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For Schizophrenia, Newer Injectables Not Necessarily Better

Science Update

female patient with doctor

When it comes to antipsychotic medications, newer may not always be better. A recent study, published in JAMA by National Institute of Mental Health (NIMH)-funded researchers, found that the second-generation drug paliperidone palmitate was no more effective than the older drug haloperidol decanoate in treating adult patients with schizophrenia or schizoaffective disorder. However, patients on paliperidone gained weight and had increases in the reproductive hormone prolactin, while those on haloperidol did not.


Treatment adherence is a problem among people with schizophrenia, who may not take medications because they don’t perceive its need or benefit, don’t like the side effects, or forget. Two forms of antipsychotic drugs exist: oral and injectable. Oral medications need to be taken daily whereas long-acting injectable (LAI) medications are administered every 2–4 weeks. LAIs are used to help improve treatment adherence.

The development of second-generation or “atypical” antipsychotics in the 1990s provided hope of improvement over the older conventional or “typical” antipsychotics from the 1950s and 1960s. Second-generation drugs dominate oral antipsychotic sales. These drugs were expected to take over the LAI market as well. However, all of the second-generation LAIs are still on patent and often cost at least ten times more than the older drugs. Newer and older LAIs had not been compared on a large scale before this study.

“Long-acting drugs are an important option—they help ensure that people take prescribed medicine,” said study author Scott Stroup, M.D., M.P.H., who directs the Schizophrenia Trials Network that conducted the study. “Haloperidol is a well-known conventional drug that works reliably but is known to cause neurological side effects. In this study we used it at lower doses than have been used in most previous studies, and we found that it worked well and was tolerated by most patients.”

Previous findings from NIMH’s Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial revealed that the atypical medications were not more effective than the typical antipsychotic drug perphenazine. Furthermore, some of the newer antipsychotics can cause major weight gain and other health concerns such as high cholesterol and diabetes. In this current trial, called ACLAIMS (A Comparison of Long-Acting Injectable Medications for Schizophrenia), 311 adult patients diagnosed with schizophrenia or schizoaffective disorder were randomly assigned to receive either the second generation LAI drug paliperidone palmitate or the older LAI antipsychotic haloperidol decanoate. In addition to ascertaining therapeutic efficacy of these drugs, metabolic makers, such as weight gain, blood glucose levels, cholesterol, and prolactin, were also measured.

Results of the Study

This randomized controlled trial found no evidence that paliperidone was superior to haloperidol in preventing efficacy failure, as defined by psychiatric hospitalization, a need for crisis stabilization, increased outpatient visits, inability to discontinue oral antipsychotic after starting LAIs, common adverse effects of antipsychotic medications, or a clinician’s decision that the LAI provided no therapeutic benefit. When compared to haloperidol, paliperidone had no significant advantages in ratings of severity of abnormal involuntary movements, parkinsonism, or incidence of tardive dyskinesia. Patients on haloperidol, however, did have more akathisia (restlessness). Haloperidol was tolerated better than expected, most likely due to the use of lower doses than given in previous studies.


“Our study confirms that the newer antipsychotics don’t have a lot of overall advantages over the older treatments. Individuals may respond differently to the various drugs, but it is good news that a reasonably priced, long-acting injectable antipsychotic works well,” said Stroup. He emphasized that everyone taking an antipsychotic medication should be monitored carefully for adverse effects.

The results are consistent with previous research that did not find large differences in the effectiveness of newer versus and older antipsychotic medications.

What's Next

Schizophrenia is associated with considerable disability. In addition, obesity is common among people with serious mental illnesses such as schizophrenia and contributes to a higher risk for cardiovascular disease and a shortened life expectancy. Stroup’s group continues to look for strategies to help improve outcomes for people with schizophrenia. Such approaches include using metformin to reduce weight gain, smoking cessation, and switching medications to those that have fewer or lesser side effects. Also under investigation are efforts to enhance cognitive performance, which may promote better outcomes and recovery.


McEvoy JP, Byerly M, Hamer RM, Dominik R, Swartz MS, Rosenheck RA, Ray N, Lamberti JS, Buckley PF, Wilkins TM, Stroup TS. Effectiveness of Paliperidone Palmitate vs. Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial. JAMA . May 21, 2014. 311(19):1978–1986.


5R01MH081107-06  (Dr. Stroup) and 5R01MH081234-05  (Dr. McEvoy)