Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials

Martin Osugo; Thomas Whitehurst; Ekaterina Shatalina; Leigh Townsend; Oisin O'Brien; Tsz Lun Allenis Mak; Robert McCutcheon; Oliver Howes

doi:10.1016/j.neubiorev.2022.104568

Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials

Martin Osugo^*, Thomas Whitehurst, Ekaterina Shatalina, Leigh Townsend, Oisin O'Brien, Tsz Lun Allenis Mak, Robert McCutcheon, Oliver Howes

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

8 Citations (Scopus)

Abstract

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10^-17), negative (SMD=−0.29,p = 2.2 × 10-³¹) and total symptoms (SMD =−0.39,p = 1.7 × 10^-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

Original language	English
Article number	104568
Journal	Neuroscience and Biobehavioral Reviews
Volume	135
Early online date	21 Feb 2022
DOIs	https://doi.org/10.1016/j.neubiorev.2022.104568
Publication status	Published - 30 Apr 2022

Keywords

Dopamine
Meta-analysis
Negative symptoms
Partial agonism
Prodopaminergic
Psychosis
Schizophrenia
Stimulants
Treatment

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10.1016/j.neubiorev.2022.104568

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title = "Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials",

abstract = "Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10-17), negative (SMD=−0.29,p = 2.2 × 10-31) and total symptoms (SMD =−0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.",

keywords = "Dopamine, Meta-analysis, Negative symptoms, Partial agonism, Prodopaminergic, Psychosis, Schizophrenia, Stimulants, Treatment",

author = "Martin Osugo and Thomas Whitehurst and Ekaterina Shatalina and Leigh Townsend and Oisin O'Brien and Mak, {Tsz Lun Allenis} and Robert McCutcheon and Oliver Howes",

note = "Funding Information: Dr Howes has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Astra-Zeneca, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Invicro, Jansenn, Lundbeck, Lyden-Delta, Mylan, Neu-rocrine, Otsuka, Sunovion, Rand, Recordati, and Roche. Neither Dr Howes or his family have been employed by or have holdings/ a financial stake in any pharmaceutical company. Dr McCutcheon has received honoraria for educational talks from Otsuka. No other authors report conflicts of interest. Funding Information: This study was funded by Medical Research Council -UK (no. MC- A656-5QD30 ), Maudsley Charity (no. 666 ), Brain and Behavior Research Foundation, and Wellcome Trust (no. 094849/Z/10/Z ) grants to Dr Howes and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: This study was funded by Medical Research Council-UK (no. MC- A656-5QD30), Maudsley Charity (no. 666), Brain and Behavior Research Foundation, and Wellcome Trust (no. 094849/Z/10/Z) grants to Dr Howes and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

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AU - Townsend, Leigh

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AU - Mak, Tsz Lun Allenis

AU - McCutcheon, Robert

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N2 - Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10-17), negative (SMD=−0.29,p = 2.2 × 10-31) and total symptoms (SMD =−0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

AB - Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10-17), negative (SMD=−0.29,p = 2.2 × 10-31) and total symptoms (SMD =−0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

KW - Dopamine

KW - Meta-analysis

KW - Negative symptoms

KW - Partial agonism

KW - Prodopaminergic

KW - Psychosis

KW - Schizophrenia

KW - Stimulants

KW - Treatment

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U2 - 10.1016/j.neubiorev.2022.104568

DO - 10.1016/j.neubiorev.2022.104568

M3 - Review article

C2 - 35131396

AN - SCOPUS:85124907624

SN - 0149-7634

VL - 135

JO - Neuroscience and Biobehavioral Reviews

JF - Neuroscience and Biobehavioral Reviews

M1 - 104568

ER -

Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials

Abstract

Keywords

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