Institute for Translational Medicine and Pharmacology at Mount Sinai

The Psychoneuroimmunology Research Program represents an initiative to understand and address the biological origins of mental health conditions. Led by Dolores Malaspina, MD, MS, MSPH, Professor of Psychiatry and Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, and Julie Spicer, PhD, Assistant Professor of Psychiatry and Pharmacological Sciences, Icahn School of Medicine, the program integrates cutting-edge research across psychoneuroimmunology with genetics, and endocrinology to unravel the complex mechanisms underlying depression, anxiety, and psychosis. By identifying the biological pathways that drive these conditions, our research aims to transform clinical care through the development of targeted, personalized interventions for mental health disorders that have long been poorly understood and inadequately treated.

Perimenopause and Mental Health: Uncovering Hormonal Triggers

One of the most significant yet understudied challenges in women's mental health occurs during the perimenopausal transition—the years leading up to menopause, when hormonal fluctuations can profoundly impact psychological wellbeing. Approximately a third of women experience new or worsening symptoms of depression and anxiety during this period, with some developing severe manifestations, including late-onset psychosis. Despite the prevalence and often debilitating nature of these symptoms, the underlying biological mechanisms have remained largely unknown, leaving clinicians without effective strategies for prevention or targeted treatment.

With support from the National Institutes of Health, our research program is testing an innovative biological model that challenges conventional understanding of perimenopausal mental health. While most prior research has focused exclusively on declining estrogen levels as the culprit, our work examines the potentially critical roles of two other hormones: follicle-stimulating hormone (FSH) and ghrelin. Our central hypothesis proposes that these hormones trigger psychiatric symptoms by promoting systemic inflammation, a pathway that, if confirmed, could open entirely new avenues for therapeutic intervention.

Emerging evidence reveals that both FSH and ghrelin possess powerful regulatory functions that extend far beyond their traditionally recognized roles in reproduction and appetite regulation, respectively. FSH, which rises dramatically during perimenopause, may influence neuroinflammation and cognitive function through mechanisms independent of its effects on ovarian function. Ghrelin, often called the "hunger hormone," also modulates mood, stress response, and neuroplasticity. By examining how these hormones interact with inflammatory pathways to affect brain function and mental health, we aim to identify novel biomarkers and therapeutic targets.

To rigorously test this model, we have designed a longitudinal menopause study that recruits women undergoing prophylactic oophorectomy (surgical removal of the ovaries) to reduce their future cancer risk, alongside a comparison group of women undergoing other gynecological procedures. This study design allows us to track hormonal changes and mental health outcomes with unprecedented precision, examining how rapid hormonal shifts influence inflammatory markers, brain function, and psychiatric symptoms. The findings from this research have the potential to fundamentally reshape how we understand and treat perimenopausal mental health conditions, moving beyond one-size-fits-all approaches to personalized interventions based on individual hormonal and inflammatory profiles.

The Gut-Brain Axis: From Microbiome to Mental Health

In a complementary line of investigation, our program explores inflammation as a central pathway to mood and psychotic symptoms through the lens of the gut-brain axis. This research integrates three interconnected biological systems: the gut microbiome (the trillions of microorganisms residing in the digestive tract), the autonomic nervous system (which mediates communication between the gut and brain), and neuroinflammation (inflammatory processes within the brain itself). Understanding how these systems interact provides crucial insights into the biological origins of mental illness and offers promising new strategies for intervention.

The gut microbiome has emerged as a major regulator of both physical and mental health. A balanced and diverse gut microbial community—a state called eubiosis—is associated with lower levels of systemic inflammation and better overall health outcomes. Conversely, reduced microbial diversity accompanied by an increased abundance of pro-inflammatory bacterial taxa creates a state of dysbiosis that promotes chronic inflammation throughout the body, including the brain. Dysbiosis is now recognized as an established pathogenic mechanism in conditions such as inflammatory bowel disease, obesity, and metabolic syndrome. Our recent research has demonstrated that dysbiosis can also produce brain inflammation, providing a direct mechanistic link between gut health and mental health.

Building on these findings, we have uncovered a pathway connecting diet, the microbiome, and brain function. Our work demonstrated that poor dietary patterns in individuals with dysbiosis are associated with specific gut microbial compositions that impair brain signaling by hydrogen sulfide (H₂S), a critical neuromodulator and neuroprotective molecule. H₂S plays essential roles in fundamental brain processes, including learning and memory formation, and dysregulation of H₂S signaling has been implicated in psychotic disorders. Specifically, H₂S facilitates long-term potentiation—the cellular basis of learning and memory—and modulates N-methyl-D-aspartate receptor function, which is crucial for synaptic plasticity and cognitive function. When dietary patterns promote microbial communities that disrupt H₂S signaling, the consequences can extend to impaired cognition and increased psychiatric symptoms.

These discoveries have inspired the next phase of our research: a "food as medicine" dietary intervention study for individuals at risk for severe mental illness. This innovative trial will test whether targeted dietary modifications can reshape the gut microbiome composition to optimize H₂S signaling pathways, thereby improving learning, memory, and psychiatric symptoms. Unlike traditional psychiatric treatments that target brain chemistry directly through medications, this approach works upstream, modifying the gut ecosystem to naturally restore healthy brain function. If successful, this research could establish dietary intervention as a safe, accessible, and effective strategy for preventing or treating serious mental illness, offering hope to individuals who may not respond adequately to conventional treatments or who seek non-pharmacological approaches to mental health care.