White matter changes associated with antipsychotic treatment in first-episode psychosis

Philip R. Szeszko, Delbert G. Robinson, Toshikazu Ikuta, Bart D. Peters, Juan A. Gallego, John Kane, Anil K. Malhotra

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


Second-generation antipsychotics are utilized extensively in the treatment of psychotic disorders and other psychiatric conditions, but the effects of these medications on human brain white matter are not well understood. We thus investigated the effects of second-generation antipsychotics on white matter integrity using tract-based spatial statistics in patients experiencing a first episode of psychosis with little or no prior antipsychotic exposure, and how potential changes were associated with metabolic side effects. Thirty-five (26 men/9 women) patients experiencing a first episode of psychosis received diffusion tensor imaging (DTI) exams, clinical assessments, and provided fasting blood samples at the onset of antipsychotic treatment, and then again after 12 weeks of treatment with either risperidone or aripiprazole in a double-blind randomized clinical trial. In addition, 35 (26 men/9 women) healthy volunteers received DTI exams at a baseline time point and then after 12 weeks. Patients demonstrated significant (p<0.05; family-wise error corrected) fractional anisotropy reductions within the parietal and occipital white matter following antipsychotic treatment. Greater overall fractional anisotropy reduction was significantly correlated with greater increases in low-density lipoprotein. There were no significant fractional anisotropy increases among patients following treatment. Moreover, healthy volunteers did not demonstrate either significant increases or decreases in fractional anisotropy across a comparable 12-week interval. The use of antipsychotics may be associated with a subtle loss of white matter integrity that is related to greater side effects, thus raising potentially important considerations regarding risk/benefit in their usage. Limitations of the current study, however, include a prior history of substance use among patients and our inability to exclude the possibility of disease progression.

Original languageEnglish
Pages (from-to)1324-1331
Number of pages8
Issue number6
StatePublished - May 2014
Externally publishedYes


  • antipsychotic
  • diffusion tensor imaging
  • first-episode psychosis
  • white matter


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