Lifetime Psychiatric Comorbidity of Illicit Drug Use Disorders

What is comorbidity? Psychiatric comorbidity refers to the occurrence of 2 or more mental or substance use disorders within a certain period. Research shows that comorbidity of substance use and other psychiatric disorders is common and often worsens the prognosis for each disorder; increases the personal disease burden; increases the frequency of hospitalization (revolving-door effect); increases the risk of other medical and psychosocial consequences, including suicide; and makes treatment more difficult. What follows is a brief review of the epidemiology of comorbidity of illicit drug use disorders and major mental disorders, summarizing the results of several large epidemiologic studies conducted in the United States over the past 2 decades.

In order to maximize the ability to compare findings and draw conclusions across these studies, this review focuses on comorbidity of illicit drug use disorders and several mental disorders that have been consistently associated with them: antisocial personality disorder (ASPD), mood disorders, and anxiety disorders. Following a brief review of the published literature, we offer some interpretations and clinical implications of such comorbidity. Readers are directed elsewhere for reviews of the comorbidity of psychiatric disorders with alcohol use disorders in adulthood,¹ nicotine dependence in adulthood,^2,3 and substance use disorders in childhood and adolescence.⁴

Major US epidemiologic studies
Several large epidemiologic studies have directly examined the comorbidity of mental and illicit drug use disorders among adults in the United States. Major studies with published comparable data on this topic include the Epidemiologic Catchment Area(ECA) study, the National Comorbidity Survey (NCS), and the National Epidemio- logic Survey on Alcohol and Related Conditions (NESARC). These studies survey individuals from the general population, apply advanced sampling strategies to maximize generalizability and case yield, use standardized assessment instruments, define psychiatric disorders according to DSM, and administer structured interview schedules by carefully trained interviewers. A snapshot of the methods of these studies is presented in Table 1.

From a statistical perspective, the probability of co-occurrence of mental and drug use disorders is indicated most commonly by the odds ratio (OR), which is an estimate of the likelihood that a certain event is the same for 2 groups. The OR is a convenient and widely used index of comorbidity that is readily interpretable and comparable across different epidemiologic studies.⁵ An OR of 1.0 means that the event is equally likely to occur in both groups of individuals; an OR exceeding 1.0 means that the event is more likely in the first group; an OR that is less than 1.0 means that the event is less likely in the first group.

Major findings
Epidemiologic studies report extensive lifetime psychiatric comorbidity among people who have drug use disorders. Some of the most extensive and consistent findings have been reported among drug use disorders and ASPD, mood disorders, and anxiety disorders. Table 2 presents the associations between drug use disorders (separately for drug abuse and drug dependence) and these mental disorders according to published reports from the ECA study, NCS, and NESARC.^6-9

Several observations are apparent from the pattern of results in Table 2. First, the 3 studies show that drug use disorders are highly comorbid with ASPD, mood disorders, and anxiety disorders. The ORs are nearly universally greater than 1.0 and are statistically significant.

Second, the risk of ASPD, mood disorders, and anxiety disorders is notably greater for individuals with drug dependence than for those with drug abuse. The association between drug dependence and ASPD, for example, is 3 to 5 times greater than the association between drug abuse and ASPD. Regarding internalizing disorders, the association between drug dependence and any mood or anxiety disorder is 2 to 3 times greater than the association between drug abuse and any mood or anxiety disorder. Table 2 also shows higher ORs for drug dependence than for drug abuse across nearly all subtypes of mood and anxiety disorders, although it is particularly evident for bipolar disorder, mania, and panic with agoraphobia. Other findings from the NESARC show greater associations for dependence than for abuse across 8 specific drug use disorders.^6,10

Third, ASPD is the mental disorder most strongly associated with drug abuse or dependence. Across the 3 studies, the ORs between drug abuse or dependence and ASPD are consistently much higher (range, 2.5 to 16.7) than between drug abuse or dependence and any mood disorder (range, 1.7 to 7.1) or any anxiety disorder (range, 1.4 to 4.9).

Fourth, there is mixed evidence that mood disorders are more highly associated with drug use disorders than are anxiety disorders. The ECA study and the NESARC report ORs between drug use disorders and any mood disorder that are greater than the corresponding ORs for any anxiety disorder. Recent findings from the NESARC also show greater associations for mood disorders than for anxiety disorders across 8 specific drug use disorders, with the greatest associations between each of the specific drug use disorders and comorbid mood and anxiety disorder, followed by pure mood disorder, and then pure anxiety disorder.⁶ In contrast to the findings from the ECA study and the NESARC, the NCS reported associations between drug dependence and any anxiety disorder that exceed that for any mood disorder, whereas the OR for drug abuse and any mood disorder exceeded that for any anxiety disorder.

Table 3 presents additional findings from the NESARC indicating that certain pairwise associations between specific mental disorders and specific drug use disorders are greater than others.^6,10 This level of matching is made possible for the first time by the large sample size of the NESARC study. Results show that although nearly every specific mental disorder is positively and significantly associated with each specific drug use disorder, the magnitude of the associations is inversely related to the prevalence of the specific drug use disorder. That is, marijuana use disorder is by far the most prevalent drug use disorder, followed by cocaine use disorder, yet these drug use disorders generally show the weakest associations with mood, anxiety, and antisocial personality disorders. Conversely, low-prevalence drug use disorders (eg, sedative, opioid, and tranquilizer abuse or dependence) are more strongly associated with those mental disorders. Regarding the specific mental disorders, the largest ORs are seen for mania and panic disorder with agoraphobia. These mental disorders are most strongly associated with several less prevalent drug use disorders involving sedatives, tranquilizers, and opiates. The ORs for these associations range from 6.2 to 8.4.

Interpretations of key findings
Across major epidemiologic studies of adults living in the United States, there is a strong consensus that drug use disorders co-occur at higher-than-chance levels with ASPD, mood disorders, and anxiety disorders. The accord across the ECA study, NCS, and NESARC is particularly impressive given the nontrivial methodological differences across studies presented in Table 1.

The extensive comorbidity among these psychiatric disorders can be interpreted in several ways, although more fine-grained research is needed to understand the complexity of these co-occurring disorders. First, comorbid disorders are independent disorders with distinct courses that co-occur either by chance alone or because of methodologic issues that overestimate comorbidity. Large epidemiologic studies can be especially prone to overestimation if they focus only on lifetime diagnoses in mixed-age samples and use assessments that include subthreshold conditions as diagnoses.^5,11 Yet, it is noteworthy that significantly elevated ORs are reported throughout the literature despite important methodological variations, including epidemiologic sample, assessment tools, diagnostic system, and time for estimating comorbidity (eg, lifetime, past year, past month).

A second interpretation poses that one disorder may influence the onset and/or course of the other disorder. On the one hand, comorbid mental disorders may increase the risk of progression from heavy misuse of drugs to addiction. The plausibility of this interpretation is supported by order-of-onset information from both epidemiologic studies and longitudinal studies that show that the first onset of a mood, anxiety, or conduct (the precursor to ASPD) disorder usually precedes the first onset of the comorbid drug use disorder.^4,8,12-16

Individuals with mood or anxiety disorders may use drugs to self-medicate, whereas individuals with externalizing problems may, by virtue of their deviant behavior, increase their opportunities to use drugs. Of interest, mania and panic disorder with and without agoraphobia were most strongly related to specific drug use disorders involving sedatives, tranquilizers, and opiates-perhaps suggesting a preference for substances that suppress CNS activity. On the other hand, drug use may influence the onset or course of mental disorders by mediating biologic and environmental factors.

Habitual drug use alters neuroanatomy in long-lasting ways, and these changes may increase vulnerability to psychiatric disorders.^17,18 A recent review suggests that substance-induced mood and anxiety disorders are fairly common and that substance-induced psychopathology may necessitate treatment approaches that differ from disorders that are independent of drug addiction.¹¹

Third, drug use disorders and mental disorders co-occur because of shared causes that give rise to both disorders. Regarding the association between drug use disorders and ASPD, for instance, numerous researchers propose that neurobehavioral disinhibition is a common underlying vulnerability factor of both drug use disorders and antisocial syndromes.

Coupled with evidence linking self-regulatory deficits and substance use disorders to certain mesocorticolimbic brain circuits,^19,20 it is plausible that disinhibited individuals are prone to chronically misuse drugs and engage in deviant behavior because of a lack of inhibitory mechanisms to appropriately modify their conduct. The notion of a shared cause for comorbid conditions is supported by evidence from longitudinal studies^13,21,22 as well as twin studies implicating common genetic factors for all externalizing syndromes, including alcohol, drug, conduct, and antisocial personality disorders.^21,23-26

Clinical implications
The clinical impact of comorbidity is substantial. Comorbid disorders are more serious and chronic than single disorders,²⁷ worsen treatment prognosis,^28,29 and increase use of services and health care costs.³⁰ Substance use can have a significant impact on the course of a comorbid mental disorder and the effect may vary depending on the type of drug misused, route of administration, severity of addiction, and the presence of physical dependence. Similarly, mental disorders can impact the outcome of the addiction depending on the severity of the mental disorder, level of cognitive impairment, and availability of internal resources to develop motivation to quit.³¹ In particular, several studies have shown that co-occurring depression or ASPD worsens the course of treatment in persons who have drug use disorders.^28,29

In the treatment of patients with comorbid disorders, it is important to understand that the combinations of disorders may create new patterns of behavioral and emotional manifestations of the single disorders. Some drugs can cause depressed mood, anxiety, mania, delirium, or symptoms that may resemble a bipolar, anxiety, or psychotic disorder. On the other hand, some mental disorders can be evidenced, worsened, or masked by drug use. For example, nicotine, caffeine, marijuana, and other drugs are sometimes used to ameliorate the discomfort of a psychotic disorder or the side effects of antipsychotic medications. In fact, polysubstance use may be the most frequent drug use pattern in this population, yet associated drug use disorders may go unreported. Therefore, as a rule, all patients with mental disorders should be assessed for all drug use disorders and vice versa.³²

There is long-standing controversy about how to treat patients with concurrent drug use and other mental disorders. Should mental disorders be treated in the setting of ongoing addiction treatment? Should addiction be treated in psychiatric settings? Recent recommendations suggest that addiction should not be a barrier for the treatment of mental disorders and vice versa. Integrated treatment approaches that offer a flexible blend of mental health and addiction treatments may provide the best therapeutic effect.³³ However, because some psychiatric comorbidities can be the result of drug-induced disorders or drug abstinence,¹¹ there is no consensus about whether it is necessary to wait to rule out the primary or secondary mental disorder in order to start treatment.

The treatment plan for patients with comorbid disorders should include a comprehensive strategy to manage the mental and drug use disorders and their interactions. Psychotherapy either with or without pharmacotherapy is the most common treatment approach. In fact, some types of psychotherapy can be effective for both disorders. Interventions such as motivational interviewing, motivational enhancement therapy, contingency management, and relapse prevention can help improve the mental condition as well as help initiate drug abstinence or prevent drug use relapse. Although abstinence may not be achieved quickly, it should be the ultimate treatment goal. In the meantime, the therapy may focus on developing a therapeutic alliance, promoting treatment adherence, developing family and social support, reducing drug use, preventing the consequences of drug use, and improving mental health status.^32,34,35

Little research has been conducted testing the efficacy of medications for the treatment of comorbid disorders. The pharmacotherapy of comorbid disorders poses important clinical challenges. A medication may help reduce the symptoms of one disorder but may worsen the other; it may be contraindicated for one disorder (eg, medications with abuse liability in patients with drug use disorders), precipitate withdrawal symptoms (eg, naltrexone for alcoholism in opiate addicts), or interact with other concurrently prescribed medications (eg, disulfiram and antipsychotics).^36,37 However, some medications indicated for one disorder may help improve the comorbid disorder. A recent meta-analysis evaluating the efficacy of antidepressants for the treatment of depression and cocaine dependence suggests that when antidepressants are effective in treating depression, they also help in improving the drug use disorder.³⁸

The treatment of comorbid drug use and mental disorders can be challenging for the clinician and the health care system. Careful evaluation of the symptoms of each disorder is required, followed by formulation of an individualized integrative treatment plan that clearly weighs the risks and benefits of intervention. Given that the treatment needs of this population cut across multiple systems of care, coordinated efforts to develop true integration of services are needed to overcome existing barriers and provide adequate care to this vulnerable and needy population.