Antipsychotics are the best defense against relapse schizophreniaEven if that protection often comes at the expense of cognitive function. It is unclear which drugs will provide the greatest benefit at the lowest cost.
This is partly because approximately 80% of patients with schizophrenia who take antipsychotics are randomized due to somatic comorbidities, use of other psychotropic medications, or suicidal tendencies or a history of suicidal tendencies. This is because they are not subject to controlled trials (RCTs). drug abuse.
Additionally, clinical trials rarely directly compare drugs and are often short-term, making it difficult to measure long-term outcomes, says Alexi Hamina, a researcher at Niuvanniemi Hospital in Kuopio, Finland. The Ph.D. (Pharmacy) says this. said Medscape Medical News.
Two new studies comparing antipsychotic drugs aim to fill that gap. The first experiment, led by Hamina, compared the effectiveness of different antipsychotic drugs and oral medications. olanzapine and found paliperidone Three-month long-acting injectables (LAIs) were more effective than other drugs in preventing relapse.
A second analysis showed that while specific antipsychotics did not provide greater cognitive benefits, first-generation antipsychotics did provide greater cognitive benefits. dopamine Blockers performed worse when it came to maintaining attention, concentration, and memory.
Both studies yielded results that contrasted with popular opinion, raising the question: “Will the water become clearer or more cloudy?”
Comparisons of antipsychotics are lacking
Research shows that relapses can harm people with schizophrenia, reduce their quality of life, and have significant economic consequences.
Although previous research suggested that clozapine Although LAIs were particularly effective in preventing relapse, many of the studies relied on the absence of antipsychotics, and little was known about how different antipsychotics compared.
“This information is critical to allowing clinicians to assess which drugs should be prioritized,” Hamina et al. wrote in the study. Published online on October 9th JAMA network open.
The new study included 131,476 participants (mean age 46 years, 53% male) diagnosed with schizophrenia spectrum disorder from 2006 to 2021 and followed for a median of 12 years. .
Researchers used data from linked Swedish health-related registries to examine outpatient antipsychotic drug use and hospital admissions, and to estimate when drug use began and ended. They classified the formulations as oral antipsychotics and LAIs and compared them to olanzapine, the most frequently used oral antipsychotic.
During follow-up, 48.5% of the cohort experienced at least one recurrence.
Prioritize LAI
Researchers found that compared to oral olanzapine, the drug with the lowest risk of recurrence was paliperidone with a 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 a 1-month LAI with paliperidone. Hamina said he would like to know whether the superior performance of the 3-month formulation is due to increased compliance, less frequent injections, or something to do with the drug itself.
When compared directly to their oral counterparts, LAIs were associated with a 19% lower risk of recurrence overall (pooled aHR, 0.81; 95% CI, 0.79-0.84).
“These results suggest that prioritizing antipsychotics that are available as injectables may be a good option,” Hamina said.
Quetiapine The drug, one of the most used antipsychotics in this study, had the highest risk of relapse (aHR, 1.44; 95% CI, 1.38-1.51), and this risk persisted even in a sensitivity analysis that excluded low-dose use. Ta. Quetiapine also increases the risk of metabolic problems such as significant weight gain, diabetes, and cardiac side effects. That’s why quetiapine “probably should not be considered a first-line maintenance treatment option in schizophrenia,” the authors write.
New antipsychotics — cariprazine — Ranked similarly to other second-generation drugs (aHR, 0.97; 95% CI, 0.68-1.36).
It’s too early to know how the recently approved first-in-class Cobenfi will be classified as an antipsychotic in terms of relapse, Hamina said. This combination of xanomeline and trospium does not involve blocking dopamine receptors.
“It will be very interesting to see how the drug works, 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 to capture the accumulated data.”
Should I start clozapine early?
For this current analysis, the researchers studied an onset cohort (those with no schizophrenia spectrum disorder diagnosis before January 1, 2006) and a prevalence cohort (all others with a schizophrenia spectrum disorder). (people) were investigated separately.
Compared with oral olanzapine, antipsychotic efficacy was generally similar in these two subcohorts, but clozapine was shown to have a significantly lower risk of relapse in the incident cohort.
The finding that clozapine is more effective when started early in the disease is “a very interesting finding,” Hamina said. “Typically, clozapine is reserved for people whose guidelines say they need to take at least two other antipsychotics that are ineffective.”
The researchers also looked at treatment failures (a combination of psychiatric hospitalizations, deaths, and changes in antipsychotic medication). During follow-up, 71% of patients experienced this outcome at least once.
Again, paliperidone 3-month LAI had the lowest risk compared with oral olanzapine, followed by aripiprazole, olanzapine, and paliperidone 1-month LAI.
Recruitment of cognitive function improvers
While this study showed significant differences between antipsychotics in preventing relapse, another paper Published online on October 16th JAMA Psychiatry It turns out that these drugs are not clearly distinguishable in terms of their effects on cognition.
The analysis included 68 randomized clinical trials lasting at least three weeks that compared antipsychotics or antipsychotics with a placebo in 9,526 people (mean age 35 years, 30% women). Median study duration was 12 weeks.
In most cases, there were no clear differences between antipsychotics. This is partly due to small sample size, short study period, or uncertainty in the evidence (broad CIs overlap with 0).
However, a network meta-analysis showed that first-generation dopamine blockers were: haloperidol, Fluphenazineand clozapine fared relatively poorly in terms of cognitive effects. Haloperidol and fluphenazine are potent dopamine blockers and are known to affect cognition, while clozapine may have negative effects due to its anticholinergic and sedative effects, the authors write. .
This suggests that clinicians should avoid prescribing these drugs if there are cognitive concerns, said study author Stefan, professor of psychiatry at the Technical University of Munich in Munich, Germany. said Leucht, MD. Medscape Medical News.
But “if you’re acutely ill and you have hallucinations and delusions, cognition is not the main target,” he says.
The finding underscores the need for “cognitive-enhancing drugs” that don’t block dopamine receptors, Leucht said. He mentioned one such drug, iclepertine, an inhibitor of glycine transporter 1. It targets cognition and is being studied in phase 3 trials.
In the current analysis, Molindon and Thioridazine ranked the best in terms of impact on cognition, but the results for each drug were based on a single study with a small sample size and in only one cognitive domain (processing speed); called the results “unreliable.”
Chlorpromazine was also ranked relatively high, but the total number of participants was still small. And while related RCTs were published in the 1960s and 1970s, “that was a different era,” Leucht said.
Studies on sertindole and paliperidone are more recent and cover more cognitive areas, and these two drugs were found to have moderate mean effect sizes compared with placebo. Other studies have associated these agents with reduced sedation, which may 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 not provide firm guidance for the selection of individual drugs, but may help clinicians choose the appropriate drug for their patients. says Adrian Preda, M.D., professor of clinical medicine. Psychiatry and Human Behavior at the University of California, Irvine School of Medicine. Medscape Medical News.
“LAIs tend to have better long-term data than oral drugs, not necessarily because oral drugs are better,” but perhaps because of “near-ideal adherence rates.” , as this is often not the case for required oral medications. Take it daily, he said.
In general, regardless of drug or indication, “the more frequently a drug is used, the higher the nonadherence rate,” he added.
However, something that was a little surprising to Preda was that the 3-month LAI was released before the 1-month formulation. He noted that the U.S. Food and Drug Administration does not require efficacy data for long-term formulations.
“We just need bioequivalence data, which means that if we are formulating a drug for a long period of time, we just need to prove that the levels of the drug in our system are equivalent to a drug that is formulated for a shorter period of time.” ” said Preda.
“All else being equal, they should be equally effective,” he added.
The overlap in CIs for the top four drugs (paliperidone 3-month LAI, aripiprazole LAI, olanzapine LAI, and clozapine) indicates that there is no clear distinction between them in terms of efficacy, Preda said.
Preda said it is important to emphasize that drug comparisons are not based on head-to-head trials. These data come from registries and only show that patients received a prescription, not necessarily that they took the drug, he added.
LAI should be a priority, but cost and insurance coverage can be barriers, Preda said. None of the drugs included in the study are available as generics at this time, he noted. This may help explain the significantly lower prescription rate for LAIs in the United States compared to Europe.
A second study confirms that some older antipsychotics worsen cognitive function and that newer antipsychotics do not improve it, but the findings related to clozapine were a “surprise” to Preda. It was.
This drug was initially thought to have the potential to be beneficial for: cognitive impairmentBut this study shows just the opposite, he added.
This finding suggests that clinicians should “pay close attention” to the potential dose effects of clozapine on cognition and should not assume that clozapine is benign when it comes to cognitive function. he added.
Preda agreed that antipsychotic drugs that don’t block dopamine are needed.
“Dopamine antagonism is very problematic,” he said, adding that there are few alternatives available. “This is an important direction for research,” he says.
Hamina’s research was funded by a grant from the Sigrid Juselius Foundation and used data from the REWHARD (Relationships, Work and Health Across the Life Course – Research Data) consortium supported by a grant from the Swedish Research Council. did. Hamina had no relevant conflicts. Leucht’s research was funded by the German Ministry of Education and Research. Mr. Leucht is a member of Angelini, Aspen, Boehringer Ingelheim, Eisai, Ecademia, Gedeon Richter, Janssen, Karna, Kinexis, Lundbeck, Medichem, Medscape Medical News, Mitsubishi, Neurotorium, Otsuka, Novo Nordisk, and Recorder. Tee, Lovi, reported personal commissions from outside Teva. Submitted work. Preda had no relevant conflicts of interest.
