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Published in: Journal of Neural Transmission 11/2012

01-11-2012 | Biological Child and Adolescent Psychiatry - Original Article

The feasibility and safety of S-adenosyl-l-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial

Authors: Tamar Green, Lital Steingart, Amos Frisch, Omer Zarchi, Abraham Weizman, Doron Gothelf

Published in: Journal of Neural Transmission | Issue 11/2012

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Abstract

The goal of this trial was to assess the feasibility and safety of using S-adenosyl-l-methionine (SAMe) to treat depressive disorder, attention deficit/hyperactivity disorder (ADHD) and cognitive deficits in individuals with the 22q11.2 deletion syndrome (22q11.2DS). SAMe supposedly enhances the activity of the COMT enzyme. Because individuals with 22q11.2DS have only one copy of the gene responsible for the enzyme, COMT haploinsufficiency may be associated with their psychiatric morbidity and cognitive deficits. We assessed twelve 22q11.2DS individuals with depressive disorder or ADHD in a randomized double-blind cross-over placebo-controlled trial, using SAMe 800 mg bid. Individuals were evaluated for treatment safety and effectiveness during the trial and upon completion at sixth week. Compared to placebo, there were no significant differences in the rate of reported side effects between SAMe and placebo. Despite a general concern that SAMe might induce mania in vulnerable individuals, no manic or psychotic symptoms were exhibited during the SAMe treatment. Individuals with 22q11.2DS with comorbid depressive disorder with or without psychotic symptoms (n = 5) had a larger numerical improvement on relevant clinical scales compared to placebo. No treatment effect was found on ADHD symptoms in subjects who suffered from 22q11.2DS with comorbid ADHD (n = 7). Cognitive performance did not improve or deteriorate following treatment with SAMe compared to placebo. In conclusion SAMe treatment up to 1,600 mg/day for 6 weeks in 22q11.2DS individuals appears to be safe, well tolerated and with no serious side effects. No significant benefit in depressive or ADHD symptoms was detected.
Literature
go back to reference Alpert JE, Papakostas G, Mischoulon D, Worthington JJ 3rd, Petersen T, Mahal Y, Burns A, Bottiglieri T, Nierenberg AA, Fava M (2004) S-Adenosyl-l-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol 24(6):661–664PubMedCrossRef Alpert JE, Papakostas G, Mischoulon D, Worthington JJ 3rd, Petersen T, Mahal Y, Burns A, Bottiglieri T, Nierenberg AA, Fava M (2004) S-Adenosyl-l-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol 24(6):661–664PubMedCrossRef
go back to reference Aneja A, Fremont WP, Antshel KM, Faraone SV, AbdulSabur N, Higgins AM, Shprintzen R, Kates WR (2007) Manic symptoms and behavioral dysregulation in youth with velocardiofacial syndrome (22q11.2 deletion syndrome). J Child Adolesc Psychopharmacol 17(1):105–114PubMedCrossRef Aneja A, Fremont WP, Antshel KM, Faraone SV, AbdulSabur N, Higgins AM, Shprintzen R, Kates WR (2007) Manic symptoms and behavioral dysregulation in youth with velocardiofacial syndrome (22q11.2 deletion syndrome). J Child Adolesc Psychopharmacol 17(1):105–114PubMedCrossRef
go back to reference Antshel KM, Shprintzen R, Fremont W, Higgins AM, Faraone SV, Kates WR (2010) Cognitive and psychiatric predictors to psychosis in velocardiofacial syndrome: a 3-year follow-up study. J Am Acad Child Adolesc Psychiatry 49(4):333–344PubMed Antshel KM, Shprintzen R, Fremont W, Higgins AM, Faraone SV, Kates WR (2010) Cognitive and psychiatric predictors to psychosis in velocardiofacial syndrome: a 3-year follow-up study. J Am Acad Child Adolesc Psychiatry 49(4):333–344PubMed
go back to reference Balcioglu A, Ren JQ, McCarthy D, Spencer TJ, Biederman J, Bhide PG (2009) Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice. Neuropharmacology 57(7–8):687–693PubMedCrossRef Balcioglu A, Ren JQ, McCarthy D, Spencer TJ, Biederman J, Bhide PG (2009) Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice. Neuropharmacology 57(7–8):687–693PubMedCrossRef
go back to reference Bassett AS et al (1998) 22q11 Deletion syndrome in adults with schizophrenia. Am J Med Genet 81:328–337PubMedCrossRef Bassett AS et al (1998) 22q11 Deletion syndrome in adults with schizophrenia. Am J Med Genet 81:328–337PubMedCrossRef
go back to reference Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990) Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53(12):1096–1098PubMedCrossRef Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990) Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53(12):1096–1098PubMedCrossRef
go back to reference Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O’Leary LA, Wong LY, Elixson EM, Mahle WT, Campbell RM (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112(1 Pt 1):101–107PubMedCrossRef Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O’Leary LA, Wong LY, Elixson EM, Mahle WT, Campbell RM (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112(1 Pt 1):101–107PubMedCrossRef
go back to reference Carney MW, Chary TK, Bottiglieri T, Reynolds EH (1989) The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry 154:48–51PubMedCrossRef Carney MW, Chary TK, Bottiglieri T, Reynolds EH (1989) The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry 154:48–51PubMedCrossRef
go back to reference Cohen SM, Nichols A, Wyatt R, Pollin W (1974) The administration of methionine to chronic schizophrenic patients: a review of ten studies. Biol Psychiatry 8(2):209–225PubMed Cohen SM, Nichols A, Wyatt R, Pollin W (1974) The administration of methionine to chronic schizophrenic patients: a review of ten studies. Biol Psychiatry 8(2):209–225PubMed
go back to reference Diamond A, Briand L, Fossella J, Gehlbach L (2004) Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 161(1):125–132PubMedCrossRef Diamond A, Briand L, Fossella J, Gehlbach L (2004) Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 161(1):125–132PubMedCrossRef
go back to reference Diamond A, Barnett WS, Thomas J, Munro S (2007) Preschool program improves cognitive control. Science 318(5855):1387–1388PubMedCrossRef Diamond A, Barnett WS, Thomas J, Munro S (2007) Preschool program improves cognitive control. Science 318(5855):1387–1388PubMedCrossRef
go back to reference DuPauI GAA, Power T, Reid R, Ikeda M, McGoey K (1998) Parent ratings of attention-deficit/hyperactivity disorder symptoms: factor structure and normative data. J Psychopathol Behav Assess 20(1):83–102CrossRef DuPauI GAA, Power T, Reid R, Ikeda M, McGoey K (1998) Parent ratings of attention-deficit/hyperactivity disorder symptoms: factor structure and normative data. J Psychopathol Behav Assess 20(1):83–102CrossRef
go back to reference Feinstein C, Eliez S, Blasey C, Reiss AL (2002) Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 51(4):312–318PubMedCrossRef Feinstein C, Eliez S, Blasey C, Reiss AL (2002) Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 51(4):312–318PubMedCrossRef
go back to reference First M, Gibbon M, Spitezer R, Williams J (1996) User’s guide for the structural clinical interview for DSM-IV Axis I disorders: research version. Biometric Research, New York First M, Gibbon M, Spitezer R, Williams J (1996) User’s guide for the structural clinical interview for DSM-IV Axis I disorders: research version. Biometric Research, New York
go back to reference Goren JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM (2004) Bioavailability and lack of toxicity of S-adenosyl-l-methionine (SAMe) in humans. Pharmacotherapy 24(11):1501–1507PubMedCrossRef Goren JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM (2004) Bioavailability and lack of toxicity of S-adenosyl-l-methionine (SAMe) in humans. Pharmacotherapy 24(11):1501–1507PubMedCrossRef
go back to reference Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci 8(11):1500–1502PubMedCrossRef Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci 8(11):1500–1502PubMedCrossRef
go back to reference Gothelf D, Feinstein C, Thompson T, Gu E, Penniman L, Van Stone E, Kwon H, Eliez S, Reiss AL (2007) Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry 164(4):663–669PubMedCrossRef Gothelf D, Feinstein C, Thompson T, Gu E, Penniman L, Van Stone E, Kwon H, Eliez S, Reiss AL (2007) Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry 164(4):663–669PubMedCrossRef
go back to reference Green T, Gothelf D, Glaser B, Debbane M, Frisch A, Kotler M, Weizman A, Eliez S (2009) Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry 48(11):1060–1068PubMedCrossRef Green T, Gothelf D, Glaser B, Debbane M, Frisch A, Kotler M, Weizman A, Eliez S (2009) Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry 48(11):1060–1068PubMedCrossRef
go back to reference Green T, Weinberger R, Diamond A, Berant M, Hirschfeld L, Frisch A, Zarchi O, Weizman A, Gothelf D (2011) The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome. J Child Adolesc Psychopharmacol 21(6):589–595PubMedCrossRef Green T, Weinberger R, Diamond A, Berant M, Hirschfeld L, Frisch A, Zarchi O, Weizman A, Gothelf D (2011) The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome. J Child Adolesc Psychopharmacol 21(6):589–595PubMedCrossRef
go back to reference Hedges DW, Brown BL, Shwalb DA (2009) A direct comparison of effect sizes from the clinical global impression-improvement scale to effect sizes from other rating scales in controlled trials of adult social anxiety disorder. Hum Psychopharmacol 24(1):35–40PubMedCrossRef Hedges DW, Brown BL, Shwalb DA (2009) A direct comparison of effect sizes from the clinical global impression-improvement scale to effect sizes from other rating scales in controlled trials of adult social anxiety disorder. Hum Psychopharmacol 24(1):35–40PubMedCrossRef
go back to reference Lamango NS, Charlton CG (2000) Farnesyl-l-cysteine analogs block SAM-induced Parkinson’s disease-like symptoms in rats. Pharmacol Biochem Behav 66(4):841–849PubMedCrossRef Lamango NS, Charlton CG (2000) Farnesyl-l-cysteine analogs block SAM-induced Parkinson’s disease-like symptoms in rats. Pharmacol Biochem Behav 66(4):841–849PubMedCrossRef
go back to reference Levkovitz Y, Alpert JE, Brintz CE, Mischoulon D, Papakostas GI (2011) Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry(in press) Levkovitz Y, Alpert JE, Brintz CE, Mischoulon D, Papakostas GI (2011) Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry(in press)
go back to reference Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34(13):4202–4210PubMedCrossRef Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34(13):4202–4210PubMedCrossRef
go back to reference Mischoulon D, Fava M (2002) Role of S-adenosyl-l-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr 76(5):1158S–1161SPubMed Mischoulon D, Fava M (2002) Role of S-adenosyl-l-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr 76(5):1158S–1161SPubMed
go back to reference Papakostas GI (2009) Evidence for S-adenosyl-l-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry 70 (Suppl 5):18–22PubMedCrossRef Papakostas GI (2009) Evidence for S-adenosyl-l-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry 70 (Suppl 5):18–22PubMedCrossRef
go back to reference Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M (2010) S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 167(8):942–948PubMedCrossRef Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M (2010) S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 167(8):942–948PubMedCrossRef
go back to reference Shanee N, Apter A, Weizman A (1997) Psychometric properties of the K-SADS-PL in an Israeli adolescent clinical population. Israel J Psychiatry Related Sci 34(3):179–186 Shanee N, Apter A, Weizman A (1997) Psychometric properties of the K-SADS-PL in an Israeli adolescent clinical population. Israel J Psychiatry Related Sci 34(3):179–186
go back to reference Strous RD, Ritsner MS, Adler S, Ratner Y, Maayan R, Kotler M, Lachman H, Weizman A (2009) Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol 19(1):14–22PubMedCrossRef Strous RD, Ritsner MS, Adler S, Ratner Y, Maayan R, Kotler M, Lachman H, Weizman A (2009) Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol 19(1):14–22PubMedCrossRef
go back to reference van Amelsvoort T, Henry J, Morris R, Owen M, Linszen D, Murphy K, Murphy D (2004) Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr Res 70(2–3):223–232PubMedCrossRef van Amelsvoort T, Henry J, Morris R, Owen M, Linszen D, Murphy K, Murphy D (2004) Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr Res 70(2–3):223–232PubMedCrossRef
go back to reference Wechsler D (1991) Wechsler Intelligence Scale for children, 3rd edn manual, Psychological Corp, San antonio, TX Wechsler D (1991) Wechsler Intelligence Scale for children, 3rd edn manual, Psychological Corp, San antonio, TX
go back to reference Werner P, Di Rocco A, Prikhojan A, Rempel N, Bottiglieri T, Bressman S, Yahr MD (2001) COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against l-dopa toxicity in vitro. Brain Res 893(1–2):278–281PubMedCrossRef Werner P, Di Rocco A, Prikhojan A, Rempel N, Bottiglieri T, Bressman S, Yahr MD (2001) COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against l-dopa toxicity in vitro. Brain Res 893(1–2):278–281PubMedCrossRef
go back to reference Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435PubMedCrossRef Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435PubMedCrossRef
Metadata
Title
The feasibility and safety of S-adenosyl-l-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial
Authors
Tamar Green
Lital Steingart
Amos Frisch
Omer Zarchi
Abraham Weizman
Doron Gothelf
Publication date
01-11-2012
Publisher
Springer Vienna
Published in
Journal of Neural Transmission / Issue 11/2012
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI
https://doi.org/10.1007/s00702-012-0831-x

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