Timothy Wilens, MD

Timothy Wilens, MD, talks about the presentation of the APSARD 2021 conference on ADAIR Pharmacokinetics and Pharmacodynamic Data. More on the presentation can be found 

is chief of the Division of Child and Adolescent Psychiatry and is co-director of the Center for Addiction Medicine at Massachusetts General Hospital.

Videos

What observations are being noted in the field with new agents for the treatment of ADHD?

New Deterrent Stimulants for ADHD

Academy of Pediatrics Clinical Practice Guidelines

Screening for ADHD and Comorbidities

Collaborative Management: Pediatricians and Psychiatrists

Managing ADHD During the COVID-19 Pandemic

The Impact of COVID-19 Pandemic on Pediatrics 

Practical Advice for Caregivers During COVID-19 Pandemic 

Medicine Management During COVID-19 Pandemic

Unmet Needs in Pediatric ADHD Management

Stimulant Abuse in Pediatric ADHD Populations

The Future of the ADHD Treatment Landscape

A discussion on the multidisciplinary management of ADHD, challenges in treatment during COVID-19, and the impact of human abuse potential of ADHD medications. 

ADHD: Strategies for Developing a Further Dialogue

Substance use disorders (SUDs) are associated with significant morbidity and mortality that affects individuals and their families. Problems with substance use most often emerge during adolescence and young adulthood. Adolescent-onset SUDs are becoming the most significant public health problem affecting adolescents.

 Recent work by Merikangas and colleagues

 showed that 11.4% of adolescents have an SUD, yet only 15.4% of those youths receive treatment. Preventing the onset of an SUD in adolescence remains a critical area of clinical and public health significance.

Familial influence-biological and behavioral

Clinicians and researchers have long observed that SUDs frequently affect multiple members within families over different generations. Researchers have found that approximately 50% of the risk of substance abuse or dependence in adolescence is genetically influenced.

 The transition between stages of use, from regular use to abuse and dependence is also genetically influenced, although the relative genetic contribution compared with environmental influences varies by substance.

 found that a common genetic influence accounts for comorbid substance use during adolescence, specifically problem use of tobacco, alcohol, and cannabis.

Behavioral modeling of substance use through exposure to parental substance use early in life also accounts for part of the familial association in SUDs. The association between exposure to parental SUDs and the development of an SUD in offspring is consistent with social learning theory. A review by Petraitis and colleagues

 further described social learning theory as the hypothesis that children model their behavior on people who are important to them and those they frequently interact with, such as their parents. The researchers also reviewed social control theory, which hypothesizes that children who are closely attached to their parents are less likely to break rules because they want to connect with their parents. Children who are closely monitored by their parents and have clear rules are also more likely to conform to their parent’s rules and are less likely to act out by abusing substances.

There is evidence that supports the principles of social learning theory and social control theory. Researchers have examined components of both theories by assessing the relationship between adolescent substance use and parental attitudes toward substances, parental substance use, the quality of the relationship between parent and child, and parental monitoring. Bahr and colleagues

 found that the family factors that were most strongly associated with an increased prevalence of binge drinking, cigarette use, cannabis use, and illicit drug use were tolerant parental attitudes and sibling substance use. In addition, adolescents who had parents who were tolerant of substance use interacted with higher-risk peers and were more likely to have friends who were substance users.

Exposure to parental substance use increases children’s risk

To understand familial patterns of SUD, family-based research has focused on differentiating between risk mediated primarily by genetics from risk mediated primarily by behavioral modeling through exposure to parental SUD and delineating the risk posed by the combination of both. In a larger longitudinal study of predominantly males with and without ADHD, Biederman and colleagues

 found an association between exposure to parental SUD and SUD in offspring after controlling for both family history and ADHD.

We recently evaluated a predominantly female sample with and without ADHD.

 In this study of 552 individuals of whom 71% were female, a specific association was found between exposure to maternal drug use disorders (primarily cannabis) and drug use disorders in female offspring after controlling for family history and ADHD. In other words, mothers who abused drugs increased the likelihood that their daughters would also abuse drugs. Interestingly, research findings have not shown consistent sex patterns when the risk associated with exposure to parental substance abuse was examined.

 Our finding of a specific risk between mothers and daughters may reflect the greater impact that interpersonal relationships have on an adolescent girl’s risk of using substances relative to the risk in adolescent boys.

It is also important to consider whether the developmental timing of exposure to parental substance use may influence the chances that the child will develop an SUD. For instance, Biederman and colleagues

 assessed offspring risk of developing an SUD connected with exposure to parental SUD during different developmental stages. Predominantly, boys were at significantly greater risk for developing an SUD when they were exposed to parental SUDs during adolescence than when they were exposed during preschool and latency years.

In our predominantly female sample, we also found that exposure to parental SUD during adolescence was specifically associated with an increased risk of developing an SUD.

 It is unclear why adolescents are particularly vulnerable to exposure to parental substance use; it may be that behavioral modeling of use at a time when adolescents have greater ease of access to substances partially accounts for their increased risk.

What is already known about familial influences and adolescent substance use disorders (SUDs)? 
? The development of adolescent-onset SUDs is influenced by both genetic and environmental risk factors. Familial environmental risk factors include behavioral modeling of substance use, parental attitudes toward substance use, and parental monitoring.

What new information does this article provide? 
? Adolescent girls exposed to maternal drug use disorders are at increased risk for developing a drug use disorder. Exposure to parental SUDs specifically during adolescence increases a child’s risk of developing an SUD.

What are the implications for psychiatric practice? 
? Practitioners may be able to prevent adolescent-onset SUDs by screening for parental SUDs and educating families about the risks associated with exposure to parental SUDs.

While genetic risk for SUD is a nonmodifiable risk factor that influences the development of adolescent-onset SUD, exposure to parental SUD is something that can, theoretically, be changed. Psychiatrists may help decrease the risk of adolescent SUD by educating parents about the power of behavioral modeling. Many parents of adolescents, for instance, still smoke marijuana regularly without considering the consequences of such use on their children.

Clinicians should assess parents for substance use in a nonjudgmental manner.

 Brief interventions such as the Substance Abuse and Mental Health Services Administration’s recent screening, brief intervention, and referral to treatment (SBIRT) initiative have been shown to be effective in decreasing both alcohol and drug use.

 Parental screening and subsequent modifications in patterns of substance use may thus decrease the risk of development of SUDs in children.

Kate, a 13-year-old girl with ADHD and general anxiety who you have been treating for 2 years, presents for a routine psychopharmacological appointment with her mother. Kate’s mother reports that things have been more stressful at home. You remember that the patient’s mother has a psychiatric history significant for previous marijuana dependence.

Because Kate’s mother has a history of marijuana dependence, it is important to privately check with her to ask about recent marijuana use as well as other substance use. Discuss with the mother how her marijuana use may increase her daughter’s risk for drug abuse.

George, a 40-year-old father with depression who has a 10-year-old son and a 13-year-old daughter, presents with increasing alcohol use. Lately he has been passing out after drinking in the evening. George does not think that his drinking is a problem.

In this case, it may be useful to carefully query George about his perception of how his drinking is affecting his family. It would also be helpful to educate him about his adolescent daughter’s increased risk of substance use problems given her exposure to his choices and behavior patterns.

In addition to modifying an adolescent’s risk of developing an SUD by minimizing his or her exposure to a parent’s modeling substance use, clinicians can educate parents about the principles of social control theory. The risk of SUD onset is decreased in children whose parents know what their children are doing. Parental control also decreases the risk that the child will have friends who use alcohol or drugs.

SUDs in adolescents interfere with emotional and cognitive development and can be associated with long-term medical and legal consequences. There is a substantial genetic influence on the development of SUDs. The aggregate data also show that other familial factors that can be modified, such as exposure to parental SUDs particularly during adolescence, are significant as well. Conscious efforts to screen for parental SUDs and educate families about exposure risk may help prevent the onset of substance abuse during adolescence.

 The National Center on Addiction and Substance Abuse at Columbia University. Adolescent Substance Use: America’s #1 Public Health Problem. June 2011.

 http://www.casacolumbia.org/templates/NewsRoom.aspx?articleid=631&zoneid=5

 Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental disorders in US adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). 

 Merikangas KR, He JP, Burstein M, et al. Service utilization for lifetime mental disorders in US adolescents: results of the National Comorbidity Survey-Adolescent Supplement (NCS-A). 

 Lynskey MT, Agrawal A, Heath AC. Genetically informative research on adolescent substance use: methods, findings, and challenges. 

 Young SE, Rhee SH, Stallings MC, et al. Genetic and environmental vulnerabilities underlying adolescent substance use and problem use: general or specific? 

Petraitis J, Flay BR, Miller TQ. Reviewing theories of adolescent substance use: organizing pieces in the puzzle. 

 Bahr SJ, Hoffmann JP, Yang X. Parental and peer influences on the risk of adolescent drug use. 

 Biederman J, Faraone SV, Monuteaux MC, Feighner JA. Patterns of alcohol and drug use in adolescents can be predicted by parental substance use disorders. 

 Yule AM, Wilens TE, Martelon MK, et al. Impact of exposure to parental substance use disorders (SUD) on SUD risk in girls and their siblings. Poster presented at: 57th Annual American Academy of Child and Adolescent Psychiatry Meeting; October 27, 2010; New York.


 Chassin L, Curran PJ, Hussong AM, Colder CR. The relation of parent alcoholism to adolescent substance use: a longitudinal follow-up study. 

 Yeh MY, Chiang IC, Huang SY. Gender differences in predictors of drinking behavior in adolescents. 

 Eisenberg ME, Neumark-Sztainer D, Fulkerson JA, Story M. Family meals and substance use: is there a long-term protective association? 

 Simmons LA, Havens JR, Whiting JB, et al. Illicit drug use among women with children in the United States: 2002-2003. 

Articles

Substance use disorders are associated with significant morbidity and mortality that affects individuals and their families. Preventing the onset of an SUD in adolescence remains a critical area of clinical and public health significance.

Familial Influences on Adolescent Substance Use

The overlap between attention-deficit/ hyperactivity disorder and alcohol or drug abuse or dependence (referred to here as substance use disorders [SUDs]) in adolescents has been an area of increasing clinical, research and public health interest. Appearing in early childhood, ADHD affects from 6% to 9% of children and adolescents worldwide (Anderson et al., 1987) and up to 5% of adults (Kessler, in press). Longitudinal data suggest that childhood ADHD persists into adolescence in 75% of cases and into adulthood in approximately one-half of cases (for review, see Weiss, 1992). Substance use disorders usually appear in adolescence or early adulthood and affect between 10% to 30% of U.S. adults and a less defined, but sizable, number of juveniles (Kessler, 2004). The study of comorbidity between SUDs and ADHD is relevant to both research and clinical practice in developmental pediatrics, psychology and psychiatry with implications for diagnosis, prognosis, treatment and health care delivery.

Structured psychiatric diagnostic interviews assessing ADHD and other disorders in substance-abusing groups have indicated that from one-third to one-half of adolescents with SUDs have ADHD (DeMilio, 1989; Milin et al., 1991). For example, aggregate data from government-funded studies of mainly cannabis-abusing youth indicate that ADHD is the second most common comorbidity with from 40% to 50% of both girls and boys manifesting full criteria for ADHD. Data largely ascertained from adult groups with SUDs also show an earlier onset and more severe course of SUD associated with ADHD (Carroll and Rounsaville, 1993; Levin and Evans, 2001).

ADHD as a Risk Factor or Precursor for SUD

The association of ADHD and SUDs is particularly compelling from a developmental perspective as ADHD appears to manifest itself earlier than the SUD; therefore, the SUD is an unlikely risk factor for ADHD. Thus, it is important to evaluate to what extent ADHD is a precursor of SUDs. Prospective studies of children with ADHD have provided evidence that the group with conduct or bipolar disorders co-occurring with ADHD have the poorest outcome with respect to developing SUDs and major morbidity (Biederman et al., 1997; Mannuzza et al., 1993). As part of an ongoing prospective study of ADHD, it was found that differences in the risk for SUDs in adolescents with ADHD (mean age=15) compared to controls without ADHD were accounted for by comorbid conduct or bipolar disorders (Biederman et al., 1997). However, it also has been shown that the age of risk for SUD onset in adolescents without comorbid ADHD is approximately 17 years in girls and 19 years in boys (Biederman et al., in press-a; Milberger et al., 1997b). These findings were confirmed by Katusic and associates (2005) and Molina and Pelham (2003), who have shown elevated risk of SUDs in adolescents with ADHD.

. Clarification of the critical influence of ADHD treatment in youth on later SUDs remains hampered by methodological issues. Since prospective studies in youth with ADHD are naturalistic, and hence not randomized for treatment, attempts to disentangle positive or deleterious effects of treatment from the severity of the underlying condition(s) are hampered by serious confounds. Whereas concerns of the abuse liability and potential kindling of specific types of abuse (e.g., cocaine) secondary to early stimulant exposure in children with ADHD have been raised (Drug Enforcement Administration, 1995; Vitiello, 2001), the preponderance of clinical data do not appear to support such a contention.

To reconcile findings in this important area, my group completed a meta-analysis of the literature (Faraone and Wilens, 2003; Wilens et al., 2003). We included studies examining the later risk of SUDs in children exposed to stimulant pharmacotherapy, identifying two studies into adolescence and five studies into adulthood. We found that stimulant pharmacotherapy did not increase the risk for later SUDs. In fact, we found that stimulant pharmacotherapy protected against later SUDs (odds ratio of 1.9) and that the effect was stronger in adolescents relative to adults (Wilens et al., 2003). It is notable that the magnitude of risk reduction (e.g., 50% reduction in risk) indicated that the ultimate risk of SUDs in treated individuals with ADHD may approximate the level of risk in individuals without ADHD (general population).

An increasing body of literature shows an intriguing association between ADHD and cigarette smoking. It has been previously reported that ADHD is a significant predictor for early initiation of cigarette smoking (before age 15) and that conduct and mood disorders comorbid with ADHD put youth at particularly high risk for early-onset smoking (Milberger et al., 1997a) (

). Data also suggest that one-half of smokers with ADHD go on to later SUDs (Biederman et al., in press-b). This is not surprising given that not only does smoking lead to peer group pressures and availability of illicit substances, but that nicotine exposure may make the brain more susceptible to later behavioral disorders and SUDs (Trauth et al., 2000). Furthermore, nicotinic-modulating agents are increasingly being evaluated for the treatment of ADHD (Wilens et al., in press-b). Of interest, prospective data funded by the National Institute on Drug Abuse suggest that stimulant treatment of ADHD reduces not only the time to onset but also the incidence of cigarette smoking (Monuteaux, 2004).

The precise mechanism(s) mediating the expression of SUDs in ADHD remains to be seen. The self-medication hypothesis is compelling in ADHD considering that the disorder is chronic and often associated with demoralization and failure, factors frequently associated with SUDs in adolescents. Moreover, it has been found that among substance-abusing adolescents with and without ADHD, adolescents with ADHD reported using substances more frequently to attenuate their mood and to help them sleep. No evidence of differences in types of substances has emerged between substance-abusing teen-agers with or without ADHD (Biederman et al., 1997). In addition, the potential importance of self-medication needs to be tempered against more systematic data showing the strongest association between ADHD and SUDs is comorbidity and familial contributions, such as exposure to parental SUDs during vulnerable developmental phases.

Evaluation and treatment of comorbid ADHD and SUDs should be part of a plan in which consideration is given to all aspects of the teen-ager's life. Any intervention in this group should follow a careful evaluation of the adolescent including psychiatric, addiction, social, cognitive, educational and family evaluations. A thorough history of substance use should be obtained that includes past and current usage and treatments. Although no specific guidelines exist for evaluating the patient with an active SUD, in my experience at least one month of abstinence is useful in accurately and reliably assessing for ADHD symptoms. Semi-structured psychiatric interviews or validated rating scales of ADHD are invaluable aids for the systematic diagnostic assessments of this group.

The treatment needs of individuals with SUDs and ADHD need to be considered simultaneously; however, the SUD needs to be addressed initially (Riggs, 1998). If the SUD is active, immediate attention needs to be paid to stabilization of the addiction(s). Depending on the severity and duration of the SUD, adolescents may require inpatient treatment. Self-help groups offer a helpful treatment modality for many with SUDs. In tandem with addiction treatment, adolescents with co-occurring SUDs and ADHD require intervention(s) for the ADHD as well as other co-occurring psychiatric disorders.

Medication serves an important role in reducing the symptoms of ADHD and other concurrent psychiatric disorders. Effective agents for adolescents with ADHD include the stimulants, noradrenergic agents and catecholaminergic antidepressants (Wilens et al., 2002). Findings from a meta-analysis of 10 studies of open and controlled trials suggest that medications used in adolescents and adults with ADHD plus SUDs have only a meager effect on the ADHD, but have little effect on substance use or cravings (Riggs et al., 2004; Schubiner et al., 2002; Wilens et al., 2005). Of interest, no evidence exists that treating ADHD pharmacologically through an active SUD exacerbates the SUD. This is consistent with the work of Grabowski et al. (2004), who used stimulants to block cocaine and amphetamine abuse. Also consistent with these findings, earlier work by Volkow et al. (1998) demonstrated significant differences between binding at the dopamine transporter between methylphenidate and cocaine, suggesting a much smaller abuse risk for methylphenidate in contrast to cocaine.

In ADHD adults with SUDs, the nonstimulant agents (atomoxetine [Strattera]), antidepressants (bupropion [Wellbutrin]), and extended-release or longer-acting stimulants with lower abuse liability and diversion potential are preferable (Riggs, 1998). While of particular interest because of the drug's broad spectrum of activity in ADHD and lack of abuse liability (Heil et al., 2002), results from ongoing trials of atomoxetine in SUDs are not yet available. In individuals with SUDs and ADHD, frequent monitoring of pharmacotherapy should be undertaken--including evaluation of compliance with treatment, use of questionnaires (Gignac et al., 2005), random toxicology screens as indicated, and coordination of care with addiction counselors and other caregivers.

. Surprisingly, limited information is available on the inappropriate use of stimulants in terms of the magnitude of the problem and the characteristics of misuse in individuals for whom they are prescribed. Musser et al. (1998) surveyed 161 children with ADHD responding to methylphenidate in order to assess diversion. The authors reported that 16% of children had been approached to sell or give away their prescribed medication; however, the actual rates of diversion were not reported. Marsh et al. (2000), using a retrospective review of the medical charts of 240 adolescents with ADHD, reported that 12% had misused their methylphenidate, although the characteristics of those youth were not reported. Poulin (2001) surveyed 13,549 students in grades 7 through 12 and found that 8.5% had used nonprescribed stimulants in the year prior to the survey. Of those students who were receiving prescribed stimulants, 14.7% had given their medications and 7.3% had sold their medication to other students. Similar to other studies, those to whom the stimulants were diverted misused the stimulants in context with other substances of abuse.

Similarly, we recently found that 11% of adolescents and young adults with ADHD diverted (sold) and 22% had misused their stimulants (e.g., escalated dose, used with other substances, became euphoric) (Wilens et al., in press-a). We also found that ADHD individuals with conduct disorder or SUDs accounted for the misuse and diversion and that there appeared to be more misuse and diversion of immediate-release compared to extended-release stimulants (Wilens et al., in press-a).

There is a strong literature supporting a relationship between ADHD and SUDs. Both family/genetic and self-medication influences may be operational in the development and continuation of SUDs in ADHD. Adolescents with ADHD and SUDs require multimodal interventions incorporating addiction and mental health treatment. Pharmacotherapy in individuals with ADHD and SUDs needs to take into consideration timing, misuse and diversion liability, potential drug interactions, and compliance concerns.

While the existing literature has provided important information on the relationship of ADHD and SUDs, it also points to a number of areas in need of further study. The mechanism by which untreated ADHD leads to SUDs, as well as the risk reduction of ADHD treatment on cigarette smoking and SUDs, needs to be better understood. Given the prevalence and major morbidity and impairment caused by SUDs and ADHD, prevention and treatment strategies for these adolescents need to be further developed and evaluated.

This research was supported by National Institutes of Health grants R01 DA14419 and K24 DA016264 to Dr. Wilens.

 Anderson JC, Williams S, McGee R, Silva PA (1987), DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population. Arch Gen Psychiatry 44(1):69-76.


 Biederman J, Monuteaux M, Mick E et al. (in press-a), Young adult outcome of attention deficit hyperactivity disorder: a controlled 10 year prospective follow-up study. Psychol Med.


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 Biederman J, Wilens T, Mick E et al. (1997), Is ADHD a risk for psychoactive substance use disorder? Findings from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 36(1):21-29.


 Carroll KM, Rounsaville BJ (1993), History and significance of childhood attention deficit disorder in treatment-seeking cocaine abusers. Compr Psychiatry 34(2):75-82.


 DeMilio L (1989), Psychiatric syndromes in adolescent substance abusers. Am J Psychiatry 146(9):1212-1214.


 Drug Enforcement Administration (1995), Methylphenidate Review Document. Washington, D.C.: Office of Diversion Control, Drug and Chemical Evaluation Section.


 Faraone SV, Wilens T (2003), Does stimulant treatment lead to substance use disorders? J Clin Psychiatry 64(suppl 11):9-13.


 Gignac M, Wilens TE, Biederman J et al. (2005), Assessing cannabis use in adolescents and young adults: what do urine screen and parental report tell you? J Child Adolesc Psychopharmacol 15(5):742-750.


 Grabowski J, Shearer J, Merrill J, Negus SS (2004), Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29(7):1439-1464.


 Heil SH, Holmes HW, Bickel WK et al. (2002), Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 67(2):149-156.


 Katusic SK, Barbaresi WJ, Colligan RC et al. (2005), Psychostimulant treatment and risk for substance abuse among young adults with a history of attention-deficit/hyperactivity disorder: a population based, birth cohort study. J Child Adolesc Psychopharmacol 15(5):764-776.


 Kessler R (in press), A recent replication of the National Comorbidity Study estimating the prevalence of adult ADHD among persons 18-44 in the US. Psychol Med.


 Kessler RC (2004), The epidemiology of dual diagnosis. Biol Psychiatry 56(10):730-737.


 Levin FR, Evans SM (2001), Diagnostic and treatment issues in comorbid substance abuse and adult attention-deficit hyperactivity disorder. Psychiatric Annals 31(5):303-312.


 Mannuzza S, Klein RG, Bessler A et al. (1993), Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 50(7):565-576.


 Marsh LD, Kay JD, Payne TP (2000), Methylphenidate misuse in substance abusing adolescents. Journal of Child and Adolescent Substance Abuse 9(3):1-14.


 Milberger S, Biederman J, Faraone SV et al. (1997a), ADHD is associated with early initiation of cigarette smoking in children and adolescents. J Am Acad Child Adolesc Psychiatry 36(1):37-44.


 Milberger S, Biederman J, Faraone SV et al. (1997b), Associations between ADHD and psychoactive substance use disorders. Findings from a longitudinal study of high-risk siblings of ADHD children. Am J Addict 6(4):318-329.


 Milin R, Halikas JA, Meller JE, Morse C (1991), Psychopathology among substance abusing juvenile offenders. J Am Acad Child Adolesc Psychiatry 30(4):569-574.


 Molina BS, Pelham WE (2003), Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. J Abnorm Psychol 112(3):497-507.


 Monuteaux MC (2004), A randomized, double-blind, placebo-controlled clinical trial of bupropion for the prevention of smoking in youth with attention-deficit/hyperactivity disorder. Presented at the National Cancer Institute's Tobacco Investigators' Meeting: Synthesizing Research for the Public's Health. San Diego; June 2-4.


 Musser CJ, Ahmann PA, Theye FW et al. (1998), Stimulant use and potential for abuse in Wisconsin as reported by school administrators and longitudinally followed children. J Dev Behav Pediatr 19(3):187-192.


 Poulin C (2001), Medical and nonmedical stimulant use among adolescents: from sanctioned to unsanctioned use. CMAJ 165(8):1039-1044 [see comment].


 Riggs PD (1998), Clinical approach to treatment of ADHD in adolescents with substance use disorders and conduct disorder. J Am Acad Child Adolesc Psychiatry 37(3):331-332.


 Riggs PD, Hall SK, Mikulich-Gilbertson SK et al. (2004), A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents. J Am Acad Child Adolesc Psychiatry 43(4):420-429.


 Schubiner H, Saules KK, Arfken CL et al. (2002), Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10(3):286-294.


 Trauth JA, Seidler FJ, Slotkin TA (2000), Persistent and delayed behavioral changes after nicotine treatment in adolescent rats. Brain Res 880(1-2):167-172.


 Vitiello B (2001), Long-term effects of stimulant medications on the brain: possible relevance to the treatment of attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11(1):25-34.


 Volkow ND, Wang GJ, Fowler JS et al. (1998), Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155(10):1325-1331.


 Weiss G (1992), Child and Adolescent Psychiatric Clinics of North America: Attention-Deficit/Hyperactivity Disorder. Philadelphia: W.B. Saunders Company.


 Wilens TE, Biederman J, Spencer TJ (2002), Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med 53:113-131.


 Wilens TE, Faraone SV, Biederman J, Gunawardene S (2003), Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111(1):179-185.


 Wilens TE, Gignac M, Swezey A et al. (in press-a), Characteristics of adolescents and young adults with ADHD who divert or misuse their prescribed medications. J Am Acad Child Adolesc Psychiatry.


 Wilens TE, Monuteaux MC, Snyder LE, Moore H (2005), The clinical dilemma of using medications in substance abusing adolescents and adults with ADHD: what does the literature tell us? J Child Adolesc Psychopharmacol 15(5):787-798.


 Wilens TE, Verlinden MH, Adler LA et al. (in press-b), ABT-089, a neuronal nicotinic receptor modulator, for the treatment of ADHD in adults: results of a pilot study. Biol Psychiatry.

There has been increasing interest in the overlap between attention-deficit/hyperactivity disorder and substance use disorders. Pharmacotherapeutic treatment of ADHD in children reduces the risk for later SUD in adolescence and adulthood. In contrast, medication treatment of substance-abusing adolescents with ADHD does not reduce the SUD. Diagnostic and treatment strategies for adults with ADHD plus SUDs are discussed.

Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders in Adolescents

Recent work has established that, contrary to being uncommon, childhood-onset bipolar disorder (BD) may account for a significant number of child psychiatry referrals (Faedda et al., 1995; Geller and Luby, 1997; Weller et al., 1995; Weller et al., 1986). Studies indicate that up to 16% of youth in child psychiatry clinics may have BD (Wozniak et al., 1995). Moreover, children with major depression are at high risk to develop BD (Geller et al., 1994; Strober and Carlson, 1982). Bipolar disorder in children and adolescents is often familial (Chang et al., 2000; Strober, 1992; Strober et al., 1988). Current limited data suggest children with BD have a chronic course of the illness, characterized by continued morbidity, comorbidity and mood cyclicity (Geller et al., 2001; Geller et al., 2002). 

By adult standards, children with BD present with an atypical clinical picture, with irritability, mixed presentation and chronicity (Ballenger et al., 1982; Weller et al., 1995; Wozniak et al., 2001). While severe irritability can be a common characteristic in children with or without a psychiatric diagnosis, the irritability associated with mania has a much more hostile, vicious and attacking quality (Davis, 1979). In addition to a general level of irritability, children with mania also present with extremely impairing dysphoric, explosive episodes that generally occur daily with little or no precipitant. These explosions can last up to an hour or longer and may involve destruction of property such as kicking holes in walls and throwing and breaking household items. During these rages, children are hard to calm and often lash out physically at those around them. Swearing and hostile comments are also common. Parents almost universally say they "walk on eggshells" out of fear of these unpredictable outbursts (Wozniak et al., 2001).

Descriptions of euphoric moods are generally elicited by inquiring for giddy, goofy, hyperexcited, silly states with laughing fits. Parents often describe the child acting in an immature, clownish manner to the extent of alienating others. Grandiosity or flight of ideas can occur in the euphoric or irritable states. Parents also describe their children as having an extreme degree of grandiose defiance, refusing to comply with authority at home or at school. Children with BD often have comorbid oppositional defiant disorder (Wozniak et al., 2001). The defiant state has a grandiose quality that generates problems at home, in school, and in sports or other activities. Children will believe themselves to "know better" than adults around them and on this basis refuse to comply with what they see as petty or "stupid" demands put on them. These children are often labeled as having "an attitude problem" and inspire the anger of adults. 

Little is known about the variations between mania and depression in children and adolescents with BD. In our sample of children meeting criteria for mania, 86% have also had a depressive episode, and 90% have had the depressive episode overlap in time with the manic episode, representing a mixed state (Wozniak et al., 1995; Wozniak et al., 1993). This is usually described as children unpredictably switching in and out of depression, irritable mania with explosions and euphoric mania throughout the day, almost every day, with very little time spent in a regular age-appropriate mood state. Such a state has been referred to as 

 (Geller et al., 1995) and has been noted by a number of investigators (Findling and Calabrese, 2000; Wozniak et al., 1995). Because of the switching among these mood states, it is very difficult for some parents to agree that the child has had a full week of irritability or a full week of euphoria as required by some clinicians. On the other hand, parents describe periods of a mix of abnormal mood states spanning years with little normalcy. A better characterization, then, would be abnormal moods present almost every day, most of the days, for a majority of the time. 

Bipolar disorder generally has an insidious onset in children. In our sample, nearly one-quarter of parents could not identify an age of onset, but felt that the child had "always" had an abnormal mood, even by infant standards (Wozniak et al., 1995). Of the children with the abnormal mood states noted above, the average age of onset of the manic syndrome was 4.4 years with 70% described as beginning under age 5. 

Preschoolers with BD share many clinical characteristics of BD with their older counterparts. We recently described the clinical characteristics and functioning of 44 preschoolers (4 to 6 years of age) with BD and compared them to 29 school-aged children (7 to 9 years) with BD (Wilens et al., 2002). We found that preschoolers had similar rates of comorbid psychopathology of attention-deficit/hyperactivity disorder, disruptive disorders and anxiety disorders compared to school-aged youth. Preschoolers and school-aged children with BD typically manifest symptoms of mania and depression simultaneously (mixed states). Both preschoolers and school-aged children had substantial impairment in (pre)school, social and overall functioning. 

Whereas children under age 12 with BD have almost universal comorbidity with ADHD, there is a 57% rate of ADHD in adolescent-onset BD and a 13% rate of ADHD in adult-onset BD (Sachs et al., 2000; West et al., 1995; Wozniak et al., 1995). These aggregate findings have led to the conclusion that comorbidity with ADHD might be a marker for very-early-onset BD (Faraone et al., 1997). Bipolar disorder may also develop in youth with ADHD. In a well-characterized sample of boys with ADHD followed longitudinally, analysis of structured interview data revealed that at ascertainment, 11% of the sample met criteria for mania. Four years later at follow-up,  an additional 12% of the subjects had developed mania (Biederman et al., 1996a, 1996b).

Diagnostically, BD and ADHD share many symptoms. In one sample, however, 76% of children with mania still retained full or subthreshold diagnostic status even when subtracting the overlapping symptoms from the algorithm (Milberger et al., 1995). Studies that attempt to distinguish children with mania from children with ADHD note that children with mania generally have greater psychopathology and poorer functioning (Nieman and DeLong, 1987). Children with mania versus children with ADHD also have statistically significantly lower functioning, as well as statistically significantly higher scores on the Child Behavior Checklist (CBCL) subscales of aggression, psychosis and anxiety/depression (Biederman et al., 1995). The ADHD rating scales typically cannot distinguish children with mania and children with ADHD from each other. However, if an instrument such as the Mania Rating Scale (which asks questions specific to symptoms of mania) is used, children with mania can be identified (Fristad et al., 1992). In general, it is important to note that the ADHD criteria do not include a mood component. Thus, if the chief complaint or presenting symptom on examination is "severe moodiness," a mood disorder diagnosis should be considered (Wilens et al., in press).

In addition to ADHD, children with BD have high levels of comorbidity with conduct, anxiety and substance use disorders. Conduct disorder (CD) is a severe condition both from an individual as well as public health perspective, as it represents early antisocial behavior and many of these youngsters come to the attention of the criminal justice system. Various reports have documented an overlap between BD and CD, noting that the comorbid condition heralds a more complicated course. Family genetic work comparing rates of mania and antisocial disorders, as well as the combined condition in relatives of probands stratified by the presence or absence of these disorders, revealed high rates of conduct disorder or antisocial personality disorder (ASPD) in the relatives (Biederman et al., 1997). Further analysis demonstrated the presence of two types of CD/ASPD in the relatives of children with both CD and BD: CD/ASPD with mania ("dysphoric conduct disorder") and CD/ASPD without mania. The issue is clinically an important one: When an irritable and grandiose youngster with mania lies, steals or vandalizes, is it due to the disinhibition of the manic state or is it due to a coexisting antisocial personality? In such cases, if the mania is well-treated, would the conduct problems improve? The answers to these questions, not fully answered, could determine whether such a child should be treated in the mental health care system or enter the criminal justice system.

Juvenile-onset BD may be an important risk factor for substance use disorders (SUD) as well (West et al., 1996; Wilens et al., 2000; Wilens et al., 1999). We have shown that juvenile BD is a risk factor for early cigarette smoking (Wilens et al., 2000) and substance use (Wilens et al., 1999). Of interest, the highest risk for SUD is in individuals with adolescent-onset BD--who have as marked a risk for developing SUD as adolescents with CD (Wilens et al., 1999). It appears that the bulk of SUD in relationship to BD occurs secondary to mania--probably representing some form of self-medication phenomena; however, important family genetic contributions to SUD in this group cannot be ruled out. Of interest, in one controlled study by Geller and associates (1998), lithium (Eskalith, Lithobid) treatment decreased symptoms of both SUD and BD in adolescents, highlighting the importance of a careful clinical history for SUD in BD as well as BD in SUD adolescents--especially those with binge or remarkably excessive patterns of SUD. 

Few studies are available to guide empirically the treatment of BD in children and adolescents. A small literature has addressed the use of mood-stabilizing medications (valproic acid [Depakote], carbamazepine [Tegretol], lithium carbonate) in this patient population, however, much of this literature is limited by the lack of controlled clinical trials. Lithium, alone and in combination with other medications, is one of the original treatments for bipolar states in youth and continues to be an effective agent, albeit with a number of adverse effects and the need for aggressive monitoring (DeLong, 1978; DeLong and Aldershof, 1987; Kafantaris, 1995).

As part of a multisite study of divalproex sodium, Wagner and colleagues (2002) recently reported improvement in children with BD, replicating work by others (West et al., 1994). Biederman et al. (1998) systemically reviewed the clinical records of all pediatric referral patients with BD and showed that mood stabilizers were associated with significant improvement, albeit relatively slow, of the symptoms of BD. For both lithium and carbamazepine, higher doses and blood levels predicted greater clinical improvement. 

More recently, Kowatch et al. (2000), in an open study, showed significant improvement in BD symptoms with divalproex, lithium and carbamazepine. In this study, in which chlorpromazine (Thorazine) rescue was used, approximately 30% to 50% of youth improved. Similarly, Findling (2002) reported on preliminary findings from an ongoing 12-week study of lithium and valproate for youth with BD. Improvements not only in mania, but also in depressive features and overall functioning, were reported with this combination.

The advent of the atypical antipsychotics has provided an alternative treatment for this difficult-to-treat population. In a retrospective chart review study of 28 children and adolescents with BD treated with risperidone (Risperdal), 82% of subjects improved rapidly in manic and aggressive symptoms (Frazier et al., 1999). Furthermore, in an eight-week open study of olanzapine (Zyprexa) monotherapy in 23 children and adolescents, significant improvement was noted in both symptoms of mania and depression on doses ranging from 2.5 mg/day to 20 mg/day (Frazier et al., 2001). Both risperidone and olanzapine were well-tolerated. An interesting study by Delbello and colleagues (2002) showed that combined treatment of adolescents with BD with valproate plus quetiapine (Seroquel) resulted in a better outcome compared to valproate alone. Of note, more subjects in the combined group were reported to be "remitted" from their BD.

While the results associated with these studies of the atypical antipsychotic medications are promising, there is a continued need for additional short- and long-term controlled trials of mood-stabilizing medications of all classes. While well-tolerated, weight gain and the possible risk of tardive dyskinesia limit the utility of the atypical antipsychotic medications.

Because childhood-onset BD is a highly comorbid condition, in addition to being treated for BD, most subjects will require a combined pharmacotherapy approach (Wozniak and Biederman, 1996). For instance, when treating BD plus ADHD, studies suggest better outcome and tolerability when treating the BD first and then addressing the ADHD (Biederman et al., 1999). While serotonergic antidepressants are useful in the treatment of depression in BD, careful observation for manic activation is necessary (Biederman et al., 2000). In addition, individuals may require medications for treatment of symptoms of anxiety and obsessive-compulsive disorder that should also be sequenced after the treatment of mania. Because additional medications for ADHD, anxiety and depression may activate mania, these agents must be used cautiously, watching for exacerbation of mood instability.

This work was supported in part by grant RO1 DA12945 (TW).

Dr. Wilens is director of substance abuse services in the pediatric psychopharmacology unit at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School.

Dr. Wozniak is assistant professor of psychiatry at Harvard Medical School.

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