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among individuals with anxiety and mood disorders. Cognitive control has been shown to be a targetable and malleable factor in treatment [92], and some research among individuals with depression showed that targeting cognitive control reduced depressive symptoms [93]. However, no research has examined the impact of tar- geting cognitive control for individuals with comorbid anxiety and mood disorders.
Future Directions
Calling into question the diagnostic validity of the current diagnostic system (DSM-5), the high rates of comorbidity among mood and anxiety disorders sug- gest that they may be alternative clinical manifestations of the same underlying pathophysiological process instead of distinct entities [94, 95]. If etiological research stays within the constraints of the DSM-5 diagnostic categories, poten- tially important mechanistic overlaps between disorders could be overlooked [94]. Therefore, the National Institute of Mental Health has created the Research Domain Criteria (RDoC) initiative which aims to explore biological, neurologi- cal, and psychological etiological mechanisms that span current DSM-5 diagno- ses [94, 96]. As RDoC research informs and transforms the classification of psychiatric disorders, changes to the classification system that are informed by etiological understanding may better account for the co-occurrence of mood and anxiety disorders [97]. Nevertheless, within the current diagnostic system, it remains important to identify comorbid anxiety and mood disorders within clini- cal practice [98]. This identification allows for appropriate treatment approaches to be taken in order to optimize outcomes.
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Epidemiology and Impact
Given that substance use disorders are varied, the majority of research examining prevalence and incidence rates in the context of anxiety disorders has focused on substance use, and substance use disorders generally, rather than on particular classes of substance. A large body of work using the Netherlands Mental Health Survey and Incidence Study (NEMESIS) examined rates of substance use disorders occurring in the context of anxiety disorders and found that 10.5% of individuals with an anxiety disorder also met criteria for a substance use disorder [101]. Other studies have found that, among those with substance use disorders, upwards of 17%
also meet criteria for any anxiety disorder [3]. Another related line of work has examined the comorbidity of anxiety disorders and substance use disorders among individuals with pre-existing mood disorders and found that these individuals may represent a distinct subgroup of individuals with mood disorders that may be par- ticularly chronic and difficult to treat [102, 103].
Some research has documented elevated rates of substance use in the context of specific anxiety disorders. Social anxiety disorder has been consistently linked to elevated substance use, and theoretical models have postulated that coping motives (to cope with fears prior to and rumination after being embarrassed) are strongly associated with later substance use disorder diagnosis [100, 104]. While social anxi- ety disorder seems to have the most robust associations with substance use, panic disorder has also been associated with elevated substance use problems, with between 10 and 20% of individuals with panic disorder using substances to cope with elevated negative affect [105]. Less work has focused on the intersection of generalized anxiety disorder and substance use disorders, but of the work that does exist, similar patterns of increased use have been identified [106].
Substance use and substance use disorders in the context of anxiety disorders are clinically important, as they are associated with a host of negative outcomes greater than outcomes associated with any one disorder alone. Importantly, the comorbidity of anxiety and substance use disorders is associated with greater symptom severity and higher levels of disability [106, 107]. Consistent with the literature presented above, recovery from social anxiety was significantly slowed among individuals with comorbid alcohol and substance use disorders [108]. This pattern was also reflected among individuals with any anxiety disorder [109].
Key Clinical Features
Unlike anxiety and mood disorder comorbidity, there is less symptom overlap between anxiety disorders and substance use disorders. However, it is clinically important to recognize that anxiety and irritability may be a common symptom of substance use disorders, particularly when an individual may be in a phase of sub- stance deprivation [1]. Despite the lack of symptom overlap, there is still considerable
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comorbidity observed. Given this, understanding the function of substance use in the context of anxiety disorders may be particularly important in treatment planning and treatment success. One avenue that has recently garnered attention is substance use motives and expectancies. Typically, individuals that report using substances to cope with increased negative affect, as well as those expecting substance use to reduce negative affect, have the poorest prognosis [110]. Therefore, collecting information as to the function of substance use may be important.
Considerable work has been dedicated to understanding the temporal relations that exist between anxiety disorders and substance use disorders. A large longitudi- nal study found that baseline anxiety disorders were associated with later develop- ment of substance use disorders, but baseline substance use disorders were not associated with the later development of anxiety disorders [111]. Other work has found associations with early substance use disorders and later anxiety disorders but also found that neuroticism (general tendency to experience negative affect) in the context of substance use disorders was associated with later anxiety disorders [101].
Importantly, a number of individual difference factors have been found to be associ- ated with the transition from anxiety disorders alone to anxiety comorbid with sub- stance use disorders. Specifically, female gender, younger age, lower education, and unemployment were all associated with increased rates of anxiety occurring comor- bidly with substance use disorders [112]. Other research also suggests that a history of childhood trauma and stressful events, as well as functional disability, may be associated with this transition [101]. These temporal findings highlight the impor- tance of a thorough assessment of anxiety and related conditions early in life to identify those at highest risk for developing a later substance use disorder.
Family and Genetics
Few studies have examined family and genetic collective risk factors for anxiety and comorbid substance use disorders. It has been shown that there exists, albeit small in magnitude, overlap in genetic factors between anxiety and substance use disor- ders [113]. Yet some early research does suggest, however, that family transmission of these comorbid disorders can be best accounted for by shared, underlying vulner- ability factors [114, 115]. Therefore, to best understand family and genetic risk factors for comorbid anxiety and substance use disorders, it is important to examine the family and genetic underpinnings of shared vulnerability factors. For instance, dysphoria and “acting out” behaviors have been shown to be independently associ- ated with anxiety and substance use disorders, and these features have been shown to be transmitted generationally with moderate specificity [115]. However, one risk factor that has been consistently shown to confer heightened risk for both anxiety and substance use disorders is impulsivity [116].
Impulsivity has been shown to be an important feature of anxiety disorders [117]
and substance use disorders [118], independently. Initial research has identified that HTR2B stop codon gene to be present in a number of animals and humans displaying
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impulsive behavior [119]. Additionally, twin studies examining heritability of impul- sivity using a delay discounting impulsivity task found that there was significant heritability in task performance (up to 62%; [120]).
Environmental Risk
Certain environmental risk factors have been identified as unique contributors to the development of comorbid anxiety and substance use disorders. A large body of work has focused on stressors occurring during childhood. One factor with consis- tent associations to anxiety and substance use disorders is childhood sexual abuse [121]. Research found that more severe forms of childhood sexual abuse were asso- ciated with a greater collective risk for developing psychiatric disorders, with an emphasis on anxiety and substance use disorders. Importantly, childhood sexual abuse was found to be associated with heightened risk after controlling for parental psychopathology and other family background characteristics.
Additional studies among women found that parental loss may, in fact, be a unique stressor associated with increased risk of psychopathology [122]. While all types of loss were associated with an increase in anxiety symptoms and disorders, the act of being separated from a parent was associated with both anxiety and alco- hol problems. Importantly, this particular study documented that parental loss could account for up to 5% of variance in psychopathology outcomes and could account for up to 20% of shared psychiatric disorders between siblings. It is clear that the relationship and subsequent loss of a parent may be integral to better understanding shared vulnerabilities for anxiety and substance use disorders.
Similarly, parenting style has also been associated with greater risk for comorbid anxiety and substance use disorders. Specifically, coldness and authoritarian styles of parenting were found to be associated with anxiety and substance use disorders [123]. What’s more, when examined concurrently, coldness was uniquely associ- ated with anxiety and substance use disorders, and these associations did not differ between mother and father. However, the relationship between parenting style, anx- iety, and substance use disorders was determined to be in a direction. Specifically, the relationship between parenting style (coldness) and substance use disorders was largely mediated by anxiety symptoms and disorders.
Cognitive and Personality Correlates
Given the dearth of research examining the comorbidity of anxiety and substance use disorders, little research has identified cognitive and personality correlates spe- cifically associated with anxiety and substance use comorbidity. However, there are a number of risk factors that have been identified to be individually associated with each of these disorders, and therefore, there may be utility in reviewing them here
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for future research. Some of these cognitive and personality factors that have been associated with anxiety and substance use disorders are neuroticism, anxiety sensi- tivity, and distress tolerance.
Neuroticism is a stable individual difference factor associated with psychiatric disorders. Most commonly, neuroticism has been associated with anxiety symptoms and disorders [124]. However, more recent research has linked neuroticism to sub- stance use disorders as well [71, 112]. Importantly, in the referenced studies, neu- roticism was examined as a predictor of these disorders in the context of other personality traits, and it was consistently found to be the strongest predictor of all disorders.
Anxiety sensitivity is another individual difference factor that has been associ- ated with anxiety and substance use disorders. The majority of work examining anxiety sensitivity on anxiety substance use comorbidity has focused on cigarette smoking. Overall, anxiety sensitivity has been found to be a putative risk factor for smoking and problems associated with smoking in the context of anxiety [125, 126].
More specifically, anxiety sensitivity has been associated with negative affect- related smoking cognitions, suggesting that anxiety sensitivity is associated with an increased belief that smoking will decrease negative affect associated with anxiety.
Some other work has examined anxiety sensitivity in the context of anxiety and marijuana use, and anxiety sensitivity was similarly associated with using marijuana to cope with negative emotions [127].
Finally, distress tolerance, or the ability to withstand negative psychological states [128], has been linked to anxiety and substance use comorbidity. A large review of the literature found distress tolerance to be associated with all psychopa- thology [129]. Looking more specifically, some research has identified distress tol- erance to be associated with both anxiety symptoms and substance use problems, but the strength of these associations differed by demographic characteristics [130].
Additionally, similar to anxiety sensitivity, distress tolerance was found to be spe- cifically associated with marijuana coping motives [127]. Overall, it is likely that distress tolerance is a putative risk factor for anxiety substance use comorbidity, and future research should examine how distress tolerance is associated with the tempo- ral relationships between anxiety and substance use.
Treatment Considerations and Future Directions
Treatment for comorbid disorders generally presents numerous challenges due to the more severe and chronic nature of all disorders, but the intersection of anxiety and substance use disorders seems to present a particularly difficult clinical profile to treat. There is also considerable debate as to the best strategy to treat these co- occurring disorders. Some clinical theoretical orientations believe it is important to achieve abstinence from a substance prior to initiating treatment for anxiety disor- ders, while others believe in treating them concurrently [131]. Various strategies, including pharmacotherapy and psychotherapy, have proven useful for these
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comorbid conditions. Additionally, novel treatment research has begun to identify new and innovative ways to reduce the overall disease burden associated with anxi- ety and substance use comorbidity.
Pharmacotherapies have shown efficacy for comorbid anxiety and substance use disorders, but particular treatment recommendations should be considered prior to initiating treatment with medication in this population [132]. First, it is important to acknowledge that individuals with substance use disorders may be more likely to abuse prescription medication. Additionally, substance use disorders have been found to be one of the biggest contributors to medication noncompliance, which is a significant concern in the context of anxiety disorders [133]. However, there have been studies examining the efficacy of pharmacotherapies for comorbid anxiety and substance use disorders, with the greatest body of research focusing on alcohol use disorder in the context of anxiety disorders. Of the studies reviewed [132], SSRIs have been shown to be safe and effective for treating anxiety disorders in the context of substance use disorders, and some studies have even shown that these medica- tions may also reduce alcohol use. Importantly, research and clinical guidelines consistently state the benzodiazepines should be explicitly avoided for individuals with comorbid anxiety and substance use disorders due to high abuse potential for these medications.
It is also important to note that, in some cases, pharmacotherapy may be required, depending on the nature and severity of the substance use disorders [131].
Particularly in the case of alcohol use disorder and opioid use disorder, current clinical guidelines require the use of pharmacotherapies to prevent the medically dangerous symptoms associated with substance withdrawal. Oftentimes, benzodi- azepines are used for individuals with alcohol use disorder and medication- assisted treatments such as methadone or buprenorphine are used for individuals with opioid use disorders. Particularly in these high-risk cases, integrated care from a medical doctor as well as a mental health clinician may be warranted to improve the clinical outcomes.
Psychotherapies have also had mixed results treating these comorbid disorders [107]. In individuals with comorbid anxiety and substance use disorders, targeting anxiety alone reduced anxiety symptoms but had little effect on substance use outcomes [134]. The same was found with treatment targeting substance use but not anxiety improving the substance use outcomes but not the anxiety. Given this lack of generalization, more recent research has focused on developing and imple- menting integrated treatments for anxiety and substance use disorders comor- bidly. While still in their infancy, one treatment examining an integrated CBT protocol for anxiety and substance use disorders, compared to a treatment for anxiety alone, showed comparable reductions in anxiety and greater reductions in substance use behaviors [135]. Importantly, while a number of these treatments are still being developed and tested, integrated treatments seem to be the most effective for comorbid anxiety and substance use disorders. Further, and perhaps the most important, is that targeting one disorder in the context of another is not associated with worse outcomes for the other disorder [107]. This is particularly
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important as the field moves to develop more efficacious treatments for all psychi- atric disorders that occur alone or comorbid with other disorders.