Introduction

Opioid toxicity deaths, commonly referred to as opioid overdose has become a global crisis [1, 2] that has intensified during the COVID-19 pandemic [3]. Some evidence exists to suggest that opioid overdose is commonly experienced by individuals with co-occurring mental disorder [4,5,6,7] but literature that examines these two phenomena together is sparse. This review summarizes the evidence on mental disorder and the risk of opioid overdose to advance understanding of this relationship.

Although past research indicates that individuals with mental disorders are at increased risk for overdose [8,9,10,11,12], there are multiple considerations that have precluded definitive conclusions from being made in this area. First, disentangling the symptoms of substance use disorders, other non-substance use psychiatric disorders, and medication side effects can be challenging, which complicates the identification of the relationship between mental disorder and opioid overdose. For example, individuals with mental disorders are often prescribed opioids or other psychotropic medications [13] that may interact or cumulate with non-prescription or illicit opioids to increase overdose risk. In addition, the historical expansion of diagnostic scope for mental disorders may contribute to over-pathologizing drug use, criminality, and social deviance [14]. Thus, there is difficulty in distinguishing between the presence of a mental disorder and behaviors attributable to the use of drugs, leading to imprecision in the evidence base on mental disorder and opioid use [15].

It is also unclear whether there is an identifiable causal relationship between mental disorder and opioid overdose. While stigma, stress and social exclusion commonly experienced alongside opioid use may produce poor psychological outcomes, opioids may also be used as a form of self-medication for coping with emotional pain or mental disorder symptoms [16]. Otherwise stated, the direction of causality and potential moderators in the relationship are not well understood. Another possibility in discussions about causality, and one consistent with a framework introduced by Dasgupta and colleagues [17], would reflect a process of social causation (also known as indirect selection) [18, 19], where a third factor or set of factors produces suboptimal outcomes in both areas. In this case, where opioid use and mental disorder are both hypothesized to be occurring within processes of social causation, both outcomes may be responses to social and economic precarity [16]. Importantly, scholars have also proposed a countervailing theory of social selection or social drift [20] to explain the connection between mental disorder and socioeconomic marginalization which argues for the reverse: that experiencing mental disorder causes a downward shift in social class. Given these complex pathways, a fulsome understanding of these relationships is unlikely to produce a unidirectional explanation, these pathways likely co-exist, each contributing to understandings of the complexity of the relationship between opioid overdose and mental disorder.

Despite the clear need for conclusive evidence about the intersections between mental disorder and opioid overdose, this relationship has not been clarified or summarized in a systematic way. Specifically, gaps exist in the literature in: 1) establishing the volume and strength of literature supporting the connection is between mental disorder and overdose risk; and 2) understanding the empirical evidence that exists to support the theoretical relationships hypothesized between these phenomena.

The systematic review of the extant literature on mental disorder and opioid overdose presented here began as part of a larger investigation of the literature related to socioeconomic marginalization and opioid overdose, in which we found a preponderance of scientific evidence pointing to the potential role of mental disorder [21]. This systematic review employed an integrated knowledge translation process [22] whereby we partnered with decision makers in establishing the focus of the review, refining review questions and methodology, data retrieval and retrieval tool development, interpretation of review findings, identification of gaps, crafting of recommendations, and dissemination and application of review findings. Given our initial findings, the need for an independent review on mental disorder and overdose specifically was informed by decision-makers in the local community, municipal, provincial, and federal government who required further clarity regarding the evidence on mental disorder and overdose risk. This review responds to that need and systematically summarizes the literature on whether or not broadly defined mental disorder (including both symptoms of disorder and diagnosed mental disorder) are associated with opioid overdose. The review was designed to address the above omissions, summarize existing published research, provide a knowledge base for effective prevention and response strategies, and identify future directions for policy in this area.

Methods

Search strategy and selection criteria

Using the Systematic Reviews and Meta-Analyses (PRISMA) checklist, the search sought studies that included measures of mental disorder and opioid-related fatal and non-fatal overdose published in English peer-reviewed journals or by governmental sources between January 1, 2000 and January 4, 2021. Only studies conducted in North America, Europe, the United Kingdom, Australia, and New Zealand were eligible for inclusion, as study stakeholders expressed a desire for a review of studies with the highest contextual and policy comparability. The specific terms related to mental disorder included in the search strategy are summarized in Table 1, and a summary of the Medline search terms used in the review is provided in Appendix A. The PECOS framework (Population, Exposure, Comparison, Outcome, Study Design) used to frame our specific mental disorder and opioid overdose research question [23] is listed in Table 1. Two research assistants first conducted title and abstract screening, and subsequently independently assessed full text articles to determine final inclusion eligibility. Differences in opinion about inclusion were resolved by a senior team member. More details about study selection are provided in the protocol, published on the Open Science Framework site [24].

Table 1 Search strategy
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Data collection and extraction

Two research assistants used a standardized form to extract data from the included studies, including year, journal, and type of publication, author’s name, study location, sample, study period, study design, recruitment and sampling, sample size, response rates, age range, operationalization of mental disorder, type of opioid overdose outcome, and statistical analysis. Inconsistencies in the extracted data were noted by the research assistants and resolved through discussion with a senior team member.

Study selection and data synthesis

This review approached the relationship between mental disorder (including both diagnosed disorder—medically diagnosed, assessed, or self-reported—and symptoms of disorder) and opioid overdose broadly and purposely allowed inclusion of different study types, as long as they provided evidence on the review question regarding whether mental disorder and associated symptoms are associated with increased occurrence of opioid overdose (including fatal and non-fatal overdose, overdose-related hospitalizations, and intentional vs. unintentional overdose). As a result, we employed the lumping synthesis technique where all evidence related to mental disorder and opioid overdose was included despite differences between study design and outcome measures [25]. This strategy allows for synthesis and identification of common findings in the relationships between mental disorder and opioid overdose that remain despite minor differences in study participants, context, and design, similar to the approach taken by others investigating determinants of overdose [26]. Substantial conceptual and methodological heterogeneity across the included studies precluded meta-analysis. Instead, findings are summarized by mental disorder variables. The data extraction process for this review included an assessment of bias, for which we used the study quality tools of the National Heart, Lung, and Blood Institute (presented in Table 3) [27]. Two independent reviewers assessed risk of bias.

Table 2 Study design and sample characteristics of included studies
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Results

Overall findings

The number of studies retained in each step of the review process can be found in the PRISMA flow diagram in Fig. 1. The primary search strategy found 7200 original articles that met the initial screening criteria. The review and screening process led to a final dataset of 38 articles on mental disorder and overdose.

Fig. 1
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PRISMA flow diagram

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Eleven studies had fatal overdose as the outcome or drew their sample from a population who had experienced fatal overdose [28,29,30,31,32,33,34,35,36,37,38]. Thirteen included only non-fatal overdose as the sole overdose outcome in their studies [15, 39,40,41,42,43,44,45,46,47,48,49,50], and twelve articles included both fatal and non-fatal overdose [51,52,53,54,55,56,57,58,59,60, 63, 64]. Two studies included data from emergency department (ED) visits and hospitalizations for overdose but did not specify whether the overdoses were fatal or not [61, 62]. Most studies either did not report intention of overdose (n = 17) [15, 33, 35, 39,40,41, 46, 48, 51,52,53, 58, 59, 61,62,63,64] or examined both intentional and unintentional overdose (n = 17) [30,31,32, 36,37,38, 42,43,44,45, 47, 49, 54,55,56,57, 60] with four examining only unintentional overdose [28, 29, 34, 50]. Many studies (n = 20) included overdose that was attributable to prescription and non-prescription opioids [29, 32, 35,36,37, 41,42,43,44,45,46,47, 49, 50, 56,57,58, 60, 63, 64], while eleven investigated only prescription opioid overdoses [28, 33, 34, 38, 48, 51,52,53,54, 61, 62] and two investigated only non-prescription opioid overdoses [15, 39]. Five studies did not report what type of opioids were included in their data [30, 31, 40, 55, 59]. The included studies analyzed data from the United States (n = 28) [28,29,30,31,32, 34, 35, 42,43,44,45,46, 48,49,50,51,52,53,54,55,56,57,58,59, 61,62,63,64], Australia (n = 4) [15, 36, 39, 47], Canada (n = 4) [33, 37, 38, 60], Italy (n = 1) [40] and Spain (n = 1) [41]. Study designs included nine cross-sectional analyses [15, 29, 37, 39, 40, 42, 45, 49, 50], fourteen cohort studies [32, 35, 41, 43, 44, 46, 51,52,53,54,55, 58, 59, 63], eight case–control studies [33, 34, 38, 47, 56, 57, 60, 64] two studies that used nested case–control designs [48, 61] two ecological studies [30, 31] one study that used panel data [36] and one study that used a case-cohort design [28]. A summary of the study design, data sources, and sample characteristics for the 38 included studies can be found in Table 2.

The majority of the 38 included studies operationalized mental disorder through diagnosed mental disorder, with only six studies reporting on symptoms of disorder [29, 38,39,40, 42, 45]. Overall, 37/38 of these studies found a significant association with the mental disorder and opioid overdose variables used, with the direction of the association suggesting that people experiencing mental disorder and associated symptoms were more likely to overdose than those who were not. Only one study presented results in the opposite direction [32]. A summary of measures and findings for the 38 included studies can be found in Table 3.

Table 3 Summary of measures and findings for included studies
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Risk of bias within included studies

The risk of bias assessments indicated a mix of bias-related concern with 10/38 of the original papers having ‘poor’ assessments, 20/38 having ‘fair’ assessments, and 8/38 studies having ‘good’ assessments. Many studies only measured exposure variables once during the study; failed to include multivariable controls for potential confounding variables; did not report information about power, effect estimates, or sample size justifications; or presented bivariable relationships only. The most serious concerns about risk of bias in the included studies arise from mental disorder variables only being assessed once or being assessed after the outcome [15], and inconsistent measurement of mental disorder across groups [29]. The dataset is largely observational, limiting causal conclusions. Results from included studies are organized in the below summary by mental disorder categories.

Internalizing disorders

The evidence on internalizing mental disorders and opioid overdose, including depressive disorders, anxiety disorders, obsessive–compulsive and related disorders, trauma and stressor-related disorders are summarized by specific disorder below.

Mood disorders

Twenty-four studies examined the connection between mood disorders and overdose, and 17/24 of these studies found mood disorders to be significantly and positively associated with opioid-related overdose. This association has been found in the general population: across US states (AIRR 1.26, 95% CI 1.01–1.58 [30]), in California and Florida (AOR 2.71, 95% CI 2.46–2.97, p < 0.001 [44]), in Ontario, Canada (AOR 1.80, 95% CI 1.00–3.24; [33]),and in British Columbia (men: 34.0% vs. 7.9%, p < 0.01; women: 52.0% vs. 13%, p < 0.01; [60]. Depression has been found to be associated with opioid overdose among Medicare/Medicaid enrollees: in Pennsylvania (adjusted OR 1.29, 95% CI 1.12–1.50) [53], in Oregon (28.0% vs. 10.9%, p < 0.001 [57]), and nationally in the US (56.8% vs. 30.2%; [32]. Associations between depression and overdose were also present in samples that studied those with substance use disorders specifically: in New South Wales (non-fatal overdose and suicide attempt AOR 1.71, 95% CI 1.17–2.51, p < 0.05Footnote 1 [47]), in Boston (AOR 2.46, 95% CI 1.24–4.89; [43]),and in Madrid (AOR 2.20, 95% CI 1.01–4.74; [41].

This association has also been found among patients with opioid prescriptions in two national US studies (311/100,000 person-years, 95% CI 203–441 vs. 96/100,000 person-years, 95% CI 62–137) [54] and (AOR 3.12, 95% CI 2.84–3.42) [48] and in North Carolina (AHR 2.30, 95% CI 1.98–2.68) [51].Footnote 2 Significant associations were additionally found using data from community hospitals across the US (prescription opioids, males: ARR 1.10 (95% CI 1.05–1.15, p < 0.001), females: ARR 1.12 (95% CI 1.08–1.15, p < 0.001)) [50], electronic health records data (repeat overdose, AHR 1.38, 95% CI 1.02–1.73 [63]). A connection between depression and overdose was also present in studies of commercially insured adolescents (AHR 2.77, 95% CI 2.26–3.34 [62]), pregnant/postpartum women (depression prevalence with overdose 84.8% vs. opioid use disorder 61.2% vs. neither 18.9%, p < 0.001 [59], and Veterans Health Administration claims (56.4% vs. 36.7%, p < 0.0001 [46]. Non-significant findings or findings that did not retain significance in multivariable analysis include those from a study with Veterans Health Administration patients [64], those eligible for Medicaid in Oklahoma [34],the general population of US adults [31], repeat overdose events [49, 58],commercially insured individuals [55], and young people who use heroin in Australia [39].

Anxiety disorders

Seventeen studies examined the connection between anxiety disorders and overdose, and 12 of these studies found a significant association. Those with anxiety disorders were more likely to experience opioid overdose in Ontario (cases 63.2% vs. controls 54.9%, standardized difference = 0.13; [38]), in British Columbia (men: 30.0% vs. 6.8%, p < 0.01; women: 45.0% vs. 11.0%, p < 0.01; [60]), and in people presenting to an emergency department in Pennsylvania (repeat overdose AHR 1.41, 95% CI 1.13–1.77; [63]). These association were also seen in two national samples of the Medicare enrollee population (adjusted OR 1.26, 95% CI 1.07–1.48) [53] (63.4% vs. 30.9%) [32], as well as the commercially insured population in four studies: three with adult populations (AOR (95% CI) 1.64 (1.50–1.80) [48]), AOR 1.24, 95% CI 1.12–1.36 [55], repeat overdose events for those with anxiety 39.5% vs. 47.0%, p = 0.013 [58]), and one with adolescents (prescription opioid overdose AHR 1.65, 95% CI 1.33–2.06; [62]). Other samples where this relationship was seen include those with substance use disorder in New South Wales (non-fatal overdose and suicide attempt AOR 1.71, 95% CI 1.17–2.51, p < 0.05Footnote 3,association not present in subgroup analysis [47]),among Veterans Health Administration claims (anxiety in those with overdose 22.3% vs. non-opioid related hospitalizations 15.1%, p < 0.05Footnote 4; [46], and in a cohort of pregnant/postpartum women (prevalence of anxiety among those with overdose 82.1% vs. opioid use disorder 60.2%, vs. neither 18.3% p < 0.001 [59]. Non-significant findings were present in Veterans Health Administration patients [64], decedents eligible for Medicaid in Oklahoma [34], samples of inpatient populations [42, 50] and people with substance use disorders in Boston [43].

Posttraumatic stress disorder (PTSD), obsessive compulsive disorder and adjustment disorders

Ten studies examined other internalizing disorders including posttraumatic stress disorder, obsessive compulsive disorder, and adjustment disorders. Six of these studies found significant associations, five of which were in the hypothesized direction. Studies in this review found a significant positive association between PTSD and opioid overdose among people with substance use disorders in Boston (non-fatal overdose AOR 2.77, 95% CI 1.37–5.60; [43]), those recruited from methadone or residential detox programs in New Jersey (AOR 3.84, 95% Cl l.41–10.46, p = 0.01 [45]), and in Veterans Health Administration claims (claims for opioid overdose hospitalizations vs. non-opioid hospitalizations 30.4% vs. 19.0%, p < 0.0001Footnote 5) [46]. Similar trends were seen with past year affective disorder in Ontario (case 11.2% vs. controls 5.6%, Standardized Difference = 0.19 [38]Footnote 6), and past 5-year adjustment disorder in British Columbia (men: cases 16.0% vs. controls 2.4%, p < 0.01, women: 25.0% vs. 4.7%, p < 0.01) [60]. Conversely, one study found a negative association with PTSD and fatal opioid overdose among Medicare enrollees in the US (AOR 0.73, 95% CI 0.58–0.92 [32]). Four studies failed to find significant associations or found bivariable associations that did not retain significance in multivariable models in the commercially insured population [48, 55], veterans [48, 64], and Medicare enrollees in Pennsylvania [53].Footnote 7

Externalizing disorders

The evidence on opioid overdose and externalizing disorders is summarized below by disorder type, in this case, for personality disorders and attention deficit hyperactivity disorder.

Personality disorders and antisocial behavior

Five studies examined personality disorders and associated antisocial behaviors and 4/5 of these studies found significant associations with higher rates of opioid overdose. Associations between antisocial personality disorder and non-fatal opioid overdose were seen in two studies conducted with people who use heroin in Australia (OR 2.20, 95% CI 1.15–4.21 [15], Wald’s statistic: 8.21, p < 0.01 [39]). Those who experienced overdose were more likely to have had a prior personality disorder compared to those with no overdose when measured in a cohort of Medicare enrollees in the United States (9.8% vs 4.1%, p < 0.001) [32], and in British Columbia (for men past year personality disorder 3.3% vs. 0.16%, p < 0.01, and women 5.2% vs. 0.16%, p < 0.01) [60]. One study done in a cohort of Medicare enrollees in Pennsylvania found no significant associations [53].

Attention deficit hyperactivity disorder

Four studies in this review investigated the association between attention deficit hyperactivity disorder (ADHD) and opioid overdose. Two of these studies found significant associations. Those who experienced overdose were more likely to have ADHD compared to those with no overdose when measured in a cohort of Medicare enrollees in the United States (12.0% vs 4.6%, p < 0.001) [32], and in British Columbia (for men past year prevalence 1.9% vs. 0.35%, p < 0.01, and women 1.2% vs. 0.30%, p < 0.01) [60]. Studies done with the commercially insured [48] and veteran population [48, 64] found no association with opioid overdose.

Thought and other disorders

Similar to other reviews in this area [65], we have additionally summarized the evidence for thought disorders and overdose, including bipolar disorder, and schizophrenia and psychoses (otherwise undefined).

Schizophrenia and psychoses

Schizophrenia and psychoses were examined in eight included studies, and five found significant associations with opioid overdose. A relationship between psychoses and overdose was seen among people prescribed opioids in the commercially insured population (schizophrenia AOR 2.06, 95% CI 1.17–3.69) [48], the general population in California and Florida (psychoses and hospitalization AOR 5.40, 95% CI 4.85–6.00, p < 0.001, psychoses and frequency of ED visits AOR 1.44, 95% CI 1.25–1.65, p < 0.001 for opioid overdose) [44], and patients with hospital stays for opioid overdose in a US-based national cohort (AOR: 1.25, 95% CI:1.01–1.53) [49]. Those who experienced overdose were more likely to have schizophrenia or psychoses compared to those with no overdose when measured in a cohort of Medicare enrollees in the United States (18.8% vs 11.5%, p < 0.001) [32], and in British Columbia (for men past year prevalence 7.0% vs. 0.93%, p < 0.01, and women 7.3% vs. 0.38%, p < 0.01) [60].

Non-significant findings between schizophrenia and opioid overdose came from studies done with veterans [64], patients receiving methadone [33], and ED patients in Pennsylvania [63].

Bipolar disorders

Ten studies examined bipolar disorder and opioid overdose, and nine found associations with overdose. Bipolar disorder was associated with overdose in an Australian study of people with substance use disorder (OR 3.37, 95% CI 1.44–7.88) [15], in commercially insured (OR 2.18, 95% CI 1.83–2.60) [48] and veteran populations prescribed opioids in the US,(OR 1.68, 95% CI 1.17–2.43) [48], and for females (ARR 1.05, 95% CI 1.00–1.12, p < 0.05) but not males who were prescribed opioids [50]. Those who experienced overdose were more likely to have bipolar disorder than controls when measured: in a cohort of Medicare enrollees across the US (AOR 1.51, 95% CI 1.28–1.79) [32], among members of Oklahoma’s Medicaid program (AOR 1.78, 95% CI 1.20–2.65) [34], in patients of the Veterans Health Administration (AOR 1.7, 95% CI 1.2–2.4, p = 0.005) [64], among patients with repeat overdose in California (22.3% vs. 14.8%, p < 0.001) [58], in those with both opioid overdose and suicide attempt in New South Whales (AOR 2.29, 95% CI 1.55–3.34, p < 0.001Footnote 8 [47]), and in both men (past year disorder 6.3% vs. 0.82%, p < 0.01) and women (11% vs. 1%, p < 0.01) in British Columbia [60]. A multivariable analysis on a retrospective cohort of persons with non-fatal opioid overdose in Pennsylvania did not find a significant association with bipolar disorder [63].

Any disorder and psychological distress

Some included papers looked at combined measures of any mental disorder and opioid overdose or investigated symptoms of mental disorder in the form of suicidality and hopelessness, or intent of opioid overdose. The results of those papers are summarized below.

Any disorder

Twelve studies included in the review examined any combined measures of mental disorder and 10/12 found significant associations with opioid overdose events. Mental disorder diagnosis was significantly associated with overdose: among those prescribed long-term opioid therapy in Colorado (adjusted matched OR 2.97, 95% CI 1.57–5.64) [56], for commercially insured patients in the US (AOR 3.14; 95% CI 2.40–4.12) [52], among three subpopulations of US veterans who were prescribed opioids (those with chronic pain AHR 1.87, 95% CI 1.48–2.38; acute pain AHR 1.77, 95% CI 1.19–2.65; and substance use disorder AHR 1.73, 95% CI 1.10–2.72) [28], and in ED patients in Pennsylvania (repeat overdose AHR 1.32, 95% CI 1.08–1.61) [63]. Similar trends were seen for former inmates who received prior in-prison mental disorder treatment (1-year post release AHR: 2.2, 95% CI: 1.7–2.9) [35], and in patients on Medicaid with a history of mental disorder (hospitalization/ED visit for overdose AOR 1.73, 95% CI 1.31–2.29) [61]. When compared to controls, those with overdose were more likely to have a history of mental disorder or serious mental illness, a trend present among patients of mental hospitals in the US (72.2% vs. 50.0%, p = 0.013) [42], in a study of US veterans prescribed opioids (24.2% vs 9.7%, p < 0.0001 for opioid related hospitalizations) [46], in young people using heroin in Australia (Wald’s statistic: 4.15, p < 0.05) [39], and in fatal opioid overdose cases in Utah [50.0% vs. 15.0%, p < 0.001Footnote 9) [29]. However, two bivariable analyses found no association between mental disorder and non-fatal opioid overdose in California [58], or in therapeutic communities in Italy [40].

Suicidality and self-harm

Three studies examined symptoms of mental disorder and opioid overdose and 2/3 found significant associations. Opioid overdose was associated with hopelessness in young people who use heroin in Australia (hopelessness, Wald’s statistic: 6.12, p < 0.01; self-harm, non-significant) [39] and with history of suicide among adults recruited from psychiatric hospitals in the US (50% vs. 17.2%, p = 0.001) [42]. In a cross-sectional study in New Jersey, no significant bivariable relationship was detected between suicidal ideation and non-fatal opioid overdose [45].

Intentionality

Three of the papers that grouped mental disorders together or examined symptoms of mental disorder specifically looked at associations with likelihood of an intentional (vs. unintentional) opioid overdose, and all found disorders/symptoms to be associated with intentional overdose. These bivariable associations were seen in Australia, for those with a history of mental health problems recorded in the National Coronial Information System (OR: 2.1, 95% CI: 1.6–2.7) [36] and in Ontario, for those with a diagnosed disorder (OR: 2.1, 95% CI: 1.4–3.2, p = 0.0005) [37]. In a different study of Ontario residents, people with fatal intentional opioid overdose were more likely to have a history of self-harm in the year preceding death than people with fatal accidental opioid overdose (standardized difference: 0.26) [38].

Discussion

Summary of findings

Overall, 37/38 studies included in this review show a connection between mental disorders and opioid overdose with only one association reported that was not in the hypothesized direction. The largest volume of evidence was found for internalizing disorders generally and mood disorders specifically, although there was also moderate evidence to support the relationship between anxiety disorders and opioid overdose. The presence of thought disorders (e.g., schizophrenia, BPD) appears to be associated with opioid overdose. When studies included multiple disorders together in their analyses, evidence was found for the association between any disorder and overdose. Fewer studies investigated externalizing disorders, but most studies that looked at personality and anti-social disorders found significant associations with opioid overdose. The relationship between mental disorder and opioid overdose appears to be present in the general population, among people who use prescription opioids, Medicare/Medicaid enrollees, youth, and veterans. Included studies did not examine variations in these relationships by race/ethnicity, and very few examined differences by gender. Mental disorders may be more common among those who have intentional opioid overdose than unintentional opioid overdose, but more evidence is required to confirm this. Given our findings, it is apparent that mental disorder plays a role in opioid overdose. However, there was substantial variation in measurement and type of independent and dependent variables examined, as well as in the populations and study settings, limiting more nuanced conclusions about this relationship.

Limitations

We reviewed the literature on a wide range of mental disorder issues and opioid overdose. To make the results of our review widely applicable for those making decisions in the overdose crisis, we chose to include studies with any type of opioid overdose measure in the review. By undertaking a broad review, we were able to explore whether the associations between mental disorder and opioid overdose were similar across different disorders, different settings, and different populations. A narrower review would have reduced the number of included studies and thus may have been more susceptible to erroneous conclusions [66]. However, including a variety of outcome measures also presents limitations, including the inability to identify unique risks from different outcomes (e.g., fatal and non-fatal overdose) and the inability to conduct statistical meta-analyses. There were no experimental study designs or mediation analyses among the included papers and this limits any ability to derive causal pathways or make more definitive conclusions about the way mental disorder is related to opioid overdose.

Future directions

The lack of conclusive findings on causal relationships connecting mental disorder to opioid overdose is a challenge that could be first met with qualitative research conducted to elucidate the pathways and mechanisms linking these two phenomena. In recognition of the structural factors intersecting with the opioid crisis including, for example, diminished economic opportunity, colonization, racialization, increasing isolation, and income inequality, more attention should be given to the way these shared root causes impact mental disorder and opioid use [17, 67] and the potential for variation in outcomes for people affected by these structural factors.

Additionally, more quantitative research is needed to determine causal direction in the relationships and whether the connection between mental disorder and opioid overdose is in part a result of a connection to socioeconomic marginalization either through social selection [20], social causation [68, 69], or both. Although none of the studies included in this review examined casual direction, given the severity of the overdose emergency, it remains imperative that we pursue such an understanding in efforts to mitigate the catastrophic crisis. Recent studies have examined “diseases of despair,” or the connected trends of increasing fatal drug overdose, suicide, and alcohol-related illness [18, 19, 70] and found common causes to each population health challenge. Analyzing these trends reveals complex and interrelated environmental, contextual and social issues associated with the increase in overdose [71] including deepening socioeconomic marginalization, [72,73,74] chronic physical pain, [75] disconnection, and hopelessness [70]. These same factors are also associated with mental disorder, leading scholars to suggest that the connection between these phenomena may have roots in social distress and economic hardship [17] that require further investigation.

The literature included in this review largely focused on diagnosed mental disorder. This is further complicated by the variety of different types of mental disorders, and the possibility exists that the relationships differ by type of disorder, an area worthy of further investigation. We included search terms designed to identify studies that measured exclusion, hopelessness, isolation, stigma, and symptoms of mental disorder more broadly, but found little empirical research published in this area. Thus, more research is needed on not just diagnosed mental disorder and opioid overdose, but also the associated phenomena that may be affecting overdose risk.

Individuals struggling concurrently with mental disorder and opioid use experience higher levels of complexity in symptoms, face more pronounced exclusion, require more integrated treatment, have poorer outcomes, and incur higher costs [76]. Therefore, integrated clinical, policy, and programmatic responses are critically needed, and future research should focus on developing evidence that can support such a response.

In conclusion, based on the included studies, those with mental disorders appear to be at increased risk of intentional and unintentional fatal and non-fatal opioid overdose, with both prescription and non-prescription opioids, and these associations have been found to exist in a wide variety of subpopulations. A complete understanding of the relationship requires more empirical evidence related to directionality, the social and structural root causes of mental disorder, and the implications for different subgroups of the population and for disorders with differing etiology [77].