Most Benefit, Least Cost: Choosing the Right Antipsychotic

Antipsychotics are the best defense against relapse in schizophrenia, even though that protection often comes at the expense of cognitive function. Which drugs offer the greatest benefit with the least cost is unclear.

That’s partly because about 80% of individuals with schizophrenia who use antipsychotics aren’t eligible for randomized controlled trials (RCTs), mostly due to somatic comorbidities, use of other psychotropic drugs, or history of suicidality or substance abuse.

In addition, the trials rarely compare drugs head-to-head, and they’re often short in duration, making measurement of long-term outcomes difficult, Aleksi Hamina, PhD (Pharm), a researcher with Niuvanniemi Hospital, Kuopio, Finland, told Medscape Medical News.

Two new studies that compared antipsychotics seek to fill that gap. The first, which Hamina led, measured the efficacy of various antipsychotics vs oral olanzapine and found paliperidone 3-month long-acting injectable (LAI) outperformed other agents in preventing relapses.

The second analysis showed that while no specific antipsychotic offered greater cognitive benefit, first-generation dopamine blockers fared worse for preserving attention, concentration, and memory.

Both studies yielded findings that contrast with prevailing opinion, raising the question: Do they provide clarity or muddy the water further?

Antipsychotic Comparisons Lacking

Research suggests relapses can lead to harm, reduce the quality of life, and have a heavy economic impact on patients with schizophrenia.

While prior studies had suggested clozapine and LAIs were especially effective at relapse prevention, much of the research relied on the nonuse of antipsychotics as a reference, revealing little about how different antipsychotics compare with one another.

“This information is of the utmost importance so that clinicians can assess which agents to prioritize,” Hamina and colleagues wrote in a study published online on October 9 in JAMA Network Open.

The new research included 131,476 participants (mean age, 46 years; 53% men) diagnosed with a schizophrenia spectrum disorder from 2006 to 2021 who were followed for a median of 12 years.

Using data from linked Swedish health-related registries, researchers examined outpatient antipsychotic use and hospitalizations and estimated when drug use started and ended. They divided drug formulations into oral antipsychotics and LAIs and compared them with oral olanzapine, the most frequently used antipsychotic.

During the follow-up, 48.5% of the cohort experienced a relapse at least once.

Prioritize LAIs

Researchers found that compared with oral olanzapine, agents with the lowest risk for relapse were paliperidone 3-month LAI (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.51-0.86), aripiprazole LAI (aHR, 0.77; 95% CI, 0.70-0.84), olanzapine LAI (aHR, 0.79; 95% CI, 0.73-0.86), and clozapine (aHR, 0.82; 95% CI, 0.79-0.86).

These were followed by other LAIs, including paliperidone 1-month LAI. Hamina said he would like to know if the superior performance of 3-month formulation is due to better compliance, because of less frequent injections, or if it’s something to do with the drug itself.

When compared directly with their oral counterparts, LAIs were collectively associated with a 19% lower risk for relapse (pooled aHR, 0.81; 95% CI, 0.79-0.84).

“The results suggest it might be a good option to prioritize those antipsychotics that are available as injectables,” Hamina said.

Quetiapine — one of the most used antipsychotics in the study — had the worst risk for relapse (aHR, 1.44; 95% CI, 1.38-1.51), which persisted in a sensitivity analysis that removed small-dose use. Quetiapine also raises the risks for metabolic issues, including significant weight gain, diabetes, and cardiac side effects. That’s why quetiapine “perhaps should not be considered a first-line maintenance treatment option in schizophrenia,” the authors wrote.

A newer antipsychotic — cariprazine — ranked similarly to other second-generation agents (aHR, 0.97; 95% CI, 0.68-1.36).

It’s too soon to know how the recently approved first-in-class Cobenfy might fall among antipsychotics in terms of relapse, Hamina said. This agent, which combines xanomeline and trospium, doesn’t involve dopamine receptor blockade.

“It will be very interesting to see how that drug performs, but again, it’s too early to tell,” he said. “The problem with registry-based research is that it takes time for people to actually use the drug, and then it takes time for us to get the accumulated data.”

Start Clozapine Earlier?

For this current analysis, researchers separately examined an incident cohort (those without a previous diagnosis of schizophrenia spectrum disorder before January 1, 2006) and a prevalent cohort (all others with schizophrenia spectrum disorder).

Compared with oral olanzapine, antipsychotic effectiveness was generally similar across these two sub-cohorts, but clozapine showed a significantly lower risk for relapse in the incident cohort.

That clozapine works better if started at an earlier stage of the illness is “a very interesting finding,” said Hamina. “You would usually reserve clozapine for people who the guidelines say have to go through at least two other antipsychotics that don’t work.”

Researchers also looked at treatment failure (composite of psychiatric hospitalization, death, or change in antipsychotic medication). During follow-up, 71% of patients experienced this outcome at least once.

Here, again, paliperidone 3-month LAI had the lowest risk compared with oral olanzapine, followed by aripiprazole, olanzapine, and paliperidone 1-month LAI.

A Call for Cognitive Enhancers

While this study showed significant differences among antipsychotics for relapse prevention, another paper published online on October 16 in JAMA Psychiatry found these drugs are not clearly distinguishable in terms of cognitive impact.

This analysis included 68 randomized clinical trials lasting 3 or more weeks that compared antipsychotics, or antipsychotics with placebo, in 9526 people (mean age 35 years; 30% women). The median study duration was 12 weeks.

For the most part, there were no clear differences between antipsychotics. That’s due in part to small sample sizes, short study durations, or uncertainty of the evidence (wide CIs overlapping with 0).

However, the network meta-analysis showed that first-generation dopamine blockers like haloperidol, fluphenazine, and clozapine fared relatively poorly for cognitive impact. Haloperidol and fluphenazine are potent dopamine blockers, which are known to affect cognition, while clozapine may have negative effects due to its anticholinergic and sedating profile, the authors wrote.

This suggests clinicians should avoid prescribing these drugs when cognition is a concern, study author Stefan Leucht, MD, professor of psychiatry, Technical University of Munich, Munich, Germany, told Medscape Medical News.

However, “if you’re acutely ill, and you have hallucinations or delusions, then cognition is not the main target,” he said.

The findings underscore the need for “pro-cognitive drugs” that don’t block dopamine receptors, said Leucht. He referred to one such drug: Iclepertin, an inhibitor of glycine transporter 1, which targets cognition and is being investigated in a phase 3 trial.

In the current analysis, molindone and thioridazine ranked the best in terms of cognitive impact, but Leucht called the findings “unreliable” because results for each drug were based on a single study with a small sample size that had only one cognitive domain (speed of processing).

Chlorpromazine also ranked relatively high, but the total number of participants was still small. And the relevant RCTs were published in the 1960s and 1970s, which “was a different era,” said Leucht.

Studies on sertindole and paliperidone, which were more recent and covered more cognitive domains, found these two drugs had medium average effect sizes compared with placebo. Other research has linked these drugs to less sedation, which might explain their relatively favorable cognitive profile.

What Do the Findings Mean?

While these two studies confirm much of what is already known about the benefits and risks of antipsychotics, they do provide some direction for clinicians selecting an appropriate agent for their patients albeit no firm guidance on individual drug choices, Adrian Preda, MD, professor of clinical psychiatry and human behavior, School of Medicine, University of California at Irvine, told Medscape Medical News.

“LAIs tend to have better data long-term than oral medications, and that’s not necessarily because those medications are better,” but perhaps because of “close to ideal rates of compliance,” which is often not the case for oral medications that need to be taken daily, he said.

In general, across medications and indications, “the higher the frequency of a drug, the higher the rate of non-adherence,” he added.

What was a bit surprising for Preda, though, was that a 3-month LAI came out ahead of its 1-month formulation. He noted the US Food and Drug Administration doesn’t require efficacy data for longer-term formulations.

“They just require bio-equivalency data, meaning if you’re going to have a longer formulation of a drug, you just need to prove that the levels of the drug in the system are equivalent to the shorter formulation drug,” said Preda.

“Everything else being equal, they should be sort of equally effective,” he added.

The overlap in CIs in the four top-ranked drugs (paliperidone 3-month LAI, aripiprazole LAI, olanzapine LAI, and clozapine) indicates no clear separation between them in terms of efficacy, said Preda.

It’s important to stress the comparison of medications was not based on head-to-head trials, said Preda. These data come from a registry, which indicates only that patients received the prescriptions, not necessarily that they took the medication, he added.

While LAIs should be prioritized, cost and securing insurance coverage can be barriers, said Preda. As of now, none of the medications included in the study is available as a generic, he noted. This might help explain the significantly lower rate of prescriptions for LAIs in the United States than in Europe.

While the second study confirms some older antipsychotics worsen cognition and newer ones don’t improve it, the findings related to clozapine were “surprising” to Preda.

This drug was initially considered potentially beneficial for cognitive deficits, but this study indicates the exact opposite, he added.

This finding suggests clinicians should “pay closer attention” to a potential dose effect of clozapine on cognition and not assume the drug is innocuous when it comes to cognitive function, he added.

Preda agreed that there is a need for antipsychotics that don’t block dopamine.

“Dopamine antagonism is very, very problematic,” he said, adding that there are few alternatives available. “It’s an important direction for research,” he said.

Hamina’s study was funded by a grant from the Sigrid Jusélius Foundation and used data from the REWHARD (RElations, Work and Health across the Life-Course – A Research Data) consortium supported by a grant from the Swedish Research Council. Hamina had no relevant conflicts. Leucht’s study was funded by the German Ministry for Education and Research. Leucht reported personal fees from Angelini, Aspen, Boehringer Ingelheim, Eisai, Ekademia, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape Medical News, Mitsubishi, Neurotorium, Otsuka, Novo Nordisk, Recordati, Rovi, and Teva outside the submitted work. Preda had no relevant conflicts of interest.