (0·33–2·02) (0·29–7·55) (0·26–24·20) (0·14–8·80) (0·27–6·99) (0·26–6·46) (0·20–5·42)

1·10 TCA plus FGA 1·15 1·12 2·68 0·89 1·61 2·72 1·23 1·51 1·43 1·13
(0·61–1·97) (0·69–1·93) (0·26–4·81) (0·59–12·17) (0·32–2·48) (0·39–6·73) (0·35–21·03) (0·18–8·21) (0·37–6·21) (0·35–5·73) (0·26–4·84)

1·17 1·06 TCA 0·97 2·33 0·77 1·40 2·36 1·07 1·31 1·24 0·98
(0·71–1·91) (0·78–1·45) (0·21–4·57) (0·56–9·65) (0·32–1·87) (0·37–5·31) (0·30–18·71) (0·17–6·64) (0·35–4·90) (0·34–4·51) (0·25–3·83)

1·23 1·12 1·05 TCA plus 2·39 0·80 1·44 2·43 1·10 1·35 1·28 1·01
(0·42–3·56) (0·46–2·73) (0·41–2·70) placebo (0·29–19·63) (0·13–4·74) (0·19–11·13) (0·20–30·04) (0·10–12·07) (0·18–10·33) (0·17–9·59) (0·13–7·95)

1·82 1·66 1·56 1·48 SSRI 0·33 0·60 1·02 0·46 0·57 0·53 0·42
(0·91–3·64) (0·85–3·25) (0·86–2·83) (0·49–4·53) (0·07–1·59) (0·09–4·23) (0·08–12·53) (0·05–4·66) (0·08–3·93) (0·08–3·64) (0·06–3·03)

2·25 2·05 1·93 1·83 1·24 SNRI 1·81 3·06 1·38 1·70 1·60 1·27
(1·27–3·98) (1·10–3·83) (1·12–3·32) (0·62–5·45) (0·70–2·18) (0·37–8·96) (0·32–28·99) (0·18–10·51) (0·35–8·29) (0·33–7·66) (0·25–6·43)

5·18 4·72 4·44 4·22 2·85 2·30 SSRI plus SGA 1·69 0·76 0·94 0·88 0·70
(0·28–97·03) (0·26–86·13) (0·25–79·68) (0·20–88·10) (0·15–54·31) (0·12–43·46) (0·14–19·75) (0·08–7·31) (0·68–1·30) (0·64–1·22) (0·53–0·92)

3·45 3·14 2·96 2·81 1·90 1·53 0·67 FGA 0·45 0·56 0·52 0·42
(1·00–11·88) (1·03–9·57) (0·95–9·18) (0·67–11·71) (0·53–6·82) (0·44–5·38) (0·03–14·82) (0·03–7·14) (0·05–6·45) (0·05–6·00) (0·03–4·94)

3·74 3·40 3·20 3·04 2·05 1·66 0·72 1·08 NaSSA 1·23 1·16 0·92
(1·06–13·14) (1·03–11·27) (1·01–10·17) (0·68–13·55) (0·56–7·54) (0·46–5·95) (0·03–16·18) (0·21–5·47) (0·13–11·72) (0·12–10·90) (0·09–9·00)

8·22 7·48 7·04 6·69 4·51 3·65 1·59 2·38 2·20 SGA 0·94 0·75
(0·44–154·14) (0·41–136·83) (0·39–126·57) (0·32–139·94) (0·24–86·28) (0·19–69·04) (1·01–2·51) (0·11–53·06) (0·10–49·42) (0·74–1·20) (0·49–1·14)

9·79 8·91 8·38 7·97 5·38 4·35 1·89 2·84 2·62 1·19 Placebo 0·79
(0·54–176·22) (0·51–156·37) (0·49–144·62) (0·40–160·22) (0·29–98·67) (0·24–78·94) (1·17–3·04) (0·13–60·80) (0·12–56·64) (0·73–1·94) (0·52–1·21)

.. .. .. .. .. .. .. .. .. .. .. SGA plus
placebo

Figure 4: Head-to-head comparison of efficacy and acceptability of treatments for psychotic depression, grouped by mechanism of action
Data are RR (95% CI). Treatments grouped by mechanism of action are reported according to surface under the cumulative ranking curve. Efficacy describes the proportion of participants with a
treatment response, whereas acceptability refers to the proportion of participants who discontinued treatment for any reason. For efficacy, RRs higher than 1 favour the column-defining treatment,
whereas for acceptability, RRs less than 1 favour the row-defining treatment. RR=risk ratio. FGA=first-generation antipsychotic. NaSSA=noradrenergic and specific serotonergic antidepressant.
SGA=second-generation antipsychotic. SNRI=serotonin–noradrenaline reuptake inhibitor. SSRI=selective serotonin reuptake inhibitor. TCA=tricyclic antidepressant.

A B C
Amitriptyline plus
perphenazine NaSSA
SGA NaSSA
Fluvoxamine
Amitriptyline Imipramine SGA plus PLA FGA

Amoxapine
Venlafaxine
Placebo plus quetiapine SNRI TCA plus
Fluoxetine plus placebo
olanzapine
SNRI plus TCA plus FGA
Mirtazapine SGA
Perphenazine SSRI TCA
Venlafaxine
Olanzapine SSRI plus SGA

Figure 5: Networks of eligible comparisons for the network meta-analyses of acceptability for specific treatments in subnetwork one (A) and
subnetwork two (B), and for treatments grouped by mechanism of action (C)
Node size is proportional to the number of participants receiving the treatment in the included randomised controlled trials. The edges between nodes represent the
presence of direct comparisons between two treatments and their width is proportional to the number of randomised controlled trials in which the treatments were
compared. FGA=first-generation antipsychotic. NaSSA=noradrenergic and specific serotonergic antidepressant. SGA=second-generation antipsychotic.
SNRI=serotonin–noradrenaline reuptake inhibitor. SSRI=selective serotonin reuptake inhibitor. TCA=tricyclic antidepressant.

We then considered the treatments grouped by SGAs, SNRIs, SNRIs plus SGAs, SSRIs,
mechanism of action in a network (k=11; n=674) that SSRIs plus SGAs, TCAs, TCAs plus FGAs,
included ten different interventions (FGAs, NaSSAs, and TCAs plus placebo) and placebo (figure 2C).

www.thelancet.com/psychiatry Vol 11 March 2024 215

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 Articles
Compared with placebo, only the combination of SSRIs
plus SGAs was associated with a higher proportion of
participants with a treatment response (RR 1·89
[95% CI 1·17–3·04]; figure 4). For head-to-head
comparisons of treatments grouped by mechanism of
action, a significantly higher proportion of participants
had responses to an SNRI plus an SGA than to a
NaSSA (3·74 [1·06–13·14]) or an SNRI (2·25
[1·27–3·98]); to a TCA and an FGA than to a NaSSA
(3·40 [1·03–11·27]), FGA (3·14 [1·03–9·57]), or
SNRI (2·05 [1·10–3·83]); to a TCA than to a
NaSSA (3·20 [1·01–10·17]) or an SNRI (1·93 [1·12–3·32]);
and to an SSRI plus an SGA than to an
SGA (1·59 [1·01– 2·51]; figure 4; appendix pp 42–43).
Figures 5A and 5B show the networks of eligible
comparisons for the acceptability of specific drugs and
drug combinations. No significant differences in
acceptability were noted in head-to-head comparisons
(figure 3; appendix pp 44–47). In the comparison of
treatments grouped by mechanism of action (figure 5C),
the network (k=12; n=1000) included 11 different
interventions—FGAs, NaSSAs, SGAs, SGAs plus
placebo, SNRIs, SNRIs plus SGAs, SSRIs, SSRIs plus
SGAs, TCAs, TCAs plus FGAs, and TCAs plus placebo—
and placebo. A lower proportion of dropouts was noted
among participants taking an SSRI and an SGA than
among those taking an SGA and placebo (RR 0·70
[95% CI 0·53–0·92]; figure 4; appendix pp 48–49).
For the secondary efficacy outcome of changes in
scores on depression symptom scales (appendix
pp 50–55), fluoxetine plus olanzapine (SMD –0·64
[95% CI –1·05 to –0·22]) and olanzapine (–0·37
[–0·67 to –0·08]) were associated with significant
improvements compared with placebo. Significant
improvements in scores were also noted for venlafaxine
plus quetiapine and imipramine compared with
mirtazapine; for amoxapine, amitriptyline plus
perphenazine, and amitriptyline compared with
perphenazine, and for amitriptyline plus perphenazine
compared with amitriptyline (appendix pp 50–55).
Significant improvements in scores on depression
symptom scales were noted for SSRIs plus SGAs and
SGAs alone compared with placebo; for SSRIs plus SGAs
compared with SGAs plus placebo; and for TCAs plus
placebo, SNRIs plus SGAs , TCAs plus FGAs , and TCAs
alone compared with FGAs (appendix pp 56–59).
The combination of an SSRI and an SGA was
associated with higher likelihood of remission than an
SGA plus placebo (RR 1·76 [95% CI 1·21–2·54]). The
combination of an SGA plus placebo resulted in a
higher proportion of dropouts due to adverse events
than placebo alone (5·94 [1·03–34·14]). We noted no
other significant differences in frequency of remission
(appendix pp 60–65) or in the overall frequency of
dropouts due to adverse events (appendix pp 66–75) in
comparisons of individual treatments or of treatments
grouped by mechanism of action.
216
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The results of specific network meta-analyses for the
adverse events asthenia, blurred vision, constipation,
dizziness, xerostomia, somnolence, and tremor are
presented in the appendix (pp 76–91). Asthenia was
significantly less likely to be reported by participants
taking SNRIs than by those taking an SNRI and
an SGA or a TCA and an FGA (appendix pp 76–77).
TCAs were associated with a higher risk of
xerostomia than were SNRIs, as was combination of a
TCA and an FGA compared with SNRIs and with the
combination of an SNRI and an SGA (appendix
pp 83–85).
The measures of global and local heterogeneity and
consistency for each network are shown in the appendix
(pp 92–107). Global heterogeneity was low for nearly all
outcomes. Heterogeneity was high only in the network
that explored mean changes in scores on depression
symptom scales and included FGAs, NaSSAs, SNRIs,
SNRIs plus SGAs, SSRIs, TCAs, TCAs plus FGAs, and
TCAs plus placebo (I²=56·8% [95% CI 0·0–87·7]). No
instances of local or global inconsistency were
identified. No publication bias was detected (appendix
pp 108–09).
In sensitivity analyses (appendix pp 110–227)
including only studies in which analysis was by
intention to treat, only studies of adults, only studies of
participants with major depressive disorders, and only
studies of participants with severe depression, a higher
proportion of overall responses to treatment was noted
for fluoxetine plus olanzapine compared with placebo,
similar to in the main analysis. Overall, the findings of
the sensitivity analyses were largely similar to those of
the main analysis. Because of insufficient data, we
could not confirm the efficacy of fluoxetine plus
olanzapine in the sensitivity analysis including only
inpatients. All other sensitivity analyses supported the
superiority of combination therapies over mono­
therapies, and the superiority of TCAs over other
monotherapies. The CINeMA assessment for the
primary outcomes and for each comparison is detailed
in the appendix (pp 228–38). Overall, confidence in the
evidence was very low.
Discussion
To our knowledge, this network meta-analysis is the
first of pharmacological treatments for psychotic
depression. Our analyses suggest that, compared
with placebo, a combination of an SSRI and an
SGA, particularly fluoxetine plus olanzapine, could
represent the most balanced approach in terms of
efficacy and tolerability. Direct comparisons between
different treatment options further suggested that
combinations of antipsychotics and antidepressants
were more efficacious than monotherapy with
either class. Among monotherapies, TCAs
were associated with the most favourable response
profile.
www.thelancet.com/psychiatry Vol 11 March 2024

In addition to its efficacy on overall treatment
response, the combination of fluoxetine and olanzapine
was associated with greater improvements in scores on
depression symptom scales compared with placebo,
and no significant differences from placebo in terms of
safety outcomes were apparent. Several mechanisms
could explain the efficacy of this treatment regimen.
Olanzapine exerts its antidepressant effects25,26 primarily
via serotonin receptor antagonism, particularly the
potent 5HT2C receptor.27 Unlike other SSRIs, fluoxetine
also antagonises this receptor,28 acting synergistically
with olanzapine to produce rapid onset of antidepres­
sant effects.29 The combined modulation of the
serotoninergic system is the rationale for the use of
this combination in treatment-resistant unipolar
depression.30 Notably, when given individually, both
fluoxetine and olanzapine exhibit mood-stabilising
effects,31 and their combination is a recommended
treatment option for treatment-resistant bipolar
depression.32 Furthermore, olanzapine has a favourable
efficacy profile, with rapid onset of antipsychotic effects
and a good safety profile compared with other
antipsychotics.26 Beyond the antidepressant and
antipsychotic effects, the synergistic action of
olanzapine and fluoxetine could substantially modulate
some of the characteristic symptoms of psychotic
depression. Patients with psychotic depression
frequently have symptoms of anxiety and psychomotor
agitation,33 along with emotion dysregulation,34 which is
closely linked to mood symptoms in affective
disorders.35 Fluoxetine and olanzapine might play an
important role in addressing these symptoms,36
potentially via olanzapine’s sedative effect.37 This
sedative effect could, in turn, alleviate the activation
symptoms frequently induced by fluoxetine as a result
of its effects on the noradrenergic system.38 The
sensitivity analyses supported the superiority of the
combination of fluoxetine plus olanzapine over placebo.
In addition, the trials included in our network meta-
analysis did not have high risk of bias for the response
outcome. However, we could not confirm the superiority
of the combination in patients hospitalised for the
entirety of their treatment. The studies supporting the
safety and efficacy of the combination involved patients
hospitalised for at least a week after treatment initiation,
with the possibility of discharge thereafter on the basis
of their clinical condition. While discharge could
suggest the rapid efficacy of the treatment, we cannot
rule out the possibility of selection bias for people with
less severe illness. This limitation, combined with the
very low confidence in the evidence, precludes definitive
conclusions, and underscores the importance of
considering clinical and individual patient factors in
the prescribing process.39,40
Direct comparisons between active treatments
consistently showed that treatment with both an
antipsychotic and an antidepressant was associated
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Articles
with a higher proportion of participants with treatment
responses than was monotherapy within either drug
class. Amitriptyline plus perphenazine was more
efficacious than perphenazine alone, fluoxetine plus
olanzapine was more efficacious than olanzapine, and
venlafaxine plus quetiapine was more efficacious than
venlafaxine. Similarly, combinations of TCAs and
FGAs or of SNRIs and SGAs were more efficacious
than SNRI, FGA, or NaSSA monotherapy, and the
combination of SSRIs plus SGAs outperformed
SGA monotherapy. Overall, these findings are
concordant with previous evidence from pairwise meta-
analyses,4–6 and are consistent with guideline
recommendations.7
Our analysis also suggested that, among mono­
therapies, TCAs (ie, amoxapine and imipramine) were
more efficacious than SNRIs (ie, venlafaxine) and
NaSSAs (ie, mirtazapine) in terms of overall treatment
response, and than FGAs (ie, perphenazine) in terms of
improving scores on depression symptom scales. These
findings collectively suggest the heightened efficacy of
TCA monotherapy for psychotic depression, in line
with the findings of a 2018 network meta-analysis in
which amitriptyline was identified as the most
efficacious antidepressant for major depressive
disorder.41 The broad mechanisms of action of TCAs,
which involve different neurotransmitter systems and
biological pathways, could provide a notable advantage
in the treatment of psychotic depression. For example,
TCAs have sedative effects, which could contribute to
the attenuation of agitation and anxiety in psychotic
depression.33 However, TCAs also carry potential
side-effects and the possibility of interactions with
other medications.42 In our analyses of individual
adverse events, TCAs were associated with xerostomia.
Such side-effects need to be carefully assessed
when considering the use of TCA in psychotic
depression.
Our study has several limitations. First, all the
randomised controlled trials included in the network
meta-analysis are at least 11 years old (published
between 1985 and 2013). Thus, new drugs that have
become available more recently could not be analysed.
For example, preliminary results suggest that ketamine
or esketamine could be effective in treating psychotic
depression, have a rapid onset of action,43 and seem to
work well both in people with major depressive order
and in those with bipolar disorder.44 However, in recent
studies of major depressive disorder and bipolar
depression, people with the most severe disease, such
as those with psychotic depression, have systematically
been excluded, preventing subanalyses or post-hoc
analyses that could have improved knowledge about
treatment of psychotic depression.45 This exclusion is
even more pronounced in particularly vulnerable
populations, such as postpartum women,46 in whom no
studies have been done. Second, the small sample sizes
217
 Articles
of some of the included trials,10,11,14,15,17,18,24 and the small
number of trials included in our meta-analysis, might
have limited statistical power, thereby affecting the
precision of effect estimates and 95% CIs. This
limitation also precluded the calculation of prediction
intervals. Third, the risk of bias at the study level within
the included studies was significant, with only one study
with a low risk of bias.21 Fourth, one could argue that
our study violated the transitivity assumption. Our
study includes both people with major depressive
disorder and patients with bipolar disorder.10–12,18,22–24
Even previous meta-analyses that ostensibly excluded
people with bipolar disorder included studies with
mixed samples.5 From a diagnostic standpoint,
psychotic depression is considered to manifest in both
major depressive disorder and bipolar disorder,
potentially aligning more closely with the spectrum
view of bipolar disorder.47 This association is reinforced
by the observation that people with psychotic depression
tend to have a longitudinal illness trajectory that
eventually ends with a diagnosis of bipolar disorder
rather than major depressive disorder, and psychotic
symptoms are more frequently associated with episodes
of bipolar depression than with episodes of unipolar
depression.1 Our rationale for including people with
bipolar disorder was to offer a comprehensive
assessment of treatments, acknowledging the existing
evidence. Additionally, we did sensitivity analyses on
studies including exclusively patients with major
depressive disorder, which largely supported the results
of the main analysis, and the transitivity assumption
was supported by the assessment done. Fifth, the small
number of studies affected heterogeneity assessments
and hindered a thorough assessment of publication
bias. Definitive exclusion of publication bias for many
outcomes is challenging because of the analyses relying
on fewer than ten studies in the networks. Sixth, our
network meta-analysis specifically examined short-term
pharmacological treatments for psychotic depression,
and we excluded other potential therapeutic approaches,
such as electroconvulsive therapy. Additionally, mife­
pristone, a potential treatment for psychotic depression,
was excluded from our analysis (thereby aligning us
with previous meta-analyses5), because unspecified
antidepressants were concurrently administered
alongside mifepristone or placebo. Finally, the quality
of evidence was very low, pointing to a high level of
uncertainty in the estimates for most comparisons.
Our systematic review and meta-analysis is, to our
knowledge, the first study to comprehensively and
quantitatively synthesise the scientific literature on
pharmacological treatments for psychotic depression.
New randomised controlled trials are essential to better
define the most effective and safe treatments for
psychotic depression, both in the short term and for
maintenance, and to establish any differences in
outcomes relative to primary diagnosis.
218
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Contributors
VO and CP conceptualised and planned the study with input from
EV and AS. VO managed and coordinated research planning and
execution, for which EV and AS had oversight and leadership
responsibility. VO, CP, MDP, and GFi screened the literature and
extracted the data. VO, CP, and MDP reviewed the data and did the
statistical analyses, with the supervision of JR. All authors interpreted the
results. VO and CP prepared the first draft of the Article, with important
contributions from MDP, GFi, GFa, and CF. All authors critically
reviewed and commented on the Article, and approved the final version.
All authors had full access to all the data in the study and had final
responsibility for the decision to submit for publication. VO, CP, MDP,
and JR directly accessed and verified the underlying data reported.
Declaration of interests
GA has received honoraria for continuing medical education (CME) or
consulting fees from Angelini, Casen Recordati, Janssen-Cilag,
Lundbeck, Otsuka, and Rovi. AM has received grants and served as a
paid consultant, adviser or CME speaker for Angelini, Idorsia, Janssen,
Lundbeck, and Sanofi-Aventis. AdB has received grants and served as a
paid consultant, adviser, or CME speaker for Angelini, Lundbeck,
Newron, Otsuka, and Viatris. MS has received honoraria or been a
consultant for AbbVie, Angelini, Lundbeck, and Otsuka. EV has received
grants and served as a paid consultant, adviser, or CME speaker for
AB-Biotics, Abbott, AbbVie, Adamed, Angelini, Biogen, Biohaven,
Boehringer Ingelheim, Cambridge University Press, Casen-Recordati,
Celon, Compass, Dainippon Sumitomo, Elsevier, Ethypharm, Ferrer,
Galenica, Gedeon Richter, GH Research, GlaxoSmithKline, Janssen,
Lundbeck, Medincell, Merck, Novartis, Oxford University Press, Orion,
Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda,
and Viatris. AS has received consultation fees from Taliaz. CF has
received speaker fees from Janssen. All other authors declare no
competing interests.
Data sharing
Requests to see any data that are not included in the Article or the
appendix should be directed to the corresponding author.
Acknowledgments
GFi received the support of a fellowship from La Caixa Foundation
(ID 100010434, fellowship code LCF/BQ/DR21/11880019). GA is
supported by a Rio Hortega 2021 grant (CM21/00017) and the Marco de
la Acción Estratégica en Salud mobility fellowship (MV22/00058) from
the Spanish Ministry of Health financed by the Instituto de Salud
Carlos III and co-financed by the Fondo Social Europeo Plus. DH-M is
supported by a Juan Rodés (JR18/00021) grant from the Instituto de
Salud Carlos. AM is supported by the Spanish Ministry of Science and
Innovation (PI19/00672, PI22/00840) integrated into the Plan Nacional
de Investigación Científica, Desarrollo e Innovación Tecnológic and
co-financed by the Instituto de Salud Carlos III–Subdireccion General
de Evaluación and the Fondo Europeo de Desarrollo Regional. JR is
supported by the Spanish Ministry of Science and Innovation
(PI22/00261), integrated into the Plan Nacional de Investigación
Científica, Desarrollo e Innovación Tecnológic and co-financed by
European Regional Development Fund funds from the European
Commission and the Centres de Recerca de Catalunya Program
Generalitat de Catalunya and Secretaria d’Universitats i Recerca del
Departament d’Economia I Coneixement (2021 SGR 01128). EV is
supported by the Spanish Ministry of Science and Innovation
(PI18/ 00805, PI21/00787) integrated into the Plan Nacional de
Investigación Científica, Desarrollo e Innovación Tecnológic and
co-financed by the Instituto de Salud Carlos III–Subdirección
General de Evaluación and the Fondo Europeo de Desarrollo
Regional, the Biomedical Research Networking Center of Mental
Health, the Secretaria d’Universitats i Recerca del Departament
d’Economia i Coneixement (2017 SGR 1365), the Centres de
Recerca de Catalunya programme, and the Departament de
Salut de la Generalitat de Catalunya for the Pla estratègic de recerca i
innovació en salut (SLT006/17/00357). EV is also supported by
the EU Horizon 2020 research and innovation programme (754907
and 945151). CF, AS, VO, and EV received support from Psych-STRATA,
a project funded by the EU’s Horizon Europe (101057454).
www.thelancet.com/psychiatry Vol 11 March 2024

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