Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia

Keks, Nicholas A; Hope, Judy; Schwartz, Darren; McLennan, Harold; Copolov, David L.; Meadows, Graham

doi:10.1007/s40263-020-00718-4

Cited by 47 publications

(56 citation statements)

References 137 publications

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“…When stratified according to trial duration, aripiprazole was additionally more favorable for total cholesterol levels (short-term), glucose levels (short-term), and sedation (long-term), but was less favorable for akathisia (short-term). These results are largely consistent with existing evidence that aripiprazole has antidepressant effects and a lower tendency to cause hyperprolactinemia, metabolic dysregulation, and sedation [34][35][36][37][38] .…”

Section: Discussionsupporting

confidence: 91%

“…Several mechanisms of action that are unique to aripiprazole may explain such results. Aripiprazole’s D 2 partial agonistic properties have prolactin-sparing effects 34 , 35 . Its partial agonistic activity at postsynaptic 5-HT 1A and 5-HT 2C receptors, coupled with desensitization of presynaptic 5-HT 1A receptors, would lead to an increased serotonergic tone, which may play a role in improving depressive and anxiety disorders 38 , 39 .…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis

et al. 2021

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Early intervention is essential for favorable long-term outcomes in schizophrenia. However, there is limited guidance in the scientific literature on how best to choose between dopamine D2 receptor (D2R) partial agonists and D2R antagonists in early stages of schizophrenia. The aim of this meta-analysis was to directly compare D2R partial agonists with D2R antagonists for efficacy and tolerability, using randomized controlled trials (RCTs) that involved participants diagnosed with first-episode psychosis, schizophrenia, or related psychotic disorders with a duration of illness ≤5 years. Fourteen RCTs, involving 2494 patients, were included in the meta-analysis. Aripiprazole was the only identified D2R partial agonist, and was not significantly different from pooled D2R antagonists for overall symptom reduction or all-cause discontinuation. However, aripiprazole was more favorable than pooled D2R antagonists for depressive symptoms, prolactin levels, and triglyceride levels. Specifically, aripiprazole was more favorable than paliperidone for triglyceride levels and more favorable than risperidone and olanzapine, but less favorable than ziprasidone, for weight gain. In addition, aripiprazole was less favorable for akathisia compared with second-generation D2R antagonists, in particular olanzapine and quetiapine, and less favorable for discontinuation due to inefficacy than risperidone. Lastly, aripiprazole was more favorable than haloperidol for various efficacy and tolerability outcomes. In conclusion, aripiprazole’s efficacy did not differ substantially from D2R antagonists in the early course of schizophrenia, whereas differential tolerability profiles were noted. More double-blind RCTs are required comparing the efficacy and tolerability of aripiprazole as well as other D2R partial agonists with D2R antagonists in early stages of schizophrenia.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis

et al. 2021

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“…Moreover, since we used human islets from cadaveric donor pancreata, there could be potential confounding factors including postmortem interval and cause of death that may impact islet function. Additionally, aside from the APDs used in our present studies, the impacts of APDs including partial D 2 -like receptor agonists (e.g., aripiprazole, brexpiprazole) 99,100 and other secondgeneration antipsychotics with a lower risk for weight gain (e.g., ziprasidone) 101 on αand β-cell DA signaling have yet to be studied. Future work will therefore examine these outstanding issues.…”

Section: Discussionmentioning

confidence: 99%

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

et al. 2021

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Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.

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“…DRPAs have even proven effective in lowering prolactin concentrations in patients with hyperprolactinemia induced by other (antipsychotic) drugs. 6 Compared to high-potency first-generation antipsychotic drugs, which cause treatment-emergent prolactin elevation in 40%-90% of treated patients, 6 prevalence of hyperprolactinemia under treatment with aripiprazole is 3.1%-9.0%. 27 To the best of our knowledge, this is the first published case of hyperprolactinemia under monotherapy with cariprazine.…”

Section: Case 4-hyperprolactinemiamentioning

confidence: 99%

“…5,9 Cariprazine exerts little to no anticholinergic activity. 6 Cariprazine is primarily metabolized via the cytochrome P450 isoenzyme (CYP) 3A4 and, to a lesser extent, by CYP2D6. 10 Two active metabolites of cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), substantially contribute to the drug's antipsychotic activity.…”

Section: Introductionmentioning

confidence: 99%

A case series of serious and unexpected adverse drug reactions under treatment with cariprazine

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Stichtenoth

et al. 2021

Clinical Case Reports

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Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia

Cited by 47 publications

References 137 publications

Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis

Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

A case series of serious and unexpected adverse drug reactions under treatment with cariprazine

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