Abstract
Background Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature. Methods We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992–93 (sample 1), 1996–2000 (sample 2), and 2005–09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates. Findings In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11–3·53) and suicidal ideation (2·47, 1·19–5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation. Interpretation The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors. Funding National Institute on Drug Abuse, National Institutes of Health, Australian National Health and Medical Research Council.
| Original language | English |
|---|---|
| Pages (from-to) | 706-714 |
| Number of pages | 9 |
| Journal | The Lancet Psychiatry |
| Volume | 4 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2017 |
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Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins : a retrospective cohort study. / Agrawal, Arpana; Nelson, Elliot C.; Bucholz, Kathleen K. et al.
In: The Lancet Psychiatry, Vol. 4, No. 9, 09.2017, p. 706-714.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins
T2 - a retrospective cohort study
AU - Agrawal, Arpana
AU - Nelson, Elliot C.
AU - Bucholz, Kathleen K.
AU - Tillman, Rebecca
AU - Grucza, Richard A.
AU - Statham, Dixie J.
AU - Madden, Pamela AF
AU - Martin, Nicholas G.
AU - Heath, Andrew C.
AU - Lynskey, Michael T.
N1 - Funding Information: The research was funded by the National Institute on Drug Abuse (NIDA) with additional support for aspects of data collection and personnel support from the National Institutes of Health (NIH) and the Australian National Health and Medical Research Council (NHMRC). The funders had no role in study design, data collection, data analysis and interpretation, or writing of the study. AA and RT had full access to all data. AA submitted the study for publication. Funding Information: In this large retrospective study using data from three samples taken from the Australian Twin Registry, we found that early and frequent cannabis use were associated with MDD and suicidal thoughts and behaviours, even after controlling for confounders. When these associations were examined within identical twin pairs, frequent use remained associated with MDD and suicidal ideation, suggesting that factors beyond those shared by identical twins might contribute to the association. The similarity in the ORs across dizygotic and monozygotic twin pairs indicates that genetic factors play only a modest role in the association between cannabis involvement and MDD and suicidal thoughts and behaviours, even though previous studies with samples 2 and 3 suggested moderate genetic correlations. 21,22 The importance of the present study lies in our ability to disentangle predisposing factors that are related to genetic liability and early familial environment from environmental factors that are individual specific. Twins who report frequent cannabis use were more likely to report MDD and suicidal ideation than their identical twin who either did not use cannabis or used it less frequently. Unadjusted and adjusted ORs from the discordant pair analyses were similar to the full population, suggesting that the associations might be due to individual-specific factors, possibly of a causal nature. These results are broadly consistent with but more conservative than our previous discordant twin study that made use of data from sample 2 and reported an association between early cannabis use and suicide attempt as well as between cannabis dependence and both suicidal ideation and attempt. 13 However, that study found no evidence for a residual association between MDD and early cannabis use or cannabis dependence in discordant monozygotic pairs. We see an identical null finding for early cannabis use but note that frequent use did increase liability to MDD in these twin pairs, perhaps because of the larger sample size seen in the study reported here. Several mechanisms might explain these associations. Evidence from animal 23 and human studies 24 suggests that the endocannabinoid system might be crucial in modulation of mood, especially in the context of stress. MDD and suicidal ideation were among the adverse side-effects in clinical trials of the endocannabinoid receptor (CB1) inverse agonist. 25,26 Frequent cannabis use might result in similar modifications in the endocannabinoid system and a corresponding increase in negative mood. The strong differences between pairs (ie, concordant frequent vs concordant monozygotic twins who were less frequent users or had never used cannabis) and within pairs (ie, monozygotic discordant pairs who either frequently used cannabis or who used cannabis less frequently or never used cannabis) in rates of suicidal ideation as a function of frequent cannabis use imply that such a direct effect is plausible. For ideation, there was little evidence that the presence of an unexposed twin modified an individual's liability to suicidal ideation, hinting at a potential direct biological effect of cannabis exposure. Alternatively, frequent cannabis use might lead to increased exposure to environmental factors (eg, increased trauma exposure) 27 or outcomes (eg, diminished life opportunities, other drug use) 4 that might also increase the likelihood of MDD and suicidal ideation. For MDD, the twins who used cannabis less frequently than their frequent-use twin were at an increased likelihood of reporting MDD than concordant unexposed twins, suggesting that the environment related to the twin's frequent cannabis use might modify liability to MDD. Accordingly, we cannot discount the possibility that an unmeasured individual-specific factor (eg, deviant peers, other traumas) is contributing to these associations in monozygotic pairs. Causal inferences regarding the effects of frequent cannabis use on the subsequent onset of MDD and suicidal thoughts and behaviours cannot be drawn from these cross-sectional data. Even though we only included individuals with onset of MDD and suicidal thoughts and behaviours subsequent to onset of cannabis use, we might not have adequately accounted for confounders. However, post-hoc analyses found inconsistent associations when this temporal ordering was reversed. We have previously noted that cannabis use is negatively correlated with MDD and suicidal thoughts and behaviours that precede it. 28 On the basis of earlier examinations of the gateway theory, these results support the importance of temporal ordering of onsets, and hint at causal pathways. 29 One strength of the current study is that suicidal ideation and suicide attempt were assessed in all individuals, regardless of their MDD status. Although suicidal thoughts and behaviours are noted to be a feature of MDD, they are also frequently viewed as distinct psychiatric entities that are related, in equal part, to the internalising aspects of mood disorders as well as to externalising behaviours (eg, subtypes of suicide attempt that relate to impulsive aggression). 30–32 Possibly, suicidal thoughts and behaviours are an early index of a broader liability to emotion dysregulation, with a subset of ideators who progress to MDD. Comparisons of MDD and suicidal ideation prevalence across less frequent or never users from concordant and discordant pairs also hint at potential differences (ie, no effect of co-twin status for suicidal ideation). Therefore, the associations between frequent cannabis use, MDD, and suicidal thoughts and behaviours might reflect partly distinct causative processes. Our study has some limitations. First, our sample is restricted to Australians, and sample 1 was older and is likely to represent secular differences. To address this possibility, we excluded the earliest-born members of sample 1 (born in 1902–40). To show the generalisability of the discordant pair analyses, future studies should attempt to validate the model in independent datasets. Second, we were limited by the available cannabis-related variables in the data and could not test for discordance of other indices of cannabis use. Similarly, we were unable to look in a more nuanced way at subgroups of individuals with suicidal ideation and suicide attempt (eg, severity). Third, even though we only studied early-onset behaviours as covariates, some covariates might have occurred subsequent to the onset of cannabis use. In such cases, our covariate correction might be viewed as overly conservative. Fourth, it is possible that interactions between early and frequent use are more strongly related to MDD and suicidal thoughts and behaviours than either measure is alone. Studies of larger samples might be able to model such interaction effects within a discordant twin framework. Fifth, to create discordant pairs, we selected thresholds to represent early and frequent use. Although our choice of age and frequency cutoffs might have influenced our estimates, results were consistent with post-hoc analyses of continuous discordance in frequency of use. Finally, even though our discordant monozygotic twin design is powerful in excluding possible causal explanations, it cannot be used to prove causation. On the basis of these results, we are unable to exclude the possibility that frequent cannabis use might increase risks for MDD and suicidal ideation, independent of shared predisposing influences. Although we cannot identify the nature of this increased susceptibility, such a persisting increase in likelihood of MDD and suicidal ideation in frequent cannabis users is important to consider, especially against the backdrop of evidence supporting a role of the endocannabinoid system in mood regulation. However, interventions aiming to curb cannabis use should form only one part of the broader strategies to reduce its mental health correlates. Risk and protective influences that encourage cannabis use in one individual but not their sibling can also exacerbate their liability to MDD or suicidal thoughts and behaviours, and the identification of such factors that generate discordance in cannabis use within twin pairs is of considerable importance. Contributors AA and MTL conceived the study. AA and RT analysed all data. AA was responsible for writing the first draft of the manuscript. ECN, KKB, RAG, DJS, ACH, and MTL provided expertise on the analytical model, choice of outcomes, and covariates. PAFM, DJS, NGM, ACH, and MTL developed instruments, and collected, processed, and coded all data. Declaration of interests AA and RAG have received NIH funding and compensation for grant reviews for NIH outside the submitted work. All other authors declare no competing interests. Acknowledgments The analyses outlined in this study are supported by funds from the National Institute on Drug Abuse (NIDA) grants R01DA040411 and K02DA032573 . Additional support for data collection was via National Institutes of Health grants: AA07728, AA10248, AA13321, AA09022, AA10249, AA11998 (ACH), and DA18267 (MTL) . Data collection was also supported by the National Health and Medical Research Council via 628911, 951023, and 981351 . ACH acknowledges AA017688; NGM acknowledges support from the Australian NHMRC Centre for Research Excellence on Suicide Prevention (CRESP). Funding sources were not involved in any aspect of the current research. Publisher Copyright: © 2017 Elsevier Ltd
PY - 2017/9
Y1 - 2017/9
N2 - Background Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature. Methods We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992–93 (sample 1), 1996–2000 (sample 2), and 2005–09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates. Findings In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11–3·53) and suicidal ideation (2·47, 1·19–5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation. Interpretation The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors. Funding National Institute on Drug Abuse, National Institutes of Health, Australian National Health and Medical Research Council.
AB - Background Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature. Methods We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992–93 (sample 1), 1996–2000 (sample 2), and 2005–09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates. Findings In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11–3·53) and suicidal ideation (2·47, 1·19–5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation. Interpretation The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors. Funding National Institute on Drug Abuse, National Institutes of Health, Australian National Health and Medical Research Council.
UR - http://www.scopus.com/inward/record.url?scp=85025584828&partnerID=8YFLogxK
U2 - 10.1016/S2215-0366(17)30280-8
DO - 10.1016/S2215-0366(17)30280-8
M3 - Article
C2 - 28750823
AN - SCOPUS:85025584828
SN - 2215-0366
VL - 4
SP - 706
EP - 714
JO - The Lancet Psychiatry
JF - The Lancet Psychiatry
IS - 9
ER -