Mental illness is caused by the whole body - not just the brain

Mental illnesses affect one in four people at some point in life. Yet, treatment often remains a guessing game. Traditional drugs target brain chemicals like serotonin and dopamine, ignoring how the immune system may also affect the brain.

But many patients do not benefit. A new study from the University of Bristol may explain why. The research links immune system activity to several neuropsychiatric disorders, including depression and schizophrenia.

This work, led by Dr. Christina Dardani and Professor Golam Khandaker, suggests we must think beyond the brain. Immune signals in the blood and brain both appear involved in mental illness. This insight could help develop new, more effective treatments.

Why brain drugs fail for some

Most mental health drugs act on neurotransmitters. But these therapies fail in about one-third of patients.

That failure points to deeper biological roots. Immune system involvement is one such possibility. Immune-activating drugs, for example, often trigger depression. Infections and autoimmune diseases are also linked with mental illness.

This new study used Mendelian randomization – a method that analyzes genetic data to find causal relationships. The researchers studied 736 immune-related proteins found in human blood and brain. They examined how these proteins relate to seven mental conditions.

Immune proteins in the brain and blood

The researchers applied a three-tier system to assess causality. They looked at depression, schizophrenia, bipolar disorder, Alzheimer’s disease, ADHD, autism, and anxiety.

From over 700 proteins, the team identified 29 linked with these disorders. These findings met strict statistical and biological standards.

Among the 29, some were already known drug targets. Twenty of the proteins had drugs either approved or in trials for other diseases. These include ACE, CD40, AGER, TNFRSF17, and SERPING1. Their link with mental illness now opens paths for drug repurposing.

Linking disorders to specific proteins

For schizophrenia, the experts identified 57 immune biomarkers. Four met the strictest Tier A standard. Notable ones included AGER, PDIA3, and NAGA. These genes are involved in glycosylation, a process tied to brain function.

Depression had 24 related proteins, including EP300 and FCN1. Bipolar disorder shared some markers with schizophrenia, especially CD40 and DNPH1.

Alzheimer’s disease showed 28 immune-related markers. APOC1 and CR1 were among the strongest candidates. These proteins had already been linked to Alzheimer’s in earlier studies.

The risk of mental illness

“Our study demonstrates that inflammation in the brain and the body might influence the risk of mental health conditions,“ noted Golam Khandaker, Professor of Psychiatry and Immunology.

“The findings challenge the centuries-old Cartesian dichotomy between the body and the mind, and suggests that we should consider depression and schizophrenia as conditions affecting the whole person.”

This viewpoint encourages treatment approaches that account for both brain and body.

From biomarkers to medicines

Drug development for mental health has slowed in recent decades. Many trials on anti-inflammatory drugs for depression and schizophrenia failed.

A reason might be the poor selection of targets. This study narrows the field using strong genetic and molecular data.

ACE plays a role in both schizophrenia and Alzheimer’s disease and already has approved medications for heart conditions.

CD40 is implicated in schizophrenia and bipolar disorder, and its involvement in multiple conditions suggests it could serve as a cross-disorder therapeutic target.

Using immune drugs on the brain

Some biomarkers affect mental health through both blood and brain. For example, CD40 and ACE act in both tissues. But this could lead to side effects if drugs affect the wrong organs.

CD40 has low tissue specificity, and ACE is mostly active in the gut. These features must be considered before using these targets in new treatments.

Some biomarkers influence multiple disorders. ACE may contribute to both schizophrenia and Alzheimer’s, perhaps by impairing memory.

CD40 might increase risk for both bipolar and schizophrenia by promoting psychosis. Shared symptoms suggest overlapping biological roots.

But timing also matters. Schizophrenia begins early, while Alzheimer’s emerges much later. The effects of immune proteins may differ at each stage. Future research must examine this complexity.

Hope for treating mental illness

The researchers plan to test their findings using health records, animal studies, and clinical trials. They also urge caution. Most data come from people of European ancestry. More diverse studies are needed.

The research paves the way for novel therapies. But success will depend on careful trial design, consideration of side effects, and better understanding of immune signaling.

By exploring the full biology of the immune system and brain, this work offers fresh hope for millions of people living with mental illness.

The study is published in the journal Molecular Psychiatry.

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