expert roundtables

Newer Antipsychotic Therapies: Safety and Tolerability

by Leslie Citrome, MD, MPH; John M. Kane, MD; and Jonathan M. Meyer, MD

Overview

Even the most efficacious antipsychotic therapy will fall short if it is not well tolerated or if there are adherence issues. The search for antipsychotic medications with improved tolerability continues, and significant gains have been made in recent years.

Q:

Given the current treatment landscape, how do you factor in the side-effect profiles of newer antipsychotic agents when you are selecting therapy?

Leslie Citrome, MD, MPH

Clinical Professor, Psychiatry and Behavioral Sciences
New York Medical College
Valhalla, NY

“For me, the 3 adverse events that I think about with every patient are activation or akathisia, the degree of sedation or somnolence, and changes in weight that they may have experienced with previous treatments.”

Leslie Citrome, MD, MPH

Selecting an antipsychotic is dependent on the patient’s previous experience with treatment, their preferences, and their values. I must make sure that whatever I am prescribing is going to reduce symptoms, first and foremost. This involves a discussion with the patient regarding their prior experiences. In addition, there are several adverse events that can occur with any antipsychotic medicine, and they often vary individually, such that a particular side effect may be experienced by some patients but not others. 

For me, the 3 adverse events that I think about with every patient are activation or akathisia, the degree of sedation or somnolence, and changes in weight that they may have experienced with previous treatments. These adverse events are relatively common with the medications that we use today, and the patient’s history of and susceptibility to these effects influence which agents I gravitate toward and which agents I tend to avoid. To continue taking a particular medication, the patient needs to perceive that it is a reasonable choice for them.

With respect to individual agents, if we look historically at the antipsychotics that have been available over the past half century, all of them were fairly similar in their significant association with drug-induced movement disorders. The second-generation antipsychotics, consistent with their definition as atypical, are less likely to cause movement disorders; however, this side effect is not eliminated completely. Early second-generation antipsychotics can cause weight gain, some to a more significant degree than others; with continued treatment, metabolic disturbances may develop, sometimes rather quickly. 

The most recently introduced second-generation antipsychotics have a lower risk of metabolic side effects, and I welcome having these additional options. The more choices that we have that are different, the better we will be able to select the right medication for each patient. What I find particularly exciting on the horizon are the novel antipsychotics with completely different mechanisms of action. Time will tell whether these agents will be better tolerated and more efficacious than previous agents for certain patients.

John M. Kane, MD

Senior Vice President, Behavioral Health Services
Northwell Health
Zucker Hillside Hospital
Professor and Chairman, Department of Psychiatry
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
New Hyde Park, NY

“In a situation where we do not have any information about prior antipsychotics (eg, first-episode or early phase patients), we really want to choose an agent that is well tolerated because it is going to have a tremendous impact on whether the patient will continue to take it.”

John M. Kane, MD

As Dr Citrome suggested, when selecting an antipsychotic medication, it is very important to have a process of shared decision making with the patient to understand what their prior experience has been and what their preferences are. Many patients perceive weight gain as the most troubling side effect, but there are certainly other side effects that may be troublesome but not as widely appreciated.

First-episode patients and early phase patients who are just beginning treatment with antipsychotic drugs are in a very critical stage that can really lay the foundation for what follows. We know that since the patient is drug naive, they are probably going to have a more significant response to lower doses of an antipsychotic medication compared with a more chronic patient. At the same time, since they have never taken these medicines, they will likely also be more sensitive to some of the side effects.

Early in the course of illness, many patients do not accept the fact that they are ill, and therefore many individuals do not really want to take medication. So, if they are taking treatment and they do experience side effects, it may provide an additional reason for them to discontinue that medication. In fact, we see a lot of data illustrating how frequently first-episode or early phase patients discontinue their treatment. In a situation where we do not have any information about prior antipsychotics (eg, first-episode or early phase patients), we really want to choose an agent that is well tolerated because it is going to have a tremendous impact on whether the patient will continue to take it.

The long-term side effect that patients have been particularly concerned about with the older drugs is tardive dyskinesia, which still occurs with some of the newer agents, but the risk is lower. However, the newer agents are also being used more broadly in patients with affective disorders, so we need to be on the lookout for tardive dyskinesia in a broader patient population. At present, the 3 novel agents that carry a low risk of tardive dyskinesia are brexpiprazole, cariprazine, and lumateperone, and, among the newer agents, lumateperone has a very good adverse-effect profile and is unusually well tolerated. Other long-term side effects that we are most concerned about are the metabolic side effects, and the newer drugs also, in general, have less propensity to produce these effects. That is good news.

Jonathan M. Meyer, MD

Clinical Professor of Psychiatry
University of California, San Diego
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, CA

“The introduction of newer agents has improved on certain aspects of tolerability that may have been problematic for earlier second-generation antipsychotics.”

Jonathan M. Meyer, MD

As my colleagues have stated, the advantages of the newer antipsychotics have been predominantly related to improvements in tolerability. The last 3 antipsychotic agents to be approved by the US Food and Drug Administration were brexpiprazole, cariprazine, and lumateperone. Brexpiprazole and cariprazine, as dopamine partial agonists, are unlikely to raise serum prolactin. Hyperprolactinemia is an issue for many patients because it can result in endocrine adverse effects. Lumateperone, a dopamine D2 antagonist with only modest D2 receptor occupancy, is also unlikely to cause prolactin-related adverse effects or extrapyramidal symptoms. In clinical trials, the rate of extrapyramidal symptoms, including akathisia, with lumateperone was very low. Numerically, the rate of akathisia was even lower in the lumateperone group than in the placebo group. Lumateperone also has a very high affinity for serotonin 5HT2A receptors, and antagonism of these receptors may contribute to its antipsychotic mechanism. This affinity for 5HT2A receptors also helps to mitigate dopamine D2–related adverse effects. 

As Dr Citrome said, the introduction of newer agents has improved on certain aspects of tolerability that may have been problematic for earlier second-generation antipsychotics. I think that one important advantage of having these newer agents, as Dr Kane alluded to, is that many patients do not want to be on a particular medication simply due to adverse effects. If we can find a medication to which a patient responds and that they also tolerate, it is really a win for everybody.

References

Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17(3):330-340. doi:10.1002/wps.20579

Correll CU, Davis RE, Weingart M, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2020;77(4):349-358. doi:10.1001/jamapsychiatry.2019.4379

Correll CU, Skuban A, Hobart M, et al. Efficacy of brexpiprazole in patients with acute schizophrenia: review of three randomized, double-blind, placebo-controlled studies [published correction appears in Schizophr Res. 2017;190:191-194]. Schizophr Res. 2016;174(1-3):82-92. doi:10.1016/j.schres.2016.04.012

Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial [published correction appears in Schizophr Res. 2018;192:493]. Schizophr Res. 2016;176(2-3):264-271. doi:10.1016/j.schres.2016.06.030

Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis [published correction appears in Lancet. 2019;394(10202):918]. Lancet. 2019;394(10202):939-951. doi:10.1016/S0140-6736(19)31135-3

Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164(1-3):127-135. doi:10.1016/j.schres.2015.01.038

Koblan KS, Kent J, Hopkins SC, et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497-1506. doi:10.1056/NEJMoa1911772

Krogmann A, Peters L, von Hardenberg L, Bödeker K, Nöhles VB, Correll CU. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr. 2019;24(S1):38-69. doi:10.1017/S109285291900124X

Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011;168(6):603-609. doi:10.1176/appi.ajp.2011.10081224

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