Although the underlying biology of depression has not been fully elucidated, it is clear that several key systems are involved. These include the serotonergic, glutamatergic, noradrenergic, and dopaminergic systems. Other putative pathophysiologic processes include neuroinflammation, hypothalamic-pituitary-adrenal axis dysfunction, and neuroplasticity.

Genetic factors are thought to be relevant due to the high heritability of mood disorders, estimated at about 30% to 40%. The data from twin studies indicates that environmental factors also play an important role in the expression of mood disorders. Nonetheless, the risk of becoming ill increases two- to threefold for first-degree family members of patients with mood disorders. Of note, despite early suggestions that bipolar disorder is more heritable than depressive disorders, the evidence that genetic vulnerability or heritability of mood disorders differs between bipolar and unipolar conditions is mixed and far from definitive.

The serotonergic system plays a key role in depression, with studies demonstrating an overall decrease in serotonin (5-HT) function. Brain imaging studies demonstrate increased 5-HT1A-receptor binding and fewer brain 5-HT reuptake sites. Tryptophan (serotonin’s precursor) depletion has been shown to produce rapid depressive relapses in patients with a history of depression but no change in subjects with no personal or familial history of mood disorders. This suggests that low levels of 5-HT in the brain are not sufficient to cause depression but may act in concert with other factors in vulnerable individuals to cause symptoms. Indeed, many antidepressants exert their action through modulation of serotonin transmission.

Other neurotransmitter systems have been implicated in depression as well. For example, norepinephrine is linked to the pathophysiology of severe depression, as is dopamine, a neurotransmitter involved in incentive behavior and reward. Low cerebrospinal fluid levels of the dopamine metabolite, homovanillic acid, have been documented in depressed patients and exposure to dopamine-depleting drugs such as reserpine is known to precipitate depression. Changes in other neurotransmitters such as glutamate have also been identified. Glutamate, the main excitatory neurotransmitter appears to be increased in major limbic and cortical systems, possibly in response to stress, and may exert pathogenic effects either by limiting neurogenesis or dendritic remodeling directly or in concert with other factors that have similar effects on neuroplasticity.

Stress is implicated in the pathophysiology of depression, not only as mediated through glutamatergic changes in response but also as exemplified by prominent changes to the neuroendocrine system, especially in the hypothalamic-pituitary axis (HPA). Under normal conditions, stress prompts the HPA axis to secrete serum cortisol. In mood disorders, the HPA axis may become unresponsive to normal negative feedback loop, leading to a failure to restore cortisol to normal levels once the stressor is removed. These changes may be accompanied by the loss of normal diurnal variation in cortisol levels. Whether these changes are linked to early life experiences, leading to enduring changes in the HPA axis thereby increasing the probability of developing a mood disorder later in life, is not known.

Another hypothesis about the pathophysiology of depression posits that depression is a neuroinflammatory process, a concept bolstered by the observation that depressive symptoms (fatigue, anhedonia, anorexia, etc.) could be viewed as “sickness behaviors.” Indeed, changes in inflammatory markers, such as increased interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels have been consistently found in patients with depression. Furthermore, administration of therapeutic cytokines has been shown to cause significant depressive symptoms in 50% of exposed individuals, providing further evidence for the role of neuroinflammation.

As noted earlier, neuroplastic changes in the hippocampus have been linked to depression. Chronic stress is associated with decreased hippocampal neurogenesis, a phenomenon often observed in animal models of depression and postmortem tissue. Treatments with antidepressants seem to reverse these hippocampal deficits in neurogenesis. Both stress and antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF), which is normally highly expressed in hippocampus and prefrontal cortex and plays a major role in neuronal growth, survival, and maturation. BDNF also seems to have antidepressant-like actions and can induce molecular transcription in several key pathways.

Most psychosocial models focus on loss as the cause of depression in vulnerable, or less resilient, individuals. Exogenous factors may include social rejection or loss (interpersonal, financial, or health-related). Certainly, loss of income, job, social status, or the failure to achieve a life goal may produce profound mourning. Regardless, clinical manifestations in response to these stressors are ultimately mediated through brain circuitry and neurochemistry.

The pathophysiology of bipolar disorder is still being clarified, but studies have shown both structural and functional changes in those with the condition. Structural evidence from brain imaging studies shows a reduction of neurons and glial cells in areas such as the prefrontal cortex, amygdala and striatal regions, as well as white matter hyperintensities. Positron emission tomography (PET) studies suggest serotonergic abnormalities reflected in fewer serotonin transporters and more serotonin 1a receptors. Other relevant neurotransmitters include dopamine and glutamate. For instance, drugs that increase dopamine release, such as amphetamines, can induce manic-like symptoms. Similarly, decreased dopamine reuptake and reductions in dopamine transporter availability are linked to bipolar disorder. In addition, increased cortical glutamate levels and vesicular glutamate transporter gene expression are also implicated in the neurobiology of bipolar disorder.

As with depression, bipolar disorder can be viewed as a disorder related to synaptic plasticity involving dysfunction of neuroprotective pathways and impaired neuronal resilience. Multiple pathways related to plasticity are implicated including impaired regulation of calcium signaling cascades, associated with oxidative stress, and mitochondrial and endoplasmic reticulum stress response dysfunction.

Several intracellular molecular pathways affected by lithium and pertinent to neuroplasticity have been investigated as potential pathophysiologic contributors. The phosphoinositol pathway, involved in protein kinase C activation, regulates expression of several genes including BDNF. In fact, altered levels of BDNF are posited to contribute to the polarity switch process. Another lithium target, glycogen synthase kinase-3 (GSK3) is a key component of Wnt signaling and has effects on neurotransmission, neuroplasticity, neuronal growth, and metabolism.