Aripiprazole versus typicals for schizophrenia

Bhattacharjee, Jayanti; El‐Sayeh, Hany

doi:10.1002/14651858.cd006617.pub2

Cited by 14 publications

(3 citation statements)

References 49 publications

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“…It has been postulated that through this dopamine and serotonin system stabilisation, a partial D 2 agonist would be able to act as an antagonist in pathways where abundance of dopamine was producing psychosis, yet it would stimulate receptors as an agonist at sites in which low dopaminergic tone would produce side-effects (such as movement disorders). Despite this postulated mechanism of action, a Cochrane review 13 concluded that aripiprazole was equally effective as typical and atypical antipsychotics.…”

Section: Pharmacologymentioning

confidence: 99%

Antipsychotics in the treatment of schizophrenia

Parker¹

2009

Prog Neurol Psychiatry

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In the second of a new series of articles on the major psychiatric drug groups, produced in association with the College of Mental Health Pharmacists, the author discusses the use of antipsychotics through a review of the clinical literature. Pharmacology, interactions and side‐effects as well as drug choice and information to give to patients are discussed. Copyright © 2009 Wiley Interface Ltd

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Section: Pharmacologymentioning

confidence: 99%

Antipsychotics in the treatment of schizophrenia

Parker¹

2009

Prog Neurol Psychiatry

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“…It also prevents D2R/D3R hyper-activation during periods of excessive pre-synaptic dopamine release (as observed in the striatum of schizophrenic patients) (13,14). Pharmacologically, the partial agonists succeed because their slow k off rates mean that they remain bound to the D2R/D3R -even when dopamine levels transiently spike to pathological levels (15).…”

Section: Introductionmentioning

confidence: 99%

The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors

Hardy

Chung

et al. 2023

Preprint

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Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent "third"-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~5-15% of patients. However, it is not fully understand how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.

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“…Specifically, aripiprazole (first approved for schizophrenia in the USA in 2002, with approximately 6 million prescriptions in 2017 [ 12 ]) functions as a partial D2R/D3R agonist and alleviates hyper-activation of dopaminergic circuits by competing for receptor binding with dopamine. It also prevents D2R/D3R hyper-activation during periods of excessive pre-synaptic dopamine release (as observed in the striatum of schizophrenic patients) [ 13 , 14 ]. Pharmacologically, the partial agonists succeed because their slow k off rates mean that they remain bound to the D2R/D3R—even when dopamine levels transiently spike to pathological levels [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors

Hardy,

Chung,

et al. 2023

Biol Direct

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Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent ‘third’-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.

show abstract

Aripiprazole versus typicals for schizophrenia

Cited by 14 publications

References 49 publications

Antipsychotics in the treatment of schizophrenia

Antipsychotics in the treatment of schizophrenia

The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors

The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors

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