The link between myelination, psychosis and antipsychotics

The hypothesis that myelin alterations play a critical role in the development of psychosis is receiving increasing scientific interest. Studies also suggest that dopamine antagonists, particularly long-acting injectables, are associated with a remyelination effect and that this effect is correlated with improvement in clinical symptoms in patients with schizophrenia, as reported at WSFBP Virtual 2021. 

It has been hypothesised that myelin alterations are a critical factor in the development of psychosis, and there is increasing evidence for a central role of white matter pathologies in schizophrenia, explained Professor Paolo Brambilla, University of Milan, Pathophysiology and Transplantation, Italy.

Myelin alterations could be critical in the development of psychosis

Abnormal white matter integrity has been reported among drug-naïve, first episode schizophrenia patients and has been associated with negative symptoms and cognitive impairment.1

More specifically, psychotic symptoms in patients with schizophrenia have been associated with integrity of the frontal fasciculi, and in these patients, six weeks of short-acting dopamine receptor blockade had a remyelinating effect, normalizing the white matter.2

Dopamine antagonists, particularly long-acting injectables, are associated with a remyelination effect


Long-acting injectables may have a more pronounced effect on white matter

Long-acting injectables (LAIs) may have a more pronounced effect on white matter volume than oral antipsychotics. In a study evaluating frontal lobe white matter volume after six months of treatment with a LAI or an oral antipsychotic, the volume of frontal lobe white matter remained stable in patients treated with the LAI but decreased in those treated with the oral antipsychotic.3


Increased myelination correlates with improvement in negative symptoms

These myelination effects are clinically meaningful, as was demonstrated in preliminary results of a study from Professor Brambilla’s group, which evaluated changes in symptomology in 10 patients with affective and non-affective psychosis, who were treated with an LAI, and the correlation with myelin water fraction changes over 12 months.

Results showed that reductions in negative symptoms evaluated by the Positive and Negative Syndrome Scale (PANSS) correlated with increased myelination in several regions of the brain over time, including in the corpus callosum, the internal capsule, and particularly, in the inferior frontal occipital fasciculus.4

Increased myelination correlated with improvements in the PANSS

Many psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia, depression and bipolar. This may indicate that psychiatric symptoms and treatments may share a common mechanism, making myelin a potential novel and innovative therapeutic target in psychiatry.5

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


  1. Zeng B, et al. Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment. Schizophr Res. 2016;172:1-8.
  2. Ebdrup BH, et al. Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade. J Psychiatry Neurosci. 2016;41:133-41.
  3. Bartzokis G, et al. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011;132:35-41. 
  4. Brambilla P. University of Milan, Italy. Preliminary results. Presented at WSFBP Virtual 2021.
  5. Bartzokis G. Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments. Neuropharmacology. 2012;62:2137-53.