Induced pluripotent stem cell-derived neuronal models in psychiatry: Mechanistic insights and translational horizons

Table 1 Summary of induced pluripotent stem cell-derived neuronal findings in psychiatry

Disorder	Primary model	Key reported phenotypes	Ref.
Schizophrenia	Forebrain/cortical neurons; NPC → neurons; 22q11.2DS neurons; single-cell RNA-seq	Neurite/synaptic and connectivity deficits; catecholamine-release abnormalities; WNT/progenitor dysregulation; 22q11.2DS shows mitochondrial and developmental transcriptomic defects; single-cell heterogeneity shifts	[15-22]
Bipolar disorder	Neurons (electrophysiology); NPCs; cortical spheroids	Hyperexcitability with lithium-linked rescue; functional subgrouping; NPC calcium-entry and differentiation changes; lithium effects in spheroids; mitochondrial/bioenergetic abnormalities	[23-28]
Autism spectrum disorder	Neurons (syndromic/idiopathic); CNV/risk-gene cohorts; neuron-astrocyte co-culture; MEA/patch; iPSCs (NO assay)	Synapse/network phenotypes; 16p11.2 dosage effects; CNTN5/EHMT2 network hyperactivity; convergent expression modules; astrocyte modulation; nitric-oxide signature in iPSCs	[29-38]
Major depressive disorder	Serotonergic/forebrain neurons; cortical neurons; NPC → neurons; GABA interneurons; dopaminergic neurons	SSRI-resistance phenotypes including serotonin-evoked hyperactivity; antidepressant-response signatures; bioenergetic/electrophysiology changes; HTR2C-linked interneuron activity with rescue; ketamine plasticity pathways	[1,39-45]
ADHD	NSCs/NPCs; telencephalon organoids; cortical neurons; dopaminergic neurons (PARK2 CNVs)	Progenitor proliferation deficits; early cortical organization changes in organoids; glutamatergic and calcium-network hypoactivity; stress-modulated bioenergetic deficits	[47-52]
Anorexia nervosa	Neuronal cultures	Limited evidence; transcriptomic dysregulation signals; major gap in functional phenotyping	[53]
OCD	iPSC line resources	Mostly line derivation/validation; limited neuronal phenotyping	[54]

NPC: Neural progenitor cell; RNA-seq: RNA sequencing; CNV: Copy number variation; MEA: Multielectrode array; iPSCs: Induced pluripotent stem cells; NO: Nitric oxide; GABA: Gamma-aminobutyric acid; ADHD: Attention-deficit/hyperactivity disorder; SSRI: Selective serotonin reuptake inhibitor; NSCs: Neural stem cells; OCD: Obsessive-compulsive disorder.

Table 2 Functional phenotyping platforms for induced pluripotent stem cell-derived neuronal models in psychiatry

Platform	Primary readout	Strengths	Limitations	Best suited for
Patch clamp	Single-cell electrophysiology (action potentials, synaptic currents, ion-channel function)	Highest functional resolution; direct measurement of neuronal physiology	Low throughput; technically demanding	Mechanistic studies and validation of ion-channel or synaptic phenotypes
MEA	Network activity, burst dynamics, synchrony	Non-invasive, longitudinal recordings; suitable for moderate-throughput screening	Limited single-cell resolution; influenced by culture density and maturity	Drug screening, network phenotyping, subgroup identification
Calcium imaging	Single-cell and network activity dynamics	Higher throughput than patch clamp; enables population-level analysis	Indirect measure of electrical activity; lower temporal resolution	Functional comparison between donor groups and pharmacological studies
High-content imaging	Neurite morphology, synaptic markers, cell survival	Scalable and highly multiplexed	Primarily structural rather than functional	Morphological phenotyping and toxicity/rescue assays
Single-cell/spatial transcriptomics	Cell identity, pathway activity, cellular composition	High molecular resolution; identifies disease-associated cell states	Destructive, expensive, not a direct functional assay	Molecular characterization, organoid quality control, pathway discovery

MEA: Multielectrode array.