Interventions for reducing loneliness: An umbrella review of

intervention studies

Author
Veronese, N, Galvano, D, D’Antiga, F, Vecchiato, C, Furegon, E, Allocco, R, Smith, L, Gelmini, G,
Gareri, P, Solmi, M, Yang, L, Trabucchi, M, De Leo, D, Demurtas, J

Published
2020

Journal Title
Health and Social Care in the Community

Version
Accepted Manuscript (AM)

DOI

10.1111/hsc.13248

Rights statement
© 2020 John Wiley & Sons Ltd. This is the peer reviewed version of the following article:
Interventions for reducing loneliness: An umbrella review of intervention studies, Health
and Social Care in the Community, 2020, which has been published in final form at https://
doi.org/10.1111/hsc.13248. This article may be used for non-commercial purposes in
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 FACTORS ASSOCIATED WITH LONELINESS:
AN UMBRELLA REVIEW OF OBSERVATIONAL STUDIES

Marco Solmi*1,2, Nicola Veronese*, Daiana Galvano, Angela Favaro, Edoardo G Ostinelli, Vania Noventa,
Elisa Favaretto, Florina Tudor, Matilde Finessi, Ji Shin, Lee Smith, Ai Koyanagi, Alberto Cester, Francesco
Bolzetta, Antonino Cotroneo, Stefania Maggi, Jacopo Demurtas, Diego De Leo, Marco Trabucchi

1
Neurosciences Department, University of Padua, Padua, Italy
2
Neuroscience Center, University of Padua, Padua, Italy

1
 ABSTRACT

Background: Evidence provides inconsistent findings on risk factors and health outcomes associated with
loneliness, and no umbrella review has attempted to summarize evidence from meta-analyses and systematic
reviews. The aim of this work was to grade the evidence on risk factors and health outcomes associated with
loneliness, using an umbrella review approach.
Methods: For each meta-analytic association, random-effects summary effect size, 95% confidence intervals
(CIs), heterogeneity, evidence for small-study effect, excess significance bias and 95% prediction intervals
were calculated, and used to grade significant evidence (p<0.05) from convincing to weak. For narrative
systematic reviews, findings were reported descriptively.
Results: From 210 studies initially evaluated, 14 publications were included, reporting on 18 outcomes, 795
studies, and 746,706 participants. Highly suggestive evidence (class II) supported the association between
loneliness and incident dementia (relative risk, RR=1.26; 95%CI: 1.14-1.40, I2 23.6%), prevalent paranoia
(odds ratio, OR=3.36; 95%CI: 2.51-4.49, I2 92.8%) and prevalent psychotic symptoms (OR=2.33; 95%CI:
1.68-3.22, I2 56.5%). Pooled data supported the longitudinal association between loneliness and suicide
attempts and depressive symptoms. In narrative systematic reviews, factors cross-sectionally associated with
loneliness were age (in an U-shape way), female sex, quality of social contacts, low competence, socio-
economic status and medical chronic conditions.
Conclusions: This works is the first meta-evidence synthesis showing that highly suggestive and significant
evidence supports the association between loneliness and adverse mental and physical health outcomes.
More cohort studies are needed to disentangle the direction of the association between risk factors for
loneliness and its related health outcomes.

Key words: loneliness; meta-analysis; risk factor; health outcome; umbrella review.

2
Introduction
Loneliness is a perceived deficit between actual and desired quality or quantity of relationships,
which is different from objective social isolation. 1-3
Several social and clinical factors have been proposed as putative risk factors for loneliness. For
instance, coping strategies4, socio-economic status5, psychotic illness6, depressive disorder7, among others
have been proposed as putative risk factors of loneliness.
Also, a number of mental and physical health outcome have been associated with loneliness, and an
increased mortality has also been shown in older subjects experiencing loneliness.8 Among neuro-psychiatric
disorders, anxiety disorders9, depressive disorders10,11, schizophrenia spectrum disorders12, even in its early
phases12, Alzheimer’s disease13 and ultimately sucicide14 have been associated with loneliness. Also, among
subjects with mental illness, loneliness has been associated with more severe symptoms, less recovery and
poorer social functioning.15
However, most studies investigating associations between loneliness and mental or physical health
outcomes were cross-sectional, hence precluding any causal inference between lonliness and putative risk
factors or health outcomes.16 For instance, several biases may be affecting literature on aforementioned
associations, including publication bias, small sample sizes, excess of significance, or high heterogeneity.
Finally no umbrella review has graded the available evidence on risk factors and health outcomes of
loneliness based on objective criteria, nor ncompassing both meta-analyses and narrative systematic reviews
to the best of our knowledge.
The aim of the present work is to provide an overview of risk factors and health outcomes nomimally
associated with loneliness according to systematic reviews and meta-analyses, and where feasible to grade
the evidence according to strict objective and widely accepted criteria, in the context of an umbrella review.

3
Methods
A protocol for this study was registered on PROSPERO 2019: CRD xxx. We performed a systematic
review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)
recommendations 17 and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines.18

Search strategy and selection criteria

We searched PubMed and PsycInfo databases, last search performed October 16th, 2019, to identify
systematic reviews or meta-analyses pooling observational (cross-sectional, case-control, cohort) studies
examining any association between putative risk factors or mental/physical health outcomes, and loneliness.
The following search key was used: “(loneliness) AND (Meta-Analysis[ptyp] OR metaanaly*[tiab] OR
metaanaly*[tiab] OR Systematic review [ptyp] OR “systematic review” [tiab])).mp. [mp=ti, ab, ot, nm, hw,
fx, kf, ox, px, rx, ui, an, sy, tc, id, tm, mh]”. Two reviewers (DG, NV) independently searched titles/abstracts
for eligibility, and assessed the full text of those articles surviving title/abstract phase. A third reviewer
resolved any conflict (MS).
When more than one meta-analysis assessed the same risk factor or the same outcome, we only
include the one with the larger number of studies, as previously described.19-21
Exclusion criteria were: 1) meta-analyses of randomized controlled trials (RCTs) 2) published in
languages other than English, 3) meta-analyses assessing the association between risk factor or health
outcomes and construct similar but different from loneliness, such as social isolation.

Data extraction
The same two investigators that performed the screening independently extracted data in a pre-defined
excel spreadsheet. For each meta-analysis, we extracted PMID/DOI, first author, publication year, population
included in the study, factor associated with loneliness, study design, age of participants, number of included
studies and the total sample size.
For each primary study, we recorded information on first author, year of publication, study design
(i.e., cohort or case-control), number of cases (subjects having loneliness in studies assessing risk factors and
number of developing the health outcomes in studies assessing the outcome of loneliness), adjusted (or
unadjusted) effect sizes (ESs), with their 95% confidence intervals (CIs), and study location.
For meta-analyses only providing pooled estimates, we also extracted at meta-analytical level the
effect size with their 95%CI, and the I2 as a measure of heterogeneity.
For narrative reviews, we also extracted the narrative synthesis of main results of included studies.
The methodological quality of each included meta-analysis was assessed with the Assessment of
multiple systematic reviews (AMSTAR) 2 tool (available at https://amstar.ca/Amstar-2.php), which is a
recent update of AMSTAR,22 by same two investigators (DG, NV).

4
Data analysis
For each association of meta-analyses providing individual studies data, we extracted effect sizes of
individual studies and re-performed the meta-analysis calculating the pooled ES and the 95% confidence
intervals, with random-effects models to compare homogeneously analyzed results.23 Heterogeneity was
assessed with the I2 statistic.24 Additionally, we calculated the 95% prediction intervals for the summary
random ESs providing the possible range in which the ESs of future studies is expected to fall.25
We also tested the presence of small-study effect bias,19,26-28 which is deemed present in case of both
pooled estimate larger than the individual largest study, and publication bias(Egger’s regression asymmetry
test (p≤0.10)). We finally assessed the existence of excess significance bias by evaluating whether the
observed number (O) of studies with nominally statistically significant results (“positive” studies, p≤0.05)
were different from the expected number (E) of studies with statistically significant results (significance
28,29
threshold set at p≤0.10) , a. test designed to assess whether the published meta-analyses comprise an
over-representation of false positive findings.28
No additional analysis was performed for meta-analyses providing pooled estimates and for narrative
systematic reviews.

Assessment of the credibility of the evidence

Credibility of meta-analyses providing individual studies data was assessed according to stringent
criteria based on previously published umbrella reviews.21,26,27,30-32 In brief, associations that presented
nominally significant random-effects summary ESs (i.e., p < 0.05) were ranked as convincing, highly
suggestive, suggestive, and weak evidence based on number of events, strength of the association, and the
presence of several biases (criteria available in Supplementary Table 1).
Quality of included meta-analyses and narrative systematic reviews were assessed by means of
AMSTAR2.

5
Results

Search
The flow-diagram of search, selection and inclusion process is fully reported in Figure 1. Out of 269 hits
initially identified, after duplicate removal 206 were assessed at title/abstract level. Fifteen papers were
excluded with specific reasons, namely they did not follow a systematic approach to the literature (k=7), they
did not focus on loneliness (k=5), or on any health-outcome (k=2) or risk factor, or only included one single
study (k=1). Finally, 14 systematic reviews were included in this umbrella review.15,33-45 The list of
references of excluded studies, with reason, is available as Supplementary Table 2.

Supplementary Table 3 shows the quality assessment using the AMSTAR 2. Of 14 papers included, one
was rated as high quality, nine as moderate, four as critically low.

Meta-analyses providing individual studies data

Grading and results of meta-analyses providing individual studies data are reported in Table 1. Median
number of included studies was 13 (range 3 to 31), median sample size was 21,221, three meta-analyses
included only cohort studies 43-45, while two meta-analyses included cross-sectional designs.41,42 All included
meta-analyses reported a significant association of investigated factors with loneliness, but heterogeneity was
high in four, small study effect was present in three, prediction intervals included null value in three, and
excess of significance bias was present in one. Three associations were supported by highly suggestive
evidence (class II), namely prevalent paranoia (k=18, n=33,355, OR 3.36, 95%CI 2.51-4.49, I2 92.8%) and
prevalent psychotic symptoms (k=13, n=2,668, OR 2.33, 95%CI 1.68-3.22, I2 56.5%), which were based on
cross-sectional studies, and incident dementia (k=8, n=3,345, RR 1.26, 95%CI 1.14-1.4, I2 23.6%), based on
cohort studies. A significant association also emerged for the association between mortality and incident
coronary heart disease, based on cohort studies, but such associations were only supported by suggestive and
weak credibility, respectively.

Meta-analyses providing pooled estimates

Results of the umbrella review of narrative systematic reviews are reported in Table 2. Three papers38-40,
including seven different outcomes and providing pooled estimates, reported a significant association
between loneliness and investigated factors. All meta-analyses included cross-sectional studies. Loneliness
was associated with increased suicide attempts, depressive symptoms, with age following a U-shaped curve
(i.e. younger and older individuals experienced more frequently loneliness), female gender, poor quality of
social network, low competence, and low socio-economic status.

6
Narrative systematic reviews
Results of the umbrella review of narrative reviews are reported in Table 3. Six narrative systematic
reviews15,33-37 were included in the present umbrella review. Four of them included cross-sectional studies.
One included only cohort studies, and one include both cross-sectional and cohort studies. Authors
concluded that loneliness was associated with autism, emotion-focused coping strategies, acute stress
reactivity, poorer cognitive function in cross-sectional studies, that loneliness increased the risk of depression
in longitudinal studies, and with presence of chronic disease according to mixed cross-sectional and cohort
studies.

7
Discussion
Our work includes 14 systematic reviews and 18 outcomes, 795 studies, and 746,706 participants.
The present umbrella review shows that several risk factors and both mental and physical health outcomes
are nominally significantly associated with loneliness. Mental illness such as autism and female gender are
plausible risk factors for loneliness, while depression, suicide attempts, and dementia are plausible health
outcomes associated with loneliness. Mainly cross-sectional evidence focused on the association between
loneliness ad psychotic symptoms, cognitive functioning, coping strategies, and a number of medical
conditions which could either be a risk factor or a consequence of loneliness itself.
We believe that our findings are important for several reasons. First, and most important, loneliness
is a highly prevalent condition in adult and older people. It is estimated that loneliness, in North America,
may range from 17% to 57% in the general population, being higher in some vulnerable populations such as
people suffering on heart disease, depression, anxiety, or dementia.46 Similar data and characteristics are
similar in Europe.47 Given that this condition is a highly prevalent and often associated with negative health
outcomes, as also our umbrella review confirms, recently the United Kingdom Government proposed a
specific ministry for loneliness.48 At the end of 2017, in fact, an UK government commission helped by more
than a dozen non-profit organizations observed that 9 million Britons suffer from loneliness, equal to 14% of
48
the population. This “provocative” political action was well-received in all the world as confirmed by a
seminal article in the New York Times defining loneliness as a health epidemy.49 Second, our umbrella
review confirms the important role of loneliness as potential risk factor for some medical conditions,
particularly neurological and psychiatric ones. The re-analysis of already published data shown in our work
suggested that a highly suggestive evidence (i.e. an evidence poorly biased) supported the association
between loneliness and incident dementia and with prevalent paranoia/psychotic symptoms, and pooled data
indicated a significant association between loneliness and suicide attempts and depressive symptoms in
longitudinal studies. The lack of social contacts which is associated with loneliness
Finally, our work also evidenced the importance of some (risk) factors for loneliness, namely age (in
a U-shaped mode), female sex, quality of social contacts, low competence and socio-economic status. Taken
together, after excluding not modifiable factors, our umbrella review supports the importance of social
factors in indicating people that can suffer on loneliness, even if this evidence is limited by the cross-
sectional nature of these studies.
As previously observed in a previous overview of systematic reviews without a quantitative
assessment of the evidence, some authors proposed some biological explanations that can associate
loneliness to the higher presence and incidence of health outcomes.50 Some authors have in fact indicated
that loneliness is associated with reduced levels of protective hormones leading to adverse effects on heart
rate, blood pressure and the repair of blood vessel walls51 and to a downregulation of the immune system and
to a neuroendocrine dysregulation51, potentially justifying the epidemiological evidence that we found in our
work. Moreover, people experiencing loneliness may be more likely to initiate harmful health behaviors such
as smoking, excess alcohol consumption, overeating or food restriction as a psychological relief mechanism

8
and all of them are well-known risk factors and correlates for psychiatric conditions.52,53 Moreover,
loneliness has been shown to be associated with poor physical activity,54 which in turn is cross-sectionally
and longitudinally associated with depression and psychosis among other mental health outcomes.55-57 Hence
low physical activity might have mediated or moderated the association between loneliness and health
outcomes. Loneliness has been shown to be associated with psychosis throughout the whole course of
psychosis, since the very beginning of psychotic symptoms, namely from at risk mental state58 to multi-
episode schizophrenia.59 Subjects with psychosis predominantly show negative symptoms in the long term,
which are responsible for the poor functioning together with cognitive function.60-62 Hence, given the
relevance of poor social interactions with a potential involvement of loneliness in maintaining negative
symptoms, a pilot study has also started to target loneliness in subjects at risk for psychosis, confirming that
loneliness is clinically relevant construct not only in the elderly population, but also in young subjects at risk
or with early phases of mental illness.63 However, these hypotheses, mainly based on observational data,
must be confirmed by large collaborative long-term cohort studies adjusting for confounders,50 and any role
of loneliness in the treatment of negative symptoms of young subjects at risk for psychosis, or with psychosis
should be tested in well-designed and adequately powered randomized controlled trials.
The strength of the present work is it being the first umbrella review providing a qualitative evidence
synthesis on the risk factors and health outcomes associated with loneliness, including both meta-analyses
and narrative systematic reviews. Second, it applies stringent quantitative criteria to grade the evidence.
Third, it indicates future research directions in order to accumulate evidence to eventually reach convincing
evidence threshold for risk factors or health outcomes related with loneliness. The main limitations of the
present work are related and due to the included studies. Specifically, two out of three among the
associations reaching highly suggestive evidence, as well as evidence from narrative systematic reviews
yield from cross-sectional studies. Hence any direction cannot be inferred from such study designs, and both
prevalent paranoia and psychotic symptoms could either be risk factors or health outcomes associated with
loneliness.
In conclusion, there is highly suggestive evidence from meta-analyses that loneliness increases the
risk of dementia, and that paranoia and other psychotic symptoms could either be a risk factors or an health
outcome associated with loneliness. Moreover, meta-analyses providing only pooled data show that
loneliness is associated with depressive symptoms and suicide attempts. Narrative systematic reviews
suggests that loneliness increases the risk of depression, and that cognitive function, coping strategies, and
medical conditions are associated with loneliness. More longitudinal cohort studies matching subjects for a
multi-dimensional propensity score should assess risk factors and health outcomes associated with
loneliness.

9
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62. Strauss GP, Esfahlani FZ, Galderisi S, et al. Network Analysis Reveals the Latent Structure of
Negative Symptoms in Schizophrenia. Schizophrenia bulletin. 2019;45(5):1033-1041.
63. Lim MH, Rodebaugh TL, Eres R, Long KM, Penn DL, Gleeson JFM. A Pilot Digital Intervention
Targeting Loneliness in Youth Mental Health. Front Psychiatry. 2019;10:604.

12
 Table 1. Grading of evidence from meta-analyses of observational studies on factors associated with loneliness

Excess Largest
Small
Factor associated Number Type of Effect size signific study Sample Level of
Population Design P I2 study Cases PI
with loneliness of studies metric (95%CI) ance signifcan size evidence
effects
bias t
1.26 1.03-
General population Incident Dementia Cohort 8 RR 8.97E-06 23.6 yes no yes 3345 33355 II
(1.14-1.40) 1.55
Cross R to 3.36 1.18-
Psychosis Prevalent Paranoia 18 3.56E-16 92.8 yes NA yes NA 21221 II
sectional OR (2.51-4.49) 9.58
Prevalent Psychotic Cross R to 2.33 0.93-
Psychosis 13 3.64E-07 56.5 yes NA yes NA 2668 II
symptoms sectional OR (1.68-3.22) 5.81
1.22 0.71-
General population Incident Mortality Cohort 31 RR 0.0003 94.5 no NA yes NA 51053 III
(1.10-1.36) 2.10
Incident Coronary 1.80 0-
General population Cohort 3 RR 0.04 65.3 no yes no 430 2722 IV
Heart Disease (1.02-3.17) 999

Abbreviations: PI, Prediction Interval

13
 Table 2. Evidence from the meta-analyses reporting pooled data of the observational studies included

study type of n of sample Publication

population outcome ES p-value Heterogeneity Main findings
design effect studies size bias
Loneliness is associated
cross- 2.24 with a higher rate of
Older people Suicide attempts OR 3 NR NR no NR
sectional (1.73-2.90) suicidal attempts in olde
people
Loneliness had a
Subjects with cross- Pearson’s 0.50
Depressive symptoms 88 40068 NR NR NR moderately significant
depression sectional R (0.44-0.55)
effect on depression
Age U-shaped association
General cross- Pearson’s -0.01
(as risk factor for 106 62363 NR yes NR between age and loneline
population sectional R (-0.02 to -0.0001)
loneliness) is identified
Gender Female sex is associated
General cross- Pearson’s -0.08
(as risk factor for 91 73213 NR yes NR with higher loneliness
population sectional R (-0.09 to -0.07)
loneliness) perception
Quality of social network
Social contacts
General cross- Pearson’s -0.18 correlated more strongly
(as risk factor for 235 93934 NR yes NR
population sectional R (-0.19 to -0.17) with loneliness, compare
loneliness)
to quantity
Competence and Activity Low competence is
General cross- Pearson’s -0.12
(as risk factor for 67 38796 NR yes NR associated with higher
population sectional R (-0.13 to -0.11)
loneliness) loneliness feeling
Low socioeconomic statu
General Socio economic status (as cross- Pearson’s -0.13
62 39319 NR yes NR is associated with higher
population risk factor for loneliness) sectional R (-0.14 to -0.12)
loneliness presence

14
Table 3. Evidence from the systematic reviews of the observational studies included

Number of
Studies design Outcome Sample size Main findings
studies
Social
Compared to controls, people with autism had a greater loneliness
Cross sectional participation 2 53
perception
in autism
Significant association between loneliness and coping consistently
showed that problem-focused coping styles were associated with
Coping
Cross sectional 12 3124 lower levels of loneliness, and emotion-focused coping styles with
strategies
higher levels of loneliness.

The majority of studies reported positive associations between

loneliness and acute stress responses, such that higher levels of
Acute stress loneliness were associated with exaggerated
Cross sectional 11 1585
reactivity physiological reactions. Unclear effect on blood pressure, heart
frequency

Loneliness is significantly and negatively correlated with cognitive

function, specifically in domains of global cognitive function or
Cognitive
Cross sectional 10 260079 general cognitive ability, intelligence quotient, processing speed,
function
immediate recall, and delayed recall.

Greater loneliness predicts poorer depression outcome in terms of

Longitudinal Depression 2 NA severity and remission of depression

Loneliness is a significant biopsychosocial stressor that is prevalent

Presence of
Longitudinal, in adults with heart disease, hypertension, stroke, and lung disease.
chronic 33 23153
cross-sectional The relationships among loneliness, obesity, and metabolic
disease
disorders are understudied.

15
 Figure 1. PRISMA flow-chart

Records identified through Additional records identified

Identification

database searching in PubMed, through manual search

PsychInfo, Embase (n = 0)
(n = 269)

Records after duplicates were removed

(n = 206)

Records screened Records excluded based on

Screening

(n = 206) title/abstract
(n =177)

Publications excluded (n =15)

Full-text articles
Non-systematic reviews (n=7)
assessed for eligibility
No loneliness (n=5)
Eligibility

(n =29)
No health outcomes (n=2)
Only one study (n=1)
Included

Systematic reviews
included in the umbrella
review
(n = 14)

16
Supplementary table 1. Credibility assessment criteria for meta-analyses of observational
studies

Evidence classification Criteria

Associations with p < 0.000001;

>1,000 cases (or >20 000 participants for
continuous outcomes)
having the event of interest;
the largest component study reporting a nominal
Convincing (class I) statistically
significant result (p < 0.05);
a 95% PI that excluded the null;
no large heterogeneity (I2 <50%);
no evidence of small-study effect (p > 0.10);
no excess significance bias (p > 0.10).
Associations with P < 0.000001;
>1000 cases (or >20 000 participants for
continuous outcomes)
Highly suggestive (class II) having the event of interest;
the largest component study reporting a
statistically
significant result (p < 0.05).
Associations with P < 0.001;
>1000 cases (or >20 000 participants for
Suggestive (class III)
continuous outcomes)
having the event of interest
Remaining statistically significant associations
Weak (class IV)
with P < 0.05.

Abbreviations: PI = prediction interval; RCT = randomized controlled trial.

17
Supplementary Table 2. List of excluded references, with reasons.
Non-systematic reviews (n=7)
Abdellaoui A, Sanchez-Roige S, Sealock J, et al. Phenome-wide investigation of health outcomes
associated with genetic predisposition to loneliness. bioRxiv. 2018:468835.
Bessa B, Ribeiro O, Coelho T. Assessing the social dimension of frailty in old age: A systematic review.
Arch Gerontol Geriatr. 2018;78:101-113.
Kitzmuller G, Clancy A, Vaismoradi M, Wegener C, Bondas T. "Trapped in an Empty Waiting Room"-
The Existential Human Core of Loneliness in Old Age: A Meta-Synthesis. Qualitative health research.
2018;28(2):213-230.
Mund M, Freuding MM, Mobius K, Horn N, Neyer FJ. The Stability and Change of Loneliness Across the
Life Span: A Meta-Analysis of Longitudinal Studies. Personality and social psychology review : an
official journal of the Society for Personality and Social Psychology, Inc. 2019:1088868319850738.
Leigh-Hunt N, Bagguley D, Bash K, et al. An overview of systematic reviews on the public health
consequences of social isolation and loneliness. Public Health. 2017;152:157-171.
Hagan R, Manktelow R, Taylor BJ, Mallett J. Reducing loneliness amongst older people: a systematic
search and narrative review. Aging Ment Health. 2014;18(6):683-693.
Levine MP. Loneliness and eating disorders. The Journal of psychology. 2012;146(1-2):243-257.
No health outcomes (n=2)
Lindsay Smith G, Banting L, Eime R, O'Sullivan G, van Uffelen JGZ. The association between social
support and physical activity in older adults: a systematic review. The international journal of behavioral
nutrition and physical activity. 2017;14(1):56.
Dyal SR, Valente TW. A Systematic Review of Loneliness and Smoking: Small Effects, Big Implications.
Substance use & misuse. 2015;50(13):1697-1716.
No loneliness (n=5)
Heidari Gorji MA, Fatahian A, Farsavian A. The impact of perceived and objective social isolation on
hospital readmission in patients with heart failure: A systematic review and meta-analysis of observational
studies. Gen Hosp Psychiatry. 2019;60:27-36.
Teo AR, Lerrigo R, Rogers MA. The role of social isolation in social anxiety disorder: a systematic review
and meta-analysis. Journal of anxiety disorders. 2013;27(4):353-364.
Seabrook EM, Kern ML, Rickard NS. Social Networking Sites, Depression, and Anxiety: A Systematic
Review. JMIR mental health. 2016;3(4):e50.
Hashem MD, Nallagangula A, Nalamalapu S, et al. Patient outcomes after critical illness: a systematic
review of qualitative studies following hospital discharge. Critical care. 2016;20(1):345.
Mezuk B, Rock A, Lohman MC, Choi M. Suicide risk in long-term care facilities: a systematic review. Int
J Geriatr Psychiatry. 2014;29(12):1198-1211.
Only one study (n=1)
Smagula SF, Stone KL, Fabio A, Cauley JA. Risk factors for sleep disturbances in older adults: Evidence

18
from prospective studies. Sleep medicine reviews. 2016;25:

19
 Supplementary Table 3: AMSTAR 2 quality assessment of included papers.

AMSTAR 2 items a, c
Author, Year Overall rating (ba
1 2b 3 4b 5 6 7b 8 9b 10 11 b 12 13 b 14 15 b 16
[Reference] on critical domain
Boss, 2015 Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Moderate
Brown, 2017 No Yes No No Yes Yes Yes Yes Yes No Yes No No No Yes Yes Moderate
Chang, 2017 No Yes Yes Yes No Yes No Yes Yes Yes No No Yes No No Yes Moderate
Partial
Chau, 2019 Yes Yes Yes Yes Yes Yes Yes Partial Yes Yes Yes Yes Yes No Yes Yes High
Yes
No
No meta- No meta-
da Rocha, 2018 Yes Yes Yes Yes Yes No No Yes Yes No Yes Yes meta- Yes Moderate
analysis analysis
analysis
Deckx,2018 Yes No Yes Yes Yes No No No No No Yes Yes No No No Yes Critically Low
Yes Partial Yes Yes No
Erzen, 2018 Yes Yes Yes Partial Yes No No Yes Yes No Yes Yes Moderate
Yes
Lara, 2019 Yes Yes Yes Yes Yes Yes No Yes Yes No Yes Yes No Yes No Yes Moderate
Partial
Petitte, 2015 Yes Yes No No Yes No Yes Yes Partial Yes Yes Yes Yes No No Yes Moderate
Yes
Pinquart, 2001 No No No No No Yes Yes No Yes No No No Yes Yes Yes No Critically Low
Rico-Uribe, 2018 Yes Yes Yes Partial Yes No No Yes Partial Yes Partial Yes Yes Yes Yes Yes No No Yes Moderate
Tobin, 2013 Yes Yes No No No Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Moderate
Valtorta, 2015 Yes Yes No No Yes No No No No Yes Yes Yes No No Yes No Critically Low
Wang, 2018 Yes Yes Yes Yes Yes No No Yes No No Yes No No No Yes Yes Critically Low

a
Yes, No, Other
b
Critical Domains
c
AMSTAR 2 items:
1. Did the research questions and inclusion criteria for the review include the components of PICO (Population, Intervention, Comparator group, Outcome)?
YES/NO. For yes, must have all four.
2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify
any significant deviations from the protocol? YES, PARTIAL YES, NO. For Partial YES: the authors state that they had a written protocol or guide that included
ALL the following (review question(s), a search strategy, inclusion/exclusion criteria, a risk of bias assessment). For YES: as for partial yes, plus the protocol should be
registered and should also have specified: a meta-analysis/synthesis plan, if appropriate, and a plan for investigating causes of heterogeneity, justification for any
deviations from the protocol.
20
3. Did the review authors explain their selection of the study designs for inclusion in the review? YES/NO. For YES, the review should satisfy one of the following:
explanation for including only RCTs, or explanation for including only NRSI, or explanation for including both RCTs and NRSI.
4. Did the review authors use a comprehensive literature search strategy? YES, PARTIAL YES, NO. for PARTIAL YES must have all of the following: searched at
least 2 databases (relevant to research question), provided key word and/or search strategy, justified publication restrictions (eg. Language). For YES should also have
all of the following: searched the reference lists/biographies of included studies, searched trial/study registries, included/consulted content experts in the field, searched
for grey literature where relevant, conducted search within 24 months of completion of the review.
5. Did the review authors perform study selection in duplicate? YES/NO. for YES, either ONE of the following: at least two reviewers independently agreed on
selection of eligible studies and achieved consensus on which studies to include OR two reviewers selected a sample of eligible studies and achieved good agreement (at
least 80 per cent) with the remainder selected by one reviewer.
6. Did the review authors perform data extraction in duplicate? YES/NO. For YES, either one of the following: at least two reviewers achieved consensus on which
data to extract from included studies OR two reviewers extracted data from a sample of eligible studies and achieved good agreement (at least 80 per cent) with the
remainder extracted by one reviewer.
7. Did the review authors provide a list of excluded studies to justify the exclusions? YES, PARTIAL YES, NO. FOR partial yes must provide a list of all potentially
relevant studies that were read in full text form but excluded from the review. For YES must also have justified the exclusion from the review of each potentially
relevant study.
8. Did the review authors describe the included studies in adequate detail? YES, PARTIAL YES, NO. For PARTIAL YES, must describe all of the following:
populations, interventions, comparators, outcomes, research designs. For YES should also have all of the following: described populations in detail, described
intervention and comparator in detail (including doses where relevant), described study setting, timeframe or follow-up.
9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? For RCTs: YES,
PARTIAL YES, NO, INCLUDES ONLY NRSI. For PARTIAL YES must have assessed RoB from unconcealed allocation and lack of blinding of patients and assessors
when assessing outcomes (unnecessary for objective outcomes such as all cause mortality); for YES must also have assessed RoB from allocation sequence that was not
truly random and selection of the reported result from among multiple measurements or analyses of a specified outcome. For NRSI (Non Randomized Studies of
Intervention): YES, PARTIAL YES, NO, INCLUDES ONLY RCTs. For PARTIAL YES must have assessed RoB from confounding and from selection bias. For YES,
must also have assessed methods used to ascertain exposures and outcomes, and selection of the reported results from among multiple measurements or analyses of a
specified outcome.
10. Did the review authors report on the sources of funding for the studies included in the review? YES/NO. For YES: must have reported on the sources of funding
for individual studies included in the review. Note: reporting that the reviewers looked for this information but it was not reported by study authors also qualifies
11. If meta-analysis was performed, did the review authors use appropriate methods for statistical combination of results? For RCTs: YES, NO, NO META-
ANALYSIS. For YES: the authors justified combining the data in a meta-analysis and they used an appropriate weighted technique to combine study results and
adjusted for heterogeneity if present and investigated the causes of heterogeneity. For NRSI: YES, NO, NO META-ANALYSIS CONDUCTED. For YES: the authors
justified combining the data in a meta-analysis and they used an appropriate weighted technique to combine study results, adjusting for heterogeneity if present, and they
statistically combined effects estimates from NRSI that were adjusted for confounding, rather than combining raw data, or justified combining raw data when adjusted
effect estimates were not available, and they reported separate summary estimates for RCTs and NRSI separately when both were included in the review.
12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other
evidence synthesis? YES, NO, NO META-ANALYSIS INCLUDED. For YES: included only low risk of bias RCTs or, if the pooled estimate was based on RCTs
and/or NRSI at variable RoB, the authors performed analysis ton investigate possible impact of RoB on summary estimates of effect.
13. Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review? YES/NO. for YES: included only low risk of
bias RCTs or, if RCTs with moderate or high RoB, or NRSI were included, the review provided a discussion of the key impact of RoB on the results
14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? YES/NO. For Yes:
there was no significant heterogeneity in the results OR if heterogeneity was present the authors performed an investigation of sources of any heterogeneity in the results
and discussed the impact of this on the results of the review
21
 15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely
impact on the results of the review? YES, NO, NO META-ANALYSIS CONDUCTED. For YES: performed graphical statistical tests for publication bias and
discussed the likelihood and magnitude of impact of publication bias
16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? YES/NO. For Yes: the
authors reported no competing interests OR the authors described their funding sources and how they managed potential conflicts of interest.
d
Rating overall confidence in the results of the review:
HIGH: no on one non-critical weakness: the systematic review provides an accurate and comprehensive summary of the results of the available studies that address the question
of interest
MODERATE: more than one non critical weakness (multiple non-critical weaknesses may diminish confidence in the review and it may be appropriate to move the overall
appraisal down from moderate to low confidence): the systematic review has more than one weakness but no critical flaws. It may provide an accurate summary of the results of
the available studies that were included in the review
LOW: one critical flaw with or without non-critical weaknesses: the review has a critical flaw and may not provide an accurate and comprehensive summary of the available
studies that address the question of interest
CRITICALLY LOW: more than one critical flaw with or without non-critical weaknesses: the review has more than one critical flaw and should not be relied on to provide an
accurate and comprehensive summary of the available studies.

22