Addiction and ADHD - The Bullet Points

Figure 1.  from Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment.  BMC Med. 2012 Sep 4 10:99 (see ref 6 below).

One of the main concerns in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) is whether treatment improves outcomes.  The outcomes measure of interest may depend on the clinical population that you are focused on treating.   In primary care settings, my impression is that a lot of the adults treated by internists are relatively stable and that they do not have a lot of problems with other mental illnesses or addictions.  That is my speculation based on some of the numbers of adults I have heard are seeing primary care physicians and the fact that seeing those numbers with even a fraction of patients who have additional psychiatric problems or addictions would be unsustainable.  I have also directly observed the pattern that many patients who are discharged from primary care for stimulant overuse or psychiatric complications like mania end up seeing psychiatrists.  As a psychiatrist working in a residential setting that treats substance use problems - trends in overprescribing, misdiagnosis and confusion about the concept of addiction and ADHD treatment are readily observed.  It is very clear that people with clear ADHD can misuse stimulants and continue to insist on using stimulants.  It is clear than many of these people develop insight into this and can say at one point that they can no longer take stimulants even though they have a bona fide ADHD diagnosis.  It is also clear that there is a lot of confusion among treating professionals about the issue of whether or not a stimulant should be prescribed to a person with an addiction.  

There is a lot of overlap between the diagnosis and treatment of Attention-Deficit/Hyperactivity Disorder and addiction or substance use disorders.  Discovering this overlap depends on clinical experience, training and exposure to patients with addictions.  It is fairly common to read studies about ADHD outcomes that may not look at addictions as outcomes.  Like many areas in medicine, some of the early studies in this area have not been borne out by subsequent studies.  The study of this problem has only been a relatively recent endeavor.   The original AHRQ report in 1999 (1) looked at 77 randomized controlled clinical trials included in the time period from 1971 to 1999.  Half of the studies were published since 1990.  At that time there were only 13 adult studies.  The outcome variables were generally improvement on symptomatic rating scales, neuropsychological tests or educational achievement tests.    

Connor's review (2) looks at the studies prior to 2006.  At the time he states that there were a total of 14 studies that looked at potential abuse issues.  One of the studies supported the idea of behavioral sensitization or stimulant administration leading to craving and eventual self administration.   That study did not control for Conduct Disorder, a comorbid condition  that increase the risk of substance use disorders.  The other studies found no increased risk, and in some cases a decreased risk of substance use disorders.  There were no review elements that looked at addictions or substance use disorders.  A meta-analysis of 6 studies by Wilens, et al showed a 1.9 fold reduction in risk in the stimulant treated patients.  Connor's conclusion is that "...in uncontrolled environments, active substance abuse is a relative contraindication to prescribing stimulant medications."  the use of atomoxetine or antidepressants with a known efficacy for ADHD was encouraged (p. 626).

A more recent review by Shaw, et al from 2012 takes a different approach.  The authors looked at studies between 1980 and 2010 with a minimum follow-up period of two years or more (prospective or retrospective) or cross sectional studies that compared two ages differing by two years of more.  Nine separate outcome measures were examined as indicated in Figure 1 at the top of this page.  Since some studies reported more than one outcome measure, a total of 636 outcomes were examined from the 351 studies reviewed for this paper.  Drug use or addictive behavior was one of the most frequently examined outcomes with a total of 160 results.  The next most frequent result was academic functioning with 119 results.  The data is represented as percentage comparisons as improved, similar, or poorer than the comparators.  As an example in Figure 1, the last 4 categories show that treatment was beneficial in 67% of the drug/addictive, 50% of the antisocial, 50% of the service use outcomes, and 33% of the occupational outcomes.  The authors conclude that in these four treatment groups there was no benefit conferred by treatment.  They looked at the issue of treatment of these four groups in the rest of the world and found that there was substantially better outcomes for this subgroup.  There were significant methodological problems noted in the studies including the need to control for Conduct Disorder, Oppositional Defiant Disorder, and a number of other comorbid psychiatric disorders.  Other potential comparison issues between the American and non-American studies included the fact that the American studies were largely prospective, the non-American studies used more stringent ICD-10 codes.  One of the main variables that addiction psychiatrists are focused on clinically is when the addiction is established.  Did it occur before, during, of after the ADHD diagnosis in childhood?  What does that spectrum suggest for the impact of stimulant treatment on an addiction outcome?

Where does all of this leave clinicians today?  It is possible to find clinicians who believe that they are treating addiction with stimulants because they are reducing impulsivity associated with ADHD.  There are also clinicians who believe that stimulants must be avoided at all costs, even in people with a diagnosis of ADHD.  Is there a rational approach to discuss what is known about the diagnosis and treatment with the patient as part of their overall treatment program that might optimize treatment outcomes?  I think that there is and have written it down in this worksheet entitled 28 Discussion Points for Stimulant Treatment of ADHD.  The worksheet is intended to address problematic diagnosis as the first point of variance.  It discusses the relevant addiction and safety considerations.  There is also a framework for exploring the decision to use a stimulant in the broader context of a treatment plan that may include non-medical therapists and treatment programs and housing programs that may limit or prohibit the patient from using stimulants.  It does not incorporate the therapeutic alliance and overprescribing considerations.  One of the most difficult tasks for physicians is not prescribing a medication with addictive potential when a person believes it is necessary for their life or they are demanding it.

Remembering that people with addictions are compelled to take stimulants whether they improve outcomes or not is an important part of providing quality care to this population.
 

George Dawson, MD, DFAPA



References:

1:  Jadad AR, Boyle M, Cunningham C, et al.  Treatment of Attention-Deficit/Hyperactivity Disorder.  Evidence Report/Technology Assessment No. 11 (Prepared by McMaster University under Contract No. 290-97-0017).  AHRQ Publication No. 00-E005.  Rockville, MD:  Agency for Healthcare Research and Quality.  November 1999.

2:  Connor DF.  Stimulants.  In: Barkley DF.  Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment.  3rd ed.  New York, NY.  The Guilford Press, 2006: 608-647.

3:  Barkley RA, Fischer M, Smallish L, Fletcher K. Does the treatment of attention deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics. 2003 Jan;111(1):97-109. PubMed PMID: 12509561.

4:  Wilens TE, Faraone SV, Biederman J, Gunawardene S.  Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003 Jan;111(1):179-85. PubMed PMID: 12509574.

5: Biederman J, Monuteaux MC, Spencer T, Wilens TE, Macpherson HA, Faraone SV. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry. 2008 May;165(5):597-603. doi: 10.1176/appi.ajp.2007.07091486. Epub 2008 Mar 3. PubMed PMID: 18316421.

6:  Shaw M, Hodgkins P, Caci H, Young S, Kahle J, Woods AG, Arnold LE. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med. 2012 Sep 4;10:99. doi: 10.1186/1741-7015-10-99. Review. PubMed PMID: 22947230.  online at: http://www.biomedcentral.com/1741-7015/10/99


Attribution:

The graphic at the top of this post is from reference 6 above and is posted per the open access license at that site.

Robust Doses of Extended-Release Mixed Amphetamine Salts To Treat Cocaine Use Disorder

JAMA Psychiatry. 2015 Jun 1;72(6):593-602

This article (2) caught my eye in JAMA Psychiatry.  Stimulant (methamphetamine, cocaine, prescription stimulants, and various synthetics) use disorders (previously called addictions) are difficult problems to treat.  That is especially true because of the epidemic of adult Attention Deficit~Hyperactivity Disorder diagnoses and the cross contamination from the cognitive enhancement movement as well as new indications for stimulant prescriptions.   Stimulant medications are widely available and generally work at some level for most people who take them leading to the common impression that:  "I took my cousin's Adderall and it worked!  Therefore I must have ADHD and need my own Adderall prescription."  By the time that has happened it is usually very difficult for any physician to explain to this patient why a positive response to a stimulant does not equate to an ADHD diagnosis, especially if the prospective patient has been functioning at a high level and is presenting for diagnosis and treatment after doing extremely well in college and their first few years of professional school.

A second problem with the ADHD stimulant use issue is the misconception that people with "true" ADHD are less susceptible to the positive reinforcing effects of stimulants than people without ADHD.  There are certainly subgroups of person with this diagnosis that do not like to take stimulants.  They find that stimulants decrease their appetite, given them increased anxiety and insomnia, and in many cases leave them feeling more restricted, affectively blunted and less spontaneous.  I find that these patients are generally selected out by the time they are adults.  They had true ADHD diagnoses in middle school, did not like the stimulants, or in many cases their parents did not like the effect they were seeing and they were taken off of them.  They may have developed significant coping strategies based on their dislike of stimulant effects.  Like many adult psychiatric disorders there is no one uniform phenotype, and the phenotype of the person who was diagnosed either as a child or an adult and who gets a euphorigenic effect from stimulants and escalates the dose clearly exists and is seen in treatment centers.  In many cases they have an iatrogenic diagnosis of bipolar disorder from a pattern of taking the month's prescription of stimulant in the first one or two weeks and then either going into withdrawal or using a depressant like alcohol, benzodiazepines, or opioids to treat the dysphoria and cravings associated with stimulant withdrawal.

There is also the situation where a person has been using high dose prescribed stimulants (taking more than prescribed) or using high doses of meth or cocaine off the street, where they develop a residual state that is identical to ADHD, but where the cause of the ADHD is the stimulant.  I think it is an error to treat that residual state with stimulants.  That residual state is generally associated with a profound level of impairment and lack of insight.  The patient is aware of significant cognitive problems, attributes them to ADHD and often insists on treatment with stimulants despite a clear addiction to stimulants.  They may insist that years or decades of stimulant use was their attempt to self diagnose and treat their own ADHD.  It is very common for patients with substance abuse problems to give a history of no formal diagnosis in childhood, no school or occupational impairment, but to offer the opinion that they think they may have ADHD.  All of these considerations lead to associated problems in providing care to people who have clear ADHD and stimulant use diagnoses.  

That leads me to this multisite study (2) on the effects of high doses of extended release mixed amphetamine (ER MA) salts on both ADHD and cocaine use in patients who have both of these diagnoses.  The doses used were 60 and 80 mg/day.  The most commonly used current prescription versions of these drugs typically recommend a maximum dose in adults of 30 mg/day (1), but interestingly there is a "titrate to tolerability" statement in the package insert of a drug where 20 - 60 mg/day were used in trials with the statement  "There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit."  The authors describe their dosing selections as "robust" and suggest that there is evidence that higher doses are needed to treat cocaine use problems.

Looking at authors methodology, their screening for this trial is instructive of the problems encountered in clinical practice.  Of a total of 1614 patients screened, only 126 were ultimately randomized to placebo, 60 mg/day ER MA, or 80 mg/day ER MA.  Five hundred and sixty two were screened out due to medical or psychiatric exclusion criteria.  It is common in older populations of stimulant users to find significant cardiovascular morbidity in the form of cardiomyopathy, coronary artery disease, and arrhythmias and these were some of the exclusion criteria.  The other aspect of this study that I really liked and would suggest implemented in everyday practice is the authors approach to blood pressure and heart rate specifically:

"Participants with blood pressure higher than 140/90 mm Hg or heart rate higher than 100 beats/min for 2 weeks or with single readings of blood pressure higher than 160/110mmHg or heart rate higher than 110 beats/min were discontinued from study medication." 

It is always shocking to hear from a person who has been on stimulants for years that nobody has ever checked their blood pressure or pulse, especially when they are sitting in front of you and are hypertensive and tachycardic.  This basic procedure should be done on any person taking stimulants, antipsychotics, antidepressant and for that matter any CNS active drug.  If similar effects are noted with any of these medications they should be discontinued.

Another important aspect of this study is that although the patients were well screened, they were complex from a substance use standpoint with current alcohol (18.6 - 27.9%), cannabis (7 - 14%), and nicotine (45-65.1%) use disorders.  The high levels of nicotine use are not surprising considering the epidemiological correlations between smoking and cocaine use and recent evidence about the epigenetic effects of nicotine in substance use disorders.  The authors do not comment on whether there were different outcomes for the non-smokers in this study.

On the primary outcome measure for ADHD - a 30% reduction in the AISRS (Adult ADHD Investigator Symptom Rating Scale) 58.1% of the high strength group and 75% of the low strength group achieved that outcomes with odds ratios of 2.27 and 5.23 respectively (see text for confidence intervals).  In terms of cocaine use outcomes the 80 mg dose resulted in fewer cocaine positive weeks (by any positive toxicology or report) and abstinence in the last three weeks.  The numbers are given in the table below:

High dose MA ER resulted in both a significant reduction in cocaine positive weeks over the 14 weeks of the study.  The 60 and 80 mg doses were actually fairly equivalent form a statistical standpoint and both were superior to placebo in terms of ADHD and cocaine outcomes.  But the real question is whether this is a reasonable clinical approach to this problem?  This was an intent-to-treat analysis with significant drop out rates.  The drop out rates are illustrated in the rapid decline in denominators in each group in Table 2.

In my experience, a substantial number of patients with ADHD and either cocaine or amphetamine use disorder reach the end of the prescribing algorithm where they have failed or relapsed.  In many cases that failure does not lead to a prescription being stopped for many reasons, a lack of information to the prescribing physician being foremost among them.  In the real world there is no clinic that will follow patients three times a week with toxicology screens at most of those visits and offer them all cognitive behavioral therapy.  Models currently funded by managed care companies and governments consist of patients being seen every one to three months for 20 or 30 minutes.  Many of those  visits are done by clinicians with little to no addiction experience.  Within the medication maintenance literature, particularly with buprenorphine maintenance there are studies that suggest psychotherapy adds nothing to the outcomes.  But even without that data what business manager would consider those therapists "cost effective" beyond the stimulant prescription?

A key element that I never see in these studies is the patient's subjective response to the stimulant at increasing doses.    I have found that Koob's definition of addiction is generally predictive:

"Addiction is a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement."

A euphorigenic, hypomanic effect is usually the high risk positive reinforcer regardless of the substance taken.  One of the theories of abuse deterrent approaches is that the pharmacokinetics of the substance used prevents rapid availability in the brain and this decreases abuse potential.  Many abuse deterrent preparations fail because multiples of the dose can be taken and result in the positive reinforcing aspects of the addiction cycle.  I consider the authors' paper to be elegant in its experimental approach.  The graphic at the top of this page is first-rate as a source of information.  It also illustrates the problem of coming up with a clinical trial that can be translated into practice.  I would not consider implementing this strategy as a clinical approach until there was a long term study that looked thoroughly at all of the outcomes.  At this time, I don't think the modest results of this short term study warrant the widespread practice of using extended release mixed amphetamine salts for cocaine use disorders.  There are also legal issues with prescribing maintenance doses of controlled substances in order to "maintain an addiction" as some laws are currently written.  I would have liked to see an attempt to characterize the subjective responses to methamphetamine use measured along with an analysis of whether the non-smokers did better than the smokers.

George Dawson, MD, DFAPA



References:

1:  Drug Facts and Comparisons.  Wolters Kluwer Health.  St. Louis, MO, 2013.

2: Levin FR, Mariani JJ, Specker S, Mooney M, Mahony A, Brooks DJ, Babb D, Bai Y,Eberly LE, Nunes EV, Grabowski J. Extended-Release Mixed Amphetamine Salts vs Placebo for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cocaine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jun 1;72(6):593-602. doi: 10.1001/jamapsychiatry.2015.41. PubMed PMID: 25887096; PubMed Central PMCID: PMC4456227

Attribution:

1.  The figure at the top of this post is from reference 2 above and is used with permission from the American Medical Association, License Number 3660331303348.  Copyright © 2015 American Medical Association.  All rights reserved.

Cognitive Enhancement IS Cheating

One of my colleagues posted a recent commentary from Nature on how the idea of the smart pill has been oversold.  The basic theme of the commentary is that there is no good evidence that treatment of ADHD with stimulants improves academic outcomes.  The author reviews a few long term studies and contends that differences between the medication and placebo seem to wash out over time and therefore there is no detectable difference.  Her overall conclusions seem inconsistent with her view that:  "For most people with ADHD, these medications — typically formulations of methylphenidate or amphetamine — quickly calm them down and increase their ability to concentrate. Although these behavioural changes make the drugs useful, a growing body of evidence suggests that the benefits mainly stop there..."

A question for any cognitive psychologists out there - is it possible to improve your concentration and have that not improve learning?  I can't imagine how that happens.  If you go from not being able to read 2 pages at a time to suddenly reading chapters at a time, how is that not enhanced cognitive performance?  If you go from staring out the window all day and daydreaming to being able to focus on what the teacher is saying how will that not lead to an improved outcome?  The idea that improved attention - a central factor in human cognition will not affect anything over time suggests to me that the measures being used for follow up are not very robust or that this is a skewed sample of opinion.   

For the purpose of cognitive enhancement, the typical users are students trying to gain an edge by increasing their study time.  Anyone who has experienced college and professional school realizes that here is a large amount of information to be mastered and it is not presented in an efficient way.  I can never recall a professor who advised us of the important guideposts along the way or gave us any shortcuts.  The usual message is study all of this material in depth every day or you will fall behind.  That approach in general is consistent with gaps in the ability to study either through the normal course of life or the competition for intellectual resources by 3 or 4 other professors who regard their courses as important.  That typically results in a pattern of cramming for specific key exams.  Although I have not seen any specific studies, stimulant medications are generally used for this purpose and in many cases the use is widespread.  There is a literature on the number of college students who may be feigning ADHD symptoms in order to get a prescription and that number could be as high as 50% (4,5). 

What  about the issue of stimulants acting as a smart pill in people who don't have ADHD?  In the most comprehensive review I could find on the subject (6) the authors review laboratory studies and conclude that in those settings stimulants enhance consolidation of declarative learning to varying degrees, had mixed effects on working memory, and mixed effects on cognitive control.  On 8 additional tests of executive function, the authors found that stimulant medication enhance performance on two of those tests - non-verbal fluency and non-verbal intelligence.  They have the interesting observation that small effects could be important in a competitive environment.  Their review also provides an excellent overview of the epidemiology of stimulant use on campuses that suggests that the overall prevalence is high and the pattern of use is consistent with cramming for exams.  They cite a reference that I could not find (7) that was a reanalysis of NSDUH data suggesting that as many as 1 in 20 stimulant users may have a problem with excessive use and dependence.     

Getting back to the theme of the Nature commentary, it is ironic that the smart pill theme is being called into question when it was the subject of a Nature article years earlier advocating for the use of cognitive enhancement.  In that article Greely, et al come to the somewhat astounding conclusion: 

"Based on our consideration, we call for a presumption that mentally competent adults should be able to engage in cognitive enhancement using drugs."

They arrive at that conclusion by rejecting three arguments against this practice.  Those arguments include that it is cheating, it is not natural and it is drug abuse.  Their rejection of the cheating argument is interesting because they accept the idea that performance enhancing drugs (PEDS) in sports is cheating.  They reject that in cognitive enhancement claiming that there would need to be a set of rules outlining what forms of enhancement would be outlawed and what would not (e.g. drugs versus tutors).  To me that seems like a stretch.  I think that sports bodies select performance enhancing drugs as a specific target because it clearly alters body physiology in a way that cannot be altered by any other means.  There is also plenty of evidence that the types of PEDS are dangerous to the health of athletes and associated with deaths.  Their conclusion about drug abuse: "But drugs are regulated on a scale that subjectively judges the potential for harm from the very dangerous (heroin) to the relatively harmless (caffeine).  Given such regulation the mere fact that cognitive enhancers are drugs is no reason to outlaw them."   That is a serious misread of the potential addictive properties of stimulants and the previous epidemics that occurred when the drugs were FDA  approved for weight loss, the epidemic of street use in the 1970s and the current and ongoing epidemic of meth labs and methamphetamine use throughout much of the USA.

These authors go on to outline four policy mechanisms that they believe would "support fairness, protect individuals from coercion, and minimize enhancement related socioeconomic disparities."  At first glance these lofty goals might seem reasonable if society had not already had in depth experience with the drugs in question.  The clearest example was the FDA approved indication of amphetamines for weight loss.  What could be a more equitable application than providing amphetamines to any American who wanted to use them for weight loss?  The resulting epidemic and reversal of the FDA decision is history.  A similarly equitable decision to liberalize opioids in the treatment of chronic pain had resulted in another epidemic of higher lethality due to differences in the toxicology of opioids and amphetamines. 

The contrast between these two commentaries in Nature also highlight a couple of the issues about the way medical problems and treatment is portrayed in the media.  This first is that you can't have it both ways.  Quoting a researcher or two out of context does not constitute an accurate assessment of the science involved.   Some of the authors in the first commentary are highly respected researchers in cognitive science and they clearly believe that cognitive enhancement occurs and it should be widely applied.  Nature or any other journal cannot have it both ways.  A more realistic appraisal of the problem is addressed in reference 6.   The second issue is that in both cases the authors seem blind to the addictive properties of stimulants and they are ignorant of what happens when there is more access as exemplified by the FDA misstep of approving stimulants for weight loss.  Do we really need a new epidemic to demonstrate this phenomenon again?  Thirdly, all of this comes paying lip service to non - medication strategies for cognitive enhancement.  We can talk about the importance of adequate sleep - a known cause of ADHD like symptoms and if we are running universities and workplaces in a manner that creates sleep deprived states, the next step is reaching for pills to balance an unbalanced lifestyle.  The new rules for residency training are a better step in the right direction.  Fourth, college is a peak time for alcohol and substance use in the lives of most Americans.  These substances in general can lead to a syndrome that looks like ADHD.  It is highly problematic to make that diagnosis and provide a medication that can be used in an addictive manner.  It is also highly problematic to think that treating an addicted person with a stimulant will cure them of the addiction and yet it happens all of the time.

There is plenty of evidence to suggest that cognitive enhancement is cheating.   Much of my career has been spent correcting the American tendency of trying to balance one medication against another and using medications to tolerate a toxic lifestyle or workplace.  It does not work and the current group of medications that are being put forward as cognitive enhancers are generally old drugs with bad side effect profiles particularly with respect to the potential for addiction.

If you want safe cognitive enhancers that can be made widely available, they have not been invented yet.  

George Dawson, MD, DFAPA




References:

1: Sharpe K. Medication: the smart-pill oversell. Nature. 2014 Feb 13;506(7487):146-8. doi: 10.1038/506146a. PubMed PMID: 24522583.

2: Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ.

Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008 Dec 11;456(7223):702-5. doi: 10.1038/456702a. Erratum in: Nature. 2008 Dec 18;456(7224):872. PubMed PMID: 19060880.

3: Feldman HM, Reiff MI. Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med. 2014 Feb 27;370(9):838-46. doi: 10.1056/NEJMcp1307215. PubMed PMID: 24571756.  

4: Green P, Lees-Haley PR, Allen LM., III The word memory test and the validity of neuropsychological test scores. J Forensic Neuropsychol. 2002;2:97–124. doi: 10.1300/J151v02n03_05

5: Suhr J, Hammers D, Dobbins-Buckland K, Zimak E, Hughes C.  The relationship of malingering test failure to self-reported symptoms and neuropsychological findings in adults referred for ADHD evaluation.  Arch Clin Neuropsychol. 2008 Sep; 23(5):521-30.

6: Smith ME, Farah MJ. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011 Sep;137(5):717-41. doi: 10.1037/a0023825. Review. PubMed PMID: 21859174 

7: Kroutil LA, Van Brunt DL, Herman-Stahl MA, Heller DC, Bray BM, Penne MA. Nonmedical use of prescription stimulants in the United States. Drug and Alcohol Dependence. 2006; 84:135–143.10.1016/j.drugalcdep.2005.12.011 [PubMed: 16480836]

The “Spike” in ADHD diagnoses

There was the usual furor in the press earlier this week about a CDC Study that suggested that ADHD diagnoses have spiked up to 11%.  A previous post on this blog suggests that the real prevalence of ADHD is closer to 6-8%.  The  press predictably implicates overdiagnosis, overprescribing, a Big Pharma based culture that suggests there is a pill for everything, and of course the DSM5 – even though it has not yet been released.  What is really going on?

Before getting into my theories let me express my profound disappointment in the Centers for Disease Control (CDC).  As far as I can tell they have no actual research document on this issue, at least they did not sent me that document or link when I requested it.  The closest I can come is the web page that suggests that it may contain the data.  You can find for example – the full text of the survey that was used for this data.  If you are interested in that actual data that lists several data files that require specialty software.  So we apparently have a “scoop” by the New York Times based on getting and analyzing the data files and other interested people (like me) do not have access to the original data.  That is really not acceptable for a government funded agency.  If I am wrong here – please send me the link or the raw data, but I am very clear that the CDC did not respond to my direct request for clarification and they always have in the past.

Rather than debate the limitations of the study which is not possible because there apparently is no published version of the study, the easiest thing to do is accept that the increase is diagnoses as estimated by surveys is in fact true and go from there.  When I think about drugs that are truly overprescribed by comparison, the first class that comes to mind is antibiotics.  This trend is so well known that the CDC has run a campaign about it since 1995.  There is some consensus that progress has been made but a recent commentary describes the overall effort as a failure with antibiotic overuse as high as 50-100% in some areas and suggests a comprehensive strategy.  The table below highlights a few problems especially with regard to treating infections caused by viruses with antibiotics in the past two years.

Problem	Findings	Reference
Acute sinusitis 3 million outpatient visits/yr in US	Antibiotics prescribed in 83% of visits 50% of patient diagnosed received a macrolide or quinolone and only 20% received amoxicillin – the recommended drug	Fairlie T, Shapiro DJ, Hersh AL, Hicks LA. National Trends in Visit Rates and Antibiotic Prescribing for Adults With Acute Sinusitis.Arch Intern Med. 2012;172(19):1513-1514.
Acute Strep Pharyngitis	56% received an antibiotic and only 19.5% had a confirmed diagnosis	Nakhoul GN, Hickner J. Management of Adults with Acute Streptococcal Pharyngitis: Minimal Value for Backup Strep Testing and Overuse of Antibiotics. J Gen Intern Med. 2012 Oct 6.
Febrile Respiratory Illness (AFI)	The context (number of cases recently seen and pandemic status) affected whether or not physicians prescribe antibiotics for AFI.	Courtney Hebert, Jennifer Beaumont, Gene Schwartz, Ari Robicsek; The Influence of Context on Antimicrobial Prescribing for Febrile Respiratory IllnessA Cohort Study. Annals of Internal Medicine. 2012 Aug;157(3):160-169.
Unnecessary fluroquinolone use in hospitalized patients	39% of fluroquinolone use was unnecessary as defined as excessive duration of therapy or use for non bacterial infection.	Werner NL, Hecker MT, Sethi AK, Donskey CJ. Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect Dis. 2011 Jul 5;11:187. doi: 10.1186/1471-2334-11-187.

A direct comparison of antibiotic over prescription and the possible over prescription of stimulants is instructive from several perspectives.  It may not be obvious but a clinician faced with whether or not a patient has a bacterial infection or whether they have ADHD has similar problems.  In both cases, the therapy may precede the diagnosis.  By that I mean it is often impossible on purely clinical grounds to determine whether an infection is caused by bacteria or the patient's behavioral or cognitive complaints are cause by ADHD.  If at the end of an assessment the physician comes to the conclusion of bacterial infection or ADHD a medication is prescribed.  Nobody makes a probability statement and there is often the element of an “empirical trial” – if the patient improves the treatment and the diagnosis were correct.   Since any misdiagnosed viral infections will usually improve and most people given stimulants will experience cognitive enhancement whether they have ADHD or not – the empirical trial is a highly flawed approach but one of many biases in an area of diagnostic uncertainty.

Another issue is the expectations of the patient.  Pediatricians often face irate parents if they don’t prescribe antibiotics for certain infections that are likely to be viral.  Internists and family physicians face the same problem explaining why acute bronchitis generally does not require antibiotic therapy.  Patients often have stories about multiple antibiotic failures to treat their bronchitis when it is likely that the process was viral and happened to resolve on its own after the most recent antibiotic trial.  Many patients taking stimulants for no clear reason have similar reactions when their use of stimulants is questioned.

There is the issue of complications of both therapies.  I do think that the potential harm of antibiotic overprescribing far exceeds the harm of stimulant overprescribing and that is the basis for the CDC having an initiative in this area for nearly 20 years.  On the basis of acute complications and medical side effects stimulant medications are some of the safest around.  On the other hand, I have also treated stimulant abusers who were routinely taking several times the recommended dose for years or who went on to use cocaine or other stimulants regularly and had the expected complications from addiction.

An important area of divergence between these classes of prescription drugs is the potential for addiction with stimulant medications and the new cultural movement that has been described as “cognitive enhancement”.  Both of these factors add the dimension that patients can misrepresent themselves to physicians with the intent of getting a stimulant prescription.  That does not happen with antibiotics, but the scope of the problem in terms of which drug is overprescribed more seems decidedly in favor of antibiotics at this time.  That does not bode well for the potential for even higher rates of stimulant overutilization in the future and in fact it seems obvious to me that there is no reason why it would not rise to at least the same level of antibiotics.

The reaction to these parallel problems in the press is instructive.  Rather than seeing the possible over prescription of medications as a problem inherent in the practice of medicine (like antibitotics) – a common reaction in the press is that this is a problem with over diagnosis and leaps to suggesting that the unreleased DSM5 will lead to even more diagnoses.  They quote several experts who respond strictly on the issue of whether the numbers are “real” or not.  The Director of the CDC – Thomas R. Frieden, MD makes an accurate comparison of the problem to both antibiotics and pain medications but concludes:  “The right medications for A.D.H.D., given to the right people, can make a huge difference. Unfortunately, misuse appears to be growing at an alarming rate.”  Clear diagnostic criteria for bacterial infections has not been the solution nearly 20 years of antibiotic over prescribing.  From what we know about trends in overprescribing, I would expect stimulant prescriptions to continue to increase irrespective of the release of the DSM5.  It will prove to be an easy scapegoat for a poorly understood problem.

The unfortunate focus of the New York Times article is the familiar: “Are drugs good or bad?”  The appropriate focus for physicians is focusing on the process and how individual and group practices can be modified to reduce overprescribing.  In most cases that would involve four additional steps – a discussion of cognitive enhancement and why it is not a good idea, screening for an addiction diagnosis, making sure that there is a clear level of functional impairment, and urine toxicology.  The effects of an assembly line approach to managing physicians and inadequate time for complex diagnostic thinking cannot be minimized.  A central collaborative model used by the University of Wisconsin for the diagnosis and treatment of dementia could be adapted to a network of clinics to treat ADHD.  This could provide the best solution to practice drift and provide clear markers for uniform prescribing.

George Dawson, MD, DFAPA

Allen Schwartz, Sarah Cohen.  ADHD Seen in 11% of US Children as Diagnoses Rise.  NYTimes March 31, 2013.

Merikangas KR, He J, Rapoport J, Vitiello B, Olfson M. Medication Use in US Youth With Mental Disorders. JAMA Pediatr.2013;167(2):141-148. doi:10.1001/jamapediatrics.2013.431.

Rubin D. Conflicting Data on Psychotropic Use by Children: Two Pieces to the Same Puzzle. JAMA Pediatr. 2013;167(2):189-190. doi:10.1001/jamapediatrics.2013.433.

Fairlie T, Shapiro DJ, Hersh AL, Hicks LA. National Trends in Visit Rates and Antibiotic Prescribing for Adults With Acute Sinusitis.  Arch Intern Med. 2012;172(19):1513-1514. doi:10.1001/archinternmed.2012.4089

Gonzales R, Ackerman S, Handley M. Can Implementation Science Help to Overcome Challenges in Translating Judicious Antibiotic Use Into Practice?: Comment on “National Trends in Visit Rates and Antibiotic Prescribing for Adults With Acute Sinusitis” and “Geographic Variation in Outpatient Antibiotic Prescribing Among Older Adults”. Arch Intern Med.2012;172(19):1471-1473. doi:10.1001/2013.jamainternmed.532

Damschroder LJ, Aron DC, Keith RE, Kirsh SR, Alexander JA, Lowery JC. Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science. Implement Sci. 2009 Aug 7;4:50. doi: 10.1186/1748-5908-4-50. PubMed PMID: 19664226; PubMed Central PMCID: PMC2736161.

Hebert C, Beaumont J, Schwartz G, Robicsek A. The influence of context on antimicrobial prescribing for febrile respiratory illness: a cohort study. Ann Intern Med. 2012 Aug 7;157(3):160-9. doi: 10.7326/0003-4819-157-3-201208070-00005. PubMed PMID: 22868833.

ADHD and Crime

There has been a lot of commentary on the NEJM article on the association between stimulant treatment of Attention Deficit Hyperactivity Disorder (ADHD) and less crime in a cohort of patients with ADHD.  Two of my favorite bloggers have commented on the study on the Neuroskeptic and Evolutionary Psychiatry blogs.  As a psychiatrist who treats mostly patients with addictions who may have ADHD and teaches the subject in lectures - I thought that I would add my opinion.

Much of my time these days is spent seeing adults who are also being treated for alcoholism or addiction. I also teach the neurobiological aspects of these problems to graduate students and physicians.  In the clinical population that I work with - ADHD is common and so is stimulant abuse/dependence and diversion.  Cognitive enhancement is a widely held theory on college campuses and in professional schools.  That theory suggests that you can study longer, harder, and more effectively under the influence of stimulants.  They are easy to obtain.  Stimulants like Adderall are bought, sold, and traded.  It is fairly common to hear that a feeling of enhanced cognitive capacity based on stimulants acquired outside of a prescription is presumptive evidence of ADHD.  It is not.  It turns out that anyone (or at least most people) will have the same experience even without a diagnosis of ADHD.

There is very little good guidance on how to treat ADHD when stimulant abuse or dependence may be a problem.  Some literature suggests that you can treat people in recovery with stimulants - even if they have been previously addicted to stimulants.  Anyone making the diagnosis of ADHD needs to makes sure that there is good evidence of impairment in addition to the requisite symptoms.  Ongoing treatment needs to assure that the stimulants are not being used in an addictive manner.  I would define that as not accelerating the dose, not taking medications for indications other than treating ADHD (cramming for an exam, increased ability to tolerate alcohol, etc), not attempting to extract, smoke, inject, or snort the stimulant, not obtaining additional medication from an illegal source, and not using the stimulant in the presence of another active addiction.  Addressing this problem frequently requires the use of FDA approved non stimulant medication and off-label approaches.

With the risk of addiction that I see in a a population that is selected on that dimension, why treat ADHD and more specifically why treat with medications?  The literature on the treatment of ADHD is vast relative to most other drugs studied in controlled clinical trials.  There have been over 350 trials and the majority of them are not only positive but show very robust effects in terms of treatment response.  The safety of these medications is also well established.

Enter the article from the NEJM on criminality and the observation that stimulants treatment may reduce the criminality rate.  This was a Swedish population where the research team had access to registries containing data on all persons convicted of a crime, diagnosed with ADHD, getting a prescription for a stimulant, and to assign 10 age, sex, and geography matched controls to each case.  Active treatment was rather loosely defined as any time interval between two prescriptions as long as that interval did not exceed six months.  The researchers found statistically significant reductions during the time of active treatment for both men (32%) and women (41%).      

I agree that this is a very high quality article from the standpoint of epidemiological research - but my guess is the editors of the NEJM already knew that.  This study gets several style points from the perspective of epidemiological research.  That includes the large data base and looking for behavioral correlates of another inactive medication for ADHD - serotonin re-uptake inhibitors or SSRIs.  There is a robust correlation with stimulants but not with self discontinued SSRIs.  They also analyzed the data irrespective of the order of medications status to rule out a reverse causation effect (treatment was stopped because of criminal behavior) and found significant correlations independent of order.

Apart from the usual analysis clinical and researchers in the field ranging from neurobiologists to researchers doing long term follow up studies do not find these results very surprising.  The Medline search below gives references of varying quality dating back for decades.  The pharmacological treatment certainly goes back that far.  The accumulating data suggests that where the disorder persists, it requires treatment on an ongoing basis.  A limited number of studies suggest that cognitive behavioral therapy (CBT) may be useful for adults with ADHD but not as useful for children or adolescents.  The practice of "drug holidays" prevalent not so long ago - no longer makes sense when the diagnosis is conceptualized as a chronic condition needing treatment to reduce morbidity ranging from school failure to decreased aggression to better driving performance.

One of the typical criticisms of epidemiological research of this design is that association is not causality, I think it is time to move beyond that to what may be considered causal.  In fact, I think it may be possible at this time to move beyond the double blind placebo controlled trial to an epidemiological standard and I will try to pull together some data about that approach.

George Dawson, MD, DFAPA

Lichtenstein P, Halldner L, Zetterqvist J, Sjölander A, Serlachius E, Fazel S, Långström N, Larsson H. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med. 2012 Nov 22;367(21):2006-14. doi: 10.1056/NEJMoa1203241.

Criminality and ADHD:  Medline Search

ADHD - The Scientific Evidence versus the Political Hype

I attended a day long seminar by Russell Barkley, PhD.  It is part of my ongoing mission of seeing the experts in person who I have read and collected in my library over the past 30 years.  My earliest exposure to Dr. Barkley's work was the book Hyperactive Children that I acquired while I was in Medical School and used when I was treating children in the first clinic I worked in as a psychiatrist.  Interestingly he was working at the same medical school I had attended.  Dr. Barkley has an impressive surveillance system for current literature and in the seminar was presenting work that had literally been published or put into prepublication the day before.  His scholarship is impressive and he is one of the most widely published authors in the field.  He has a clear scientific approach and does not recommend treatments that have not gone through randomized and blinded clinical trials.  He gave many examples of ADHD treatments that seemed effective until the raters were blinded to the treatment or the methods were used by researchers who had no vested interest in the outcome.

All of his information was presented on PowerPoint as is the standard.  His PowerPoint slides were information dense, frequently presenting dimensions and data points from several studies on the same line.

A few of the highlights that you will not read in the New York Times:

1.  On the "overdiagnosis" issue - at this time about 40% of kids and 10% of adults with the disorder are treated.
2.  On the DSM issue - the categories of ADHD are going away.  Like categories of schizophrenia and autism spectrum disorder they are not unique entities.   This of course runs counter to the usual DSM criticism that there is a proliferation of diagnostic categories   Another positive was that the age of onset criteria is changing from age 7 to age 12.  Barkley points out that an age cutoff for a developmental process is arbitrary and suggested a further change to "onset in childhood or adolescence".  On the other hand, it does appear that the committee in charge is responding to political pressure from the government and insurance companies to not make any changes that would increase the prevalence of the disorder.  He presented clear criteria that would improve the diagnosis of ADHD in adults that will apparently not be included or possibly on a parenthetical basis.
3.  The problem with the treatment of children is not overtreatment, but that fact that most children who need treatment discontinue their medications as teenagers.
4.  The resulting complications of untreated ADHD are significant from an educational, public health, and psychiatric perspective.  As one example, untreated ADHD is associated with high risk of dropping out of school.  Every person who drops out and does not complete school represents a cost of $450K to the community.
5.  Stimulant medications have a 40 year record of use and there have been over 350 studies documenting the efficacy and safety.  They have the greatest effect size of any psychiatric medications and that includes up to 90% response rates across all stimulants.
6.  Response to treatment is robust and the best of any psychiatric disorder.  Evidence based studies show that patients treated with stimulants show improved outcomes across 20 parameters and that treatment with atomoxetine is associated with improvement across 23 parameters.
7.  These medications have an unprecedented safety record.
8.  There is a potential steep cost in many areas of not adequately treating the disorder.

It is very disappointing to hear that the DSM committee may be yielding to political pressure when it comes to implementing new evidence based DSM criteria particularly give the poor quality of these arguments.  A professional organization should be above political influence when it comes to scientific findings and this revision of criteria was supposed to be based on science.  The APA does have a long history of not providing any resistance to the managed care industry or government initiatives to reduce the quality of psychiatric care in favor of the managed care industry.  If true it will be ironic that the ADHD section of the DSM5 will be be directly influenced by the usual managed care forces and that they are aligned with all of the media rhetoric about the proliferation diagnoses and increased prevalence.

So the usual media hype is wrong - psychiatrists and pharmaceutical companies are not plotting to put more people on medication.  The government, managed care companies, and the anti-biological antipsychiatrists are trying to keep them off even when they are indicated.  In that political divide - the science is left out.

George Dawson, MD, DFAPA

Dr. Russell A. Barkley, PhD.  Official Web Site.

Dr. Russel A. Barkley, PhD.  Professional Workshop on ADHD.  ADHD Across the Life Span: Diagnosis, Life Course, Management, and Comorbidity.  Minnetonka, Minnesota.  Thursday November 15, 2012.

International Consensus Statement on ADHD (excerpt) - read this statement signed by scientists explaining that this diagnosis is not controversial and that the percentage of patients treated is about the same in the past decade.