Grim report: the use of stimulant medications may increase the risk of sudden death in teens

June 28, 5:43 PMPittsburgh Medical Technology ExaminerRuben Dagda

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    There has been an increased incidence of sudden or unexplained deaths in young adults related to use of medical prescribed stimulants or depressants; not to mention the number of high-profile deaths related to use of medically prescribed drugs including Heath Ledger, Anna Nicole Smith and possibly Michael Jackson. Of major concern, is the use of amphetamine substances and tricyclic antidepressants used to treat a variety of neurological disorders such as depression, narcolepsy, mood disorders and attention deficit and hyperactivity disorder (ADHD).
      ADHD is the most commonly diagnosed neuropsychiatric disorder in children (about 2-3% of all children globally). ADHD is a chronic, early-onset, incurable, developmental disorder that affects about 20-30% children whose symptoms are manifested well into adulthood (about 4% of adult Americans have ADHD-like symptoms). Symptoms include impulsiveness, disorganized

Artistic illustration of Ritalin tablets.
Obtained from www.asapfilms.com;
Documentary video may be downloaded.

thoughts, hyperactivity, impaired learning, inefficient term memory and unfocused attention. Although the pathophysiology of ADHD remains largely unknown, different theories have been proposed. For instance, CAT and PET/SPECT imaging studies suggests that the frontal and temporal cortex in ADHD children are approximately three years underdeveloped and have reduced cerebral blood flow/glucose utilization compared to normal children suggesting that a hypoxic (low oxygen or metabolic status) state in children's ADHD brains may be linked to developing the disease. There are studies that suggest a genetic association with ADHD. For instance, children harboring mutations in genes that encode for the dopamine transporter receptors and the serotonin receptor suggest an association with ADHD (Swanson et al., 2000; Roman et al., 2004). Currently, the most efficient and most common therapy for treating ADHD is the use of amphetamine-related drugs that include methylphenidate (Ritalin), dextroamphetamine (Dexedrine), dextromethamphetamine (Desoxyn) and mixed amphetamine salts (Adderall).

   How do these drugs work in treating ADHD and narcolepsy? The mechanism by which these stimulants work to treat ADHD and narcolepsy is by raising the extracellular concentrations of neurotransmitters  (dopamine and norepinephrine) at the synaptic cleft of neurons. Amphetamine is a substrate for serotonin and norepinephrine uptake transporters. Once transported by neurons, amphetamine competes against dopamine and norepinephrine for its uptake into storage vesicles, thus displacing norepinephrine and dopamine and causing an increase in the concentration of these neurotransmitters in the cytoplasm of neurons. Excess dopamine and norepinephrine are transported out of the neurons causing increased neurotransmission and brain activity. Cocaine also increases the extracellular concentration of norepinephrine and dopamine in the synapse in a similar way to amphetamines but with a different mechanism of action: by inhibiting the dopamine transporter. Given this observations, it is not surprising that long-term use of medically prescribed ADHD drugs are highly addictive and can induce suicidal thoughts in children. 

         Although stimulants have shown to be effective in treating the lack of mental awareness, forgetfulness and unfocused attention in ADHD children, many symptoms are associated with the use of these stimulants. Even when appropriately used at their therapeutic range, there is always the high potential for abuse and addiction since all these drugs are structurally related to methamphetamine. Over the past three decades, there has been a controversy on the use of stimulants to treat ADHD with cardiovascular related events and sudden infant or teen related deaths. Indeed, one study recently published on June 16 of this year at the American Journal of Psychiatry suggested an association on the use of psychostimulants with the occurrence of sudden and unexplained deaths in teens (Gould et al., 2009). Although the sample population used in this study is small compared to other population studies, the authors of this study elegantly compared 564 teens that died from unexplained causes (identified from mortality data and death certificates)  to their appropriate matched “control” cases of teens that died from motor-vehicle passenger related deaths which increases the validity and statistical power of the study. Through matched pair analyses, the authors of the study showed that teens in 10 cases (1.8% of the sample population) were identified to have used stimulants (methylphenidate) just prior to their deaths. Interestingly, the use of tricyclic anti-depressants was also found to be associated in six cases with sudden and unexplained death in teens. Only two teens in two matched control cases were identified to having used stimulants prior to their deaths in motor vehicle related accidents. Although the authors of this study acknowledged certain caveats in the study such as potential recall bias (the interval between date of death and informant survey) and a higher bias in the mean threshold postmortem blood levels of stimulants for the experimental group, none of these factors significantly altered the findings of the study. Thus the authors of this study concluded that the chances of teens using stimulant medications (mainly methylphenidate) were approximately seven times greater for the cases of sudden unexplained death than the control group (motor vehicle passenger accident related deaths) suggesting an association on the use of stimulants with sudden death in teens. However, the authors acknowledge that a major limitation of their conclusion is based on the fact that the methodology employed in the study does not enable them to establish causality but only an association on the use of stimulants to sudden deaths. Nevertheless, their findings suggest that the use of medically prescribed amphetamine-related drugs in teens is associated with a higher incidence of mortality.  Thus more comprehensive studies with greater statistical power (a much larger sample population) are needed to make this finding conclusive in the future. Moreover, a more direct study addressing the use of stimulants in ADHD patients should be performed.

    Based on this study, is it reasonable to severely limit or ban the use of stimulants for children with ADHD or related disorders (ie.,oppositional defiant disorders)? Not at all, but extreme precautions should be taken to lessen the risk of children and young adults taking these medications. Even in light of this study and others, there is still no clear indication whether the use of medically prescribed stimulants within their therapeutic range  will have deleterious health-related consequences. Even before this study was done, about 34 sudden cardiac deaths were documented between 1995 to 2005 in children taking Ritalin and Concerta, Adderall and Dexedrine. Clearly, dextroamphetamine and methylphenidate (Ritalin) can produce serious side-effects such as hypertension, dizziness, headaches, irritability, increased aggressiveness, tremors, convulsions and arrhythmias. Moreover, as previously mentioned in this article, medically prescribed methamphetamine-related drugs are highly addictive, especially in children. Alternatively, other  pharmacological treatments are available for ADHD children who do not tolerate amphetamine-related drugs. Most notably, Atomoxetine (Strattera) is the only FDA approved drug used for the treatment of ADHD that is not addictive. However, as vigilant and responsible parents, one must be aware that even long-term use of Atomoxetine causes hypertension, increases blood pressure and may cause arrythmias. Similar to amphetamine related stimulants and tricyclic anti-depressants, the central nervous system side-effects of Atomoxetine includes delirium and suicidal thoughts; underscoring the need to improve dosing regimens and monitor patients more carefully to lessen the risk of  developing cardiovascular related complications. As we live in a society that is becoming increasingly dependent on the use of psychostimulants and anti-depressants to treat many symptoms associated with neurobehavioral related disorders, other safer and more amenable therapies available for treating ADHD are often overlooked. Future therapies and medical related technologies should focus on providing a combination of computer assisted education/psychotherapy (educational video games), cognitive and behavioral therapy, interpersonal psychotherapy and family therapy (parent training and intervention) for  ADHD children.

Bibliography

Gould MS, Walsh BT, Munfakh JL, Kleinman M, Duan N, Olfson M, Greenhill L, Cooper T. 2009 “Sudden Death and Use of Stimulant Medications in Youths” Am J Psychiatry; (in-press)

Roman T, Rohde LA, Hutz MH. 2004. "Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder." American Journal of Pharmacogenomics 4(2):83–92

Swanson JM, Flodman P, Kennedy J, et al. 2000 "Dopamine Genes and ADHD." Neurosci Biobehav Rev. ;24(1):21–5

For more info: 

Press release of the AJP study: www.nydailynews.com/lifestyle/health/2009/06/18/200906 18_children_taking_adhd_medication_may_have_an_increased_risk_of_sudden_cardiac_dea.html

  or click this link to download the AJP article: ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2009.09040472v1

Scientific commentary regarding the validity of the AJP study: ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2009.09050619v1