Attention Deficit Hyperactivity Disorder (ADHD)

Attention Deficit Hyperactivity Disorder, or ADHD is a brain disorder characterized by hyperactivity, impulsivity and inattentiveness. It is believed to be caused by a deficiency in dopamine (or an excess of dopamine transporters) and an excess of glutamate. The main treatment option for ADHD includes stimulants such as Ritalin (Methylphenidate), Dexedrine (Dextroamphetamine) and Adderall (Dextroamphetamine and Amphetamine). Also used are NRIs such as Strattera (Atomoxetine). NMDA receptor antagonists may be useful in the treatment of ADHD as Memantine is currently used off label for treatment and other NMDA antagonists such as Dextromethorphan may reduce some symptoms of the disorder.[1] This is evidenced by the ability of NMDA receptor antagonists to reduce glutamate receptor activation through uncompetitive antagonism of NMDA receptors which can increase dopamine and may help reduce some symptoms of ADHD.

The NMDA receptor seems to be involved in the pathology of ADHD. Dizocilpine (MK-801), an NMDA receptor antagonist, seems to share some biological properties with Methylphenidate, a stimulant commonly used to treat symptoms of ADHD.[2] In humans, NMDAR antagonists have been used in some preliminary clinical trials to treat the symptoms of ADHD.

Human Studies
Compound	Dose used	Medications used concurrently	# of patients in study	Details
Dizocilpine	up to 0.4 mg per day in three divided doses	none	10	Patients with ADD,RT were given three doses a day with most responders falling into the 0.1 - 0.3mg range. There was a 68% improvement in mood, 57% improvement in hyperactivity, temper and emotional reactivity and a 43% improvement in concentration. Several of the patients were outspoken in favor of MK-801. Even months later, several felt that they did better on MK-801: that with it they were more calm, in better control, and less reactive. Two would not return to stimulants after being on MK-801. MK-801 appeared to be effective in the treatment of ADD,RT and its response appeared to be qualitatively different from that observed with the normal stimulant medications.[3]
Memantine	10–20 mg per day	none	18	An open-label, dose-finding, 8-week, trial was conducted in outpatients 6-12 years old with ADHD combined type. Memantine oral solution (2 mg/mL) was titrated to 10 mg/day (n = 8) or 20 mg/day (n = 8). There were no discontinuations due to adverse events (AEs), serious AEs, deaths, or suicides. Most AEs were mild and occurred during the first week of treatment. The 20 mg/day memantine dose was associated with a higher rate of completion and larger mean improvement on the ADHD-IV and CGI-S than 10 mg/day memantine. Pharmacokinetic analyses suggest response to memantine may be dose-dependent beyond an initial threshold concentration. This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted. [4]

^ Wong BY, Coulter DA, Choi DW, Prince DA (February 1988). "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neuroscience Letters 85 (2): 261–6. http://dx.doi.org/10.1016%2F0304-3940%2888%2990362-X
^ Husson, I., Mesplès, B., Medja, F., Leroux, P., Kosofsky, B., & Gressens, P. (2004). Methylphenidate and MK-801, an N-methyl-d-aspartate receptor antagonist: shared biological properties. Neuroscience, 125(1), 163-170. http://dx.doi.org/10.1016/j.neuroscience.2004.01.010
^ Reimherr, F. W., Wood, D. R., & Wender, P. H. (1986). The use of MK-801, a novel sympathomimetic, in adults with attention deficit disorder, residual type. Psychopharmacology Bulletin, 22(1), 237-242.
^ Findling, R. L., McNamara, N. K., Stansbrey, R. J., Maxhimer, R., Periclou, A., Mann, A., & Graham, S. M. (2007). A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. Journal of Child and Adolescent Psychopharmacology, 17(1), 19-33. http://dx.doi.org/10.1089/cap.2006.0044

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