Antipsychotics and Loss of Brain Matter

What are antipsychotics doing in your brain besides preventing psychosis? This is a report on a study conducted from 1991 to 2009 that looked at that question.

Here is the context:

Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics... 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.

Before I get to what the study revealed, here is the investigator, National Medalist of Science winner, Nancy Andreasen.

Note: The interview was recorded twenty-five+ years after the study began and reflects a development in the questions pursued.

Objective of the study:

To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change.

What they did:
  • Over nearly 20 years, the investigators followed 211 patients with schizophrenia, beginning shortly after the first psychotic episode. The patients answered surveys, as did their family members, about their general functioning (measured by Global Assessment Scale), their medication use, and their substance use. They received 2-5 MRI scans over time.
  • The investigators then compared brain volumes and cerebrospinal fluid volumes for each patient over time. [Brain volume and fluid volume are inversely proportionate. Fluid fills the space inside the skull where there isn't grey matter or white matter.]
  • They controlled for each of the variables: illness duration, antipsychotic treatment, illness severity, and substance use.
  • They also compared results for different antipsychotics in three classes: clozapine, typical antipsychotics not clozapine, and atypicals. [Over the course of the study, prescribing practices shifted away from the earlier meds to the atypicals. The investigators converted all medication dosages to the equivalent dose of clozapine in order to standarize dosage.]

What they found:
  • Schizophrenia, the disease itself is progressive. Independent of severity, treatment, or substance use, it is associated with loss of brain matter. Duration of follow-up was associated with loss of total cerebral tissue and other specific regions. [Refer to the study for details.]
  • Antipsychotic treatment (independent of severity, duration, or substance use) also was associated with loss of cerebral volume. There were also areas (white matter) where the effect was magnified with treatment over time. Higher doses were also associated with greater effects. [Again, refer to the study for details.]
  • Severity of illness (independent of duration, treatment, or substance use) was associated with loss of cerebral and frontal volumes.
  • Substance use was not associated with any brain volume changes (independent of severity, treatment, or duration). Note: The numbers of this cohort were smaller, 31.7% of the sample.
  • Different classes of antipsychotics all had the effect of lower brain volume. There were variations in the areas affected depending on the medication class .

  • The investigators remind readers that association does not necessarily imply causation. There may be something else going on here that the study does not take into account.
  • The study is limited by ethical considerations. It was not possible to have a control group that received no treatment at all, nor to give antipsychotics to people who do not have schizophrenia.
  • Nevertheless, the study finds confirmation in other studies of brain matter loss in both humans and macaque monkeys who received antipsychotics.

Questions raised by the investigators:
  • Are these volume reductions "bad" for patients? 
Given that patients begin with brain volume deficits and that the disease progression will add to them, the assumption is that they can't be good. [The present author notices that the changes occur in the frontal lobes. Schizophrenia causes problems with cognition, which would seem to be connected to those changes.]
  • What is the mechanism for these changes?
This is a current area of research, but has not been demonstrated yet. The fact that antipsychotics produce changes in the brain similar to the changes produced by the disease itself suggests interesting areas of investigation regarding the disease process itself.
  • How does this information shift the cost/benefit ratio?
These medications have immensely improved the quality of lives of people with schizophrenia. They are effective for what they are intended to do. Anti+psychotic. They address the positive symptoms of schizophrenia, the psychosis. They do not seem to address the underlying disease mechanism and may contribute to the progressive problem.


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. Hormone therapy relieves menopausal symptoms but increases stroke risk... 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.

Should you take antipsychotics?

No way in hell am I going to answer that question.

I do have some thoughts. First:

You can get that t-shirt from CafePress. thanks to Jerod Poore for creating it.

Schizophrenia is a terrible disease. While there is a range of severity, most people are not able to function without these medications. A little more brain loss (the disease itself will cost you) or a life in the hospital/jail/the streets. What a horrible choice to have to make.

That said, there are people who live happy, fulfilling, productive lives, independent and well-employed despite the challenges of this condition. I know some of them personally. They don't get a lot of press. But come back next week for their stories. There is hope. There is promise.

Oh yes, and they take their meds.

Andreasen recommends using the lowest effective dose, since the amount of loss is dose and duration dependent. That makes immanent sense to me. The dose prescribed in the hospital sometimes is not adjusted once the crisis has passed. Dosage level is an issue worth pursuing with your doctor.

Andreasen also raises concerns about the increasing use of antipsychotics for off-label purposes, including children who may be at risk for schizophrenia, the elderly for tranquilizing purposes, and people with bipolar and depression, issues of cost/benefit analysis beyond the scope of the study and beyond the scope of this post.

Closing reflections

This is how basic science works. This is one study. It built on similar studies and adds to their confirmation. It is one piece of the puzzle that will contribute to an understanding of how the brain works. While it was not designed to invent a treatment, it does have preliminary implications for treatment protocols.

I will continue to post about schizophrenia, the people who live with it, and I hope, more on the people involved with this study. Keep your stick on the ice. We're all in this together.

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