Ivn D. Montoya, MD, MPH

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,

 and substance use disorders in childhood and adolescence.


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 

 and administer structured interview schedules by carefully trained interviewers. A snapshot of the methods of these studies is presented in 

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.

 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.


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. 

 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.

Several observations are apparent from the pattern of results in 

. 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.

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.

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.

 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.

 presents additional findings from the NESARC indicating that certain pairwise associations between 

 drug use disorders are greater than others.

 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.


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 

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.

 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.

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.

 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.

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,

 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

 as well as twin studies implicating common genetic factors for all externalizing syndromes, including alcohol, drug, conduct, and antisocial personality disorders.


The clinical impact of comorbidity is substantial. Comorbid disorders are more serious and chronic than single disorders,

 and increase use of services and health care costs.

 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.

 In particular, several studies have shown that co-occurring depression or ASPD worsens the course of treatment in persons who have drug use disorders.

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.

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.

 However, because some psychiatric comorbidities can be the result of drug-induced disorders or drug abstinence,

 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.

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).

 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.

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.

Articles

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.

Lifetime Psychiatric Comorbidity of Illicit Drug Use Disorders

Compliance is a crucial determinant of the treatment outcome of any medicalcondition. Poor treatment compliance may affect the therapeutic alliance;create skepticism in both therapist and patient; create resistance; worsen thedisease or the prognosis; and increase health care costs (Osterbergand Blaschke, 2005). Unfortunately, poor treatmentcompliance is often associated with blame, and noncompliant patients aresometimes punished with involuntary administrative discharge from treatment.

There are multiple indicators of treatment compliance that can be measuredusing direct or indirect methods. Among the direct methods, investigators andclinicians have used actual attendance to therapy sessions, direct observationor video-recording of sessions, measurement of medication blood levels,surrogate markers of medication, or expected changes in laboratory values. Theindirect methods include self-reported compliance, pill counts, evidence orabsence of expected side effects, and electronic monitoring devices.Unfortunately, the direct methods are expensive, and the indirect ones can besubject to biases.

In psychiatry, treatment compliance may be affected by factors associatedwith the therapist's characteristics, the service, the nature of the treatmentand the patient's idiosyncrasies. The therapist may not adhere to therecommended treatment guidelines or the therapy manual. The services may affectcompliance if they are hard to access or have long wait times, long lapsesbetween appointments or complex administrative procedures. Treatments thatinvolve complex procedures, are hard to follow, have unpleasant side effects,take a while to produce the desired effect, and are either unavailable ordifficult to access may increase the chances of poor compliance. Thecharacteristics of the patient, such as the presence of comorbidmental illness and substance use disorders (SUDs),can greatly affect treatment compliance.

The interest in psychiatric comorbidity increasedwith the publication of results from the Epidemiologic CatchmentArea Study (Regier et al., 1990) and the National Comorbidity Study (Kessler et al., 1994). More recently,Kessler et al. (2005) showed that the relative magnitude of associations ofhaving at least one substance use disorder in the past 12 months wassignificant for all but two mental conditions. The prevalence of mental healthservice use in the past year was only 41.1% and 38.1% for individuals who hadany mental disorder or any substance use disorder in that time period,respectively (Wang et al., 2005).

Unfortunately, little is known about the proportion of individuals in thegeneral population who use mental health services and actually adhere to theirtreatment plan. A survey of psychiatrists showed that 40% of their patientswith SUDs had treatment compliance problems (Herbeck et al., 2005). Both clinical and nonclinical factors appeared to be associated withtreatment compliance problems. Among the clinical factors, patients with lowtreatment compliance were more likely to have personality disorders, lowerglobal assessment of functioning scores and medication side effects than thosewithout treatment compliance problems (Herbeck etal., 2005).

It has been reported that the rates of completion of clinical trials forchronic medical conditions are only between 43% and 78% (Osterbergand Blaschke, 2005). It is likely that for those withpsychiatric disorders, particularly with comorbid SUDs, this percentage may be even lower. According to ameta-analysis of medication compliance, the mean compliance rate for patientswith physical disorders was 76%, whereas the ratio for patients takingantidepressants was 65% and 58% for antipsychotics(Cramer and Rosenheck, 1998). It has been estimatedthat medication noncompliance accounts for about 40% of re-hospitalizations ofpatients with schizophrenia (Weiden and Olfson, 1995).

The concurrence of mental illness and SUD seems to have a negativesynergistic effect. It has been suggested that comorbidpsychiatric disorders can further increase the risk of relapse and can haveimportant implications for predicting treatment outcomes (Compton et al.,2003). The rates of treatment compliance among patients with SUD vary greatly,depending on the type of SUD and treatment, severity of the disorder, degree ofpsychosocial support, and the presence and severity of psychiatric comorbidity. Patients with only alcohol use disorders havesignificantly higher treatment retention rates (42%) than those with drug usedisorders (20%) or combined alcohol and drug use disorders (26%) (McCaul et al., 2001).Furthermore, clinical trials of treatments for cocaine and other stimulant usedisorders have difficulty retaining participants. In contrast, clinical trialsof opioid agonist medications have better compliancerates (De Castro and Sabate, 2003).

Some psychiatric comorbidity factors that canaffect SUD treatment include the type of psychiatric disorder, severity of the comorbid psychiatric condition, early onset of illness andlevel of cognitive impairment (Broome et al., 1999; Rowe et al., 2004). Theclinical features of some types of psychiatric disorders may become riskfactors for poor treatment compliance. For example, among patients withschizophrenia, the lack of awareness of the illness, paranoid ideation,persecutory delusions and lack of initiative can worsen treatment compliance(Owen et al., 1996).

One of the psychiatric aspects that can greatly affect SUD treatmentcompliance is the patient's level of neurocognitivefunctioning (Aharonovich et al., 2003; Fals-Stewart and Schafer, 1992a). Attention, mentalreasoning and spatial processing are some of the cognitive domains that aresignificantly affected among noncompliant patients (Aharonovichet al., 2003).

More severe comorbidity has been associated withpoorer therapeutic alliance, and treatment alliance can predict patientretention (Barber et al., 2000). Patients with moderate and severe psychiatricproblems are not likely to remain in treatment unless they develop a strongtherapeutic relationship with their therapist (Petryet al., 2001).

Studies have documented that treatment compliance can be affected by theconcurrent presence of substance abuse (Keck et al., 1997; Lambert et al.,2005; Olfson et al., 2000). In patients withschizophrenia, medication noncompliance has been significantly associated withsubstance abuse, this in turn with a greater symptom severity than other groups(Olfson et al., 2000; Owen et al., 1996).

For patients with bipolar disorder (BD), noncompliance was significantlyassociated with the presence of a comorbid SUD, andthe most common reported reason was denial of need for treatment. In a study byWeiss et al. (1998), compliance was significantly associated with treatmentwith divalproex (Depakote),compared to treatment with combined lithium (Eskalith,Lithobid). The study also showed that patients withBD and SUD who were prescribed benzodiazepines, neurolepticsand tricyclic antidepressants tended to take moremedication than prescribed.

With regard to comorbid personality disorders and SUDs, results are not conclusive. However, borderline andantisocial personality disorders predict lower treatment retention rates(Marlowe et al., 1997). In addition, the concurrent presence of Axis IIdisorders on top of the Axis I disorders and SUD seems to worsen treatmentcompliance even more. A study showed that inpatients with triple comorbidity (Axis I and Axis II disorders plus SUD) wereless likely to be compliant with the treatment plan than those without triple comorbidity (Ross et al., 2003).

Adolescents with comorbid mental illness andsubstance abuse are a unique clinical population because of the high risk thatthe problems will continue or worsen during adulthood. A retrospective recordreview of one year of admissions to a residential adolescent substance abusetreatment program showed that patients with attention-deficit/hyperactivitydisorder and those with conduct disorder had the lowest treatment compliance(Wise et al., 2001).

In another study, investigators showed that adolescents with SUD who have comorbid affective and adjustment disorders have bettercompliance, whereas patients with conduct disorders have poorer compliance.Furthermore, patients who received psychotropic medications have bettertreatment compliance (Kaminer et al., 1992).

Successful interventions to improve treatment compliance can belabor-intensive but ultimately cost-effective (Haynes et al., 2002). Theyshould address factors such as the characteristics of the therapist, theservice, the nature of the treatment and the patient.

Interventions to enhance treatment compliance have been categorized into theaffective, behavioral and cognitive (ABC) domains (Schaffer and Yoon, 2001).They require an understanding of the therapeutic regimen; counseling about theimportance of adherence; organizing medication-taking; rewarding andrecognizing the patient's efforts to follow the regimen; and enlisting socialsupport from family and friends (Haynes et al., 2002)

Some of the most promising strategies for improving treatment compliance arebased on cognitive/motivational interviewing and behavioral techniques such asreinforcement (Carroll et al., 2005; Zygmunt et al.,2002). A review of the literature of measures to enhance treatment adherenceamong patients with BD showed that cognitive-behavioral therapy, interpersonalgroup therapy, group sessions for partners and education about the illness areeffective in improving treatment adherence (Owen et al., 1996; Sajatovic et al., 2004).

Contingency management interventions that reinforce treatment compliancehave been shown to improve SUD treatment outcome. These interventions canreinforce one or multiple aspects of the treatment plan such as therapeuticactivities, counseling, attendance at AlcoholicAnonymous meetings or simply compliance with prescribed medications (Petry et al., 2001). Good attendance to individualstandardized interpersonal cognitive psychotherapy has been positivelycorrelated with objective measures of treatment outcome (e.g., urine drugtesting) in patients with comorbid cocaine and heroindependence (Montoya et al., 2005). Given that poor compliance is likely torecur, booster interventions are needed to reinforce and consolidate gains (Zygmunt et al., 2002).

Patients with comorbid mental illness and SUD canbenefit from the simultaneous treatment of both disorders. A study of substanceabusers dually diagnosed with obsessive-compulsive disorder showed that thosewho received a combined intervention that addressed their obsessive-compulsivesymptoms and substance abuse stayed longer in treatment than a second groupthat received only substance abuse treatment (Fals-Stewartand Schafer, 1992b).

Clinicians, services, patients and treatment regimens should work in tandemto meet the particular clinical needs of patients with comorbiddisorders. Patients need to be supported and not blamed or punished withadministrative discharges for poor treatment compliance. Innovative approachesto improve treatment compliance for patients with comorbidmental illness and SUD can be cost-effective and make a significant publichealth contribution.

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Treatment compliance is a crucial determinant of the outcome of any disease. Poor treatment compliance can worsen the prognosis and significantly increase health care costs. Effective methods to improve treatment compliance for individuals with comorbid mental illness and SUDs will translate in better outcome for the patients and significant health care cost savings.

Ivn D. Montoya, MD, MPH

Articles

Lifetime Psychiatric Comorbidity of Illicit Drug Use Disorders

Treatment Compliance in Patients With Co-Occurring Mental Illness and Substance Abuse