cariprazine and brexpiprazole

We sought to review the effects of Dopamine Receptor Partial Agonist (DRPA) antipsychotic medications on milk supply and breastfeeding.. Narrative review of selected literature including animal and human data.. Scant case study evidence suggests that DRPAs may lead to reduced milk supply for some.. Women taking DRPAs should be advised of the possibility that these may affect milk supply, and reporting should be encouraged to aid future research.

Topics: Animals; Aripiprazole; Breast Feeding; Dopamine Agonists; Female; Humans; Milk; Mothers

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Humans; Piperazines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiophenes

Second generation antipsychotics (SGAs) are effective options in the treatment of schizophrenia and mood disorders, each with characteristic efficacy and safety features. In order to optimize the balance between efficacy and side effects, it is of upmost importance to match compound specificity against patient clinical profile. As the number of SGAs increased, this review can assist physicians in the prescription of three novel SGAs already on the market, namely lurasidone, brexpiprazole, cariprazine, and lumateperone, which is in the approval phase for schizophrenia treatment at the FDA. Besides schizophrenia, EMA and/or FDA approved lurasidone for bipolar depression, brexpiprazole as augmentation in major depressive disorder and cariprazine for the acute treatment of manic or mixed episodes associated with bipolar I disorder. These new antipsychotics were developed with the aim of improving efficacy on negative and depressive symptoms and reducing metabolic and cardiovascular side effects compared to prior SGAs, while keeping the risk of extrapyramidal symptoms low. They succeeded quite well in containing these side effects, despite weight gain during acute treatment remains a possible concern for brexpiprazole, while cariprazine and lurasidone show higher risk of akathisia compared to placebo and other SGAs such as olanzapine. The available studies support the expected benefits on negative symptoms, cognitive dysfunction and depressive symptoms, while the overall effect on acute psychotic symptoms may be similar to other SGAs such as quetiapine, aripiprazole and ziprasidone. The discussed new antipsychotics represent useful therapeutic options but their efficacy and side effect profiles should be considered to personalize prescription.

Topics: Animals; Antipsychotic Agents; Heterocyclic Compounds, 4 or More Rings; Humans; Lurasidone Hydrochloride; Mental Disorders; Piperazines; Quinolones; Thiophenes

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.

Topics: Antipsychotic Agents; Aripiprazole; Delayed-Action Preparations; Humans; Injections, Intramuscular; Paliperidone Palmitate; Piperazines; Quinolones; Schizophrenia; Tetrabenazine; Thiophenes; Valine

Increased prescribing of antipsychotics and availability of new antipsychotics has resulted in increased exposures in children. Current data on aripiprazole, brexpiprazole, and cariprazine are limited.. This was a retrospective database study utilizing the National Poison Data System from 2015 through 2021. We included cases of single substance exposures to aripiprazole, brexpiprazole, cariprazine, or lumateperone in children ages 0 to 5 years old with follow-up to a known outcome. Key outcomes were medical outcomes, clinical effects, and level of care if treated in a healthcare facility.. There were 3,573 aripiprazole, 137 brexpiprazole, 249 cariprazine, and one lumateperone exposure over the period. Primary outcomes were evaluated in 2,655 cases (2,390 aripiprazole, 96 brexpiprazole, and 169 cariprazine). Fifty-one percent were male and 77% were between 0 and 2 years old. Moderate effect was coded in 16.6% of aripiprazole, 23% of brexpiprazole, and 12% of cariprazine exposures. Major effect was coded in 0.6% of aripiprazole, 1% of brexpiprazole, and 2.4% of cariprazine exposures. Duration of symptoms was mostly between 8 and 24 h for 34.6% of aripiprazole, 30% of brexpiprazole, and 32% of cariprazine exposures. Over 60% of the children seen in a health care facility were discharged from the emergency department. The lowest doses resulting in at least a moderate effect and admission to a health care facility was 0.46 mg/kg for aripiprazole, 2.1 mg/kg for brexpiprazole, and 1.9 mg/kg for cariprazine. Important clinical effects included central nervous system depression, tremors, tachycardia, agitation, and vomiting.. Reported ingestions of aripiprazole, brexpiprazole, or cariprazine may result in neurologic symptoms like central nervous system depression or seizures in children. The prolonged duration of symptoms resulted in admission for at least a day for many cases. Further research should address optimal monitoring time and location for these exposures.

Topics: Antipsychotic Agents; Aripiprazole; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Poisons; Retrospective Studies; United States

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.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Drosophila melanogaster; Electron Transport; Mice

Topics: Antipsychotic Agents; Aripiprazole; Piperazines; Quinolones; Thiophenes

The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

Topics: Adenosine Triphosphate; Animals; Antipsychotic Agents; Electron Transport Chain Complex Proteins; Energy Metabolism; Hydrogen Peroxide; Loxapine; Lurasidone Hydrochloride; Mitochondria; Monoamine Oxidase Inhibitors; Oxygen Consumption; Piperazines; Quinolones; Reactive Oxygen Species; Receptors, Neurotransmitter; Swine; Thiophenes

Topics: Antipsychotic Agents; Lurasidone Hydrochloride; Piperazines; Quinolones; Thiophenes

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Depressive Disorder, Major; Dopamine Agonists; Drug Administration Schedule; Drug Interactions; Humans; Piperazines; Quinolones; Schizophrenia; Thiophenes