Research Article
No access
Published Online: 1 February 2018

Simvastatin as an Adjunctive Therapy to Risperidone in Treatment of Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Publication: Journal of Child and Adolescent Psychopharmacology
Volume 28, Issue Number 1

Abstract

Objectives: Providing novel treatments for autism has been a subject of long-standing research. Based on etiopathological findings, we aim at assessing potential therapeutic effects of statins, here simvastatin, on autism symptoms for the first time.
Methods: In this randomized, double-blind, placebo-controlled, parallel-group 10-week clinical trial, 70 drug-free children aged 4 to 12 years old with diagnosis of autistic disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, who had an Aberrant Behavior Checklist-Community (ABC-C) scale irritability subscale score of ≥12, were equally randomized to receive either simvastatin (20–40 mg/day) or placebo as an adjunct to risperidone (1–2 mg/day) whereas administration of both drugs was started simultaneously from baseline. Patients with comorbid psychiatric disorders, active medical conditions, severe intellectual disability, seizure disorders, history of any treatments for autism in the past 6 months, or history of current anti-inflammatory drug consumption were excluded. Primary outcome was defined as the difference in mean change of the ABC-C scale irritability subscale score from baseline to the endpoint (www.irct.ir; IRCT201602041556N86).
Results: Significant differences in change of the ABC-C scale irritability (mean difference [95% confidence interval (CI)] = −3.45 [−5.37 to −1.54], p = 0.001; Cohen's d = 0.89) and hyperactivity/noncompliance (mean difference [95% CI] = −4.27 [−6.69 to −1.86], p = 0.001; Cohen's d = 0.87) subscales scores were detected between the two arms. No significant difference was detected in case of the other three subscales.
Conclusions: This study provides preliminary evidence for potential therapeutic effects of simvastatin in the treatment of autism that warrants further investigations.

Get full access to this article

View all available purchase options and get full access to this article.

References

Acosta MT, Kardel PG, Walsh KS, Rosenbaum KN, Gioia GA, Packer RJ: Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: Phase I study. Pediatr Neurol 45:241–245, 2011.
Akhondzadeh S, Fallah J, Mohammadi M-R, Imani R, Mohammadi M, Salehi B, Ghanizadeh A, Raznahan M, Mohebbi-Rasa S, Rezazadeh S-A: Double-blind placebo-controlled trial of pentoxifylline added to risperidone: Effects on aberrant behavior in children with autism. Prog Neuropsychopharmacol Biol Psychiatry 34:32–36, 2010.
Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA: Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: A double-blind randomized placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 32:1879–1883, 2008.
Aman MG, Singh NN, Stewart AW, Field CJ: Psychometric characteristics of the Aberrant Behavior Checklist. Am J Ment Defic 89:492–502, 1985a.
Aman MG, Singh NN, Stewart AW, Field CJ: The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. Am J Ment Defic 89:485–491, 1985b.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC: American Psychiatric Association; 2000.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
Asadabadi M, Mohammadi M-R, Ghanizadeh A, Modabbernia A, Ashrafi M, Hassanzadeh E, Forghani S, Akhondzadeh S: Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: A randomized, double-blind, placebo-controlled trial. Psychopharmacology 225:51–59, 2013.
Boris M, Goldblatt A, Edelson SM: Improvement in children with autism treated with intravenous gamma globulin. J Nutr Environ Med 15:169–176, 2005.
Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams JB, Feinstein DL: Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation 4:1–7, 2007.
Buchovecky CM, Turley SD, Brown HM, Kyle SM, Mcdonald JG, Liu B, Pieper AA, Huang W, Katz DM, Russell DW: A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat Genet 45:1013–1020, 2013.
Buitelaar JK, Van Engeland H, De Kogel K, De Vries H, Van Hooff J, Van Ree J: The adrenocorticotrophic hormone (4–9) analog ORG 2766 benefits autistic children: Report on a second controlled clinical trial. J Am Acad Child Adolesc Psychiatry 31:1149–1156, 1992.
Buitelaar JK, Van Engeland H, Van Ree JM, De Wied D: Behavioral effects of Org 2766, a synthetic analog of the adrenocorticotrophic hormone (4–9), in 14 outpatient autistic children. J Autism Dev Disord 20:467–478, 1990.
Çaku A, Pellerin D, Bouvier P, Riou E, Corbin F: Effect of lovastatin on behavior in children and adults with fragile X syndrome: An open-label study. Am J Med Genet A 164:2834–2842, 2014.
Chouinard G, Margolese HC: Manual for the extrapyramidal symptom rating scale (ESRS). Schizophr Res 76:247–265, 2005.
Christensen DL: Prevalence and characteristics of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill Summ 65:1–23, 2016.
Das UN: Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 29:1175–1185, 2013.
Defilippis M, Wagner KD: Treatment of autism spectrum disorder in children and adolescents. Psychopharmacol Bull 46:18–41, 2016.
Dickinson A, Jones M, Milne E: Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations. Brain Res 1648:277–289, 2016.
Estes ML, Mcallister AK: Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16:469–486, 2015.
Ghaleiha A, Alikhani R, Kazemi M-R, Mohammadi M-R, Mohammadinejad P, Zeinoddini A, Hamedi M, Shahriari M, Keshavarzi Z, Akhondzadeh S: Minocycline as adjunctive treatment to risperidone in children with autistic disorder: A randomized, double-blind placebo-controlled trial. J Child Adolesc Psychopharmacol 26:784–791, 2016.
Ghaleiha A, Rasa SM, Nikoo M, Farokhnia M, Mohammadi M-R, Akhondzadeh S: A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res 229:181–187, 2015.
Ghanizadeh A, Moghimi-Sarani E: A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry 13:196, 2013.
Ghanizadeh A, Rezaee Z, Dehbozorgi S, Berk M, Akhondzadeh S: Lovastatin for the adjunctive treatment of schizophrenia: A preliminary randomized double-blind placebo-controlled trial. Psychiatry Res 219:431–435, 2014.
Handen BL, Melmed RD, Hansen RL, Aman MG, Burnham DL, Bruss JB, McDougle CJ: A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder. J Autism Dev Disord 39:796–805, 2009.
Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R: A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 71:956–961, 2012.
Ji NY, Findling RL: An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Curr Opin Psychiatry 28:91–101, 2015.
Kaat AJ, Lecavalier L, Aman MG: Validity of the aberrant behavior checklist in children with autism spectrum disorder. J Autism Dev Disord 44:1103–1116, 2014.
Krab LC, De Goede-Bolder A, Aarsen FK, Pluijm SMF, Bouman MJ, Van Der Geest JN, Lequin M, Catsman CE, Arts WFM, Kushner SA: Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: A randomized controlled trial. JAMA 300:287–294, 2008.
Ling Q, Tejada-Simon MV: Statins and the brain: New perspective for old drugs. Prog Neuropsychopharmacol Biol Psychiatry 66:80–86, 2016.
Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24:659–685, 1994.
Macdowell KS, García-Bueno B, Madrigal JLM, Parellada M, Arango C, Micó JA, Leza JC: Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation. Int J Neuropsychopharmacol 16:121–135, 2013.
Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ: Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: A meta-analysis. Transl Psychiatry 5:e640, 2015.
Nikoo M, Radnia H, Farokhnia M, Mohammadi M-R, Akhondzadeh S: N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: A randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. Clin Neuropharmacol 38:11–17, 2015.
Rossignol DA, Frye RE: Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol 5:150, 2014.
Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS: Statins as neuroprotectants: A comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimers Dis 23:307–318, 2011.
Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, Shariat SV, Rezaei F, Salehi B, Akhondzadeh S: Simvastatin adjunct therapy for negative symptoms of schizophrenia: A randomized double-blind placebo-controlled trial. Int Clin Psychopharmacol 32:87–94, 2017.
Van Der Most PJ, Dolga AM, Nijholt IM, Luiten PGM, Eisel ULM: Statins: Mechanisms of neuroprotection. Prog Neurobiol 88:64–75, 2009.
Van Elst K, Bruining H, Birtoli B, Terreaux C, Buitelaar JK, Kas MJ: Food for thought: Dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev 45:369–378, 2014.
Vincenzi B, Stock S, Borba CPC, Cleary SM, Oppenheim CE, Petruzzi LJ, Fan X, Copeland PM, Freudenreich O, Cather C: A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: Effect on inflammation, psychopathology, cognition and lipid metabolism. Schizophr Res 159:395–403, 2014.
Wang H: Lipid rafts: A signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders. Front Behav Neurosci 8:104, 2014.
Westmark CJ, Sokol DK, Maloney B, Lahiri DK: Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism. Mol Psychiatry 21:1333–1341, 2016.
Willsey AJ, State MW: Autism spectrum disorders: From genes to neurobiology. Curr Opin Neurobiol 30:92–99, 2015.
Wong CT, Wais J, Crawford DA: Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders. Eur J Neurosci 42:2742–2760, 2015.
Young A, Campbell E, Lynch S, Suckling J, Powis S: Aberrant NF-kappaB expression in autism spectrum condition: A mechanism for neuroinflammation. Front Psychiatry 2:27, 2011.
Young AMH, Chakrabarti B, Roberts D, Lai M-C, Suckling J, Baron-Cohen S: From molecules to neural morphology: Understanding neuroinflammation in autism spectrum condition. Mol Autism 7:9, 2016.

Information & Authors

Information

Published In

cover image Journal of Child and Adolescent Psychopharmacology
Journal of Child and Adolescent Psychopharmacology
Volume 28Issue Number 1February 2018
Pages: 82 - 89
PubMed: 28719227

History

Published in print: February 2018
Published online: 1 February 2018
Published ahead of print: 18 July 2017

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Ehsan Moazen-Zadeh*,
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Fatemeh Shirzad*
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Mohammad-Ali Karkhaneh-Yousefi*
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Rasoul Khezri*
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Mohammad-Reza Mohammadi
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Shahin Akhondzadeh
Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Notes

*
The first four authors contributed equally in this study.
Contributed also as statistical consultant.
Funding: This study was supported by a grant to Prof. Shahin Akhondzadeh (Grant number 30327) from Tehran University of Medical Sciences (TUMS).
Address correspondence to:Shahin Akhondzadeh, PhDPsychiatric Research CenterRoozbeh Psychiatric HospitalTehran University of Medical SciencesSouth Kargar StreetTehran 13337Iran
E-mail: [email protected]

Disclosures

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top