PREFACE:  Done’s Patient-First Philosophy

It would be prudent to assume that all organizations engaged in health care practice a “patient-first philosophy.”  If one studies the policies and publications of such organizations then that assumption appears to be verifiable.  However, if one examines the actions of those organizations and of the people that comprise them, then an objective observer will likely arrive at a different conclusion.

The goal of ADHD treatment is for the patient to achieve optimal attention and executive function.  Absent other diagnoses such as psychosis, substance misuse, severe personality disorders or motivation purely for secondary gain, the best indication of whether this optimum state has been reached is the patient’s report.  

Sadly, despite promoting the notion of “patient-first,” most clinicians are still in thrall to one or more authorities other than the patient to make an assessment.  For example, if a dose decreed as “maximum” by “authorities” has been reached, and if the patient’s cognitive deficits are not adequately improved, the provider may nevertheless refuse the patient’s request for more vigorous therapy. Without doing significant research of their own, the innocent provider may not realize that the authority’s rationale for declaring the higher dose out of bounds may be nebulous, arbitrary, or simply unknowable. 

In fact, “upper limits” on medication dosage are always mere recommendations, not boundaries beyond which it is illegal to transgress. If the clinical necessity for the higher dose is well documented, then the commonly feared consequences of lawsuits or disciplinary actions are extremely unlikely. 

The factors that inhibit the delivery of care in a patient-first manner are not necessarily of flesh and blood, nor do they always have a real existence in the present.  Virtually all clinicians suffer from “phantom courtroom syndrome,” characterized by flashbacks to a musty lecture hall or painfully bright hospital corridor, where a tweed-jacket clad researcher or white-coated attending physician intones, “Imagine yourself on the stand in court before you [insert mildly or minimally risky clinical action here].” In other words, a fear of litigious consequences versus a focus on the patient’s needs.

Psychiatry is a clinical discipline in which accurate assessment is dependent on the clinician being mentally present and focused only on the patient during the evaluation.  It is difficult enough to achieve such a receptive state even under ideal psychological conditions. If the mind of the evaluator is distracted by memories regarding hypothetical legal problems during an attempt to make an assessment, the result of that assessment will inevitably be poor enough to make the risk of legal problems greater than it would have been without such obsessive legal concerns.

 

INTRODUCTION: The best strategy is the one that works.

In 2018, the “Consensus Statement on Diagnosis and Treatment of ADHD” proclaimed

“Despite strong evidence on the clinical presentation, genetics, neurobiology, the burden of the disorder, and on safe and effective treatment for ADHD in adults, many people are still underdiagnosed and undertreated.”

 The following guidelines are meant to help frontline clinicians to meet the challenge of identifying and treating this severely disabling disorder.

 The most current research on the  treatment of ADHD in adults agrees that first-line treatment should be medication.  While studies have indicated that cognitive behavioral therapy and medication have similar long-term efficacy, and that the ideal treatment it is probably a combination of the two, in view of the restrictions of the telehealth platform and of the difficulties ADHD patients typically experience in accessing psychotherapy – as well as the far quicker onset of the therapeutic effect of medications – the remainder of these guidelines will focus on pharmacologic treatment.

 

HOW TO CHOOSE THE RIGHT MEDICATION:

Stimulants are the treatment of choice in almost all cases.  

According to the latest studies, it's not too difficult (in most cases) to choose the right medication to treat adult ADHD:

The first decision point in the medication treatment algorithm is stimulant (various formulations of amphetamine and methylphenidate) versus nonstimulant (for adults, primarily atomoxetine [Strattera].) According to an up to date site that summarizes recent clinical research (called, surprisingly, “UpToDate”), “Meta-analyses have shown that effect sizes in short-term trials of adult ADHD are greater for stimulants compared with non-stimulant medications, including atomoxetine and atypical antidepressants (bupropion, tricyclic antidepressants, and venlafaxine.)”2

Once the ADHD clinician has accepted that treating with a stimulant is usually the best course, the choice must be made between amphetamines and methylphenidate.  In 2018, a meta-analysis of 51 clinical drug trials concluded that, in adults, “amphetamines were moderately more efficacious in reducing core ADHD symptoms compared with methylphenidate.”2  Another study found “the first pharmacological choice for ADHD in children and adolescents is methylphenidate, and amphetamines in adults.   

In fact, in adults, amphetamines were not only the most efficacious compounds, as rated by clinicians and by self-report, but also as well tolerated as methylphenidate and the only compounds with better acceptability than placebo.” [A possible exception to the choice of amphetamine over methylphenidate is in the case of a patient already on a serotonergic agent. There is some evidence that methylphenidate has less risk of interacting with such agents, and precipitating some form of serotonin toxicity (see section headed “When the patient is on antidepressants? below.)]

Thus, rather than asking “when should we prescribe stimulants for adult ADHD?” – it is better to ask: 

 

WHEN SHOULD WE NOT PRESCRIBE A STIMULANT?

History is always the most important criterion: when the patient has had an adverse reaction to a stimulant, or when stimulants are absolutely contraindicated, we must find another way to treat.  

In my opinion, the absolute contraindications to stimulant therapy are: 

  1. hypersensitivity to the medication, 
  2. treatment with monoamine oxidase inhibitors currently or in the past 14 days, 
  3. and severe psychotic disorders such as schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features.

The rest of this section will be devoted to describing certain other circumstances traditionally regarded as contraindicating stimulant treatment, and providing evidence that stimulants can be prescribed (as always, with care) to patients that could benefit from their therapeutic action even in those circumstances:

PRESCRIBE A STIMULANT (WITH CARE) EVEN IF THE PATIENT SUFFERS FROM THE FOLLOWING CONDITIONS (“COMORBIDITIES”):

One of the more recent treatment algorithms for adult ADHD suggests that the two contraindications for stimulants are: 

  • history of heart attack or arrhythmia 
  • stimulant use disorder.                              

It is important to critically examine any rationales for the contraindication of stimulants, as the treatment most likely to help patients should not be denied unless the risk outweighs the probable benefits.  As well as discussing cardiac and substance misuse issues, several other conditions commonly thought to contraindicate stimulant treatment will be covered:

 

A. Stimulant-use disorder

Stimulant use disorder, a subclass of substance-related disorders, is a common comorbidity among ADHD patients, and the neuroanatomical and neurochemical substrates for the two disorders are interrelated. 

Stimulant use disorder is of special relevance to the treatment of adult ADHD for two reasons:

  1. The medications of choice for adult ADHD are the same molecules that are misused, sometimes with catastrophic health consequences, by patients suffering from stimulant use disorder.
  2.     The two disorders not only share elements of pathophysiology, but having one increases the probability of having the other.

 There is a growing body of evidence that stimulant use disorder itself may be best treated with long-acting amphetamines or long-acting methylphenidate.  Thus, whether treating someone with ADHD with a stimulant use disorder comorbidity or treating uncomplicated stimulant use disorder, the clinician is faced with prescribing a substance for therapy that is essentially identical with a substance of misuse.  

This has led to an understandable aversion to treating ADHD patients with stimulants if they suffer from stimulant use disorder as well. This reluctance is perhaps exacerbated by negative association, triggered by the health care system’s preoccupation with lawsuits, of appearing “on the stand” in an intimidating courtroom setting.

Examination of the evidence-based literature shows that this reluctance does not serve the interests of the ADHD patients.  Studies have demonstrated that stimulants are an effective treatment for cocaine-use disorder, and that stimulant or atomoxetine treatment for ADHD reduces the risk of substance-related visits to emergency rooms.

 What percentage of adult ADHD patients will receive suboptimal treatment if we deny stimulant treatment to all who suffer from a substance use disorder?   

It is said that “individuals with ADHD are twice as likely to experience substance abuse or dependence,” and “possibly the most common comorbid condition with ADHD is SUD, particularly alcohol and/or nicotine, cannabis and cocaine use.” Furthermore, “[children] with ADHD were about 2–3 times more likely to develop nicotine, alcohol, marijuana, cocaine, and/or other substance use disorders than those without ADHD” in adolescence or adulthood.”  

As about 8% of American adults have a substance use disorder, by multiplying that by a factor of two or three, we arrive at the rough estimate of 16-24% of adult ADHD patients having a substance use disorder. Clearly, denying stimulant  treatment to all who have a history of a substance use disorder is a strategy that would do more harm than good, as it would result in up to 1/4 of all adult ADHD patients receiving suboptimal treatment.

 To summarize, stimulant use disorder is a contraindication to treating ADHD with stimulants only if the person is actively misusing. If there has been a reasonable period of abstinence, stimulants remain the first line treatment, both because they overall give the best probability of response, and because stimulant treatment of the ADHD may ameliorate the brain pathophysiology that underlies the stimulant  use disorder.

 

B. Opioid-Use Disorder

Please see my separate article entitled “Suboxone  and ADHD Treatment.”

 

C. History of a heart attack or arrhythmia

The idea that stimulants elevate the risk of cardiovascular morbidity and mortality has become part of clinical folklore. How this largely incorrect idea arose has become more a matter for historians of medicine than a practical clinical concern, for the most recent studies have demonstrated essentially no increased risk of cardiovascular morbidity or mortality. 

It is well documented that stimulants are associated with small increases in resting heart rate and systolic blood pressure, averaging, according to one meta-analysis, 5.7 beats per minute and  2.0 millimeters of mercury.  While it is generally accepted that such small increases are not clinically relevant, their mere presence increases practitioner anxiety about cardiovascular issues. This anxiety, when combined with unsubstantiated reports of problems more serious than mildly elevated vitals, led to the inflation of any possible risks far beyond their actual magnitude.

Any concern about cardiac complications must of course be taken very seriously.  An account of the origins of these concerns is helpful and relevant, for if an idea does not originate from firm ground, it makes the case for its lack of validity more compelling.

Consider the following “scientific statement” about this issue, published by the American Heart Association in 2008: 

“In 1999, concerns over potential cardiovascular effects of psychotropic drugs, especially tricyclic antidepressants but including stimulants, prompted the American Heart Association (AHA) scientific statement “Cardiovascular Monitoring of Children and Adolescents Receiving Psychotropic Drugs.” At that time, no specific cardiovascular monitoring was recommended for the use of stimulant medications. Since that time, a constellation of circumstances have come together, necessitating a second look at this complicated issue. These circumstances include an increased awareness of the presence of attention deficit/hyperactivity disorder (ADHD) in the general population and in children with preexisting cardiac conditions; public concerns about the side effects and toxicities of medications, especially psychotropic medications in children; and regulatory factors and warnings issued by the US Food and Drug Administration (FDA) and by the pharmaceutical industry in response to the FDA. This writing group was convened in response to FDA concerns with regard to the safety of the ADHD drugs and with regard to the identification of children with underlying cardiovascular abnormalities…In February 2005, Health Canada, the Canadian drug regulatory agency, suspended the sale of Adderall XR in the Canadian market. The Canadian action was based on US postmarketing reports of sudden deaths in pediatric patients…Despite the lack of data to support limiting the use of the stimulant medications in children with heart disease, in August 2005, the FDA added a warning to the Adderall labeling, titled “Sudden Death and Preexisting Structural Cardiac Abnormalities,” which states, “Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalities. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities.” (Italics added by me).

This “scientific statement,” promulgated by the most prestigious cardiology organization in the nation, had no compunction about pointing out that there was no data to support limiting the use of the stimulant medications in children with heart disease. However, this lack of data did not prevent the FDA from adding a warning which effectively did limit such use.  Later in the same statement, the American Heart Association group says that it is “reasonable” to order an EKG for children taking stimulant agents. This exceedingly vague and nonbinding recommendation nevertheless had an effect, presumably because physicians did not want to seem to ignore even a vague recommendation from a body as important and well known as the American Heart Association (not to mention the Food and Drug Administration). To hopefully forestall unintended consequences of the statement, such as increases in substance abuse and academic problems due to limiting children’s access to effective ADHD treatment, in 2009, the American Academy of Pediatrics pointed out that the American Heart Association's recommendation contradicted evidence-based recommendations from the American Academy of Child and Adolescent Psychiatry as well as from themselves. This response stated, “There is no evidence that routine ECG screening before beginning medical therapy for ADHD prevents sudden death. … The AAP encourages physicians to continue to follow current recommendations for ADHD treatment, including the use of stimulants, without obtaining routine ECG before beginning therapy.”  (Italics added by me).

The controversy was reignited in 2012 when a study found that initiation of methylphenidate in adults was associated with a 1.8 fold increase in the risk of sudden death or ventricular arrhythmia. Dosage was inversely associated with risk, leading the authors to suggest that methylphenidate did not actually cause the adverse events.

Despite that disclaimer, this study was alarming enough that several more studies were performed in the ensuing years, with results that should prove reassuring (if the phenomenon of the brain exhibiting better retention of negative than positive can be overcome.)  A 2017 update  summarizing the results of at least 10 studies that observed a total of greater than 5,000,000 patient-years(!), concluded that “sudden death or other serious events (e.g. myocardial infarction, stroke, ventricular arrhythmia, all-cause mortality) are extremely rare amongst stimulant users and do not appear to occur beyond the risk of non-users in the general population.”  Another review flatly states, “Among adult patients who are either current or new users of stimulant medications, there appears to be no increased risk of serious CV events.” 

Even with the pushback from the American Academy of Pediatrics and the recent studies with millions of patient years worth of data that are summarized above, the current FDA-approved labeling for Adderall XR simply repeats the warning from 2005, which states, “Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalities. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities.” For adults, the FDA states that patients with “serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems… should also generally not be treated with stimulant drugs.”  For Ritalin LA, the current FDA-approved labeling says, “Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems.”  

If there was a well-documented increased incidence of serious cardiovascular events among users of therapeutically prescribed amphetamine or methylphenidate, or if they had only very limited benefits to those which received those prescriptions, it would be more defensible to retain the recommendation to avoid their use in patients with cardiovascular problems.  

However, since those benefits can in many cases be life changing or even lifesaving, any reasonable benefit versus risk analysis would recommend allowing their use in such patients. One can only speculate as to why this language has been retained over the many years since evidence has been available demonstrating the very low risk and very high benefits. My personal opinion is that it is another example of the effects of the stigma of mental illness being acted out, perhaps unconsciously, but acted out nonetheless.  

The idea that ADHD has received this unfair treatment in government-agency-approved prescription manuals due to the stigma of psychiatric in substance use disorders becomes even more plausible when one considers the fact that ADHD’s treatment of choice is a class of molecules that are potentially misusable, often manufactured or obtained illicitly, and thus suffers from heavy stigmas of its own; it is a category of compounds in which the government has a vested interest in controlling.

 

D. Seizure disorder

The FDA summary of product characteristics for Adderall XR states that “there is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures,” although such a warning is not present in the equivalent prescribing information for methylphenidate.  

There is substantial recent research demonstrating that such concern is not justified for any stimulant medication.  A 2021 review stated, “The evidence shows that the majority of psychotropic medications are not proconvulsant when used in therapeutic doses, with the exception of a subset of medications, mainly bupropion IR and certain antipsychotic drugs such as clozapine.”  A prospective study of 995 individuals who initiated ADHD medication found no statistically significant difference in the rate of seizures during the 24 weeks before and after medication initiation, compared to the same period in the previous year.  

A large-scale study reviewed hospital admission records of children and adolescents with epilepsy who were taking stimulants versus those who were not: “The results were striking. Not only did stimulant usage in the present or recent past show no increase in seizure-related hospitalizations, it appeared that the stimulant users were actually less likely to require hospitalization. It could then be concluded, albeit with reasonable limitations, that stimulants were actually protective against seizures that required hospitalization.  The idea that stimulant medicines are protective against seizures is completely counter to what generations of epileptologists have been taught. Yet the data continues to accumulate...” 

With regard to methylphenidate in particular, “a recent systematic review identified seven prospective studies and two retrospective studies and none of these studies reported higher seizure rates after exposure to methylphenidate.” The same review concluded “epilepsy should not automatically preclude patients from receiving ADHD medications.” 

E. Tic disorders 

While there are anecdotes of exacerbation or new onset of tic disorders supposedly caused by stimulant treatment, objective research indicates that these are coincidental rather than causal relationships. A study that identified all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with ADHD and subjected 22 trials to meta-analysis found that the “risk of new onset or worsening of tics associated with psychostimulant treatment was similar to that observed with placebo.”

F.  Concurrent treatment with antidepressants

There is a drug interaction between stimulant medication and serotonergic agents.  While stimulants primarily enhance release of dopamine and norepinephrine, increased serotonin release may also occur, and thus there is some risk of serotonin toxicity from combined use. It would be important to know the incidence of this complication in patients who are prescribed serotonin reuptake inhibitors and stimulants concurrently, as the selective serotonin reuptake inhibitors are by far the most commonly prescribed antidepressants.  

A 1991 study found that the “serotonin syndrome” (another name for varying degrees of serotonin toxicity) is most commonly the result of the interaction between serotonergic agents and monoamine oxidase inhibitors, which suggests that its incidence may be rather low, as monoamine oxidase inhibitors were rarely prescribed in psychiatry in 1991, and are even less commonly prescribed currently.  

A search of the literature over the past 4 years for articles with the words "serotonin syndrome interaction” in the title netted 32 articles describing interactions of a total of 26 specific agents which led to a diagnosis of serotonin syndrome.  Not a single one of these 26 agents was a stimulant. In a 2018 review of the literature, Foong, Grindrod, Patel, and Kellar state: “most cases involve 2 drugs that increase serotonin in different ways; the most concerning combination is a monoamine oxidase inhibitor with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor”... and “cases requiring hospitalization are rare, and mild cases caused by serotonin-mediated side effects are unlikely to be fatal.” 

The same authors divide drugs that could cause serotonin syndrome into two groups, the monoamine oxidase inhibitors and all the others. They state combining two MAOI’s is to be avoided, as is combining an MAOI with one from the other group.  It is noteworthy that while amphetamine is in the second group, methylphenidate is nowhere to be found.  This is because amphetamine causes more serotonin to be released from the presynaptic terminal into the synapse, while methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor.

To summarize what can be gleaned from the literature, the agents that can cause serotonin toxicity are fewer than often supposed.  The biggest offenders are the MAOI’s, which in my experience are almost never prescribed by mental health professionals.  Furthermore, as the most concerning combination is a monoamine oxidase inhibitor given with another serotonergic agent,  the incidence of such a professional combining an already rarely-prescribed MAOI with another medication that presents even the slightest risk of causing serotonin toxicity is hopefully close to zero.

There is ample support that the concern that serotonin syndrome may be caused by the combination of stimulants and antidepressants is overblown. Nevertheless, in the interest of maximal risk reduction, it makes sense to use methylphenidate rather than amphetamine in such patients.  As with everything in medicine, benefits as well as risks must be inserted into the equation, and if a patient is not responding adequately to methylphenidate, amphetamine should be considered even if they are on antidepressants, especially in cases of severe ADHD.

PREGNANCY AND BREASTFEEDING

The potential negative effects of untreated ADHD on both mother and offspring overall outweigh the small risks of continuing treatment during pregnancy and breastfeeding.  Patient and provider anxiety about continuing medication during those sensitive times is the more likely cause of a change in treatment, rather than an objectively documented risk of continuing the treatment.

A small increased risk of cardiac malformations has been associated with intrauterine exposure of the fetus to methylphenidate during the first trimester.   No fetal structural abnormalities have been definitively associated with perinatal amphetamine exposure. The majority of human data are based on illicit amphetamine/methamphetamine exposure and not from therapeutic maternal use.  Use of illicit amphetamines during pregnancy increased the risk of prematurity and fetal growth restriction, fetal demise and neonatal and infant deaths. However, a study of pregnant women and their offspring, treated with MPD for ADHD, found no significant differences in Apgar scores and congenital malformations between neonates exposed and unexposed to MPD.  The highlights from a 2021 systematic review of parental ADHD in pregnancy and the postpartum period are worth quoting in full, as they address the risks of refraining from or discontinuing treatment due to concerns about potential birth defects or about complications from breastfeeding:

Highlights

•  Female ADHD is associated with the risk of teenage pregnancies.

•  Maternal ADHD is associated with an increased risk of pre-eclampsia, infection and caesarean section.

•  Maternal ADHD is associated with negative birth outcomes.

•  ADHD medication seems not to be major teratogens.

•  There are no severe acute complications associated with methylphenidate during breastfeeding.”

MONITORING VITAL SIGNS AND LAB TESTS

Occasional monitoring of blood pressure, heart rate and weight are to be encouraged even in young people without known medical problems. However, as the increases in blood pressure and heart rate caused by stimulants are too small to be clinically significant, it is not necessary to increase the frequency of monitoring because a patient is on stimulants.  

Please contact Dr. Brody about topics that still need treatment guidelines