The Biology of Depression

The inheritance of risk for depression is considered, at best, polygenetic—that is, a number of unknown genes each contributes a tiny risk under certain environmental conditions. None of them makes depression inevitable. The baseline risk of depression in the population is 10 percent; having a first-degree relative (parent or sibling) with depression doubles or triples an individual’s risk, to 20 to 30 percent over the course of a lifetime.

There are many non-genetic factors that contribute to risk of onset of major depression, and there are some inherited factors as well. To make matters a bit more complex, some non-genetic factors, including certain kinds of adverse childhood experience—such as repeated child abuse or neglect—can have a lasting impact on the function of genes (such as those that activate the stress system) to increase the risk of depression later on.

Variation of one gene associated with the serotonin system (the serotonin transporter gene) has been most linked to depression susceptibility—it is thought to moderate the impact of stressful life events—but the evidence has been disappointing. Life experience and lifestyle factors are believed to play more significant roles in depression risk.

Scientists know that the expression and function of many genes can be altered without doing the near-impossible—making any changes to the gene structure itself. Such changes are known as epigenetic modifications. Some life experiences can create vulnerability to depression through epigenetic changes. For example, in rat pups, lack of maternal care can permanently reset the sensitivity of receptors to stress hormones. If their mothers fail to lick and groom them, they grow up to display an exaggerated response to stress hormones and develop depression-like behavior in response to stress.

But there are also ways to strategically induce epigenetic changes to reverse symptoms of depression. For example, the nutritional supplement SAM-e, a synthetic version of a compound found in the body, contains a substance that chemically augments the activation and deactivation of genes. Some studies show it is effective against symptoms of depression.

Overexcitability of the stress response system, shifts in activity of various neurochemicals in the brain, diminished efficiency of nerve circuitry and nerve generation, disturbances in energy use nerve cells, the intrusion of inflammatory substances in the brain, upsets in the brain’s 24-hour (circadian) clock—all play a role in depression onset or progression and influence the kind and severity of symptoms.

Two major areas of the brain—the hippocampus (seat of memory) and the cortex (the thinking part of the brain)— undergo shrinkage. Both the size of nerve cells and the number of their connections with other neurons are reduced. At the same time, depressive behavior is linked to overactivation of the hypothalamus, which coordinates the stress response, and overactivity of the amygdala, which signals threat and generates negative emotions.

Reduced activity in the prefrontal cortex, which interprets and regulates emotional signals coming from the amygdala, accounts for the difficulties in decision-making and the cognitive fog that depressed people experience.

The human brain may be unique in its ability to generate new nerve connections, called neuroplasticity; this is what underlies all adaptation and learning. In depression, neuroplasticity is impaired, especially in the hippocampus. In addition, reward centers of the brain shrink and fail to activate in response to stimulation. There are changes in sensitivity to the hormones that regulate feeding behavior, resulting in changes in appetite.

Disruption of the sleep-wake cycle is one of the hallmarks of depression and is a major source the mood disturbance in major depression. Lack of sleep upsets the body’s circadian clock that orchestrates the natural daily rhythm of most biological functions, including patterns of secretion, release, and activity of many neurochemicals in the brain.

Sleep deprivation is thought to impede the transmission of neural signals. One result is that sleep deprivation makes people emotionally reactive, increasing activity in the amygdala and decreasing it in the emotion regulation center of the prefrontal cortex. Sleep deprivation impairs the brain’s ability to control negative thoughts.

Mistimed light input resulting from sleep disturbance also disrupts the dopamine-sensitive nucleus accumbens. Studies show that people with mood disorders benefit from maintaining a strict sleep/wake routine, rising in the morning and going to sleep at night at the same time every day.

Emotions are fleeting responses to stimuli; mood is a more sustained state of emotion. Like emotions, mood probably originates with activity of the amygdala, where emotions are coded. But it also involves the prefrontal cortex, which, through bundles of two-way circuitry with the amygdala, helps regulate emotional response and influences the general state of reactivity of the amygdala.

Under normal conditions, moods are relatively stable. But the persistence of negative mood in major depression suggests something is amiss in the nerve pathways between the amygdala and cortex.

Another important influence on mood is the circadian rhythm that governs the timing of much physiological activity, most prominently the sleep-wake cycle. Disturbances in biological rhythms are known to disrupt mood, and studies of depressed patients find that they exhibit abnormal patterns of many body functions, from temperature regulation to hormone secretion.

The neurotransmitter serotonin is one of many signaling chemicals in the brain associated with depressive symptoms. Under normal conditions, serotonin inhibits pain, influences the processing of various emotions, and mediates many mental capacities important in social life.

But like the other neurotransmitters involved in depression, its production and activity are affected by the hormones the body secretes in response to threat or stress, such as cortisol. One result is a functional lack of serotonin, which, among other things, disrupts the circuitry that regulates moral emotions. Growing evidence suggest that is why those who are depressed are haunted by excessive self-blame and a sense of guilt.

The neurotransmitter dopamine, which mediates motivation and desire, is one of several brain signaling chemicals that are implicated in depression. It is associated with two of the most prominent features of depression—anhedonia, or the inability to experience pleasure, and appetite alterations.

Many neurons that use dopamine to relay signals are sensitive to the effects of stress, which can alter their excitability and activity. Studies have also shown that reward-generating areas of the brain—such as the nucleus accumbens, where dopamine signals originate—may be underactive in depression.

Where once researchers and clinicians focused on the role of neurotransmitters such as serotonin in depression, they now know that neurotransmitters are only one part of a much larger story of how nerve cells function in circuits to relay messages from one part of the brain to another. In fact, many experts see depression as a nerve circuit disorder, marked by a power failure in the brain’s wiring, affecting communication between one area of the brain and another.

The nerve cell connections between the amygdala and the prefrontal cortex (PFC) are sometimes called the “depression circuit;” depression results when emotion-laden signals from the amygdala overpower the ability of the PFC to regulate the signals. The prolonged or excessive release of stress hormones can lead to a failure of activation of key nodes in neural networks or impair the strength of signals between them, especially when processing emotion-related or reward stimuli.

It’s important that depression is now seen as a nerve circuit disorder, because that influences the search for effective treatments.

Stress can be beneficial to the brain, depending on how intense and long-lasting the stressor is. In brief bursts, stress fosters alertness, learning, and adaptation. Severe or prolonged stress, however, can disrupt many aspects of brain function and lead to depression.

Such stress dysregulates the normal stress response through the overproduction of cortisol. Cortisol is especially toxic to cells in the brain’s hippocampus, and one consequence of uncontrolled stress is shrinkage of the hippocampus, manifest in the impaired memory and learning that are characteristic of depression.

Cortisol also turns off the generation of new nerve cells in some areas of the brain, affecting the circuitry of the brain. In addition, prolonged cortisol exposure affects production of the insulating myelin sheath surrounding nerve cells, diminishing the overall efficiency or nerve signaling.

Severe or sustained early life adversity shifts the course of brain development and can lastingly impair emotion regulation and cognitive development. Excessive or prolonged activation of the stress response in childhood, studies show, can sensitize the stress response system so that it overresponds to minimal levels of threat, making people feel easily overwhelmed by life’s normal difficulties.

Severe or prolonged childhood adversity can affect the function of genes important for the wiring of the brain, so that emotional control is difficult—overproducing neural connections in regions such as the amygdala that signal threat and other negative emotions while underendowing neural connectivity in brain areas responsible for behavioral control, reasoning, and planning.

Nevertheless, adult brains retain the capacity for neuroplasticity. Although it takes effort, and often the guidance of psychotherapy, people can learn to overcome many of the ill effects of early adversity.

Many areas of the brain contribute to the symptoms of depression, such as the hippocampus, which is the seat of memory and learning, and the superchiasmatic nucleus, which is the “body clock” that paces all physiologic activity, notably the sleep-wake cycle. But brain imaging studies suggest that there is a primary “depression circuit,” consisting of the amygdala, which flags emotion-related stimuli; the prefrontal cortex, which analyzes and interprets experience, modulates emotional reactivity, and controls attention; and the two-way network of nerve fibers that connect them.

In this model of depression, the amygdala becomes hyperactive, sending out a constant flood of emotions, and the PFC becomes hypoactive, unable to regulate the stream of emotional input. Through feedback loops, the failure of the PFC further dysregulates the amygdala and leaves unchecked its inherent bias toward negative emotions.

Some types of brain imaging, such as CT scans and magnetic resonance imaging (MRI), take static pictures of the brain to determine whether any specific structures are larger or smaller than normal in depressed patients. Positron emission tomography (PET) scans and functional magnetic resonance imaging (fMRI) look at the brain in action, to see whether and where there are problems in the way the brain processes specific types of information.

In fMRI studies, normal controls and depressed patents are typically given some task to perform in the scanner. For example, subjects may be asked to look at a series of pictures, some of them with emotionally disturbing content, to see how the brain handles negative stimuli. The brain scanners measure blood flow or metabolic activity, based on the concentration of agents earlier injected into the bloodstream. Comparison of hot spots and dead spots of activity between controls and depressed patients highlight areas of the brain that malfunction in response to challenging stimuli.

The longer an episode of depression lasts, the greater the likelihood of a recurrence of depression. That is because depression changes the brain in ways that are only now yielding to understanding. If left untreated, depression can become a progressive disease leading to neurodegeneration.

The sustained stress that triggers depression releases a cascade of hormones linked to shrinkage of the hippocampus, a part of the brain essential for learning and storing and retrieving memories. Prominent changes to other brain areas, including the amygdala, create a sustained tendency to generate negatively coded emotions.

Untreated depression also changes the activity of substances that help regulate the mitochondria, the energy factories of all cells, especially critical to function of the brain because it is such a metabolically active organ. Depression also causes changes in the network of brain areas involved in processing physical pain, and the degree of hyperactivity in such areas as seen on brain scans correlates with the severity of depression that patients experience.

Recent studies show that like other neurodegenerative conditions, longstanding depression increases levels of inflammatory substances in the brain that further impair its function, affecting many brain regions and circuits of connectivity.

The most studied form of psychotherapy—cognitive behavioral therapy (CBT)—has been shown to produces long-lasting changes in emotion, cognition, behavior, and somatic symptoms of patients with depression and other mental health conditions. Using functional magnetic resonance imaging (fMRI), researchers find that CBT alters patterns of connections between brain regions, notably in circuits related to the processing of emotions.

Images show decreased reactivity of the brain’s amygdala, which processes emotion, and increased activity in the prefrontal cortex, the thinking and executive control center of the brain, indicating more control over emotional reactions and memories, and greater flexibility in finding solutions to problems. The changes in cognition power help reduce negative emotionality by increasing people’s ability to calmly manage experiences and thoughts that stir emotions.

Throughout life, the growth of new nerve cell connections, or neuroplasticity, is the major way brains adapt to new or challenging circumstances. It’s called learning, and it’s the brain’s major means of problem-solving. Depression is characterized by a loss of plasticity—negative neuroplasticity; patients feel imprisoned in their own repetitive negative thoughts.

It’s long been known that prolonged or excessive outpouring of stress hormones curbs the growth of nerve cells, particularly in the hippocampus, seat of memory and learning.Such changes are reflected in a smaller size hippocampus and impaired memory in depressed patients.

Changes also occur in the prefrontal cortex, undermining regulation of emotional experience, limiting the ability to set goals, and much more. All effective treatments of depression restore the capacity for mental and behavioral change and are known to stimulate the growth of new nerve cells—they enable the brain to rewire itself.

All known therapies for depression stimulate the growth of new nerve cell connections. But the growth of new nerve cell connections is not dependent on antidepressant drugs. Researchers find that there are many ways to bring about neuroplasticity.

One of the most effective ways is aerobic exercise. And it doesn’t have to be intense to have an effect. In fact, all physical activity is linked to the generation of neurotrophic factors, chemicals that stimulate the growth and recovery of brain cells.

Research also pinpoints diet, and especially intermittent fasting as a way to generate BDNF, or brain-derived neurotrophic factor, one of the best studied agents of nerve cell growth. Intermittent fasting is known to be neuroprotective, shielding brain cells from the degeneration that often accompanies aging.