Antipsychotic Medications Cause Loss of Brain Volume
Objective To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change.
Design Predictors of brain volume changes were assessed prospectively based on multiple informants.
Setting Data from the Iowa Longitudinal Study.
Patients Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (2 and as many as 5) over 7.2 years (up to 14 years).
Main Outcome Measure Brain volumes.
Results During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted.
Conclusions Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.
From press release:
Patients with schizophrenia who take antipsychotic medications appear to lose a small but measurable amount of brain tissue over time, according to a report in the February issue of Archives of General Psychiatry, one of the JAMA/Archives journals.
Schizophrenia affects 1 percent of the worldwide population and remains a leading cause of chronic disability among young adults, according to background information in the article. Progressive changes in brain volume observed in patients with schizophrenia have been thought to be an effect of the disease. "However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement," the authors write. "Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain."
Beng-Choon Ho, M.R.C.Psych., and colleagues at University of Iowa Carver College of Medicine, Iowa City, studied 211 patients with schizophrenia who underwent repeated neuroimaging beginning soon after their illness. Each patient had an average of three magnetic resonance imaging (MRI) scans over 7.2 years, for a total of 674 scans. The authors then assessed the relative contributions of four predictors -- illness duration, antipsychotic treatment, illness severity and substance abuse -- on changes in brain volume over time.
Patients who were followed for longer periods of time experienced more reductions in brain volume. Antipsychotic treatment was also associated with brain tissue reduction after controlling for the other three predictors. More intense antipsychotic treatment was associated with overall measures of brain tissue loss, smaller gray matter volume and progressive declines in white matter volume.
The other two variables, illness severity and substance abuse, had no or minimal association with brain changes after the effects of illness duration and antipsychotic treatment were considered.
"Findings from the present study raise several clinical questions. Are antipsychotic-associated gray matter and white matter volume reductions 'bad' for patients?" the authors write. Although they are assumed to be undesirable, the benefits of long-term treatment may outweigh the risks, they note. "However, our findings point toward the importance of prescribing the lowest doses necessary to control symptoms."
In addition, the results raise concerns about the use of antipsychotics for people who do not have schizophrenia, including children, older adults and patients with bipolar or depressive disorders.
"Antipsychotics are effective medications for reducing some of the target clinical symptoms of schizophrenia: psychotic symptoms. In medicine we are aware of many instances in which improving target symptoms worsens other symptoms," the authors conclude. "It is possible that, although antipsychotics relieve psychosis and its attendant suffering, these drugs may not arrest the pathophysiologic processes underlying schizophrenia and may even aggravate progressive brain tissue volume reductions."
Editorial: Results Highlight Need for Close Monitoring, Other Treatment Options
"Although proof that antipsychotic medications cause reductions in brain volume in individuals with schizophrenia remains elusive, the findings of Ho and colleagues, in concert with those of the aforementioned animal studies and prior reports in humans, raise the important question of the clinical significance of the observed brain volume changes," writes David A. Lewis, M.D., of the University of Pittsburgh, in an accompanying editorial.
"A classic maxim in clinical medicine is to treat the patient, not the laboratory test -- or in this case, the MRI," Dr. Lewis writes. "Thus, the findings of Ho and colleagues should not be construed as an indication for discontinuing the use of antipsychotic medications as a treatment for schizophrenia. But they do highlight the need to closely monitor the benefits and adverse effects of these medications in individual patients, to prescribe the minimal amount needed to achieve the therapeutic goal, to consider the addition of non-pharmacological approaches that may improve outcomes and to continue the pursuit of new antipsychotic medications with different mechanisms of action and more favorable benefit to harm ratios."
B.-C. Ho, N. C. Andreasen, S. Ziebell, R. Pierson, V. Magnotta
Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia
Archives of General Psychiatry,
University of Iowa Carver College of Medicine.