The diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) is well established in the field of psychiatry. Not only is it well accepted, but ADHD has dramatically increased over the past 10 years. Some would even say it’s an epidemic in its own right. The use of psychostimulants as a treatment is common practice, and today we are here to discuss the risk of neurotoxicity with ADHD medication.
What Are Psychostimulants
Psychostimulants include methylphenidate (MPH) and mixed amphetamine salts such as Adderall. These remain the most effective and widely used medications for the treatment of ADHD. These medications function by blocking the dopamine reuptake transporter and increase dopamine stimulation at the postsynaptic receptors. These medications work to increase attention and reduce impulsivity but the long-term implications of consistent use are largely unknown.
Substance Use and Stimulant Prescribing
Most lines of evidence in the literature indicate that these medications do not promote substance use later in life and may even decrease the potential for future substance abuse. I’ve also found lines of evidence that indicate the opposite, but the general consensus in the field is that there is not increased risk for future substance abuse. We do know that drugs that function in a similar manner to these medications result in molecular and structural changes to neurons. It is unknown if this also occurs with stimulant medications used to treat ADHD.
Neuronal Effects of Amphetamine
Methamphetamine is a known neurotoxin and several studies have indicated this in animal models. Recently exposure to amphetamine has been sown to cause impairments on the development of dendritic branching up to 3 months after stopping methylphenidate. In mice there is evidence that MPH use causes loss of dopamine neurons in the substantia nigra which may increase the risk of Parkinson’s disease. Other groups have shown alterations in nerve growth factors and brain derived neurotrophic factor in the frontal cortex after chronic MPH use. When neurons from the prefrontal cortex are exposed to MPH it alters their electrical activity. MPH was found to reduce electrical activity and it persists in a dose dependent fashion even 10 weeks post exposure. In rats the use of MPH is associated with decreased response to normal stimuli and increased response to adverse stimuli. We need to be careful extrapolating this information to humans as these studies were conducted in animal models.
Attention deficit hyperactivity disorder (ADHD) in the adult population is a topic of great debate. There are many psychiatrists who say ADHD symptoms do not suddenly disappear as a person continues into adulthood. On the other hand, there are some psychiatrists who do not think ADHD is a real diagnosis.
The term ADHD might be better thought of as attention deficit disorder (ADD). The concept of hyperactivity is more common in the child/adolescent patient population. It’s unclear if the hyperactivity is related to executive dysfunction which is the hallmark of ADHD. It may be that the hyperactivity is within the range of normal (agitation or activation) for a child, or signs of another mood disorder such as mania in bipolar illness (especially true in the adult population as bipolar diagnosis is commonly reserved for adult patients).
We can make an argument that placing children in a traditional school setting where they are asked to sit and pay attention to uninteresting material for 7 hours is unnatural and directly against the way humans evolved to function. The human body and mind evolved to move and be active not to sit in classrooms. As a result, agitation, hyperactivity, and acting out can be the result of this unnatural state.
The hallmark of ADHD is attentional impairment and executive dysfunction. Hyperactivity is not seen in adult populations with ADD.
Attention As a Trait
Attention can be thought of in the same manner as blood pressure. There is a mean blood pressure in the population but there will be individuals that fall outside the standard curve. Most people in the population will fall in the middle having a reasonable amount of attention and those with low attention levels do not necessarily have a disease although they may have consequences associated with reduced attentional activity. When someone is overly attentive it can be a symptom of disorders like obsessive compulsive disorder (OCD) or psychosis. Like blood pressure, having readings that are too high or too low can cause problems. It’s normal to have a certain amount of inattention, and we can think of attention as a spectrum with a range of normal levels.
What are the Causes of Inattention
-It could be a perfectly normal trait, as we explained some people have lower attention spans naturally as a personality trait
-Mood disorders like depression and bipolar disorder have in inattention as a possible consequence of the change in mood
-Psychotic disorders also have cognitive changes that may cause inattention (internal preoccupation)
-Anxiety disorders
-Neurocognitive disorders
-We should avoid diagnosing ADD in the setting of one of these other conditions.
Would you diagnosis ADD during a manic episode?
Prevalence of ADHD in the U.S.
-The prevalence of ADHD in the U.S. ranges from 5.6% to 15.9% and there is great variability depending on the geographic region
-For most biological diseases we should see similar prevalence rates across populations and geographic regions. For example, schizophrenia has a prevalence of about 1% worldwide. So why do we see significant differences across the U.S.?
-We do not know much about the role socioeconomic factors, diet, exercise, and other social factors play in the development of ADHD. It’s possible that these are significant contributing factors resulting in the symptoms associated with ADHD.
Is ADHD a neurodevelopmental issue?
-One way of thinking about ADHD is as a neurodevelopmental problem that eventually improves over time.
-In children with ADHD they seem to achieve peak cortical thickness later than children without ADHD, this has been confirmed on imaging studies.
-The important part is eventually these children catch up with the normal controls. It’s more a delay in brain development and not a permanent state.
-The ADHD children are about 2 years behind the normal controls and the area of greatest delay is the prefrontal cortex which is responsible for executive function.
How Common is ADHD and Does it Last into Adulthood?
Over the past decade ADHD in adult populations has gotten more attention. Some would say the prevalence in adults is 4% to 5% with equal rates being seen in men and women.
The national comorbidity survey estimated 46% of children with ADHD have symptoms that persist into adulthood. Many of these individuals had comorbid anxiety disorders and we know anxiety can be a major cause of inattention and executive dysfunction.
In other studies, similar findings were reported. What stands out to me in all these studies is the high rates of comorbid mood disorders including depression and bipolar disorder. It’s hard to make a diagnosis of adult ADHD in the presence of other conditions considering the significant overlap of symptoms and cognitive dysfunction associated with mood disorders.
It’s possible that mood and anxiety disorder can account for most adult ADHD cases and a variation of a normal trait could explain the rest (individuals with low attention)
Looking at medication response doesn’t help us much as amphetamines are helpful in everyone even those who do not have a psychiatric disorder (think college kids taking them for midterms)
When you correct for comorbidities in Adult ADHD, only about half of the young adults meeting criteria for ADHD had ADHD only. Estimates from this showed that most children diagnosed with ADHD were no longer meeting criteria in adulthood (83% no longer had symptoms). Many of the newly diagnosed cases of ADHD were in individuals who did not have ADHD as children (87% did not have ADHD as children).
This indicates that about 20% of children diagnosed with ADHD will have symptoms persist into adulthood, the other 80% will not
In animal models, amphetamines have been shown to have some dangerous effects
-Decrease response to reward stimuli
-increased anxiety
-decreased dopamine activity
-decreased long-term survival of neuronal cell in the hippocampus (excitotoxicity)
Risk of Substance Use With Stimulant Prescriptions
Most psychiatrists will tell you the risk of substance use disorder does not increase with stimulant medication treatment; in fact it’s reduced when ADHD is treated. However, a well-designed randomized controlled trial of delinquent behavior and emerging substance use in medication treated children found significantly higher rates of substance use in the stimulant treated individuals. The conclusion by Molina et al. was we need to re-evaluate the risk of substance use disorder as children age when they are prescribed stimulants. Now correlation does not equal causation, but this should give us some pause when blinding stating there is no risk for addiction with stimulant use (this claim is mostly based off observational data and not randomized controlled trial data).
-This is one of the only disorders where medication is the first line treatment in children and adolescents.
-There is a 70%-80% response rate to psychostimulants, and medication consistently outperforms behavioral interventions in RCTs.
-For preschool age children, behavioral interventions are first line and medications are considered if there is a poor response to behavioral intervention and functional impairment.
Psychostimulants
–Methylphenidate (MPH or Ritalin) should be started at 2.5 to 5 mg twice daily (before breakfast and lunch). It can be increased by 2.5 to 5 mg/day reaching an optimal dose of 1 mg/kg/day and a maximum dose of 2 mg/kg/day.
–Side effects include insomnia, decreased appetite, mood disturbance, tics, headaches, GI distress, and rarely psychosis.
-There are several long-acting preparations including Ritalin XR, Ritalin LA, metadate, Concerta, Daytrana, Focalin XR and several others. The important point about long-acting preparation is they provide a sustained second release with resulting plasma levels lasting 4-12 hours depending on the preparation.
–Amphetamine sulfate (Adderall): should be started at 2.5-5 mg once or twice per day. It can be increased by 5 mg per week with an optimal dose of 0.5-1 mg/kg/day. Dextroamphetamine is twice as potent as amphetamine. The side effect profile is similar to MPH.
Longer-acting amphetamine preparations include Adderall XR, Dexedrine, Dyanavel XR, and Vyvanse (formulated as a prodrug to reduce the risk of abuse). These will provide coverage for about 12 hours.
-There is a black box warning for the risk of abuse and dependence. In addition, there is a cardiovascular safety warning regarding the risk of sudden cardiac death in children and adolescents with structural heart defects or other severe cardiac conditions. Patients should be screened for any cardiovascular disorders, family history of sudden cardiac death, and an EKG should be performed.
-ADHD is the most common physiocratic disorder in children.
-Its prevalence is 5-11% in school-aged children
-It often presents with a classic triad of inattention, hyperactivity, and impulsivity
– However, it can present as mixed, or primarily inattentive or hyperactive
-Symptoms must include at least 6 signs of inattention and/or six signs of hyperactivity/impulsivity for 6 months.
-For patients 17 years and older on 5 symptoms are required
Symptoms of inattention include:
-failure to pay close attention
-difficulty sustaining attention on tasks or activities
-failure to listen when spoken to
-difficulty organizing tasks
-avoidance of activities that require mental effort
-losing things necessary for tasks or activities
-distractibility and forgetfulness in daily activities
Symptoms of hyperactivity:
-fidgeting with hands or feet
-inability to sit still
-running around when not appropriate
-difficulty engaging quietly in activities
-feeling on the go or driven by a motor
-talking excessively
Symptoms of Impulsivity:
-answering questions before they are completely asked
-having trouble waiting ones turn
-interrupting others
The pattern of behavior must be more severe and occur more often than in other children of the same age. The symptoms of the disorder must be present before the age of 12 years. The diagnosis can be made after 12 years of age but there must be evidence of symptoms before the age of 12. The last important point is the symptoms must occur in two different settings (e.g., home and school).
Many patients may be familiar with screening scales like the Vanderbilt or Conners which can be used to help confirm the diagnosis usually one is completed by the parent the other by a teacher.
