Association between depression and non-fatal overdoses among drug users: A systematic review and meta-analysis

Drug and Alcohol Dependence 134 (2014) 12–21

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Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep

Review

Association between depression and non-fatal overdoses among drug users: A systematic review and meta-analysis夽 Francesco Bartoli a , Giuseppe Carrà b,∗ , Giulia Brambilla a , Daniele Carretta a , Cristina Crocamo c , Julia Neufeind d , Alex Baldacchino e , Gerry Humphris d , Massimo Clerici a a

Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Milano 20126, Italy Mental Health Sciences Unit, Faculty of Brain Sciences, University College London, W1W 7EJ, UK c Department of Mental Health, San Gerardo Hospital, Monza 20900, MB, Italy d Medical and Biological Sciences Building, University of St Andrews, North Haugh, St Andrews KY16 9TF, UK e Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK b

a r t i c l e

i n f o

Article history: Received 22 July 2013 Received in revised form 23 September 2013 Accepted 13 October 2013 Available online 24 October 2013 Keywords: Depression Drug overdose Meta-analysis

a b s t r a c t Background: Assessing factors associated with non-fatal overdose is important as these could be useful to identify individuals with substance use disorders at high risk of adverse outcomes and consequences. Depression may play an important role in terms of overdose risk. We aimed to test if drug users suffering from a depressive disorder might have significantly higher risk of non-fatal overdose as compared with drug users without depression. Methods: We conducted a systematic review and meta-analysis. PubMed, Embase and Web of Knowledge were searched. The pooled analyses were based on prevalence rates, risk difference (RD) and odds ratio (OR), reporting 95% confidence intervals (CIs). The combined estimates were obtained weighting each study according to random effects model for meta-analysis. Results: Seven articles, involving 12,019 individuals, and run in the US, Canada, Sweden, Norway, and Australia, were included. Pooled analyses comparing depressed with not depressed individuals highlighted a RD (95% CIs) for non-fatal overdose of 7.3% (4.8–9.7%) and an OR (95% CIs) of 1.45 (1.17–1.79). The subgroups analyses based on specific characteristics of included studies confirmed the association between depression and overdose. Conclusions: Depressive disorders seem to be important factors associated to the risk of non-fatal overdose. Longitudinal studies might appropriately clarify causal inference issues. Future research should address the role of depressive disorders as predictors of subsequent non-fatal overdoses. © 2013 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data collection process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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夽 Supplementary material can be found by accessing the online version of this paper. See Appendix A for more details. ∗ Corresponding author at: Mental Health Sciences Unit, Faculty of Brain Sciences, University College London, Charles Bell House, 67–73 Riding House Street, London W1W 7EJ, UK. Tel.: +44 20 7679 9428; fax: +44 20 7679 9426. E-mail addresses: [email protected], [email protected] (G. Carrà). 0376-8716/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drugalcdep.2013.10.007

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

3.3. Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Association between depression and previous non-fatal overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Summary of findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Interpretation of findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Strengths and limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Clinical perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Substance use disorders are related to serious consequences, such as risk of overdose and early mortality (Cornelius et al., 2008; Kertesz et al., 2012). Heroin, cocaine, and amphetamine use disorders show standardized mortality ratios of 9.1 (CI: 8.5–9.8), 6.4 (CI: 3.9–10.0), and 6.0 (CI: 4.2–8.3), respectively (Arendt et al., 2011). The median estimated non-AIDS-related mortality rate among persons who inject drugs has been estimated 1.08% per annum (Degenhardt et al., 2006). Illicit drug overdose is a leading cause of premature death and morbidity among opioid users (Darke and Hall, 2003). Overdose-related mortality accounts for 0.65 (0.55–0.75) deaths per 100 person-years, followed by trauma and suicide related deaths, with values of 0.25 and 0.12, respectively (Degenhardt et al., 2011). People from Asia who inject drugs have the highest pooled overall crude mortality rate (5.25), followed by populations from North America (2.64) and Western Europe (2.31). An overall crude mortality is related to male gender, not being in treatment, and living in low- and middleincome countries (Mathers et al., 2013). A 2010 meta-analysis (Merrall et al., 2010) showed an increased risk of drug-related deaths during the first 2 weeks after release from prison. The risk remained high up to at least the fourth week. Furthermore, as HIV-serostatus may consistently affect outcomes of opiate dependents (Carrà et al., 2008a), HIV comorbidity seems to represent also an important factor associated with an increased risk of mortality for overdose (pooled risk ratio = 1.74; 95% CI: 1.45–2.09) (Green et al., 2012). Despite being clearly more common than fatal overdose, non-fatal overdose has received considerably less attention in the literature (Kerr et al., 2007), possibly because public health concerns have been focused on lethal consequences (Darke and Zador, 1996; Carrà et al., 2006). However, non-fatal overdose is an important cause of morbidity among illicit drug users and can result in a number of serious medical consequences, such as cardiovascular and pulmonary complications, peripheral neuropathy, anoxia-induced cognitive impairment, rhabdomyolysis, and renal failure (Warner-Smith et al., 2001). Evidence shows also that non-fatal overdoses consistently increase the risk of subsequent overdose mortality (Stoové et al., 2009). An improved assessment of non-fatal overdose rates and risk factors may help clinicians for preventing the excess of overdose fatalities (Darke et al., 2003). The prevalence rates of lifetime history of non-fatal overdose range between 13% and 69% among drug users (Bohnert et al., 2010). Evidence suggests that severity of dependence, polysubstance use, serious withdrawal symptoms, history of suicide attempt, length of drug using career, number of network members who inject drugs, homelessness, all are important risk factors for non-fatal overdoses (Backmund et al., 2009; Bohnert et al., 2010; Brugal et al., 2002; Coffin et al., 2007; Jenkins et al., 2011; Kerr et al., 2007).

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Comorbidity for a mental disorder, involving more than half of drug-abusing individuals (Regier et al., 1990), may play an important role on the likelihood of nonfatal overdose. Drug users with co-occurring mental disorders report poorer prognosis, in terms of remission and relapse likelihood (Hasin et al., 2002), emergency department use (Curran et al., 2003), family/social relationships (Carrà and Clerici, 2006; Carrà and Johnson, 2009; Carrà et al., 2012), medical comorbidity (Rosenberg et al., 2001). Little is known on the potential influence of depression on non-fatal overdose (Conner et al., 2008). Depression among drug users in residential programs is related to lower adherence and higher drop-out rates (Ravndal and Vaglum, 1994). Depressed methadone patients may be more sensitive to negative opioid effects and withdrawal (Elkader et al., 2009), and such a comorbid disorder seems associated also to an increased risk of suicide attempt and ideation among drug and opioid users (Aharonovich et al., 2002; Darke and Ross, 2002; Phillips et al., 2004). To the best of our knowledge this is the first meta-analysis that systematically analyzes the relationship between depression and non-fatal overdose. We tested the hypothesis that drug users suffering from a depressive disorder would have shown rates, and experienced risk, of non-fatal overdose significantly higher than non-depressed drug users. 2. Methods The present systematic review and meta-analysis was conducted according to the Metaanalyses Of Observational Studies in Epidemiology (MOOSE) guidelines (Stroup et al., 2000). 2.1. Search strategy We searched the Electronic databases PubMed, Embase and Web of Knowledge for papers published up to September 2012. Additionally, we explored the reference list of a relatively recent relevant systematic review (Bohnert et al., 2010) on the association between overdose and suicide attempts in samples of substance users. We searched for papers in English, Spanish, French, German, Portuguese or Italian. Search phrases combined thesaurus terms related to overdose, depression, and mental disorders. In addition, synonyms of thesaurus terms were used for free search in titles and abstracts. Full search strategies are detailed in Supplementary Material1 . 2.2. Eligibility criteria We included any observational study that provided: 1. A target population composed by adults with at least one of the following characteristics. A) a problem drug use defined as intravenous drug use and/or long duration/regular use of illicit drugs, such as opiates, cocaine and/or amphetamines (Kraus et al., 2003); B) being in treatment in an addiction service

1 Supplementary material can be found by accessing the online version of this paper. See Appendix A for more details.

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F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

Fig. 1. Flow diagram of search results.

(e.g., a specialized residential centre, a maintenance treatment clinic, a therapeutic community, or an inpatient detoxification unit); C) on medication-assisted treatment for substance use disorders (e.g., methadone, buprenorphine, naltrexone, or different pharmacological agents for non-opioid use disorders). 2. Data on prevalence rates of previous non-fatal overdoses in a sample of drugs users suffering from a depressive disorder, including major depressive disorder, dysthymic disorder, or depressive disorder NOS, according to DSM-IV-TR (American Psychiatric Association, 2000), or previous Diagnostic and Statistical Manuals, as DSM-5 (American Psychiatric Association, 2013) was released immediately after we searched and screened the literature, or to ICD-10 International Classifications of Diseases (World Health Organisation, 1992). 3. Additional rates of non-fatal overdoses in a comparison group of drug users without depression. 4. Data from clinical (inpatients or outpatients) and non-clinical (e.g., untreated, criminal justice, and institutionalized) populations.

We aimed at providing a summary result (crude cross-sectional association of non-fatal overdoses) in a very specific subgroup of subjects, i.e., drug users suffering from a depressive disorder, thus we necessarily had restrictive eligibility criteria. We did not primarily aim at investigating heterogeneity. Thus, we excluded studies if:

- They used longitudinal/prospective designs where only incidence, and not prevalence, of non-fatal overdoses was estimated. - There was data overlap with other studies included in the meta-analysis. - Raw data could not be retrieved, since results of the study were adjusted for one or more potential confounders and the authors did not provide the exact number of cases.

2.3. Data collection process We performed a preliminary screening based on titles and abstracts, in order to include potentially relevant articles. After the first screening, studies were retrieved in full text to test the final eligibility, in order to explore whether specific inclusion/exclusion criteria were met. The eligibility assessment was performed by two authors independently (FB and GC). Discordances on the inclusion or the exclusion of articles were analyzed, and disagreements were resolved by consensus. We developed a sheet for the extraction of the following information from each included study: year of publication; country; study design; inclusion criteria; setting; sample size; mean age; percentages of men and women; definition and diagnostic strategies of depression; definition of non-fatal overdose; prevalence and raw numbers of cases of non-fatal overdoses in index and control subsamples. If numerical data were not reported, they were derived from percentages. If raw data were not reported, we contacted the corresponding author in order to obtain this information.

2.4. Quality assessment Errors in measuring exposure or outcome in observational studies may cause information bias (Copeland et al., 1977; Jepsen et al., 2004). Therefore, we conducted a quality evaluation, assessing if the included studies were affected by the risk of both depression and overdose misclassification. Measurement error or misclassification may result from poor validity of instruments used. We explored if proper methods to assess depression, e.g., standardized and structured interviews such as the structured clinical interview for DSM-IV-TR for Axis I disorders (SCID-I; First et al., 2002) or the Mini-International Neuropsychiatric Interview (MINI; Sheehan et al., 1998), were used. Furthermore, we evaluated if adequate definitions of non-fatal overdose were provided, including also information on overdose related symptoms, such as loss of consciousness, seizures or respiratory depression, or the requirement of a hospitalization (Coffin et al., 2007; McGregor et al., 1998; Milloy et al., 2010; Pollini et al., 2006). Finally, we tested the potential effect of poor quality on results of our meta-analysis performing sensitivity analyses including only high quality papers with low risk of overdose/depression misclassification. 2.5. Data analysis We analyzed data using Stata version 10.0 SE. The pooled analyses were based on prevalence rates, risk difference (RD) and odds ratio (OR) with related 95% confidence intervals. Results were summarized using conventional forest plots. The pooled estimates were obtained by weighting each study according to random effects model for meta-analysis. This method weights studies more evenly and is considered more suitable for meta-analyses with substantial heterogeneity (Riley et al., 2011). We assessed the presence and the level of heterogeneity using Q statistic and I2 index, respectively. In order to explore potential sources of heterogeneity, we performed subgroup analyses based on characteristics of included studies: general characteristics (publishing journal; year of publication; geographical area); characteristics of recruited samples (size; nature of substance use disorders; source of recruitment); temporal range (current or lifetime) of overdose and depression. We conducted further subanalyses based on validity and quality of data, as described in the previous subparagraph. We checked if authors used standardized interviews to assess depression and if adequate definitions of non-fatal overdose were provided. A funnel plot was created for the visual inspection of potential risk of publication bias. The Egger’s linear regression test was used to evaluate the statistical significance of publication bias.

3. Results 3.1. Study selection PubMed, Embase and Web of Knowledge provided 521, 421 and 400 records, respectively. We searched also within 66 references from a recent relevant review (Bohnert et al., 2010). The

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

preliminary screening by reading titles and abstracts identified 66 potentially eligible papers. There were seven studies that fitted our inclusion criteria (Bohnert et al., 2011; Darke et al., 2009; Fischer et al., 2004; Hakansson et al., 2008; Havens et al., 2011; Maloney et al., 2009; Rossow and Lauritzen, 1999). Detailed reasons for ineligibility are described in flow diagram (Fig. 1). 3.2. Study characteristics Detailed characteristics of included papers are shown in Table 1. All eligible articles were in English language. Three papers were from North America (Bohnert et al., 2011; Fischer et al., 2004; Havens et al., 2011), two from Australia (Darke et al., 2009; Maloney et al., 2009), one from Sweden (Hakansson et al., 2008) and one from Norway (Rossow and Lauritzen, 1999). Two papers were published in 2011 (Bohnert et al., 2011; Havens et al., 2011), two in 2009 (Darke et al., 2009; Maloney et al., 2009), one in 2008 (Hakansson et al., 2008), one in 2004 (Fischer et al., 2004), and one in 1999 (Rossow and Lauritzen, 1999). Target populations were based on opioid and any drug users, in four (Darke et al., 2009; Fischer et al., 2004; Hakansson et al., 2008; Maloney et al., 2009) and three articles respectively (Bohnert et al., 2011; Havens et al., 2011; Rossow and Lauritzen, 1999). Sample sizes ranged from 400 (Havens et al., 2011) to 5892 individuals (Bohnert et al., 2011). Most of the participants were males, with percentages ranging from 59% (Havens et al., 2011) to 88% (Hakansson et al., 2008). Four studies (Bohnert et al., 2011; Darke et al., 2009; Maloney et al., 2009; Rossow and Lauritzen, 1999) included individuals from clinical settings, whereas three studies (Fischer et al., 2004; Hakansson et al., 2008; Havens et al., 2011) recruited subjects from non-clinical settings (drug users who were not enrolled in treatment, criminal justice clients, and rural drug users, respectively). 3.3. Quality Four papers (Darke et al., 2009; Fischer et al., 2004; Havens et al., 2011; Maloney et al., 2009) provided valid methods to assess depression, using standardized diagnostic interviews, such as MINI (Sheehan et al., 1998) or the Composite International Diagnostic Interview (CIDI; World Health Organization, 1993). Three papers used lower quality methods to assess depression, as two (Bohnert et al., 2011; Rossow and Lauritzen, 1999) did not use standardized interviews neither nor specific scales to make a diagnosis of depression, and one (Hakansson et al., 2008) used the Addiction Severity Index (ASI) (McLellan et al., 1980) for the lifetime history of depressive symptoms. An appropriate definition of overdose was provided in four papers (Bohnert et al., 2011; Fischer et al., 2004; Hakansson et al., 2008; Maloney et al., 2009). In these studies, overdose definition was not only made by asking the patients if they ever had overdosed, but also, by collecting further relevant information on related symptoms (e.g., loss of consciousness or respiratory depression) or about the need for hospitalization. 3.4. Association between depression and previous non-fatal overdose The included studies involved 12,019 individuals, 6536 suffering from depression, 5483 without depression. A lifetime history of non-fatal overdose was found in 3792 subjects. The random effect combined prevalence (95% CIs) of previous overdose(s) was 38.5% (24.4–53.5%) among people suffering from depression and 30.8% (16.7–47.1%) among people without depression. The combined RD (95% CIs) for non-fatal overdose comparing depressed and nondepressed individuals was 7.3% (4.8–9.7%; p < 0.001). The pooled

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OR (95% CIs) assessing the association between depression and a history of non-fatal overdose was 1.45 (1.17–1.79; p < 0.001). Heterogeneity was high (p < 0.001; I2 : 79.2% [49.2–88.3%]). Forest plots are shown in Figs. 2 and 3. Subgroup analyses based on specific characteristics of the pooled studies (including publishing journal, geographical area, period of publication, kind of population selected, samples size, setting, overdose and depression definitions), confirmed the association between depression and non-fatal overdoses as statistically significant (Table 2). A sensitivity analysis based just on studies providing high quality assessment of depression reported a statistically significant association between depression and a history of non-fatal overdose, OR (95% CIs) = 1.31 (1.02–1.69; p = 0.03). Similarly, analyses including only papers with robust definition of overdose showed an OR of 1.48 (1.06–2.08; p = 0.02). Funnel plot and Egger’s linear regression test for publication bias are shown in Fig. 4. 4. Discussion 4.1. Summary of findings This systematic review on the potential burden of depression on the risk of non-fatal overdose identified seven studies with data suitable for meta-analysis. The association between depression and previous non-fatal overdose(s) was statistically significant. Proportion of individuals with previous non-fatal overdose(s) was about 7% higher among depressed drug users as compared to their non-depressed counterpart. Furthermore, subjects suffering from depression were 1.5 times more likely to report a history of one or more overdoses than their counterpart without this-current or lifetime-disorder. A high level of heterogeneity among studies was found. We explored potential sources of heterogeneity performing subgroups analyses based on specific characteristics of included studies. The results did not appear to be affected by the nature of considered populations (drug users or opioid users). Furthermore, subgroups analyses based on variables, such as period of publication, geographical area, sample size, source of recruitment, time considered for assessing depression and overdose (current or lifetime), quality of reported data, consistently confirmed the association. 4.2. Interpretation of findings We found a significant association between depression and nonfatal overdose. This finding cannot be necessarily extended to cases of fatal overdose. However, previous evidence (Kinner et al., 2012; Warner-Smith et al., 2001) highlighted that causes of fatal and nonfatal overdoses are likely to be similar. Furthermore, due to the cross-sectional nature of data included in this meta-analysis, we are able to confirm the significance of the association between depression and non-fatal overdose, but we cannot assume any causal link of depression on the subsequent risk of overdose. The direction of the association remained uncertain, since most of the papers investigated lifetime overdoses and depressive disorders without explanation of temporal relationship between the events. Although some prospective studies (Britton et al., 2010; Darke et al., 2009) analyzing the role of depression as predictor of non-fatal overdose were available in the literature, additional large size longitudinal studies are required in order to explore casual inference. Factors mediating the relationship between depression and overdose remain unknown. Depression may increase the risk of non-fatal overdose, because people with depression may be more prone to use higher doses and more substances, resulting in more

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Table 1 Studies exploring association between depression and previous non-fatal overdoses. Study

Location

Population (years of data collection)

N

Mean age (±SD)*

Males (%)

Definition of depression

Definition of non-fatal overdose

Association between depression and non-fatal overdose OR (95% CIs)

Bohnert et al. (2011)

USA

5892

N/A (75% between 25 and 44)

71

History of depressive symptoms

Lifetime history of overdose requiring hospitalization

2.00 (1.73–2.31)

Darke et al. (2009)

Australia (Greater Sidney)

429

29.5 ± 8.0

65

DSM-IV MDD according to CIDI

Last 12 months history of overdose

1.33 (0.81–2.20)

Fischer et al. (2004)

Canada (Vancouver, Edmonton, Toronto, Montréal and Québec)

Individuals entering addictions treatment from multi-site study (1993–1994) Entrants to treatment for heroin dependence from 19 agencies (2001–2002) Regular illicit opioid users who were not enrolled in treatment (2002)

651

34.8 ± 9.4

67

MDD according to CIDI short form

1.73 (1.14–2.63)

Hakansson et al. (2008)

Sweden

1096

31.8 (N/A)

88

Lifetime history of depressive symptoms according to ASI

Havens et al. (2011)

USA (Appalachian county in Kentucky) Australia (New South Wales)

Subjects reporting use of opioids during the 30 days prior to incarceration from multi-site study of the Swedish Prison and Probation Service (2001–2006) Rural drug users (2008–2010)

Last 6 months overdose defined as a drug-use related experience where the subject lost consciousness and/or had convulsions because of too strong of a drug(s) or taking too much drug(s) Lifetime overdose according to ASI, defined as lifethreatening physical complications following drug intake

Median: 31 IQR: 26–38

59

MDD according to MINI

Lifetime history of overdose

1.50 (0.92–2.44)

Subjects from opioid maintenance treatment clinics (2004–2008)

1500

36.4 (N/A)

60

DSM-IV MDD according to a structured interview

1.06 (0.86–1.31)

Drug addicts admitted to treatment in the larger drug treatment clinics in Norway (1992–1993)

2051

27 ± 5.9 (men) 25 ± 6.1 (women)

64

Depression according to therapists’ clinical evaluation

Lifetime history of opioid overdose defined as an event where loss of consciousness and respiratory depression occurs that does not result in a fatal outcome Lifetime history of lifethreatening overdose

Maloney et al. (2009)

Rossow and Lauritzen (1999)

Norway

400

1.34 (1.06–1.71)

1.36 (1.14–1.62)

ASI, Addiction Severity Index; CESD, Center for Epidemiologic Studies Depression Scale; CIDI, Composite International Diagnostic Interview; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; IQR, interquartile range; MDD, major depressive disorder; MINI, Mini-International Neuropsychiatric Interview; OR, odds ratio (calculated from raw data or estimated from reported percentages). * SD, standard deviation (if available).

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

17

Fig. 2. Random effect pooled risk difference (depressed vs. non-depressed) for non-fatal overdose(s).

severe dependence syndromes. Depression may be an important trigger for high-risk injection practices, continued drug use, or drug relapse (Stein et al., 2003). Specifically, situations involving negative mood states account frequently for the risk of relapse across several types of addictive substances (Stein et al., 2004). Depressive disorders seem to reduce the likelihood of remission and to predict relapse in substance use (Hasin et al., 2002). Therefore, the relationship between non-fatal overdose and depression might be explained by the fact that depressed individuals are simply heavier drug users. Thus, depression may be not an independent factor, but a mediator of a more severe substance use disorder linked to a greater likelihood of overdose. 4.3. Strengths and limitations The well-known advantage of meta-analyses of observational studies is based on the fact that these allow the synthesis of results from a large amount of studies, providing findings more robust than those from individual studies data. However, although observational studies are an important source in epidemiological research, they are prone to many methodological issues (Egger et al., 1998; Grimes and Schulz, 2002), which could also affect our results. Since these limitations may influence confidence in results of metaanalyses, we paid critical attention to the quality of included papers. We found that some studies had methodological issues on important items, such as depression and overdose misclassification risk. Some papers provided inadequate assessments of depression and definitions of overdose. In order to reduce the effect of these limitations, we performed subanalyses based on best quality data on

depression and history of overdose assessment. These subanalyses confirmed the statistically significant association between depression and previous non-fatal overdose(s). Indeed, drug misuse is often difficult to be screened using questionnaires, because of inaccurate reporting (Fendrich et al., 1999). This may be even more true for multiple drugs or drugs other than heroin non-fatal overdoses, as these show symptoms markedly different and more difficult to be assessed than those related to opioids (Fairbairn et al., 2008; Kaye and Darke, 2004). Indeed, different types of drug use could not be controlled for, though under optimal conditions, it would be adequate to control for at least opiate vs. stimulant dependence. This further limitation needs to be acknowledged. These limitations may lead at least partially to an underestimation of the real prevalence rates of non-fatal overdoses in our meta-analysis. Furthermore, most of the included papers did not provide methods appropriate for a clear differentiation between unintentional and intentional overdoses. This issue is particularly important since depression is a well-known risk factor for intentional overdose and suicide attempts among illicit drug users (Neale, 2000; Brådvik et al., 2007). Therefore, despite previous research suggested that the majority of overdoses among drug users are likely to be unintentional (Best et al., 2000), we cannot exclude that at least a part of the association between depression and overdose is related to a self-injurious intent. Usual limitations of systematic reviews of observational studies need to be acknowledged also in our study. We actually included only published studies with sufficient data, excluding for example conference abstracts because these often cannot give reliable information on patients’ characteristics, inclusion criteria, and

18

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

Fig. 3. Random effect pooled odds ratio (depressed vs. non-depressed) for non-fatal overdose(s).

Fig. 4. Funnel plot for publication bias. Egger’s test: −1,42 [−6,85; 4,02], p = 0,53.

assessment of outcome, relevant results are often different from what is shown in the final publication, and they have not generally undergone the rigorous peer review process required for scientific journals papers. This increases the likelihood that bias influences the results (Crowther et al., 2010). However, search of

comprehensive databases, such as PubMed, Embase, and Web of Science-as well as the hand searching of references list of a relevant recent review-has largely granted an extensive coverage of published literature on the topic (Lemeshow et al., 2005). Nonetheless, as only seven papers were included, and these only focused on

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

19

Table 2 Subanalyses of included studies.

General characteristics Publishing journal Drug and alcohol dependence Other journals Period of publication 2008–2011 Before Geographical area North America Northern Europe Australia Characteristics of samples Size <1000 ≥1000 Nature Any drug users Opioid users Source of recruitment Clinical setting Non-clinical setting Overdose Temporal range Recent (within past year) Lifetime Quality of definition High Low Depression Temporal range Current Lifetime Quality of assessment High Low

I2 (%)

N studies

N subjects

Odds ratio [random, 95% CI]

3 4

7388 4631

1.63 [1.20, 2.21] 1.29 [1.07, 1.57]

0.002 0.009

76 47

5 2

9317 2702

1.42 [1.05, 1.93] 1.42 [1.18, 1.72]

0.02 <0.001

85 11

3 2 2

6943 3147 1929

1.93 [1.70, 2.20] 1.35 [1.17, 1.56] 1.10 [0.90, 1.33]

<0.001 <0.001 0.35

0 0 0

3 4

1480 10,539

1.54 [1.18, 2.01] 1.41 [1.06, 1.88]

0.002 0.02

0 89

3 4

8343 3676

1.62 [1.19, 2.20] 1.28 [1.05, 1.57]

0.002 0.02

82 42

4 3

9872 2147

1.41 [1.03, 1.95] 1.44 [1.19, 1.75]

0.03 <0.001

89 0

2 5

1080 10,939

1.56 [1.13, 2.15] 1.42 [1.10, 1.84]

0.007 0.007

0 86

4 3

9139 2880

1.48 [1.06, 2.08] 1.37 [1.17, 1.60]

0.02 <0.001

89 0

3 4

2880 9139

1.37 [1.17, 1.60] 1.48 [1.06, 2.08]

<0.001 0.02

0 89

4 3

2980 9039

1.31 [1.02, 1.69] 1.55 [1.17, 2.06]

0.03 0.002

43 86

specific narrow regions, the results here may not be generalizable to all geographical locations. We also need to consider the risk that an amount of negative or uncertain results remained unpublished. Some of included observational studies could be vulnerable to multiple analyses aimed to search for more significant results, resulting in an analysis of published studies, prone to a selective publication bias (Loder et al., 2010). Although the visual inspection of the funnel plot and the Egger’s test showed the lack of risk of publication bias, we cannot exclude that this result was due to chance, as included articles were less than 10 (Sterne et al., 2008).

p

antidepressants (Pani et al., 2010). Further data on the treatment of major depressive and dysthymic disorders, showed no difference in the reduction of depressive symptoms comparing antidepressant and placebo among individuals with comorbid opiate-use disorders (Pedrelli et al., 2011). Larger randomized trials are therefore needed, hopefully assessing also the role of more complex interventions other the pharmacological ones, such as psychosocial or behavioral interventions. Heterogeneous psychosocial treatments offered in addition to pharmacological detoxification may be effective in terms of completion of treatment, reduction of opiate use, and compliance, in terms of clinical absences during the treatment (Amato et al., 2008).

4.4. Clinical perspectives Clinicians should regularly assess symptoms of depression in people suffering from a substance use disorder (Carrà and Clerici, 2006). The accuracy of assessment and screening of depression often represents a critical issue, since tools commonly used in addiction research showed poor specificity and modest predictive power of screening (Delgadillo et al., 2011). Furthermore, a differentiation between independent mood disorders from those due to continued substance misuse is often difficult (McIntosh and Ritson, 2001). Thus, a primary depression remains frequently undetected and undertreated. This might be an important issue for establishing prognosis and optimal treatment (Mowla et al., 2008). At the same time, treatment of depression represents a challenge, because of lack of data supporting the use of a specific pharmacological intervention for depression among drug users. A relatively recent meta-analysis on pharmacological treatment of depression among individuals on an opioid agonist for heroin dependence, found low evidence supporting the clinical use of

4.5. Conclusions Despite some limitations, this systematic review and metaanalysis show that depression may be an important factor associated with the risk of non-fatal overdose. Estimate of the pooled association and related subgroup analyses confirmed our hypothesis. Accurate assessment and screening of depression, distinguishing independent disorders from those due to substance misuse, is needed for preventing the excess of overdose (Darke et al., 2003). However, also substance-induced depression has clinical significance and should not be dismissed particularly as a risk period for non-fatal overdose (Aharonovich et al., 2002). Special attention may be needed to prevent non-fatal overdose in such patients, including careful review of the history of suicidal behavior as well as previous treatment of depression. DSM-IV subtypes of depression based on the timing of the occurrence of depression in relation to substance dependence may also be important in

20

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21

evaluating non-fatal overdose risk among drug users suffering from a depressive disorder. Effective pharmacological and psychosocial treatments for depression in drug users may require careful adaptation and implementation because of clinical complexity but also for organizational barriers (Carrà et al., 2008b). Future meta-analyses should be based on longitudinal studies addressed to clarify the role of depression as potential predictor of subsequent non-fatal overdoses. Role of funding source Nothing declared. Contributors Giuseppe Carrà and Massimo Clerici designed the study; Francesco Bartoli and Alex Baldacchino wrote the protocol; Francesco Bartoli, Daniele Carretta and Giulia Brambilla performed the literature systematic search and first screening of articles; Francesco Bartoli and Giuseppe Carrà checked the papers for the definitive eligibility in the meta-analysis; Daniele Carretta and Giulia Brambilla performed the data extraction from included papers and developed the tables with all relative relevant information; Francesco Bartoli and Cristina Crocamo performed the statistical analysis; Cristina Crocamo created the figures; Francesco Bartoli and Giuseppe Carrà wrote the first and the second draft of the manuscript; Alex Baldacchino, Gerry Humphris, Julia Neufeind revised and edited first and second draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest The authors have no conflict of interest in relationship to this paper. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.drugalcdep. 2013.10.007. References Aharonovich, E., Liu, X., Nunes, E., Hasin, D.S., 2002. Suicide attempts in substance abusers: effects of major depression in relation to substance use disorders. Am. J. Psychiatry 159, 1600–1602. Amato, L., Minozzi, S., Davoli, M., Vecchi, S., Ferri, M.M., Mayet, S., 2008. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst. Rev. 4, CD005031. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC (text rev.). American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric Publishing, Arlington, VA. Arendt, M., Munk-Jørgensen, P., Sher, L., Jensen, S.O., 2011. Mortality among individuals with cannabis, cocaine, amphetamine, MDMA, and opioid use disorders: a nationwide follow-up study of Danish substance users in treatment. Drug Alcohol Depend. 114, 134–139. Backmund, M., Schuetz, C., Meyer, K., Edlin, B.R., Reimer, J., 2009. The risk of emergency room treatment due to overdose in injection drug users. J. Addict. Dis. 28, 68–73. Best, D., Gossop, M., Man, L., Finch, E., Greenwood, J., Strang, J., 2000. Accidental and deliberate overdose among opiate addicts in methadone maintenance treatment: are deliberate overdoses systematically different? Drug Alcohol Rev. 19, 213–216. Bohnert, A.S., Roeder, K., Ilgen, M.A., 2010. Unintentional overdose and suicide among substance users: a review of overlap and risk factors. Drug Alcohol Depend. 110, 183–192. Bohnert, A.S., Roeder, K.M., Ilgen, M.A., 2011. Suicide attempts and overdoses among adults entering addictions treatment: comparing correlates in a U.S, National Study. Drug Alcohol Depend. 119, 106–112. Brådvik, L., Frank, A., Hulenvik, P., Medvedeo, A., Berglund, M., 2007. Heroin addicts reporting previous heroin overdoses also report suicide attempts. Suicide Life Threat. Behav. 37, 475–481.

Britton, P.C., Wines Jr., J.D., Conner, K.R., 2010. Non-fatal overdose in the 12 months following treatment for substance use disorders. Drug Alcohol Depend. 107, 51–55. Brugal, M.T., Barrio, G., De La Fuente, L., Regidor, E., Royuela, L., Suelves, J.M., 2002. Factors associated with non-fatal heroin overdose: assessing the effect of frequency and route of heroin administration. Addiction 97, 319–327. Carrà, G., Clerici, M., 2006. Dual diagnosis – policy and practice in Italy. Am. J. Addict. 15, 125–130. Carrà, G., Lusignani, G.S., Sciarini, P., Barale, F., Marinoni, A., Clerici, M., 2008b. And how shall we deal with adaptation and implementation of NICE schizophrenia guidelines in Italy? Epidemiol. Psichiatr. Soc. 17, 258–262. Carrà, G., Johnson, S., 2009. Variations in rates of comorbid substance use in psychosis between mental health settings and geographical areas in the UK. Soc. Psychiatry Psychiatr. Epidemiol. 44, 429–447. Carrà, G., Johnson, S., Bebbington, P., Angermeyer, M.C., Heider, D., Brugha, T., Azorin, J.M., Toumi, M., 2012. The lifetime and past-year prevalence of dual diagnosis in people with schizophrenia across Europe: findings from the European Schizophrenia Cohort (EuroSC). Eur. Arch. Psychiatry Clin. Neurosci. 262, 607–616. Carrà, G., Montomoli, C., Monti, M.C., Clerici, M., 2008a. Does HIV serostatus affect outcomes of dually diagnosed opiate dependents in residential treatment? Epidemiol. Psichiatr. Soc. 17, 77–81. Carrà, G., Scioli, R., Monti, M.C., Marinoni, A., 2006. Severity profiles of substance abusing patients in Italian community addiction facilities: influence of psychiatric concurrent disorders. Eur. Addict. Res. 12, 96–101. Coffin, P.O., Tracy, M., Bucciarelli, A., Ompad, D., Vlahov, D., Galea, S., 2007. Identifying injection drug users at risk of nonfatal overdose. Acad. Emerg. Med. 14, 616–623. Conner, K.R., Pinquart, M., Holbrook, A.P., 2008. Meta-analysis of depression and substance use and impairment among cocaine users. Drug Alcohol Depend. 98, 13–23. Copeland, K.T., Checkoway, H., McMichael, A.J., Holbrook, R.H., 1977. Bias due to misclassification in the estimation of relative risk. Am. J. Epidemiol. 105, 488–495. Cornelius, J.R., Reynolds, M., Martz, B.M., Clark, D.B., Kirisci, L., Tarter, R., 2008. Premature mortality among males with substance use disorders. Addict. Behav. 33, 156–160. Crowther, M., Lim, W., Crowther, M.A., 2010. Systematic review and meta-analysis methodology. Blood 116, 3140–3146. Curran, G.M., Sullivan, G., Williams, K., Han, X., Collins, K., Keys, J., Kotrla, K.J., 2003. Emergency department use of persons with comorbid psychiatric and substance abuse disorders. Ann. Emerg. Med. 41, 659–667. Darke, S., Zador, D., 1996. Fatal heroin ‘overdose’: a review. Addiction 91, 1765–1772. Darke, S., Hall, W., 2003. Heroin overdose: research and evidence-based intervention. J. Urban Health 80, 189–200. Darke, S., Mattick, R.P., Degenhardt, L., 2003. The ratio of non-fatal to fatal heroin overdose. Addiction 98, 1169–1172. Darke, S., Mills, K., Teesson, M., Ross, J., Williamson, A., Havard, A., 2009. Patterns of major depression and drug-related problems amongst heroin users across 36 months. Psychiatry Res. 166, 7–14. Darke, S., Ross, J., 2002. Suicide among heroin users: rates, risk factors and methods. Addiction 97, 1383–1394. Degenhardt, L., Bucello, C., Mathers, B., Briegleb, C., Ali, H., Hickman, M., McLaren, J., 2011. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. Addiction 106, 32–51. Degenhardt, L., Hall, W., Warner-Smith, M., 2006. Using cohort studies to estimate mortality among injecting drug users that is not attributable to AIDS. Sex. Transm. Infect. 82, 56–63. Delgadillo, J., Payne, S., Gilbody, S., Godfrey, C., Gore, S., Jessop, D., Dale, V., 2011. How reliable is depression screening in alcohol and drug users? A validation of brief and ultra-brief questionnaires. J. Affect. Disord. 134, 266–271. Egger, M., Schneider, M., Davey Smith, G., 1998. Spurious precision? Metaanalysis of observational studies. BMJ 316, 140–144. Elkader, A.K., Brands, B., Dunn, E., Selby, P., Sproule, B.A., 2009. Major depressive disorder and patient satisfaction in relation to methadone pharmacokinetics and pharmacodynamics in stabilized methadone maintenance patients. J. Clin. Psychopharmacol. 29, 77–81. Fairbairn, N., Wood, E., Stoltz, J.A., Li, K., Montaner, J., Kerr, T., 2008. Crystal methamphetamine use associated with non-fatal overdose among a cohort of injection drug users in Vancouver. Public Health 122, 70–78. Fendrich, M., Johnson, T.P., Sudman, S., Wislar, J.S., Spiehler, V., 1999. Validity of drug use reporting in a high-risk community sample: a comparison of cocaine and heroin survey reports with hair tests. Am. J. Epidemiol. 149, 955–962. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research. New York State Psychiatric Institute, New York. Fischer, B., Brissette, S., Brochu, S., Bruneau, J., el-Guebaly, N., Noël, L., Rehm, J., Tyndall, M., Wild, C., Mun, P., Haydon, E., Baliunas, D., 2004. Determinants of overdose incidents among illicit opioid users in 5 Canadian cities. CMAJ 171, 235–239. Green, T.C., McGowan, S.K., Yokell, M.A., Pouget, E.R., Rich, J.D., 2012. HIV infection and risk of overdose: a systematic review and meta-analysis. AIDS 26, 403–417. Grimes, D.A., Schulz, K.F., 2002. Bias and causal associations in observational research. Lancet 359, 248–252. Hakansson, A., Schlyter, F., Berglund, M., 2008. Factors associated with history of non-fatal overdose among opioid users in the Swedish criminal justice system. Drug Alcohol Depend. 94, 48–55.

F. Bartoli et al. / Drug and Alcohol Dependence 134 (2014) 12–21 Hasin, D., Liu, X., Nunes, E., McCloud, S., Samet, S., Endicott, J., 2002. Effects of major depression on remission and relapse of substance dependence. Arch. Gen. Psychiatry 59, 375–380. Havens, J.R., Oser, C.B., Knudsen, H.K., Lofwall, M., Stoops, W.W., Walsh, S.L., Leukefeld, C.G., Kral, A.H., 2011. Individual and network factors associated with non-fatal overdose among rural Appalachian drug users. Drug Alcohol Depend. 115, 107–112. Jenkins, L.M., Banta-Green, C.J., Maynard, C., Kingston, S., Hanrahan, M., Merrill, J.O., Coffin, P.O., 2011. Risk factors for nonfatal overdose at Seattle-area syringe exchanges. J. Urban Health 88, 118–128. Jepsen, P., Johnsen, S.P., Gillman, M.W., Sørensen, H.T., 2004. Interpretation of observational studies. Heart 90, 956–960. Kaye, S., Darke, S., 2004. Non-fatal cocaine overdose among injecting and non-injecting cocaine users in Sydney, Australia. Addiction 99, 1315–1322. Kerr, T., Fairbairn, N., Tyndall, M., Marsh, D., Li, K., Montaner, J., Wood, E., 2007. Predictors of non-fatal overdose among a cohort of polysubstance-using injection drug users. Drug Alcohol Depend. 87, 39–45. Kertesz, S.G., Khodneva, Y., Richman, J., Tucker, J.A., Safford, M.M., Jones, B., Schumacher, J., Pletcher, M.J., 2012. Trajectories of drug use and mortality outcomes among adults followed over 18 years. J. Gen. Intern. Med. 27, 808–816. Kinner, S.A., Milloy, M.J., Wood, E., Qi, J., Zhang, R., Kerr, T., 2012. Incidence and risk factors for non-fatal overdose among a cohort of recently incarcerated illicit drug users. Addict. Behav. 37, 691–696. Kraus, L., Augustin, R., Frischer, M., Kümmler, P., Uhl, A., Wiessing, L., 2003. Estimating prevalence of problem drug use at national level in countries of the European Union and Norway. Addiction 98, 471–485. Lemeshow, A.R., Blum, R.E., Berlin, J.A., Stoto, M.A., Colditz, G.A., 2005. Searching one or two databases was insufficient for meta-analysis of observational studies. J. Clin. Epidemiol. 58, 867–873. Loder, E., Groves, T., Macauley, D., 2010. Registration of observational studies. BMJ 340, c950. Maloney, E., Degenhardt, L., Darke, S., Nelson, E.C., 2009. Are non-fatal opioid overdoses misclassified suicide attempts? Comparing the associated correlates. Addict. Behav. 34, 723–729. Mathers, B.M., Degenhardt, L., Bucello, C., Lemon, J., Wiessing, L., Hickman, M., 2013. Mortality among people who inject drugs: a systematic review and metaanalysis. Bull. World Health Organ. 91, 102–123. McGregor, C., Darke, S., Ali, R., Christie, P., 1998. Experience of non-fatal overdose among heroin users in Adelaide, Australia: circumstances and risk perceptions. Addiction 93, 701–711. McIntosh, C., Ritson, B., 2001. Treating depression complicated by substance misuse. Adv. Psychiatr. Treat. 7, 357–364. McLellan, A.T., Luborsky, L., Woody, G.E., O’Brien, C.P., 1980. An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J. Nerv. Ment. Dis. 168, 26–33. Merrall, E.L., Kariminia, A., Binswanger, I.A., Hobbs, M.S., Farrell, M., Marsden, J., Hutchinson, S.J., Bird, S.M., 2010. Meta-analysis of drug-related deaths soon after release from prison. Addiction 105, 1545–1554. Milloy, M.J., Fairbairn, N., Hayashi, K., Suwannawong, P., Kaplan, K., Wood, E., Kerr, T., 2010. Overdose experiences among injection drug users in Bangkok, Thailand. Harm Reduct. J. 7, 9. Mowla, A., Kianpor, M., Bahtoee, M., Sabayan, B., Chohedri, A.H., 2008. Comparison of clinical characteristics of opium-induced and independent major depressive disorder. Am. J. Drug Alcohol Abuse 34, 415–421. Neale, J., 2000. Suicidal intent in non-fatal illicit drug overdose. Addiction 95, 85–93.

21

Pani, P.P., Vacca, R., Trogu, E., Amato, L., Davoli, M., 2010. Pharmacological treatment for depression during opioid agonist treatment for opioid dependence. Cochrane Database Syst. Rev. 9, CD008373. Pedrelli, P., Iovieno, N., Vitali, M., Tedeschini, E., Bentley, K.H., Papakostas, G.I., 2011. Treatment of major depressive disorder and dysthymic disorder with antidepressants in patients with comorbid opiate use disorders enrolled in methadone maintenance therapy: a meta-analysis. J. Clin. Psychopharmacol. 31, 582–586. Phillips, J., Carpenter, K.M., Nunes, E.V., 2004. Suicide risk in depressed methadonemaintained patients: associations with clinical and demographic characteristics. Am. J. Addict. 13, 327–332. Pollini, R.A., McCall, L., Mehta, S.H., Vlahov, D., Strathdee, S.A., 2006. Nonfatal overdose and subsequent drug treatment among injection drug users. Drug Alcohol Depend. 83, 104–110. Ravndal, E., Vaglum, P., 1994. Self-reported depression as a predictor of dropout in a hierarchical therapeutic community. J. Subst. Abuse Treat. 11, 471–479. Regier, D.A., Farmer, M.E., Rae, D.S., Locke, B.Z., Keith, S.J., Judd, L.L., Goodwin, F.K., 1990. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA 264, 2511–2518. Riley, R.D., Higgins, J.P., Deeks, J.J., 2011. Interpretation of random effects metaanalyses. BMJ 342, d549. Rosenberg, S.D., Goodman, L.A., Osher, F.C., Swartz, M.S., Essock, S.M., Butterfield, M.I., Constantine, N.T., Wolford, G.L., Salyers, M.P., 2001. Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am. J. Public Health 91, 31–37. Rossow, I., Lauritzen, G., 1999. Balancing on the edge of death: suicide attempts and life-threatening overdoses among drug addicts. Addiction 94, 209–219. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22–33. Stein, M.D., Herman, D.S., Solomon, D.A., Anthony, J.L., Anderson, B.J., Ramsey, S.E., Miller, I.W., 2004. Adherence to treatment of depression in active injection drug users: the Minerva study. J. Subst. Abuse Treat. 26, 87–93. Stein, M.D., Solomon, D.A., Herman, D.S., Anderson, B.J., Miller, I., 2003. Depression severity and HIV injection risk behaviors. Am. J. Psychiatry 160, 1659–1662. Sterne, J.A.C., Egger, M., Moher, D., 2008. Chapter 10: Addressing reporting biases. In: Higgins, J.P.T., Green, S. (Eds.), Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series. John Wiley & Sons, Ltd, Chichester, UK, Available from www.cochrane-handbook.org (accessed on 13.07.13). Stoové, M.A., Dietze, P.M., Jolley, D., 2009. Overdose deaths following previous non-fatal heroin overdose: record linkage of ambulance attendance and death registry data. Drug Alcohol Rev. 28, 347–352. Stroup, D.F., Berlin, J.A., Morton, S.C., Olkin, I., Williamson, G.D., Rennie, D., Moher, D., Becker, B.J., Sipe, T.A., Thacker, S.B., 2000. Meta-analysis of observational studies in epidemiology: a proposal for reporting, Metaanalysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283, 2008–2012. Warner-Smith, M., Darke, S., Lynskey, M., Hall, W., 2001. Heroin overdose: causes and consequences. Addiction 96, 1113–1125. World Health Organization, 1992. ICD-10 Classifications of Mental and Behavioural Disorder: Clinical Descriptions and Diagnostic Guidelines. World Health Organization, Geneva. World Health Organization, 1993. Composite International Diagnostic Interview (version 1.1). World Health Organization, Geneva.