To our knowledge, this is the first report to study the independent associations between anxiety disorders and SUDs in bipolar disorder by controlling for other potential confounding factors through regression analyses. A history of any anxiety disorder was associated with increased risk for a recent SUDs and recent alcohol dependence. Among the individual anxiety disorders, only a history of GAD was independently associated with the increased risk for a lifetime SUDs, lifetime alcohol dependence, and lifetime and recent marijuana dependence. On the other hand, a history of OCD was associated with the trended decrease in the risk for lifetime SUDs and lifetime marijuana dependence. In contrast, a history of panic disorder was not independently associated with any SUD.
The finding of patients with co-occurring anxiety disorders had a greater severity of SUDs than those without anxiety disorders () is consistent with previous studies.16,17
The higher risk for alcohol dependence in those with comorbid any anxiety disorder has also been observed in other bipolar studies,16,17
however, this is the first study to report that bipolar patients with GAD had a significantly higher risk for marijuana dependence than those without GAD even after controlling potential confounding factors. Due to the retrospective nature of our study, a causal relationship between GAD and alcohol or marijuana dependence could not be established. Longitudinal studies in non-bipolar populations have shown that there is a reciprocal causal relationship between alcohol dependence and anxiety disorders.26,27
In addition, self-medication behavior with alcohol or drugs has been observed in patients with primary anxiety disorders.28–30
In the National Comorbidity Survey-Replication study,28
the onset of anxiety disorders were earlier than the substance use disorders. It is possible that the increased risk for alcohol and marijuana dependence in patients with GAD might be the consequence of self-medication. Clearly, longitudinal prospective study is warranted to confirm or refute this finding.
The finding of the trended decrease in the risk for the lifetime SUDs and recent marijuana dependence in patients with a history of OCD was unexpected as well as the lack of association between a history of panic disorder and any SUD. These results should be interpreted with caution since the prevalence rate of obsessive compulsive disorder in this sample were low, about 8% in patients with bipolar I disorder and 7% with bipolar II disorder.19
Therefore, the sample size might not be large enough to detect significant associations. In terms of panic disorder, preclinical and clinical studies have shown that cocaine is a powerful anxiogenic agent.31–33
It is quite possible that patients with GAD, panic disorder, and/or OCD did not have a higher risk of cocaine use disorders than those without three anxiety disorders simply due to the unwanted anxiogenic effect from cocaine. However, several studies have shown that patients with primary PTSD are more likely to self-medicate with cocaine.34,35
In bipolar patients with SUDs, those with PTSD have been reported to have higher rates of cocaine and amphetamine use disorders than those without PTSD.14–16
The logistic regression results between anxiety disorders and SUDs from the current study support our previous findings that there are differential associations between anxiety disorders and SUDs.19
The disappearance of a significant association between panic disorder and SUDs after controlling bipolar subtype, gender, and other confounding variables in the current study supports the finding that there is panic-bipolar connections.36–42
Moreover, in a study of the National Epidemiological Survey on Alcohol Related Conditions (NESARC),43
Compton and colleague reported that after adjusting for demographic characteristics all anxiety disorders were associated with an increased risk for drug used disorders and drug dependence. However, after adjusting for demographic variables and other psychiatric disorders, only GAD was still associated with an increased risk for drug dependence. This suggests that future studies evaluating the associations between anxiety disorders and SUDs in patients with bipolar disorder should analyze each individual anxiety disorder separately. Moreover, key variables such as bipolar subtype, gender, and other potential confounding factors should be controlled through regression modeling
The reciprocal independent associations between alcohol use disorder and drug use disorders were consistent with previous studies in non-bipolar population.43–45
It is not surprising that male gender is a risk factor for increased risk of any SUD, alcohol use disorder, and cocaine use disorder. Increased risk for alcoholism and drug use disorder in male than in female patients with bipolar disorder was reported previously.12,46
Previous studies in non-bipolar population have shown that males had a higher rate of marijuana use disorders than females.47–49
Therefore, a similar risk for marijuana use disorders in both genders in our study was unexpected.
The independent association of bipolar I subtype with increased risks of different SUDs is consistent with some previous studies in which higher rates of SUDs in patients with bipolar I disorder than in those with bipolar II disorder were observed.8,9,11
Since other potential confounding factors were controlled for in our study, it suggests that bipolar I disorder with SUDs may represet a different phenotype of bipolar disorder irrelevant to gender and/or comorbid anxiety disorders.
Interestingly, some variables related to the clinical course were associated with the increased risk for SUDs. One such variable is the age of onset of mania/hypomania. Earlier onset of first mania/hypomania was associated with increased risk for lifetime SUDs (5% increase per year) and recent marijuana dependence (12% increase per year). More importantly, the time to first mood stabilizer treatment, an indication of correct diagnosis and treatment of bipolar disorder, was negatively associated with the risk for recent SUDs (8% decrease per year). This suggests that early diagnosis and proper treatment with a mood stabilizer in bipolar disorder may reduce the risk for SUDs.
The finding that a history of physical abuse was associated with an increased risk for lifetime substance use disorder and recent marijuana dependence is consistent with previous studies in bipolar and non-bipolar population.50–52
A history of sexual abuse being associated with decreased risk for recent SUDs and recent alcohol dependence were unexpected although it was also associated with a trend increase in risk for lifetime cocaine dependence (). Since majority of missing data in our study was due to the lack record of a history of sexual abuse, it remains unclear if these missing cases had impacted the regression results.
Taken together, it may be advantageous for clinicians to pay more attention to drug and alcohol problem in patients with male gender, bipolar I subtype, comorbid anxiety disorder, especially GAD, and history of trauma, especially physical abuse during an initial interview and treatment. In addition, it may be important to ask substance abuse related questions when alcohol problem is present or vice versa.
These findings should be considered in view of several methodological limitations. First, data obtained in this study was retrospective, cross-sectional, and involved four studies. Second, not all anxiety disorders were assessed, so some individuals with other anxiety disorder alone (e.g., PTSD, social phobia) could be misclassified as having no anxiety disorder. Third, as with most psychiatric cross-sectional phenomenological studies relying upon the recall of history by patients, the diagnoses and historical variables might not be accurate, although the required presence of a significant other(s) during the initial evaluation was used to minimize such potential inaccuracy. Fourth, since differences in clinical correlates between bipolar patients with RCBD and those without RCBD have been reported,36,53
therefore, our results might not be generalizable to other bipolar populations. Fifth, not adjusting for multiple comparisons may increase the chance of Type I error. Sixth, although we tried to control for potential confounding factors, factors were not forced to remain in the model could still potentially affect the final results.