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Ten years ago, in 2011, Dr. Beng-Choon Ho and colleagues, including Nancy Andreasen, a distinguished schizophrenia researcher, published a study of 211 first-episode psychosis patients whom they had followed for an average of 7 years. During that follow-up, these patients had at least 2 MRI scans, some as many as 5. Their widely published finding was that more antipsychotic treatment was associated with smaller gray matter volumes. Was this because patients with more severe illness received more antipsychotics? Were the brain volume reductions due to the illness or the treatment?
Hi! Jim Phelps here for the Psychopharmacology Institute. That was 2011. Do we have more insight now 10 years later? Here’s a review article on that subject from Chengmin Yang and colleagues. They gathered 36 studies with data on brain volumes and antipsychotic doses. The result is not clear. Overall, the data go in different directions depending on which region of the brain is examined, which antipsychotic was used, and the duration of psychosis before treatment. A few regions even appeared to increase in volume in association with antipsychotic use. Among the most recent studies, some used functional MRI to look at brain networks and fractional anisotropy to look at white matter volumes, but the outcomes were no clearer there either.
One finding that emerges from Yang and colleagues’ review is that if antipsychotics do indeed cause brain volume losses, the effect is dose related. So, use the lowest effective dose.
Well, that doesn’t get you anywhere, does it? Of course, you’re already trying to find that lowest dose, if only to minimize side effects and tardive dyskinesia risk. Maybe these brain data provide one more reason to do so.
What’s not so clear is how aggressively one should attempt to taper antipsychotics after first-episode psychosis. If the illness is severe enough to warrant antipsychotic treatment in the first place, then too early a discontinuation carries its own risks, including everything that can be lost through recurrence of severe psychosis, such as a person’s relationships, job, education, and financial security. On the other hand, given that there are multiple reasons to try to taper an antipsychotic, including the possibility that it can cause brain volume losses, when should that begin and how fast should it go? Well, patients take this decision into their own hands all the time, right? Yet some data would help in trying to forecast for them the risks of stopping on their own.
Enter HAMLET—not Shakespeare’s Hamlet, but the Netherlands’ HAMLETT. This is an acronym for a study called Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment, a single-blind study being led by a whole slew of mostly Dutch investigators. This study seeks to compare antipsychotic continuation vs tapering and discontinuation. The article in which they described the trial’s protocols is entitled, “To Continue or Not to Continue”. Get it? Hamlet—to be or not to be, right? The study is slated to be completed in 2026. They started recruiting their intended initial 200 patients in 2017. Perhaps we’ll see some interim data, but otherwise, we’ve got a while to wait.
One more statement of the relatively obvious: It’s ironic that studies we conduct to look for potential harm from our treatments like antipsychotics and possible effects on brain volume can be used to lambast us. At the same time, though, we really need to listen to our critics and continue to search for data that support their concerns, not just data supporting our longstanding practices. Clearly, results must be handled carefully to avoid causing undue fear for patients and families regarding treatments that might at a particular moment be far better than no treatment for avoiding disastrous consequences. Balancing risk and benefit is clearly complex here in this realm. No one should oversimplify it.
In summary, this new review of studies with long-term brain imaging and antipsychotic exposure does not really move the needle regarding risks and benefits of these medications. It does illustrate how hard it is to determine the potential risks of long-term antipsychotic use. There were reasons to minimize antipsychotics even without brain imaging, but how fast to proceed and whether to continue or not to continue, that is the question.
For more on this, you might try a responsible description of the Critical Psychiatry Network’s perspective on psychosis by 2 of its proponents, Drs. Moncrieff and Middleton. The full text is linked here in the Psychopharmacology Institute.
Abstract
A large number of neuroimaging studies have detected brain abnormalities in first-episode schizophrenia both before and after treatment, but it remains unclear how these abnormalities reflect the effects of antipsychotic treatment on the brain. To summarize the findings in this regard and provide potential directions for future work, we reviewed longitudinal structural and functional imaging studies in patients with first-episode schizophrenia before and after antipsychotic treatment. A total of 36 neuroimaging studies was included, involving 21 structural imaging studies and 15 functional imaging studies. Both anatomical and functional brain changes in patients after treatment were consistently observed in the frontal and temporal lobes, basal ganglia, limbic system and several key components within the default mode network (DMN). Alterations in these regions were affected by factors such as antipsychotic type, course of treatment, and duration of untreated psychosis (DUP). Over all we showed that: (a) The striatum and DMN were core target regions of treatment in schizophrenia, and their changes were related to different antipsychotics; (b) The gray matter of frontal and temporal lobes tended to reduce after long-term treatment; and (c) Longer DUP was accompanied with faster hippocampal atrophy after initial treatment, which was also associated with poorer outcome. These findings are in accordance with previous notions but should be interpreted with caution. Future studies are needed to clarify the effects of different antipsychotics in multiple conditions and to identify imaging or other biomarkers that may predict antipsychotic treatment response. With such progress, it may help choose effective pharmacological interventional strategies for individuals experiencing recent-onset schizophrenia.
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Reference
Yang, C., Tang, J., Liu, N., Yao, L., Xu, M., Sun, H., … & Lui, S. (2021). The Effects of Antipsychotic Treatment on the Brain of Patients With First-Episode Schizophrenia: A Selective Review of Longitudinal MRI Studies. Frontiers in Psychiatry, 12:593703.
Related References
- Ho, B. C., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. (2011). Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68(2), 128–137.
- Begemann, M., Thompson, I. A., Veling, W., Gangadin, S. S., Geraets, C., van ‘t Hag, E., Müller-Kuperus, S. J., Oomen, P. P., Voppel, A. E., van der Gaag, M., Kikkert, M. J., Van Os, J., Smit, H., Knegtering, R. H., Wiersma, S., Stouten, L. H., Gijsman, H. J., Wunderink, L., Staring, A., Veerman, S., … Sommer, I. (2020). To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial. Trials, 21(1), 147.
- Middleton, H., & Moncrieff, J. (2019). Critical psychiatry: a brief overview. BJPsych Advances, 25(1), 47-54.
