Sleep Medicine Reviews 57 (2021) 101429

Contents lists available at ScienceDirect

Sleep Medicine Reviews

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

CLINICAL REVIEW

Sleep disturbances and first onset of major mental disorders in

adolescence and early adulthood: A systematic review and meta-
analysis
Jan Scott a, b, c, *, Havard Kallestad c, d, e, Oystein Vedaa c, e, f, g, Borge Sivertsen c, f, h,
Bruno Etain b, i, j
a
Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK
b
Universite de Paris, Paris, France
c
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway
d
Department of Research and Development, St. Olavs University Hospital, Trondheim, Norway
e
Department of Mental Health Care, St. Olavs University Hospital, Trondheim, Norway
f
Department of Health Promotion, Norwegian Institute of Public Health, Bergen, Norway
g
Voss District Psychiatric Hospital, NKS Bjorkeli, Voss, Norway
h
Department of Research and Innovation, Helse-Fonna HF, Haugesund, Norway
i
AP-HP Paris Nord, GH Saint-Louis-Lariboisiere-Fernand-Widal, Departement de Psychiatrie et de Medicine Addictologique, DMU Neurosciences, Paris,
France
j
Inserm UMRS 1144, Paris, France

a r t i c l e i n f o s u m m a r y

Article history: Despite several high-quality reviews of insomnia and incidence of mental disorders, prospective longi-
Received 20 June 2020 tudinal relationships between a wider range of sleep disturbances and first onset of a depressive, bipolar,
Received in revised form or psychotic disorders during the peak age range for onset of these conditions has not been addressed.
31 August 2020
Database searches were undertaken to identify publications on insomnia, but also on other sleep
Accepted 1 September 2020
Available online 19 January 2021
problems such as hypersomnia, short sleep duration, self-identified and/or generic ‘sleep problems’ and
circadian sleep-wake cycle dysrhythmias. We discovered 36 studies that were eligible for systematic
review and from these publications, we identified 25 unique datasets that were suitable for meta-
Keywords:
Sleep
analysis (Number>45,000; age ~17). Individuals with a history of any type of sleep disturbance (how-
Meta-analysis ever defined) had an increased odds of developing a mood or psychotic disorder in adolescence or early
Adolescence adulthood (Odds ratio [OR]:1.88; 95% Confidence Intervals:1.67, 2.25) with similar odds for onset of bi-
Mania polar disorders (OR:1.72) or depressive disorders (OR:1.62). The magnitude of associations differed ac-
Depression cording to type of exposure and was greatest for sleep disturbances that met established diagnostic
Psychosis criteria for a sleep disorder (OR: 2.53). However, studies that examined observer or self-rated symptoms,
also reported a significant association between hypersomnia symptoms and the onset of a major mental
disorder (OR:1.39). Overall study quality was moderate with evidence of publication bias and meta-
regression identified confounders such as year of publication. We conclude that evidence indicates
that subjective, observer and objective studies demonstrate a modest but significant increase in the
likelihood of first onset of mood and psychotic disorders in adolescence and early adulthood in in-
dividuals with broadly defined sleep disturbances. Although findings support proposals for interventions
for sleep problems in youth, we suggest a need for greater consensus on screening strategies and for
more longitudinal, prospective studies of circadian sleep-wake cycle dysrhythmias in youth.
© 2021 Elsevier Ltd. All rights reserved.

Introduction

In 1989, an epidemiological catchment area study by Ford and

* Corresponding author. Institute of Neuroscience, Newcastle University, New-
castle, UK.
Kamerow [1] demonstrated that the odds of onset of an adult-
E-mail address: jan.scott@newcastle.ac.uk (J. Scott). pattern mental disorder was increased significantly in individuals

https://doi.org/10.1016/j.smrv.2021.101429
1087-0792/© 2021 Elsevier Ltd. All rights reserved.
J. Scott, H. Kallestad, O. Vedaa et al.
List of Abbreviations
AAO Age at onset
B, BD Bipolar disorders
CI Confidence intervals
D days
D, DD Depressive disorders
DSM Diagnostic and statistical manual
DSM-IV(R) The diagnostic and statistical manual, 4th edition
(Revised)
HMO Health maintenance organization
HR High Risk
IRR Incidence Rate Ratio
who one-year earlier had demonstrated insomnia (Adjusted Odds
Ratio (OR):1.6) or hypersomnia (Adjusted OR: 2.4). Over the
following decades, similar studies were published, followed by
several systematic reviews and meta-analyses [2e7]. Most of the
latter focused on selected measures of exposure, usually insomnia,
with limited examination of other sleep profiles (such as hyper-
somnia). Additionally, most reviews focused only on one specific
outcome (usually depression) [2,3] and only a few of these
considered research findings for children or adolescents [5e7].
Despite these relatively selected parameters for the reviews and
pooled analyses, the evidence supported the notion that the
prevalence of mental disorders is increased in individuals with
sleep, circadian or sleep-wake cycle disruptions (which we will
refer to as sleep disturbances) [2e7].
Detailed examination of meta-analyses published in the last
decade shows that most include studies of sleep patterns in in-
dividuals with established mental disorders. Whilst these findings
have helped promote awareness of the need to specifically address
sleep disturbances in adults with mental disorders, much less is
known about the longitudinal associations between sleep distur-
bances and the development of the first full-threshold episode of a
major mental disorder [8e10]. Also, systematic reviews and meta-
analyses of subthreshold or clinical high-risk syndromes have
largely encompassed cross-sectional and caseecontrol studies,
which precludes the opportunity to investigate links between sleep
patterns and disease progression [11e16]. Recently, some research
groups have started to address these gaps in the knowledgebase
[17,18]. For example, a systematic review [17] and a meta-analysis
[18] have separately explored first onsets of a range of mental
disorders in individuals with insomnia (symptoms and/or disor-
der). However, nearly all the eligible studies had recruited middle-
aged adults (only 20% included samples of younger people), and
neither of these publications examined unipolar, bipolar, and psy-
chotic disorders together. This is noteworthy and suggests that
further explorations on this topic would be helpful. We think the
examination of sleep disturbances and onset of mood and psychotic
disorders is relevant for three reasons. First, because the available
articles do not address a wider range of sleep-wake disturbances,
such as hypersomnia. This is important as some sleep disturbances
occur more often in youth than older adults [1,5,19]. Second, three
of the four most globally burdensome conditions in adolescents
and young adults are depressive, bipolar, and psychotic disorders
[20]. So, a greater understanding of associations between sleep
disturbances and onset of mood and psychotic disorders is war-
ranted. Third, 75% of individuals who develop a mood or psychotic
disorder report an age at first onset ¼<30 y [21,22]. Taken together,
a more detailed understanding of sleep disturbances that might be
2
Sleep Medicine Reviews 57 (2021) 101429
ICD International classification of diseases
LR High Risk
MDD Major Depressive Disorder
NR Not Reported
OR Odds ratio
P Psychotic disorders
PSG Polysomnography
RCT Randomized Controlled Trial
REM Rapid eye movement
RR Relative risk
SOL Sleep onset latency
UHR Ultra High Risk
y Year
associated with increased likelihood of a major mental disorder
could promote greater awareness of the need to screen for and/or to
intervene early to prevent or treat any sleep difficulties.
In summary, given the current interest in identifying modifiable
risk factors for onset of major mental disorders in adolescence and
early adulthood [23,24] and increasing evidence that a range of
cost-effective interventions are available for many sleep wake
disturbances [25,26], we decided to (i) synthesize findings on
exposure to self, observer or objectively recorded sleep distur-
bances and first onset of the three most globally burdensome
mental disorders of adolescence and early adulthood (i.e., depres-
sion, bipolar disorders and psychosis) and (ii) quantify the magni-
tude of any longitudinal associations according to the nature of any
exposure or outcome (i.e., first onset diagnosis).
Methods
The project adheres to the preferred reporting for systematic
reviews and meta-analyses (PRISMA) and meta-analysis of obser-
vational studies in epidemiology (MOOSE) guidelines and the
protocol was lodged with the international prospective register of
systematic reviews (PROSPERO: CRD4202078267; copy available
upon request). A PRISMA flowchart (Fig. 1S) and a PRISMA checklist
(Appendix 1S) are provided in the online supplementary materials.
Full details for the methodology (including references) and search
strategy are provided in Appendix 2S. An abbreviated version of the
procedure and methodology is provided below.
Overview of procedure
To summarize the procedure for the study, after a scoping exer-
cise (undertaken by JS, in discussion with BE), a protocol was sub-
mitted and underwent peer-review by PROSPERO. The initial
literature searches (described below) were undertaken by the first
author (JS). Next the last author (BE) repeated searches of some
databases (to ensure that both investigators identified the same
publications). Screening of publications was again undertaken by JS
and uncertainties regarding eligibility of publications was resolved
by consensus with BE. Having identified the publications that met
eligibility criteria for the systematic review, the other authors (HK,
BS, OV) then undertook independent ratings of a set of publications
sent to them in a zip file. As an additional test of reliability of review
criteria, the zip file included 2e3 studies that were ineligible. These
reviewers were required to assess the studies independently and to
categorize publications into three groups: studies eligible for sys-
tematic review only, those eligible for systematic review and meta-
analysis and to specify which studies should be excluded.
J. Scott, H. Kallestad, O. Vedaa et al.
Fig. 1. Forest plot for the random effects meta-analysis showing pooled Odds Ratios (OR) and 95% Confidence Intervals (CI) for 25 studies reporting 28 outcomes (first onset of
depressive, bipolar and/or psychotic disorders) in individuals with a prior history of any type of sleep-wake disturbance (compared to those without such disturbance). In the
pooled analysis an OR>1.0 indicated increased risk of mental disorder onset.
Independent ratings were then compared, and any uncertainties
were resolved by consensus. All authors were involved in data
extraction and quality assurance ratings (see below and Appendix 2).
Search strategy
A systematic strategy was employed and search terms were
operationalized to identify (i) the exposure of interest (sleep wake
disturbances identified using subjective, observer or objective
measures) and (ii) the outcome of interest (first onset of a
depressive, bipolar or psychotic disorders that met internationally
agreed diagnostic criteria or clinical significance criteria), cross-
referenced with (iii) terms used to identify the chronological
sequence of these phenomena (i.e., sleep disturbances preceding
onset of mental disorders) and preferred study methodology
(longitudinal, observational, prospective, cohort, etc.). Additional
terms were applied to narrow the search to studies of first onset or
incident cases of major mental disorder and to samples comprised
wholly or mostly of individuals in the peak age range for the onset
of those disorders. Citation lists were examined, and original in-
vestigators contacted as appropriate.
Selection criteria
The search was limited to publications from 1st January 1994 (to
coincide with the introduction of the DSM IV approximately) until
30th June 2020. Manuscripts written in English, French, Spanish,
German, Italian, Portuguese, Norwegian and Scandinavian lan-
guages were eligible.
Articles were eligible for inclusion in the systematic review if
they met the following criteria:
1) The study sample (a) had a mean age 30 y at the time of
assessment of any sleep disturbances or (b) the mean age at
onset of the sleep disturbances was <30 y and (c) the ages at
onset of sleep and mental disorders were recorded prospec-
tively or assessed using reliable research instruments (such as
lifetime assessment tools or longitudinal interval follow-ups).
3
Sleep Medicine Reviews 57 (2021) 101429
2) The study specified (a) the assessment procedure for and nature
of any sleep disturbances; (b) reported baseline rates for 1
exposure of interest; and (c) recorded any associations with the
onset of the mental disorder being studied.
3) The study included a minimum follow-up of 1 y following
assessment of exposure and assessment of new onsets of adult-
pattern mental disorders were completed between ages 11e30.
4) The study reported, or data were available regarding first onset
or incident cases of depressive, bipolar or psychotic disorders
that occurred in individuals aged <31 y.
5) First onset mental disorders were ascertained (a) using estab-
lished diagnostic criteria; (b) identified by clinical diagnosis
and/or treatment; or (c) were detected using established cut-off
scores (for caseness) on reliable symptom rating scales.
6) The study reported 1 recognized measure of the magnitude of
the association between sleep disturbances and mental disor-
ders (e.g., adjusted or unadjusted OR) or these could be esti-
mated or obtained.
Exclusion criteria were:
1) Studies of samples with a specific physical disorder or recruited
from medical settings.
2) Studies where sleep assessments were restricted only to infants
and toddlers (age<4).
3) Studies of emotional and behavioral disorders in pre-pubertal or
young children (age¼<11) only, and/or that reported disorders
that employed selective criteria e.g., conditions described as
‘pediatric depression’, ‘juvenile bipolar disorders’, etc.
4) Studies reporting composite outcomes e.g., ‘anxiety/depression’
or ‘psychological distress’.
For inclusion in the primary meta-analysis, we applied addi-
tional criteria for studies employing repeated follow-up or with
broad age-ranges:
1) A publication reporting an outcome of interest for repeated
waves could be included in the meta-analysis if data were
available to allow our investigators to independently (i)
J. Scott, H. Kallestad, O. Vedaa et al.
estimate the effects and magnitude of association for each wave
and (ii) differentiate first onsets of mental disorder from other
‘new’ onsets (that may represent recurrences between waves,
etc.).
2) A publication with only a subsample of participants in the pre-
determined age range could be included in the meta-analysis
if (i) specific data for the eligible subgroup were available (to
allow confirmation of chronological sequence of exposures and
outcomes) and/or (ii) data were available to allow effect sizes to
be estimated independently.
Publications that included the key search terms in the title,
abstract, or index term fields were screened, and full text articles
obtained as appropriate. After de-duplication and removal of inel-
igible studies, the selected records were examined, and key data
extracted (see Appendix 2S). For statistical measures, we noted the
magnitude of any associations and whether unadjusted and
adjusted estimates were reported (we prioritized adjusted effects).
If summary statistics were not reported, we estimated these from
published findings or requested raw data from the original authors
(as noted in Appendix 2S, in a few studies, our estimate of the OR
differs slightly from effect sizes reported elsewhere). When 2
studies reported findings from the same dataset, we selected the
most recently published (but utilized information provided in other
publications whenever relevant).
Quality assessment
Quality of included studies was assessed independently by two
raters (arbitrary pairings of BE, HK, BS, JS and OV) using the 14-item
Quality assessment tool for observational cohort and cross-
sectional studies (available at http://nhlbi.nih.gov). Ratings were
compared and differences resolved by consensus. A jointly agreed
total score (out of 14) and quality grading (good, fair, or poor) were
recorded for each study.
Synthesis and statistical analysis
A qualitative review was undertaken to summarize findings
from all eligible studies followed by quantitative analysis of studies
eligible for inclusion in the meta-analysis. Pooled analyses were
planned for any specific outcome or exposure reported in 3
studies and were undertaken using the Comprehensive meta-
analysis software package (version 3).
As the type of effect estimate varied between studies, we con-
verted all measures into a common metric and chose OR with 95%
confidence intervals (CI). Before analyses were undertaken, the
estimated OR were coded so that higher values indicated greater
odds of first onset of a major mental disorder. If studies reported
findings for 1 sleep disturbance, we calculated an aggregate OR
for use in the main meta-analysis of all eligible studies. The OR for
each different sleep disturbance was eligible for inclusion in
sensitivity analyses. Planned meta-analyses of any subgroups were
only performed if 3 studies reported comparable information.
The pooled OR and 95% CI are based on random-effects models
to account for heterogeneity between studies. Heterogeneity was
evaluated using the Q statistic and I2 index (with an I2 ¼ 50% and
chi-squared, p < 0.05 regarded as indicative of moderate hetero-
geneity). We used a funnel plot and Egger's test to explore the risk
of publication bias and Rosenthal's fail-safe number (FSN) to
determine the number of unpublished and/or missing null studies.
The main meta-analysis reports the pooled OR for first onset of a
major mental disorder (depressive, bipolar or psychotic) according
to the presence or absence of any prior sleep disturbances. For this
analysis, we employed meta-regression to explore whether any
4
Sleep Medicine Reviews 57 (2021) 101429
study characteristics moderated the magnitude of effect (e.g.,
sample mean age, sample size, etc.).
A priori, two sensitivity analyses were planned (subject to
number of eligible studies available) to assess if effects were
observed if we selected studies where (i) the primary outcome, i.e.,
first onset of a mental disorder, was assessed using recognized
diagnostic criteria for a full-threshold depressive, bipolar or psy-
chotic disorder, and (ii) the exposures of interest, i.e., self- or
observer rated sleep disturbances, were specified (e.g., sleep dis-
order, insomnia, hypersomnia). For the second analysis, we exam-
ined objective measures of sleep metrics in a separate analysis.
Post-hoc, we reviewed how many studies that were included in
the sensitivity analyses used self- or observer ratings and note
whether this might have increased or decreased the reported effect
sizes.
Results
Systematic review
The search strategies identified up to 6731 (PubMed) publica-
tions per database (see Appendix 2S). The PRISMA flowchart
(Fig. 1Sa) demonstrates that 36 studies derived from 33 indepen-
dent datasets met criteria for inclusion in the systematic review
[27e32,34,36,38e54,57,59,60,63e67,69,70,72]; some eligible
studies reported >1 outcome within the same publication [43,51,53]
or different outcomes in a series of publications [28,63]. Overall, 24
studies examined the association between sleep disturbances and
future onset of depressive disorder (Total number (N) ¼ 38,817), 11
examined bipolar disorders (Total N ¼ 8281) and six examined
psychosis (Total N ¼ 11,398). Supplementary Tables 1Se3S provide
detailed descriptions of the studies (also, we identify additional
publications about the same sample that were informative). The key
finding from the systematic review is that most studies report a
positive and significant association between sleep disturbance and
risk of first onset of a major mental disorder [27e50, 51e72];
although a minority of studies found positive association, there
were no studies that we identified that reported a statistically sig-
nificant decrease in the odds of first onset mental disorder.
Studies included in the meta-analyses
As shown in Table 1, 30 records of mental health outcomes
(reported in 25 independent studies) were eligible for inclusion in
the main meta-analysis. As noted in Supplementary Table 4S (also
see Fig. 1Sb), some of these studies were then excluded from one or
both sensitivity analyses [39,43,45,47e49,51,54,64,66,70,72].
Table 1 indicates that the total number of participants studied
was >42,000, with about 66% recruited to studies of sleep distur-
bances and depression. Overall, 12 publications came from North
America (10 from the USA), nine from Europe, five from Australasia,
and two from China. The 25 studies meeting eligibility criteria for
the meta-analysis reported a wide range of sleep disturbances.
These ranged from self- and observer-ratings of nightmares [66]
and irregular sleep patterns [57] to circadian rhythm disturbances
[51], through to sleep disorders that met the DSM IV criteria [59].
Three small studies reported objectively recorded sleep metrics
derived from polysomnography [28,29,63]. Diagnosis of major
mental disorders was undertaken using a more circumscribed
range of assessment tools. All bipolar [43,51,53,59,60,63,65] and
two thirds of psychotic disorder outcomes [52,68] were diagnosed
according to internationally recognized diagnostic criteria. This was
also true of about 60% of depression outcomes [22,33,36,37,
40,41,43,44,50e53], although a few studies used less well-
established instruments or clinical diagnoses.
J. Scott, H. Kallestad, O. Vedaa et al. Sleep Medicine Reviews 57 (2021) 101429

Table 1
Overview of studies included in the meta-analyses (full details of each study are detailed in Tables 1Se3S in the online supplementary materials).

Variable Depressive Disorders Bipolar Disorders Psychotic Disorders

(18 records)a (8 records)a (4 records)a

Publication Year
<2000 2 0 0
2001e2010 5 1 1
2011- onwards 11 7 3
Study Location:
USA/Canada 9 3 0
Europe 4 3 2
Australia/New Zealand 3 2 2
China 2 0 0
Sample Characteristics:
Total Participants 28,481 7494 11,189
Median sample size (Range) 1420 (25e9140) 390 (26e2254) 254 (29e6796)
Median age 1st sleep assessment ~17 ys ~15 ys ~19 ys
Median % females 52% 56% 48%
Median time between exposure & outcome assessment ~6 ys ~7 ys ~2 ys
Exposures Reported 3 Studiesb
Insomnia (symptom) 5 3 1
Insomnia & daytime fatigue 3 1 1
Hypersomnia (symptom) 2 2 1
Sleep Disorder (diagnosis) 2 1 0
Objective metrics (PSG- SOL; REM Density; REM Latency) 2 1 0
Outcome Assessment:
Diagnostic Criteria 11 8 3
Other (e.g., clinical significance) 7 0 1
Quality Grading
Good 5 4 2
Fair 11 3 2
Poor 2 1 0

PSG: Polysomnography; SOL: Sleep onset latency; REM: Rapid eye movement.
a
The number of records per diagnosis exceeds the number of citations for studies included in the meta-analyses as publications that report >1 outcome are included in >1
column.
b
Some studies reported >1 exposure per disorder.

The 25 studies that were eligible for the main meta-analysis
were then re-assessed to identify those that could be included in
the sensitivity analyses (i.e., a key variable was reported in 3
studies). Regarding diagnostic outcomes, the 25 studies reported
new onsets depression (n ¼ 18), bipolar disorders (n ¼ 8) and/or
psychotic disorders (n ¼ 4). Only seven types of sleep disturbance
were appropriate for pooled analyses; four of these exposures were
assessed using self or observer assessments, whilst three were
assessed using PSG (also see Supplementary Fig. 1Sb). The self or
observer rated variables were: the symptom of insomnia (reported
in nine studies), the combination of insomnia and daytime fatigue
(n ¼ 5), the symptom of hypersomnia (n ¼ 5), the diagnosis of sleep
disorder (n ¼ 3). The studies using diagnostic criteria reported
outcomes of insomnia alone, insomnia and hypersomnia or a
generic category encompassing a range of disorders. There were
three variables in the PSG studies that could be included in pooled
analyses, these were: sleep onset latency (SOL), rapid eye move-
ment (REM) sleep density and REM sleep latency. It was noted that
the objective measures did not overlap with the self or observer
rated measures, so further combinations of exposures could be
included in the pooled analyses.
Quality assessment
The median quality rating was 9 (out of 14); 11 publications
were graded as good quality, 14 as fair and three as poor. As shown
in Table 1, 66%, 57% and 29% of studies of psychosis, bipolar disor-
ders and depression respectively achieving the highest grading
(gradings for each study are shown in Appendix 5S, with additional
information available from the authors).
Main meta-analysis (all exposures and outcomes)
As seen in Fig. 1, the Forest plot for the random effects meta-
analysis for 28 reported outcomes demonstrates a near 2-fold in-
crease in the odds of first onset of a major mental disorder
(depressive, bipolar or psychotic disorder) in individuals with a
prior exposure to 1 sleep disturbance (OR: 1.88; 95% CI: 1.67,
2.25). Visual inspection of the funnel plot (see Fig. 2S) and Eggers
test revealed evidence of publication bias, largely explained by the
lower than expected number of studies with negative findings
(regression test for funnel plot asymmetry: Z ¼ 9.72; p < 0.001;
FSN ¼ 347). Heterogeneity was moderate (I2 index ¼ 59.17%), with a
Q statistic of 51.42 (p < 0.004). Meta-regression analysis (outputs
available from authors) demonstrated that specific study charac-
teristics were significant moderators of effects, namely: sample size
(smaller samples showed larger effects; p < 0.021), time interval
between first sleep assessment and mental health outcome
assessment (longer duration showed smaller effects; p < 0.019).
Year of publication was also significant, with earlier studies showed
larger effects (p < 0.046), the extent that the OR in the earliest
decade of publications was more than twice that of the most recent
decade. We did not find any one variable that explained this
finding, but trends suggest that sample size alongside the likeli-
hood that early studies rarely reported any negative findings (i.e.,
there was likely a publication bias, which is compatible with the
funnel plot findings). Interestingly, type of assessment (objective,
observer or self-ratings) was not found to be a significant
confounder but as noted below this may be explained by the fact
that both study quality and types of exposures and accounts varied
considerably across and between studies.

5
J. Scott, H. Kallestad, O. Vedaa et al. Sleep Medicine Reviews 57 (2021) 101429

Fig. 2. Forest plot for the random effects meta-analysis showing pooled Odds Ratios (OR) and 95% Confidence Intervals (CI) for 15 reports of the first onset of bipolar disorders
(BD ¼ 6) or depressive disorders (DD ¼ 9) in individuals with self- or observer-reported sleep-wake disturbances (compared to those without such disturbances). In the pooled
analysis an OR>1.0 indicated increased risk of mental disorder onset.

Sensitivity analyses
Fourteen studies were eligible for inclusion in the pooled anal-
ysis of outcomes (Fig. 2) and 13 for the pooled analysis of exposures
(Fig. 3 in main text and Fig. 3S is the online supplementary
materials).
Fig. 2 shows the forest plot for the pooled analyses for first onset
of depressive [27,30e32,37,40,43,50,53] and bipolar disorders
[43,53,58,59,65] that met recognized diagnostic criteria (there
were insufficient eligible studies of psychosis). It is notable that all
the eligible studies used structured interviews to make the di-
agnoses, and no studies based on caseness were included. As
demonstrated, the odds for bipolar disorder onset (OR: 1.72; 95% CI:
1.41, 2.12) were marginally higher than depressive disorders (OR:
1.62; 95% CI: 1.43, 1.82). These OR are marginally increased if
studies that relied on sleep items extracted from diagnostic inter-
view schedules rather than self-ratings [59,65]. Other parameters
(e.g., heterogeneity, Egger's test, FSN) suggested that studies of
bipolar disorders were more homogeneous and less subject to
publication bias (Q ¼ 3.51, p < 0.8; 12 ¼ 11.3%; Z ¼ 5.48, p < 0.01;
FSN ¼ 11) than those of depressive disorders (Q ¼ 25.2, p < 0.001;
12 ¼ 64.3%; Z ¼ 7.58, p < 0.01; FSN ¼ 156).
Fig. 3 shows the forest plot for the pooled analysis for first onset
of any major mental disorder in individuals exposed to specific
types of self- or observer-rated sleep disturbance [27,31,32,34,
36,43,53,59,60,65]. As demonstrated, the largest OR is for sleep
disorders (OR: 2.53; 95% CI: 1.81, 3.54), whilst the smallest is for the
specific symptom of hypersomnia (OR: 1.39; 95% CI: 1.2, 1.62),
whilst symptoms of insomnia with daytime fatigue (OR: 1.74; 95%
CI: 1.41, 2.15), or the symptom of insomnia alone showed

Fig. 3. Forest plot for the random effects meta-analysis showing pooled Odds Ratios (OR) and 95% Confidence Intervals (CI) for first onset of major mental disorders in individuals
exposed to specific types of sleep-wake disturbance (self- or observer-ratings as reported in 10 independent studies). In the pooled analysis an OR>1.0 indicated increased risk of
mental disorder onset.

6
J. Scott, H. Kallestad, O. Vedaa et al.
intermediate effects (OR: 1.68; 95% CI: 1.48, 1.91). There was no
indication that the magnitude of OR would differ if the estimate
was based only on items extracted from observer assessments or on
self-rated scales or sleep-related items. The pooled analysis of co-
occurring Insomnia and Fatigue showed low levels of heterogene-
ity (all other analyses demonstrated moderately high heterogeneity
with significant Q statistics and I2>65% in each case); the FSN was
similar for Sleep Disorders (FSN ¼ 23), Hypersomnia (FSN ¼ 23) and
co-occurring ‘insomnia and fatigue’ (FSN ¼ 25), but was about 5-
times higher for the symptom of insomnia (FSN ¼ 130).
Fig. 3S (in the supplementary materials) shows the forest plot
for PSG parameters [28,29,62]; only REM density showed a signif-
icant magnitude of effect (OR: 2.64; 95% CI: 1.05 6.64), but these
data should all be treated with caution. The pooled analyses are
based on three small studies, that were published more than 18e24
y ago. Further, one of the studies (which had one of the lowest
ratings for study quality and methodology) demonstrated a very
large effect (OR>11) that significantly influenced all the findings
from the pooled analyses of objective measures [28].
Discussion
To our knowledge, this is the first systematic review and meta-
analysis to estimate the increased likelihood of experiencing the
first episode of a depressive, bipolar, or psychotic disorders during
the peak onset age range in individuals exposed to prior sleep
disturbances. The types of sleep disturbances described in the
literature ranged from self-ratings of relatively undefined ‘sleep
problems, through to self or observer rated singular symptoms of
insomnia and hypersomnia, through to sleep disorders diagnosed
using structured clinical interviews. Despite this diversity, the
systematic review and the pooled analyses offer a consistent pic-
ture, namely that sleep disturbances are significantly associated
with future onset of a major mental disorder by age 30. If self,
observer and objectively identified sleep disturbances are consid-
ered together, then there is an almost x2-fold odds of onset of a
mental disorder. Furthermore, we minimized the threat that our
analyses merely identified the prodromes of mood or psychotic
episodes by excluding studies with <1 y gap between assessment of
exposures and outcomes or studies where first onset or incidence
was indistinguishable from new episodes such as recurrences.
When type of exposure is examined, the pooled OR are highest
in those with a sleep disturbance that meets diagnostic criteria for a
sleep disorder. It was not possible to determine if any specific
diagnosis was more often associated with onset of a mood or
psychotic disorder as some studies using this approach reported
rates for insomnia and hypersomnia disorders separately, but
others included all sleep disorders (including circadian disruptions)
within a single category. Interestingly when we examined studies
that used individual symptom or item rating scores, it was clear
that insomnia symptoms appear to be only one of several different
sleep disturbances that precede future onset of mental disorder.
This is noteworthy because even those studies that used well-
regarded self- or observer-rated assessments of sleep profiles
have tended to focus primarily on measures of insomnia. This
article offers a timely reminder that individuals in the peak age
range for onset of major mental disorders are known to experience
other sleep disturbances that these potential associations merit
exploration. This is especially important as misalignments in the
timing of sleep, such as delayed sleep phase syndrome [19], that are
typical of circadian sleep-wake cycle disturbances are common in
youth, but significantly under-represented in longitudinal studies
of sleep and onset of major mental disorders in the age groups we
studies. Also, as noted by several research groups, the presence of
symptoms of insomnia does not preclude the co-existence of
7
Sleep Medicine Reviews 57 (2021) 101429
hypersomnia, nor the experience of periods of insomnia followed
by hypersomnia, or vice versa [73].
When type of mental disorder is considered, we found that there
were insufficient studies of full-threshold psychotic disorders to
estimate the odds for a new onset case. This reflects the current
literature on psychosis, which contains many studies examines sleep
profiles cross-sectionally in ‘at-risk’ and subthreshold syndromes or
reports caseecontrol studies of sleep patterns in long-established
illness. However, longitudinal studies have only targeted older
adults, with limited data regarding associations between sleep and
transition to full-threshold psychosis [9,10]. In contrast there was
more data available regarding mood disorders. This demonstrated
that odds of onset of a depressive or bipolar disorder meeting
diagnostic criteria were similar, although heterogeneity of findings
was greater for the former (probably reflecting the more diverse
ways in which depression was reported) [22,33,36,37,40,
41,43,44,50e53]. For bipolar disorders, it was noteworthy that lower
odds were reported in those studies examining illness trajectories
over several years, typically in offspring of parents with bipolar
disorders. However, the articles often report the chronological
sequence of onset of sleep, anxiety, and depressive antecedents of
hypo/mania. These studies offer insights into effects of sleep dis-
turbances on heterotypic continuity of lifetime comorbidities and/or
the possibility that sleep disorders increase risk of bipolar disorders
indirectly (e.g., via increasing likelihood of anxiety, etc)
[53,59,60,65]. At the very least the data indicate that future studies
of sleep disturbances should report and adjust analyses for other
comorbidities, including both mental and physical conditions [4e7].
Also, only one study that recruited twins or offspring reported an-
alyses adjusted for familial clustering and twin status [53].
Our findings indicate a modest but consistent longitudinal as-
sociation between sleep disturbance (however operationalized or
assessed) and onset of three major mental disorders in adolescents
and young adults. However, there were insufficient data to explore
associations between specific exposures and a particular diagnosis.
Also, the limitations of some of the available literature means that
our review and meta-analyses offer only conditional support for the
introduction of screening for sleep disturbances or interventions to
enhance sleep patterns in children and adolescents. The most
striking finding from this project was the myriad of measures used
to assess exposure. Quality ratings of studies repeatedly high-
lighted the widespread use of single items to assess an ill-defined
aspect of sleep (rating only its presence or absence), use of
selected items from a more extensive, established scales (without
evidence for reliability or validity), lack of exploration of some
phenomena e.g., sleep architecture (few studies considered sleep
stages) or melatonin, and/or limited use of more nuanced measures
of sleep phenotypes (e.g., assessments that addressed severity,
duration, and/or co-occurring phenomena, such as daytime
dysfunction). It is notable that only three eligible studies used
recognized criteria to assess sleep disorder as a specific diagnosis
and the association with onset of mental disorders [27,31,60].
Despite the small number of studies, this approach showed strong
longitudinal associations. A further weakness in the available
literature is the limited range of studies that use actigraphy, PSG or
other objective measures. The expanding literature on ecological
monitoring using actigraphy or ‘wearables’ was largely ineligible,
but the advantages of objective assessment is widely acknowledged
and these studies can overcome various problems associated with
subjective ratings (not least lack of accuracy of self-reports).
However, many objective approaches are more resource intensive
and this may limit their utility in longitudinal research, especially
laboratory-based overnight PSG recordings or blood assays in youth
cohorts. Further, the PSG findings we report must be treated with
considerable caution as the pooled analyses were significantly
J. Scott, H. Kallestad, O. Vedaa et al.
impacted by one study where only five individuals developed a
new onset of a depressive disorder [28]. Meta-regression offered
empirical support for the impression gained from the systematic
review of the literature, namely that earlier studies tended to report
larger effects, with smaller OR being reported in more recent and/or
more sophisticated studies that employed repeated follow-up
waves. Further, for all the reasons outlined here, and consider-
ation of how measures were selected or used, and the context in
which they were employed, we speculate that the non-significant
findings of the meta-regression regarding type of assessment
(objective, observer or self-rating) may not be the final answer on
this topic. It is established that statistical associations between self,
observer, and objective assessments of sleep metrics, but there
were too few studies using the same assessment procedure to
measure each specific exposure. So, at the present time, we suggest
this finding needs confirmation or refutation by other investigators.
Given the limitations of the current literature, evidence of publi-
cation bias, and meta-regression analysis suggesting smaller effects
in recent studies (which often employed more sophisticated meth-
odology), it is unsurprising that we conclude that, despite the time
lapse since the first reports [1], that the field still lacks a degree of
maturity. As such, we suggest there is a need for dialogue across
research groups and more collaborative projects to enable progress
regarding youth. For example, investigators undertaking studies of
sleep disorders in adults [74,75] and those working on neuro-
cognition and mood or psychotic disorders [76], have shown it is
possible to achieve international consensus about a set of metrics or
instruments that might be preferentially employed in research
studies [74e76]. This would be especially valuable in the field of sleep
research in adolescents at risk of major mental disorders, as the key
subjective, observer or objective measures of sleep profiles in this
population are likely to differ from recommended approaches to
adults being assessed for sleep disturbances [7,75]. A degree of con-
sistency in the core exposure variables and optimal outcome as-
sessments would allow greater cross-study comparisons of findings
in the future. It would allow more detailed examination of specific
sleep phenotypes and whether these show any unique associations
with depressive, bipolar, or psychotic disorders, or whether the as-
sociations are trans-diagnostic. Also, it would allow more nuanced
examination of whether the same directional relationship exists
during the peak age range for the onset of major mental disorders (i.e.,
post-puberty up to ~30 y) as have been reported in large-scale
epidemiological or community studies of adults [77e79] and
whether the magnitude of associations is similar [1,51,53].
Whilst we acknowledge such a consensus would take time and
commitment, we would like to offer a few observations of how the
process could proceed. For example, whilst actigraphy offers an
ecological measure with considerable appeal, also, it would allow
traditional sleep metrics (sleep onset latency, total sleep time,
wakening after sleep onset, etc) as well as circadian markers (time
of maximum daytime activity, relative amplitude, mesor, sleep
midpoint, etc) to be recorded efficiently. However, there is a sig-
nificant cost and resource implication of employing this assessment
of sleep-wake cycles in longitudinal research. An alternative would
be to utilize sleep assessment tools that can be self-rated but pro-
vide the same range of metrics. For example, there are several in-
struments that can assess circadian rhythms with well-established
psychometric properties and a wealth of data pertaining to
different age groups and different populations. Many of these
measures of morningness and eveningness or chronotype have
been abbreviated into short, easy to complete observer or self-
ratings [80]. Also, randomized controlled trial of sleep distur-
bances such as insomnia often employ consensus sleep diaries that
capture a wide range of key metrics and allow identification of
different sleep patterns and profiles [81]. These are simple
8
Sleep Medicine Reviews 57 (2021) 101429
examples that demonstrate that there are many brief, robust self
and observer ratings that can give data comparable to that obtained
via objective measures. Further, such assessment could be used as
alternative ways of capturing information about core sleep pro-
cesses and circadian sleep-wake rhythms, or they could be used in
combination, which could enable comparison of findings across
different types of measures. Lastly, in situations where continuous
longitudinal monitoring is unfeasible, studies of adults have
demonstrated that important insights gain be obtained regarding
sleep-wake profiles and their evolution over time by undertaking
intermittent re-assessments at 3e6 or even 12 m intervals [82].
Conclusions
This project identifies evidence for the longitudinal association
between sleep disturbances in youth and the onset of major mental
disorders. All effects are of modest magnitude (odds of about
1.5e2.0 for all pooled analyses), but associations were consistently
demonstrated across a disparate range of studies. The findings add
to the emerging research in this field that has recently demon-
strated an association between insomnia and first onset of a range
of mental disorders in adults, and more selectively of some child-
hood onset conditions such as ADHD [17,18]. Additionally, the
current findings offer tentative support to arguments that in-
terventions that promote healthy sleep patterns in youth might
prevent future more severe mental health difficulties downstream.
Given that many interventions are low cost and/or require minimal
resources, this is a worthwhile consideration [80,81]. However, a
more obvious conclusion from this synthesis of the existing liter-
ature is that it would be timely to try to draw together international
experts to develop a shared view of research priorities and a model
of options for good practice to inform, support and guide in-
vestigators embarking on projects in this important area.
Research agenda
 Despite the first studies on this topic being written about 3
decades ago, the limitations of the current literature mean
that the field still lacks a degree of maturity.
 A specific issue is the diversity in assessments used for
sleep patterns in youth, often relying on a singular item
measured at one time point. There is a need to consider
more nuanced approaches that are more sensitive to e.g.,
level of severity, rather than merely presence or absence
of specific sleep symptoms.
 Existing reviews on sleep disturbances and onset of
mental disorders has tended to have a narrow focus-
usually on insomnia only or primarily targeted at adult
populations. There is a need for more evaluations of sleep
in adolescents at risk of major mental disorders, but also a
need to encourage inclusion of subjective, observer or
objective measures of sleep that take into account the
potential differences in prevalence of and nature of sleep
disturbances in this age range.
 Overall, we would encourage greater dialogue across
research groups and more collaborative projects as this
might lead to development of an international consensus
about a set of metrics or instruments that might be pref-
erentially employed in research studies on sleep distur-
bances and incidence of major mental disorders in
populations in the peak age range for onset.
J. Scott, H. Kallestad, O. Vedaa et al.
Practice points
 This project identifies evidence for a modest but consis-
tent longitudinal association between sleep disturbances
in youth and the onset of major mental disorders. This is
clinically important as sleep disturbances are potentially
modifiable risk factors.
 It is worthwhile considering current assessment of sleep
problems in help-seeking youth in clinical settings, with
the aim of identifying a useful, reliable screening tool or
brief assessment protocol that could be used routinely.
 Obviously, individuals working in public health and
school settings, may wish to consider instigating pro-
tocols that can identify and monitor sleep disturbances
with a view to offering interventions. Alternatively, it may
be feasible to introduce sleep hygiene programmes.
 Several digital and online sleep programmes can be
accessed for self-directed assistance in improving sleep
patterns. These may be offered as an intervention if it is
not feasible to offer programmes in specific community
or clinical settings.
Author's contribution
We confirm that all authors made substantial contributions to
conception and design or analysis and interpretation of data. All
made substantial contributions to drafting the article or revising it
critically for important intellectual content. All authors have
approved the submitted version of the manuscript.
JS drafted the protocol; BE, HK, OV, BS, JS, undertook data
extraction and quality ratings; JS performed meta-analyses
(reviewed by BE). All authors the checked original publications
and in-house estimations of effect sizes (confirming data integrity
and checking accuracy of estimates when any differences were
found). All authors assisted in drafting of the final, submitted
version of manuscript and all authors have approved this version.
Data sharing
Not applicable: this is a meta-analysis that extracted data from
published papers. All publications referred to are available in aca-
demic journals.
Ethics approval
Not applicable.
Other declarations (for transparency)
BE reports grants from INSERM, Assistance Publique des
^pitaux de Paris, Agence Nationale pour la Recherche, Fondation
Ho
de France, Research Council of Norway, and personal fees from
SANOFI. HK, OV and BS report joint grants from the Norwegian
research council (including the NORSE studies of dCBT-I), the
Liaison Committee for education, research and innovation in Cen-
tral Norway, and funding from St Olavs research fund in Trondheim
(inpatient RCT of blue depleted light in acute psychiatric disorders).
JS reports grants from RfPB (early identification of youth at risk of
mood disorders), MRC UK (actigraphic monitoring of course and
outcome of bipolar disorders) and was funded as a visiting pro-
 de Paris, France and receives ongoing funding of
fessor at Universite
a part-time professorship at NTNU, Norway.
9
Sleep Medicine Reviews 57 (2021) 101429
Funding
None declared.
Conflicts of interest
BE, HK, OV, BS, and JS report no conflicts of interest in regard to
the submitted work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.smrv.2021.101429.
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