Novel Antipsychotics: New? Improved? Questionable?

Educational Objectives

The goal of this program is to improve use of novel antipsychotic medications for psychiatric disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Compare the efficacy and safety profiles of novel antipsychotics.
2. Summarize the relationship between mechanisms of action and clinical effects of novel antipsychotics.
3. Develop strategies for dosing novel antipsychotics to reduce the severity of side effects.

Summary

Scales: Montgomery-Asberg Depression Rating Scale (MADRS) — reduction of ≥50% is classified as a response; patients with scores ≤7 are considered to be in remission; Young Mania Rating Scale (YMRS) — widely used in screening and assessing symptom severity for mania; score >25 is considered to be severe mania; score of 19 to 24 is considered to be moderate mania; a score ≤12 is considered to be euthymia, with a score between 12 and 19 considered to be mild mania; reduction of ≥50% is considered to be a response; Positive and Negative Syndrome Scale (PANSS) — measure of psychosis; reduction of 20% to 30% is considered to be a response

Drug binding affinity: inhibition constant (Ki) <10 is considered to be high affinity, and a Ki of 10 to 100 is considered to be moderate affinity; however, strong binding affinity may not translate into clinical action

Brexpiprazole: approved in 2015 for major depressive disorder (MDD; specifically, unipolar depression) and schizophrenia; used off label for agitation and aggression in Alzheimer dementia (AD); binds strongly to dopamine and serotonin receptors; also binds to α receptors (binds more strongly compared with aripiprazole); schizophrenia — Kishi et al (2020) performed a systematic review and meta-analysis to compare the efficacy and safety between aripiprazole and brexpiprazole; few differences between aripiprazole and brexpiprazole were observed; fewer patients discontinued brexpiprazole for schizophrenia-related symptoms (eg, increasing psychosis), although schizophrenia-related outcomes were reported differently in the aripiprazole and brexpiprazole trials; agitation in AD — Grossberg et al (2020) conducted 2 studies of brexpiprazole that showed a reduction in Neuropsychiatric Inventory-Nursing Home Agitation/Aggression scores in patients with severe AD; the improvement was only significant in study 1; after excluding patients who were not titrated up to 2 mg by 4 wk, the improvement was significant; no severe adverse effects (AEs) were noted

Cariprazine: approved in 2015 for bipolar disorder and schizophrenia; off-label use includes augmentation in MDD; binds strongly to dopamine and serotonin receptors and moderately to 5-hydroxytryptamine receptor subtype 2A (5-HT2A) and histamine receptors; 5-HT2C receptor antagonism (similar to mirtazapine) may be responsible for weight gain

Bipolar depression: Durgam et al (2016) found a significant reduction in MADRS; for cariprazine 3.0 mg/day at 6 wk, the least squares mean difference in MADRS scores from baseline may not be considered clinically effective because the reduction in MADRS score was <50%

Bipolar mania: some studies showed reduction in scores of >50%; at doses >6.0 mg/day, efficacy is lost and the incidence of AEs increases at a dose of 12 mg/day; a reduction in the PANSS score of 20% to 30% was observed with doses of 3, 6, and 9 mg/day doses, but not with a dose of 1.5 mg/day

Augmentation in MDD: a study showed that a dose of 2 to 4.5 mg/day decreased the MADRS scores compared with placebo, but a dose of 1 to 2 mg/day did not; reported AEs included akathisia (22%), insomnia (13%), nausea (12%; primarily observed at higher doses)

Iloperidone: approved in 2009 for schizophrenia; binds strongly to dopamine and 5-HT2A receptors; has a lower affinity for 5-HT1A, 5-HT7, and histamine receptors; Kane et al (2008) found no difference in rates of relapse between iloperidone (4-16 mg/day) and haloperidol, and iloperidone was considered noninferior to haloperidol; rates of short-term AEs were similar; extrapyramidal symptoms (EPS; eg, bradykinesia, tremor, dystonia) were less severe with iloperidone; iloperidone has better long-term safety profile

Lumateperone: has a very strong affinity for serotonin receptors; of the antipsychotic medications, it has the strongest affinity for serotonin receptors; it has moderate affinity for dopamine receptors (covers ≈40%, whereas other antipsychotic medications require coverage of 65-80% for response); approved in 2019 for schizophrenia and bipolar disorder; in a 28-day study, no difference in the PANSS total score was observed between the 28-mg and 42-mg doses; in the PANSS positive symptom subscale, the 28-mg dose curve separated from the placebo curve at some of the time points; in the PANSS negative symptom subscale, the 28-mg and 42-mg dose curves overlapped; the number needed to treat (NNT) was 9; in a long-term study, patients were switched from standard antipsychotic treatment to lumateperone to evaluate metabolic side effects; a significant reduction in total cholesterol, low-density lipoprotein cholesterol, weight, body mass index, and waist circumference were observed; after switching to lumateperone, improvement occurred in ≈38% of patients, whereas worsening occurred in ≈13%; when administered with a high-fat meal, the maximum concentration decreased by 33% and the area under the curve increases by 9%; lumateperone is well tolerated (can be administered with food in cases of severe nausea or gastrointestinal upset); administration at bedtime is recommended if it causes sedation

Pimavanserin: does not bind to dopamine 2 receptors; has a strong affinity for serotonin receptors and acts as an inverse agonist; Tariot et al (2021) showed that patients who received pimavanserin had a lower risk for relapse to psychosis, and the trial was stopped for efficacy; common AEs include headache, constipation, urinary tract infections, and asymptomatic QT prolongation (by ≈5.4 msec)

Olanzapine-samidorphan: approved in 2021; dosed once daily; samidorphan is an opioid antagonist and may precipitate withdrawal in patients on opioids; olanzapine is effective but causes weight gain; Martin et al (2019) found that samidorphan 10 mg yielded a better response than the 5-mg dose; no significant response was observed with the 20-mg dose; overall, weight gain was 37% lower in the olanzapine-samidorphan group compared with the olanzapine group

Brilaroxazine: currently in phase 3 clinical trials; has a strong affinity for dopamine receptors and moderate affinity for 5-HT6 and nicotinic acetylcholine receptors; may improve cognition and potentially help negative symptoms (eg, avolition, anhedonia); the phase 2 trial (Cantillon et al [2017]) found a significant difference in the PANSS score with brilaroxazine compared with placebo; however, the aripiprazole curve did not separate from placebo, which contradicts prior findings

Roluperidone: has an affinity for 5-HT2A, σ2, and α1A receptors and does not bind to dopamine receptors (no EPS side effects); σ2 antagonism helps prevent neurodegeneration, and α1A receptors may also play a role; specifically targets negative symptoms on the PANSS; the phase 2 trial (Davidson et al [2017]) showed significant improvement in negative symptoms for the 32-mg/day and 64-mg/day doses; no difference in the PANSS positive scale score was observed with roluperidone compared with placebo

Risperidone subcutaneous long-acting injectable: given every 28 days; a study that evaluated impending relapse (eg, hospitalization rates, violent behavior) showed a significant benefit

Xanomeline–trospium: xanomeline is a muscarinic agonist (preferably M1 and M4 receptors) and targets central effects; trospium is a peripheral muscarinic antagonist that limits AEs; AEs include constipation, nausea, and dry mouth; Brannan et al (2021) found a significant reduction in the PANSS total score at 5 wk; activation of M4 receptors causes endocannabinoid release, which binds to cannabinoid type 2 receptors on dopamine terminals and blocks the release of dopamine (indirect blockade produces no EPS-type side effects); also decreases the production of dopamine in the terminals

Ulotaront: is a trace amine-associated receptor 1 (TAAR1) and 5-HT1A agonist; TAAR1 receptor modulates G proteins that are involved in dopamine receptors; investigational drug, and clinical trials are ongoing; Correll et al (2021) conducted a 26-wk extension study of a 4-wk double-blind, placebo-controlled study, in which patients in the placebo group were switched to ulotaront; the study showed continued decrease in the PANSS scores

Mechanism of action: activation of TAAR1 receptor creates a presynaptic dimer with the dopamine receptors, which is internalized; this reduces the firing of dopamine neurons; ulotaront also modulates vesicular monoaminergic transmission

Review of aripiprazole, brexpiprazole, and cariprazine: Citrome (2018) compared aripiprazole, brexpiprazole, and cariprazine, and evaluated the NNT, the number needed to harm (NNH), and the likelihood to help or harm (LHH) for schizophrenia, bipolar mania, and MDD; bipolar mania — the NNT is 7 for aripiprazole and 5 for cariprazine; the NNH for discontinuation due to an AE was 100 for aripiprazole and 20 for cariprazine; in LHH for response before a patient discontinues, aripiprazole outperforms cariprazine (14 vs 4); schizophrenia — the NNT is 8 for aripiprazole, 7 for brexpiprazole, and 10 for cariprazine; the LHH for somnolence is 2.5 for aripiprazole; cariprazine is associated with less discontinuation for somnolence; difference in LHH for weight gain is minimal between aripiprazole (5-HT2C agonist) and cariprazine (5-HT2C antagonist)

Practice guidelines: the American Psychiatric Association guideline does not comment on newer antipsychotic medications; network meta-analysis found that olanzapine and risperidone were more likely to result in a response compared with quetiapine and that the evidence was insufficient to differentiate between brexpiprazole and aripiprazole; for core illness symptoms, paliperidone was superior to iloperidone and lurasidone; clozapine was better than other medications except olanzapine; clozapine and quetiapine had a lower risk for all-cause mortality compared with risperidone; evidence for new medications is insufficient

Readings

Brannan SK, Sawchak S, Miller AC, et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. New England Journal of Medicine. 2021; 384(8):717-726. doi:10.1056/NEJMoa2017015; Cantillon M, Prakash A, Alexander A, et al. Dopamine serotonin stabilizer RP5063: a randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Schizophr Res. 2017; 189:126-133. doi:10.1016/j.schres.2017.01.043; Citrome L. Aripiprazole, brexpiprazole, and cariprazine: Not all the same: Understanding the key differences among these agents can help inform treatment decisions. Current Psychiatry. 2018; 17(4):24+.; Correll CU, Koblan KS, Hopkins SC, et al. Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ Schizophr. 2021; 7(1):63. doi:10.1038/s41537-021-00190-z; Davidson M, Saoud J, Staner C, et al. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017; 174(12):1195-1202. doi:10.1176/appi.ajp.2017.17010122; Durgam S, Earley W, Lipschitz A, et al. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry. 2016; 173(3):271-281. doi:10.1176/appi.ajp.2015.15020164; Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020; 28(4):383-400. doi:10.1016/j.jagp.2019.09.009; Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol. 2008; 28(2 Suppl 1):S29-35. doi:10.1097/JCP.0b013e318169cca7; Kishi T, Ikuta T, Matsuda Y, et al. Aripiprazole vs. brexpiprazole for acute schizophrenia: a systematic review and network meta-analysis. Psychopharmacology (Berl). 2020; 237(5):1459-1470. doi:10.1007/s00213-020-05472-5; Martin WF, Correll CU, Weiden PJ, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. Am J Psychiatry. 2019; 176(6):457-467. doi:10.1176/appi.ajp.2018.18030280; Tariot PN, Cummings JL, Soto-Martin ME, et al. Trial of pimavanserin in dementia-related psychosis. N Engl J Med. 2021; 385(4):309-319. doi:10.1056/NEJMoa2034634.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Miskle reported owning personal stock options in Johnson & Johnson. Members of the planning committee reported nothing relevant to disclose. Dr. Miskle's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Miskle was recorded at the 2022 Iowa Psychiatric Physicians Society Spring Symposium, held on June 3, 2022, in Des Moines, IA, and presented by the Iowa Psychiatric Physicians Society. For more information about upcoming CME activities from this presenter, please visit Iowa.psychiatry.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.50 CE contact hours.

Lecture ID:

PS512001

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.