Author’s Accepted Manuscript Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study Daniel Feingold, Jürgen Rehm, Shaul Lev-Ran www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(16)31187-8 http://dx.doi.org/10.1016/j.psychres.2017.02.027 PSY10321
To appear in: Psychiatry Research Received date: 17 July 2016 Revised date: 8 December 2016 Accepted date: 11 February 2017 Cite this article as: Daniel Feingold, Jürgen Rehm and Shaul Lev-Ran, Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2017.02.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study
Daniel Feingolda,b,*, Jürgen Rehmc,d,e and Shaul Lev-Ranb,c,f a
Ariel University, Ariel, Israel.
b2
Lev-Hasharon Medical Center, Pardesiya, Israel.
c
Social and Epidemiological Research Department, Centre for Addiction and Mental Health,
Toronto, Ontario, Canadad d
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
e
Technische Universität Dresden, Klinische Psychologie & Psychotherapie, Dresden, Germany
f
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
* Corresponding author at Lev-Hasharon Medical Center, Pardesiya, Israel. Mail address: Pardesiya, PO box 90000, Israel. Telephone: 972-(0)98981111 Email: [email protected]
Abstract Cannabis use has been reported to affect the course of various psychiatric disorders, however its effect on the course of major depressive disorder (MDD) is not yet clear. We used data from Wave 1 and Wave 2 of the National Epidemiologic survey on Alcohol and Related Conditions (NESARC). Individuals with baseline MDD (N=2,348) were included in the study. Cannabis
users without a Cannabis Use Disorder (CUDs) and individuals with a CUD were compared to nonusers using linear and logistic regression analyses controlling for sociodemographics, psychiatric disorders and substance use disorders at baseline. No differences were found in rates of remission between the groups. Level of cannabis use was associated with significantly more depressive symptoms at follow-up, particularly anhedonia, changes in body weight, insomnia or hypersomnia and psychomotor problems. After adjusting for baseline confounding factors, no associations were found between cannabis use and suicidality, functionality and quality of life. We conclude that many of the associations between cannabis use and a more severe course of MDD do not seem to be attributed to cannabis use itself but to associated sociodemographic and clinical factors. Further longitudinal studies using depression severity indices are required.
Keywords: Marijuana; Cannabis use Disorder; Depression; Course of illness; Suicidality; Symptoms; Quality of life
1. Introduction Following tobacco and alcohol, cannabis is the most widely used drug in the world (United Nations Office on Drugs and Crime, 2012) with an estimated 5% prevalence of past-year use, representing up to 200 million annual users worldwide (Degenhardt et al., 2011). Research in the past decade has pointed to the contribution of the human endo-cannabinoid system to the onset and course of various psychiatric disorders (Carvalho and Van Bockstaele, 2012). Extensive epidemiological research has supported the notion that cannabis use, and especially heavy use, may be associated with an increased risk for developing a psychotic disorder including schizophrenia (Moore et al., 2007; WHO, 2016). Moreover, it has been reported that
cannabis use may affect the course of such disorders, leading to earlier onset, higher severity and longer persistence of psychotic disorders as well as more frequent psychotic relapses over time (Foti et al., 2010; Grech et al., 2005; Linszen et al., 1994; Whiteford et al., 2013). Cannabis use may also alter the course of additional psychiatric disorders. Individuals who used cannabis were more prone to have earlier onset of panic attacks (Zvolensky et al., 2006), elevated intensity of anxiety symptoms during panic attacks (Szuster et al., 1988) and increased sensitivity to anxiety symptoms (Buckner et al., 2009). A meta-analysis suggested that among individuals diagnosed with bipolar disorder, cannabis users were approximately threetimes more prone to experience a recurring manic episode compared to nonusers (Gibbs et al., 2014). Furthermore, individuals diagnosed with bipolar disorder and co-occurring cannabis use were reported to have more depressive and manic/hypomanic episodes per year (Lev-Ran et al., 2013a), longer duration of mixed and manic episodes (Strakowski et al., 2007) and poorer life functioning (Agrawal et al., 2011) compared to nonusers. However, the effect of cannabis use on the course and outcome of depression is less clear. Major depressive disorder (MDD) is a common psychiatric disorder which contributes significantly to the global burden of disease (Whiteford et al., 2013). Several cross-sectional studies revealed strong co-occurrence between cannabis use and psychopathology (such as posttraumatic stress disorder (Kevorkian et al., 2015)), and specifically between cannabis use and depression, indicating high prevalence of cannabis use among individuals with depression and vice-versa (Chen et al., 2002; Grant, 1995). Longitudinal studies have reported conflicting results; while several longitudinal studies reported that cannabis users were more prone to develop depression at follow-up compared to nonusers (Bovasso, 2001; Gage et al., 2015; Pacek et al., 2013), others reported no significant association (Danielsson et al., 2015). An integrative
study conducted by Horwood et al. (2012) explored the extent to which cannabis use consistently predicts the onset of depressive symptoms in four Australian cohorts. Controlling for possible confounding effects, analyses revealed a significant dose-response effect between cannabis use and latter onset of depressive symptoms, with evidence indicating that this effect may be strongest in mid-adolescence and weaker in mature adulthood. In a meta-analysis conducted by Lev-Ran et al. (2013) the authors concluded that cannabis use, and particularly heavy use, may be associated with moderate yet significant increased risk for developing depression. It has been argued that the discrepancy in longitudinal evidence concerning cannabis use and depression is caused by inconsistent measuring of cannabis use and depression as well as lack of sufficient control for confounding factors (Lev-Ran et al., 2013c). In addition, CUDs may be associated with MDD in a substantially different way than cannabis use per se, as Substance Use Disorders (SUDs) and MDD presumably share common mechanisms and manifestations, including clinical similarities and neurobiological pathways and abnormalities (Brady and Sinha, 2005). Recently Feingold et al. (2015) reported that after controlling for various confounding factors, including sociodemographic variables and additional psychiatric and substance use disorders among individuals without lifetime MDD, baseline cannabis use, even daily use, was not associated with increased risk for onset of MDD at follow-up compared to nonusers. Inversely, after controlling for confounding variables among lifetime cannabis abstainers, individuals with baseline MDD were at a significantly increased risk to initiate cannabis use at follow-up (Feingold. et al., 2015). However specific effects of cannabis use on the outcome of MDD are not clear. It has been reported that among individuals with MDD cannabis use may be associated with a significantly elevated feeling of dysphoria (Ablon and Goodwin, 1974) and an incline in
number of depressive symptoms (Otten and Engels, 2013). There is evidence suggesting that cannabis use, and particularly frequent use, may reduce the efficiency of pharmacological treatment for depressive symptoms (Bricker et al., 2007). Additional cross-sectional research indicates potentially lower self-reported quality of life (QoL) among individuals with MDD who use cannabis frequently, compared to nonusers (Aspis et al., 2015). Nevertheless, longitudinal data on the effect of cannabis use on the severity and course of depression is lacking. In this study we sought to explore the effect of cannabis use and Cannabis Use Disorders (CUDs) on the course and outcome of MDD over a three-year period. Course of illness and outcome were assessed using rates of remission, depressive symptomology, suicidality measures, treatment utilization, measures of impairment in social, occupational and educational functioning and self-reported mental QoL. We hypothesized that cannabis use and CUD are associated with poorer outcome of MDD, as manifested by increased depressive symptoms, more significant impairment and lower QoL.
2. Methods 2.1. Participants We used data from the National Epidemiologic survey on Alcohol and Related Conditions (NESARC), a national representative survey designed by the National Institute on Alcohol Abuse and Alcoholism (Grant et al., 2008). The NESARC is a longitudinal survey which targeted non-institutionalized adults living in the United States, including military personnel living off-base and those in group housing (e.g. college dormitories, shelters). Wave 1 of the NESARC was conducted at 2001-2002 including a sample of 43,093 participants 18 years of age and over (Grant et al., 2003b). Wave 2 was conducted at 2003-2004 comprising 34,653 of
the Wave 1 respondents, which represent a response rate of 86.7% of eligible respondents (Grant and Kaplan, 2005). The NESARC protocol was approved by the US Census Bureau and the US Office of Budget and Management, and this study was approved by the institutional IRB. More comprehensive accounts of the NESARC database can be found elsewhere (Grant and Kaplan, 2005; Grant et al., 2003b). We selected a subgroup of individuals who qualified for a past-year diagnosis of MDD at Wave 1 and also participated in Wave 2 (N=2,348).
2.2. Measures Substance use and substance use disorders, as well as additional psychiatric disorders, were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule — DSM-IV Version (AUDADIS-IV) (Grant et al., 2003a). The AUDADIS-IV includes a list of symptom questions that operationalizes DSM-IV criteria for SUDs and additional axis I and axis II diagnoses. It has been reported to have excellent reliability and validity in the United States (Cottler et al., 1997; Grant et al., 2003a; Hasin et al., 1997; Pull et al., 1997) and internationally (Chatterji et al., 1997; Vrasti et al., 1998), test-retest reliability of the AUDADIS-IV has previously ranked excellent for alcohol (k=0.74) and drug (k=0.79) use disorders (Grant et al., 2005) and good for MDD (k=0.64) (Grant et al., 2004). 2.2.1. Major Depressive Disorder Past-year MDD at Wave 1 and Wave 2 were defined as presence of at least five out of nine symptoms during the same two-week period in the last 12 months, as diagnosed according to DSM-IV-TR criteria (American Psychiatric Association, 2000). MDD symptoms included the following: depressed mood, anhedonia, significant change in body weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or guilt, diminished ability to think or concentrate and recurrent thoughts of death. In this study only primary psychiatric disorders were included and all cases of substance-induced mental disorders were excluded (Grant et al., 2004). 2.2.2. Cannabis use and CUDs Respondents were asked about cannabis use in the time period between Wave 1 and Wave 2. In this study cannabis users were defined as those who reported using cannabis during this time period but did not qualify for a diagnosis of a CUD ("users, no CUD"). Individuals were designated as having a CUD if they qualified for a diagnosis of a CUD (abuse or dependence), as defined according to DSM-IV in the time period between Wave 1 and Wave 2. In all analyses, each of these two groups (users, no CUD and CUD) was compared to individuals reporting no use of cannabis throughout this time period (‘nonusers’). Frequency of use was based on self-report ranging from "every day" to "once a year".
2.2.3. Outcome Measures Course of illness and outcome in depression can be defined using various factors including recurrence, persistence, suicidality and various self-reported severity scales (Elhai et al., 2013; Nanni et al., 2012). In this study course of illness was assessed using measures of recurrence vs. remission, number of depressive symptoms, measures of suicidality, measures indicating impairment in social, occupational and educational functioning (being fired from work, having trouble with boss or coworker, getting divorced or separated, quitting school more than once), treatment utilization rates and self-reported mental QoL. The NESARC study does not include the DSM-IV severity specifier for MDD (American Psychiatric Association, 2000), therefore in line with other formal severity scales we used the number of depressive symptoms as
a severity measure (Hamilton, 1960; Kroenke et al., 2001). Remission from MDD was defined as not meeting criteria of MDD diagnosis in the twelve months prior to Wave 2 among individuals who met the diagnostic criteria at Wave 1. Number of depressive symptoms and prevalence of specific symptoms in the twelve months prior to Wave 2 were assessed and compared between groups. Health related QoL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12), a short and efficient format of the SF Health Survey. This is a self-reported questionnaire addressing various aspects of QoL including emotional, physical, social and work related issues which has been shown to be particularly valid and useful in large sample studies (Ware et al., 1996) and described in detail elsewhere (Aspis et al., 2015).
2.2.4. Confounding factors As baseline differences between groups may affect the course of MDD, the following baseline confounding factors were controlled for in the analyses: sociodemographic variables (Piccinelli and Wilkinson, 2000), additional past-year occurrence (i.e. any occurrence in the 12 months prior to Wave 1) of psychiatric disorders (Penninx et al., 2011) and past-year occurrence of SUDs (excluding CUD) (Sullivan et al., 2005; Swendsen and Merikangas, 2000). Additionally, in each analysis outcome variable present at baseline (i.e., in the twelve months prior to Wave 1) were controlled for in order to take into account possible preliminary differences that may increase the risk for consequent recurrence (Suominen et al., 2004).
2.3. Analytic Strategy
Cross-tabulations were conducted in order to explore baseline socio-demographic and clinical characteristics of respondents in the different categories (nonusers, users, CUD) and chisquare analyses were performed in order to explore differences in these characteristic, comparing cannabis users and individuals with CUDs to nonusers. In cases of continuous outcome measures (number of depressive symptoms, QoL) we used linear regression analyses in order to explore the association between level of cannabis use (no use, use,no CUD, CUD) and specific outcome measures. In cases of binary outcome measure (presence of specific depressive symptoms, suicidality measures, measures indicating impairment in social, occupational and educational functioning and treatment utilization) multivariate logistic regression analyses were used. In all analyses, progressive models of adjustment were used in order to compare cannabis users and individuals with CUDs to nonusers. Independent sample t-tests (two-tailed) we used for comparison of baseline QoL measures between groups. Bonferroni correction was used according to clusters of analyses and p
PII: DOI: Reference:
S0165-1781(16)31187-8 http://dx.doi.org/10.1016/j.psychres.2017.02.027 PSY10321
To appear in: Psychiatry Research Received date: 17 July 2016 Revised date: 8 December 2016 Accepted date: 11 February 2017 Cite this article as: Daniel Feingold, Jürgen Rehm and Shaul Lev-Ran, Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2017.02.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study
Daniel Feingolda,b,*, Jürgen Rehmc,d,e and Shaul Lev-Ranb,c,f a
Ariel University, Ariel, Israel.
b2
Lev-Hasharon Medical Center, Pardesiya, Israel.
c
Social and Epidemiological Research Department, Centre for Addiction and Mental Health,
Toronto, Ontario, Canadad d
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
e
Technische Universität Dresden, Klinische Psychologie & Psychotherapie, Dresden, Germany
f
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
* Corresponding author at Lev-Hasharon Medical Center, Pardesiya, Israel. Mail address: Pardesiya, PO box 90000, Israel. Telephone: 972-(0)98981111 Email: [email protected]
Abstract Cannabis use has been reported to affect the course of various psychiatric disorders, however its effect on the course of major depressive disorder (MDD) is not yet clear. We used data from Wave 1 and Wave 2 of the National Epidemiologic survey on Alcohol and Related Conditions (NESARC). Individuals with baseline MDD (N=2,348) were included in the study. Cannabis
users without a Cannabis Use Disorder (CUDs) and individuals with a CUD were compared to nonusers using linear and logistic regression analyses controlling for sociodemographics, psychiatric disorders and substance use disorders at baseline. No differences were found in rates of remission between the groups. Level of cannabis use was associated with significantly more depressive symptoms at follow-up, particularly anhedonia, changes in body weight, insomnia or hypersomnia and psychomotor problems. After adjusting for baseline confounding factors, no associations were found between cannabis use and suicidality, functionality and quality of life. We conclude that many of the associations between cannabis use and a more severe course of MDD do not seem to be attributed to cannabis use itself but to associated sociodemographic and clinical factors. Further longitudinal studies using depression severity indices are required.
Keywords: Marijuana; Cannabis use Disorder; Depression; Course of illness; Suicidality; Symptoms; Quality of life
1. Introduction Following tobacco and alcohol, cannabis is the most widely used drug in the world (United Nations Office on Drugs and Crime, 2012) with an estimated 5% prevalence of past-year use, representing up to 200 million annual users worldwide (Degenhardt et al., 2011). Research in the past decade has pointed to the contribution of the human endo-cannabinoid system to the onset and course of various psychiatric disorders (Carvalho and Van Bockstaele, 2012). Extensive epidemiological research has supported the notion that cannabis use, and especially heavy use, may be associated with an increased risk for developing a psychotic disorder including schizophrenia (Moore et al., 2007; WHO, 2016). Moreover, it has been reported that
cannabis use may affect the course of such disorders, leading to earlier onset, higher severity and longer persistence of psychotic disorders as well as more frequent psychotic relapses over time (Foti et al., 2010; Grech et al., 2005; Linszen et al., 1994; Whiteford et al., 2013). Cannabis use may also alter the course of additional psychiatric disorders. Individuals who used cannabis were more prone to have earlier onset of panic attacks (Zvolensky et al., 2006), elevated intensity of anxiety symptoms during panic attacks (Szuster et al., 1988) and increased sensitivity to anxiety symptoms (Buckner et al., 2009). A meta-analysis suggested that among individuals diagnosed with bipolar disorder, cannabis users were approximately threetimes more prone to experience a recurring manic episode compared to nonusers (Gibbs et al., 2014). Furthermore, individuals diagnosed with bipolar disorder and co-occurring cannabis use were reported to have more depressive and manic/hypomanic episodes per year (Lev-Ran et al., 2013a), longer duration of mixed and manic episodes (Strakowski et al., 2007) and poorer life functioning (Agrawal et al., 2011) compared to nonusers. However, the effect of cannabis use on the course and outcome of depression is less clear. Major depressive disorder (MDD) is a common psychiatric disorder which contributes significantly to the global burden of disease (Whiteford et al., 2013). Several cross-sectional studies revealed strong co-occurrence between cannabis use and psychopathology (such as posttraumatic stress disorder (Kevorkian et al., 2015)), and specifically between cannabis use and depression, indicating high prevalence of cannabis use among individuals with depression and vice-versa (Chen et al., 2002; Grant, 1995). Longitudinal studies have reported conflicting results; while several longitudinal studies reported that cannabis users were more prone to develop depression at follow-up compared to nonusers (Bovasso, 2001; Gage et al., 2015; Pacek et al., 2013), others reported no significant association (Danielsson et al., 2015). An integrative
study conducted by Horwood et al. (2012) explored the extent to which cannabis use consistently predicts the onset of depressive symptoms in four Australian cohorts. Controlling for possible confounding effects, analyses revealed a significant dose-response effect between cannabis use and latter onset of depressive symptoms, with evidence indicating that this effect may be strongest in mid-adolescence and weaker in mature adulthood. In a meta-analysis conducted by Lev-Ran et al. (2013) the authors concluded that cannabis use, and particularly heavy use, may be associated with moderate yet significant increased risk for developing depression. It has been argued that the discrepancy in longitudinal evidence concerning cannabis use and depression is caused by inconsistent measuring of cannabis use and depression as well as lack of sufficient control for confounding factors (Lev-Ran et al., 2013c). In addition, CUDs may be associated with MDD in a substantially different way than cannabis use per se, as Substance Use Disorders (SUDs) and MDD presumably share common mechanisms and manifestations, including clinical similarities and neurobiological pathways and abnormalities (Brady and Sinha, 2005). Recently Feingold et al. (2015) reported that after controlling for various confounding factors, including sociodemographic variables and additional psychiatric and substance use disorders among individuals without lifetime MDD, baseline cannabis use, even daily use, was not associated with increased risk for onset of MDD at follow-up compared to nonusers. Inversely, after controlling for confounding variables among lifetime cannabis abstainers, individuals with baseline MDD were at a significantly increased risk to initiate cannabis use at follow-up (Feingold. et al., 2015). However specific effects of cannabis use on the outcome of MDD are not clear. It has been reported that among individuals with MDD cannabis use may be associated with a significantly elevated feeling of dysphoria (Ablon and Goodwin, 1974) and an incline in
number of depressive symptoms (Otten and Engels, 2013). There is evidence suggesting that cannabis use, and particularly frequent use, may reduce the efficiency of pharmacological treatment for depressive symptoms (Bricker et al., 2007). Additional cross-sectional research indicates potentially lower self-reported quality of life (QoL) among individuals with MDD who use cannabis frequently, compared to nonusers (Aspis et al., 2015). Nevertheless, longitudinal data on the effect of cannabis use on the severity and course of depression is lacking. In this study we sought to explore the effect of cannabis use and Cannabis Use Disorders (CUDs) on the course and outcome of MDD over a three-year period. Course of illness and outcome were assessed using rates of remission, depressive symptomology, suicidality measures, treatment utilization, measures of impairment in social, occupational and educational functioning and self-reported mental QoL. We hypothesized that cannabis use and CUD are associated with poorer outcome of MDD, as manifested by increased depressive symptoms, more significant impairment and lower QoL.
2. Methods 2.1. Participants We used data from the National Epidemiologic survey on Alcohol and Related Conditions (NESARC), a national representative survey designed by the National Institute on Alcohol Abuse and Alcoholism (Grant et al., 2008). The NESARC is a longitudinal survey which targeted non-institutionalized adults living in the United States, including military personnel living off-base and those in group housing (e.g. college dormitories, shelters). Wave 1 of the NESARC was conducted at 2001-2002 including a sample of 43,093 participants 18 years of age and over (Grant et al., 2003b). Wave 2 was conducted at 2003-2004 comprising 34,653 of
the Wave 1 respondents, which represent a response rate of 86.7% of eligible respondents (Grant and Kaplan, 2005). The NESARC protocol was approved by the US Census Bureau and the US Office of Budget and Management, and this study was approved by the institutional IRB. More comprehensive accounts of the NESARC database can be found elsewhere (Grant and Kaplan, 2005; Grant et al., 2003b). We selected a subgroup of individuals who qualified for a past-year diagnosis of MDD at Wave 1 and also participated in Wave 2 (N=2,348).
2.2. Measures Substance use and substance use disorders, as well as additional psychiatric disorders, were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule — DSM-IV Version (AUDADIS-IV) (Grant et al., 2003a). The AUDADIS-IV includes a list of symptom questions that operationalizes DSM-IV criteria for SUDs and additional axis I and axis II diagnoses. It has been reported to have excellent reliability and validity in the United States (Cottler et al., 1997; Grant et al., 2003a; Hasin et al., 1997; Pull et al., 1997) and internationally (Chatterji et al., 1997; Vrasti et al., 1998), test-retest reliability of the AUDADIS-IV has previously ranked excellent for alcohol (k=0.74) and drug (k=0.79) use disorders (Grant et al., 2005) and good for MDD (k=0.64) (Grant et al., 2004). 2.2.1. Major Depressive Disorder Past-year MDD at Wave 1 and Wave 2 were defined as presence of at least five out of nine symptoms during the same two-week period in the last 12 months, as diagnosed according to DSM-IV-TR criteria (American Psychiatric Association, 2000). MDD symptoms included the following: depressed mood, anhedonia, significant change in body weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or guilt, diminished ability to think or concentrate and recurrent thoughts of death. In this study only primary psychiatric disorders were included and all cases of substance-induced mental disorders were excluded (Grant et al., 2004). 2.2.2. Cannabis use and CUDs Respondents were asked about cannabis use in the time period between Wave 1 and Wave 2. In this study cannabis users were defined as those who reported using cannabis during this time period but did not qualify for a diagnosis of a CUD ("users, no CUD"). Individuals were designated as having a CUD if they qualified for a diagnosis of a CUD (abuse or dependence), as defined according to DSM-IV in the time period between Wave 1 and Wave 2. In all analyses, each of these two groups (users, no CUD and CUD) was compared to individuals reporting no use of cannabis throughout this time period (‘nonusers’). Frequency of use was based on self-report ranging from "every day" to "once a year".
2.2.3. Outcome Measures Course of illness and outcome in depression can be defined using various factors including recurrence, persistence, suicidality and various self-reported severity scales (Elhai et al., 2013; Nanni et al., 2012). In this study course of illness was assessed using measures of recurrence vs. remission, number of depressive symptoms, measures of suicidality, measures indicating impairment in social, occupational and educational functioning (being fired from work, having trouble with boss or coworker, getting divorced or separated, quitting school more than once), treatment utilization rates and self-reported mental QoL. The NESARC study does not include the DSM-IV severity specifier for MDD (American Psychiatric Association, 2000), therefore in line with other formal severity scales we used the number of depressive symptoms as
a severity measure (Hamilton, 1960; Kroenke et al., 2001). Remission from MDD was defined as not meeting criteria of MDD diagnosis in the twelve months prior to Wave 2 among individuals who met the diagnostic criteria at Wave 1. Number of depressive symptoms and prevalence of specific symptoms in the twelve months prior to Wave 2 were assessed and compared between groups. Health related QoL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12), a short and efficient format of the SF Health Survey. This is a self-reported questionnaire addressing various aspects of QoL including emotional, physical, social and work related issues which has been shown to be particularly valid and useful in large sample studies (Ware et al., 1996) and described in detail elsewhere (Aspis et al., 2015).
2.2.4. Confounding factors As baseline differences between groups may affect the course of MDD, the following baseline confounding factors were controlled for in the analyses: sociodemographic variables (Piccinelli and Wilkinson, 2000), additional past-year occurrence (i.e. any occurrence in the 12 months prior to Wave 1) of psychiatric disorders (Penninx et al., 2011) and past-year occurrence of SUDs (excluding CUD) (Sullivan et al., 2005; Swendsen and Merikangas, 2000). Additionally, in each analysis outcome variable present at baseline (i.e., in the twelve months prior to Wave 1) were controlled for in order to take into account possible preliminary differences that may increase the risk for consequent recurrence (Suominen et al., 2004).
2.3. Analytic Strategy
Cross-tabulations were conducted in order to explore baseline socio-demographic and clinical characteristics of respondents in the different categories (nonusers, users, CUD) and chisquare analyses were performed in order to explore differences in these characteristic, comparing cannabis users and individuals with CUDs to nonusers. In cases of continuous outcome measures (number of depressive symptoms, QoL) we used linear regression analyses in order to explore the association between level of cannabis use (no use, use,no CUD, CUD) and specific outcome measures. In cases of binary outcome measure (presence of specific depressive symptoms, suicidality measures, measures indicating impairment in social, occupational and educational functioning and treatment utilization) multivariate logistic regression analyses were used. In all analyses, progressive models of adjustment were used in order to compare cannabis users and individuals with CUDs to nonusers. Independent sample t-tests (two-tailed) we used for comparison of baseline QoL measures between groups. Bonferroni correction was used according to clusters of analyses and p
