Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment

Choi, Hangnyoung; Kim, Jae Han; Yang, Hee Sang; Kim, Jong Yeob; Cortese, Samuele; Smith, Lee; Koyanagi, Ai; Dragioti, Elena; Radua, Joaquim; Fusar-Poli, Paolo; Shin, Jae Il; Cheon, Keun-Ah; Solmi, Marco

doi:10.1186/s13229-024-00585-6

Molecular Autism

Table 1 Summarized evidence for the efficacy of interventions for irritability in autism spectrum disorder

From: Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment

Interventions	k	Intervention group, N	Control group, N	Placebo group	Meta-analysis		Heterogeneity			Egger's test^a	RoB2^b	GRADE	Meta-regression coefficient for mean age of intervention group
Interventions	k	Intervention group, N	Control group, N	Placebo group	Hedges’ g (95% CI)	P	Q	I²	τ²	P	RoB2^b	GRADE
Pharmacological monotherapy versus placebo
Risperidone	6	187	204	Placebo	− 0.857 (− 1.263 to − 0.451)	0.0029	11.50	56.5	0.088	0.919	3L, 2M, 1H	High	0.1117 (P = 0.4215)
Aripiprazole	5	257	241	Placebo	− 0.559 (− 0.767 to − 0.351)	0.0017	2.68	0.0	0	0.415	5 L	High	0.0111 (P = 0.9580)
Lurasidone	2	99	98	Placebo	− 1.076 (− 3.884 to 1.732)	0.1289	2.09	52.2	0.051	NA	2 L	Moderate
Anti-epileptic drug	3	39	33	Placebo	− 0.196 (− 1.219 to 0.828)	0.4970	1.98	0	0.008	0.824	2L, 1M	Low
Valproate	2	29	23	Placebo	− 0.255 (− 5.127 to 4.619)	0.6270	1.83	45.3	0.133	NA	1L, 1M	Low
Levetiracetam	1	10	10	Placebo	− 0.051 (− 0.927 to 0.825)	0.9092					L
Balovaptan	1	86	81	Placebo	0.215 (− 0.089 to 0.519)	0.1654					H
Amantadine hydrochloride	1	19	19	Placebo	− 0.609 (− 1.260 to 0.042)	0.0666					M
Guanfacine	1	30	32	Placebo	− 0.481 (− 0.987 to 0.025)	0.0623					L
Arbaclofen	1	61	69	Placebo	− 0.332 (− 0.679 to 0.015)	0.0607					L
Mecamylamine	1	10	8	Placebo	− 0.180 (− 1.111 to 0.751)	0.7047					M
Bumetanide	1	37	37	Placebo	− 0.135 (− 0.592 to 0.322)	0.5623					M
Risperidone + adjuvant therapy versus risperidone
Risperidone + dietary supplementation	5	111	109	Risperidone + placebo	− 0.490 (− 1.045 to 0.066)	0.0707	8.45	52.6	0.107	0.8799	3L, 2M	Very low	0.0025 (P = 0.9924)
Risperidone + N-acetylcysteine	2	37	34	Risperidone + placebo	− 0.677 (− 5.414 to 4.060)	0.3204	2.27	55.9	0.156	NA	1L, 1M	Very low
Risperidone + sulforaphane	1	30	30	Risperidone + placebo	− 0.882 (− 1.411 to − 0.353)	0.0011					L
Risperidone + L-Carnosine	1	21	21	Risperidone + placebo	− 0.198 (− 0.804 to 0.408)	0.5217					M
Risperidone + Ginkgo biloba	1	23	24	Risperidone + placebo	− 0.028 (− 0.600 to 0.544)	0.9236					L
Risperidone + Topiramate	1	20	20	Risperidone + placebo	− 1.983 (− 2.740 to − 1.226)	< 0.0001					L
Risperidone + Pentoxifylline	1	20	20	Risperidone + placebo	− 1.785 (− 2.518 to − 1.052)	< 0.0001					L
Risperidone + Memantine	1	20	20	Risperidone + placebo	− 1.534 (− 2.240 to − 0.828)	< 0.0001					L
Risperidone + Celecoxib	1	20	20	Risperidone + placebo	− 1.276 (− 1.956 to − 0.596)	0.0002					L
Risperidone + Minocycline	1	23	23	Risperidone + placebo	− 0.911 (− 1.519 to − 0.303)	0.0033					M
Risperidone + Simvastatin	1	33	33	Risperidone + placebo	− 0.876 (− 1.382 to − 0.370)	0.0007					L
Risperidone + Palmitoylethanolamide	1	31	31	Risperidone + placebo	− 0.873 (− 1.394 to − 0.352)	0.001					L
Risperidone + Galantamine	1	20	20	Risperidone + placebo	− 0.775 (− 1.418 to − 0.132)	0.018					M
Risperidone + Pioglitazone	1	20	20	Risperidone + placebo	− 0.770 (− 1.413 to − 0.127)	0.019					M
Risperidone + Amantadine	1	20	19	Risperidone + placebo	− 0.747 (− 1.396 to − 0.098)	0.024					L
Risperidone + Prednisolone	1	13	13	Risperidone + placebo	− 0.639 (− 1.427 to 0.149)	0.1119					L
Risperidone + Pivotal Response Treatment	1	17	17	Risperidone	− 0.583 (− 1.269 to 0.103)	0.0958					H
Risperidone + Propentofylline	1	24	24	Risperidone + placebo	− 0.562 (− 1.138 to 0.014)	0.0559					L
Risperidone + Pregnenolone	1	30	29	Risperidone + placebo	− 0.503 (− 1.020 to 0.014)	0.0567					L
Risperidone + Riluzole	1	20	20	Risperidone + placebo	− 0.496 (− 1.125 to 0.133)	0.1223					M
Risperidone + Baclofen	1	29	29	Risperidone + placebo	− 0.432 (− 0.953 to 0.089)	0.1044					L
Risperidone + Resveratrol	1	31	31	Risperidone + placebo	− 0.286 (− 0.786 to 0.214)	0.2620					L
Non-pharmacological intervention versus placebo
Parent training^c	6	117	105	Waitlist control, placebo without waitlist	− 0.893 (− 1.184 to − 0.602)	0.0005	3.20	0.0	0	0.361	1M, 5H	Moderate	0.1793 (P = 0.0877)
Stepping Stone Triple P	2	41	39	Waitlist control	− 0.982 (− 1.448 to − 0.517)	0.0237	0.02	0.0	0	NA	2H	Moderate
Therapeutic horseback riding	1	50	47	Barn activity	− 0.487 (− 0.891 to − 0.083)	0.0181					M
Hyperbaric treatment (1.3 atm, 24% O₂)	1	30	26	1.03 atm, 21% O₂	− 0.445 (− 0.976 to 0.086)	0.1006					L
Electro-acupuncture	1	30	25	Sham electro-acupuncture	− 0.109 (− 0.640 to 0.422)	0.6875					L
Dietary supplementation versus placebo
N-acetylcysteine	3	80	78	Placebo	− 0.151 (− 1.701 to 1.399)	0.7161	6.21	67.8	0.254	0.764	2L, 1M	Very low
Polyunsaturated fatty acid	5	79	67	Placebo	− 0.235 (− 0.851 to 0.382)	0.3507	6.97	42.6	0.13	0.931	4L, 1M	Low	0.1690 (P = 0.3722)
Omega-3 fatty acid	4	72	61	Placebo	− 0.264 (− 1.127 to 0.599)	0.4021	6.83	56.1	0.178	0.969	3L, 1M	Very low
Omega-3,6 fatty acid	1	7	6	Placebo	− 0.039 (− 1.129 to 1.051)	0.9441					L
Vitamin D₃	2	37	36	Placebo	− 0.298 (− 7.279 to 6.683)	0.6838	5.22	80.8	0.488	NA	1L, 1M	Very low
Sulforaphane	1	26	14	Placebo	− 3.580 (− 4.599 to − 2.561)	< 0.0001					L
Omega-3 fatty acid + vitamin D₃	1	15	16	Placebo	− 0.604 (− 1.323 to 0.115)	0.0998					M
Probiotics	1	18	17	Placebo	− 0.442 (− 1.112 to 0.228)	0.1962					L
Folinic acid	1	23	25	Placebo	− 0.370 (− 0.940 to 0.200)	0.2036					L

Bold indicate the statistical significance
CI confidence interval, GRADE Grading Of Recommendations, Assessment, Development, And Evaluations, N number of participants, NA not available, k number of estimates, RoB2 risk of bias 2
^aEgger's test might not have sufficient statistical power to identify publication bias when the number of studies is limited (i.e., when k is less than 10)
^bRoB2 results of included trials are presented for each analysis (L = low, M = some concerns, H = high risk of bias)
^cIn our study, the term ‘parent training’ refers to parent training for maladaptive behaviors, as outlined in Bearrs’ taxonomy for parent training for ASD [22]

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ISSN: 2040-2392

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