Sedation and its Potential Risks in Children with Autism Spectrum Due to Drug Overlaps: A Critical Review

Alonso, Herculano Ramirez Floro; Heimer, Mônica Vilela; Calado, Rafael Vrijdags; Silva, João Victor Farias da; Lins, Renata Matos Lamenha; Romão, Dayse Andrade; Pugliesi, Daniela Maria Carvalho; Santos Junior, Valdeci Elias dos

doi:10.1590/pboci.2024.053

Herculano Ramirez Floro Alonso

Methodology

Investigation

Writing

Original Draft

Writing

Review

Editing

Project Administration

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0002-0209-662X

Mônica Vilela Heimer

Methodology

Writing

Review

Editing

Project Administration

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, University of Pernambuco, Camaragibe, PE, Brazil

https://orcid.org/0000-0003-3842-192X

Rafael Vrijdags Calado

Formal Analysis

Writing

Original Draft

Writing

Review

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0002-9635-203X

João Victor Farias da Silva

Methodology

Writing

Original Draft

Writing

Review

Editing

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Medicine, Federal University of Sergipe, Aracajú, SE, Brazil

https://orcid.org/0000-0001-8800-5540

Renata Matos Lamenha Lins

Writing

Original Draft

Writing

Review

Editing

Project Administration

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0002-2968-6849

Dayse Andrade Romão

Methodology

Writing

Original Draft

Writing

Review

Editing

Project Administration

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0002-7884-1657

Daniela Maria Carvalho Pugliesi

Conceptualization

Methodology

Writing

Original Draft

Writing

Review

Editing

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0002-7854-0416

Valdeci Elias dos Santos JuniorCorresponding author: Valdeci Elias dos Santos Júnior E-mail:valdeciodonto@gmail.com

Conceptualization

Methodology

Writing

Original Draft

Writing

Review

Editing

All authors declare that they contributed to a critical review of intellectual content

approval of the final version to be published

Department of Pediatric Dentistry, School of Dentistry, Federal University of Alagoas, Maceió, AL, Brazil

https://orcid.org/0000-0001-9748-5830

Corresponding author: Valdeci Elias dos Santos Júnior E-mail:valdeciodonto@gmail.com

Academic Editor: Wilton Wilney Nascimento Padilha

Conflict of Interest

The authors declare no conflicts of interest.

Drugs	Diazepam	Midazolam	Promethazine	Hydroxyzine	Diphenhydramine
SSRI
Citalopram [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Both increase serotonin levels. Risk of SS and NMS-like reactions.	Hydroxyzine increases Citalopram toxicity by QTc. TdP risk.	No interactions
Fluoxetine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Fluoxetine increases the level/effect of Diazepam.	No interactions	Fluoxetine increases the level/ effect of Promethazine. Both increase QTc.	Same as Citalopram.	Diphenhydramine increases the level/effect of Fluoxetine.
Escitalopram [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	No interactions	Both increase QTc.	No interactions
Paroxetine [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Same as Fluoxetine	Same as Escitalopram	Same as Fluoxetine
Sertraline [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Same as Fluoxetine, except for: Both decrease QTc.	Same as Escitalopram	No interactions
Fluvoxamine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Fluvoxamine increases the level/effect of Diazepam.	Fluvoxamine increases level/ effect of midazolam. Risk of hypoventilation, airway obstruction, or apnoea and profound and/or prolonged drug effect.	Both increase QTc.	Same as Escitalopram	No interactions
Venlafaxine [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Same as Fluoxetine	Both decrease QTc.	No interactions
sNRI
Atomoxetine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	No interactions	Both increase QTc.	Diphenhydramine increases the level/effect of Atomoxetine.
Cyclic antidepressants
Nortriptyline [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Both increase sedation.	Both increase sedation.	Both increase QTc. Both increase sedation. One increases the level of the other-additive anticholinergic effects.	Both increase QTc. Both increase sedation.	Diphenhydramine increases the level/effect of Nortriptyline. Both decrease cholinergic effects/ transmission. Both increase sedation.
Clomipramine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline
Desipramine [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline
Mirtazapine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Nortriptyline	Same as Nortriptyline	Both decrease QTc. Both increase sedation.	Same as Nortriptyline	Both increase sedation.
Trazodone [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Nortriptyline	Same as Nortriptyline	Same as Nortriptyline, except for: One increases the toxicity of the other. Additive hypotensive effects.	Same as Nortriptyline	Both increase sedation. Both decrease cholinergic effects/ transmission.

Drugs	Diazepam	Midazolam	Promethazine	Hydroxyzine	Diphenhydramine
1st Generation Antipsychotic
Loxapine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Both increase sedation.	Both increase sedation.	Risk of SS and NMS. Both increase antidopaminergic effects, including extrapyramidal symptoms and NMS. Both increase sedation.	Both increase sedation.	Diphenhydramine decreases Loxapine levels. Loxapine increases the effects of Diphenhydramine. Additive anticholinergic effects, possible hypoglycaemia. Both increase sedation.
Haloperidol [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Loxapine	Same as Loxapine	Same as Loxapine, plus: Both increase the QTc. Haloperidol increases the level/effect of Promethazine.	Same as Loxapine, plus: Both increase the QTc.	Same as Loxapine, plus: Diphenhydramine increases the level/effect of Haloperidol.
2nd Generation Antipsychotics
Aripiprazole [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Both increase sedation.	Both increase sedation.	Risk of SS and NMS. Both increase antidopaminergic effects, including extrapyramidal symptoms and NMS. Both increase sedation.	Both increase QTc. Both increase sedation.	Diphenhydramine decreases Aripiprazole levels. Aripiprazole enhances the effects of Diphenhydramine. Additive anticholinergic effects, possible hypoglycaemia. Both increase sedation. Diphenhydramine increases the level/effect of Aripiprazole.
Risperidone [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole	Same as Aripiprazole	Same as Aripiprazole, plus: Both increase QTc.	Same as Aripiprazole	Same as Aripiprazole
Olanzapine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole	Same as Aripiprazole	Same as Aripiprazole, plus: Both decrease QTc.	Same as Aripiprazole	Diphenhydramine decreases levels of Olanzapine. Olanzapine increases the effects of Diphenhydramine. Additive anticholinergic effects, possible hypoglycaemia. Both increase sedation.
Lurasidone [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	One increases the toxicity of the other. Potential for greater CNS depressant effects when used simultaneously.	One increases the toxicity of the other. Potential for greater CNS depressant effects when used simultaneously.	Risk of SS and NMS. Lurasidone increases the effects of Promethazine. Increased risk of hypotension with concurrent use. Potential for additive effects on the CNS.	One increases the toxicity of the other. Potential for greater CNS depressant effects when used simultaneously.	One increases the toxicity of the other. Potential for greater CNS depressant effects when used simultaneously.
Clozapine [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole, plus: Potential risk of cardiorespiratory collapse.	Same as Aripiprazole	Same as Aripiprazole	Hydroxyzine increases Clozapine toxicity by QTc. TdP risk. Both increase sedation.	Same as Aripiprazole
Quetiapine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole	Same as Aripiprazole	Same as Aripiprazole	Same as Clozapine	Same as Olanzapine
Ziprasidone [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole	Same as Aripiprazole	Same as Risperidone	Same as Clozapine	Same as Olanzapine
Paliperidone [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Aripiprazole	Same as Aripiprazole	Same as Risperidone	Same as Aripiprazole	Same as Olanzapine
Amisulpride [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Both increase QTc.	Both increase QTc.	No interactions
Glutamatergic antagonist
Amantadine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ,⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	No interactions	No interactions	Increased potential for anticholinergic adverse effects.

Drugs	Diazepam	Midazolam	Promethazine	Hydroxyzine	Diphenhydramine
Anticonvulsant and mood stabiliser
Topiramate [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Topiramate increases the level/effect of Diazepam. Both increase sedation.	Topiramate increases the level/effect of Midazolam. Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase sedation.
Phenytoin [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Phenytoin decreases the level/effect of Diazepam.	Phenytoin decreases the level/effect of Midazolam.	No interactions	No interactions	No interactions
Carbamazepine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Phenytoin, plus: Diazepam increases Carbamazepine levels. Carbamazepine decreases Diazepam levels.	Same as Phenytoin	No interactions	No interactions	No interactions
Oxcarbazepine [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	Same as Phenytoin, plus: Oxcarbazepine increases the level/effect of Diazepam.	Same as Phenytoin	No interactions	No interactions	No interactions
Lithium [⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Risk of neurotoxicity. Multiple mechanisms are involved.	Both increase QTc.	No interactions
GABAergic Agonist
Arbaclofen/Baclofen [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... ]	Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase sedation.

Drugs	Diazepam	Midazolam	Promethazine	Hydroxyzine	Diphenhydramine
Stimulant
Methylphenidate [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... [8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... -⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Risk of cardiac arrhythmia or sudden death.	No interactions	No interactions
Alpha-adrenergic agonist
Clonidine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... [8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... -⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	One increases the toxicity of the other. Coadministration increases CNS depressant effects.	No interactions	Additive hypotensive effects; possible delirium.	One increases the toxicity of the other. Coadministration increases CNS depressant effects.	No interactions
Guanfacine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... [8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... -⁹[9] Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, et al. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. https://doi.org/10.1016/j.pnpbp.2021.110326 https://doi.org/10.1016/j.pnpbp.2021.110... ]	No interactions	No interactions	Same as clonidine	No interactions	No interactions
Lofexidine [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ]	Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase QTc. Both increase sedation.	Both increase sedation.

Drugs	Diazepam	Midazolam	Promethazine	Hydroxyzine	Diphenhydramine
Neurohormone
Melatonin [³[3] Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32(1):3-29. https://doi.org/10.1177/0269881117741766 https://doi.org/10.1177/0269881117741766... ,⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ]	Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase sedation.	Both increase sedation.
AChEi
Donepezil [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ]	No interactions	No interactions	Both decrease QTc.	Both increase QTc.	Donepezil increases, and Diphenhydramine decreases cholinergic transmission/effects. Donepezil decreases the effects of Diphenhydramine. Diphenhydramine increases the level/effect of Donepezil.
Galantamine [⁸[8] Eissa N, Al-Houqani M, Sadeq A, Ojha SK, Sasse A, Sadek B. Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci 2018; 12:304. https://doi.org/10.3389/fnins.2018.00304 https://doi.org/10.3389/fnins.2018.00304... ]	No interactions	No interactions	No interactions	No interactions	Same as Donepezil
Other
Cannabidiol [⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... ]	Cannabidiol increases the level/effect of Diazepam.	No interactions	No interactions	No interactions	No interactions
Metformin [⁷[7] Aishworiya R, Valica T, Hagerman R, Restrepo B. An update on psychopharmacological treatment of autism spectrum disorder. Neurotherapeutics 2022; 19(1):248-262. https://doi.org/10.1007/s13311-022-01183-1 https://doi.org/10.1007/s13311-022-01183... ]	No interactions	No interactions	Promethazine decreases the effects of Metformin. Risk of hypoglycaemia.	No interactions	No interactions

[1] Corresponding author: Valdeci Elias dos Santos Júnior E-mail:valdeciodonto@gmail.com

Brasil

Brasil

Sedation and its Potential Risks in Children with Autism Spectrum Due to Drug Overlaps: A Critical Review

ABSTRACT

Objective:

Material and Methods:

Results:

Conclusion: