1) New potential leads in the biology and treatment of attention deficit-hyperactivity disorder.

Curr Opin Neurol. 2007 Apr; 20(2):119-124

Casey B, Nigg JT, Durston S.

Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, New York bDepartment of Psychology, Michigan State University, East Lansing, Michigan, USA cRudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

PURPOSE OF REVIEW: This review highlights recent neuroimaging and genetic studies of attention deficit-hyperactivity disorder that may inform biologically targeted interventions and treatments.
RECENT FINDINGS: The findings suggest that attention deficit-hyperactivity disorder is characterized by specific learning and cognitive deficits due to abnormalities in dopamine-rich prefrontal circuitry, of genetic or environmental origins. In addition to prefrontal cortical areas, the basal ganglia, cerebellum, and parietal cortex have been implicated in the condition. These regions are part of unique circuits that project both to and from the prefrontal cortex, thus providing a means for signaling prefrontal regions when top-down control of behavior needs to be imposed. Ineffective signaling of control systems by any one of these regions can lead to poor regulation of behavior. Likewise, intact signaling but inefficient top-down control could result in poor regulation of behavior.
SUMMARY: Identification of which cognitive and neural processes are altered in attention deficit-hyperactivity disorder and acknowledgement of different causes of the condition will lead to more individualized, biologically targeted interventions and treatments. This new direction in research and treatment has occurred as the result of a shift from diagnosis as a phenotype, to refined phenotypes of core cognitive deficits that can be more easily tied to the underlying biology.

2) FDA Med Watch: Attention Deficit Hyperactivity Disorder (ADHD) Drug Products Med Watch - The FDA Safety Information and Adverse Event Reporting Program

FDA notified healthcare professionals that the manufacturers of all drug products approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) have been directed to develop Patient Medication Guides to alert patients to possible cardiovascular risks and risks of adverse psychiatric symptoms associated with the medicines and to advise them of precautions that can be taken. Patient Medication Guides are handouts given to patients, families and caregivers each time a medicine is dispensed. The guides contain FDA-approved patient information that could help prevent serious adverse events.

An FDA review of reports of serious cardiovascular adverse events in patients taking usual doses of ADHD products revealed reports of sudden death in patients with underlying serious heart problems or defects, and reports of stroke and heart attack in adults with certain risk factors.

FDA recommends that children, adolescents, or adults who are being considered for treatment with ADHD drug products work with their physician or other health care professional to develop a treatment plan that includes a careful health history and evaluation of current status, particularly for cardiovascular and psychiatric problems (including assessment for a family history of such problems).

3) Sympathomimetic syndrome caused by autointoxication with methylphenidate

Ned Tijdschr Geneeskd. 2006 Dec 2; 150(48):2661-4

van Vulpen LF, Malingre MM, Lange R, Bartelink AK.

Afd. Interne Geneeskunde, Meander Medisch Centrum, Postbus 1502, 3800 BM Amersfoort.

A 31-year-old man claimed that he had ingested more than 100 tablets of methylphenidate (10 mg), 20 tablets of ibuprofen (400 mg) and 2 bottles of wine. At admission, signs of sympathomimetic syndrome were observed, including agitation, hallucinations, mydriasis and sinus tachycardia. The patient was treated with activated charcoal and an oral laxative. Given the possibly lethal dose of methylphenidate, the patient was admitted to the intensive care unit for observation. He made a full recovery and was discharged 36 hours after admission. Toxicological analysis indicated a plasma-ethanol concentration of 0.27% and a maximum serum-methylphenidate concentration of 176 microg/l (therapeutic range: 5-40 microg/l). The active metabolite ethylphenidate was also present at toxic concentrations. Treatment of potentially lethal methylphenidate poisoning includes prevention of absorption, careful observation and support of vital functions as necessary.

4) Excretion of Methylphenidate in Breast Milk

Am J Psychiatry 164:348, February 2007

Olav Spigset, M.D., Ph.D., Wenche Rodseth Brede, B.Sc. and Kolbjorn Zahlsen, M.Sc.
Trondheim, Norway

It is unknown to which extent methylphenidate is transferred to breast milk. We therefore present a case of a lactating woman from whom the levels of methylphenidate were measured in serum and breast milk.

A 31-year-old woman with narcolepsy had used methylphenidate regularly before she became pregnant. During pregnancy and the first months postpartum, the drug was discontinued. When she started work after her maternity leave, the need for methylphenidate reappeared. She had a desire to continue breast-feeding, and the question was thus raised as to whether the use of methylphenidate was compatible with breast feeding.
Her daily methylphenidate dose was 5 mg in the morning and 10 mg at noon, using immediate-release tablets (Ritalin, Novartis, Switzerland). After giving written informed consent, maternal serum and breast milk were obtained at the following five points of time: immediately before the morning dose at 8 a.m., just before the dose at noon, and 4, 8, and 21 hours after the dose at noon. The first three samples were from foremilk, whereas the two last samples were from hindmilk. Concentrations of methylphenidate were analyzed by liquid chromatography-mass spectrometry with a limit of quantification of 0.3 ng/ml.

The maternal serum concentrations in the five samples were <0.3, 2.3, 3.8, 1.7, and <0.3 ng/ml, respectively. The corresponding milk concentrations were <0.3, 2.4, 5.9, 1.4, and <0.3 ng/ml.

Accordingly, in the three samples with measurable concentrations, the mean milk/serum concentration ratio was 1.1, with variations from 0.8 to 1.6. Assuming that the mean milk concentration of 2.5 ng/ml ([0.3+2.4+5.9+1.4] ng/ml: 4) represents the true mean during a 24-hour period and that the infant ingested a standard volume of 150 ml of milk per kilogram of body weight per day, the daily infant dose can be estimated to 0.38 µg per kilogram of body weight. Compared with the maternal daily dose of 234 mg per kilogram of body weight, the infant dose was only 0.16%. This value is far below the 10% notational level of concern for drugs that are not particularly toxic. Three of the samples were foremilk samples, which tend to underestimate the infant exposure to lipid-soluble drugs. However, since the lipofilicity of methylphenidate is low, this factor would not be expected to significantly influence the exposure.

The infant’s age was 11 months, and he was only sporadically breastfed. Thus, it was not considered meaningful to measure his methylphenidate plasma concentration, since it would nevertheless not be relevant for the "worst case" scenario—a newborn who is exclusively breastfed. The infant’s general health status was excellent, and no possible adverse effects were observed.

Because methylphenidate was not detected in breast milk 20–21 hours after the previous dose, an infant would not be expected to be exposed to methylphenidate if breastfed immediately before the maternal morning dose. This finding is consistent with the short plasma elimination half-life of 2–3 hours. It is, however, important to note that only one patient was studied and that this finding is not necessarily valid in subjects with elimination half-lives that are longer than average, if the last dose is taken in the afternoon, or if a slow-release formulation is used.

5) Correct Stimulant Dose for Adults

Medscape Psychiatry & Mental Health
Craig B.H. Surman, MD

In clinical practice, many adults with attention-deficit/hyperactivity disorder (ADHD) do respond to dosing within the FDA-approved maximums, which currently are 20 mg daily for d-methylphenidate (d-MPH) XR (Focalin, Novartis) and 20 mg daily for mixed amphetamine salts (MAS) XR (Adderall, Shire). Other stimulant preparations approved for child and adolescent ADHD have not yet been approved for adults. These approved doses reflect failure of studies submitted to the FDA to demonstrate significantly greater benefit of higher doses. It is important to note, however, that such studies include fixed-dose designs in which each subject is assigned a maximum dose, rather than treatment being optimized for individual subjects.

Emerging evidence indicates that some adults with ADHD may tolerate and benefit from higher doses than those approved by the FDA. For example, in the open-label MAS XR extension study, which allowed dosing between 20 and 60 mg per day, 16% of subjects achieved the best investigator-determined combination of response (best balance of efficacy and adverse events) when receiving the currently FDA-approved 20-mg daily dose at their month-24 clinic visit, whereas the best clinical outcomes occurred for 28% of subjects receiving 40 mg and 56% of subjects receiving 60 mg of MAS XR daily.[1]

In a recent double-blind controlled clinical trial in which subjects received doses between 20 and 60 mg of MAS XR for 1 month, individuals with severe symptoms (ADHD Rating Scale score > 32) at baseline experienced significantly greater symptom reduction with the highest MAS XR dose of 60 mg per day than the 20-mg dose, and improvements seen with 60 mg daily approached significance compared with improvements seen with 40 mg daily.[2] Adverse events in this trial were typical of those seen with stimulant treatment and most were of mild-to-moderate intensity.

Methylphenidate treatment trials for adult ADHD that included dosing up to = 1.0 mg/kg/day have produced higher response rates than trials restricted to lower dosing. In one such study, 146 adults with DSM-IV ADHD participated in a double-blind, 6-week study[3] with a 6-month extension phase.[4] A total of 104 subjects were started on methylphenidate at 10 mg, 3 times daily, and the dose was increased over 6 weeks to a mean of 1.1 mg/kg/day (82 ± 22 mg of methylphenidate) and maximum of 1.3 mg/kg/day. In all, 76% of these participants were considered to be "much" or "very much" improved, compared with 19% of subjects on placebo who merited the same rating. Patients receiving active treatment reported dry mouth, appetite suppression, mood change, and mildly increased heart rate significantly more often than those in the placebo group. Fifty-seven of the participants in this 6-week trial were followed for 6 more months during which they remained on mean daily doses of 82 to 87 mg (1.0 to 1.1 mg/kg/day) of methylphenidate. During this 6-month follow-up period, the treatment benefit remained robust, and no difference was seen between the rates of side effects in individuals receiving methylphenidate and those in 9 subjects who received placebo during the same phase of the study.

Biederman and colleagues[5] also evaluated robust dosing of methylphenidate in a double-blind controlled trial that involved 67 adults with ADHD in the placebo arm and 74 adults in the OROS MPH (Concerta, McNeil) arm. Subjects on active methylphenidate received a mean dose of 0.99 mg/kg/day by the sixth week of the study. A total of 66% of participants receiving OROS MPH and 39% of those receiving placebo were evaluated to be much or very much improved by the end of the sixth week. Jitteriness; reduced appetite; dryness of eyes, nose, or mouth; and small elevations in heart rate and blood pressure occurred more often in those receiving OROS MPH than in those taking the placebo.

This sample of recent studies provides evidence that doses of stimulant medication higher than those currently approved by the FDA for adults may be well tolerated and result in significant reductions of ADHD symptoms in adults. However, further long-term studies would allow better assessment of the implications of such robust stimulant therapy. If clinicians use such higher dosing to treat residual ADHD symptoms, dosage should be increased gradually and only if lower doses have been well tolerated for at least several days. Greater vigilance for adverse effects is warranted when prescribing such higher doses.