Viable targets – psychiatric disorders – identified
The history of pharmacologic therapy for psychiatric disorders is largely one of observation and assumption. That mirrors other conditions where an absence of good model systems underpins a lack of mechanistic knowledge. This in turn leads to limited drug development. However, psychiatric disorders carry in that history the additional burden of being viewed as less about biology, and more about personality, or mental capacity.
In fact, the umbrella term of “mental health” continues to carry a stigma that suggests someone suffering ill mental health simply needs to adjust their thinking. And yet, psychiatric disorders have diagnostic features that are as clear as many other disorders and syndromes which are considered purely medical in nature. It is perhaps a question for philosophers and policy leaders as to why disorders of the mind are somehow considered, dealt with, and treated differently than disorders of the rest of the body. I shall leave that discussion for others.
The biologists among us will readily recognize the brain is governed by biology, which is itself governed by the underlying physics of existence in a world of matter. So much so, that some may reach what they consider the inescapable conclusion that despite the appearance otherwise, individuals do not in fact have free will Sapolsky, Determined: A Science of Life without Free Will. In the context of brain biology, the results of what is arguably the most complex biology, are personality, mood, reasoning, cognition, memory, and decision-making functions.
Scientists are able to delineate a wide variety of features about our personalities that appear to either stem from our genetics (and thus our lineage) as well as features that appear derived from, or at least influenced by, external exposures. Though it should be noted, external exposures still require a genetic component with which to interact and produce the resultant effect (i.e., the context of the exposure makes a difference).
This connection has not been lost on drug developers but given the relatively limited knowledge of what genes play specific roles in development and maintenance of normal brain functions, it is perhaps not surprising there is also a more profound lack of knowledge about what genes play a role when brain functions go awry.
Looking back at the history of drug development for psychiatric conditions, the bulk of earlier drugs were identified as useful merely from observation of their general psychiatric effects. Later, some very basic biologic mechanisms associated with neuronal function were thought to be the primary drivers of many psychological behaviors, and by extension in psychiatric disorders. This was despite data indicating other biology was likely at play for many, if not most.
Still, there were some positive effects from these early, biology-based drug targets, culminating in the big breakthroughs of serotonin/receptor and dopamine/receptor targets, which have dominated and were largely the only options with any noted efficacy, even if limited, for many decades. More recently, a new option has been approved for schizophrenia targeting the novel mechanism of muscarinic (cholinergic) receptors.
The once blockbuster drugs, while useful for some patients, have generally recognized limited efficacy compared to side effects. This is especially true for the broad indications of depression and anxiety. The limited druggable targets/biomarkers combined with the broad indications, appears to have resulted in a large portion of patients being refractory to available treatment options. It is therefore hard to argue with the idea that better understanding of psychiatric biology is needed in order to identify new therapeutic targets.
Recent revelations have linked immunobiology to psychiatric conditions, many by association, others through more specific markers and/or mechanisms. Still others have identified connections between the microbiome and psychiatric conditions.
These associations and underlying mechanisms are far from the past focus on neurochemical transmitters. In fact, they highlight the interactions across the entire organism that likely contribute in differing ways to the initiation, development and progression of psychiatric conditions- and conversely, the normal and highly complex nature of our very thought processes being influenced by our environment, our organismal biology, and ultimately our genes.
The good news is all this improved understanding of the systems biology and the connection to psychiatric connections means there are now many new biomarkers and thus potential druggable targets.
Christina Dardani, et al., have undertaken a herculean task seeking to identify all genetic causal contributors to psychiatric conditions. It is hard to say if their careful and thorough approach has in fact identified all causal genetic contributors, but it is clear the identified genes are associated with diverse biological processes, especially immunological. This again highlights how diverse the mechanisms of neuropsychological disorders can be.
Fortunately, Dardani found the list of potentially causative genes is relatively short, just 29 biomarkers. The exciting part is having identified these genes, we now have a focused list of new therapeutic targets. Of particular note, 20 are considered currently druggable with existing approved or late-stage drugs, setting the stage for new or expanded trials covering a range of indications with significant, continuing unmet medical need. This is exciting progress for the field with validation that many biological processes are at play and available as therapeutic targets!
Commentary
On Dardani, C., Robinson, J.W., Jones, H.J. et al. Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03032-x
Author’s Affiliation
Christopher Ballas, PhD, Cell and Gene Therapy Science and Manufacturing Executive, Philadelphia, PA, USA.
References
Determined: A Science of Life Without Free Will by Robert M. Sapolsky, Penguin Random House, Oct 15, 2024 | ISBN 9780525560999
Jung JY, Ahn Y, Park JW, Jung K, Kim S, Lim S, Jung SH, Kim H, Kim B, Hwang MY, Kim YJ, Park WY, Okbay A, O’Connell KS, Andreassen OA, Myung W, Won HH. Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation. Nat Hum Behav. 2025 Apr 14. doi: 10.1038/s41562-025-02155-z. Epub ahead of print. PMID: 40229577.
Paul, S.M., Potter, W.Z. Finding new and better treatments for psychiatric disorders. Neuropsychopharmacol. 49, 3–9 (2024). https://doi.org/10.1038/s41386-023-01690-5
Alfonso Troisi. Biological Psychiatry is Dead, Long Live Biological Psychiatry! December 2022 Clinical Neuropsychiatry 19(6):351-354 DOI:10.36131/cnfioritieditore20220601
Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28, 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0
Kaul I, Sawchak S, Walling DP, et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(8):749–756. doi:10.1001/jamapsychiatry.2024.0785
Vasile C. Mental health and immunity (Review). Exp Ther Med. 2020 Dec;20(6):211. doi: 10.3892/etm.2020.9341. Epub 2020 Oct 14. PMID: 33149775; PMCID: PMC7604758.
Kopec AM, Smith CJ, Bilbo SD. Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator? Trends Neurosci. 2019 May;42(5):337-348. doi: 10.1016/j.tins.2019.02.005. Epub 2019 Mar 16. PMID: 30890276; PMCID: PMC6486862.
Delanote, J., Correa Rojo, A., Wells, P.M. et al. Systematic identification of the role of gut microbiota in mental disorders: a TwinsUK cohort study. Sci Rep 14, 3626 (2024). https://doi.org/10.1038/s41598-024-53929-w
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Finally! Viable New Targets For Psychiatric Disorders Are Identified And Druggable! Thoughts from a non-psychiatrist/non-neurobiologist:
Viable targets – psychiatric disorders – identified
The history of pharmacologic therapy for psychiatric disorders is largely one of observation and assumption. That mirrors other conditions where an absence of good model systems underpins a lack of mechanistic knowledge. This in turn leads to limited drug development. However, psychiatric disorders carry in that history the additional burden of being viewed as less about biology, and more about personality, or mental capacity.
In fact, the umbrella term of “mental health” continues to carry a stigma that suggests someone suffering ill mental health simply needs to adjust their thinking. And yet, psychiatric disorders have diagnostic features that are as clear as many other disorders and syndromes which are considered purely medical in nature. It is perhaps a question for philosophers and policy leaders as to why disorders of the mind are somehow considered, dealt with, and treated differently than disorders of the rest of the body. I shall leave that discussion for others.
The biologists among us will readily recognize the brain is governed by biology, which is itself governed by the underlying physics of existence in a world of matter. So much so, that some may reach what they consider the inescapable conclusion that despite the appearance otherwise, individuals do not in fact have free will Sapolsky, Determined: A Science of Life without Free Will. In the context of brain biology, the results of what is arguably the most complex biology, are personality, mood, reasoning, cognition, memory, and decision-making functions.
Scientists are able to delineate a wide variety of features about our personalities that appear to either stem from our genetics (and thus our lineage) as well as features that appear derived from, or at least influenced by, external exposures. Though it should be noted, external exposures still require a genetic component with which to interact and produce the resultant effect (i.e., the context of the exposure makes a difference).
This connection has not been lost on drug developers but given the relatively limited knowledge of what genes play specific roles in development and maintenance of normal brain functions, it is perhaps not surprising there is also a more profound lack of knowledge about what genes play a role when brain functions go awry.
Looking back at the history of drug development for psychiatric conditions, the bulk of earlier drugs were identified as useful merely from observation of their general psychiatric effects. Later, some very basic biologic mechanisms associated with neuronal function were thought to be the primary drivers of many psychological behaviors, and by extension in psychiatric disorders. This was despite data indicating other biology was likely at play for many, if not most.
Still, there were some positive effects from these early, biology-based drug targets, culminating in the big breakthroughs of serotonin/receptor and dopamine/receptor targets, which have dominated and were largely the only options with any noted efficacy, even if limited, for many decades. More recently, a new option has been approved for schizophrenia targeting the novel mechanism of muscarinic (cholinergic) receptors.
The once blockbuster drugs, while useful for some patients, have generally recognized limited efficacy compared to side effects. This is especially true for the broad indications of depression and anxiety. The limited druggable targets/biomarkers combined with the broad indications, appears to have resulted in a large portion of patients being refractory to available treatment options. It is therefore hard to argue with the idea that better understanding of psychiatric biology is needed in order to identify new therapeutic targets.
Recent revelations have linked immunobiology to psychiatric conditions, many by association, others through more specific markers and/or mechanisms. Still others have identified connections between the microbiome and psychiatric conditions.
These associations and underlying mechanisms are far from the past focus on neurochemical transmitters. In fact, they highlight the interactions across the entire organism that likely contribute in differing ways to the initiation, development and progression of psychiatric conditions- and conversely, the normal and highly complex nature of our very thought processes being influenced by our environment, our organismal biology, and ultimately our genes.
The good news is all this improved understanding of the systems biology and the connection to psychiatric connections means there are now many new biomarkers and thus potential druggable targets.
Christina Dardani, et al., have undertaken a herculean task seeking to identify all genetic causal contributors to psychiatric conditions. It is hard to say if their careful and thorough approach has in fact identified all causal genetic contributors, but it is clear the identified genes are associated with diverse biological processes, especially immunological. This again highlights how diverse the mechanisms of neuropsychological disorders can be.
Fortunately, Dardani found the list of potentially causative genes is relatively short, just 29 biomarkers. The exciting part is having identified these genes, we now have a focused list of new therapeutic targets. Of particular note, 20 are considered currently druggable with existing approved or late-stage drugs, setting the stage for new or expanded trials covering a range of indications with significant, continuing unmet medical need. This is exciting progress for the field with validation that many biological processes are at play and available as therapeutic targets!
Commentary
On Dardani, C., Robinson, J.W., Jones, H.J. et al. Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03032-x
Author’s Affiliation
Christopher Ballas, PhD, Cell and Gene Therapy Science and Manufacturing Executive, Philadelphia, PA, USA.
References
Determined: A Science of Life Without Free Will by Robert M. Sapolsky, Penguin Random House, Oct 15, 2024 | ISBN 9780525560999
Jung JY, Ahn Y, Park JW, Jung K, Kim S, Lim S, Jung SH, Kim H, Kim B, Hwang MY, Kim YJ, Park WY, Okbay A, O’Connell KS, Andreassen OA, Myung W, Won HH. Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation. Nat Hum Behav. 2025 Apr 14. doi: 10.1038/s41562-025-02155-z. Epub ahead of print. PMID: 40229577.
Paul, S.M., Potter, W.Z. Finding new and better treatments for psychiatric disorders. Neuropsychopharmacol. 49, 3–9 (2024). https://doi.org/10.1038/s41386-023-01690-5
Alfonso Troisi. Biological Psychiatry is Dead, Long Live Biological Psychiatry! December 2022 Clinical Neuropsychiatry 19(6):351-354 DOI:10.36131/cnfioritieditore20220601
Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28, 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0
Kaul I, Sawchak S, Walling DP, et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(8):749–756. doi:10.1001/jamapsychiatry.2024.0785
Vasile C. Mental health and immunity (Review). Exp Ther Med. 2020 Dec;20(6):211. doi: 10.3892/etm.2020.9341. Epub 2020 Oct 14. PMID: 33149775; PMCID: PMC7604758.
Kopec AM, Smith CJ, Bilbo SD. Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator? Trends Neurosci. 2019 May;42(5):337-348. doi: 10.1016/j.tins.2019.02.005. Epub 2019 Mar 16. PMID: 30890276; PMCID: PMC6486862.
Delanote, J., Correa Rojo, A., Wells, P.M. et al. Systematic identification of the role of gut microbiota in mental disorders: a TwinsUK cohort study. Sci Rep 14, 3626 (2024). https://doi.org/10.1038/s41598-024-53929-w
Related stories you may like:
Generalized Anxiety Disorder Linked to High IFN-γ and TNF-α but Low IL-10 Peripheral Levels
Anxiety and CRP levels
Anxiety and Vulnerability to Stress May Contribute to the Development of Dementia
Substance P Promotes Th17 Phenotype in Generalized Anxiety Disorder
Magnified IL-6 Response Linked To Stress Susceptibility and Higher Risk of Depression
The ‘Old Friends’ Hypothesis and Why Living in the Modern World May Increase Vulnerability to Major Depression
Role of Peripheral Immunity in Cognitive Decline During Parkinson’s Disease
Beta2-Adrenergic Agonists for Parkinson’s Disease: Repurposing Drugs at the Crossroad of the Brain and the Immune System
Anxiety and Vulnerability to Stress Contribute to the Development of Dementia
Stress in Middle Age Women Linked to Dementia and Alzheimer’s Risk Decades Later
New Evidence Linking Clusterin and Other Complement Proteins to Alzheimer’s Progression and Prediction
New Evidence Suggests Targeting Neuroinflammation May Be One Key to Slowing Alzheimer’s Disease