Reviewing Medications for Bipolar Disorder:
Understanding the Mechanisms of Action
Gerard Sanacora, MD, PhD
From the Yale Depression Research Program, Department of Psychiatry, Yale University School of Medicine, New Haven, Conn
This activity was supported by an educational grant from Eli Lilly and Company.
In recent years, the model of the pathophysiology and treatment of mood disorders has been reconceptualized—shifting from a classical model in which mood disorders were attributed to neurochemical deficits to one in which they are attributed to changes in neuroplasticity. Neuroplasticity is the ability of the brain to reorganize itself by forming new neural connections throughout a person’s life. This allows neurons in the brain to adjust their activities in response to new situations or environmental changes and to compensate for injury and disease.
Concepts related to neuroplasticity are apoptosis, neuroprotection, neurotoxicity, resiliency, and neurotrophic factors. Apoptosis is a form of programmed cell death in multicellular organisms, and anything that prevents apoptosis is called antiapoptotic. Mechanisms within the nervous system that protect neurons and glia from apoptosis and other degeneration (including that associated with injury or neurodegenerative diseases) provide neuroprotection. Events or treatments that damage the nervous system have neurotoxicity. Resiliency is the brain’s ability to withstand or recover from cellular stressors. Certain substances called neurotrophic factors are responsible for the growth and survival of neurons during childhood development and maintenance of neurons in adulthood.
Evidence of Neuroplastic Changes in Patients With Mood Disorders
Imaging studies have shown that structural and neuroplastic changes occur in the brains of patients with mood disorders. In one of the first of these studies, Drevets and colleagues1 found reduced metabolic activity and cortical volume in the subgenual prefrontal cortex of patients with bipolar or unipolar depression. A meta-analysis by Videbech and Ravnkilde2 showed reduced hippocampal volume in patients with unipolar depression. Rajkowska and colleagues3 found reductions in neuronal and glial cell volume and density in the dorsolateral prefrontal cortex and decreased neuronal size and glial density in the caudal orbitofrontal cortex of patients with major depressive disorder (MDD). Cotter and colleagues4 also found that glial cell density and neuronal size was reduced in patients with MDD. They reported similar reductions in patients with schizophrenia but no difference in patients with bipolar disorder compared with controls. Reduced levels of brain-derived neurotrophic factor (BDNF) have been found in patients with depression in postmortem studies of the brain (hippocampus and prefrontal cortex)5,6 and studies of serum in live patients.7
The Effects of Stress on Neuroplasticity
Measuring and observing the effects of stress on the brain is one of the best ways to develop a model for describing the effects of depression on the brain. Stress has been shown to cause neuroplastic changes by inducing atrophy of pyramidal neurons in the medial prefrontal cortex of animals.8 Czéh and colleagues9 found that chronic psychosocial stress decreased hippocampal volume and reduced both the size and number of glial cells in animals (see AV 1), similar to the changes seen in several brain regions of patients with MDD.
Neurobiological Mechanisms Affected by Stress and Targeted by Mood Disorder Treatment
Chronic stress can affect various cellular mechanisms and processes, causing harmful neuroplastic changes. Normally, activation of receptors found on the cellular membrane—including ionotropic, metabotropic, steroid, and tyrosine kinase receptors—leads to stimulation of signal transduction cascades, the mechanism by which cells transcribe their effects from the synaptic membrane into the cytosol inside the cell. These cascades can lead to the phosphorylation of various kinases and enzymes that have multiple effects—structural, energetic, chemical, and epigenetic—on the brain. Activation of some signal transduction cascades can activate kinases that lead to apoptosis or neurotoxicity; activation of other cascades can activate kinases or enzymes that are antiapoptotic. A healthy brain maintains a delicate balance of apoptotic and antiapoptotic activity, and this balance of plasticity is constantly being changed throughout life by the activation of membrane receptors. Processes inside the nucleus, including gene expression and chromatin remodeling, can also be affected by these cascades.
Chronic stress can have a negative effect on the brain by attacking several different mechanisms (see AV 2). Understanding those mechanisms can aid in the development and use of drugs that act in various ways to counteract the effects of stress, thereby treating mood disorders.10,11
First, the glutamatergic system is believed to be a treatment target because it is heavily affected by stress. Glutamate is the major excitatory neurotransmitter in the brain; it is necessary for most forms of learning and is involved in most aspects of human behavior. Excessive stimulation of glutamate leads to increased calcium influx, which changes calcium-dependent enzyme activity and ultimately leads to an increase in free radicals, increased expression of apoptotic factors, and cell damage and atrophy. Research has shown that stress can cause an increase in glutamate release in the prefrontal cortex12 and hippocampus,13 causing neurotoxicity in both of these areas (see AV 3).14 Some agents that target the glutamatergic system and may help balance glutamate release are N-methyl-d-aspartate (NMDA) antagonists such as ketamine, group I metabotropic antagonists, group II metabotropic modulators, agents that act on the voltage-dependent neuronal sodium channels that modulate glutamate release such as lamotrigine, agents that activate the
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and agents that increase glutamate uptake.