From brain circuits to gut health, a new review details the complex biology of mood disorders

A comprehensive new review published in the journal Science China Life Sciences synthesizes decades of research to explain how anxiety and depression arise from a complex interplay of genetic vulnerabilities, environmental stress, and widespread changes in the brain’s biology. The authors provide a detailed roadmap of the underlying mechanisms, from malfunctioning brain circuits to the influence of gut bacteria, offering a clearer picture of why these conditions are so prevalent and pointing toward more personalized and effective treatments.

Anxiety disorders and depression represent a significant global health challenge, affecting individual well-being and placing a heavy burden on society. The review highlights the staggering scale of the problem and the urgent need for a deeper understanding of these conditions.

“Our review shows that over the past two decades, the prevalence of anxiety and depression has continued to rise. In 2021 alone, nearly 700 million people were affected globally. Together, these disorders account for more than 90 million years of healthy life lost each year,” said Professor Wei-Hua Yue, dean of the Peking University Sixth Hospital and a corresponding author of the review. “The COVID-19 pandemic further fueled this trend, adding tens of millions of new cases in 2020. The numbers are truly alarming.”

Professor Yue also pointed out that existing treatments, while beneficial for many, are not a complete solution. “Not all patients respond well. Side effects such as weight gain and emotional blunting are common, and effective options for treatment-resistant cases or older adults are limited,” she noted. “This reality makes it essential to explore the underlying biological mechanisms of these disorders, which will be fundamental for advancing precision psychiatry and tailoring interventions to individual needs.”

One of the most significant advances discussed in the review is the shift toward understanding how entire networks of brain cells, known as neural circuits, become dysfunctional. This approach moves beyond looking at single brain regions in isolation and instead examines how they communicate and work together to regulate mood and emotion.

“We think of neural circuits as the brain’s intricate wiring system, networks of neurons that communicate to regulate specific functions, such as processing emotions or making decisions,” explained Professor Bing-Xing Pan of Nanchang University, the lead researcher of the study. “Rather than studying brain regions in isolation, this approach examines how different regions connect and work together dynamically, much like an electrical grid powering a city.”

Professor Pan’s work has helped identify specific circuit breakdowns linked to symptoms. “For instance, we recently identified that hyperactivity in the prefrontal-amygdala circuit is strongly linked to anxiety-like behaviors, while reduced function in the hippocampus-nucleus accumbens circuit is associated with anhedonia, a core symptom of depression where a person loses the ability to feel pleasure,” he said. “Overactivation of the lateral habenula, often called the brain’s ‘anti-reward center,’ can significantly drive depression-like behaviors. These insights not only expand our understanding of emotional disorders but also highlight new targets for neuromodulation and circuit-based therapies.”

The review provides a thorough analysis of the multiple biological systems that go awry in anxiety and depression. For many years, the leading theory was the “monoamine hypothesis,” which suggested that these conditions were caused by a simple deficiency of neurotransmitters like serotonin, norepinephrine, and dopamine. While medications that increase these chemicals can be effective, they often take weeks to work and do not help everyone, suggesting a more complex picture. The review explains that these drugs likely initiate a cascade of downstream changes, including promoting the growth of new brain cells and altering signaling pathways, which are responsible for their therapeutic effects.

Beyond serotonin, the review details the dysfunction of the brain’s primary excitatory and inhibitory systems, governed by the neurotransmitters glutamate and GABA. Chronic stress can lead to an excess of glutamate in brain regions responsible for emotional control, like the prefrontal cortex, causing a state of over-excitation that damages neurons. At the same time, the brain’s main inhibitory system, which relies on GABA to calm neural activity, can become weakened. This imbalance between excitation and inhibition is considered a core feature of these disorders.

The authors also synthesize evidence on the role of the body’s stress response system, the hypothalamic-pituitary-adrenal (HPA) axis. This system releases the stress hormone cortisol. In many people with depression, the HPA axis becomes chronically overactive, leading to sustained high levels of cortisol that can damage the hippocampus, a brain area vital for memory and mood regulation.

Another area of focus is neuroinflammation, the inflammatory response within the brain. The review describes how chronic stress can activate the brain’s resident immune cells, called microglia. When over-activated, these cells release inflammatory molecules that can interfere with neurotransmitter systems and contribute to the death of neurons, fostering a brain environment conducive to depression and anxiety.

Expanding beyond the brain, the review explores the growing field of the body-brain axis, highlighting how peripheral systems influence mental health. The gut-brain axis has received particular attention, as the community of microorganisms in the digestive tract can produce compounds that communicate with the brain. An unhealthy balance of gut bacteria has been consistently linked to both anxiety and depression. Similar communication pathways exist between the brain and other organs, including the liver, lungs, and even bones, indicating that mental health is deeply intertwined with whole-body physiology.

Ultimately, the review serves as a bridge between foundational neuroscience and clinical practice. The detailed understanding of these biological mechanisms is already paving the way for new diagnostic tools and treatments.

“Future studies should integrate cutting-edge technologies with clinical practice, accelerate the discovery of reliable biomarkers, and support the development of cross-diagnostic treatments,” said Professor Qi-Gang Zhou of Nanjing Medical University, a co-corresponding author. “These efforts will be vital for building more precise, effective, and comprehensive strategies to manage mental health disorders.”

By consolidating what is known about the biological underpinnings of anxiety and depression, the researchers provide a framework for the next generation of mental healthcare, one that moves away from a one-size-fits-all model and toward personalized therapies aimed at correcting the specific biological dysfunctions driving an individual’s symptoms.

The study, “Unveiling the enigma of anxiety disorders and depression: from pathogenesis to treatment,” was authored by Han-Qing Pan, Tian Xia, Yu-Ya-Nan Zhang, Hui-Jie Zhang, Meng-Jie Xu, Jing Guo, Yan Liu, Xue-Ying Bai, Qian Liu, Wei-Zhu Liu, Wen-Hua Zhang, Qi-Gang Zhou, Wei-Hua Yue, and Bing-Xing Pan.