Treatment of Attention Deficit/Hyperactivity Disorder
During the evaluation and work-up of a child for ADHD, asked about risk factors such as snoring, lead exposure and testing, family history of bipolar or schizophrenia, both of which may look like ADHD, maternal smoking and drug use during pregnancy, tooth decay, and birth weight. Getting blood tests for lead and for iron deficiency (a ferritin test), appears useful. If the test for lead comes back over 20, chelating out the lead with penicillamine may be worthwhile according to one double-blind study. If iron deficiency is present, iron replacement may increase academic performance. Snoring may also play a role in ADHD, and tonsillectomy may help. A work-up of obstructive sleep apnea should be considered. I wonder if CPAP and/or melatonin might also help, but there is no research.
Before I would try any medication, I would consider a multivitamin with minerals, 2 fish oil capsules, zinc 25 mg/day, and folic acid 800 mcg per day. Of course, by the time children get to me, they are almost all already on medication and have severe ADHD problems. These supplements would probably aide other treatments. In any case, numerous studies have found that standard multivitamin with mineral supplements increase the non-verbal IQ in average children. There are also several studies showing that these supplements along with fish oil also reduce aggressive behavior in juvenile delinquents and adult prisoners. ADHD meds are mostly prescribed by pediatricians who have often haven't had time to be able to study bipolar disorder and the broader implications of these medicines. Children should be required to eat a good breakfast before school as this improves school performance. An iron supplement might also be considered if the youth has a low ferritin level. L-carnitine has two small human studies and two animal studies with favorable findings. I think it might be worth trying in view of its virtual lack of side-effects and low cost. Rhodiola, DMAE, and pycnogenol are spoken of favorably by herbally oriented psychiatrists, but I have yet to see the studies for myself and wonder about their quality.
Children are being medicated much more often than in the past. Just from the year 2000 to 2004, the number of Americans being given methlyphenidate doubled in the U.S. No other country except Canada comes close to the percentage of people being treated for ADHD, which is defined much more broadly in the U.S. More than 7 times as many Americans are being given stimulants than in the UK, Germany, or Australia and 30 times as many, percentagewise, as in Japan. Despite this, I do not sense a dramatic decrease in childhood problem behavior. In fact, I sense an increase. While I am a true oddball, I worry about overmedication and about poorly structured school environments. Seats in rows all facing the front of the room just work better as do tracking by ability level. Caution and close follow-up are important when medicating children.
I also think most Americans eat absolutely terrible diets: lots of sugar and refined flour (white pasta and white bread), lots of processed foods high in salt and partially hydrogenated fats, lots of red meat and cheese, not enough fruits and vegetables, little whole grain foods, etc. While there is no research, I can't help but think that the huge increases in ADHD and obesity are linked in part to our diets. ADHD children do tend to be obese.
Also, despite what school officials and teachers claim, stimulants have not been proven to improve learning, at least not according to the published research to date. The child may temporarily sit quietly and concentrate better, but any improved learning may be canceled out by the fact that things learned under the influence of stimulants may be more quickly forgotten.
Methylphenidate (Ritalin, Concerta) is the best studied and most popular medication for ADHD. Several other stimulants (Adderall) are also used, and appear better in individual cases. One, pemoline, has too many problems. Long-acting preparations, while somewhat more expensive, do eliminate the need for medication in the middle of the school day and may give better results. Stimulants are controlled substances and are used to get high by some drug abusers, but children and teenagers treated with them are actually somewhat less likely to get into drug abuse than peers with similar problems as they grow older. Concerta costs $110/month for 36 mg once a day and $113 for 54 mg once a day. Adderall XR is $110 for any strength from 5 to 30 mg once a day. Short acting Adderall is available as a generic for $41 for 5 to 30 mg once a day.
Clonidine is a blood pressure medication than is quite inexpensive and appears to work almost as well methylphenidate. Both medicines together work better than either individually, so if a child is not responding to one, the other may be added. Clonidine at bedtime can have a nice sleep effect. Both medicines have side-effects. Clonidine is more annoying at first, while methylphenidate has more long-term side-effects. Serious side-effects are said to be rare with either medicine although some recent reports of children with possible bipolar disorder becoming psychotic on stimulants needs urgent study.
Nortriptyline, a mostly noradrenergic tricyclic anti-depressant with an excellent safety index, has been shown effective in childhood ADHD and appears quite useful even in treatment resistant cases . I have not seen any research combining clonidine with nortriptyline or any other medication than methylphenidate. Nortriptyline is also very inexpensive ($19 for 25 mg twice a day or both at bedtime). Desipramine should be avoided because of its poor safety index.
Quite a few other medicines, primarily anti-depressants, have been found helpful as well. A new and very expensive drug ($235/mo for 18 mg. twice a day) from Eli Lilly, atomoxetine (Strattera), is being heavily promoted for ADHD. It is twice as expensive as methylphenidate and 10 times as expensive as clonidine or nortriptyline. While more research is needed, all appear about equally effective. It avoids the problem of using a controlled substance and is fairly popular. Methylphenidate and clonidine have been found to be still better when given together. No research has combined either of them with Strattera. Strattera appears to work in a manner similar to nortriptyline and, if nortriptyline doesn't help, Strattera might not.
I favor trying clonidine first, since it is much less expensive, and not a controlled substance. I would combine this with the multivitamin with minerals, 1-2 fish oil capsules, zinc 10 mg/day, and folic acid 400 mg per day extra. If that failed to have an adequate effect, I would try nortriptyline and if that failed, maybe a combination of the two. Then, I would try methylphenidate. However, starting methylphenidate first is also reasonable and is actually most common strategy having a somewhat higher success rate. I might also try bupropion (Wellbutrin), an anti-depressant found to help ADHD and which works in a very different way than nortriptyline or atomoxetine ($36 per month for 75 mg twice a day, a typical dose for children).
With the evidence that methylphenidate may cause psychotic symptoms in children with bipolar disorder who often present looking like ADHD, I just can't get excited about diving into giving children stimulants right from the start. Also, before a stimulant is used, be sure the child does not have a family history of bipolar disease and/or signs of bipolar disorder. In fact, clonidine, nortriptyline, and bupropion can also trigger mania although probably less often. Lithium or an ayptical anti-psychotic might be better with bipolars if medicine is needed.
Some authors hold that if one stimulant doesn't work, another one might. Desipramine is much more toxic in overdose than nortriptyline and has caused several deaths in children at regular treatment levels. While desipramine has been better researched, nortriptyline is fairly similar and I seriously doubt there is any value to using desipramine where nortriptyline hasn't helped. Both are inexpensive. Clonidine may be particularly useful where conduct disorder and/or insomnia are problems in ADHD patients. Both clonidine and nortriptyline appear better choices where tics are involved than methylphenidate or bupropion.
Treatment Review: There have been over 150 double-blind stimulant studies with over 5000 kids. While these studies have shown as high or higher benefits than with any other treatment, up to 30% of children don’t respond. Final height has not been impaired. Imipramine and desipramine have 29 DB studies with 93% of studies finding benefit. Desipramine dose averages 150/day. Bupropion (Wellbutrin) did better than placebo in two of two studies. With kids and one open study with adults. MAO inhibitors were of benefit in two DB including tranylcypromine. SSRIs were not helpful. Clonidine, with alpha-adrenergic agonist properties beneficial in four studies, two DB with daily dose up to 4-5 microg/kg (aver. 0.2/d). Guanfacine also mentioned but no mention of omega-3 fatty acids. J Clin Psychiatry ’98 suppl
Melatonin May Help with ADHD Sleep Onset Difficulties: Many children on stimulant medication have trouble falling asleep. A DB crossover study of nine children 7-13 years old found sleep only 51 minutes with melatonin 6 mg HS vs. 88 minutes with placebo. AACAP 50th Annual Meeting: Abstract E16. Presented Oct. 14-19, 2003. Melissa Bomben, University of British Columbia. They uses doses up to 10mg HS. Melatonin is very inexpensive at 3-5 cents for a 3 mg. tablet
ADHD Treatment up 278% from 1987 to 1997: In the U.S., outpatient treatment for ADHD increased from 0.9 per 100 children in 1987 to 3.4 per 100 children in 1997. Significant increases in the rates of treatment for ADHD were evident across nearly all sociodemographic groups, with the largest increases among children from poor, near-poor, and low-income families and children ages 12 to 18. National trends in the treatment of attention deficit hyperactivity disorder. Olfson M, Gameroff MJ, Marcus SC, Jensen PS. Am J Psychiatry. 2003 Jun;160(6):1071-7. American children are seven times more likely to receive stimulants than European children and 20 times mor likely than Japanese children.
Puerto Rico Study Says ADHD Undertreated: A community survey of 1844 children reports that only 7% of children received stimulant treatment in the previous year and only 3.6% were currently on stimulants. U Puerto Rico. Stimulant and psychosocial treatment of ADHD in Latino/Hispanic children. Bauermeister JJ, Canino G, Bravo M, Ramirez R, Jensen PS, Chavez L, Martinez-Taboas A, Ribera J, Alegria M, Garcia P. J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):851-5. Ed: I'm old fashioned and 7% seems like a lot. When I was in school, hyperactivity was simply not allowed. All 52 of us in my second grade classroom were fairly well-behaved and no one took medication. And that was with one teacher and no assistants. Times sure have changed.
Thoughts of Parents: 84% of 302 parents completed a survey of their knowledge, attitudes, and satisfaction with the ADHD medication. Two thirds of the parents believed that sugar and diet affect hyperactivity. Although few parents believed that stimulants could lead to drug abuse, 55% initially were hesitant to use medication, and 38% believed that too many children receive medication for ADHD. Parents were more satisfied with the behavioral and academic improvement relative to improvement in their child's self-esteem. Johns Hopkins, Parental perceptions and satisfaction with stimulant medication for attention-deficit hyperactivity disorder. Dosreis S, Zito JM, Safer DJ, Soeken KL, Mitchell JW Jr, Ellwood LC. J Dev Behav Pediatr. 2003 Jun;24(3):155-62
Liquid Meds: Methylphenidate and dextroamphetamine can be compounded as liquid medicines. To find a local pharmacist willing 800-927-4227. Also bupropion, sertraline, and divalproex can be obtained in liquid form.
3% College Students Abuse Methylphenidate: A survey by U Michigan of 3500 students found 3% reported doing it in past year. Illicit Methylphenidate Use in an Underground Student Sample: Prevalence and Risk Factors. CJ Teter, SE McCabe, et al. Pharmacother 6/06/03.
Tonsillectomy Helped: In a prospective study of 52 children, ages 2.5-18 with obstructive sleep apnea syndrome (OSAS), adenotonsillectomy was perfomred if the results of polysomnography showed an obstructive apnea/hypopnea index (AHI) of 5 or greater. Preoperative Behavior Assessment System for Children (BASC) t scores for all behavioral scales and composites averaged greater than 50. After surgery, improvement occurred in aggression, atypicality, depression, hyperactivity, and somatization (p </= .001). Age, ethnicity, parental education, parental income, severity of OSAS, sex, and AHI were not correlated with changes in scores.
Bupropion = Methylphenidate in DB: Fifteen 7-17yo ADHD DB crossover. Both helped equally. 14-day medication washout period, 15 ADHD subjects (7 to 17 years old) were randomized to either methylphenidate or bupropion for 6 weeks, washed out for an additional 2 weeks, and then "crossed over" to the other drug. Methylphenidate was titrated to the maximum effective dose of 0.4 to 1.3 mg/kg per day (mean 0.7 mg/kg per day) and bupropion was titrated to an effective dose ranging from 1.4 to 5.7 mg/kg per day (mean 3.3 mg/kg per day). J Am Acad Child Adolesc Psychiatry 1995 May;34 (5):649-57
Bupropion Used for ADHD with Bipolar: MGH study in 7/03 Arch Gen Psychiatry. Not DB.
Bupropion Worsens Tics in ADHD: A report of four children having their tics worsen while treated with bupropion. MGH-Harvard. Bupropion exacerbates tics in children with attention-deficit hyperactivity disorder and Tourette's syndrome. Spencer T, Biederman J, Steingard R, Wilens T. J Am Acad Child Adolesc Psychiatry. 1993 Jan;32(1):211-4
Carbamazepine Helped Some in 3 DBs: In three double-blind placebo-controlled studies, treatment effects for CBZ's superiority over placebo ranged from p = .07 to .0001. A meta-analysis of these three studies revealed that CBZ was significantly (p = .018) more effective than placebo at controlling target symptoms. Despite the general lack of attention that CBZ has received for treating ADHD, there is preliminary evidence that CBZ may be an effective alternate treatment in children with features of ADHD. Columbia U. Carbamazepine use in children and adolescents with features of attention-deficit hyperactivity disorder: a meta-analysis. Silva RR, Munoz DM, Alpert M., J Am Acad Child Adolesc Psychiatry 1996 Mar;35(3):352-8
L-Carnitine and Acetyl-L-Carnitine
Helped ADHD, Aggression in Small DB: In an 16-week DB PC crossover study of 24 ADHD children, 54% improved during the 8 weeks on 100mg/kg/day up to 4 g/day on home behavior vs. 13% of the same children during the 8 weeks on placebo (P < 0.02). In 54% on carnitine, school behavior also improved as assessed with the Conners teacher-rating score (P < 0.05). Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys (P < 0.0001). Responders showed a significant improvement of the CBCL total scores compared to baseline (P < 0.0001). In the majority of boys no side effects were seen. At baseline and after carnitine treatment, responders showed higher levels of plasma-free carnitine (P < 0.03) and acetylcarnitine (P < 0.05). Compared to baseline, the carnitine treatment caused in the responsive patients a decrease of 20-65% (8-48 points) as assessed by the CBCL total problem rating scale. Netherlands. Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Van Oudheusden LJ, Scholte HR. Prostaglandins Leukot Essent Fatty Acids 2002 Jul;67(1):33-8 (Ed: The cost of carnitine or acetyl-L-carnitine (ALCAR) at 4 g/d would be only $17/month if 1 kilo powder were purchased, an 8 months supply. A smaller 2 g/d dose might work as well since it does with most adult conditions. That reduces the cost to $9 per month. At Walmart, ALCAR costs 8 times as much.
Helped Children with Fragile X ADHD in Small Study: In a DB PC study of L-acetylcarnitine for the treatment of hyperactive behavior in 17 children with fragile X syndrome ADHD, 1 year of carnitine was reported as helpful. Torrioli MG, Vernacotola S, et al. Am J Med Genet. 1999 Dec 3;87(4):366-8 and Rev Neurol. 2001 Oct;33 Suppl 1:S65-70. L-cartinine has been shown to help in chronic fatigue, heart failure, and intermittent claudication. See The Carnitines.
ADHD: Acetyl- l-Carnitine Reduced Impulsive Behavior in Adolescent Rats: Chronic ALC helped an animal model of human hyperactivity and has no stimulant effect. Methylphenidate was also successful in the same study on other rats. The authors conclude it may help ADHD children. Adriani W, et al, Rome, Italy. Psychopharmacology (Berl). 2004 Nov;176(3-4):296-304. Epub 2004 May
Acetyl-L-Carnitine Helped Rats with Anoxic Brain Damage at Birth and Hyperactivity: Transient hyperactivity at P20-P45 postnatal days and permanent spatial memory deficits were shown by anoxic rats. A chronic ALC treatment (50 mg/kg/d injected intraperitoneally from P2, after anoxia, to P60) significantly reduced the transient increase in sniffing, rearing and locomotory activity of anoxic rats. Still more improved was the spatial memory performances in a maze at P30-P40 and in a water maze at P50-P60. No behavioral changes were seen in ALC-treated animals that received sham-exposure at birth. Authors suggest ALC may help the treatment of children who suffer anoxia at birth. Effect of acetyl-L-carnitine on hyperactivity and spatial memory deficits of rats exposed to neonatal anoxia. Dell'Anna E, Iuvone L, et al. University of Udine, Italy. Neurosci Lett. 1997 Feb 28;223(3):201-5. Ed: Hyperactivity is also transient during human life, peaking in childhood.
Chelation Therapy no Benefit for Toddlers with High Lead Levels: In a 780-child DB PC study of chelation therapy with succimer (dimercaptosuccinic acid) in children with blood lead levels at 20- 44 micro g/dL at 12 to 33 months of age, up to three 26-day courses of succimer or placebo therapy were administered depending on response to treatment. TLC subjects also received a daily multivitamin supplement before and after treatment(s) with succimer or placebo. Chelation therapy with succimer lowered average blood lead levels for approximately 6 months but resulted in no benefit in cognitive, behavioral, and neuromotor endpoints. Effect of Chelation Therapy on the Neuropsychological and Behavioral Development of Lead-Exposed Children After School Entry. Dietrich KN, Ware JH, Salganik M, Radcliffe J, Rogan WJ, Rhoads GG, Fay ME, Davoli CT, Denckla MB, Bornschein RL, Schwarz D, Dockery DW, Adubato S, Jones RL. University of Cincinnati, Harvard, Children's Hospital of Philadelphia, National Institute of Environmental Health Sciences, University of Medicine of New Jersey, Kennedy Krieger Institute, and Centers for Disease Control and Prevention. Pediatrics. 2004 Jul;114(1):19-26
Clonidine (Catapres), Guanfacine, and Lofexidine
Clonidine and Guanfacine: Both are noradrenergic alpha-2 agonists. Reduce CNS sympathetic outflow. Used to lower blood pressure in adults. Lowers the pulse rate and peripheral resistance. Half-life 12-16 hours. Withdrawal should be gradual over at least several days to avoid nervousness and headache. Side-effects: dry mouth (40%), drowsiness (33%), dizziness (16%), constipation (10%), sedation (10%). Also nausea, dizziness on standing, weakness, fatigue, nervousness, and muscle or joint pain can occur. These side-effects are usually transient. Adults are given the medicine twice a day, with larger dose at bedtime to avoid sedation. Clonidine is much less expensive than other hyperactivity medications. Clonidine is quite safe with only one fatality out of 6024 children taking overdoses reported to the poison Control Center over 19 years. A child from Texas was accidentally given 1000 times the intended dose and suffered no harmful effects. Pediatrics. 2001 Aug;108(2):471-2
Guanfacine has been shown to increase blood flow to the prefrontal lateral cortex in monkeys doing spacial tasks. Yale. Avery RA, Franowicz JS, Studholme C, van Dyck CH, Arnsten AF. Neuropsychopharmacology 2000 Sep;23(3):240-9; Noradrenergic alpha-2 agonists such as clonidine and guanfacine improve working memory performance in aged monkeys. High doses of clonidine (0.02-0.1 mg/kg) significantly improved performance of the delayed response task, a test of spatial working memory, in young adult monkeys. Lower doses (0.0001-0.01 mg/kg), similar to those used in human studies (0.001-0.003 mg/kg), had no effect on task performance. Yale. Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys. Franowicz JS, Arnsten AF. Neuropsychopharmacology 1999 Nov;21(5):611-21. Tenex is a brand name of guanfacine.
Clonidine Added to Stimulant Helped in DB: An Australian DB PC study of 67 children age 6-14 using clonidine 0.1-0.2 mg/d for 6 weeks found much better improvement on the Connor's Conduct subscale (57% vs. 21% responding) and non-significantly better results for hyperactivity as well (35% vs. 17%). Side-effects of sedation and dizziness were transient. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. Hazell PL, Stuart JE. J Am Acad Child Adolesc Psychiatry. 2003 Aug;42(8):886-94
Clonidine and Methylphenidate Helps Tic and ADHD Patients: 136 patient DB PC four groups 16 weeks. Combo group did best with methylphenidate helping inattention and clonidine helping impulsivity and hyperactivity. Clonidine alone did as well as methylphenidate alone. 26% of clonidine drowsiness. No worsening of tics. Treatment of ADHD in children with tics: a randomized controlled trial. The Tourette's Syndrome Study Group. Neurology 2002 Feb 26;58(4):527-36
Clonidine Helped ADHD MRs in Small DB: A 12-week, DB PC three fixed doses (4, 6, and 8 mcg/kg/day) using a crossover design was conducted with 10 children who had hyperkinetic disorder (mean age 7.6 years +/-.54). All had comorbid mental retardation. Both parents' ratings on the Parent Symptom Questionnaire and clinicians' ratings on the Hillside Behaviour Rating Scale showed a marked dose-related response to clonidine in hyperactivity, impulsivity, and inattention. Drowsiness was a common side effect of clonidine. It wore off by the 2nd to 4th week in most cases. Thus, clonidine is a safe and effective. Lucknow. Double-blind, placebo-controlled trial of clonidine in hyperactive children with mental retardation. Agarwal V, Sitholey P, Kumar S, Prasad M. Ment Retard 2001 Aug;39(4):259-67.
Clonidine Meta-Analysis Finds of Value: A meta-analysis of 11 double-blind studies before 2000 found a moderate effect size in reducing ADHD. Methylphenidate appears more effective. The reviewer notes that side-effects are common with clonidine. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. Connor DF, Fletcher KE, Swanson JM. J Am Acad Child Adolesc Psychiatry. 1999 Dec;38(12):1551-9. U Mass.
Clonidine for ADHD Sleep Disorder: A Harvard MGH study reports on 62 ADHD patients, some treated with stimulants, and all given clonidine just at bedtime to help with their sleep disorder. The authors report it effective in 85% and minor side-effects in 31%. Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases. The dosages range from 50-800 micrograms. Prince JB, Wilens TE, Biederman J, Spencer TJ, Wozniak JR. J Am Acad Child Adolesc Psychiatry. 1996 May;35(5):599-605; Clonidine is the most frequently prescribed sleep medication in a survey of pediatricians by Brown University (31%). It was often used with methylphenidate. Pediatrics. 2003 May;111(5 Pt 1)
Clonidine of Some Benefit for ADHD Autistic Children: A DB PC trial of eight autistic children with ADHD who had not been able to tolerate neuroleptics, methylphenidate, or desipramine found that clonidine was modestly effective. U Illinois, Chicago. Clonidine treatment of hyperactive and impulsive children with autistic disorder. Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL. J Clin Psychopharmacol. 1992 Oct;12(5):322-7
Cost: Darby 2003 1mg x100 = $18/month; Clonidine 0.1 mg/d is $5/month; 0.3mg/d is $15/month.
Guanfacine Helps ADHD with Tics: A DB PC study of 34 children for 8 weeks found guanfacine much better than placebo. There was a 37% v. 8% decrease in ADHD symptoms and 31% vs. 0% decrease in tics. Yale. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AF, Cohen DJ, Leckman JF. Am J Psychiatry 2001 Jul;158(7):1067-74
Guanfacine Mania: 5 cases in kids. UNC. 0.5mg/d. All five had bipolar risk factors, e.g. clinical or family history. Guanfacine and secondary mania in children. Horrigan JP, Barnhill LJ. J Affect Disord 1999 Aug;54(3):309-14
Increased Plasma Valproate Concentrations when Coadministered with Guanfacine. 2 cases, an 8-year-old and a 9-year-old. Ambrosini PJ, Sheikh RM. J Child Adolesc Psychopharmacol 1998;8(2):143-7
Lofexidine Also Helped Tourette's-ADHD Children: Lofexidine is another alpha-2 adrenergic agonist available in England and Europe. 47 children with TS and ADHD-combined type were in a PC DB study. After 8 weeks, 50% of lofexidine patients were rated much improved vs. 0% of placebo on ADHD symptoms. Lofexidine had a 41% decrease in symptoms vs. a 7% decrease with placebo. Tics decreased 27% with lofexidine vs. 0% with placebo. Only one lofexidine patient dropped out. A placebo-controlled study of lofexidine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Niederhofer H, Staffen W, Mair A. J Psychopharmacol. 2003 Mar;17(1):113-9
Desipramine Helps Tic-ADHD Patients: A DB PC 6 week study had desipramine titrated up to 3.5mg/kg. Some tic patients had Tourette's. Robust effect and well tolerated. 71% vs. 0% response rate with 47% decrease in symptoms. 58% vs. 8% response for tics as well. MGH. A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder. Spencer T, Biederman J, Coffey B, Geller D, Crawford M, Bearman SK, Tarazi R, Faraone SV. Arch Gen Psychiatry 2002 Jul;59(7):649-56; Desipramine has had a couple pediatric fatalities due to heart complications.
Desipramine Better than Clonidine: A Johns Hopkins study of 37 ADHD Tourette's Syndrome children using a PC DB crossover design with each child on each agent for six weeks reports that desipramine 100 mg/d was better than clonidine 0.2 mg/d and both were better than placebo. The treatment of attention-deficit hyperactivity disorder in Tourette's syndrome: a double-blind placebo-controlled study with clonidine and desipramine. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED, Denckla MB. Pediatrics. 1995 Jan;95(1):74-81
Pycnogenol vs. Methylphenidate Studied: A PC DB study of only 24 adult ADHD didn't find any superiority from either med. The lack of benefit may have been due to lower dosages being used. An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Tenenbaum S, Paull JC, Sparrow EP, Dodd DK, Green L. J Atten Disord. 2002 Sep;6(2):49-60
Open Trial Iron Claims Benefit: 30-days iron supplementation 14 healthy boys ages 7-11 with ADHD. Ferritin increased 26 to 45 ng/mL and Connors decreased 17.6 to 12.7 though no correlation with ferritin. No change teacher scores. Sever Y, et al: Iron treatment in children with attention deficit hyperactivity disorder: a preliminary report. Neuropsyc 97;35:178-80, Israel. (Ed: Open trials are not to be trusted due to the high possibility of bias)
Nortriptyline Did Well in DB Discontinuation Study: This is an odd study design with an open 6 week trial of 35 children and teens at 2mg/kg/d with DB PC termination. Nortriptyline patients improved considerably more during the open phase for both hyperactivity and oppositionality (p<.001 for each). Blood level 81 ng/ml with an average dose of 80 mg/day (1.8 mg/kg/day). No serious side-effects were reported. MGH-Harvard. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. Prince JB, Wilens TE, Biederman J, Spencer TJ, Millstein R, Polisner DA, Bostic JQ. J Child Adolesc Psychopharmacol 2000 Fall;10(3):193-204
Nortriptyline Used for Tourette's ADHD: A report of open trial experience with nortriptyline in 12 ADHD children with Tourette's Syndrome with 19 months of follow-up. Tics decreased 62% while ADHD behavior decreased 92%. Harvard-MGH. Nortriptyline treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette's syndrome. Spencer T, Biederman J, Wilens T, Steingard R, Geist D. J Am Acad Child Adolesc Psychiatry. 1993 Jan;32(1):205-10; In four cases reported by the same researchers, bupropion made the tics worse. J Am Acad Child Adolesc Psychiatry. 1993 Jan;32(1):211-4
Nortriptyline Appeared Useful for Med Resistant: In a Harvard-MGH review of 58 cases treated with nortriptyline, all but one case had failed another ADHD medication and the average failed four other ADHD medications. Despite this, 76% appeared to improved moderately to markedly on nortriptyline. Those in the adult treatment range of 50-150 ng/ml did best. Nortriptyline in the treatment of ADHD: a chart review of 58 cases. Wilens TE, Biederman J, Geist DE, Steingard R, Spencer T. J Am Acad Child Adolesc Psychiatry. 1993 Mar;32(2):343-9. Ed: Such open trial reports are not worth very much. However, the Harvard team did the honorable thing and followed up with a double-blind study noted above which did show benefit, although the design of that study was a little odd.
Pemoline Psychosis: Physician using caffeine, then amphetamines then pemoline at 75-225 mg/day. Three hospitalizations due to pemoline occurred for hallucinations, paranoia, and anger. JAMA 85;254:946-7. Also Pemoline causes mild toxic hepatitis in 2% with 13 cases hepatic failure reported as well as Tourette’s Syndrome and mania.
Poor Compliance with FDA Recommendation: 64% of 1,300 patients given pemoline received it as a first line treatment despite FDA recommendations as a back-up med only. Only 12% received baseline and 12% follow-up liver enzyme testing. Rockville. A study of compliance with FDA recommendations for pemoline (Cylert). Willy ME, Manda B, Shatin D, Drinkard CR, Graham DJ. J Am Acad Child Adolesc Psychiatry 2002 Jul;41(7):785-90;Others
Modafinil Minimal Benefit: In a very small 22-patient 5- or 6-week DB PC study of child ADHD, the 11 children on modafinil did significantly better than placebo. However, they experienced only an 11% decrease in their ADHD symptom scores. Marshall Univ. Modafinil in children with attention-deficit hyperactivity disorder. Rugino TA, Samsock TC. Pediatr Neurol. 2003 Aug;29(2):136-42. Ed: Modafinil was approved by the FDA as an "orphan" drug for narcolepsy, with reduced testing requirements, supposedly because it would be being used to help out so few people. Once approved, the drug company is paying for studies with a huge variety of diseases. This study is so extremely small as to be very preliminary and yet the researchers recommend modafinil for any child for whom methylphenidate (Ritalin) causes insomnia. This seems highly unwise. It is also quite expensive.
Risperidone Better than Placebo for ADHD with Conduct or Oppositional/Defiant Disorders: In 2 PC DB 6 week studies funded by pharmaceutical companies 5-12-year-olds with CD/ADHD, CD, OD/ADHD and OD were studied. Risperidone treated youth improved considerably more than placebo patients with a 55% vs. 22% decrease in baseline aggression scores. Improvement occurred unrelated to diagnosis, age, or IQ. John LeBlanc, Dalhousie Univ., Canada. Canadian Assoc. of Psychiatry Annual Meeting 11/1/03.
Selegiline Appeared to Help ADHD: In a 60-day DB study of 40 children ages 6-15 with ADHD, selegiline was as effective as Ritalin on reducing ADHD symptoms. Selegiline in comparison with methylphenidate in attention deficit hyperactivity disorder children and adolescents in a double-blind, randomized clinical trial. Mohammadi MR, Ghanizadeh A, et al. Tehran University, Iran. J Child Adolesc Psychopharmacol. 2004 Fall;14(3):418-25. Ed: Selegiline is a fairly expensive MAO inhibitor which does not require a special diet.
Thomas E. Radecki, M.D., J.D.