Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies—A Narrative Review
Abstract
1. Introduction
2. Genetic Markers
2.1. Major Depressive Disorder (MDD)
2.2. Generalized Anxiety Disorder (GAD)
2.3. Schizophrenia
2.4. Bipolar Disorder (BD)
- ANK3 influences the structural constituent of the cytoskeleton and protein binding and bridging.
- CACNA1C influences enzyme binding and ion channel activity.
- SYNE1 is located on chromosome 6q25.2 and is seen in the cerebellar hemisphere and cerebellum, where it encodes multiple proteins with roles in synaptic plasticity and function.
- ODZ4(TENM4) is another gene identified in BPD that belongs to the tenascin family (teneurin subfamily), and it is located on chromosome 11q14.1, with a role in protein homodimerization activity.
- TRANK1(LBA1) is located on chromosome 3p22.2, and its expression is influenced by valproic acid. Moreover, its dysregulation can disrupt neuronal development and differentiation and the synaptic plasticity of other genes.
3. Pharmacogenomics
3.1. CYP450 and Phenotypic Variations
3.1.1. Impact of CYP450 Genetic Variations on Antidepressant Response
3.1.2. Impact of CYP450 Genetic Variations on Antipsychotic Response
3.1.3. Impact of CYP450 Genetic Variations on Anxiolytic Response
3.2. Effects of CYP2D6 and CYP2C19 Variants on Neurotransmitter Regulation
3.3. Challenges
4. Metabolists
4.1. Insulin Resistance and Psychiatric Impact
4.2. Cholinesterases in Alzheimer’s Disease
4.3. Microbiota Gut–Brain Axis
4.4. Autophagy
4.5. Amyloid-Beta Peptides
5. Genetic Predisposition and Environmental Factors
5.1. Heritability of Psychiatric Disorders and Their Genetic Overlap
5.2. Fine Mapping Variants in GWAS Loci
5.3. Polygenic Risk Scores
6. Neuromodulation
6.1. Non-Invasive Brain Stimulation
6.1.1. Transcranial Magnetic Stimulation
6.1.2. Transcranial Direct Current Stimulation
6.2. Electroconvulsive Therapy
7. Neuroimaging
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Twin Pair | Twin 1 Neuroticism | Twin 1 Generalized Anxiety Disorder | Twin 2 Neuroticism | Twin 2 Generalized Anxiety Disorder |
---|---|---|---|---|
Male–male | ||||
Twin 1: neuroticism | 0.318 | 0.358 | 0.206 | |
Twin 1: generalized anxiety disorder | 0.394 | 0.174 | 0.128 | |
Twin 2: neuroticism | 0.207 | 0.074 | 0.394 | |
Twin 2: generalized anxiety disorder | 0.064 | 0.093 | 0.316 | |
Female–female | ||||
Twin 1: neuroticism | 0.569 | 0.303 | 0.327 | |
Twin 1: generalized anxiety disorder | 0.195 | 0.214 | 0.150 | |
Twin 2: neuroticism | 0.119 | 0.142 | 0.462 | |
Twin 2: generalized anxiety disorder | 0.229 | 0.186 | 0.468 | |
Opposite-sex | ||||
Twin 1: neuroticism | ||||
Twin 1: generalized anxiety disorder | 0.339 | |||
Twin 2: neuroticism | 0.113 | 0.095 | ||
Twin 2: generalized anxiety disorder | 0.038 | 0.059 | 0.211 |
Gene Symbol | Gene Description | Chromosome | Functions |
---|---|---|---|
APOE | Apolipoprotein E | 19 | A main apoprotein of the chylomicron that binds to a specific receptor on liver cells and peripheral cells; essential for the normal catabolism of triglyceride-rich lipoprotein constituents |
CFTR | Cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) | 7 | Involved in multidrug resistance; functions as a chloride channel and controls the regulation of other transport pathways |
CNTNAP2 | Contactin-associated protein-like 2 | 7 | A member of the neurexin family; functions in the vertebrate nervous system as a cell adhesion molecule and receptor |
COMT | Catechol-O-methyltransferase | 22 | Catecholamine neurotransmitter metabolism; VCFS region (22q deletion syndrome) |
DISC1 | Disrupted in schizophrenia 1 | 1 | Neurite outgrowth and cortical development; disrupted in t(1;11)(q42.1;q14.3) |
DRD2 | Dopamine receptor D2 | 11 | G protein-coupled receptor for dopamine; inhibits adenylyl cyclase |
DTNBP1 | Dystrobrevin-binding protein 1 | 6 | A component of the biogenesis of lysosome-related organelles complex 1 |
ERBB4 | V-erb-a erythroblastic leukemia viral oncogene | 2 | Receptor for neuregulins; cell differentiation |
FMR1 | Fragile X mental retardation 1 | 23 | May be involved in nucleus → cytoplasm mRNA trafficking |
HTR2A | 5-hydroxytryptamine (serotonin) receptor 2A | 13 | G protein-coupled receptor for serotonin; activates phosphoinositide hydrolysis |
NRG1 | Neuregulin 1 | 8 | Signaling protein that mediates cell–cell interactions; has roles in growth and development |
NRGN | Neurogranin | 11 | Postsynaptic protein kinase substrate; learning and memory; glutamate signaling |
NRXN1 | Neurexin 1 | 2 | Functions in the nervous system as a cell adhesion molecule and receptor |
PARK7 | Parkinson’s disease (autosomal recessive, early onset) 7 | 1 | Positive regulator of androgen receptor-dependent transcription; apparently protects neurons against oxidative stress and cell death |
SCNA | Synuclein, alpha (non-A4 component of amyloid precursor) | 4 | May serve to integrate presynaptic signaling and membrane trafficking |
TCF4 | Transcription factor 4 | 18 | Neuronal transcriptional factor; neurogenesis |
VIPR2 | Vasoactive intestinal peptide receptor 2 | 7 | Peptide that functions as a neurotransmitter and a neuroendocrine hormone |
ZNF804A | Zinc finger protein 804A | 2 | Transcription factor; neuronal connectivity in the dorsolateral prefrontal cortex |
Genotype | Enzymatic Activity | Impact of Diazepam | Clinical Consequences |
---|---|---|---|
CYP2C19 PM (Poor Metabolizer) | Low/Absent | Slow metabolism, drug accumulation | Increased risk of adverse reactions (dependence, tolerance) |
CYP2C19*2 (Allele) | Reduced activity | Slow metabolism, drug accumulation | Higher risk of side effects |
CYP2C19*17 (Allele) | Increased activity | Rapid metabolism, faster drug clearance | Reduced efficacy, possible higher dose needed |
CYP2B6 PM (Poor Metabolizer) | Low | Slow metabolism, drug accumulation | Possible need for dose reduction |
Medication | Type | Effect on Autophagy | Possible Mechanism/Notes |
---|---|---|---|
Lithium | Mood stabilizer | Promotes autophagy | Enhances autophagic activity in the brain |
Fluspirilene | Antipsychotic | Stimulates autophagy | Identified in a small-molecule screen |
Trifluoperazine | Antipsychotic | Stimulates autophagy | May help reverse the downregulation of autophagic genes in the BA22 region |
Pimozide | Antipsychotic | Stimulates autophagy | Could enhance the expression of autophagy-related proteins |
Clomipramine | Antidepressant (TCA) | Presence of autophagy-related structures, but unclear effect | May induce or inhibit autophagic flux; further experiments are required |
Desmethylclomipramine | Metabolite of clomipramine | Inhibits functional autophagy | Disrupts autophagic flux |
Amitriptyline | Antidepressant (TCA) | Enhances autophagy | Observed in primary neurons and astrocytes |
Citalopram | Antidepressant (SSRI) | Enhances autophagy | Similar effect to amitriptyline |
Venlafaxine | Antidepressant (SNRI) | No significant effect on autophagy | Does not appear to alter autophagic processes |
Vitamin | Effect on Aβ Levels | Notes |
---|---|---|
Vitamin D | ↓ Plasma Aβ42 in AD patients after supplementation | Positive correlation with Aβ42 in CSF; no association in older adults without dementia |
Vitamin B12 | Low levels correlate with ↑ Aβ42 | Deficiency may contribute to higher Aβ accumulation |
Folic Acid | Supplementation may ↓ Aβ42 levels | Potential protective effect |
Vitamin E | No significant change in Aβ42 after supplementation in AD patients | Antioxidant properties but no direct effect on Aβ levels observed |
Vitamin C | No significant change in Aβ42 after supplementation in AD patients | Similar to vitamin E; no observed reduction in Aβ |
α-Lipoic Acid | No significant change in Aβ42 after supplementation in AD patients | Antioxidant effects but no impact on Aβ levels |
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Capatina, T.-F.; Oatu, A.; Babasan, C.; Trifu, S. Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies—A Narrative Review. Int. J. Mol. Sci. 2025, 26, 4285. https://doi.org/10.3390/ijms26094285
Capatina T-F, Oatu A, Babasan C, Trifu S. Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies—A Narrative Review. International Journal of Molecular Sciences. 2025; 26(9):4285. https://doi.org/10.3390/ijms26094285
Chicago/Turabian StyleCapatina, Tudor-Florentin, Anamaria Oatu, Casandra Babasan, and Simona Trifu. 2025. "Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies—A Narrative Review" International Journal of Molecular Sciences 26, no. 9: 4285. https://doi.org/10.3390/ijms26094285
APA StyleCapatina, T.-F., Oatu, A., Babasan, C., & Trifu, S. (2025). Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies—A Narrative Review. International Journal of Molecular Sciences, 26(9), 4285. https://doi.org/10.3390/ijms26094285