More Medication Doesn’t Mean More Improvement

Patients with schizophrenia discharged from the hospital receiving antipsychotic medication in dosages within recommended ranges show improvement in some critical short-term outcomes compared with patients receiving higher dosages.

Individuals who were given high dosages of antipsychotic medication at hospital discharge (defined as more than 1,000 chlorpromazine mg equivalents) had greater severity of symptoms three months after discharge—as measured by the Brief Psychiatric Rating Scale (BPRS)—than patients who were given dosages recommended by the Patient Outcome Research Team for Schizophrenia (PORT) (300 to 1,000 chlorpromazine mg equivalents), according to a study in the September Psychiatric Services.

Those patients who were given low dosages at discharge (defined as less than 300 chlorpromazine mg equivalents) were less likely to report side effects but were slightly more likely to be nonadherent, according to the study.

“When patients with schizophrenia are leaving the hospital, higher dosages that exceed PORT guidelines are not necessarily associated with better outcomes,” study co-author Mark Olfson, M.D., M.P.H., told Psychiatric News. “Patients who received dosages in excess of 1,000 chlorpromazine mg equivalents had poorer outcomes than those who received standard dosages even after adjusting for baseline severity and other measures.”

Olfson is a professor of psychiatry at Columbia University College of Physicians and Surgeons in New York City.

Study Methodology

Data for the study were collected as part of the Rutgers Hospital and Community Survey, 1995-97. A total of 264 patients completed a three-month follow-up interview, with data available on discharge medication dosage for 246 patients.

The study patients were interviewed within three days of discharge using the Structured Clinical Interview for DSM-III-R. Clinical symptoms were assessed using the BPRS, and social engagement was assessed using a four-item scale derived from the schizophrenia PORT project measuring frequency of interaction with friends.

The patients were interviewed again using the same instruments at three months postdischarge.

Of the 246 patients, 161 were prescribed antipsychotic medication within the recommended range, 50 received high dosages, and 35 received low dosages.

Since data were collected from 1995 to 1997, before PORT recommendations were released, so the study does not speak to clinicians’ adherence to treatment guidelines.

Findings Difficult to Interpret

Despite the finding of more severe symptoms at follow-up among patients receiving higher dosages at discharge, the study found no significant differences in outcome on social and occupational functioning related to dosage level at hospital discharge. Moreover, patients who received low dosages did not show poorer outcomes.

But lead author Nancy L. Sohler, Ph.D., M.P.H., told Psychiatric News that the follow-up period may have been too short to detect a relationship between low dosages and poorer outcomes. Sohler is with the department of epidemiology and population health at Montefiore Medical Center and Albert Einstein College of Medicine, New York.

“Those patients prescribed low dosages were, however, slightly less likely to be adherent during the three-month follow-up period,” said Sohler.

This was true despite the fact that they were also less likely to experience adverse side effects, she said.

Olfson said the finding of nonadherence among patients prescribed lower dosages is difficult to interpret. It could be an artifact of treatment history—these patients may have had a history of noncompliance, leading psychiatrists to prescribe lower dosages. Or the lower dosages could be less effective, causing patients to “make a reasoned choice” to discontinue medication, Olfson said.

Sohler told Psychiatric News that social and occupational functioning is likely to be influenced by too many other factors for medication dosage alone to produce an effect. “We believe appropriate treatment that includes recommended antipsychotic dosing should impact social and occupational functioning and service utilization,” she said. “However, these outcomes are generally associated with a complex interplay among social context, resource availability, and treatment decisions, in addition to medication use. Adherence to medication dosage guidelines alone is not likely to result in strong effects on these outcomes. It is also likely that a longer follow-up period is needed to detect changes in these outcomes.”

John Kane, M.D., executive director of the Zucker Hillside Hospital in New York, emphasized the difficulty of interpreting both the surprising findings of greater nonadherence and fewer side effects among patients receiving low dosages, as well as the poorer outcomes among those receiving higher dosages.

“Nonadherence is a difficult thing to evaluate in terms of what causes it,” he told Psychiatric News. “This study demonstrates just how complicated adherence is—we shouldn’t just assume that if we diminish side effects, we will improve adherence.”

Because the patients in the study were not randomly assigned to the different dosage levels, Kane said, it is likewise difficult to interpret the finding of greater symptom severity among patients receiving the higher dosage.

“It is possible that the patients who were given the higher dosages needed those dosages to achieve the same clinical status at discharge as those who received the lower dosages,” Kane said. “Those patients who required the higher dosage at discharge had higher BPRS scores at follow-up. But it is difficult to tease out a cause and effect. Can we say they had higher scores because they were receiving higher dosages? Or were they a subgroup that required the higher dosage and even with that higher dosage experienced more severe symptoms?”

Kane said the latter supposition is supported by the fact that those patients were more likely to have frequent hospitalizations and to be receiving both oral and depot medications.

“It just shows that these are not simple relationships,” Kane said. “In order to understand all the variables that may explain these relationships, we need randomized trials where the variables can be controlled and manipulated.”

Kane added that clinical research data on how to manage patients who are more severely ill and less responsive to treatment are lacking.

“Certainly, guidelines are useful and should be the rule rather than the exception,” Kane said. “One of the things the study shows is that there are no advantages to higher dosages, though they may be necessary for some patients.”

Sohler also noted that the study was undertaken before second-generation antipsychotic medications became widely available. “It will be important to monitor how the newer generation of antipsychotic medications impacts a number of patient outcomes across a range of domains over time,” she said. “A systematic evaluation of long-term treatment outcomes across different patient groups is very important to help clinicians, patients, and their families understand better their treatment options.

“Understanding why deviations occur in recommended dosing regimens needs further study,” she added. “Clinical decision making must consider patient preferences, family and residential staff considerations, treatment resistance, as well as psychiatrists’ judgments of dosage related to issues of symptom control, safety concerns, and optimal functioning.”

The study, “Antipsychotic Dosage at Hospital Discharge and Outcomes Among Persons With Schizophrenia,” is posted on the Web at http://ps.psychiatryonline.org/cgi/content/full/54/9/1258?. ▪

Psychiatr Serv 2003 54 1258