Long-term Antipsychotic Treatment and Brain Volumes

Abstract

Context Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. 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. 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.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium

“…Notably, when we used current medication in CPZ equivalent units as a quantitative measures of antipsychotic medication (at the cost of a reduced sample size), an effect on MOFC thickness was not observed. While past studies predominantly reported volume and thickness deficits in frontal brain regions in patients treated with typical compared with those treated with atypical antipsychotics or unmedicated patients (van Haren et al 2011;Lesh et al 2015;Vita et al 2015), there have also been many conflicting findings (Cahn et al 2002;Ho et al 2011). Attempting to reconcile previous reports, it has been suggested that antipsychotic medication effects on brain structure might be substance specific (Xiao et al 2008) and might also depend on illness chronicity and the duration of untreated psychosis.…”

Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

“…In addition, widespread cortical thinning of the cerebral cortex involving not just frontotemporal regions but also parietal and occipital regions has been demonstrated in individuals with schizophrenia compared with healthy controls (Nesvåg et al, 2008;Sprooten et al, 2013). It remains unclear whether these progressive changes are inherent to the pathophysiological disease processes underlying schizophrenia or whether they are related to or are accelerated by treatment with antipsychotic agents or other illness-related factors (Ho et al, 2011;Zipursky et al, 2013).…”

Is There Evidence for the Bipolar Spectrum and the Safety of Pharmaceutical Interventions?

“…Ho, Andreasen, Ziebell, Pierson, and Magnotta (2011) recently published the results of their 14 year study in which they used images of the brains of first episode psychotic patients treated with antipsychotic (anti-dopaminergic) drugs over time (average of 7 years). They documented a notable "brain tissue volume decrement" associated with both atypical antipsychotics (quetiapine, risperidone, aripiprazole, olanzapine, clozapine, ziprasidone) and traditional neuroleptics (old drugs such as chlorpromazine).…”

“…These growth factors are vital for the health of the brain (Schwartz & Schechter, 2011;Swartz & Ziv, 2008). In reviewing the data, Ho et al (2011) acknowledged that a cost/benefit analysis might justify the use of antipsychotics for treating schizophrenia but they questioned the use of antipsychotics in mood disorders.…”

“…Even before the Ho et al's (2011) publication of the data on the brain volume decrement associated with antipsychotics, some people did become alarmed at the use of adult medications in children. Allen Frances, the previously cited co-Chairman of the DSM-IV, explaining why he was moved to become a crusader said,"kids getting unneeded antipsychotics that would make them gain 12 pounds in 12 weeks hit me in the gut.…”