Substance use disorders in adolescents with psychiatric comorbidity: When to screen and how to treat

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).