Brain disorders, encompassing psychiatric (depression affecting >300 million, schizophrenia 1%) and neurological (epilepsy 50 million, alzheimer’s >50 million, projected to triple by 2050) disorders, constitute a major global health burden, contributing 13.1% of disability-adjusted life years (DALYs) and incurring trillions in annual costs.^[1] Their multifactorial etiology involves genetic, environmental, and neurobiological factors and frequent comorbidities.^[2]

Treatment disparities are significant in LMICs, where only 25–31% of patients receive adequate care, compounded by stigma and limited resources.^[3] Translational neurotherapeutics integrates psychiatry, neurology, and pharmacy to target shared mechanisms (e.g., synaptic dysfunction and neuroinflammation) using advanced methodologies (e.g., rs-fMRI, pharmacogenomics, and AI) for personalized treatment.^[4] Innovations, such as psychedelics, neuromodulation, and nanocarriers, enhance efficacy, while multi-omics and holistic approaches (the gut-brain axis) address underlying causes.

A strategic roadmap emphasizes early detection, cost-effective interventions, interdisciplinary collaboration, adaptive therapies, and global initiatives for equitable and precision-driven care.^[5] The integration of molecular insights, drug innovation, and systems biology aims to transform the outcomes of patients with brain disorders.

Shared molecular and physiological mechanisms

Diverse brain disorders, including psychiatric (schizophrenia, depression, and anxiety) and neurological disorders (epilepsy, alzheimer’s disease (AD), parkinson’s disease (PD), and multiple sclerosis (MS), share key molecular and physiological mechanisms that inform translational strategies.

Neurotransmitter Dysregulation: Imbalances in glutamate, GABA, dopamine, and serotonin levels are central. Schizophrenia is characterized by reduced prefrontal GABA levels, elevated glutamate levels, and upregulated metabotropic glutamate receptors.^[6] Epilepsy exhibits hyperexcitability via reduced GABAergic inhibition and excess glutamate, whereas anxiety involves low GABA and high glutamate levels.^[7] PD involves dopaminergic neuron loss and serotonergic dysfunction, while MDD presents with mesolimbic dopamine deficits and serotonergic disruption.^[8]

Neuroinflammation and microglial activation: Proinflammatory cytokines (IL-6 and TNF-α) are implicated in AD, MS, and MDD, promoting amyloid-beta aggregation (AD), demyelination (MS), and impaired serotonin function/neuroplasticity (MDD).^[9] Chronically activated microglia amplify damage via the release of cytokines and neurotoxic factors in AD, MS, and PD. Therapeutic modulation (PPAR agonists and curcumin) can shift microglia to a protective phenotype.^[10]

Synaptic plasticity and connectivity: Brain-derived neurotrophic factor (BDNF), which is crucial for synaptic plasticity, is disrupted in MDD, AD, autism, and schizophrenia. Reduced BDNF (linked to Val66Met) impairs hippocampal plasticity in MDD/AD, whereas altered BDNF disrupts synaptic pruning in autism and schizophrenia.[11,12] BDNF mimetics and antidepressants aim to restore synaptic health.^[13]

Genetic and Epigenetic Overlaps: Genes such as DISC1 and COMT with pleiotropic effects (ZSCAN29/31) are implicated in schizophrenia, MDD, PD, and MS, affecting synaptic function and dopamine metabolism.[14,15] DNA methylation in NRG1/BDNF influences drug responses, with antipsychotic-induced epigenomic shifts and accelerated epigenetic aging offering precision care biomarkers.[16,17]

Translational Strategies: Integrated approaches utilize pharmacogenomics (CYP2D6 and APOE ε4) and innovations (nanocarriers, psychedelics, and CRISPR) to target these mechanisms and enhance CNS delivery/efficacy.[18,19] A strategic roadmap emphasizes interdisciplinary collaboration, multi-omics, and adaptive therapies for personalized and holistic treatment.^[5]

 Pharmacological innovations

Next-Generation Antipsychotics: Evolving from the 1970s SGAs, newer agents such as pimavanserin, cariprazine, and brexpiprazole (partial D2 agonists) mitigate metabolic and motor side effects.^[20] Emerging drugs (BRD5814, roluperidone, ulotaront, and KarXT) target negative symptoms, cognition, and oxidative stress, with TAAR1 agonists showing promise.^[21]

Rapid-Acting Antidepressants: For TRD, ketamine, esketamine (FDA-approved), and psilocybin offer rapid action via NMDA modulation and neuroplasticity^[22], enhancing glutamate, synaptogenesis, and BDNF.^[23] Alternatives (R-ketamine, dextromethorphan-bupropion, and resolvins) offer efficacy with fewer side effects.^[24] Precision medicine utilizes SLC6A4 and CYP2D6 markers.[25,26]

Anti-amyloid and Cannabinoid Therapies: In AD, anti-amyloid monoclonal antibodies (aducanumab and lecanemab) aim to slow the progression.^[27] CBD (Epidiolex) reduces seizures (epilepsy) and spasticity (MS) via endocannabinoid modulation, with minimal side effects.^[28]

Drug Delivery and Translational Advances: Nanoparticles and intranasal delivery bypass the BBB in AD and schizophrenia.[18,29,30] Sustained-release systems (depot antipsychotics, hydrogels) improve adherence. Preclinical models (organoids and zebrafish) validate targets such as levetiracetam/SV2A in epilepsy.^[31]

Interdisciplinary Precision: Pharmacy, psychiatry, and neurology converge using pharmacogenomics and AI-driven fMRI for tailored, real-time, biomarker-guided precision care.[32,33]

 Pharmacogenomics and precision medicine

Genetic polymorphisms in CYP450 enzymes (CYP2D6, CYP2C19, and CYP1A2) significantly affect psychotropic drug metabolism, thereby influencing their efficacy and side effects. Pretreatment genetic testing optimizes antidepressant and antipsychotic dosing.^[34] HLA gene variations (e.g., HLA-B1502 and HLA-A3101) predict hypersensitivity reactions to antiepileptic drugs, necessitating screening for specific ethnicities.^[35]

Biomarkers, such as neurofilament light chain (NfL), monitor neurodegeneration in Alzheimer’s disease and multiple sclerosis and guide therapeutic adjustments.^[36] C-reactive protein (CRP) level predicts psychiatric treatment response in major depressive disorder, informing anti-inflammatory strategies.^[37]

Although pharmacogenomics optimizes warfarin dosing via CYP2C9/VKORC1 genotyping, inspiring tailored psychotropic drug administration, implementation challenges include cost, access, and standardization.[38,39] In clozapine treatment for schizophrenia, HLA-DQB10602 and CYP enzyme profiling, along with NfL and CRP monitoring, can mitigate risks and personalize treatment to improve outcomes.[40,41]

 Emerging therapies at the intersection

Psychedelics and Neuroplasticity: Minimal doses of psychedelics (psilocybin, LSD) offer rapid, sustained relief from depression, PTSD, and addiction by targeting 5-HT2A receptors and enhancing neuroplasticity via synaptogenesis, dendritic growth, and BDNF upregulation, which is distinct from the effects.^[42]

Neuromodulation Techniques: DBS modulates mood circuits and is effective for Parkinson’s motor symptoms and refractory depression despite cognitive side effects.^[43] Noninvasive TMS enhances cortical excitability and synaptic activity, improving antidepressant efficacy and potentially reducing dosage.^[44]

Biologics, Gene Therapies, and Cannabinoids: Monoclonal antibodies (aducanumab) targeting amyloid-beta in Alzheimer’s disease represent disease-modifying biologics.^[45] AAV-based gene therapies deliver functional genes for rare disorders such as spinal muscular atrophy, demonstrating their safety and efficacy.^[46] THC/CBD combinations modulate the endocannabinoid system, effectively managing chronic pain, anxiety, and seizures with analgesic, anxiolytic, and anticonvulsant effects, particularly in pediatric epilepsy.[47,48]

 Translational challenges and opportunities

Preclinical to Clinical Translation: Animal models often poorly replicate the complexity of human brain disorders (depression, PTSD, and neurodegenerative diseases) owing to biological and behavioral differences.^[49] Humanized models (stem cells, tissues, and transgenic primates) combined with multi-omics offer more accurate preclinical relevance.[50,51]

Clinical Trial Design: Patient heterogeneity (genetics, severity, and comorbidities) complicates trials and reduces their generalizability.^[52] Adaptive designs that adjust parameters based on interim data and biomarker-based stratification enhance precision and efficiency.^[53]

Safety, Ethics, and Access Barriers: Emerging therapies (psychedelics and DBS) pose risks (e.g., psychosis and cognitive impairment) and require strict screening.[54,55] Genetic editing (CRISPR) and neuromodulation raise ethical concerns (consent, long-term effects, and misuse), necessitating stringent guidelines.^[56] Long approval timelines and access disparities in LMICs highlight equity challenges, necessitating streamlined regulations and global collaboration.[57,58]

Future directions

Gut-Brain Axis and AI in Neuropharmacology: The gut-brain axis and microbiome increasingly modulate drug metabolism and efficacy; specific bacteria influence bioavailability, inflammation, and neurotrophic signaling disorders. Microbiome-based interventions have shown neuroprotective potential. AI/ML enhances precision medicine by analyzing multi-omics data for target identification and response prediction, streamlining drug development, and personalizing treatments.

Clinical Integration and Emerging Therapies: Digital health platforms (wearables) enable real-time biomarker monitoring, adherence improvement, and personalized interventions. Multidisciplinary teams (pharmacists, psychiatrists, and neurologists) are crucial for providing comprehensive care. Neuroprotective compounds that target early pathological mechanisms (oxidative stress and inflammation) have the potential to delay the progression of neurodegenerative diseases. Psychedelic-assisted therapies have shown long-term efficacy for depression, PTSD, and addiction via neuroplasticity and emotional processing, with microbiome composition potentially influencing the response.

Policy, Education, and Funding: Clinicians require training in AI, pharmacogenomics, and digital health for effective implementation of advanced therapies. Robust funding and adaptive regulatory frameworks are vital for neurotherapeutic innovations. Advocacy must address translational barriers, ensure equitable access to treatment, and promote global collaboration.

Advancements in brain disorder treatment are contingent upon the integration of molecular neuroscience, digital health, and precision pharmacology. By elucidating the shared molecular foundations of psychiatric and neurological disorders and incorporating innovations such as pharmacogenomics, neuromodulation, and AI-guided therapies, neurotherapeutics can evolve from merely managing symptoms to modifying and preventing diseases. The clinical translation of these advancements necessitates not only technological progress but also systemic restructuring, including patient stratification, real-time monitoring, and multidisciplinary care.

To effectively address persistent barriers such as regulatory inertia, inequitable access, and inadequate training, it is imperative to engage in sustained investment, foster global cooperation, and develop scalable, context-sensitive interventions. The focus on the gut-brain axis, emerging neuroprotective agents, and long-term outcomes of psychedelic therapy signifies a transition towards a more holistic and personalized approach to mental health care. Ultimately, by dismantling disciplinary silos and centering translational science on patient-specific biology and lived experiences, neurotherapeutics can provide durable and equitable solutions in one of the most complex areas of medicine.

Abbreviations

General medical terms

DALYs – Disability-Adjusted Life Years, LMICs – Low- and Middle-Income Countries, CNS – Central Nervous System, TRD – Treatment-Resistant Depression, PTSD – Post-Traumatic Stress Disorder, BBB – Blood-Brain Barrier.

Disorders

MDD – Major Depressive Disorder, AD – Alzheimer’s Disease, PD – Parkinson’s Disease, MS – Multiple Sclerosis, ASD – Autism Spectrum Disorder.

Genes and molecular biology

BDNF – Brain-Derived Neurotrophic Factor, DISC1 – Disrupted in Schizophrenia 1, COMT – Catechol-O-Methyltransferase, NRG1 – Neuregulin 1, ZSCAN – Zinc Finger and SCAN Domain-Containing Protein, HLA – Human Leukocyte Antigen, AAV – Adeno-Associated Virus, NfL – Neurofilament Light Chain, CRP – C-Reactive Protein, SV2A – Synaptic Vesicle Glycoprotein 2A.

Pharmacogenomics / Enzymes

CYP450 – Cytochrome P450, CYP2D6, CYP2C19, CYP1A2 – Specific isoenzymes of Cytochrome P450 involved in drug metabolism, SLC6A4 – Solute Carrier Family 6 Member 4 (serotonin transporter gene), VKORC1 – Vitamin K Epoxide Reductase Complex Subunit 1.

Medications / Compounds

CBD – Cannabidiol, THC – Tetrahydrocannabinol, SGAs – Second-Generation Antipsychotics, TMS – Transcranial Magnetic Stimulation, DBS – Deep Brain Stimulation, AI/ML – Artificial Intelligence / Machine Learning, CRISPR – Clustered Regularly Interspaced Short Palindromic Repeats.

Genetic risk markers

APOE ε4 – Apolipoprotein E epsilon 4 allele, HLA-B1502, HLA-A3101 – Specific HLA gene variants, HLA-DQB1*0602 – HLA subtype associated with drug hypersensitivity.

Conflict of Interest

The author declares no conflicts of interest relevant to this article.