Meta-analysis Finds Antidepressants Ineffective for Children and Adolescents

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A new study seeking to clarify the efficacy of antidepressants for children and adolescents found “a very small effect size,” much lower than that found for the drugs in adults.

“Currently approved antidepressants for children and adolescents with MDD have small effect sizes, and many antidepressant trials in this population fail,” the researchers write.

The study was led by Anna Feeney at Mass General Hospital and included prolific industry-funded researchers (and antidepressant experts) Maurizio Fava and George Papakostas, among others. It was published in the Journal of Affective Disorders.

Girl On Bed Taking Pill With Glass Of Water In BedroomAntidepressants have repeatedly been found to barely beat placebo in clinical trials, even for adults. For instance, in a bombshell 2008 study published in the New England Journal of Medicine, researchers found that in half of all antidepressant trials, the drug failed to beat the placebo. Moreover, the effect of the drugs in positive studies is consistently less than 3 points better than placebo on the Hamilton Depression Scale (a 53-point measure), which is a clinically undetectable difference.

For children, the drugs are even less effective. A 2021 Cochrane review found that none of the drugs had a clinically significant effect. The researchers refer to the effects of the drugs as “small and unimportant” compared with placebo. And because the drugs are known to increase suicidality in children and adolescents, the FDA requires that SSRI antidepressants carry their strong “black box” warning.

In the current study, the researchers analyzed 15 industry-funded trials comparing the drugs to a placebo. (The researchers do not explain why they chose only industry-funded trials.) Their results:

“The [standardized mean difference] among all studies was 0.12, a very small effect size, lower than that seen in studies of adults with MDD.”

For comparison, the researchers note that the usual effect size for the drugs in adults ranges from 0.27 to 0.43, or small to moderate. They add that the effect size for psychotherapy in children ranges from a moderate 0.47 to a large 0.96.

According to the data presented by the researchers in this study, the drugs are ineffective for children, but psychotherapy is moderately—or possibly even extremely—effective.

The researchers take pains to explain away the tiny effect size they found. Their proposed explanations include the following:

  • The placebo effect is too high, masking the actual effect of the drugs;
  • The studies aren’t sensitive enough to detect the actual effect of the drugs;
  • The studies misdiagnosed kids as having depression when their symptoms were actually due to something else;
  • And lastly, the researchers offhandedly suggest the most likely explanation: the drugs simply do not work for children and adolescents. Their reasoning for this is that the drugs were “developed for adults,” which, of course, does not explain the drugs’ lack of efficacy for adults.

 

Maurizio Fava and George Papakostas report the following conflicts of interest with the pharmaceutical industry:

Maurizio Fava

Research Support: Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; BioClinica, Inc; Biohaven; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Centrexion Therapeutics Corporation; Cephalon; Cerecor; Clarus Funds; Clexio Biosciences; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; Gentelon, LLC; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; Indivior; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institutes of Health; National Institute of Mental Health (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Novaremed; Organon Pharmaceuticals; Otsuka Pharmaceutical Development, Inc.; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Praxis Precision Medicines; Premiere Research International; Protagenic Therapeutics, Inc.; Reckitt Benckiser; Relmada Therapeutics Inc.; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shenox Pharmaceuticals, LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceuticals; Tal Medical; VistaGen; WinSanTor, Inc.; Wyeth-Ayerst Laboratories.

Advisory Board/Consultant: Abbott Laboratories; Acadia; Aditum Bio Management Company, LLC; Affectis Pharmaceuticals AG; Alfasigma USA, Inc.; Alkermes, Inc.; Altimate Health Corporation; Amarin Pharma Inc.; Amorsa Therapeutics, Inc.; Ancora Bio, Inc.; Angelini S.p. A; Aptinyx Inc.; Arbor Pharmaceuticals, LLC; Aspect Medical Systems; Astella Pharma Global Development, Inc.; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; BioXcel Therapeutics; Biovail Corporation; Boehringer Ingelheim; Boston Pharmaceuticals; BrainCells Inc; Bristol-Myers Squibb; Cambridge Science Corporation; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; Clexio Biosciences; Click Therapeutics, Inc; CNS Response, Inc.; Compellis Pharmaceuticals; Cybin Corporation; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dainippon Sumitomo Pharma Co. Inc.; Dr. Katz, Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; ElMindA; EnVivo Pharmaceuticals, Inc.; Enzymotec LTD; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Esthismos Research, Inc.; Euthymics Bioscience, Inc.; Evecxia Therapeutics, Inc.; ExpertConnect, LLC; FAAH Research Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; Gate Neurosciences, Inc.; GenetikaPlus Ltd.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; Happify; H. Lundbeck A/S; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; JDS Therapeutics, LLC; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante, Inc.; Merck & Co., Inc.; Mind Medicine Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Navitor Pharmaceuticals, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neurocrine Biosciences, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Niraxx Light Therapeutics, Inc; Northwestern University; Novartis AG; Nutrition 21; Opiant Pharmecuticals; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Ovid Therapeutics, Inc.; Pamlab, LLC.; Perception Neuroscience; Pfizer Inc.; PharmaStar; PharmaTher Inc.; Pharmavite® LLC.; PharmoRx Therapeutics; Polaris Partners; Praxis Precision Medicines; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Protagenic Therapeutics, Inc; PPD; PThera, LLC; Purdue Pharma; Puretech Ventures; Pure Tech LYT, Inc.; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Relmada Therapeutics, Inc.; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; SanofiAventis US LLC.; Sensorium Therapeutics; Sentier Therapeutics; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals, LLC; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sonde Health; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex; Teva Pharmaceuticals; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; University of Michigan, Department of Psychiatry; Usona Institute, Inc.; Vanda Pharmaceuticals, Inc.; Versant Venture Management, LLC; VistaGen; Xenon Pharmaceuticals Inc.

Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Global Medical Education, Inc.; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories.

Stock/Other Financial Options:

Equity Holdings: Compellis; Psy Therapeutics; Sensorium Therapeutics.

Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd.

George Papakostas

Dr. Papakostas has served as a consultant for Abbott Laboratories, Acadia Pharmaceuticals, Inc.*, Alkermes, Inc., Alphasigma USA*, Inc., AstraZeneca PLC, Avanir Pharmaceuticals, Axsome Therapeutics*, Boston Pharmaceuticals, Inc.*, Brainsway Ltd., Bristol-Myers Squibb Company, Cala Health*, Cephalon Inc., Dey Pharma, L.P., Eleusis health solutions ltd*, Eli Lilly Co., Genentech, Inc.*, Genomind, Inc.*, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Janssen Global Services LLC*, Jazz Pharmaceuticals, Johnson & Johnson Companies*, Methylation Sciences Inc., Mylan Inc. *, Novartis Pharma AG, One Carbon Therapeutics, Inc.*, Osmotica Pharmaceutical Corp.*, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sage Therapeutics*, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Taisho Pharmaceutical Co, Ltd.*, Takeda Pharmaceutical Company LTD, Theracos, Inc., and Wyeth, Inc.

Dr. Papakostas has received honoraria (for lectures or consultancy) from Abbott Laboratories, Acadia Pharmaceuticals Inc., Alkermes Inc., Alphasigma USA Inc., Asopharma America Cntral Y Caribe, Astra Zeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway Ltd., Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec AG, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Pharmaceuticals, Grunbiotics Pty LTD, Hypera S.A., Jazz Pharmaceuticals, H. Lundbeck A/S, Medichem Pharmaceuticals, Inc., Meiji Seika Pharma Co. Ltd., Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pharma Trade SAS, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, and Wyeth Inc.

Dr. Papakostas has received research support (paid to hospital) from AstraZeneca PLC, Bristol-Myers Squibb Company, Cala Health, Forest Pharmaceuticals, the National Institute of Mental Health, Mylan Inc., Neuralstem, Inc.*, PAMLAB LLC, PCORI, Pfizer Inc., Johnson & Johnson Companies, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals, Tal Medical, and Theracos, Inc.

Dr. Papakostas has served (not currently) on the speaker’s bureau for BristolMyersSquibb Co and Pfizer, Inc.

* Asterisk denotes consulting activity undertaken on behalf of Massachusetts General Hospital.

 

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Feeney, A., Hock, S., Fava, M., Hernández Ortiz, J. M., Iovieno, N., & Papakostas, G. I. (2022). Antidepressants in children and adolescents with major depressive disorder and the influence of placebo response: A meta-analysis. Journal of Affective Disorders, 305, 55-64. https://doi.org/10.1016/j.jad.2022.02.074 (Link)

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