Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

Lucia Dutan Polit^{1

2}, Ilse Eidhof³, Rhiannon V McNeill⁴, Katherine M Warre-Cornish⁵, Cristine Marie Yde Ohki⁶, Natalie Monet Walter⁶, Carlo Sala⁷, Chiara Verpelli⁷, Franziska Radtke⁸, Silvana Galderisi⁹, Armida Mucci⁹, Ginetta Collo¹⁰, Frank Edenhofer¹¹, Maija L Castrén¹², János M Réthelyi¹³, Morten Ejlersen¹⁴, Sonja Simone Hohmann¹⁴, Mirolyuba S Ilieva¹⁴, Renate Lukjanska¹⁴, Rugile Matuleviciute¹, Tanja Maria Michel¹⁴, Femke M S de Vrij¹⁵, Steven A Kushner¹⁵, Bas Lendemeijer¹⁵, Sarah Kittel-Schneider⁴, Georg C Ziegler⁴, Doris Gruber-Schoffnegger¹⁶, R Jeroen Pasterkamp¹⁷, Amal Kasri¹⁸, Marie-Claude Potier¹⁸, Jürgen A Knoblich^{19

20}, Oliver Brüstle²¹, Michael Peitz^{21

22}, Emilio Merlo Pich²³, Adrian J Harwood²⁴, Elsa Abranches⁵, Anna Falk^{3

25}, Anthony C Vernon^{1

2}, Edna Grünblatt^{6

26

27}, Deepak P Srivastava^{1

2}

Affiliations

¹ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
² MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.
³ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴ Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, D-97080, Würzburg, Germany.
⁵ National Institute for Biological Standards and Control, South Mimms, UK.
⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich (PUK), University of Zurich, Zürich, Switzerland.
⁷ CNR Neuroscience Institute Milano, Via Raoul Follereau 3, 20854, Vedano al Lambro, MB, Italy.
⁸ Department of Child and Adolescent Psychiatry, University Hospital, University of Wuerzburg, D-97080, Würzburg, Germany.
⁹ Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁰ Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
¹¹ Department of Molecular Biology & CMBI, Genomics, Stem Cell Biology & Regenerative Medicine Group, Leopold-Franzens-University Innsbruck, Austria.
¹² Medicum, Department of Physiology, University of Helsinki, Helsinki, Finland.
¹³ Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
¹⁴ Department of Psychiatry, Department of Clinical Research, University of Southern Denmark and Psychiatry in the Region of Southern Denmark, Odense University Hospital, Odense, Denmark.
¹⁵ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁶ Department of Translational Neuroscience, Evotec SE, Essener Bogen 7, D-22419 Hamburg, Germany.
¹⁷ Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.
¹⁸ ICM Paris Brain Institute, CNRS UMR7225, INSERM U1127, Sorbonne University, Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France.
¹⁹ IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter (VBC), Vienna, Austria.
²⁰ Medical University of Vienna, Department of Neurology, Vienna, Austria.
²¹ Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Germany.
²² Cell Programming Core Facility, University of Bonn Medical Faculty, Bonn, Germany.
²³ Gelf Health, Milano, Italy.
²⁴ Neuroscience and Mental Health Innovation Institute (NMHII) and School of Biosciences, Cardiff University, UK.
²⁵ Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden.
²⁶ Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zürich, Switzerland.
²⁷ Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland.

PMID: 40655966
PMCID: PMC12244118
DOI: 10.1016/j.nsa.2023.101125

Review

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

Lucia Dutan Polit et al. Neurosci Appl. 2023.

. 2023 Mar 20:2:101125.

doi: 10.1016/j.nsa.2023.101125. eCollection 2023.

Authors

Affiliations

¹ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
² MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.
³ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴ Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, University of Würzburg, D-97080, Würzburg, Germany.
⁵ National Institute for Biological Standards and Control, South Mimms, UK.
⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich (PUK), University of Zurich, Zürich, Switzerland.
⁷ CNR Neuroscience Institute Milano, Via Raoul Follereau 3, 20854, Vedano al Lambro, MB, Italy.
⁸ Department of Child and Adolescent Psychiatry, University Hospital, University of Wuerzburg, D-97080, Würzburg, Germany.
⁹ Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁰ Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
¹¹ Department of Molecular Biology & CMBI, Genomics, Stem Cell Biology & Regenerative Medicine Group, Leopold-Franzens-University Innsbruck, Austria.
¹² Medicum, Department of Physiology, University of Helsinki, Helsinki, Finland.
¹³ Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
¹⁴ Department of Psychiatry, Department of Clinical Research, University of Southern Denmark and Psychiatry in the Region of Southern Denmark, Odense University Hospital, Odense, Denmark.
¹⁵ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁶ Department of Translational Neuroscience, Evotec SE, Essener Bogen 7, D-22419 Hamburg, Germany.
¹⁷ Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.
¹⁸ ICM Paris Brain Institute, CNRS UMR7225, INSERM U1127, Sorbonne University, Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France.
¹⁹ IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter (VBC), Vienna, Austria.
²⁰ Medical University of Vienna, Department of Neurology, Vienna, Austria.
²¹ Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Germany.
²² Cell Programming Core Facility, University of Bonn Medical Faculty, Bonn, Germany.
²³ Gelf Health, Milano, Italy.
²⁴ Neuroscience and Mental Health Innovation Institute (NMHII) and School of Biosciences, Cardiff University, UK.
²⁵ Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden.
²⁶ Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zürich, Switzerland.
²⁷ Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland.

PMID: 40655966
PMCID: PMC12244118
DOI: 10.1016/j.nsa.2023.101125

Abstract

The number of individuals suffering from neuropsychiatric disorders (NPDs) has increased worldwide, with 3 million disability-adjusted life-years calculated in 2019. Though research using various approaches including genetics, imaging, clinical and animal models has advanced our knowledge regarding NPDs, we still lack basic knowledge regarding the underlying pathophysiological mechanisms. Moreover, there is an urgent need for highly effective therapeutics for NPDs. Human induced pluripotent stem cells (hiPSCs) generated from somatic cells enabled scientists to create brain cells in a patient-specific manner. However, there are challenges to the use of hiPSCs that need to be addressed. In the current paper, consideration of best practices for neuropharmacological and neuropsychiatric research using hiPSCs will be discussed. Specifically, we provide recommendations for best practice in patient recruitment, including collecting demographic, clinical, medical (before and after treatment and response), diagnostic (including scales) and genetic data from the donors. We highlight considerations regarding donor genetics and sex, in addition to discussing biological and technical replicates. Furthermore, we present our views on selecting control groups/lines, experimental designs, and considerations for conducting neuropharmacological studies using hiPSC-based models in the context of NPDs. In doing so, we explore key issues in the field concerning reproducibility, statistical analysis, and how to translate in vitro studies into clinically relevant observations. The aim of this article is to provide a key resource for hiPSC researchers to perform robust and reproducible neuropharmacological studies, with the ultimate aim of improving identification and clinical translation of novel therapeutic drugs for NPDs.

Keywords: Cellular models; Drug discovery; Neurodevelopmental disorders; Neuropsychiatry; Neuropsychopharmacology; Sex as a biological variable (SABV).

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Global prevalence male:female ratios in neuropsychiatric disorders. The graph represents the number of diagnosed male patients for each female in neurological (green) and psychiatric disorders (blue). Male:female ratios of Obsessive Compulsive Disorder, Post-traumatic Stress Disorder and Epilepsy were extracted from (Fawcett et al., 2020; Fiest et al., 2017; Olff, 2017), respectively. Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis ratios were reported by the Global Burden Disease (GBD) 2016, while the remaining disorders were updated by the GBD 2019 (https://www.healthdata.org/gbd/2019). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 2**
The two main classes of neuropharmacological study approaches. Abbreviation: MoA, mechanism of action.

See this image and copyright information in PMC

Cited by

Assessing the effects of methylphenidate in proliferation and Wnt activity of neuronal stem cells from attention deficit/hyperactivity disorder patients.
Yde Ohki CM, Walter NM, Smigielski L, Bender A, Rickli M, Walitza S, Grünblatt E. Yde Ohki CM, et al. J Neural Transm (Vienna). 2025 Jul 28. doi: 10.1007/s00702-025-02988-y. Online ahead of print. J Neural Transm (Vienna). 2025. PMID: 40719827
Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.
Dinasarapu AR, Sutcliffe DJ, Grychowski L, Ozel E, Thite A, Visser JE, Hess EJ, Kolk SM, Jinnah HA. Dinasarapu AR, et al. Stem Cells Transl Med. 2025 Jul 24;14(8):szaf032. doi: 10.1093/stcltm/szaf032. Stem Cells Transl Med. 2025. PMID: 40751518 Free PMC article.

References

1. Abranches E., Spyrou S., Ludwig T. GMP banking of human pluripotent stem cells: a US and UK perspective. Stem Cell Res. 2020;45 - PubMed
1. Akkouh I.A., Hribkova H., Grabiec M., Budinska E., Szabo A., Kasparek T., Andreassen O.A., Sun Y.M., Djurovic S. Derivation and molecular characterization of a morphological Subpopulation of human iPSC astrocytes reveal a potential role in schizophrenia and clozapine response. Schizophr. Bull. 2022;48(1):190–198. - PMC - PubMed
1. Abud E.M., Ramirez R.N., Martinez E.S., Healy L.M., Nguyen C.H.H., Newman S.A., Yeromin A.V., Scarfone V.M., Marsh S.E., Fimbres C., Caraway C.A., Fote G.M., Madany A.M., Agrawal A., Kayed R., Gylys K.H., Cahalan M.D., Cummings B.J., Antel J.P., et al. IPSC-derived human microglia-like cells to study neurological diseases. Neuron. 2017;94(2):278–293. - PMC - PubMed
1. Albert P.R. Why is depression more prevalent in women? J. Psychiatry Neurosci. 2015;40(4):219–221. - PMC - PubMed
1. Anderson N.C., Chen P.F., Meganathan K., Afshar Saber W., Petersen A.J., Bhattacharyya A., Kroll K.L., Sahin M., Cross, I.h.s.c.w.g Balancing serendipity and reproducibility: pluripotent stem cells as experimental systems for intellectual and developmental disorders. Stem Cell Rep. 2021;16(6):1446–1457. - PMC - PubMed

Publication types

Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

Affiliations

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

LinkOut - more resources

Full Text Sources