While atypical anti-psychotics are a vital part of treating disorders with psychotic features, including bipolar disorder (BD), they do come with a significant side-effect profile that still, very much, has to be taken into account. The possible side effects such as weight gain and tardive dyskinesia are well-documented. However, findings in a recent cross-sectional study by Birner et al. (2020) have shown a significant association between atypical anti-psychotics and reduced gray matter volume in long-term use of these drugs by BD patients.
The notion that mood stabilizing drugs have an effect on overall brain circuitry and volume is not new. As it turns out, anti-epileptic medications are associated with greater rates of cortical thinning (Hibar et al., 2016). Conversely, lithium appears to confer neuroprotection, whereby lithium is associated with increased thalamic volume (and possibly, hippocampal volume) (Lyoo et al., 2010).
Additionally, a study of long-term anti-psychotic use in schizophrenic patients was also found to be associated with decreases in brain volume in all regions of the brain bar the cerebellum (Ho et al., 2011). However, in the middle of that study, the patients were subject to shifts in treatment from primarily typical anti-psychotics to their atypical counterparts, making these findings less than conclusive.
What this most recent study by Birner’s team investigated was specifically atypical anti-psychotics, through conducting T1-imaging MRI in bipolar patients who either were or were not taking atypical anti-psychotics (AAPs).
From these derived images, they computed total gray matter volumes for the patients. What they found was that the BD patients on atypical anti-psychotics had substantially lower total gray matter volumes than their counterparts not on the AAPs.
These findings were made after controlling for various potential confounding variables such as BMI, and concurrent use of the other two medications (namely, anti-epileptics and lithium). Therefore, there is something at hand there regarding the AAPs and resultant gray matter volume..
Theorized Mechanisms Underlying Decreased Gray Matter Volume
The question is whether this gray matter loss was a reflection of the atypical anti-psychotic itself, or simply an intrinsic manifestation of the sheer severity of the bipolar disorder in patients on this class of drug. (It is generally reserved for more severe cases of BD).
It must be noted that BD patients undergo fewer brain changes than their schizophrenic counterparts, and any abnormal findings in brain imaging and volume for BD patients may be less attributable to the condition itself, and more largely attributable to external factors, namely, the AAPs.
One potential mechanism postulated by the authors for this loss in gray matter was based on findings in another study in which monkeys who were administered the AAP olanzapine had a notable decrease in cortical matter. This may have been attributable to the mechanism of action underlying anti-psychotics, which block dopamine (D2) receptors.
It may be that the blockade of these D2 receptors may lead to an increase in dopamine turnover, and subsequent generation of free radicals which may elicit neurodegeneration secondary to oxidative damage (Vernon et al., 2012).
The authors propose another mechanism postulated in another study in which risperidone (another AAP) in mice elicited the remodeling of GABAergic neurons in the medial prefrontal cortex, which led to alterations in the synaptic connections of neurons in this region of the brain. This may lead to alterations in the capacity of neuroplasticity, which perhaps, may render an increase susceptibility to brain volume decreases (Mackowiak et al., 2009).
However, there are still so many questions that remain. What is the actual mechanism underlying this (potential) phenomenon? Why is it that lithium is neuroprotective, as opposed to anti-epileptics and now, AAPs, which appear to elicit reductions in total gray matter? There is a great deal of further research that is needed to elucidate the exact mechanisms underlying such findings.
Clinical Implications Outlined
As it stands, atypical anti-psychotics are still very much an essential treatment for very severe psychotic conditions such as schizophrenia and bipolar disorder. While the reductions in gray matter volume potentially add another unwanted side effect to the mix, we must remember that the benefits of these drugs still greatly outweigh the side effect profile in these patients.
These psychotic conditions are life-threatening in and of themselves, and so must still receive the priority when weighing up treatment options. However, the key is weighing up the costs and risks, and reconciling the two by the judicious use of these medications, using the lowest effective dose, and monitoring their patients every step of the way.
Ideally, as more research goes into the potential neurobiological effects of these drugs, we can further modify and optimize them in such a way that we minimize these effects, and make them even more effective and tolerable treatment options for conditions which are still much too common today.
Birner, A., Bengesser, S. A., Seiler, S., Dalkner, N., Queissner, R., Platzer, M., … Reininghaus, E. Z. (2020). Total gray matter volume is reduced in individuals with bipolar disorder currently treated with atypical anti-psychotics. Journal of Affective Disorders, 260, 722–727. doi: 10.1016/j.jad.2019.09.068
Hibar, D. P., Westlye, L. T., van Erp, T. G., Rasmussen, J., Leonardo, C. D., Faskowitz, J., … & Dale, A. M. (2016). Subcortical volumetric abnormalities in bipolar disorder. Molecular psychiatry, 21(12), 1710.
Ho, B.-C., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. (2011). Long-term Anti-psychotic Treatment and Brain Volumes. Archives of General Psychiatry, 68(2), 128. doi: 10.1001/archgenpsychiatry.2010.199
Lyoo, I. K., Dager, S. R., Kim, J. E., Yoon, S. J., Friedman, S. D., Dunner, D. L., & Renshaw, P. F. (2010). Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology, 35(8), 1743.
Maćkowiak, M., Dudys, D., Chocyk, A., & Wedzony, K. (2009). Repeated risperidone treatment increases the expression of NCAM and PSA-NCAM protein in the rat medial prefrontal cortex. European Neuropsychopharmacology, 19(2), 125-137.
Vernon, A. C., Crum, W. R., Lerch, J. P., Chege, W., Natesan, S., Modo, M., … & Kapur, S. (2014). Reduced cortical volume and elevated astrocyte density in rats chronically treated with anti-psychotic drugs—linking magnetic resonance imaging findings to cellular pathology. Biological psychiatry, 75(12), 982-990.