A Walsh Research Institute scientist presented an advanced theory of bipolar disorder at the annual meeting of the Society for Neuroscience, Neuroscience 2024.

After a multi-year investigation of recent neuroscience advances, Dr William Walsh believes he has resolved many unknowns that have puzzled researchers for a century, including the cause of bipolar disorder and an explanation for chronic cycling between mania and depression.

More than nine million Americans have been diagnosed with this disorder, which is a leading cause of suicide, unemployment and the “loss of human potential”.

Study developments

An early focus was bipolar disorder’s typical oxidative overload including superoxide, hydroxyl ions, and ONOO free radicals that assault DNA. An analysis concluded that bipolar disorder is a late onset DNA-damage illness involving creation of newly-mutated genes with advancing age.

After 30 years of failure to find a single mutated gene, a 2021 GWAS study (Mullins, et al) identified 64 low-effect genetic variants that increase bipolar disorder risk. A novel exclusion analysis removed well-known DNA damage mutations that obscure the search for ‘true’ bipolar disorder gene variants.

Evaluation of the exclusion results identified bipolar disorder’s major genetic predispositions:

1. Weakness in the team of 400+ ion-channels that orchestrate neuron firing and neurotransmissions (NTs)
2. Accelerated DNA damage

The discovery of bipolar disorder as a channelopathy guided a search for ion-channel impairments that could disrupt regulation of NTs. This led to discovery that progressive potassium-ion (K+) flooding outside the neuronal membranes could explain:

• Onset of mania
• The switch from mania to temporary depression
• Euthymia
• Chronic cycling between mania and depression

In this model, genetic weakness in ion-channels and DNA damage repair are not sufficient to trigger bipolar disorder during childhood and early adolescence. Additional ion-channel mutations after birth eventually dysregulate a vulnerable NT system that is implicated in clinical depression. Non-stop K+ flooding and shrinking rest potentials (voltages) cause initial hyperactivity followed by a major decline in activity. The switch to depression occurs when brain function is dominated by pronounced hypoactivity of the damaged NT system.

However, the NT system gradually recovers due to reduced K+ outflow while surviving K+ clearance mechanisms continue to operate. A comparative analysis of five NT systems determined that impaired serotonin neurons are responsible for the switch from mania to depression. Based on these discoveries, an advanced theory of bipolar disorder was developed.

This improved understanding of bipolar disorder and its mechanisms may lead to improved drug treatments that will improve quality of life for many patients. Future advanced scans of DNA and epigenetic factors could identify high bipolar disorder risk for children and enable effective prevention of this devasting mental illness.

Megan Thomas, Multimedia Editor, DDW