Schizophrenia is a severe mental disorder affecting around one percent of the population worldwide, and is notoriously difficult to treat. Current treatments successfully target the disorder’s positive symptoms, such as hallucinations and delusions. However, they are unable to treat negative symptoms, such as lacking motivation and social withdrawal, or cognitive symptoms, such as problems with attention or memory, which determine the long-term functional outcome of patients.

In order to develop effective treatments for the cognitive symptoms of schizophrenia, it is essential to understand the biological mechanisms behind them. In a previous study, Florian Raabe, leader of the Project Group Translational Deep Phenotyping at the Max Planck Institute of Psychiatry in Munich, and Michael Ziller from the University of Münster had already established that induced pluripotent stem cell-derived neurons from patients with schizophrenia showed synaptic deficits, and therefore may be involved in the cognitive symptoms of the disorder. These cells are made by collecting mature cells from patients, for example through a blood draw. These cells are then “reprogrammed” back to their pluripotent state, from which they can be differentiated to become any cell type in the body.

Clinical and cellular data

In their study, Florian Raabe, Michael Ziller and their teams aimed to show that the degree of synaptic impairment observed in vitro correlated with the cognitive impairments seen in vivo. To do so, the researchers combined two sets of data: First, MRI, EEG and cognitive testing data from over 400 patients and healthy controls. Second, the researchers gathered data on gene expression and synaptic density, based on induced pluripotent stem cell-derived neurons from 80 donors within this larger cohort. This allowed them to analyze clinical and cellular data from the same patients.

“Combining this data allowed us to show, for the first time, that the level of synaptic impairment seen on the cellular level actually predicted the level of cognitive impairment seen in the patient”, Raabe explains. “This is the first time we have been able to show an intraindividual mechanistic explanation for the cognitive symptoms seen in schizophrenia”. Raabe and his team hypothesize that genetic predispositions lead to reductions in synaptic density, which contribute to more wide-spread alterations in the brain, potentially amplified by environmental factors. These alterations then contribute to schizophrenia’s cognitive symptoms.

Bridging this translational gap between cellular and clinical data in schizophrenia is central to developing more targeted treatments. Since neurons derived from induced pluripotent stem cells essentially only require a blood draw from patients, these findings hold great promise for future biomarker discoveries as well as for patient stratification, in order to better understand who responds to which treatment and why.

Read the original research study here: 10.1001/jamapsychiatry.2026.0576

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Impaired decision-making in schizophrenia and OCD

These problems can be particularly pronounced in people with certain mental health conditions. Patients with schizophrenia tend to make hasty decisions and place excessive confidence in them—a cognitive bias known as jumping to conclusions, which is closely linked to the formation of delusions. In contrast, obsessive-compulsive disorder (OCD) is marked by persistent doubt. Individuals with OCD may spend hours gathering information, even when faced with relatively simple decisions.

Even though these decision-making difficulties cause significant distress, they have hardly been treated in a targeted manner to date, and the underlying brain processes in schizophrenia and obsessive-compulsive disorder remain unclear. This is precisely what the research project aims to change. “Our goal is to decode the neural mechanisms that lead to these distorted thought patterns and to develop new therapies for treating the symptoms using state-of-the-art computational models,” explains Tobias Hauser, professor at Tübingen University Hospital and the project’s head. “We want to find out whether the symptoms in both conditions are caused by similar neural changes,” he adds. “By exploring the similar symptom patterns in both mental disorders, we also hope to help break the stigma that surrounds schizophrenia and OCD.”

A comprehensive research approach

The project, set to begin in February 2026, will combine different approaches: Using functional magnetic resonance imaging, the researchers aim to collect the largest dataset to date on indecision in obsessive-compulsive disorder and on jumping to conclusions in schizophrenia. In parallel, experiments with mouse models will examine how alterations in dopamine function during information gathering impact the brain networks involved in cognitive control. “We already know that dopamine plays various key roles in decision-making,” says Peter Dayan, Director at the Max Planck Institute for Biological Cybernetics, who will oversee the modelling of all research data—from mouse models to patient datasets. “It encodes unexpected changes in long-run outcomes, which is crucial for sculpting our behavior. However, the full picture of its roles, variability, and dysfunctions is still unclear.”

Improved therapies for better quality of life

In the long term, the project aims to contribute to the development of targeted therapies that directly address impaired decision-making. This could help both people who tend to jump to conclusions and those who get lost in endless thought loops.

The research initiative is set to run for five years. The University Medical Center Hamburg-Eppendorf, the National Institute Of Mental Health & Neuro Sciences in Bengaluru (India) and the Fundació de Recerca Clínic Barcelona (Spain) are also involved.

Founded in 1936, the Wellcome Trust invests nearly half a billion dollars annually in biomedical studies, particularly in basic research.

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Scientists showed that the genetic risk for schizophrenia accumulates not only in neurons, but also in oligodendrocytes. For the first time, they are now able to name a mechanism behind the cognitive disorders seen in schizophrenia. Several previous findings have linked impairments of oligodendrocytes and myelination with schizophrenia. The researches now wanted to know more about the morphology and properties of schizophrenia oligodendrocytes, specifically whether impairments are a secondary consequence of neuronal deficits or, at least in parts, genetically driven and cell-autonomous. 

Schizophrenia is a debilitating mental disorder affecting around 1 per cent of the population worldwide, and is notoriously difficult to treat. Current medications for schizophrenia can ameliorate positive symptoms, such as hallucinations and delusions. However, there is still a huge unmet medical need for treating negative symptoms, including social withdrawal and lack of motivation, and cognitive symptoms, including impaired attention and memory function. 

Peter Falkai, Director of the LMU University Hospital of Psychiatry and Director of the Research Hospital of the Max Planck Institute of Psychiatry (MPI), and his team led by former PhD student from the International Max Planck Research School for Translational Psychiatry (IMPRS-TP) Florian Raabe, established a rapid and robust protocol for induced-pluripotent stem cell (iPSC)-derived oligodendrocytes.

Oligodendrocytes are a type of cell in the nervous system that produce myelin, which insulates a neuron’s axon, thereby allowing signals to travel from neuron to neuron more quickly. The team collected blood samples from schizophrenia patients with clinical white matter impairments to produce iPSCs, which differentiated into oligodendrocytes in the cell culture. Schizophrenia patients seem to show widespread white matter disturbances. 

The scientists were curious about the morphology and properties of the schizophrenia oligodendrocytes. Surprisingly, the LMU team, alongside IMPRS student and first author of the recently published study Man-Hsin Chang, revealed a more complex morphology in these schizophrenia oligodendrocytes compared to iPSC-derived oligodendrocytes from healthy controls. These schizophrenia oligodendrocytes seemed to be more “mature” than the control oligodendrocytes in the cell culture, which is quite interesting as most postmortem studies show impaired oligodendrocytes and disturbed myelination in the brain of schizophrenia patients. 

The team hypothesized that this feature could indicate a “prematuration” phenotype in the early developmental stage of oligodendrocytes. The protocol used in this study allowed the team to look only at the early stages of development, which is quite different from the late stage of oligodendrocyte development seen in postmortem studies. 

“This current study is just a preliminary investigation, there are still many experiments to work on. First, we would need to increase the sample size to see if these findings are applicable to a bigger cohort. Second, we would like to know the functionality of these schizophrenia oligodendrocytes: Whether their myelination capability is impeded as well and how they interact with other cells”, Raabe explains. He is now Leading Senior Physician at the MPI Research Hospital and will continue his work in culturing these oligodendrocytes with iPSC-derived neurons or even generate three-dimensional spheroids or organoids to recreate the environment of human brains.

Looking back, Falkai now summarizes many years of successful research: “In the initial postmortem study 13 years ago I thought the interneurons must be involved, but never dreamed that there would be also a reduction of the oligodendrocytes. Although we still can not confidently answer the question whether oligodendrocyte pathology is mainly primary or secondary in schizophrenia, we believe that oligodendrocytes definitely play a pivotal role in the pathogenesis of schizophrenia and serve as a novel target to develop better treatments. The very first mechanism for cognitive disorders in schizophrenia that we found should hopefully be further investigated in the coming years. Moreover, we believe that schizophrenia is a heterogeneous disorder. We only studied samples from schizophrenia patients with white matter deficits: If these phenotypes are specific to a certain group of patients, it may imply a potential stratification of patients for personalized medicine in the future.”

Chang, MH., Waldeck, J.B., Stephan, M. et al. iPSC-modelling reveals genetic associations and morphological alterations of oligodendrocytes in schizophrenia. Transl Psychiatry 15, 287 (2025). Link

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Researchers at the Max Planck Institute of Psychiatry (MPI), Helmholtz Munich and the University of Sydney identified biological mechanisms that are shared across psychiatric disorders. To do so, the team analyzed postmortem brain tissue samples from the dorsolateral prefrontal cortex (DLPFC). The DLPFC is the center for reasoning and emotions in the brain, and is often implicated in psychiatric disorders. Samples from affected individuals, most of whom were schizophrenia patients, and healthy controls were included in the study.

What makes this study special: The research team combined several different layers of genetic data. “In contrast to studies that look at gene expression as a whole, we analyzed the exon level to better understand the structure of the genes. This detailed approach gave us a better understanding of how genetic variation influences disease risk”, first author Karolina Worf explains. 

Exons are the essential, information-containing segments of a gene. In addition to providing the blueprint for building proteins, they also determine which versions of a protein ultimately arise from a gene. This happens through alternative splicing, a process that occurs in over 95 percent of human genes.

Including the exon level in the analysis was an important step: While samples from psychiatric patients and healthy controls were not significantly different at the gene level, they were significantly different at the exon level. “The risk of developing a psychiatric disorder seems to therefore not just depend on what genes you have, but how your genes are expressed”, Janine Knauer-Arloth, leader of the Project Group Medical Genomics at the MPI, explains. 

The team integrated different genetic data, including variations in individual base pairs of DNA (single nucleotide polymorphisms, or SNPs), rare genetic variants and polygenic risk scores, which summarize a person’s disease risk by aggregating all relevant genetic variants. This way, the researchers discovered disruptions in pathways related to the circadian rhythm, the release of the stress hormone cortisol, and the neurotransmitter dopamine — across all three included disorders.

These results show that psychiatric disorders share a common biological basis. In the long-term, this knowledge can help researchers to classify psychiatric disorders not only based on symptoms, but also based on biological mechanisms. This paradigm shift is significant a step towards more precise diagnoses and treatment.

Worf, K., Matosin, N., Gerstner, N. et al. Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons. Transl Psychiatry 15, 153 (2025). Link

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Researchers analyzed the genetic connection of retinal cells and several neuropsychiatric disorders. By combining different datasets, they found that schizophrenia risk genes were associated with specific neurons in the retina. The involved risk genes suggest an impairment of synapse biology, so the ability of neurons to communicate with each other. This impairment might also be present in the brain of schizophrenia patients.

The retina is an outgrowth of the brain and shares the same genetics, making it an easily accessible way for scientists to study brain disorders. In a previous study, the Project Group Translational Deep Phenotyping at the Max Planck Institute (MPI) of Psychiatry, headed by Florian Raabe, found alterations in the retina of schizophrenia patients that became more severe with increased genetic risk. Accordingly, the researchers suspected that retinal alterations are not only a consequence of common comorbidities like obesity or diabetes, but might be caused by schizophrenia-driven diseases mechanisms directly.

If this is the case, knowing more about these alterations could help researchers understand the biological mechanisms behind the disorder. In addition to schizophrenia, retinal alterations have been observed in patients with bipolar disorder, depression, multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease and stroke. Using data from large studies in the literature, Raabe and first author Emanuel Boudriot (MPI of Psychiatry and LMU Munich) combined genetic risk data from neuropsychiatric disorders with retinal RNA sequencing data. This showed which risk genes were associated with different retinal cells in the above-mentioned disorders.

In two disorders, the data showed a clear connection: First, the genetic risk for MS was associated with retinal immune cells, in keeping with the autoimmune nature of the disorder. Second, risk genes for schizophrenia were associated with a specific class of retinal neurons, the amacrine cells. They are involved in synaptic function, and determine the ability of neurons to communicate with each other. To translate these findings from the cellular to the structural level, the researchers collaborated with Philipp Homan’s working group from the University of Zürich and used results from a UK-based biobank study, which had collected extensive biological data from over 36,000 healthy participants. In this sample, the research team found that the higher the genetic risk for schizophrenia, the thinner the synaptic layer in the amacrine cells was.

Accordingly, both at the cellular and the structural level, Raabe, Boudriot and colleagues showed that neuronal connectivity seems to be impaired in the retina of schizophrenia patients. “Finding this impairment in the eye suggests that processes in the retina and in the brain are very similar – this would make the retina a great proxy for studying neuronal disorders, because we can examine the retina of patients with a much higher resolution than the brain,” Raabe explains. Understanding the biological mechanisms should help researchers develop more effective and more individualized treatment options.

Jama Psychiatry (2025) Read More

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Researchers at the Max Planck Institute of Psychiatry analyzed EEG recordings with supervised machine learning to identify distinct neural signatures of schizophrenia, major depressive disorder, and abnormal aging. The analysis showed that it is possible to differentiate between these mental health conditions using resting-state EEG, and also introduced a novel normative Electrophysiological Age Gap Estimation (EphysAGE) model to measure brain aging processes in healthy people and patients with neuropsychiatric conditions.

Key highlights of the paper:

• Robust classification models separating schizophrenia and depression from healthy controls using EEG data.
• Identification of alpha power decreases as a predictive feature for schizophrenia and depression.
• The development of the EphysAGE model, revealing how aging processes affect the brain differently in mental health disorders.
• Insights into how aging impacts diagnostic separability, paving the way for potential clinical biomarkers.

Schizophrenia Bulletin (2025) Link

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In a new study, researchers discovered that the retina of schizophrenia patients differs from the retina of healthy participants. These changes could help psychiatrists to recognize who will have a particularly severe course of illness.

From an evolutionary perspective, the retina is an outgrowth of the brain and shares the same genetics. In illnesses such as schizophrenia, which is marked by genetic changes, the retina is an easily accessible alternative for researchers to study the central nervous system. First author Emanuel Boudriot from the Max Planck Institute of Psychiatry and his colleagues examined the retina of around 230 schizophrenia patients and healthy controls. They recorded the layers of the retina using light-based optical coherence tomography (OCT) and measured the electrical signals of the individual nerve cells.

“Our results show that some retinal layers were significantly thinner in schizophrenia patients, and electrophysiological signals were significantly altered,” study lead Florian Raabe explains. For the first time, scientists were also able to show that the retinal changes were particularly pronounced in more severely ill patients, and in patients with a higher burden of genetic risk factors. This correlation indicates that the retinal changes are caused by the disease itself and not only by other factors such as smoking, obesity or diabetes (which are generally more common in schizophrenia patients than in the rest of the population).

The cross-sectional study, now published in Biological Psychiatry, provides snapshots. Longitudinal studies are needed to confirm whether patients with pronounced retinal changes generally have a more severe illness progression. This involves following patients over a longer period of time, starting from the time of diagnosis. In the future, measuring the retina at the time of diagnosis could help psychiatrists to predict which patients are particularly at risk and require closer observation.

Emanuel Boudriot, Vanessa Gabriel, David Popovic, … Florian J. Raabe,
Signature of Altered Retinal Microstructures and Electrophysiology in Schizophrenia Spectrum Disorders Is Associated With Disease Severity and Polygenic Risk, Biological Psychiatry, 2024. Link

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Our nervous systems have left-right differences that are important for correct functioning. Handedness is probably the best-known asymmetry arising from the development of the nervous system. This is observed very early on: embryos of eight weeks already tend to move their right arms more often than their left arms. At this ‘age’ signals are not sent from the brain to the arms yet, but only from the spinal cord. A few weeks later, left-right differences also become visible in the shape and size of the premature brain.

A team of scientists from the Netherlands, the UK and China searched for genes that contribute to left-right differences in the nervous system, in the period between four and eight weeks after fertilisation. The genetic analysis showed that the left and right sides of the spinal cord develop at different paces.

The left side of the spinal cord matures slightly faster than the right side. Sets of key genes that control growth and maturity were found to reach a more advanced profile of activity on the left side than the right. In the hindbrain, an area which is the predecessor for some adult parts of the brain, this was the other way around.

“This seems logical, since many nerve fibers cross over from one side to the other at the boundary between the hindbrain and spinal cord,” says Carolien de Kovel, lead author of the study and researcher at the Max Plank Institute for Psycholinguistics (MPI). “How exactly this left-right genetic difference in the spinal cord leads to right-handedness is, however, not yet clear.”

Clyde Francks, head of the MPI research group ‘Brain and behavioral asymmetries’ and Research Fellow at the Donders Institute at the Radboud University, explains, “We think that these very early left-right differences in the spinal cord may act to trigger some of the later asymmetries of the brain, such as the eventual dominance of the left hemisphere for language functions in most adults’.

Asymmetry and schizophrenia

“Around 85% of humans are right-handed; it seems the standard in human development,” De Kovel adds, “but genetic and environmental factors may provide alternative paths of development, such as left-handedness or two-handedness. Interestingly, disturbances in such asymmetries seem to be more common in people with psychiatric conditions such as schizophrenia.”

Hence, De Kovel and her colleagues also compared the results of their study with genetic factors that influence the risk of schizophrenia. It was found that genes which exhibit the largest left-right differences in the embryos also tended to be involved in the risk of schizophrenia. “The findings do not prove directly that these genes cause schizophrenia by their actions in the spinal cord, because the same genes are also active in the grown-up brain. However this does provide us with clues on which we can base further research,” De Kovel explains.

The research was funded by an Open Programme grant from the Netherlands Organization for Scientific Research (NWO), and is published in the journal Biological Psychiatry.

Original Publication:
De Kovel, C. G. F., Lisgo, S., Karlebach, G., Ju, J., Cheng, G., Fisher, S. E., & Francks, C. (2017). Left-right asymmetry of maturation rates in human embryonic neural development. Biological Psychiatry. Advance online publication.
DOI: http://dx.doi.org/10.1016/j.biopsych.2017.01.016

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