To investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders.
The 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months.
Of the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group.
Cannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.
Cannabis use is common in psychiatric populations;
Previous studies of bipolar disorder have found that cannabis use is more frequent in males than in females.
Our 24-month prospective study investigated the impact of cannabis use on the clinical course of patients with bipolar spectrum disorders with a focus on long-term remission of mood symptoms according to gender and type of medication. The present study analyzed data from the Bipolar Comprehensive Outcomes Study (BCOS),
The rationale and design of the BCOS have been detailed previously.
Diagnoses were confirmed by the Mini-International Neuropsychiatric Interview (MINI) version
The primary outcome measure of this study was the rate of achieving remission over the nine evaluation points (number of remissions/9) during the 24 months. Missing data resulting from non-visits were operationally defined as indicative of non-remission. Symptomatic remission was defined as a Young Mania Rating Scale (YMRS)
Our key independent variable was cannabis use. Participants were questioned about cannabis use at visit 1 using the Habits form.
Sociodemographic and clinical variables of the cannabis user and non-user groups were compared using independent chi-squared tests, t-tests, or Mann-Whitney U-tests as appropriate. The effect of cannabis use on total, 21-item Hamilton Depression Rating Scale (HAMD-21), and the Young Mania Rating Scale (YMRS) remission rates during the 24-month follow-up period were compared using the Mann-Whitney U-test. Additionally, comparisons were made across gender and medication type. Spearman's correlation test was used to assess the relationship between age and remission rates. In order to explore the effect of tobacco smoking on remission rate, the participants were divided into three subgroups: concurrent cannabis and tobacco smoking, tobacco smoking only, and non-smoking. Remission rates among the three groups were compared using the Kruskal-Wallis test and post hoc paired comparisons were conducted using the Mann-Whitney U-test with the Bonferroni correction. Statistical significance was defined as p-values of ≤0.05. All statistical tests were two tailed.
A total of 239 participants were enrolled in the BCOS study. We were unable to obtain information on cannabis use from 5 of the 239 participants. Of the 234 participants whose data were analyzed, 213 (91.0%) completed the 24-month study. The mean age of participants was 41.8±12.7 years and 59.4% were female. A total of 172 participants were diagnosed with bipolar I disorder and 62 were diagnosed with schizoaffective disorder, bipolar type.
Sociodemographic and clinical characteristics were compared according to cannabis use (
The Spearman's correlation coefficients revealed no significant difference between age and total (rho=0.066; p=0.312), HAMD-21 (rho=0.065; p=0.314), or YMRS (rho=0.102; p=0.114) remission rates.
The analysis of remission rates in cannabis users and non-users across gender and medication type revealed that cannabis use was significantly associated with lower total remission and HAMD-21 remission rates in females (n=139), whereas it was significantly associated with lower YMRS, but not HAMD-21, remission rates in males (n=95). Cannabis use was significantly associated with lower total remission and HAMD-21 remission rates among patients who were prescribed mood stabilizers alone (n=151); however, cannabis use was significantly associated with lower YMRS remission rates in patients who took olanzapine and/or mood stabilizers (n=83).
Our findings show that cannabis use is associated with decreased likelihood of long-term remission in bipolar spectrum disorders. In particular, we observed interaction effects of cannabis use and mood symptoms on gender and medication type. That is, cannabis use was associated with lower remission rates for depressive symptoms in females and for manic symptoms in males. Moreover, remission rates for depressive symptoms were lower in cannabis users prescribed mood stabilizers alone, whereas remission rates for manic symptoms were lower in cannabis users prescribed olanzapine. To our knowledge, this study is the first to demonstrate differing effects of cannabis use on polarity specific long-term remission rates (24-month period) according to gender and type of medication in patients with bipolar spectrum disorders.
A few studies have demonstrated an association between cannabis use and severe manic symptoms, but not depression, in patients with bipolar disorder.
Our finding of an association between cannabis use and lower remission rates for depressive symptoms in females supports a previous study showing that cannabis use in teenage girls, but not boys, predicted high rates of depression.
Cannabis may diminish the effect of medications used to treat bipolar spectrum disorders. Our results showed that olanzapine was associated with lower remission rates for manic symptoms in patients with bipolar spectrum disorder who were cannabis users. Investigations into the effect of cannabis on the inhibition and induction of human liver cytochrome P450 (CYP450) isoforms generally reflect a low risk of clinically significant drug interactions with most use, although
A high rate of co-use of cannabis with tobacco smoking and alcohol use has been observed in patients with bipolar and other psychiatric disorders.
Substance use disorders including cannabis use often go unrecognized or are viewed as a secondary problem in psychiatric treatment settings.
Our study has several limitations that should be considered when interpreting our results. First, cannabis use was investiinvestigated only cross-sectionally and there was no longitudinal evaluation. Regular checks on cannabis use in patients with bipolar spectrum disorders would provide more information about longitudinal outcomes. In addition, the investigation of the relative sequence of cannabis use onset and bipolar disorder onset would provide a deeper understanding of the complex associations between these two conditions. Second, the potential impact of concomitant psychosocial therapies on the outcomes was not evaluated in this study. Third, HAMD-21 and YMRS scores were used to evaluate symptoms in the week prior to the assessment visit. Given the fluctuating course of symptoms, this timing may not adequately reflect the symptoms across the 3-month interval between visits. However, the 2-year prospective observation period provided an extended period of observation that enabled examination of the fluctuating course of illnesses and outcomes. Finally, our sample and setting might have resulted in selection bias and unmeasured confounding variables. In addition, the quality of treatment was not controlled strictly in this study. However, our prospective, pragmatic study design, high 2-year retention rate, and inclusion of patients at all levels of symptom severity and treatment allows for broad generalizability.
In conclusion, regular cannabis use has a negative effect on the clinical course of bipolar spectrum disorders. Individuals with bipolar spectrum disorders who are regular cannabis users are a vulnerable population.
The Bipolar Comprehensive Outcomes Study (BCOS) was funded by an unconditional research grant provided by Eli Lilly Australia. Lilly had no role in the collection, analysis, interpretation of data, the writing of the report, and in the decision to submit the paper for publication.
SWK is supported by Research Institute of Medical Sciences, Chonnam National University, Korea. LB is supported by an Alfred Deakin Postdoctoral Research Fellowship. PBF is supported by an NHMRC Practitioner Fellowship (606907). MB is supported by a NHMRC Senior Principal Research Fellowship (1059660).
*p<0.05. SD: standard deviation, HAMD-21: 21-item Hamilton Depression Rating Scale, YMRS: Young Mania Rating Scale, IQR: interquartile range
Values indicate median and interquartile range. *p<0.05. HAMD-21: 21-item Hamilton Depression Rating Scale, YMRS: Young Mania Rating scale