Applied Developmental Neurobiology – Carl Sellgren research group

The clinical data collection is coordinated by Centre for Psychiatry Research, an organisation joining psychiatric healthcare and researchers.

Patients with first-episode psychosis are currently recruited from four different clinics in Stockholm (Psykiatri Nordväst , Norra Stockholms Psykiatri, Södra Stockholms Psykiatri and Praktikertjänst).

Most patients are naïve to antipsychotic drugs at the time of investigation, made possible by a close interaction between clinical staff and researchers. The first patient was recruited in 2015 and we are currently also performing follow-up investigations after 1.5 and 5 years. In parallel, matched healthy volunteers are continuously enrolled in the program.

All included individuals undergo a lumbar puncture for cerebrospinal fluid (CSF) collection, blood sampling, multimodal magnetic resonance imaging (MRI), positron emission tomography (PET), genetic analysis and extensive clinical characterization including an assessment of cognitive functions. 

Within the project, we prioritize observational studies that take advantage of the unique multi-modal dataset to perform integrated analyses capturing different aspects of brain functioning in the disease states. The collection of longitudinal data then allows for studies aiming to identify biomarkers of biological trajectories that are anchored in defined clinical outcomes. 

Relevant disease models are key for identifying causal biological mechanisms that can be targeted with pharmacological treatments in schizophrenia. In Karolinska Schizophrenia Project, we use patient-derived human models in which our experimental findings can directly be translated back to the patient. The platform is built on a collection of small skin biopsies (as part of the clinical platform), and fibroblasts from these biopsies are reprogrammed to so-called induced pluripotent stem cells (iPSCs) that can be used to generate living 2D and 3D models of the developing brain. 

Our work includes model development (basic science), modeling of genetic and environmental risk variants for schizophrenia, and ex vivo drug testing. To cover aspects that are lost in the dish, we also use animal models, and combine human and animal models by transplanting patient-derived brain organoids into rodents. To ensure relevance for the living human brain, we also strive to validate our experimental findings directly in the contributing patients. For this, we utilize the comprehensive collection of brain imaging data and CSF.  

The principal investigator is Carl Sellgren  and the project is coordinated by a steering committee that consists of Carl Sellgren (Dept. of Physiology and Pharmacology, KI), Sophie Erhardt (Dept. of Physiology and Pharmacology, KI), and Simon Cervenka (Dept. of Clinical Neuroscience, KI, and Dept. of Medical Sciences, Uppsala Universitet). The research is performed in close collaboration with SLSO psykiatri and is coordinated by Centre for Psychiatry Research. The infrastructure is built to encourage cross-disciplinary and collaborative research, and the project also involves a large number of international and national collaborators. 

Patients who experience their first psychotic episode are recruited from the major psychiatric clinics in Stockholm, Sweden. If you are a clinician working at one of these clinics, we appreciate if you ask your patient if they would like to have more information about the study. If the patient agrees, contact one of our research nurses that will ask you a few questions to make sure that the patient is a candidate for the study. The research nurse will then contact the patient and leave more information about the study. If the patient agrees to participate, all investigations including the clinical characterizations will be performed by personnel working within the project. The battery of investigations also to a large degree cover the recommended Swedish care program for patients with a first-episode psychosis.

Call or send text message to 072-522 39 07 (Lena Lundberg). 

Karolinska Schizophrenia project is committed to clarifying the roots of the disease and to accelerate the transition from basic biological insights into new therapeutic approaches that impact the daily life of the individuals that suffer from the schizophrenia.

Overview of the study platform integrating observational and experimental data. High-resolution observational data from carefully phenotyped patients and controls are integrated with experimental data generated in patient-specific cellular models. Created with BioRender.com

Large-scale unbiased genetic association studies have revealed a growing number of variations in the DNA sequence that associates with schizophrenia. This data offers an unpreceded opportunity to understand disease mechanisms and advance therapeutics. Yet, successful exploitation of these results requires a commitment to invest in disease models that capture the daunting polygenicity of schizophrenia while offering linkage with high-resolution phenotyping. 

In KaSP, we address these challenges by collecting a variety of biological data from meticulously phenotyped first-episode psychosis and distinguish clinical trajectories by performing follow-up investigations. Experimental models are based on cells obtained from the patients, and by cellular reprogramming we generate models of the developing brain that are unique for each patient. This enables us to translate our experimental findings directly back to each patient by performing e.g., targeted measurements in collected cerebrospinal fluid our by analyzing collected brain imaging (MRI and PET) data and ensure relevance for the living human brain. To cover aspects that are lost in the dish, our in vitro models are also complemented by animal models, in which we also transplant patient-derived brain organoids.

Schizophrenia is a severe brain disease of neurodevelopmental origin and is characterized by chronic or relapsing episodes of psychosis.

Approximately half a percent of the worldwide population is estimated to suffer from schizophrenia and the majority experience their first symptoms already in their late teens or in early adulthood. This makes schizophrenia one of the major public health challenges, and the estimated costs for the disease is estimated to be greater than those for all cancers combined. 

The clinical presentation shows considerable variability, but the core symptoms typically make a profound impact on thoughts, emotions, and behavior. The diagnosis is criteria based and the diagnostic assessment rely on repeated clinical interviews and mental status examinations. Despite the lack of objective biomarkers, a diagnosis of schizophrenia shows considerable stability over time.

Continuous antipsychotic medication is the mainstay of treatment for schizophrenia. However, disabling symptoms persist in many patients, and some suffer from unwanted side effects.

Genetic risk factors are the main cause of schizophrenia and unbiased large-scale genetic studies have identified a growing number of variations in the DNA sequence that associates with schizophrenia. Several environmental risk factors have also been identified. These include maternal immune activation as well as use of cannabis.

Large brain imaging studies and repeated investigations of brain tissue obtained from deceased individuals with schizophrenia have revealed indisputable structural brain abnormalities. Foremost, a reduction in frontal cortical thickness have been observed and can largely be explained by a loss of connections between the nerve cells, the so-called synapses. 

Investigations to understand how risk factors causes brain changes and symptoms in the patients are ongoing but much of the pathophysiology remains elusive. However, with such knowledge more precise and personalized drug targeting is possible. 

Schizophrenia is believed to have accompanied mankind through history. However, it took until 1887 before the disease was given its own identity by Dr. Emile Kraepelin in 1887.

The disease is mentioned in documents that can be traced to the ancient Pharaonic Egypt. At that time it was supposed that mental disorders, in general, were caused by an evil possession of the body, and as a consequence, the appropriate treatment was exorcising of demons.

The German physician, Emile Kraepelin was the first to classify mental disorders into various categories. He used the term "dementia praecox" for individuals with symptoms that we now associate with schizophrenia.

Eugen Bleuler, a Swiss psychiatrist, changed the name of the disease to "schizophrenia" in 1911 since it was obvious that Kraepelin's name “dementia praecox” was misleading. The name schizophrenia originates from the Greek roots “schizo” (split) and “phrene” (mind) and was ment to reflect the disoriented thinking of individuals with the disorder. Bleuler was also the first to describe the symptoms of the disease terms of "positive" or "negative." The disease is nowadays defined according to the criteria of DSM-5.

For many years effective pharmacological treatment was lacking. The first medicines were developed during the 1950s, one of the first was haloperidol (1958). This drug was one of several substances known as the first-generation antipsychotics, and many of these drugs are still in use. During the 1970s new drugs with more beneficial side effects were introduced, for example, clozapine, known as one the most efficient antipsychotics.

Patients who experience their first psychotic episode are recruited from the major psychiatric clinics in Stockholm, Sweden.

If you are a clinician working at one of these clinics, we appreciate if you ask your patient if they would like to have more information about the study. If the patient agrees, contact one of our research nurses that will ask you a few questions to make sure that the patient is a candidate for the study. The research nurse will then contact the patient and leave more information about the study. If the patient agrees to participate, all investigations including the clinical characterizations will be performed by personnel working within the project. The battery of investigations also to a large degree cover the recommended Swedish care program for patients with a first-episode psychosis.

Contact:
Call or send text message to 072-522 39 07 (Caroline Westerberg Hake/Lena Lundberg). 

Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia.
Gracias J, Orhan F, Hörbeck E, Holmén-Larsson J, Khanlarkani N, Malwade S, Goparaju SK, Schwieler L, Demirel İŞ, Fu T, Fatourus-Bergman H, Pelanis A, Goold CP, Goulding A et al.
Nat Commun 2022 Nov;13(1):6427

Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms.
Larsson C, Lee M, Lundgren T, Erhardt S, Sellgren CM, Cervenka S, Borg J, Bölte S, Fatouros-Bergman H
Heliyon 2022 Sep;8(9):e10424

Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients.
Shang P, Ho AM, Tufvesson-Alm M, Lindberg DR, Grant CW, Orhan F, Eren F, Bhat M, Engberg G, Schwieler L, Fatouros-Bergman H, Imbeault S, Iverson RM, Dasari S, Piehl F, Cervenka S, Sellgren CM, Erhardt S, Choi DS
Transl Psychiatry 2022 Jun;12(1):229

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.
Mätlik K, Garton DR, Montaño-Rodríguez AR, Olfat S, Eren F, Casserly L, Damdimopoulos A, Panhelainen A, Porokuokka LL, Kopra JJ, Turconi G, Schweizer N, Bereczki E, Piehl F, Engberg G, Cervenka S, Piepponen TP, Zhang FP, Sipilä P, Jakobsson J, Sellgren CM, Erhardt S, Andressoo JO
Mol Psychiatry 2022 Aug;27(8):3247-3261

Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis.
Plavén-Sigray P, Ikonen Victorsson P, Santillo A, Matheson GJ, Lee M, Collste K, Fatouros-Bergman H, Sellgren CM, Erhardt S, Agartz I, Halldin C, Farde L, Cervenka S
Mol Psychiatry 2022 Feb;27(2):1233-1240

Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis.
Theorell J, Ramberger M, Harrison R, Mgbachi V, Jacobson L, Waters P, Erhardt S, Sellgren CM, Cervenka S, Piehl F, Irani SR
Transl Psychiatry 2021 Nov;11(1):566

No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis.
Lee M, Fatouros-Bergman H, Plavén-Sigray P, Ikonen Victorsson P, Sellgren CM, Erhardt S, Flyckt L, Farde L, Cervenka S
NPJ Schizophr 2021 Sep;7(1):46

Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.
Becklén M, Orhan F, Piehl F, Cervenka S, Sellgren CM, Flyckt L, Erhardt S, Fatouros-Bergman H
Sci Rep 2021 Apr;11(1):7527

Disrupted sensorimotor gating in first-episode psychosis patients is not affected by short-term antipsychotic treatment.
Hedberg M, Imbeault S, , Erhardt S, Schwieler L
Schizophr Res 2021 Feb;228():118-123

Brain Age Prediction Reveals Aberrant Brain White Matter in Schizophrenia and Bipolar Disorder: A Multisample Diffusion Tensor Imaging Study.
Tønnesen S, Kaufmann T, de Lange AG, Richard G, Doan NT, Alnæs D, van der Meer D, Rokicki J, Moberget T, Maximov II, Agartz I, Aminoff SR, Beck D, Barch DM, Beresniewicz J et al.
Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Dec;5(12):1095-1103

Reproducibility in the absence of selective reporting: An illustration from large-scale brain asymmetry research.
Kong XZ, , Francks C
Hum Brain Mapp 2022 Jan;43(1):244-254

The genetic architecture of human brainstem structures and their involvement in common brain disorders.
Elvsåshagen T, Bahrami S, van der Meer D, Agartz I, Alnæs D, Barch DM, Baur-Streubel R, Bertolino A, Beyer MK, Blasi G, Borgwardt S, Boye B, Buitelaar J, Bøen E, Celius EG et al.
Nat Commun 2020 Aug;11(1):4016

CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.
Xu C, Sellgren CM, Fatouros-Bergman H, Piehl F, Blennow K, Zetterberg H, Brinkmalm A, Santillo AF, Lundgren S, Cervenka S, Engberg G, Erhardt S,
IBRO Rep 2020 Jun;8():136-142

Synthesis and Preclinical Evaluation of 6-[18F]Fluorine-α-methyl-l-tryptophan, a Novel PET Tracer for Measuring Tryptophan Uptake.
Krasikova R, Kondrashov M, Avagliano C, Petukhov M, Vazquez-Romero A, Revunov E, Johnström P, Tari L, Tóth M, Häggkvist J, Erhardt S, Cervenka S, Schou M
ACS Chem Neurosci 2020 Jun;11(12):1756-1761

Common brain disorders are associated with heritable patterns of apparent aging of the brain.
Kaufmann T, van der Meer D, Doan NT, Schwarz E, Lund MJ, Agartz I, Alnæs D, Barch DM, Baur-Streubel R, Bertolino A, Bettella F, Beyer MK, Bøen E, Borgwardt S, Brandt CL, Buitelaar J et al.
Nat Neurosci 2019 Oct;22(10):1617-1623

Neurogranin as a potential synaptic marker in the cerebrospinal fluid of patients with a first episode psychosis.
Santillo AF, Lundgren S, Xu C, Orhan F, Fatouros-Bergman H, Blennow K, Zetterberg H, Portelius E, , Cervenka S, Jönsson EG, Erhardt S, Engberg G
Schizophr Res 2019 Jun;208():490-492

Increased peripheral levels of TARC/CCL17 in first episode psychosis patients.
Malmqvist A, Schwieler L, Orhan F, Fatouros-Bergman H, Bauer M, Flyckt L, Cervenka S, Engberg G, Piehl F, , Erhardt S
Schizophr Res 2019 Aug;210():221-227

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?
van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, Pearlson GD, Yao N, Fukunaga M, Hashimoto R, Okada N, Yamamori H, Clark VP, Mueller BA, de Zwarte SMC, Ophoff RA et al.
Biol Psychiatry 2019 Apr;85(7):e35-e39

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.
van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, et al
Biol. Psychiatry 2018 11;84(9):644-654

PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data.
Plavén-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes O, Mizrahi R, Pomper MG, Rusjan P, Veronese M, Wang Y, Cervenka S
Biological Psychiatry 2018 02; 1171

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.
Orhan F, Schwieler L, Fatouros-Bergman H, Malmqvist A, Cervenka S, Collste K, et al
Acta Psychiatr Scand 2018 11;138(5):432-440

Cerebrospinal fluid levels of sphingolipids associate with disease severity in first episode psychosis patients.
Checa A, Malmqvist A, Flyckt L, Schwieler L, Samuelsson M, Skogh E, et al
Schizophr. Res. 2018 09;199():438-441

First-episode psychosis patients display increased plasma IL-18 that correlates with cognitive dysfunction.
Orhan F, Fatouros-Bergman H, Schwieler L, Cervenka S, Flyckt L, Sellgren CM, et al
Schizophr. Res. 2018 05;195():406-408

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.
Walton E, Hibar DP, van Erp TG, Potkin SG, Roiz-Santiañez R, Crespo-Facorro B, et al
Acta Psychiatr Scand 2017 May;135(5):439-447

CSF GABA is reduced in first-episode psychosis and associates to symptom severity.
Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, , et al
Mol. Psychiatry 2018 05;23(5):1244-1250

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.
Collste K, Plavén-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, et al
Mol. Psychiatry 2017 06;22(6):850-856

Tryptophan Metabolism Along the Kynurenine Pathway Downstream of Toll-like Receptor Stimulation in Peripheral Monocytes.
Orhan F, Bhat M, Sandberg K, Ståhl S, Piehl F, , et al
Scand. J. Immunol. 2016 Nov;84(5):262-271

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.
Walton E, Hibar DP, van Erp TGM, Potkin SG, Roiz-Santiañez R, Crespo-Facorro B, et al
Psychol Med 2018 Jan;48(1):82-94