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SAMe Use in Children and Adolescents

We describe the use of S-adenosyl-methionine (SAMe) for Major Depression in three youth. SAMe is made by the body and is a metabolite present in all living cells. Unlike current psychopharmacologic options, SAMe is an agent that is indigenous to the body, and may offer another option for treatment-resistant Major Depression in children and adolescents. SAMe is not a newly identified substance -- its chemical structure was described as early as 1952.1 It has been in use for decades in Europe, and is a prescription medication in such countries as Italy, Spain, Germany and Russia.2

The first clinical study of SAMe's use for depression appears to have been completed in the 1970s,3 and since then has been repeatedly studied. Specifically, SAM-e has been found effective for treating major depressive disorder in 13 trials comparing it to placebo, and 19 trials comparing it to tricyclic antidepressants with more than 1,400 patients studied. From 1973 to 1988, 14 double-blind, European studies showed that intravenous and intramuscular preparations of SAM-e were more effective than placebo and comparable to imipramine, amitriptyline and clomipramine for treatment of major depression. Since then, SAMe has been evaluated for various disorders in more than 75 clinical trials involving over 23,000 people.4, 5

The mechanism for SAMe's effectiveness in Major Depression is unclear.6 Yet some propose a mechanism that since SAMe functions as a precursor to methylation, aminopropylation and transulfuration pathways, it is the most important methyl donor in the brain and is essential for polyamine synthesis. Brain methyl group deficiency has been implicated in depression, and polyamine phosphorylation enhancement of neuronal proteins may be involved in its antidepressant mechanisms.7, 8

SAMe has been studied in adults using both IM and oral routes. For example, two multicenter double-blind studies, examined both intramuscular (400mg) and oral SAMe (1600 mg) in adults and compared it with 150 mg of imipramine (IMI) in patients with Major Depression. Specifically, one study noted antidepressant effects in a double blind multi-center study in which 147 treated patients were given SAMe intramuscularly at a dose of 400 mg/d vs. 148 patients treated with 150 mg/d of oral imipramine (IMI) over 4 weeks. A Major Depression diagnosis included a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >/=18. A "response" included a fall in HAMD scores of at least 50% with respect to baseline. SAMe and IMI did not differ significantly on any efficacy measure. SAMe and IMI both showed a significant antidepressant response -- a HAMD improvement of at least 50%. These data show 400 mg/d of intramuscular SAMe to be comparable to 150 mg/d of oral IMI in terms of anti-depressive efficacy. In the other study, a total of 143 patients received 1600 mg of oral SAMe and 138 received IMI for a period of 6 weeks. Therefore, both intramuscular (400mg) and oral SAMe (1600 mg) in adults was comparable to 150 mg of imipramine (IMI). SAMe was better tolerated than IMI in both studies.9, 10

Neurology studies support SAMe's antidepressant effects. In a double-blind, placebo-controlled, crossover study, using random infusions of 800 mg of SAMe, Electroencephalograms (EEGs), event-related potentials (ERPs) and low-resolution brain electromagnetic tomography identified SAMe as an antidepressant with effects greater than placebo.11

Further, SAMe appears to have a fairly rapid onset of action. When 195 patients were given 400 mg of intramuscular SAMe for 15 days, their depressive symptoms showed remission on both day 7 and 15 of treatment with SAMe.12

Child Cases

Two girls aged 11 and 8 were brought in for a consult by a pediatrician and his spouse, a nutritionist. Both parents had studied SAMe, and preferred "a trial" before traditional anti-depressants. They noted SAMe was in "most large pharmacies" and believed "it should be considered more in depression treatment." Both parents had a strong family history of Dysthymia or Major Depression (MD). Both parents were taking SAMe themselves and "felt" it provided full remission of their depression, at 1200-1400 mg per day.

Since these medically educated parents were going to offer the children some of their own SAMe, we agreed to supervise the trials. The parents understood that SAMe was a non-FDA regulated nutrient, had variable potency depending on the brand, and that we had no knowledge of literature on the use of SAMe in children. We also were clear that if they were going to use this product they should not assume adult doses would be either safe or needed. They agreed to start at the lowest manufactured size.

Case 1. An 11-year-old girl (34 kg.) developed increased irritability, boredom, eccentric crying, withdrawal, decreased appetite, middle insomnia, new school performance problems and sadness. She began to discuss death themes and became preoccupied with heaven, despite no new exposures to these topics.

She met DSM-IV TR criteria for Major Depression, had no significant stressors in her life, and on the Children's Depression Inventory (CDI),13 scored a 34.

She was placed on a 200 mg SAMe enteric-coated tablet each morning, before eating for a week. Subsequently, the dose was raised to 400 mg. She showed modest improvement over 3 weeks on this higher dose. Improvement began after 4 days on 400 mg. At three weeks, it was increased to 600 mg a day, with rapid and complete resolution of her depressive symptoms in 2 days. She had no signs of mania, anxiety, insomnia, diarrhea, abdominal pain or nausea. Her CDI fell to a 4. She has been on this dose for over 6 months.

Case 2. An 8 year-old girl (24 kg.) developed new problems with crying, sadness, decreased play, and an inability to be consoled. She made new negative identity comments, i.e., "I'm no good Mommy." The child was well liked by adults and peers, but felt "no one liked her," She also began saying she "hated school" even though she was in the top 1/3rd of her class. Her symptoms began 4-5 months after her sister's MD began.

She met DSM-IV TR criteria for Major Depression and on the Children's Depression Inventory scored 29. She was treated with 200 mg of SAMe and in 2 days showed signs of improvement, especially in increased play and decreased crying. In 11 days, the child was at baseline with no side effects. Her CDI decreased to 6 and 7. After 3 months, she was "a little sad like before" per her mother, and was increased to 200 mg each am and afternoon with a CDI of 6. She has remained on this dose for over 6 months.

Case 3. A 16 year-old male (86 kg.), unrelated to the girls described above, was diagnosed with Major Depression and Oppositional Defiant Disorder based on DSM-IV TR criteria from a clinical interview with parents and patient. He refused diagnostic scales. His parents reported a 1 1/2 year history of irritability, boredom, reactivity, decreased interest in all activities but computer games, sadness, excess sleep, fatigue, hopelessness, and trouble concentrating. His school materials showed a similar time line and his grades had fallen from the B/C level to D's and F's. Extensive laboratory testing and family doctor physical exam were negative.

The youth refused a trial of traditional antidepressants, saying, he did not want "a drug" or "something which was foreign or poison." After extensive discussion with the patient and his parents, he was willing to try SAMe, because it was "natural" and "made in the body." Both parents and patient understood that we were not aware of "studies in adolescents."

The patient was started on 200 mg and surprisingly raised himself to 1800 mg in a 10-day period. He developed a slight tremor and slight anxiety. When both dose and side effects were noticed, and that he had ignored the suggested taper, his dose was reduced to 1400 mg with loss of both side effects. His mood and function improved to his baseline over 1-2 weeks according to parents, teacher and psychiatrist. Yet he had residual oppositionality. After 2-3 months the youth stopped his SAMe due to "being sick of all the pills." He had been taking 7 x 200 mg tablets daily. He relapsed over the course of 3 weeks to "1/2" his initial baseline depression per patient and parents. Again, he refused quantitative depression scales. Behaviorally, he stopped returning calls, became bored again, and had decreased homework performance with no identifiable new stressors. Restoring the SAMe to three 400 mg tablets -- 800 mg per am and 400 after school -- restored him to baseline in 5-8 days from parent report confirmed with diagnostic interview. He has remained on this dosing for approximately 22 weeks.

The SAMe benefit has persisted at least 22 weeks in all three patients. Yet, some might see their improvement as a placebo effect, sibling imitation or spontaneous remission. These cases raise questions. Should SAMe be used in children or adolescents? Do children and adolescents make the same amount of SAMe as adults in their liver each day? What is a reasonable dosing plan for children and adolescents, when adults generally take 350-400 mg intramuscularly or 1200-2000 mg orally? Should one wait a week or a month before increasing a dosage? How does one determine treatment failure besides unacceptable side effects, i.e. what is a preadolescent or adolescent ceiling dose? Does oral SAMe influence the amount of SAMe made in the liver in the short or long term? Would baseline quantitative laboratory measurements serve in identifying deficient subgroups that might benefit from this treatment or establish therapeutic ranges? How might genetic polymorphisms effect SAMe dosing? Since 200 mg can induce hypomania and mania in bipolar adults, what is the safest starting dosing for a depressed youth with a chance of having bipolar disorder?

However, since the clinical world has very finite treatment options for treatment resistant depression in youth, SAMe should be seriously considered as an option, as a primary agent or as an add-on to antidepressants, omega 3 essential fatty acids or mood stabilizers. Certainly systematic studies would be useful, perhaps starting with an open treatment trial with larger numbers of children. We propose that any open trial should start with 200 mg of SAMe orally in the am and allow a week before any 200 mg increase. We also suggest that those with a personal or primary family history of mania should be excluded from the study, since our experience is that doses of 400 mg can induce mania.

In conclusion, clinicians interested in prescribing SAMe, should appreciate that the potency and quality of SAMe preparations vary. One independent testing laboratory, consumerlab.com, has repeatedly evaluated SAMe products. Recently, eleven products met their label claims for potency, but one contained only 30% of the active ingredient.14

James L. Schaller, MD, MAR, PA
Naples, Florida
USA

John Thomas, MD, MPH
Life Counseling Services
Medical Director
Paoli, PA
USA

Anthony J. Bazzan, MD
Functional Wellness Institute
Medical Director
Jeffersonville, PA
USA

References

  1. Cantoni GL. The nature of the active methyl donor formed enzymatically from L-methionine and adenosinetriphosphate. J Am Chem Soc 1952;74:2942-2943.
  2. Brown R, Bottiglieri T, Colman C. Stop Depression Now: SAMe 1999:Berkly, New York, pg. 5
  3. Agnoli A, Andreoli V, Casacchia M, Cerbo R (1976), Effect of S-adenosyl-L-methionine (SAMe) upon depressive symptoms. J Psychiatr Res 1976;13:43-54.
  4. Janicak PG, Lipinski J, Davis JM et al. (1988), S-adenosylmethionine in depression. A literature review and preliminary report. Ala J Med Sci 1988;25:306-313.
  5. Knowlton L. Investigating SAM-e. Geriatric Times 2001;2:no page listed. www.geriatrictimes.com/g010923.html. Accessed December 15, 2003.
  6. Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL, Cohen BM, Renshaw PF. S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects Biol Psychiatry 2003;54:833-9.
  7. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr 2002;76:1151S-7S.
  8. Benelli A, Filaferro M, Bertolini A, Genedani S. Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats. Br J Pharmacol 1999;127:645-54
  9. Delle Chiaie R, Pancheri P, Sapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2002;76:1172S-6S.
  10. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002;5:287-94.
  11. Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography. Am J Clin Nutr 2002;76:1162S-71S.
  12. Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi GP. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res 1995;56:295-7.
  13. Kovacs M. The children's depression inventory (CDI). Psychopharmacology Bulletin 1985;21:995-998.
  14. consumerlab.com/results/same.asp. Accessed December 14, 2003.
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