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Comorbid Psychiatrie and Substance Abuse Disorders: Recent Treatment Research

Paula Riggs, MD Frances Levin, MD Alan L Green, MD Frank Vocci, PhD

ABSTRACT. Psychiatric comorbidity is defined as the co-occurretice of a psychiatric disorder iti a patient with a substance use disorder. Psychiatric disorders in substance abuse patients can antedate the substance use disorder or be a consequence of the substance abuse. There is etTierging evidence that drug use in adolescence may alter the onset of certain psychiatric disorders in vulnerable individuals. Patients with coticurrent comorbid disorders present special challetiges for the substance abuse treatment system in terms of diagnosis atid management because each disorder has the capability of exacerbating the other.

This tnanuscript is a sunitnary of an ISAM sytnposium that featured three speakers who discussed the following topics:

1. Etiology and treatment of comorbid psychiatric and substance use disorders in adolescents; 2. Treatment of ADHD and substance use disorders in adults; 3. Effects of substance abuse on the onset, severity, and treatment of schizophrenia.

Recotiimendations for further research will be presented.

KEYWORDS. Adolescence, cottiorbidity, depression, attention deficit hyperactivity disorder, schizophrenia

Paula Riggs is affiliated with the Department of Psychiatry, University of Colorado Health Science Center, Denver, CO 80224.

Frances Levin is affiliated with the Department of Psychiatry, Colutnbia University Medical Center/New York State Psychiatric Institute, Division of Substance Abuse, New York, NY 10032.

Alan I. Green is affiliated with the Departtnent of Psychiatry, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756.

Frank Vocci is affiliated with the National Institute on Drug Abuse, NIH, DHHS. Address correspondence to: Frank Vocci, PhD, National Institute on Drug Abuse, National Institutes of

Health, Department of Health and Human Services, 6001 Executive Boulevard, Room 4133, Bethesda, MD 20892 (E-mail: [email protected]).

Dr. Green is supported in part by NIH grants DA-13196, AA-014644, MH-62197, and R21 DA-019215. Dr. Green reports grant support, honoraria, or advisory board service for Eli Lilly, Janssen, Bristol Myers, Forest, and AstraZeneca. Dr. Levin is supported in part by NIH grant DA K0200465. Dr. Riggs is supported byNIDAROl DA 13176 and NIDA U lO-DA-1-3716 and also receives hotioraria from Shire as a consultant and advisory board member.

Drs. Green, Levin, and Riggs presented at a symposium, chaired by Dr. Vocci, on comorbidity and substance abuse disorders at the VIII International Society of Addiction Medicine Annual Meeting atid Scientific Conference, Oporto, Portugal. Each author contributed equally to the development of the article. Dr. Vocci's contribution was part of his official duties.

Substance Abuse, Vol. 29(3) 2008 Available online at http://suba.haworthpress.com

© 2008 by The Haworth Press. All rights reserved. doi: 10.1080/08897070802218794 5/

52 SUBSTANCE ABUSE

EPIDEMIOLOGY OF COMORBID SUBSTANCE ABUSE AND

PSYCHIATRIC DISORDERS

Experimentation with alcohol and drugs of- ten begins in adolescence and carries significant prognostic features if it progresses to a substance use disorder (SUD) during adolescence. Early onset of substance abuse is associated with a higher risk of progression to substance depen- dence and continuation in adulthood (1,2), in- creased psychiatric comorbidity (3) and an in- creased number of suicide attempts (4).

Psychiatric comorbidity is the rule rather than the exception among adolescents with substance use disorders, ranging from 60 to 85% in clini- cal samples (see Waxmonsky and Wilens (5) for a detailed review) and epidemiological surveys (3) and the Oregon Adolescent Depression Project (OADP) (6). Kandel et al. (3) analyzed a subset of 401 adolescents, aged 14-17 years old, and reported on drug use patterns and comor- bidity of the disorders and psychiatric disorders. Rates of psychiatric disorders (affective or dis- ruptive disorders) among adolescents with a cur- rent substance abuse disorder were three times higher than for adolescents without a substance abuse disorder. In the OADP, adolescents with a lifetime substance abuse disorder had more that twice the rate of anxiety, depression, or a dis- ruptive behavioral disorder. Tlie rates of comor- bidity reported by Kandel et al. (3) were higher in the nontreatment group for conduct disorders (68%) and depression (32%) than those noted in an adolescent treatment sample: 55 and 9%, respectively (7).

Rates of comorbidity have also been esti- mated from a convenience sample of patients treated at a hospital-based adolescent medicine clinic (8). In this study, 538 adolescents, aged 14-18, receiving routine medical care were screened for substance abuse problems using the Problem Oriented Screening Instrument for Teenagers (POSIT) Substance Use/Abuse scale and the Adolescent Diagnostic Interview of the Diagnostic and Statistical Manual (DSM)-IV (23). Eighteen percent of the group was diag- nosed with substance use problems and another 16 percent with a substance use disorder. Psychi- atric symptomatology was compared across the

non-users, users, and dependent subgroups. Sig- nificant increases in depression, mania, eating disorders, attention deficit disorder, and conduct disorders were noted in the drug using groups.

ETIOLOGY AND TREATMENT OF COMORBID PSYCHIATRIC AND

SUBSTANCE USE DISORDERS IN ADOLESCENTS

Genetic and neurobiological vulnerabili- ties (e.g., difficult temperament) coupled with chronic environmental adversities throughout development put children at risk for develop- ment of psychiatric disorders and substance use disorders (SUD) in adolescence (9). Biologi- cal vulnerabilities include genetic risk factors that may influence development of "difficult temperament" or neurobehavioral disinhibition in early childhood, characterized by poor at- tention and persistence, impulsivity, executive function deficits, hyperactivity, aggression, and poor frustration tolerance (10,11). Children with such temperaments are at higher risk for devel- oping academic problems and childhood onset psychiatric disorders such as oppositional defi- ant disorder (ODD), attention deficit hyperactiv- ity disorder (ADHD), learning disorders (LD), conduct disorder (CD), and affective disorders (9,11). Family risk factors, such as abuse, ne- glect, and parental or sibling substance abuse are also important. These problems synergistically contribute to increasing social marginalization, association with deviant peers, as well as early experimentation with drugs of abuse, often with rapid progression to SUD during adolescence.

By the time such youths enter drug treat- ment, psychiatric comorbidity is the rule rather than the exception (9,12). Research shows that commonly co-occurring psychiatric disor- ders, such as ADHD and depression, often go untreated in community drug treatment pro- grams, which may contribute to poorer substance treatment outcomes compared to non-comorbid adolescents with SUD (13). Although a num- ber of family-based, behavioral, and cognitive- behavioral interventions have been shown to have efficacy in the treatment of adolescent SUD, there is a paucity of controlled treatment

Riggs et al. 53

outcome research evaluating the effectiveness of combined or integrated treatment of psychiatric comorbidity and SUD (14).

To our knowledge, only 3 controlled trials have been conducted to date evaluating the safety and efficacy of pharmacotherapy targeting a co- occurring psychiatric disorder in adolescents with SUD. One small study (n = 22) supported the safety and efficacy of lithium carbonate for bipolar disorder in adolescents with concurrent SUD ( 15). Another controlled trial evaluated the safety and efficacy of pemoline (a schedule-IV psyciiostimulant) for attention deficit hyperac- tivity disorder (ADHD) in 69 out-of-treatment adolescents with active SUD (16). (Diagnostic criteria and treatment studies of ADHD in adults are presented in the section following the discus- sion on adolescents.) Results showed that pemo- line had a good safety profile and a comparable effect size to that reported for ADHD in ado- lescents without SUD despite non-abstitience in most study participants. However, in the absence of specific behavioral treatment for SUD, phar- macotherapy for ADHD had no impact on drug use, which did not significantly decrease in either tieatment group (16).

Another recently completed controlled trial evaluated the safety and efficacy of fluoxetine vs. placebo in 126 adolescents with DSM-IV diag- noses of major depressive disorder (MDD), CD, and SUD (17,18). Adolescents in both medica- tion groups received weekly, individual, manu- alized CBT for their SUD during the 16-week trial (18). Thus, the study also evaluated the impact of pharmacotherapy for depression on change in drug use, substance treatment compli- ance, and retention. Results showed that fluoxe- tine had a good safety profile and demonstrated superior efficacy (.78 effect size) to placebo for depression, despite non-abstinence in the major- ity of study participants. Most adolescents also decreased their drug use, about 5-7 days per month on average. However, only about 10% of the sample (n = 12/126) achieved sustained ab- stinence of at least 1 month and there was no difference between fluoxetine and placebo treat- ment in change in drug use. Since rates of depres- sion remission were unexpectedly high in both the ñuoxetine -I- CBT (75%) and the placebo + CBT (64%) treatment groups but rates of ab-

stinence were relatively low, researchers con- cluded that most depressions did not remit due to abstinence. However, the limitations of the study design did not allow more definitive con- clusions to be drawn about the temporal rela- tionships or directionality of change in depres- sion and change in substance use. Researchers also speculated that CBT most likely contributed to the higher than expected depression response rates despite its pritnary focus on the treat- ment of SUD. More definitive conclusions about the contribution of CBT to depression response rates cannot be made because all study partic- ipants received the manualized CBT as outpa- tient treatment for SUD during the medication trial. Post hoc analyses indicated that remission of depression was a stronger predictor of change in drug use than medication treatment. Those whose depressions remitted, regardless of med- ication assigntnent, significantly decreased their drug use, whereas non-remitters' drug use did tiot decrease from baseline levels of use despite similar rates of treatment compliance and re- tention. If replicated, the clinical implications of this study indicate that co-occurring depres- sion in substance-abusing adolescents may remit without antidepressant pharmacotherapy or ab- stinence, in the context of individual outpatient CBT for SUD. However, if depression does not remit, their drug use may not decrease even if they continue with substance treatment. Thus, in dually diagnosed adolescents, if depression does not appear to be improving early in the course of substance treattnent (e.g., within the first month of treatment) it appears to be safe, efficacious, and clinically prudent to initiate flu- oxetine, with careful monitoring, even if not yet abstinent, because ongoing depression may im- pede abstinence achievement.

Taken together, preliminary results of these adolescent studies indicate that some medi- cations for common co-occurring psychiatric disorders such as ADHD and deptession in ado- lescents with SUD may be safe and effective even if non-abstinent, but treatment of psychi- atric comorbidity alone is not likely to impact drug use without concutTent and specific be- havioral therapy for SUD. Results must be in- terpreted with caution due to the small number of controlled trials conducted to date and their

54 SUBSTANCE ABUSE

limitations. For example, studies conducted to date lack sufficient sample size to detect the full range of clinically significant effects of ADHD or depression treatment on substance use or other clinical outcomes. Existing studies have not yet been able to address the separate and combined influences of pharmacotherapy and behavioral interventions for comorbid psychi- atric and substance use disorders. More research is clearly needed in larger samples with ap- propriate design before definitive conclusions can be drawn that may guide development of clinical practice parameters in dually diagnosed adolescents.

ATTENTION DEFICIT HYPERACTIVITY DISORDER

AND SUBSTANCE ABUSE DISORDERS IN ADULTS

Attention-deficit/hyperactivity disorder (AD- HD) is characterized by inattention, hyperactiv- ity and impulsivity. ADHD imposes a substantial individual and public burden. It has been es- timated that the excess U.S. health care and work-related costs for individuals with ADHD and their family exceeds $32 billion/year (19). Although it was once believed that children "outgrew" ADHD when they reached adult- hood, recently conducted community surveys estimate that up to 60% of children with ADHD continue to have symptoms into adolescence and adulthood (20,21).

In the National Comorbidity Survey Repli- cation (NCS-R), ADHD was found to occur in 4.4% adults (22). Further, the individuals with ADHD had significantly higher rates of comor- bid substance use disorders compared to those without ADHD (15.2% versus 5.6%). Similarly, in samples of individuals seeking treatment for substance abuse, the rates of adult ADHD us- ing DSM-IV-TR criteria (23) are substantially higher than what would be expected based on population estimates, with rates ranging from 10 to 25%. Importantly, substance abusers with ADHD may progress less well or may be more likely to drop out of treatment compared to those without ADHD (24-26). These data indi-

cate that ADHD commonly co-occurs with sub- stance use disorders and impacts the outcome of treatment.

While the exact cause of ADHD is un- known, there is converging evidence from ge- netic and imaging studies that genes and brain regions associated with dopaminergic transmis- sion are altered in individuals with ADHD (27, 28). Repeatedly, medications that increase dopamine, such as stimulants, have been shown to improve ADHD symptoms, suggesting a key role of dopamine in the pathophysiology of ADHD. Given that ADHD is overrepresented in substance-abusing populations, and may neg- atively impact on treatment, it is incumbent on clinicians to learn how to diagnosis and treat ADHD.

According to DSM-IV-TR, an individual with ADHD can be diagnosed with inattentive type, impulsive-hyperactive, or combined type de- pending on the number of symptoms (see APA (23) for a description of diagnostic criteria). Because the diagnosis of ADHD in adults of- ten depends on obtaining symptomatology from childhood, it can be challenging to garner ade- quate information in substance-abusing popula- tions, particularly those who may have cognitive difficulties as a direct result of their alcohol or drug abuse. There are common factors that may lead to both under-diagnosis and over-diagnosis of ADHD in substance abusers. Common rea- sons that lead to under-diagnosis include: (1) inability to recall symptoms prior to the age of 7, (2) assuming that the presence of other psychiatric disorders (e.g., hypomania, depres- sion) preclude the diagnosis of ADHD, (3) un- structured clinical interviews that depend on the clinician querying about ADHD symptoms, and (4) not recognizing that ADHD symptoms may be fewer, less obvious, or be compensated for in adulthood. DSM-IV requires that individu- als with ADHD have symptoms prior to the age of 7. This is problematic when evaluating adults who may not recall how they behaved in first or second grade and there may not be any older family members available to provide historical information. Increasingly, experienced clinicians have questioned the validity of the "before age 7" criterion (29,30). An individ- ual who otherwise meets criteria for ADHD

Riggs et al. 55

but does not recall whether his symptoms be- gan before the age of 7 may be diagnosed with ADHD, NOS (not otherwise specified); how- ever, clinicians may unfortunately forgo mak- ing the diagnosis since the individual does not meet full ADHD criteria and not commence with treatment. Also, there are numerous reasons for over-diagnosis. These include (1) not obtaining an adequate longitudinal history, (2) relying on screening instruments alone, (3) not ensuring that symptoms occur in more than one setting, (4) not ensuring that the symptoms cause impair- ment, and (5) the potential for secondary gain on being diagnosed with ADHD such as special consideration with test-taking or stimulant med- ication prescriptions. While these possibilities should not be ignored, overwhelmingly, in sub- stance abuse treatment settings, under-diagnosis is much more common.

It still remains controversial regarding how to best treat co-occurring ADHD individuals with SUD. To date, there are few empirical data to guide treatment. Although there have been numerous open trials suggesting that both nonstimulants and stimulants may reduce ADHD symptoms and substance use (31,32), there are only a few double-blind controlled trials in individuals with active substance abuse with ADHD. To date, the data are mixed. Two studies suggest that ADHD may be improved with either methylphenidate (adults) (33) or pemoline (adolescents, aforementioned) even if non-abstinent (16). Two other adult studies did not demonstrate a greater improvement in ADHD symptoms in methadone mainte- nance patients receiving methylphenidate or bupropion or cocaine-dependent patients with ADHD (34,35). For those cocaine-dependent individuals who had an improvement in ADHD symptoms based on clinician ratings, the methylphenidate group was more likely to show a reduction in cocaine use over time compared to placebo. Even in placebo subjects with reduction of ADHD symptoms, cocaine use did not remit. However, none of these studies found that active medication was superior to placebo in reducing substance use on primary outcome measures. Thus, the hypothesis that reduction in ADHD symptoms would lead to reduction in drug use has not been substantiated. It should

be noted that the lack of a difference between medication and placebo groups does not allow for a conclusion regarding a specific mediated effect of medication in the latter studies. Larger studies, which presumably would show differ- ences between medications and placebo groups on ADHD symptoms, are needed to determine whether medications for ADHD in adults have a salutary effect on concurrent substance abuse.

There has been some evidence that direct ag- onist treatment with amphetamines may reduce cocaine use (36,37), but to date only one of the studies with ADHD cocaine abusers has found some evidence on a secondary outcome mea- sure that methylphenidate reduces cocaine use over time. Because of the relatively small sam- ple sizes of these trials, high dropout rates, and high placebo response rates, it is difficult to draw firm conclusions from these findings. However, it may be that ADHD medication works best for those who are able to achieve a period of absti- nence, when greater diagnostic clarity is better attained and the acute toxicity of psychoactive substances is reduced (38).

Although there are few empirical data to guide the treatment of co-occurring substance use dis- orders with ADHD, clinical experience suggests that stimulants can be used effectively under closely monitored conditions. While it is prudent to first try medications with a low abuse and di- version liability such as atomoxetine (which is an FDA-approved treatment for ADHD) or bupro- pion (which does not have an FDA itidication for ADHD), this should not necessarily preclude the use of stimulants if these agents are not effec- tive. Prior to initiating a trial of stimulants, cer- tain questions need to be asked: (1) Have other nonstimulant medications been tried or are there specific reasons why stimulants make sense as a first-line treatment? (2) Is the patient a cur- rent or past substance abuser? (3) Has the pa- tient had an established period of abstinence?

(4) If the patient is a current substance abuser, is he in ongoing substance abuse treatment? (5) Is there a history of amphetamine or other stimulant abuse? (6) If the individual abused stimulants, what were the reasons for taking nonprescribed stimulants in the past?to get work done or to get high?

56 SUBSTANCE ABUSE

In general, it a reasonable to first try a med- ication with little abuse potential, such as ato- moxetine or bupropion. However, data suggest that these medications have lower effect sizes in their efficacy in treating ADHD compared to stimulant medication (39). Thus there are cer- tain clinical circumstances when implementing a stimulant may be a rational first choice. For example, a patient who has been in remission from alcohol dependence for 10 years, with no other intervening drug use, might be reasonably initiated on a long-acting stitnulant. However, other important questions to consider prior to starting a stimulant in a patient with a current or past history of substance abuse include: (1 ) Is the patient reliable? (2) Are there family members who can be involved in the treatment plan? (3) Has the patient and/or family been adequately informed of the potential risks involved in using stimulants? Although the research conducted in cocaine-dependent individuals with and without ADHD have shown little evidence of abuse of prescribed stimulants (34,36,37,40,41), misuse of prescribed medication is a significant public health problem (42-44) and a certain percentage of individuals with ADHD, particularly adoles- cents, will report giving or selling their medi- cation to others or will report getting high from their medication (44,45).

Since the long-acting formulations are more difficult to tamper with, it is less likely that in- dividuals will take these formulations in non- prescribed routes (e.g., intranasally or intra- venously). Further, long-acting stimulants may be associated with less abuse potential than short-acting stimulants (46,47). Thus, in most circumstances, long-acting stimulant formula- tions should be chosen rather than immediate- release preparations.

Modafinil is a stimulant medication with some abuse potential. It has been established that 200 mg of modafinil given to ADHD patients under controlled conditions improved work- ing memory, visual memory, spatial planning, and stop-signal reaction time (48). The spa- tial planning accuracy was accompanied by increased response latency, suggesting that modafinil increases reflective cognition. Addi- tionally, modafinil increased sustained attention in the ADHD patients. Such data provide a ratio-

nale for extending the study to comorbid ADHD substance abuse populations.

Although the emphasis has been on the use of medications to treat ADHD, there is a grow- ing literature on the potential utility of non- pharmacologic interventions such as cognitive remediation (49) and other cognitive behavioral approaches (50) to treat ADHD. Whether these interventions are effective alone in adult sub- stance abusers with ADHD or are best when combined with medication requires further eval- uation. However, at present, medications remain the mainstay of treatment for adult ADHD. Al- though various classes of medications may prove effective in reducing ADHD symptoms and psy- choactive substance use in ADHD adults with comorbid substance abuse, many questions re- main, such as when to initiate treatment, what is the optimal dosing, under what circumstances are stimulants a reasonable choice, and un- der what circumstances should stimulants be avoided. Future research should help address these issues.

SUBSTANCE ABUSE AND THE ONSET, SEVERITY, AND TREATMENT

OF SCHIZOPHRENIA: PHARMACOTHERAPEUTIC

INTERVENTION

Schizophrenia, characterized by both positive (e.g., hallucinations) and negative (e.g., anhe- donia) symptoms, as well as cognitive deficits, occurs in about 1 % of the population. The symp- toms of schizophrenia tend to present initially in late adolescence or early adulthood. Modem approaches to treatment emphasize effective in- tervention at the earliest stages of the illness in an attempt to limit the long-term disability that is often associated with schizophrenia.

Substance use disorder (SUD) is very com- mon in patients with schizophrenia and dra- matically worsens their outcome (51). The Epi- demiological Catchment Area study suggested that nearly 50% of patients with schizophrenia have a lifetime history of SUD, a rate approx- imately 3 times that seen in the general popu- lation (52). An elevated rate of SUD is seen in

Riggs et al. 57

both chronic and first episode patients. SUD is known to complicate the course of schizophrenia and is associated with increased levels of symp- toms, noncompliance with treatment, hospital- izations, violence, suicidality, victimization, and medical costs (53). Alcohol and cannabis ap- pear to be the 2 most commonly used substances in these patients; cannabis is more common in first episode patients and some investigators have suggested that cannabis use may trigger the on- set of psychosis in vulnerable individuals (54). A number of studies have suggested that cannabis use is associated with an early age of onset of schizophrenia (54).

The basis of substance use in these patients has been addressed by a number of inves- tigators. Various authors have suggested that their substance use is related to an attempt to self-medicate positive or negative symptoms of schizophrenia (55) or to decrease neurologi- cal side effects of the antipsychotic medica- tions used to treat the patients (56). Studies that have assessed this, however, have been unable to substantiate the causal association of the self- medication hypothesis (57). We and others have proposed an alternative but not totally contra- dictory theory—that of a brain reward circuitry dysfunction in patients with schizophrenia that underlies their substance use (57-59).

The pathophysiology of schizophrenia is thought to involve dysfunctional mesocortico- limbic pathways mediated by the neurotransmit- ter dopamine. These pathways also comprise a component of the brain reward circuit. We have proposed, based on a series of animal studies (60), that use of substances (all of which re- lease dopamitie in the nucleus accumbens, part of the reward circuit) serves to transiently im- prove functioning of the reward circuitry, even as it makes the course of schizophrenia worse (57). Studies in our laboratory and elsewhere are underway in an attempt to provide evidence to confirm this theory.

The use of functional magnetic imaging is one way to study the brain reward circuit. Us- ing monetary gambling procedures, investiga- tors have demonstrated the ability to activate the ventral striatum and the cortex, key components of the brain reward circuit (61). Interestingly, re- ports from 2 investigators in recent years (62,63)

have demonstrated abnormal brain reward cir- cuitry in patients with schizophrenia. Studies in our laboratory (53) are underway to confirm and extend these findings.

Treatment of patients with schizophrenia and co-occurring SUD optimally involves a hybrid treatment system, in which one treatment team delivers medication management, as well as sub- stance abuse and psychosocial services (54,64). One such treatment program, known as inte- grated dual diagnosis treatment (IDDT), has been demonstrated to be useful for such patients (54,64,65). Integrated or hybrid programs should involve services that are consistent with the indi- vidual's motivation for change, and they must be given with recognition that successful treatment requires a long-term perspective.

Antipsychotic medications are the mainstay for pharmacological treatment of schizophre- nia, as they have been since the 1950s. Stud- ies over many years have suggested, however, that although the first-generation (or typical) antipsychotic medications are effective in pa- tients with schizophrenia, they are not particu- larly helpful in such patients if they also have a co-occurring SUD (53). In fact, some reports suggest that substance use may increase in pa- tients given these first-generation antipsychotics (66). There is some evidence, however, that the newer, second-generation (or atypical) antipsy- chotics, e.g., clozapine and the medications in- troduced after clozapine, may be more effective in patients with schizophrenia and co-occuiTÍng SUDs (67).

Clozapine is generally considered the most effective antipsychotic for the treatment of schizophrenia (68). Unfortunately, it is also the most toxic, with important side effects that generally limit its use to patients known to be refractory to treatment with other antipsy- chotics. Interestingly, however, data from a num- ber of investigators have begun to suggest that clozapine may be highly efficacious in patients with schizophrenia and co-occurring SUDs and may limit substance use in these patients (53,54,67,69). These data, obtained from a num- ber of studies, while still preliminary (in the ab- sence to this point of a rigorous, adequately pow- ered randomized controlled trial), consistently demonstrate this. For example, case reports have

58 SUBSTANCE ABUSE

suggested clozapine's ability to decrease cocaine use and tobacco smoking, retrospective studies have demonstrated an ability to decrease alco- hol and cannabis use, and a naturalistic study indicated that clozapine use was associated with decreases in alcohol and cannabis abuse at a rate greater than typical antipsychotics (53).

The data are even more preliminary, and seemingly less consistent, with regard to the other second-generation, atypical antipsychotic medications. A recent review has summarized the current data regarding these agents (53). The most accurate statement that can be made at this time about these non-clozapine second- generation agents in this population is as follows: while clinicians tend to use second-generation antipsychotics for patients with co-occurring disorders (perhaps because they are thought to potentially have somewhat greater efficacy for negative symptoms), data to support this clinical practice is only beginning to be ac- quired. Nonetheless, given the reports that first- generation antipsychotics appear to be of lim- ited value in these patients, even the modest data about the newer agents suggest their appropriate preferential use in this population (70). Clini- cians, however, must be aware of the metabolic side effects of many of these second-generation antipsychotics and need to weigh their potential benefits against the likelihood that such side ef- fects may develop. Clearly, further research is needed to adequately clarify the optimal use of clozapine and other second-generation antipsy- chotics in patients with schizophrenia and co- occurring SUD.

Our group has proposed a neurobiological hy- pothesis to explain clozapine's apparent ability to limit alcohol, cannabis, and potentially co- caine use in patients with schizophrenia (57). We have suggested that clozapine's broad spectrum of effects, particularly its weak blockade of dopamine D2 receptors, its potent blockade of norepinephrine alpha 2 receptors, as well as its ability to release norepinephrine in brain and plasma, may allow this medication to ameliorate the brain reward circuit deficit in patients with schizophrenia that underlies their substance use (57). Preclinical studies in alcohol-drinking ani- mals as well as clinical neuroimaging studies are underway to substantiate this hypothesis.

Beyond the antipsychotic medications them- selves, other adjunctive agents are also beginning to be tested in this population. Nal- trexone, for example, which is approved for use in the treatment of alcoholism, has been re- cently shown to also limit alcohol use in patients with schizophrenia, although liver toxicity from this medication is a potential worry in these pa- tients (53,72,73). In addition, disulfiram appears to also limit alcohol use in this population, al- though it must be used with caution because of its potential to increase psychosis and produce liver toxicity (53,65,71). Other medications have been tried in patients with alcoholism (such as acamprosate), although they have yet to be tested in patients with schizophrenia. Lastly, bupropion has been shown to help decrease cigarette smok- ing in patients with schizophrenia (74), topira- mate has been demonstrated in 2 case reports to limit alcohol use in this population (75), and tricyclic antidepressants have been reported to potentially limit cocaine use in patients with schizophrenia (76). Clearly, all of these reports are quite preliminary and more studies need to be done before a clear recommendation can be given regarding the optimal adjunctive treatment approaches for these patients.

Schizophrenia, a serious mental illness that usually presents in late adolescence and early adulthood, is worsened by co-occurring substance abuse. Alcohol and cannabis are the 2 most often used substances in schizophrenic patients. The use of these agents as self- medication for positive or negative symptoms or to counteract dysphoric effects of antipsychotic medication has been proposed by a number of investigators. An alternate to these notions is that a reward deficiency/imbalance exists in the mesolimbic and mesocortical dopamine-linked circuits. Patients abusing drugs or alcohol are thought to be attempting to compensate for the reward deficiency, even if it worsens the disease pathology. Clozapine, a second-generation an- tipsychotic, has been reported to reduce alcohol and cannabis use in schizophrenic patients (53). More rigorous clinical trials of this agent and other agents such as topiramate and naltrexone are necessary to develop definitive evidence that could establish new treatment guidelines for schizophrenic patients with co-occurring

Riggs et al. 59

substance abuse disorders. Also needed are mechanistic studies utilizing noninvasive imag- ing techniques to confirm the hypothesized derangements and their amelioration by second- generation antipsychotic medications.

While it is clear that the optimal pharmaco- logical approach to these co-occurring patients is still developing, the field is quickly recogniz- ing that limiting substance use in patients with schizophrenia, particularly those in the early phase of the disorder, is crucial if we are to achieve the goal of improving the course of this severe psychiatric disorder. Moreover, the field further recognizes that any new pharmacologi- cal agent, to be used in any phase of the disor- der, will optimally be given in conjunction with an active psychosocial intervention program to achieve maximal therapeutic benefit.

SUMMARY AND CONCLUSIONS

Important advances in research have clearly increased our knowledge and understanding of the complex etiology of genetic, neuro- biological, and environmental vulnerabilities and adversities that put children at risk for developing substance use disorders (SUDs) and psychiatric comorbidity. Research advances have also deepened our appreciation of the importance of understanding the onset and progression of addiction from a developmental perspective. We have learned that many child- hood psychiatric disorders increase the risk of drug abuse during adolescence; that the onset of drug abuse in adolescence increases the risk of developing psychiatric comorbidity; and that the majority of substance-dependent adults began experimenting with substances of abuse during adolescence, progressing to more serious SUD, psychosocial problems, and comorbidity into adulthood. We have also learned that a severe psychiatric disorder, schizophrenia, which has an onset in late adolescence or early adulthood, is commonly associated with substance use disorders and that use of substances worsens the course of schizophrenia. Research advances in these areas have sparked a growing interest to further our understanding of the impact of treatment for psychiatric comorbidity on substance abuse and treatment outcomes.

The 3 presentations in this workshop have highlighted the results of key studies that have advanced research in the field, focusing on those that have evaluated the safety and efficacy of various pharmacotherapies for comorbid depres- sion, ADHD, and schizophrenia and the impact of such treatment on substance abuse. Prelimi- nary conclusions from the studies presented in- dicate that some medications may be safe and efficacious for comorbid disorders even in pa- tients who have not yet achieved abstinence from substances of abuse. Although results must be interpreted with caution, there is some indica- tion that adolescents with comorbid depression or ADHD may be somewhat more responsive to medications for co-occurring disorders com- pared to adults with more chronic and severe his- tories of substance dependence. Taken together, results of current research indicate that pharma- cotherapy for a co-occurring psychiatric comor- bidity alone does little or nothing to reduce drug use in the absence of specific behavioral therapy for SUD. And it is not yet clear that concur- rent treatment of psychiatric comorbidity and SUD improve outcomes for both disorders. Fac- tors related to patient age, comorbidity, chronic- ity, severity, and predominant type of substance abused are all likely to have influenced study out- comes and interpretation of the mixed research findings to date. These factors coupled with the methodological limitations of current research have not yet produced sufficiently clear and con- vergent results to enable derivation of generaliz- able clinical implications. Important directions for future research include:

1. Research, with appropriate design method- ology, is needed to enhance our under- standing of the separate and combined effects of behavioral interventions and pharmacotherapy for SUD and comorbid- ity in adolescents and adults.

2. Research is needed to identify similar- ities of symptoms and neurobiology of common co-occurring disorders and ad- diction. Understanding cotnmon features/ overlapping neurobiological similarities/ symptoms could help guide medication de- velopment of pharmacotherapies to poten- tially target not one but both SUD and comorbidity (see below).

60 SUBSTANCE ABUSE

3. We need to develop and test medications that have the potential to directly tar- get both SUD and comorbidity through amelioration of the presumed underly- ing neurobiological (e.g., brain reward) dysfunction. We also need to conduct larger controlled trials of medications al- ready showing promise, including:

a. Clozapine—an atypical antipsy- chotic with the seeming ability to decrease alcohol and other substance abuse in patients with schizophrenia.

b. Bupropion—an antidepressant that is therapeutically helpful for ma- jor depressive disorder, ADHD, and nicotine dependence, as well as potentially reducing metam- phetamine/cocaine (77) use and craving, or cannabis craving.

4. We need medication development to aug- ment psychosocial treatment outcomes and bolster relapse prevention efforts. Consid- erations in medication development for adolescents with SUD include:

a. New medications are needed that can target both SUD and one or more psychiatric comorbidities (e.g., be- yond bupropion and clozapine).

b. Existing and new medications should be evaluated for use in pa- tients with cannabis use disorder, the most common SUD bringing teenagers into treatment.

5. Research is needed to evaluate neuro- biological/HPA axis, neuroimaging, or other relevant biomarker responses to both pharmacotherapy and behavioral/ psychotherapy treatment modalities.

a. Does treatment impact your brain re- ward system?

b. Is internalized motivation that allows for sustained abstinence able to mod- ify brain reward dysfunction? Know- ing this will allow us to determine what types of interventions may be most helpful therapeutically.

6. Research is needed to develop sophisti- cated study design methods and innova- tive biostatistical approaches to data to disentangle the directionality and/or tem- poral relationships between change in drug use and change in depression or symptoms from other psychiatric comorbidities.

7. Research is needed to refine assessment instruments evaluating withdrawal/craving and symptoms of common co-occurring psychiatric conditions.

8. Research is needed to establish the utility of managing adult ADHD patients with co- occurring substance abuse disorders. New psychostimulants and new formulations of old psychostimulants should be evaluated for their ability to improve symptoms of ADHD and also to reduce substance abuse in patients with ADHD.

9. Mechanistic studies should be carried out in substance abusing patients with ADHD to establish pharmacological effects on cognition as a function of dose and time.

10. More research is needed on the effect of second-generation antipsychotic med- ications on the management of substance abuse in patients with schizophrenia, par- ticularly those in the early phase of illness. Special emphasis should be given to cloza- pine.

11. More research is needed in schizophrenic patients on ancillary medications such as naltrexone and topiramate for their possi- ble ability to reduce substance abuse.

12. Mechanistic research is needed to vali- date the hypothesis of an imbalance in dopaminergic systems in patients with schizophrenia and its possible ameliora- tion by medications.

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