Bipolar disorder is a complex brain condition defined by extreme, periodic shifts in a person’s mood, energy, and ability to function. These emotional states are categorized as manic or hypomanic episodes, characterized by an abnormally elevated or irritable mood, and major depressive episodes, marked by intense sadness or a loss of interest. The pathophysiology of bipolar disorder refers to the functional and structural changes within the brain that underlie and drive these intense mood swings. The disorder is not rooted in a single cause, but rather involves a complex interplay of inherited risk, chemical imbalance, and structural abnormalities in the brain’s regulatory circuits.
The Genetic Contribution to Risk
Bipolar disorder exhibits one of the highest heritability estimates among psychiatric conditions, suggesting that genetic factors play a strong role in determining an individual’s risk. Twin studies indicate that the heritability of the disorder is estimated to be between 60% and 85%.
The disorder is not typically caused by a single, simple genetic fault but follows a polygenic model of risk. This means that hundreds of different genes, each contributing only a very small effect, collectively increase an individual’s susceptibility to the disorder. Genome-Wide Association Studies (GWAS) have identified numerous common genetic variations associated with the condition.
These genetic factors often influence pathways related to brain development, cell signaling, and communication between neurons. A family history of bipolar disorder or other mood disorders represents one of the strongest risk factors for developing the condition. The overall genetic loading is summarized by a Polygenic Risk Score, which quantifies the cumulative effect of these many small genetic variants.
Neurotransmitter and Chemical Dysregulation
The brain’s chemical messengers, or neurotransmitters, are deeply implicated in the mood cycling characteristic of bipolar disorder. The traditional monoamine hypothesis suggests that the levels and activity of chemicals like dopamine, norepinephrine, and serotonin are dysregulated, correlating with the mood state.
During a manic episode, there is often evidence of increased dopaminergic activity, which is linked to feelings of euphoria, heightened energy, and impulsivity. Conversely, in the depressive phase, a reduction in dopamine and norepinephrine activity is thought to contribute to symptoms like low energy, apathy, and persistent sadness. Serotonin, which regulates mood, sleep, and appetite, also exhibits an imbalance, which may be involved in triggering the transition between manic and depressive states.
Beyond the monoamines, the brain’s main excitatory and inhibitory neurotransmitters, glutamate and Gamma-aminobutyric acid (GABA), are also affected. Glutamate is the primary excitatory signal, and its overactivity has been observed in manic episodes, potentially contributing to racing thoughts and emotional highs. Reduced GABA function, the primary inhibitory signal, has been linked to a loss of inhibitory control and hyperactivity seen in mania. Dysregulation of these two systems can lead to an unstable, over-excited state in neural circuits.
Structural and Functional Brain Abnormalities
Neuroimaging studies consistently reveal structural and functional differences in the brains of individuals with bipolar disorder, particularly in regions that govern emotion and cognition. The prefrontal cortex (PFC), which is responsible for executive functions like planning, decision-making, and emotional regulation, often shows gray matter volume reductions.
One of the key subcortical areas in this emotional circuitry is the amygdala, which processes and generates strong emotions like fear and stress. In bipolar disorder, the amygdala often displays a hyper-responsiveness or increased activation, even during periods of stable mood. The hippocampus, which is involved in memory and stress response, is another limbic structure that shows volume reduction in some studies.
The functional connection between the PFC and the amygdala appears to be impaired, which is thought to be a core mechanism of emotional dysregulation. This weakened connection means the PFC cannot effectively dampen the hyperactive signals from the amygdala, leading to uncontrolled or exaggerated emotional responses characteristic of mood episodes.
Cellular Stress and Immune System Involvement
Newer research highlights that the pathophysiology of bipolar disorder extends down to the cellular and molecular level, involving chronic stress and inflammation within the brain. Neurons and glial cells often show signs of mitochondrial dysfunction, leading to an energy deficit in brain cells. Mitochondria are the cellular powerhouses that generate adenosine triphosphate (ATP), the cell’s energy currency.
This energy problem is closely linked to oxidative stress, which occurs when there is an imbalance between harmful reactive oxygen species (ROS) and the cell’s ability to neutralize them. Because the brain consumes a large amount of oxygen, it is particularly vulnerable to this kind of cellular damage, which can harm neuronal components and interfere with neurotransmitter function.
Furthermore, bipolar disorder is associated with a state of chronic, low-grade neuroinflammation. Studies frequently detect elevated levels of pro-inflammatory cytokines, which are signaling molecules released by immune cells. This persistent inflammatory state can disrupt the delicate environment necessary for healthy neuronal function and survival, potentially contributing to the damage and structural changes observed in brain regions involved in mood regulation.