Journal of Affective Disorders 339 (2023) 633–639

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review article

Effectiveness of atypical antipsychotics for unipolar and bipolar depression

in adolescents and young adults: A systematic review and meta-analysis
Louise Garcia-Rodriguez a, b, *, Daniel J. Burton a, b, Christine A. Leonards c,
Christopher G. Davey a
a
Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
b
NorthWestern Mental Health, Melbourne Health, Victoria, Australia
c
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Antipsychotic medications are increasingly used for difficult-to-treat depression in young people.
Adolescent However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical
Depression antipsychotics in treating unipolar and bipolar depression in adolescents and young adults.
Pharmacotherapy
Method: We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies
Treatment-resistant
Young adults
(RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary
outcome of interest was change in depressive symptoms from baseline to trial endpoint.
Results: No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar
depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combina­
tion, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies
used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean
difference (WMD) was − 4.58 (95 % CI, − 6.59 to − 2.57) between antipsychotic and placebo-treated groups.
Response and remission rates were also significantly in favor of antipsychotic treatment.
Limitations: There were few studies, several did not address risk-of-bias domains and there was a lack of non-
industry sponsored studies.
Conclusion: There is an absence of evidence for the use of antipsychotic medications in treatment of youth
unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of anti­
psychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with
bipolar depression. However, this evidence is limited and more studies investigating the use of these medications
in young people are needed.

1. Introduction
Depression is one of the leading causes of disability across the life­
span (Ferrari et al., 2013; Kessler et al., 2003; Vos et al., 2015), and a
leading and increasing cause for young people (Racine et al., 2021). For
many people with depression, first-line antidepressant therapy alone is
ineffective (Berlim and Turecki, 2007; Rush et al., 2006; Trivedi et al.,
2006) and augmentation strategies, such as antipsychotics, are often
employed (Malhi et al., 2020). Research and clinical experience indicate
antipsychotics are increasingly being prescribed (Alexander et al., 2011)
for depression in adults (Gerhard et al., 2014), as well as in children and
adolescents (Rani et al., 2008; Olfson et al., 2012; Varimo et al., 2020).
Although there is evidence to support their use for both unipolar and
bipolar depression in adults (Spielmans et al., 2013; Zhou et al., 2015;
Mulder et al., 2018), there is some question as to whether this is justified
for young people (Pringsheim et al., 2015; Mulder et al., 2018).
There are many RCTs evaluating the effectiveness of adjunctive
atypical antipsychotics for unipolar depression in adults, especially in
the setting of ‘difficult-to-treat’ depression or after failure of antide­
pressants alone. In particular olanzapine, quetiapine, risperidone and
aripiprazole have been studied. Meta-analyses concluded that all atyp­
ical antipsychotics were more efficacious than placebo with no signifi­
cant differences between medications. Their use as adjuncts has been
recommended with caution due to the side effect burden which includes

* Corresponding author at: Department of Psychiatry, Royal Melbourne Hospital, Level 1 North, 300 Grattan Street, Parkville, Victoria 3050, Australia.
E-mail address: garciarodrig@unimelb.edu.au (L. Garcia-Rodriguez).

https://doi.org/10.1016/j.jad.2023.07.082
Received 20 August 2022; Received in revised form 13 July 2023; Accepted 14 July 2023
Available online 17 July 2023
0165-0327/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
L. Garcia-Rodriguez et al.
akathisia (aripiprazole), weight gain (all, particularly olanzapine) and
sedation (olanzapine, quetiapine and aripiprazole), whilst quetiapine
was the most discontinued for any reason (Nelson and Papakostas, 2009;
Spielmans et al., 2013; Zhou et al., 2015). In adult bipolar depression the
evidence is more conclusive. The use of antipsychotics is commonly
recommended in guidelines and employed in clinical practice as both
adjuncts and monotherapy (Selle et al., 2014; Malhi et al., 2020; Kadakia
et al., 2021). Specifically, there is RCT evidence for use of olanzapine,
lurasidone, cariprazine and quetiapine, with the latter often cited in
guidelines as the first choice of the atypical antipsychotics after
weighing the efficacy and tolerability (Malhi et al., 2020).
Research investigating the effectiveness of atypical antipsychotics
for unipolar and bipolar depression in younger people is limited. Sub­
sequently, clinicians who treat young people are left having to extrap­
olate evidence from the adult population. However, applying evidence
from adult research to young people is undermined by youth being
biologically and psychodevelopmentally different to adults. (Giedd
et al., 1999; Wahlstrom et al., 2010; Erikson, 1994). These differences
between age groups are relevant to treatment in clinical practice and
medication tolerability can differ (Hammad et al., 2006). Thus, the aim
of this systematic review was to synthesize and assess the available ev­
idence for the efficacy and tolerability of atypical antipsychotics for both
unipolar and bipolar depression in young people.
2. Methods
The analyses were conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement. The trial was registered with PROSPERO on 20/01/2021
(registration number #CRD42021224271). Prior to registration an
initial scoping study was performed, indicating that there was likely to
be a small number of relevant studies.
2.1. Eligibility criteria
The population for inclusion were young people aged 10–25 years
old. We examined this broader age range because it incorporates a
continuous period of brain development and recognizes the design of
clinical services in many parts of the world. We included young people
with a current diagnosis of major depressive episode as part of major
depressive disorder (‘unipolar depression’) or bipolar disorder (‘bipolar
depression’) in order to ensure both types of primary depressive disor­
ders were included. Diagnosis could be established by a diagnostic
interview using a classification manual (i.e., Diagnostic and Statistical
Manual; DSM or International Classification of Disease; ICD), or by a
score on a standardized depression rating scale that was higher than a
predetermined cut-off value. Studies were included if they examined
treatment with an atypical antipsychotic agent, either as monotherapy
or adjunctive treatment, for the indication of depression, compared with
a control group treated with placebo or another agent.
Studies that examined populations with a diagnosis of a primary
psychotic disorder (such as schizophrenia) were excluded. However,
depression with psychotic features was not set as an exclusion criteria,
so that all potentially relevant studies of primary depressive disorders
would be captured for review. Studies that focused on the treatment of
mania were excluded. Studies that did not examine the acute phase of
treatment, such as maintenance phase or prophylaxis studies, were also
excluded. The focus of this review was on the evidence for second
generation (‘atypical’) antipsychotic medications, hence studies that
used first generation (‘typical’) antipsychotics were excluded.
2.2. Search strategy and study selection
We searched MEDLINE/PubMed, EMBASE, PsychINFO and
Cochrane CENTRAL using search strings indicative of depression,
youth/adolescence and antipsychotic medication. The full search
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Journal of Affective Disorders 339 (2023) 633–639
strategy is described in the Supplementary Material in Supplementary
Table 1. Similar terms were used to search clinicaltrials.gov and other
trial registers. Our initial search was conducted in December 2020 and
updated in January 2021. Initial screening for inclusion or exclusion was
independently performed by two researchers (LG-R & DB). Studies that
did not specify information relevant to the age group in the title or ab­
stract were deemed to be adult studies and thus excluded. All studies
which met the initial criteria were included for full text review. Full text
screening was conducted by the same two independent researchers (LG-
R & DB). Any conflicts were resolved through discussion between the
two researchers. If the conflict could not be resolved, a third supervising
researcher (CD) was consulted to resolve the conflict. As a secondary
search strategy, and to ensure inclusion of all relevant studies, reference
lists of all full text primary and review articles, obtained through the
initial literature search, were examined for additional studies.
2.3. Data extraction
Data extraction was initially performed using the software Covidence
(Veritas Health Innovation) and was then transferred to RevMan v5.4
(The Cochrane Collaboration) for further analysis. It was performed by
two researchers working independently (LG-R & DB). Data was extrac­
ted using the population characteristics, study design and intervention
details, as outlined in Table 1. The primary outcome measure was the
change in depressive symptoms, as measured by the change in any
depression rating scale from baseline to end-point of the study. Sec­
ondary outcomes included response and remission rates (markers for
efficacy), overall discontinuation rates (marker for acceptability) and
discontinuation rates due to adverse effects (marker for tolerability).
2.4. Quality assessment
The Cochrane Risk of Bias tool (Higgins et al., 2011) was used to
assess the quality of the individual studies included. Judgements of high,
low or unclear risk of bias were made independently by two researchers
(LG-R & DB) for each subsection of the tool. Disagreements were
resolved with an overall consensus for the risk of bias being reached
through discussion between the two researchers. Sections of the tool
included 1) sequence generation (randomization); 2) allocation
concealment; 3) blinding of participants and personnel; 4) blinding of
outcome assessors; 5) incomplete outcome data; 6) selective outcome
reporting; and 7) other biases. The Grading of Recommendations
Assessment, Development and Evaluation (GRADE; Guyatt et al., 2008)
approach was used as a basis to determine the strength of
recommendations.
2.5. Data synthesis
Numerical data synthesis, although not based on a complete apriori
analysis plan, was deemed to be appropriate based on the identified
studies. All RCT's identified for inclusion in the meta-analysis used the
same continuous scale for the primary outcome measure and therefore a
weighted mean difference (WMD) was appropriate to measure the dif­
ference between placebo and treatment arms. A WMD with a 95 %
confidence interval (CI) was calculated for each study using the pro­
vided standard deviation (SD), or by calculating the SD using a provided
standard error (SE). Using the WMD for each study, the inverse variance
(IV) model was then used to calculate the pooled mean-change size with
95 % CI, as this is the appropriate model for continuous outcomes.
Additionally, we included an analysis using standardized mean differ­
ence (SMD). This SMD represents Hedges' g, which is appropriate when
there are a low number of studies included in the analysis.
Dichotomous outcomes were calculated and displayed as relative
risk (RR). RR's were applied to four outcomes: response rates, remission
rates, discontinuation for any reason and discontinuation due to adverse
events. The pooled RR with 95 % CI was calculated with the
L. Garcia-Rodriguez et al. Journal of Affective Disorders 339 (2023) 633–639

Table 1
Characteristics of included RCT's investigating antipsychotic treatment of bipolar depression in young people.
Study name Number of Age range of Sex, Length of Medication used Dose range of Response criteria Remission criteria
randomized participants female study in study medication
participants (years) (%) (weeks)

DelBello 32 12–18 68.8 8 Quetiapine IR 300–600 mg ≥50 % reduction in the ≤28 in the CDRS-R
et al., CDRS-R total score scores and CGI-BP-I ≤ 2
2009 (25)
Findling 193 10–17 49.5 8 Quetiapine XR 150 mg–300 ≥50 % reduction in the ≤28 in the CDRS-R
et al., mg CDRS-R total score scores
2014 (26)
Detke et al., 291 12–18 49.0 8 Olanzapine/ 6/25 mg ≥50 % reduction in the ≤28 in the CDRS-R,
2015 (27) fluoxetine − 12/50 mg CDRS-R total score and CGI-BP-I overall
combination YMRS item 1 score ≤ 2 at severity ≤3, YMRS total
end-point score ≤ 8
DelBello 350 10–17 50.0 6 Lurasidone 20–80 mg ≥50 % reduction in the ≤28 in the CDRS-R,
et al., CDRS-R total score CGI-BP-I overall
2017 (28) severity ≤3, YMRS total
score ≤ 8

Abbreviations: CDRS-R, Children's Depression Rating Scale–Revised; CGI-BP-I, Clinical Global Impression–Bipolar Version Improvement. YMRS, Young Mania Rating
Scale.

Mantel–Haenszel technique, which is appropriate for dichotomous

outcomes.
A random effects model was used to synthesize all statistical out­
comes in this study as it was not plausible to assume that the studies
were homogenous. Heterogeneity was assessed by visual inspection of
forest plots and by calculating I2. Values for I2 which are >50 % are
considered to be higher risk for heterogeneity.
To evaluate the risk of bias across studies it was determined that a
funnel plot would be produced if there were >10 studies for inclusion, as
with fewer than 10 studies test power cannot distinguish chance from
true asymmetry (Sterne et al., 2011).

3. Results

3.1. Selection and inclusion of studies

After removing duplicates, 3358 studies were identified for

screening, of which 94 were eligible for full text review. No additional
unpublished data or trials were identified for screening through our
secondary search strategy. At full text review 90 were excluded: see the
PRISMA diagram (Fig. 1) to view the reasons and numbers for exclusion
at each stage. Four studies were deemed appropriate for inclusion in the
systematic review and statistical meta-analysis.

3.2. Characteristics of included studies

No RCT's were identified that examined antipsychotic treatment in

young people for unipolar depression. The four RCT's identified for in­
clusion were studies that investigated young people with a diagnosis of
bipolar depression. All studies compared treatment with an antipsy­
chotic medication to placebo. One study was of lurasidone monotherapy
(DelBello et al., 2017) and one was of olanzapine/fluoxetine combina­
tion (Detke et al., 2015). Two studies were of quetiapine monotherapy,
of these, one was of instant release (IR) form quetiapine (DelBello et al.,
2009) and the other was of extended release (XR) form quetiapine
(Findling et al., 2014). All studies used the Children's Depression Rating
Scale-Revised (CDRS-R; Poznanski and Mokros, 1996) as a measure of
depressive symptoms. The primary outcome for all studies was the
change in CDRS-R score from baseline to end-point of the study. De­
mographic details and trial designs were similar across studies. Further
characteristics of the studies are outlined in Table 1.

3.3. Risk of bias

Fig. 1. PRISMA study flow diagram outlining the search, screening and selec­
The risk of bias was low or unclear, except for one paper in which tion of studies for inclusion.

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there were concerns about attrition bias (Detke et al., 2015). This was
due to different datasets being used for each outcome measure, the
reasons for which were not clearly accounted for. A diagrammatic rep­
resentation of the results is shown in Fig. 2.
3.4. Data extraction
In order to reduce the risk of attrition bias all data was extracted with
a view to perform an intention-to-treat (ITT) analysis. DelBello et al.
(2009) used an ITT dataset whilst the remaining studies used a modified
intention-to-treat (mITT) analysis. In both DelBello et al. (2017) and
Findling et al. (2014) mITT included participants who received at least
one dose of the medication and had at least one post-baseline assess­
ment. The mITT criteria in Detke et al. (2015) was defined differently;
they excluded those that had not received the study drug and also
excluded a sizeable cohort of patients (n = 32) from 2 of their study sites
who had ‘data integrity violations’, where the data was deemed ‘unre­
liable’, with no further detail available. These ITT or mITT datasets (as
described on the CONSORT diagrams) were used in our statistical
analysis.
The secondary outcomes of response and remission, as measures of
treatment efficacy, were defined differently across the studies (Table 1).
Where these dichotomous outcomes were expressed as a percentage,
raw numbers were extrapolated from the percentages if not available in
the text. If any percentages were unclear, raw numbers were sought from
the authors via email correspondence. Clarification with Detke et al.
(2015) was required to gather response and remission numbers, as they
had been calculated from a smaller and further modified dataset beyond
the mITT, with the reasons for this modification not able to be provided
to us. Overall, to keep analysis conservative and consistent, it was
Fig. 2. Risk of bias summary of included studies for treatment with antipsy­
chotic versus placebo in young people with bipolar depression.
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Journal of Affective Disorders 339 (2023) 633–639
agreed all outcomes would be calculated from the stated ITT or mITT
dataset available on the study CONSORT diagram, regardless of how
they were reported within the text of the review or from direct corre­
spondence with authors.
Discontinuation rates for any reason (acceptability) were not always
explicitly stated as outcomes in each study. However, in those cases we
used the CONSORT diagram to calculate the results. The rates were
derived from the number of dropouts for any reason compared to the
total number of participants randomized to each arm of the study. The
total number randomized to each arm of the study was irrespective of
whether or not the first dose of medication was received or a post-
baseline assessment occurred; hence, our calculation of acceptability
represents an ITT analysis and not a mITT dataset. Similarly to accept­
ability, tolerability rates were not explicitly described in most studies,
however, CONSORT diagrams again provided the data for an ITT
analysis.
3.5. Outcome measures: efficacy measures
3.5.1. Primary outcome: change in CDRS-R from baseline
The pooled WMD mean-changed scores in CDRS-R between anti­
psychotic and placebo-treated groups was statistically significant with a
WMD of − 4.58 (95 % CI: − 6.59, − 2.57) I2 = 0 % (Fig. 3). The I2 value
suggested the studies were not heterogeneous. Studies of quetiapine, in
both IR and XR forms, produced no statistically significant improve­
ments in CDRS-R score (quetiapine IR: 1.00 [− 9.88,11.88]; quetiapine
XR: − 2.30 [− 6.80, 2.20]), whilst olanzapine/fluoxetine combination
and lurasidone produced statistically significant improvements (olan­
zapine/fluoxetine combination: − 5.00 [− 8.64, − 1.36]; lurasidone:
− 5.7 [− 8.66, − 2.74]).
Analysis with SMD was also calculated and is summarized in the
Supplementary Material in Supplementary Fig. 1. A supplementary
analysis was also undertaken excluding Detke et al. (2015) due to this
study using a combination medication approach. This analysis also
revealed a statistically significant difference between treatment and
placebo and can be found in the Supplementary Material in Supple­
mentary Fig. 2.
3.5.2. Response and remission rates
The pooled response rate difference between antipsychotic and
placebo-treated groups was statistically significant with a RR of 1.32
(95 % CI: 1.1, 1.59) I2 = 46 % (Fig. 4). The I2 value suggested the studies
were not significantly heterogeneous. The pooled remission rate differ­
ence between antipsychotic and placebo-treated groups was statistically
significant with a RR of 1.35 (95 % CI: 1.1, 1.63) I2 = 0 % (Fig. 5). The I2
value suggested the studies were not heterogeneous.
3.6. Outcome measures: discontinuation
The pooled discontinuation rate (acceptability) difference between
antipsychotic and placebo-treated groups was not statistically signifi­
cant, with a RR of 0.93 (95 % CI: 0.72, 1.20) I2 = 11 % (Fig. 6).The I2
value suggested the studies were not significantly heterogeneous.
The pooled discontinuation rate due to adverse events (tolerability)
difference between antipsychotic and placebo-treated groups was not
statistically significant with a RR (95 % CI) of 0.90 (0.28, 2.88) I2 = 61 %
(Fig. 7). The I2 value suggested that the studies were significantly het­
erogeneous. This could mostly be explained by a large number of pa­
tients excluded for the aforementioned ‘data integrity violations’ in
Detke et al.
4. Discussion
Our evaluation of the efficacy of atypical antipsychotics for depres­
sion in young people has revealed limited evidence for their use. Most
notably, there is a marked absence of evidence for antipsychotic
L. Garcia-Rodriguez et al. Journal of Affective Disorders 339 (2023) 633–639

Fig. 3. Forest plot of comparison of mean-changed CDRS-R scores from baseline, in antipsychotic versus placebo-treated groups in young people with bipo­
lar depression.

Fig. 4. Forest plot of the comparison of RR (95 % CI) for response rates of antipsychotic versus placebo-treated groups in young people with bipolar depression.

Fig. 5. Forest plot of the comparison of RR (95 % CI) for remission rates of antipsychotic versus placebo-treated groups in young people with bipolar depression.

Fig. 6. Forest plot of comparison of RR (95 % CI) for discontinuation rates of antipsychotic versus placebo-treated groups in young people bipolar depression.

treatment of unipolar depression in young people, despite use of anti­
psychotics for this indication in clinical practice. Nevertheless, the evi­
dence that exists lends support for the use of antipsychotic medications
for bipolar depression, with significant effects on change in depression
severity, response, and remission.
For bipolar depression, 4 RCT's investigated 3 atypical antipsychotic
medications. In terms of the primary outcome measure, 2 studies of
quetiapine (DelBello et al., 2009; Findling et al., 2014) showed no sta­
tistically significant differences from placebo, while the 2 more recent
and larger studies of lurasidone (DelBello et al., 2017) and olanzapine/
fluoxetine (Detke et al., 2015) both produced statistically significant
results in favor of the antipsychotic. Due to the higher number of ran­
domized participants in the latter 2 studies, the overall pooled effect of
the meta-analysis was in favor of antipsychotics. Quetiapine studies may
have demonstrated a negative finding due to quetiapine not being
effective for depressive symptoms, or due to their smaller sample sizes
not providing sufficient power to show a difference.
The different findings of the studies, in part related to their different
sizes, might also be explained by the use of different atypical antipsy­
chotic medications. Another consideration is the potential effect of the

637
L. Garcia-Rodriguez et al.
Fig. 7. Forest plot of comparison of RR (95 % CI) for discontinuation rates due to adverse events of antipsychotic versus placebo-treated groups in young people with
bipolar depression.
inclusion of one study that assessed a combination (olanzapine/fluoxe­
tine) medication (Detke et al., 2015). Although this study was eligible
for inclusion according to our predefined criteria, a combination medi­
cation could potentially confound the apparent effect of the antipsy­
chotic medication. As the comparison was with placebo, we were not
able to estimate the effects of olanzapine alone. Therefore, it is possible
that some of the improvements seen with olanzapine/fluoxetine com­
bination were attributable to fluoxetine or synergistic effects. However,
even with this study excluded, we found that the primary outcome
measure still demonstrated a statistically significant difference in favor
of the antipsychotic, albeit less pronounced (see Supplementary Fig. 2).
In this systematic review we also identified that older youth, from 18
to 25 years, were under-represented as a research population. All studies
identified in this review comprised adolescent populations; none
included young adults, who appear to be routinely grouped with older
adult populations in research settings and study designs. One potential
approach to clarify this would be to contact the authors of the relevant
adult studies to obtain the raw data for young adults, lending to the
possibility of collating this information for a patient-level meta-analysis.
However, this is likely to be a lengthy and challenging process and given
the biopsychodevelopmental differences between 18- to 25-year-olds
and older adults, original studies of the young adult population would
better inform evidence-based practice.
There were several limitations of this systematic review. First, rec­
ommendations can only be made for treatment of acute depressive ep­
isodes. This systematic review does indicate that in acute treatment
antipsychotic acceptability and tolerability are similar to placebo.
However, common problematic side effects of atypical antipsychotic
medications, such as weight gain and dyslipidaemia often take several
months to become evident. Therefore, the balance between benefits and
harms may change over a longer course of treatment and maintenance
studies are required to evaluate if between-group differences in
discontinuation rates and other secondary adverse effects become more
pronounced.
Second, there were some risk-of-bias concerns for the included
studies. Risk-of-bias domains were sometimes not addressed in the
manuscripts and hence unclear. Furthermore, there were inconsistencies
in the definitions of what constitutes a mITT dataset, which was used for
study analyses rather than an ITT dataset in 3 of the 4 studies. We
attempted to address this by using a consistent and conservative
approach to calculate outcomes and clearly describing this approach in
our methodology. We enquired with the authors of the papers directly to
obtain raw data to enter into our analysis. Nonetheless, some risk of
attrition bias remains. Furthermore, our analysis of tolerability and
acceptability was numerical and whilst this is useful to compare across
studies a descriptive analysis may yield further detail.
Finally, all trials were industry sponsored and may have been subject
to publication bias. There is evidence that studies which are industry
sponsored are more frequently produce evidence in favor of the phar­
maceutical agent (Lexchin et al., 2003).
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Journal of Affective Disorders 339 (2023) 633–639
5. Conclusion
In conclusion, no RCT's have examined the effectiveness of antipsy­
chotic medications for the treatment of unipolar depression in youth.
Therefore, there is a lack of evidence to guide recommendations on their
use in clinical practice. However, we did identify four studies for bipolar
depression and the results of this meta-analysis do suggest that anti­
psychotics are effective in the treatment of youth bipolar depression,
with reasonable tolerability. However, with such a limited number of
studies available and contrasting study outcomes, this recommendation
is made tentatively.
Overall, however, there is a paucity of primary clinical research for
both unipolar and bipolar youth depression and, given trends of
increasing antipsychotic prescribing among young people, further non-
industry sponsored research is clearly needed if the use of antipsy­
chotic medication is to be used, with confidence, in clinical settings for
the treatment of depression in youth.
Funding and disclosure statement
This research did not receive any grant from funding agencies in the
public, commercial or not-for-profit sectors.
CRediT authorship contribution statement
First/corresponding/submitting author Louise Garcia-Rodriguez,
Daniel J. Burton, Christine Leonards and Christopher Davey conceived
the project and designed the study.
Louise Garcia-Rodriguez and Daniel Burton performed the data
collection.
Louise Garcia-Rodriguez, Daniel Burton, Christine Leonards and
Christopher Davey were all involved in the data analysis and
interpretation.
Louise Garcia-Rodriguez drafted, edited and finalised the article.
Louise Garcia-Rodriguez, Daniel Burton, Christine Leonards and Chris­
topher Davey were all actively involved in critical revision of the
manuscript and approval of the final submission of the article to the
journal.
Declaration of competing interest
All authors declare no conflicts of interest.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jad.2023.07.082.
L. Garcia-Rodriguez et al. Journal of Affective Disorders 339 (2023) 633–639

References Mulder, R., Hamilton, A., Irwin, L., Boyce, P., Morris, G., Porter, R.J., Malhi, G.S., 2018.
Treating depression with adjunctive antipsychotics. Bipolar Disord. 20 (Suppl. 2),
17–24. https://doi.org/10.1111/bdi.12701.
Alexander, G.C., Gallagher, S.A., Mascola, A., Moloney, R.M., Stafford, R.S., 2011.
Nelson, J.C., Papakostas, G.I., 2009. Atypical antipsychotic augmentation in major
Increasing off-label use of antipsychotic medications in the United States,
depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am. J.
1995–2008. Pharmacoepidemiol. Drug Saf. 20, 177–184. https://doi.org/10.1002/
Psychiatry 166 (9), 980–991. https://doi.org/10.1176/appi.ajp.2009.09030312.
pds.2082.
Olfson, M., Blanco, C., Liu, S.-M., Wang, S., Correll, C.U., 2012. National trends in the
Berlim, M.T., Turecki, G., 2007. Definition, assessment, and staging of treatment-
office-based treatment of children, adolescents, and adults with antipsychotics. Arch.
resistant refractory major depression: a review of current concepts and methods.
Gen. Psychiatry 69 (12), 1247–1256. https://doi.org/10.1001/
Can. J. Psychiatr. 52, 46–54. https://doi.org/10.1177/070674370705200108.
archgenpsychiatry.2012.647.
DelBello, M.P., Goldman, R., Phillips, D., Deng, L., Cucchiaro, J., Loebel, A., 2017.
Poznanski, E., Mokros, H., 1996. Children's Depression Rating Scale–Revised (CDRS-R)
Efficacy and safety of lurasidone in children and adolescents with bipolar I
WPS, Los Angeles.
depression: A double-blind, placebo-controlled study. J. Am. Acad. Child Adolesc.
Pringsheim, T., Gardner, D., Patten, S.B., 2015. Adjunctive treatment with quetiapine for
Psychiatry 56 (12), 1015–1025. https://doi.org/10.1016/j.jaac.2017.10.006.
major depressive disorder: are the benefits of treatment worth the risks? BMJ. 350,
DelBello, M.P., Chang, K., Welge, J.A., Adler, C.M., Rana, M., Howe, M., Bryan, H.,
569. https://doi.org/10.1136/bmj.h569.
Vogel, D., Sampang, S., Delgado, S.V., Sorter, M., Strakowski, S.M., 2009. A double-
Racine, N., McArthur, B.A., Cooke, J.E., Eirich, R., Zhu, J., Madigan, S., 2021. Global
blind, placebo-controlled pilot study of quetiapine for depressed adolescents with
prevalence of depressive and anxiety symptoms in children and adolescents during
bipolar disorder. Bipolar Disord. 11 (5), 483–493. https://doi.org/10.1111/j.1399-
COVID-19: a meta-analysis. JAMA Pediatr. 175 (11), 1142–1150. https://doi.org/
5618.2009.00728.
10.1001/jamapediatrics.2021.2482.
Detke, H.C., Delbello, M.P., Landry, J., Usher, R.W., 2015. Olanzapine/fluoxetine
Rani, F., Murray, M.L., Byrne, P.J., Wong, I.C.K., 2008. Epidemiologic features of
combination in children and adolescents with bipolar in depression: a randomized,
antipsychotic prescribing to children and adolescents in primary care in the United
double-blind, placebo-controlled trial. J. Am. Acad. Child Adolesc. Psychiatry 54 (3),
Kingdom. Pediatrics 121 (5), 1002–1009. https://doi.org/10.1542/peds.2007-2008.
217–224. https://doi.org/10.1016/j.jaac.2014.12.012.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D.,
Erikson, E.H., 1994. Identity and the Life Cycle. W. W. Norton & Company, New York.
Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J.,
Ferrari, A.J., Charlson, F.J., Norman, R.E., Patten, S.B., Freedman, G., Murray, C.J.L.,
Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute and
Vos, T., Whiteford, H.A., 2013. Burden of depressive disorders by country, sex, age,
longer-term outcomes in depressed outpatients requiring one or several treatment
and year: findings from the global burden of disease study 2010. PLoS Med. 10 (11),
steps: a STAR*D report. Am. J. Psychiatry 163 (11), 1905–1917. https://doi.org/
e1001547 https://doi.org/10.1371/journal.pmed.1001547.
10.1176/ajp.2006.163.11.1905.
Findling, R.L., Pathak, S., Earley, W.R., Liu, S., DelBello, M.P., 2014. Efficacy and safety
Selle, V., Schalkwijk, S., Vázquez, G.H., Baldessarini, R.J., 2014. Treatments for acute
of extended-release quetiapine fumarate in youth with bipolar depression: an 8
bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of
week, double-blind, placebo-controlled trial. J. Child Adolesc. Psychopharmacol. 24
anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry. 47 (2), 43–52.
(6), 325–335. https://doi.org/10.1089/cap.2013.0105.
https://doi.org/10.1055/s-0033-1363258.
Gerhard, T., Akincigil, A., Correll, C.U., Foglio, N.J., Crystal, S., Olfson, M., 2014.
Spielmans, G.I., Berman, M.I., Linardatos, E., Rosenlicht, N.Z., Perry, A., Tsai, A.C., 2013.
National trends in second-generation antipsychotic augmentation for nonpsychotic
Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-
depression. J. Clin. Psychiatry 75 (5), 490–497 (doi:10.4088%2FJCP.13m08675).
analysis of depression, quality of life, and safety outcomes. PLoS Med. 10 (3),
Giedd, J.N., Blumenthal, J., Jeffries, N.O., Castellanos, F.X., Liu, H., Zijdenbos, A.,
e1001403 https://doi.org/10.1371/journal.pmed.1001403.
Paus, T., Evans, A.C., Rapoport, J.L., 1999. Brain development during childhood and
Sterne, J.A.C., Sutton, A.J., Ioannidis, J.P.A., Terrin, N., Jones, D.R., Lau, J.,
adolescence: a longitudinal MRI study. Nat. Neurosci. 2 (10), 861–863. https://doi.
Carpenter, J., Rücker, G., Harbord, R.M., Schmid, C.H., Tetzlaff, J., Deeks, J.J.,
org/10.1038/13158.
Peters, J., Macaskill, P., Schwarzer, G., Duval, S., Altman, D.G., Moher, D.,
Guyatt, G.H., Oxman, A.D., Vist, G.E., Kunz, R., Falck-Ytter, Y., Alonso-Coello, P.,
Higgins, J.P., 2011. Recommendations for examining and interpreting funnel plot
Schünemann, H.J., GRADE Working Group, 2008. GRADE: an emerging consensus
asymmetry in meta-analyses of randomised controlled trials. BMJ. 343, d4002
on rating quality of evidence and strength of recommendations. BMJ. 336 (7650),
https://doi.org/10.1136/bmj.d4002.
924–926. https://doi.org/10.1136/bmj.39489.470347.ad.
Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A.A., Warden, D., Ritz, L.,
Hammad, T.A., Laughren, T., Racoosin, J., 2006. Suicidality in pediatric patients treated
Norquist, G., Howland, R.H., Lebowitz, B., McGrath, P.J., Shores-Wilson, K.,
with antidepressant drugs. Arch. Gen. Psychiatry 63 (3), 332–339. https://doi.org/
Biggs, M.M., Balasubramani, G.K., Fava, M., Team SDS, 2006. Evaluation of
10.1001/archpsyc.63.3.332.
outcomes with citalopram for depression using measurement-based care in STAR*D:
Higgins, J.P.T., Altman, D.G., Gøtzsche, P.C., Jüni, P., Moher, D., Oxman, A.D.,
implications for clinical practice. Am. J. Psychiatry 163, 28–40. https://doi.org/
Savovic, J., Schulz, K.F., Weeks, L., Sterne, J.A., Cochrane Bias Methods Group,
10.1176/appi.ajp.163.1.28.
Cochrane Statistical Methods Group, 2011. The Cochrane collaboration’s tool for
Varimo, E., Saastamoinen, L.K., Rättö, H., Mogk, H., Aronen, E.T., 2020. New users of
assessing risk of bias in randomised trials. BMJ 343, d5928. https://doi.org/
antipsychotics among children and adolescents in 2008–2017: a nationwide register
10.1136/bmj.d5928.
study. Front. Psychiatry 11, 316. https://doi.org/10.3389/fpsyt.2020.00316.
Kadakia, A., Dembek, C., Heller, V., Singh, R., Uyei, J., Hagi, K., Nosaka, T., Loebel, A.,
Vos, T., Barber, R.M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F.,
2021. Efficacy and tolerability of atypical antipsychotics for acute bipolar
Davis, A., Degenhardt, L., Dicker, D., et al., Global Burden of Disease Study 2013
depression: a network meta-analysis. BMC Psychiatry 21 (1), 249. https://doi.org/
Collaborators, 2015. Global, regional, and national incidence, prevalence, and years
10.1186/s12888-021-03220-3.
lived with disability for 301 acute and chronic diseases and injuries in 188 countries,
Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J.,
1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
Walters, E.E., Wang, P.S., National Comorbidity Survey Replication, 2003. The
Lancet 386 (9995), 743–800. https://doi.org/10.1016/s0140-6736(15)60692-4.
epidemiology of major depressive disorder: results from the National Comorbidity
Wahlstrom, D., Collins, P., White, T., Luciana, M., 2010. Developmental changes in
Survey Replication (NCS-R). JAMA 289 (23), 3095–3105. https://doi.org/10.1001/
dopamine neurotransmission in adolescence: behavioral implications and issues in
jama.289.23.3095.
assessment. Brain Cogn. 72 (1), 146–159. https://doi.org/10.1016/j.
Lexchin, J., Bero, L.A., Djulbegovic, B., Clark, O., 2003. Pharmaceutical industry
bandc.2009.10.013.
sponsorship and research outcome and quality: systematic review. BMJ. 326 (7400),
Zhou, X., Keitner, G.I., Qin, B., Ravindran, A.V., Bauer, M., Del Giovane, C., Zhao, J.,
1167. https://doi.org/10.1136/bmj.326.7400.1167.
Liu, Y., Fang, Y., Zhang, Y., Xie, P., 2015. Atypical antipsychotic augmentation for
Malhi, G.S., Bell, E., Bassett, D., Boyce, P., Bryant, R., Hazell, P., Hopwood, M.,
treatment-resistant depression: a systematic review and network meta-analysis. Int.
Lyndon, B., Mulder, R., Porter, R., Singh, A.B., Murray, G., 2020. The 2020 Royal
J. Neuropsychopharmacol. 18 (11), pyv060. https://doi.org/10.1093/ijnp/pyv060.
Australian and New Zealand College of Psychiatrists clinical practice guidelines for
mood disorders. Aust. N. Z. J. Psychiatry 55 (1), 7–117. https://doi.org/10.1177/
0004867420979353.

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