The Hypothesis Dump

Opinion,

Western psychiatry insists to a great extent on a reductionist, micro-categorical framework that can still lead to viewing mental and physical health as distinct entities. Although psychiatry is gradually shifting from this view, I argue for a systemic reconfiguration toward a unified, systemic view of human health, hypothesizing that chronic stress sensitivity, neurodivergence, affective disorders, and neurodegenerative conditions share an overlapping genetic vulnerability that is actively “programmed” by the prenatal and early-life neuroimmune milieu. By capitalizing on the hypotheses linking the gut-brain axis, mitochondrial dysfunction, and the antimicrobial properties of amyloid-beta, I seek to illustrate that psychiatric symptoms are local expressions of a highly interconnected, systemic immunometabolic response.

For decades, clinical psychology and psychiatry have looked through a microscope at isolated systems, creating an ever-expanding registry of discrete diagnostic labels. While beneficial for clinical practice, this hyper-categorization has also had consequences, namely prompting us to miss the broader narrative. The human body operates as a single, wholly interconnected system. For example, high heritability overlaps across ostensibly distinct disorders, such as autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, which could mean that we are not dealing with isolated genetic defects, but rather a shared pool of pleiotropic genes that dictate generalized neural and immune sensitivity (Bourque et al., 2024).

The trajectory from genetic predisposition to clinical pathology is fundamentally carved out in early development. And by that, I mean as early as the prenatal milieu and early-life adversity, which act as potent epigenetic sculptors (van Bodegom et al., 2017). When a pregnant mother or developing child is exposed to chronic, unremitting stress, elevated pro-inflammatory cytokines cross the placental and blood-brain barriers, permanently altering the development of fetal microglia (Akhtar et al., 2017). This early-life adversity effectively “programs” the hypothalamic-pituitary-adrenal (HPA) axis, inducing glucocorticoid receptor resistance, flattening the diurnal cortisol curve, and locking the sympathetic nervous system into a chronic state of over-activation (Warren et al., 2024).

Another culprit in this interplay is the gastrointestinal tract. Under chronic stress exposure, the tight junctions of the intestinal epithelium can degrade, leading to increased intestinal permeability, or “leaky gut” (Cryan et al., 2019). This allows lipopolysaccharides (LPS) to translocate into the bloodstream, triggering a low-grade, systemic immune cascade. Circulating cytokines breach the blood-brain barrier (BBB), activating the microglia, the brain’s “housekeeper” immune cells, and shifting the brain into a state of chronic neuroinflammation. This low-grade neuroinflammation is now heavily implicated not only in major depressive disorders but also in the atypical synaptic pruning observed in neurodivergent spectrums like ADHD and ASD (de Silva et al., 2018).

Another observation I have made, which I think is very much along the same lines, is the emergence of repetitive, obsessive, and stereotypical behaviors under high neural “arousal”. These behaviors are not random neurological malfunctions, but rather potentially somatosensory regulatory mechanisms designed to soothe a hyper-aroused nervous system. When top-down cortical structures are overwhelmed by anxiety, subcortical structures (such as the basal ganglia) initiate rhythmic, repetitive motor loops to physically lower sympathetic tone.

The neuroimmunological nature of these loops is starkly visible in early-onset disorders. Obsessive-compulsive disorder (OCD) frequently manifests in early childhood because the cortico-striato-thalamo-cortical (CSTC) circuits mature early (Meyer et al., 2021). Another indication of this somatic-immune linkage is found in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS), where post-infectious molecular mimicry causes antibodies to directly assault the basal ganglia, inducing severe OCD overnight (Swedo et al., 2012). We may be witnessing a global scale-up of this exact mechanism in long COVID, where persistent viral reservoirs and microglial activation manifest as severe executive dysfunction, anxiety, and obsessive-focused distress (Caliman-Sturdza et al., 2025).

If we go deeper to the cellular level, this systemic strain can lead to “metabolic crisis”, causing dysfunctional mitochondria to leak cell-free mitochondrial DNA (mtDNA) into the cytoplasm (Venkatesan et al., 2026). It is important to note that besides them being the “powerhouse of the cell”, mitochondria also serve as cell-danger security systems. The immune system flags this as a bacterial pathogen, activating autoreactive T-cells that turn against host tissues, a mechanism suggesting both peripheral autoimmune conditions (e.g., Hashimoto’s thyroiditis) and neurodegenerative pathways like ALS.

This immune-driven perspective re-contextualizes the hallmark pathology of diseases that plague our modern world, such as Alzheimer’s disease. Emerging research indicates that amyloid-beta is not merely metabolic waste, but an active antimicrobial peptide (Bruno et al., 2022). When the brain perceives a neuroinflammatory threat or barrier breach, it may build a protective “web” of amyloid-beta to entrap pathogens and neutralize inflammation. In a chronically stressed system, this protective mechanism over-activates, resulting in the neurotoxic plaque accumulations characteristic of Alzheimer’s.

Finally, any unified theory of neuroimmunology must account for the profound sex asymmetry in these conditions; women carry a double risk for depression, anxiety, PTSD, and autoimmune disorders. This is driven by a biological intersection of genetics and endocrinology. The X chromosome contains the human genome’s densest concentration of immune-related genes, giving individuals with an XX genotype a hyper-vigilant immune response (Feng et al., 2024). When paired with the immune-amplifying properties of fluctuating estrogen, the female system is evolutionarily optimized for highly aggressive defence against pathogens. The evolutionary trade-off of this hyper-reactive system is a significantly elevated vulnerability to autoimmune self-attack and chronic neuroinflammation under prolonged allostatic load (cumulative wear from chronic stress).

If our brains and bodies are shouting that they operate as a single, interconnected system, why does psychiatry persist in treating them in fragments? It is time to step back from the microscope and listen to the whole organism. Let’s get to work and restructure medicine and education!

Declaration of AI use: The author used Gemini AI for spelling, grammar-checking and wording during the preparation of this article.

References

Akhtar, F., Rouse, C. A., Catano, G., Montalvo, M., Ullevig, S. L., Asmis, R., … & Maffi, S. K. (2017). Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress. Journal of Neuroinflammation, 14(1), 195. https://doi.org/10.1186/s12974-017-0965-8

Bourque, V. R., Poulain, C., Proulx, C., Moreau, C. A., Joober, R., Forgeot d’Arc, B., … & Jacquemont, S. (2024). Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment. Translational Psychiatry, 14(1), 171. https://doi.org/10.1038/s41398-024-02866-3

Bruno, F., Malvaso, A., Canterini, S., & Bruni, A. C. (2022). Antimicrobial peptides (AMPs) in the pathogenesis of Alzheimer’s disease: implications for diagnosis and treatment. Antibiotics, 11(6), 726. https://doi.org/10.3390/antibiotics11060726

Caliman-Sturdza, O. A., Gheorghita, R., & Lobiuc, A. (2025). Neuropsychiatric manifestations of long COVID-19: a narrative review of clinical aspects and therapeutic approaches. Life, 15(3), 439. https://doi.org/10.3390/life15030439

Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., … & Dinan, T. G. (2019). Microbiota-Gut-Brain Axis. Physiological Reviews, 99(4), 1877–2013. https://doi.org/10.1152/physrev.00018.2018

de Silva, P. N. (2018). Do patterns of synaptic pruning underlie psychoses, autism and ADHD? BJPsych Advances, 24(3), 212–217. https://doi.org/10.1192/bja.2017.27

Feng, Z., Liao, M., & Zhang, L. (2024). Sex differences in disease: sex chromosome and immunity. Journal of Translational Medicine, 22(1), 1150. https://doi.org/10.1186/s12967-024-05990-2

Meyer, J. (2021). Inflammation, obsessive-compulsive disorder, and related disorders. In The neurobiology and treatment of OCD: accelerating progress (pp. 31–53). Cham: Springer International Publishing. https://doi.org/10.1007/7854_2020_210

Swedo, S. E., Leckman, J. F., & Rose, N. R. (2012). From research to clinic: PANDAS and PANS. American Journal of Psychiatry, 169(4), 345–350. https://doi.org/10.1176/appi.ajp.2011.11060879

Van Bodegom, M., Homberg, J. R., & Henckens, M. J. (2017). Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Frontiers in Cellular Neuroscience, 11, 87. https://doi.org/10.3389/fncel.2017.00087

Venkatesan, S., Comi, C., De Marchi, F., Esposito, T., Gramaglia, C., Smirne, C., … & Grossini, E. (2026). Mitochondrial dysfunction: the cellular bridge from emotional stress to disease onset: a narrative review. Biomolecules, 16(1), 117. https://doi.org/10.3390/biom16010117