Saturday, December 15, 2018

This review provides the following:

  • information about the diagnosis of ADHD
  • how ADHD drugs act on the brain
  • a review of the safety and efficacy of ADHD drugs (including their long-term effects)
  • a review of clinical care guidelines for ADHD

Diagnosis of ADHD

The American Psychiatric Association (APA) sets the criteria for making a psychiatric diagnosis in its Diagnostic and Statistical Manual (DSM). The APA first created a diagnosis called Attention Deficit Disorder in 1980, when it published the third edition of its DSM.  In subsequent editions, the name of the diagnosis was changed to Attention Deficit Hyperactivity Disorder (ADHD.)

There is no biological test for ADHD. According to DSM criteria, a diagnosis of ADHD can be made if a child is perceived to be  “inattentive,” “hyperactive” or “impulsive,” and such behaviors “interfere” with “functioning and development.” The child who fidgets in school, or doesn’t pay attention to the teacher, is displaying “symptoms” of ADHD.

Given that there is no biological marker for the disorder, there is an obvious subjective element to making the diagnosis. What may be seen as a problem in one setting—by a parent, teacher, or pediatrician—may be considered normal behavior in another situation.

Gender, age, and cultural differences affect diagnostic patterns. Boys are two to three times more likely than girls to be diagnosed with ADHD; the youngest children in the classroom are up to 50% more likely than the oldest children to be so diagnosed and medicated; and whereas 13% of elementary-school children in the United States are said to have ADHD, the diagnosis is not used at all in the UK. Instead, in the UK, about 2% of children are diagnosed with hyperkinetic syndrome.

Since most children who have trouble paying “attention” also have behavioral problems, the diagnosis of ADHD often overlaps with other diagnoses: oppositional defiant disorder, disruptive mood dysregulation disorder, conduct disorder and other behavioral problems. The treatments for these different diagnoses overlap too, with stimulants often prescribed for children with such behavioral difficulties.


How ADHD Drugs Act on the Brain

As parents seek to assess the merits of psychiatric medications for their children, and their possible risks and benefits, it is helpful to understand how these drugs “act” on the brain.

How brain neurons communicate

There are an estimated 100 billion neurons in the brain. Messages are passed along neuronal pathways in the brain via molecules, known as neurotransmitters, that act as “chemical messengers.”

The first neuron releases a neurotransmitter into the tiny gap between neurons, which is known as the synaptic cleft, and the neurotransmitter binds with receptors on the second neuron. The neurotransmitter is said to fit into the receptor like a “key into a lock.”

This binding action either causes the second neuron to fire, or inhibits its firing. An excitatory response passes the message along the neuronal pathway; an inhibitory response dampens this neuronal activity. To end the message, the chemical messenger is then “transported” back into the first neuron and stored for later re-use.

Image: GSLC, University of Utah


The chemical imbalance hypothesis
 

In the 1960s, researchers discovered how antipsychotics and antidepressants interfered with this messaging process, and their discoveries led to a hypothesis that mental disorders are due to chemical imbalances in the brain, which are then “fixed,” or put back to normal, by psychiatric drugs.

For example, antidepressants were found to increase levels of serotonin in the brain, and thus researchers hypothesized that depression was due to too little serotonin. Antipsychotics were found to block dopamine pathways in the brain, and so researchers hypothesized that schizophrenia was due to too much dopamine in the brain.

To test these hypotheses, researchers conducted studies to determine whether people with depression  had too little serotonin in their brain, or whether people with schizophrenia regularly had too much dopamine activity. Decades of research failed to provide the confirming evidence.

In 2005, Kenneth Kendler, coeditor in chief of Psychological Medicine summed up these research findings in this succinct way: “We have hunted for big simple neurochemical explanations for psychiatric disorders and have not found them.”

A paradigm for understanding psychotropic drugs

In a 1996 paper, then NIMH director Stephen Hyman provided a good description of how psychiatric medications actually “work.” The drugs are better understood as agents that create abnormalities in brain function.

Psychotropic drugs, Hyman noted, all perturb normal neurotransmitter activity in the brain. The brain, however, has various feedback mechanisms to monitor its neurotransmitter activity, and in response to the drug’s perturbation of its normal functioning, it goes through a series of “compensatory adaptations.” The brain is seeking to maintain its normal functioning.

For instance,  if a drug raises serotonin levels, the brain decreases its own serotonergic activity. If a drug blocks dopamine receptors, then the brain increases its dopaminergic activity. And so forth. At the end of this compensatory process, Hyman wrote, the brain is now functioning in a manner that is both “qualitatively as well as quantitatively different from the normal state.”

ADHD medications alter dopamine function

Ritalin and other stimulants prescribed for ADHD increase dopamine levels in the brain. They do so either by increasing the release of dopamine from the neurons, or by blocking the normal re-uptake of dopamine from the synaptic cleft. Cocaine increases dopamine levels in this latter manner as well.

 

Image: National Institute of Drug Abuse

 

Dopamine is a major “neurotransmitter” in the brain, and in compensatory response to such treatment, the brain decreases its own dopaminergic functions. Brain neurons may begin to release less dopamine and decrease the density of their brain receptors for dopamine; there is evidence that the number of dopaminergic neurons may decrease too.

The easiest way to understand this process is through a metaphor. Ritalin and other ADHD drugs act as an accelerator on dopamine activity in the brain; in response, the brain puts down the brake on such activity. The brain is now changed by the presence of the drug.

The long-term effects of ADHD drugs on the brain are not well understood, or even well studied. However, in 2016, researchers reported that after four months of exposure to an ADHD drug, there is evidence of brain changes in children that may be long-lasting, and even permanent.

With this understanding in mind, parents can now ask: how do these changes in brain function affect a child or adolescent, both over the short term and longer periods of time? What does the evidence show?


The Right to Informed Consent

Most clinical guidelines for ADHD treatments urge that decision-making include the health care professional, the parents/carers, and the child with ADHD. Health care professionals are reminded to provide full “informed consent” to the parents and child, which requires discussing the evidence of the risks and benefits of different approaches, including their long-term effects.

More on shared decision-making

  • “A Bill of Rights for Children and Adolescents Considering Psychiatric Medications”
  • Canadian Paediatrics Society guidelines for ADHD.
  • NICE guidelines for ADHD.


Risks and Benefits of ADHD drugs

Short-term effects

The first studies of methylphenidate (Ritalin) for ADHD in children found that the drug reliably decreased their motor movement and social engagement with others. Researchers reported that medicated children became more “passive” and “submissive.” Stimulants, wrote the Oxford Textbook of Clinical Psychopharmacology and Drug Therapy, curb hyperactivity by “reducing the number of behavioral responses.”

This change is viewed as positive on the ADHD scales used to measure the efficacy of ADHD medications. The drugs, investigators at the National Institute of Mental Health wrote in 1995, are highly effective “in dramatically reducing a range of core ADHD symptoms such as task irrelevant activity (e.g., finger tapping, fidgetiness, fine motor movement, off-task [behavior] during direct observation), and classroom disturbance.”

The child, in this new subdued state, may “focus” more intently on an arithmetic problem, or other school work. This too is seen as evidence of drug efficacy: the child is paying more “attention” in school. However, in a 2002 review, Canadian investigators concluded that in spite of this change in a child’s “attentiveness,” there is “little evidence for improved academic performance.”

Risks

Ritalin and other ADHD medications may cause a long list of physical, emotional and psychiatric adverse effects. The physical problems include drowsiness, appetite loss, lethargy, headaches, abdominal pain, motor abnormalities, facial and vocal tics, jaw clenching, skin problems, liver disorders, weight loss, growth suppression, hypertension and sudden cardiac death. The emotional difficulties include depression, apathy, a general dullness, mood swings, crying jags, irritability, anxiety, and a sense of hostility toward the world. The psychiatric problems include obsessive-compulsive symptoms, mania, paranoia, psychotic episodes and hallucinations.

Source: T. Smith, “Subjective report of side effects of prescribed and non-prescribed psychostimulant use in young adults.” Substance Use Misuse 52 (2017):548-552.

 

These various adverse effects also increase the risk that a medicated youth will turn “bipolar.” In one study at Massachusetts General Hospital, researchers reported that 11% of children diagnosed with ADHD and treated with stimulants developed bipolar symptoms, which were not present at initial diagnosis, within four years. Researchers at the University of Cincinnati Medical Center investigating this risk determined that two-thirds of the adolescent patients hospitalized for mania at their center had been on stimulants “prior to the onset of an affective episode.” Stimulants, they concluded, may “precipitate depression and/or mania in children who would not have otherwise developed bipolar disorder.”

The following graphic details how the recognized adverse effects of stimulants are very similar to the symptoms that are used to diagnose bipolar in children and adolescents.

 

Source: R. Whitaker, Anatomy of an Epidemic, p. 238.


Long-term outcomes

In 1994, after 14 years of studies on ADHD drugs, the APA’s Textbook of Psychiatry concluded that “stimulants do not produce lasting improvements in aggressivity, conduct disorder, criminality, education achievement, job functioning, marital relationships, or long-term adjustment.”

Given this conclusion, the NIMH then mounted a study, called the Multisite Multimodal Treatment Study of Children with ADHD, to further investigate the long-term effects of stimulants. This study is still cited today as providing the best evidence regarding the longer term effects of stimulants.

At first, the results were positive. At the end of 14 months, the investigators announced that stimulants, when prescribed by ADHD experts, had proven to be superior to “behavioral treatment” in reducing core ADHD symptoms, and there was a hint that the medicated children had fared better on reading tests too.

However, the study continued, and by the end of three years, the results had flipped. Medication use was now “a significant marker not of beneficial outcome, but of deterioration,” the researchers wrote. “That is, participants using medication in the 24-to-36 month period actually showed increased symptomatology relative to those not taking medication.” The medicated youth also had higher delinquency scores at the end of three years, and were shorter and weighed less than their off-med counterparts.

At the end of six years, medication use was associated with worse hyperactivity-impulsivity and oppositional defiant symptoms, and with greater “overall functional impairment.” The medicated youth were also more likely to be diagnosed with depression or anxiety.

Other long-term studies have produced similar results. For example, the Western Australian Department of Health, in a study of the  ten-year outcomes of children with ADHD, reported that the medicated youth had slightly worse ADHD symptoms and were ten times more likely to be identified as performing poorly in school than the unmedicated youth. Long-term stimulant use was also associated with elevated blood pressure.

A large Canadian study, which assessed medication use for ADHD youth in Quebec over a 14-year period, determined that increased use of the drugs was associated with increases in unhappiness, a deterioration in relationships with parents, more anxiety and depression among girls, and a deterioration in educational outcomes.

In a 2012 op-ed for the New York Times, Alan Sroufe, a psychology professor at the University of Minnesota who had been conducting research on ADHD for 30 years, summed up the evidence in this way: “No study has found any long-term benefit of attention-deficit medication on academic performance, peer relationships, or behavior problems, the very things we want to improve.”

Animal studies

Animal studies have found that stimulants may cause permanent negative behavioral changes. For example, repeated exposure to stimulants was found to cause rhesus monkeys to exhibit “aberrant behaviors” long after the drug exposure had stopped. Preadolescent rats treated with stimulants moved around less as adults, were less responsive to novel environments, and showed a “deficit in sexual behavior.” The animal studies have led at least few investigators to conclude that stimulants may damage the brain’s “reward system,” and thus to a concern that medicating a child may produce an adult with a “reduced ability to experience pleasure.”

Summing up the evidence


Clinical Practice Guidelines

There is significant variation in the clinical practice guidelines for ADHD developed by different groups in different countries, especially with regard to the use of stimulant medication.

As can be seen in the table below, which reviews the guidelines issued by twelve groups from the United States and other countries, only those issued by the American Academy of Child and Adolescent Psychiatry recommend medication as a first-line treatment for attention problems in children six and under. Eight guidelines recommend that behavioral therapies be tried first, and two of the eight discourage any use of medication in this age group. Three provide no specific recommendation for this age group.

For adolescents and children older than six, the twelve guidelines provide mixed advice. Five of the twelve recommend medication as a first-line treatment; the others recommend behavioral therapy as a first-line treatment, or its use in combination with medication.

Most of the guidelines, when recommending the use of ADHD drugs, focus on the evidence for their efficacy in ameliorating symptoms over the short term, without assessing their longer term benefits or harms. The National Institute of Clinical Evidence guidelines in the UK are the most conservative regarding the use of ADHD drugs, recommending that medication be used, even for those seven and older,  “only after environmental modifications have been tried.”


In 2014, Spanish researchers who reviewed the evidence for ADHD medications, including their long-term effects, concluded that the clinical practice guidelines should be revised to reflect the drugs’ lack of long-term benefits and their potential to cause harm. They wrote: “These drugs are the same stimulants whose harmful consequences are well known in other uses in adults. In this paper we have carried out an exhaustive review of the sources from scientific evidence regarding the short and long term effectiveness of the medication . . . The result is disappointing and should lead to a modification of the [Clinical Practice Guidelines] to the use of drugs as tools of last resort, in a small number of cases for limited and short periods of time.”

For more info on ADHD diagnosis, medications and guidelines:

Book: Anatomy of an Epidemic, pages 218-227

Slide presentation: “Medicating ADHD: If long-term outcomes are considered, is this an evidence-based practice?

On guidelines: Murphy, JM. “Alternative national guidelines for treating attention and depression problems in children: comparison of treatment approaches and prescribing rates in the United Kingdom and the United States.”

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Copyright: Mad in America Foundation, 2018