The Recent Takedowns of Adult ADHD

 

Psychiatry seems doomed to argue endlessly about whether certain conditions exist or not and whether they can be characterized by written criteria. The latter condition is the most easily dismissed since clinical training is necessary to recognize conditions. You cannot just sit in an office, read the DSM and call yourself a psychiatrist. Whether conditions exist or not is more debatable but often slides into rhetoric that suggests inadequate training, ignorance, and/or significant conflict of influence or undue influence by the pharmaceutical industry. Consideration of the undue influence can easily be applied at the global level since Pharma has massive marketing efforts, direct to consumer advertising in the US, and at least one major political party pulling for them.

That brings me to the recent commentaries about adult ADHD (1, 2). The first reference (1) doubts that adult ADHD exists for the most part and sees the diagnosis primarily as the result of a marketing scheme by Eli Lilly for atomoxetine and ignoring affective temperaments and other states that may affect attention. Atomoxetine was invented as a norepinephrine reuptake inhibiting antidepressant and like other members of this class of drugs – it did not work for depression. Since it is not technically a stimulant it was tested for ADHD and found to be effective. It is unique relative to other ADHD medications and not surprisingly it was heavily marketed while on patent. The patent expired on May 2017. The years on the market patent protected were 2002-2017. The first references to the diagnosis of adult ADHD were noted in the 1980s. Reference 2 suggests that the diagnosis of ADHD in children in the US is around 2-3% with adult numbers half that based on the work of one author.  Contrasting numbers of a lifetime prevalence in adults as 8.1% and surveys estimating current prevalence at 4.4% are described as “absurdly high” but qualified on methodology (surveys vs interviews).  Some authors have the opinion that books published about adult ADHD like Ratey and Hollowell's  Driven to Distraction were a major source of public interest in the diagnosis and instrumental in getting it into the public vernacular. 

Before I get started – let me say that the only stake I have in this argument is making sure that the complexity of the situation is adequately described. Practically all the pro/con arguments in psychiatry are gross oversimplifications and based on what I know about the literature – I had no reason to expect that this was any different.  I am already on record on this blog describing how to diagnose and treat ADHD and not fall into the common problems of misdiagnosis, prescribing to people with substance use problems, or prescribing to people who view these medications as performance enhancers. I have successfully treated adult ADHD with both on and off label medications and can attest to the fact that it is a valid and treatable diagnosis.

Let me start out by looking at the prevalence estimates. These figures are very popular in the press to indict diagnosticians in the United States compared with some European countries and sell more papers. The problem with prevalence estimate is that the range can vary significantly due to methodological differences in the surveys. That question was looked at (3) and the title of that paper asked if ADHD was “an American condition”.  The authors reviewed 22 studies based on DSM-III criteria and 19 studies based on DSM-IV criteria.  Twenty prevalence estimates were done on the US and 30 were done in other countries.  They demonstrated that the range of prevalence across all studies was approximately the same and that ADHD was not just an American condition. Since then numerous prevalence studies have been done in other countries – more recently using DSM-5 criteria showing similar ranges.

On the issue of adult ADHD, a recent review looked at the issue adult ADHD and symptomatic adult ADHD prevalence by the 6 WHO regions (4).  Their overall goal was to determine the worldwide prevalence of adult ADHD. They looked at the issue of persistent or childhood onset ADHD and symptomatic adult ADHD with no evidence of childhood onset and estimated the prevalence of those two groups separately.  The pooled prevalence of persistent adult ADHD was 4.6% and for symptomatic ADHD it was 8.83%.  These authors also looked at prevalence by a list of demographic factors, diagnostic criteria, addition to geographic areas as well as the decreasing prevalence by age groups.   

 

Study	Target Population	Prevalence % (US vs Non-US) ranges or pooled
Faraone, et al (2002)	DSM-III ADHD DSM-III-R ADHD DSM-IV	(9.1-12.1) vs. (5.8-11.2) (7.1-12.8) vs. (3.9-10.9) (11.4-16.1) vs. (2.4-19.8)
Polanczyk, et al (2007)	Pooled prevalence estimates of ADHD by geographic location.  N= number of studies in each WHO designated location	North American (N=32)  6% Europe (N=32)  4.5% Oceana (N=6) 4.5% South American (N=9) 12% Asia (N=15) 4% Africa (N=4) 8% Middle East (N=4) 2.5%
Song, et al (2021)	Pooled estimates and ranges of Adult ADHD worldwide by WHO designated geographic areas	North America (N=3) 6.06% Europe (N=10) 7.12% Oceana (N=4) 9.67% South America (N=3) 6.06% Asia (N=1) 25.6% Africa (N=1) 9.17% Middle East (N=2) 16.58%

 

This study raises the issue of whether ADHD can be acquired rather than be a childhood onset illness. The reality is that there are many paths to acquired attentional deficit that have been treated over the course of my 35 years in the field.  The best examples are neurodegenerative diseases, strokes, and brain injuries. Neuropsychiatrists have written about treating the associated cognitive, mood, and motivational deficits with stimulants.  But a more relevant question is whether mechanisms exist that can result in people with none of these acquired brain injuries.  The answer comes from modern genetics. Polygenic risk scores (of all diseases) suggest that there are high risk individuals who show no evidence of an illness as adults. These examples of incomplete penetrance are usually explained as environmental factors, additional genetic dynamics such as aging or protective factors. I see no reason why these factors could not occur in an ADHD genotype after childhood. The other significant genetic factor is spontaneous mutation or as a recent commentator put it: “You don’t die with the genome you were born with.” Psychiatry has focused on familial studies for the past 50 years, but it is likely that significant numbers of most conditions occur as the result of spontaneous mutations rather than strictly hereditary transmission. That is borne out in clinical practice every day.

The authors (1) make the argument that ADHD is not a “scientifically valid” diagnosis. They explain “these symptoms have not been shown to be the result of a scientifically valid disease (adult ADHD) and better explained by more classic and scientifically validated psychiatric conditions, namely diseases or abnormalities of mood, anxiety, or mood temperament.”  Mood temperament is a stretch.  It is rarely commented on in adult psychiatry and then in extreme cases.  It is not contained in the DSM. Part of the reason is selection bias.  Psychiatrists are seeing people who have failed multiple other treatments and I have referred to this as being the treatment provider of last resort. 

Another factor is that ADHD is a quantitative rather than qualitative disorder – that is the cognitive symptoms are at the extreme end of normalcy and it is difficult to draw a line to demarcate illness from normal in many cases. A comparable example from medicine is hypertension.  The cutoff for what is considered hypertension has varied significantly over the decades (9, 10) and even now considers antihypertensive side effects as a qualifier for treatment.  That means that for any 2 people with the same marginally elevated blood pressure only one might get consistently treated. At one point hypertension was considered by some physicians to be a necessary compensatory mechanism that should not be treated (10). On the issue of quantitative aspects of psychiatric disorders in general – dimensional approaches are often suggested as a solution and the question is whether they work any better than the impairment criteria used in the DSM.  That is especially true in a clinical setting where a patient is presenting with a clear problem that they are asking for help with

On the issue of validity, studies have been done demonstrating reliability and validity (8) on both the DSM criteria as well as various rating scales for adult ADHD that are consistent with the diagnosis. There have also been detailed discussions of how to approach the problem clinically (11).  Those discussions include how to differentiate mood disorders from ADHD and how to approach the functional impairment criteria in the clinical interview.

That brings me to the issue of temperaments mentioned in reference 1.  Temperaments have been researched in various contexts in psychiatry over the past decades.  Most psychiatrists of my generation first heard about them on child psychiatry rotations and the work of Stella and Chess. In adults, temperaments are more descriptions of hyperthymia, cyclothymia, and dysthymia and are generally considered in the differential diagnosis of subclinical mood disorders.  The best example is hyperthymia and it has been referred to both as a temperament and a personality. Hyperthymic people are generally high energy, require less sleep, and are social, talkative, and outgoing. They may be very productive and have increased libido relative to their peers. In clinical interviews they may say that their friends think they are “bipolar” and need to be treated. But careful interviewing demonstrates that they lack the symptom severity and degree of impairment necessary for a diagnosis of bipolar disorder.  Ideally the initial interview results in that formulation and the psychiatrist can advise the person about why treatment is not necessary.

Reference 12 looks at the issue of temperaments in a retrospective controlled study of patients being treated with stimulants who were referred to a mood disorders clinic.  The authors acknowledge the selection bias in their study design. I can not think of a better design to pick up misdiagnosed patients than this one. To cite one example – of the 87 amphetamine treated referrals only 50% had a past diagnosis of ADHD. The authors acknowledge that there is no standard way to determine affective temperaments and decide to use the TEMPS-A with a cutoff of 75% of the items. If you are able to find a copy of the TEMPS-A (it is not easy) – you will find a list of 50 true-false questions like “I’m usually in an upbeat or cheery mood.” The questions are reminiscent of the Minnesota Multiphasic Personality Inventory (MMPI) except there are far fewer questions. The scoring guide suggests that the TEMPS-A can discriminate between hyperthymic, cyclothymic, dysthymic, and irritable temperaments. It is validated in the usual ways.  The relevant question is whether any diagnosis made with this checklist would deter you from treating a comorbid condition - like Adult ADHD?  It is one thing to survey a misdiagnosed group with the TEMPS-A and consider the clinical implications, but another to consider the presenting problem possible ADHD and whether it should be treated.

The arguments in reference 2 about overdiagnosis, the existence of adult ADHD, and the idea that ADHD can occur in adults without a childhood diagnosis can be challenged with the facts and references provided here.  The fact that we are in the midst of a multigenerational drug epidemic in an increasingly intoxicant permissive society does not mean that a diagnosis, treatment, or problem does not exist. It does mean that all psychiatrists from the moment they enter practice must exercise extreme caution when prescribing substances that reinforce their own use. 

The most likely cause of overdiagnosis is not because adult ADHD does not exist, not because of drug promotion (most are generic including the non-stimulant alternatives), or because MDs are careless.  There are basically two reasons.  First – the difficulty of diagnosing quantitative conditions. Second – sociocultural factors that exist in the US. Performance enhancement is built on the myth that you can tune your brain (or any organ) with supplements, nutrients, or medications to become a superior human being. The reality is you can alter your conscious state to believe that – but in the case of stimulants it is unlikely. The only real performance enhancement occurs because you can stay awake longer to read more and there is some evidence that your belief system is altered so that you believe you are smarter (14). These are just two of the reinforcing properties of stimulants that can lead to accelerated use and addiction.

That is my brief summary of the complexity of this situation. For more on my approach to adult ADHD (I only treat adults) – see this post.

 

George Dawson, MD, DFAPA

 

References:

1:  Ruffalo ML, Ghaemi N.  The making of adult ADHD: the rapid rise of a novel psychiatric diagnosis.  Psychiatric Times 2023 40(9): 1, 18-19.

https://www.psychiatrictimes.com/view/the-making-of-adult-adhd-the-rapid-rise-of-a-novel-psychiatric-diagnosis

2:  Frances A.  Containing The Adult ADHD Fad — With a Rejoinder from ChatGPT. 9/21/23. 

https://www.psychotherapy.net/blog/title/containing-the-adult-adhd-fad-with-a-rejoinder-from-chatgpt

3:  Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry. 2003 Jun;2(2):104-13. PMID: 16946911  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525089/

4:  Song P, Zha M, Yang Q, Zhang Y, Li X, Rudan I. The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis. J Glob Health. 2021 Feb 11;11:04009. doi: 10.7189/jogh.11.04009. PMID: 33692893; PMCID: PMC7916320.

5: Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007 Jun;164(6):942-8. doi: 10.1176/ajp.2007.164.6.942. PMID: 17541055.

6:  Kim DS, Burt AA, Ranchalis JE, Wilmot B, Smith JD, Patterson KE, Coe BP, Li YK, Bamshad MJ, Nikolas M, Eichler EE. Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2017 Jun;174(4):381-9.

7: McGough JJ, Barkley RA. Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2004 Nov;161(11):1948-56. doi: 10.1176/appi.ajp.161.11.1948. PMID: 15514392.

8: Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW, Rijnders CA, Hodiamont PP. Internal and external validity of attention-deficit hyperactivity disorder in a population-based sample of adults. Psychol Med. 2005 Jun;35(6):817-27. doi: 10.1017/s003329170400337x. PMID: 15997602.  

9:  Saklayen MG, Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016 Feb 23;3:3. doi: 10.3389/fcvm.2016.00003. PMID: 26942184; PMCID: PMC4763852.

10:  Kotchen TA. Historical trends and milestones in hypertension research: a model of the process of translational research. Hypertension. 2011 Oct;58(4):522-38. doi: 10.1161/HYPERTENSIONAHA.111.177766. Epub 2011 Aug 22. PMID: 21859967.

11:  Murphy KR, Gordon M.  Assessment of adults with ADHD. In: Barkley RA. Attention-Deficit Hyperactivity Disorder, 3^rd edition.  The Guilford Press, New York, 2006: 425-450.

12:  Mauer S, Ghazarian G, Ghaemi SN. Affective Temperaments Misdiagnosed as Adult Attention Deficit Disorder: Prevalence and Treatment Effects. J Nerv Ment Dis. 2023 Jul 1;211(7):504-509. doi: 10.1097/NMD.0000000000001626. Epub 2023 Apr 11. PMID: 37040539.

13:  Akiskal HS, Mendlowicz MV, Jean-Louis G, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL. TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord. 2005 Mar;85(1-2):45-52. doi: 10.1016/j.jad.2003.10.012. PMID: 15780675.

14:  Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology. 2013 Jan;64:496-505. doi: 10.1016/j.neuropharm.2012.07.021. Epub 2012 Aug 1. PubMed PMID: 22884611.

 

 

 

 

The Myth of "Rescue" Medications

First off a clarification.  I am talking about the specific case where a short acting medication is added to a long acting form of the same medication and not "as needed" medication in order to determine the correct daily dosage.   In my line of work it occurs in two situations, long acting stimulants and their immediate release versions and long acting opioids and their immediate release versions.  I will illustrate that these practices are driven by myths about the medication rather than pharmacokinetics.  There is always the additional consideration about addiction lurking in the background, but the conscious and unconscious determinants of addiction frequently depend on the myths that I will be discussing about medication effects.

The example that I will use here is Concerta (long acting methylphenidate) compared with immediate release methylphenidate.  The graph from the package insert above shows the plasma concentration from a single 18 mg dose of Concerta and three successive 5 mg doses of immediate release methylphenidate.  As noted in the comparison of the curves and additional pharmacokinetic parameters the curve associated with three successive doses of immediate release methylphenidate is nearly identically replicated by a single dose of Concerta.

What is happening when additional doses of a immediate release methylphenidate are prescribed to a person who is already taking Concerta?  I  have seen this happen with sustained release stimulants and sustained release opioids.  I have seen it happen as a single dose of the immediate release preparation or multiple doses over the course of the day.  The patient is usually advised that this is a "rescue" medication that they should take if needed.  The first possibility is that the dose of sustained release medication has not been optimized and a higher dose of the sustained release medication needs to be given.  That is usually not the case.  The most frequent reason for taking the rescue medication is that the patient believes they are experiencing breakthrough symptoms and for a moment they need a higher dose of a medication.  There are serious problems with that concept.  As can be seen from the curves comparing Concerta and methylphenidate it does not make pharmacokinetic sense.  Any additional dose of immediate release methylphenidate on top of Concerta would greatly increase the expected plasma concentration at that point.

The main problem is that both ADHD and non-cancer pain are chronic conditions.  By definition they do not respond well to medications and they will not resolve typically with any amount of the medication.  Many people who take stimulants for ADHD assume that the human brain can be fine tuned with a medication.  There is also a widespread myth that they are cognitive performance enhancing drugs.  The real effects of stimulants are modest at best and there is no good research evidence to support a cognitive enhancing effect.  A similar bias exists for the use of opioids for chronic non-cancer pain.  The person believes that "If I take enough of this medication - my pain will be gone."  Study after study of opioids for chronic non-cancer pain shows that pain relief with opioids is modest at best, with results very similar to what would be expected with non-opioid medications like gabapentin and antidepressants.

There are secondary problems with believing a medication will produce perfect cognition or perfect pain relief.  The first is a tendency to see any medication with such powerful abilities as being able to solve a number of problems that are not the primary indication for the medication.  As an example, with a stimulant - if this medication has such a profound effect on my cognition maybe it can help with with other difficult problems like excessive appetite and weight problems or feeling like I don't have enough energy at certain times during the day.  With the opioid the  thought typically is that it can be used for mental pain as well as physical pain and it is used to treat anxiety, depression, and insomnia.  Whenever a medication is not used strictly for the prescribed indication there is a risk that it will be used for "what ails you."  The danger is dose escalation and addiction.  There is also the risk of attributing too much of an effect to the medication when it does not appear to be doing much.  A person may start to believe that they can't function without the medication but a detailed review of their target symptoms and ability to function shows that there has been a negligible effect.  And finally there is the danger of taking a medication that may produce euphoria, increased energy, and create a sense of well being and not realizing that at some point that is the only reason the medication is being taken.  I have had many people tell me that the medicine did nothing for their pain or cognition but that they kept getting refills because they "liked taking it."

There is what I call the Talisman effect, but probably to a lesser extent than with benzodiazepines.  Many people develop the idea that they are taking a medication that is much more effective than it really is and therefore they have to take it with them wherever they go.  They are conferring what are essentially magical properties to the medication and at some level thinking that they are unable to function in life without it.  They get anxious if they think about not having it or running out.  This not only causes a lot of unnecessary anxiety, but it also prevents the person from using other psychological or conditioning techniques that may work as well or much better than the medication.

These are some of the problems with the idea of taking a rescue medication if you are already on a long-acting form of the medicine.  Physicians in general do not do a good job of explaining these potential problems or even the basic problem of taking a medication that causes euphoria or reinforces its own use.  A more widespread recognition of these problems would go a long way toward curbing overprescription, overuse, and addiction to these medications.    

        

George Dawson, MD, DFAPA

References:

1.  Graph of plasma concentrations of Concerta and methylphenidate is from the package insert on FDA web site at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021121s014lbl.pdf

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.

How Do So Many People End Up on Stimulants?

There is no question that thousands if not millions of people end up taking stimulants unnecessarily these days.  Addiction psychiatrists,  have a unique perspective on this that I thinks goes beyond a typical approach to the problem.  I like to consider it to be grounded in behavioral pharmacology and neuroscience.   For the sake of this essay I will limit my remarks to all adults who are college aged or older and should not be taking stimulants.  Neuroscientific discoveries in the area of brain maturation suggest that a significant portion of the college-aged individuals might not make the same decisions they make a decade later, but the practical consideration is that there are millions of people in college making decisions about stimulants every day.  There are several ways to look at the problem.  The best approach I can think of is to look at the various ways that patients present for treatment.  The request for stimulant treatment can be subtle or overt.  Unlike some the papers in the current literature, I don't think that the diagnostic questions here are subtle.  During an initial clinical assessment - diagnosis and treatment commonly overlap and in some cases that I will illustrate treatment considerations become primary in the initial minutes of the interview.

The general psychiatric interview has always been a screen of sorts.  My recollection is that it was typically more problem focused in the past.  Over time, that interview started to incorporate more disorders as a focus of inquiry.  On the outpatient side the disorders added been primarily Post Traumatic Stress Disorder and Attention Deficit-Hyperactivity Disorder in non-geriatric populations.  Any time a screening is being done whether it uses a symptoms checklist or a lengthy interview there is always the chance of missing the true diagnosis or adding a diagnosis that is probably not there.  Here are a few examples.

1.  "I have been depressed for the past ten years...."  An inquiry about mood disorders at some point will focus on concentration.   Impaired concentration and attention span occurs in a number of psychiatric disorders.  Combined with some developmental history and a history of chronicity it is easy to see the problem as a missed diagnosis of ADHD and initiate treatment for that disorder in addition to the primary mood disorder.  There are problems with that approach especially when the history of the mood disorder is clear and it has never been adequately treated.

2.  "I have a diagnosis of bipolar disorder - manic and these medications aren't working...."  ADHD in adults rarely presents as hyperactivity so severe that it could be mistaken for mania.  Manic episodes are also phasic disturbances making it very unlikely that there would be many patients in any single practice who were both manic and had ADHD.  In the cases where it does happen stimulant treatment complicates the treatment of bipolar disorder and can lead to worsening mania, delusional thinking and hallucinations.

3.  "My son/daughter has ADHD....."  There are two variations in this interaction.  In the first, the parent is told about the high heritability of ADHD and advised that they also probably have it and can be assessed for it or mention to their primary care physician that they may need treatment for it.  In the second, the parent of a child with an ADHD diagnosis reads the diagnostic materials and comes into an appointment and says: "You know, I have read the symptoms and think that I have them.  Should I be treated for ADHD?"

4.  "I have always had a problem reading and I was  never any good in school..."  A common approach is to view this as ADHD, do the screening and proceed with treatment.  Physicians in general have had very little training in the assessment or treatment of learning disorder and although there is comorbid ADHD and learning disorders there is also a significant population of people with pure learning disorders who do not have ADHD.

5.  "I took my friend's Adderall and felt like I could concentrate and study for the first time in my life.  I did a lot better on that test...."  The population-wide bias is that stimulants are a specific treatment for ADHD rather than a drug that will temporarily improve anyone's energy level and attention span.  There is also the cultural phenomenon of cognitive enhancement or using stimulants as performance enhancing drugs that may be driving this request.  It is known that the availability of stimulants on campuses and in professional schools is widespread.  This is associated with students selling their prescriptions for profit and availability of stimulants illegally obtained for the purpose of cognitive enhancement.  The issue is further confused by position statements in scientific journals that support this practice.  I have not seen it studied, but it would be interesting to see questions and responses about cognitive enhancement asked at student health centers and practices that see a lot of college and professional students.

6.  "I have ADHD and need a prescription refill...."  It may be true that the patient has a clear-cut documented diagnosis prior to the age of 12 (DSM-5 criteria).  But what has happened since that initial diagnosis in childhood and now is critical history.  Has there been continuous treatment since then or has the treatment been disrupted.  Common causes of disruption include stimulant side effects, symptom resolution with age,  and co-occuring substance use problems.  A detailed history of the course of treatment since childhood is needed to make the decision to continue or reinitiate treatment.

7.  "I heard you had a test for ADHD...."  This question often initiates screening at a higher level.  There are any number of places with extended neuropsychological batteries, brain  imaging tests, or EEG tests that they claim will definitively diagnose ADHD.  In fact, there are no tests with that capability.  I have heard one of the top experts in the world on ADHD make that same statement and he was also a neuropsychologist.  I have had several years of experience with quantitative EEG machines and know their limitations.   At this point several hours of extended testing adds nothing to a detailed interview, review of collateral information, and symptom checklists to basically assure that all of the questions have been asked.

8.  "My meds need to be adjusted....."  This could be a question from a person in treatment for another problem or a person already being treated for ADHD.  The unstated issue here is the underlying belief that by adjusting a medication one's mental processes will be closer to perfection.  A child psychiatrist that I work with said it best:   "The goal in treating ADHD is to get them more functional, not to perfect their functioning."  I think the unrealistic goal of perfection drives a lot of prescriptions that exceed the recommended FDA limits.  It also explains a lot of "rescue medications" superimposed on sustained release preparations like Adderall.  Anyone familiar with the pharmacokinetics of sustained release drugs should realize why rescue medications (like immediate release Adderall on top of sustained release Adderall XR) are unnecessary.

9.  "I can't stay sober if I can't get treated for ADHD....."  This can be a complicated and confusing situation.  The child psychiatry literature had suggested initially that children with treated ADHD were less likely to have substance use disorders as adults than children with untreated ADHD.  As the evidence accumulates that is less clear.  Many adult psychiatrists and some addiction psychiatrists have extrapolated those equivocal findings to mean that treating a known or new diagnosis of ADHD in an adult will improve treatment outcomes for ADHD.  There is no evidence that is true.  Some addiction psychiatrists believe that the opposite is true, that there is a cross addiction phenomenon and that treating a person with an addiction makes it more difficult to stay sober from their drug of choice.  If the person is addicted to stimulant medication and has a clear history of accelerating the dose of stimulants or using them in unorthodox ways (intravenously, smoking, snorting, etc) it is very unlikely that person will be able to take a stimulant prescription in a controlled manner.  It is also very possible that the person making this request has a long history of experiencing prescription or street drugs as being necessary to regulate mental functioning.  That can be highly reinforcing even if the effects are sustained for hours or less.

10.  "I have been sober for one month and can't focus or remember anything......" Subjective cognitive problems are frequent during initial sobriety.  The substance used and total amount used over time probably determine the extent that the cognitive changes persist, but it is a difficult problem to study for those same reasons.  Clinicians know that there are cognitive effects but there is no standard approach to the problem.  From my experience, I think that two months sober is the absolute minimum time to consider evaluating subjective cognitive problems.  Even at that time getting collateral history about the person's cognitive and functional capacity and problem solving with them on work arounds would probably be the biggest part of the treatment.

The above scenarios are not exhaustive and I probably could come up with another 5 or 10 but they are illustrative of pathways to questionable stimulant use.  The common thread here is that anyone in these scenarios can endorse all of the symptoms of ADHD.  Figuring out what those symptoms are is fairly obvious on many checklists.  One of these checklists shows the symptoms and checkboxes necessary to make the diagnosis in grayed out panels.  It is easy to fake the symptoms in an interview or on a diagnostic checklist.  It takes a lot of hard work on the part of the physician to figure out not only who might be faking but also who has the symptoms but not the diagnosis.  One of the features of the DSM that was attacked by several critics during the pre-release hysteria was the "generic diagnostic criterion requiring distress or disability" to establish disorder thresholds (DSM-5 p 21).  In the case of ADHD that is Criterion D "There is clear evidence that the symptoms interfere with or reduce the quality of social, academic, or occupational functioning."  (DSM-5 p 60).

The diagnosis of ADHD is generally not the diagnosis of a severe functional disorder.  As a psychiatrist who practiced in a hospital setting most of the people I assessed clearly met the functional criteria by the time I saw them and diagnosed severe mood disorders, psychotic disorders, substance use disorders or dementias.   Many of them were by definition unable to function outside of a hospital setting.  It is an entirely different assessment when faced with a successful professional who has worked at a high degree of competence for 20 years who presents with any one of the above problems because they think they have ADHD.  It takes more than a review of the diagnostic criteria.   It takes an exploration of the patient's motivations for treatment.  What do they hope to accomplish by treatment?

It also takes a conservative prescribing bias on the part of the prescriber.  Stimulants are potent medications that can alter a person's state of consciousness.  They are potentially addicting medications and that can result in craving or wanting to take the medication irrespective of any therapeutic effect.  The wide availability of stimulants led to the first amphetamine epidemic in the United States.   When I first started out in psychiatry, I was still seeing people who became addicted to stimulants when they were widely prescribed for weight loss.   It is well known that the medications were ineffective for weight loss but people continued to take them at high doses in spite of the fact that they had not lost any weight.  In talking with people about what drives this many people feel like they are only competent when taking stimulants.   They believe that their cognitive and functional capacities are improved despite the fact that there is minimal evidence that this is occurring from their descriptions of what they are doing at work or in their family.

There are a number of strategies in clinical practice to avoid some of the problems with excessive stimulant prescriptions that I will address in a separate post.  My main point with this post was to look at some ways that people with mild subjective cognitive concerns, addictions, people seeking cognitive enhancement, people who have been functioning well but believe that they can function better come in to treatment for ADHD and get stimulant prescriptions.


George Dawson, MD, DFAPA

Supplementary 1:  Literature was used to construct these hypothetical scenarios.

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]

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