Studies Highlight Benefits of Aripiprazole and Other Third-Generation Antipsychotics for Schizophrenia

Schizophrenia is a chronic and debilitating mental disorder that can be managed only with lifetime use of antipsychotics that help relieve but do not eliminate symptoms.

The drugs also produce side effects so severe that many patients stop taking them, frequently sending them spiraling into homelessness and poor health that can shave decades off their life expectancy.

Multiple schizophrenia subtypes further complicate medical management and require highly personalized doctoring, made even more difficult by the social milieux in which patients often find themselves.

First- and second-generation antipsychotics have been around for years. Third-generation medications began appearing in the early 2000s. They may be better at reducing symptoms of psychosis, such as hallucinations and delusions, and minimizing negative symptoms, such as the flattening of emotions and inability to experience pleasure (anhedonia). They also cause fewer side effects. But their specific effects vary.

Comparative analysis of third-generation antipsychotics

A narrative review study published June 14 in International Clinical Psychopharmacology looks at the efficacy, effectiveness and side effects of the third-generation antipsychotics aripiprazole, brexpiprazole, and cariprazine. Aripiprazole is under the brand name Abilify, among others. Brexpiprazole is sold under the brand name Rexulti, and cariprazine under the brand name Vraylar.

These drugs, like their predecessors, work by blocking dopamine receptors in the brain. (The review does not include an entirely new drug, xanomeline and trospium chloride, sold as Cobenfy, which targets proteins in the brain called muscarinic receptors and was approved by the FDA in September 2024.)

First and corresponding author Valerio Ricci, M.D., Ph.D., medical director at San Luigi Gonzaga Hospital and a contract teacher at the University of Turin, both in Orbassano, Italy, and colleagues, all in Italy, focus on treatment of the first episode of schizophrenia, which typically occurs in late adolescence or young adulthood. Treatment of the initial episode is considered critical to minimizing social and vocational deterioration.

Ricci and his colleagues conclude that all three third-generation antipsychotics exhibit comparable efficacy to second-generation drugs with the advantage of having fewer side effects. But they reviewed far more studies on aripiprazole (42), which was approved in 2002, than cariprazine (four) and brexpiprazole (one), both of which the FDA approved in 2015.

“Aripiprazole demonstrates stronger evidence compared to cariprazine and brexpiprazole, yet even the latter two show commendable safety profiles,” they write. “While aripiprazole’s clinical efficacy parallels that of other antipsychotics, such data are lacking for other TGAs [third-generation antipsychotics] due to insufficient clinical trials and comparative studies.”

This generation of drugs, they add, “shows particular efficacy in ameliorating cognitive and negative symptoms of psychotic onset, which often remain inadequately addressed by other pharmacotherapies.” (Clinical observations are available only for aripiprazole.) “The capacity of these medications to enhance cognitive functioning and alleviate negative symptoms underscores their potential to improve overall quality of life and long-term outcomes for patients.”

The researchers also point out that schizophrenia is a multidimensional disorder and its several subtypes each have distinct neurobiological underpinnings. Symptoms can vary significantly from patient to patient. The authors note the importance of personalized treatment plans as well as a multidisciplinary approach that integrates psychiatric care with psychological support, social services and vocational training.

10-year study of long-acting injectable aripiprazole

Adherence to regimens for daily medications that are only partially effective and accompanied by significant side effects — even if both are better than older-generation antipsychotics — is a major challenge for people with schizophrenia. The disease causes cognitive impairment and often leads to social decline, with many patients lacking stable living conditions and health providers, both crucial to sticking to medication recommendations.

In 2013, both the FDA and the European Medicines Agency approved an extended-release injectable version of aripiprazole intended to help patients stay on the drug. It’s the only third-generation antipsychotic available as a long-acting formulation in four-, six-, and eight-week versions that must be given by a healthcare provider. It is sold under various brand names, including Abilify Maintena and Aristada.

Although studies have found long-acting injectable antipsychotics to be effective in preventing hospital admission—relapses are frequent in schizophrenia and other psychotic disorders — many experts consider them to be underutilized, and there has been little long-term research.

The benefits are substantial, according to a new, real-world longitudinal study that examined hospital admission rates and treatment retention rates over five years in an adult cohort at a large urban mental health service in London. The findings were published June 23 in Schizophrenia.

Sofia Pappa, Ph.D.

Corresponding author Sofia Pappa, Ph.D., a professor of practice in psychiatry at the Imperial College, London, a specialty lead in mental health for the National Institute for Health Research, and mood and psychosis research lead at West London National Health Service Trust, where the paper’s other author, Joshua Barnett, also has an appointment, enrolled 135 people in the study, 63% with schizophrenia and 37% with other diagnoses, such as schizoaffective disorder or bipolar disorder.

They compared the data in three ways: for the same patients five years before and five years after initiation of monthly injections; for patients who continued the injections for up to five years compared with those who stopped; and for patients with schizophrenia compared with others (the results were similar).

Of the 85 schizophrenia patients, approximately 1 in 4 stopped in the first year, with progressively smaller numbers discontinuing each additional year. By the end of the study, nearly half had discontinued the injections, but that means that more than half (52.9%, to be precise) of participants were still getting monthly injections after five years. That’s a notably higher proportion than those found in studies of daily antipsychotics.

The main reasons listed for discontinuing were poor compliance (25.9%) and ineffectiveness (15.3%); only 4.7% cited poor tolerability.

Among those who continued receiving injections, hospital admission rates plummeted 88.5%, from an average of 1.29 during the five years before their first injection to 0.11 during the five years of monthly shots. Average length of stay dropped 90.3%, from 86 days to 8.

By comparison, among those who discontinued at some point, there was a statistically insignificant reduction in admissions from 1.98 in the previous five years to 1.48 during the study. The decline in average length of stay (from 124 to 74 days) was statistically significant but numerically much less robust compared with the group that continued the injections for five years.

Pappa and her co-authors emphasize that both the frequency and duration of hospitalizations were sustained through the full five years, with few patients discontinuing injections or requiring hospitalization in the fourth and fifth years.

Long-acting injectable aripiprazole promotes patient stability and improves long-term recovery outcomes, they write. The findings also have “important implications for the economic strain that hospital admissions impose on healthcare systems,” they add.

“By reducing hospitalizations, these treatments not only alleviate financial burden but also enhance the quality of care and continuity for patients with chronic psychiatric conditions.”

Pappa and a colleague reside in the United Kingdom, and the study site is part of the country’s publicly funded National Health Service. The paper makes no reference to the United States, where drug insurance coverage and hospital finances may be on much shakier ground.