Long Term Antipsychotics – Adverse Effects on Brain?

AntipsychoticsThis post is a bit off topic. I have tried to not focus on medication issues in this blog on the grounds that there are many, many websites that talk about medications and very little else.

However one of the blog’s most loyal readers sent in an email about long term antipsychotic medications and potential adverse effects on brain function and I decided to take the opportunity to review the literature on the topic.

This brief overview is based on a literature search of all articles that matched the search criteria “psychosis – drug treatment” and “long term care” (LTC is the best search term to approximate long term outcome).

In order to limit the review I did not look at the many, many other uses of antipsychotics (other than psychosis)… I looked just at schizophrenic and schizoaffective patients treated and followed for at least 2 years and up to 10 years ( which is the length of the longest study we have that looks at brain structure and function).

BIG CAVEAT: This review does not address people with bipolar and treatment resistant depression – but note also that we have even fewer studies looking at long term outcomes with antipsychotics for those conditions…

Here are my conclusions –

  1. Both relapse and antipsychotics are associated with brain volume reductions. The effect of relapse appears somewhat greater (1). As the authors of the largest study on this question notes, this puts clinicians in a tricky dilemma. Essentially, it says that if you know that someone is at low risk of relapse your should consider reductions or discontinuation of medication, but knowing that is not really possible.
  2. Quality of Life appears overall better in schizophrenic patients on longer term antipsychotics. This finding is based on the most unbiased source in medicine – the Cochrane Reviews (2).
  3. Haloperidol seems to be the worst in terms of brain effects. Some atypicals, especially olanzapine, might have fewer negative effects. The evidence of better effects from some agents is not strong, although the haloperidol versus olanzapine comparison came from one of the largest studies. Another study suggested that, at least for quetiapine, higher doses were worse… However the authors didn’t do the obvious control for effects of worse positive psychotic symptoms, which would be expected to drive higher doses. (3, 4).
  4. Overall there does appear to be dose response relationship. Higher doses for longer periods of time are associated with greater changes, even controlling for severity of illness. (3)
  5. In first episode patients who achieve a full remission (they have no psychotic symptoms at all) longer term outcomes appear better if there is a trial of dose reduction or discontinuation. (5). We puzzled over this study for quite a while since it seems at odds with the Cochrane Review. But then the solution to the puzzle presented itself, this refers to a subset of all patients with first onset psychosis, those whose symptoms go away entirely. We do know that the odds of another episode are very high, but it appears that the negative effects of medications in that group may outweigh the positive effects of reducing the risk of another episode of psychosis.
  6. Older patients should especially have a thoughtful review of the use of antipsychotics because the benefits may be lower than in younger patients, and the negative effects are clearly greater. This is especially true because for most conditions that antipsychotics are used to treat there is a reduction of acute symptoms later in life for many patients. (6)



(1) Relapse Duration, Treatment Intensity, and Brain Tissue Loss in Schizophrenia: A Prospective Longitudinal MRI Study. Am J Psychiatry 2013; 170:609–615.

(2) Maintenance treatment with antipsychotic drugs for schizophrenia (Review). Cochrane Reviews. 2012.

(3) Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews 37 (2013) 1680–1691.

(4) Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms. International Journal of Neuropsychopharmacology (2011), 14, 69–82.

(5) Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy. JAMA Psychiatry. 2013;70(9):913-920.

(6) Comparison of Long Term Safety and Effectiveness of Four Atypicals in Patients Over 40. J Clinical Psychiatry. 74: 10 – 18. 2013.