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What causes depression?

What causes depression?

(This article was first printed in Understanding Depression, a Special Health Report from Harvard Medical School.)

It’s often said that depression results from a chemical imbalance, but that figure of speech doesn’t capture how complex the disease is. Research suggests that depression doesn’t spring from simply having too much or too little of certain brain chemicals. Rather, depression has many possible causes, including faulty mood regulation by the brain, genetic vulnerability, stressful life events, medications, and medical problems. It’s believed that several of these forces interact to bring on depression.

To be sure, chemicals are involved in this process, but it is not a simple matter of one chemical being too low and another too high. Rather, many chemicals are involved, working both inside and outside nerve cells. There are millions, even billions, of chemical reactions that make up the dynamic system that is responsible for your mood, perceptions, and how you experience life.

With this level of complexity, you can see how two people might have similar symptoms of depression, but the problem on the inside, and therefore what treatments will work best, may be entirely different.

Researchers have learned much about the biology of depression. They’ve identified genes that make individuals more vulnerable to low moods and influence how an individual responds to drug therapy. One day, these discoveries should lead to better, more individualized treatment (see “From the lab to your medicine cabinet”), but that is likely to be years away. And while researchers know more now than ever before about how the brain regulates mood, their understanding of the biology of depression is far from complete.

What follows is an overview of the current understanding of the major factors believed to play a role in depression.

The brain

Popular lore has it that emotions reside in the heart. Science, though, tracks the seat of your emotions to the brain. Certain areas of the brain help regulate mood. Researchers believe that — more important than levels of specific brain chemicals — nerve cell connections, nerve cell growth, and the functioning of nerve circuits have a major impact on depression. Still, their understanding of the neurological underpinnings of mood is incomplete.

Regions that affect mood

Increasingly sophisticated forms of brain imaging — such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) — permit a much closer look at the working brain than was possible in the past. An fMRI scan, for example, can track changes that take place when a region of the brain responds during various tasks. A PET or SPECT scan can map the brain by measuring the distribution and density of neurotransmitter receptors in certain areas.

Use of this technology has led to a better understanding of which brain regions regulate mood and how other functions, such as memory, may be affected by depression. Areas that play a significant role in depression are the amygdala, the thalamus, and the hippocampus (see Figure 1).

Research shows that the hippocampus is smaller in some depressed people. For example, in one fMRI study published in The Journal of Neuroscience, investigators studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus. Stress, which plays a role in depression, may be a key factor here, since experts believe stress can suppress the production of new neurons (nerve cells) in the hippocampus.

Researchers are exploring possible links between sluggish production of new neurons in the hippocampus and low moods. An interesting fact about antidepressants supports this theory. These medications immediately boost the concentration of chemical messengers in the brain (neurotransmitters). Yet people typically don’t begin to feel better for several weeks or longer. Experts have long wondered why, if depression were primarily the result of low levels of neurotransmitters, people don’t feel better as soon as levels of neurotransmitters increase.

The answer may be that mood only improves as nerves grow and form new connections, a process that takes weeks. In fact, animal studies have shown that antidepressants do spur the growth and enhanced branching of nerve cells in the hippocampus. So, the theory holds, the real value of these medications may be in generating new neurons (a process called neurogenesis), strengthening nerve cell connections, and improving the exchange of information between nerve circuits. If that’s the case, medications could be developed that specifically promote neurogenesis, with the hope that patients would see quicker results than with current treatments.

In the meantime, animal research lends credence to the theory. A 2003 study in Science found that when neurogenesis is blocked in mice, the benefits of antidepressants seem to disappear. After receiving antidepressants for four weeks, mice exhibited less anxious or depressed behavior (they became bolder about retrieving food from a brightly lit place). These treated mice had 60% more dividing cells in the hippocampus. However, when researchers impeded new cell growth by dousing the hippocampus with x-rays, drug treatment failed to reduce anxious behavior in the mice. While more work needs to be done to determine the role of neurogenesis in depression, this is an interesting avenue of research.

Figure 1: Areas of the brain affected by depression

Areas of the brain affected by depression

Amygdala: The amygdala is part of the limbic system, a group of structures deep in the brain that’s associated with emotions such as anger, pleasure, sorrow, fear, and sexual arousal. The amygdala is activated when a person recalls emotionally charged memories, such as a frightening situation. Activity in the amygdala is higher when a person is sad or clinically depressed. This increased activity continues even after recovery from depression.

Thalamus: The thalamus receives most sensory information and relays it to the appropriate part of the cerebral cortex, which directs high-level functions such as speech, behavioral reactions, movement, thinking, and learning. Some research suggests that bipolar disorder may result from problems in the thalamus, which helps link sensory input to pleasant and unpleasant feelings.

Hippocampus: The hippocampus is part of the limbic system and has a central role in processing long-term memory and recollection. Interplay between the hippocampus and the amygdala might account for the adage “once bitten, twice shy.” It is this part of the brain that registers fear when you are confronted by a barking, aggressive dog, and the memory of such an experience may make you wary of dogs you come across later in life. The hippocampus is smaller in some depressed people, and research suggests that ongoing exposure to stress hormone impairs the growth of nerve cells in this part of the brain.

Nerve cell communication

The ultimate goal in treating the biology of depression is to improve the brain’s ability to regulate mood. We now know that neurotransmitters are not the only important part of the machinery. But let’s not diminish their importance either. They are deeply involved in how nerve cells communicate with one another. And they are a component of brain function that we can often influence to good ends.

Neurotransmitters are chemicals that relay messages from neuron to neuron. An antidepressant medication tends to increase the concentration of these substances in the spaces between neurons (the synapses). In many cases, this shift appears to give the system enough of a nudge so that the brain can do its job better.

How the system works. If you trained a high-powered microscope on a slice of brain tissue, you might be able to see a loosely braided network of neurons that send and receive messages. While every cell in the body has the capacity to send and receive signals, neurons are specially designed for this function. Each neuron has a cell body containing the structures that any cell needs to thrive. Stretching out from the cell body are short, branchlike fibers called dendrites and one longer, more prominent fiber called the axon.

A combination of electrical and chemical signals allows communication within and between neurons. When a neuron becomes activated, it passes an electrical signal from the cell body down the axon to its end (known as the axon terminal), where chemical messengers called neurotransmitters are stored. The signal releases certain neurotransmitters into the space between that neuron and the dendrite of a neighboring neuron. That space is called a synapse. As the concentration of a neurotransmitter rises in the synapse, neurotransmitter molecules begin to bind with receptors embedded in the membranes of the two neurons (see Figure 2).

The release of a neurotransmitter from one neuron can activate or inhibit a second neuron. If the signal is activating, or excitatory, the message continues to pass farther along that particular neural pathway. If it is inhibitory, the signal will be suppressed. The neurotransmitter also affects the neuron that released it. Once the first neuron has released a certain amount of the chemical, a feedback mechanism (controlled by that neuron’s receptors) instructs the neuron to stop pumping out the neurotransmitter and start bringing it back into the cell. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitter molecules into smaller particles.

When the system falters. Brain cells usually produce levels of neurotransmitters that keep senses, learning, movements, and moods perking along. But in some people who are severely depressed or manic, the complex systems that accomplish this go awry. For example, receptors may be oversensitive or insensitive to a specific neurotransmitter, causing their response to its release to be excessive or inadequate. Or a message might be weakened if the originating cell pumps out too little of a neurotransmitter or if an overly efficient reuptake mops up too much before the molecules have the chance to bind to the receptors on other neurons. Any of these system faults could significantly affect mood.

Kinds of neurotransmitters. Scientists have identified many different neurotransmitters. Here is a description of a few believed to play a role in depression:

  • Acetylcholine enhances memory and is involved in learning and recall.
  • Serotonin helps regulate sleep, appetite, and mood and inhibits pain. Research supports the idea that some depressed people have reduced serotonin transmission. Low levels of a serotonin byproduct have been linked to a higher risk for suicide.
  • Norepinephrine constricts blood vessels, raising blood pressure. It may trigger anxiety and be involved in some types of depression. It also seems to help determine motivation and reward.
  • Dopamine is essential to movement. It also influences motivation and plays a role in how a person perceives reality. Problems in dopamine transmission have been associated with psychosis, a severe form of distorted thinking characterized by hallucinations or delusions. It’s also involved in the brain’s reward system, so it is thought to play a role in substance abuse.
  • Glutamate is a small molecule believed to act as an excitatory neurotransmitter and to play a role in bipolar disorder and schizophrenia. Lithium carbonate, a well-known mood stabilizer used to treat bipolar disorder, helps prevent damage to neurons in the brains of rats exposed to high levels of glutamate. Other animal research suggests that lithium might stabilize glutamate reuptake, a mechanism that may explain how the drug smooths out the highs of mania and the lows of depression in the long term.
  • Gamma-aminobutyric acid (GABA) is an amino acid that researchers believe acts as an inhibitory neurotransmitter. It is thought to help quell anxiety.

Figure 2: How neurons communicate

How neurons communicate

  1. An electrical signal travels down the axon.
  2. Chemical neurotransmitter molecules are released.
  3. The neurotransmitter molecules bind to receptor sites.
  4. The signal is picked up by the second neuron and is either passed along or halted.
  5. The signal is also picked up by the first neuron, causing reuptake, the process by which the cell that released the neurotransmitter takes back some of the remaining molecules.

Genes

Every part of your body, including your brain, is controlled by genes. Genes make proteins that are involved in biological processes. Throughout life, different genes turn on and off, so that — in the best case — they make the right proteins at the right time. But if the genes get it wrong, they can alter your biology in a way that results in your mood becoming unstable. In a genetically vulnerable person, any stress (a missed deadline at work or a medical illness, for example) can then push this system off balance.

Mood is affected by dozens of genes, and as our genetic endowments differ, so do our depressions. The hope is that as researchers pinpoint the genes involved in mood disorders and better understand their functions, treatment can become more individualized and more successful. Patients would receive the best medication for their type of depression.

Another goal of gene research, of course, is to understand how, exactly, biology makes certain people vulnerable to depression. For example, several genes influence the stress response, leaving us more or less likely to become depressed in response to trouble.

A 2003 discovery supports this idea. Researchers found that people with a particular variant in a serotonin-transporter gene (5-HTT) were more likely to become depressed in response to stress. Each person inherits two copies of this gene — one from each parent. The gene comes in “short” (less efficient) and “long” (more efficient) versions. No combination of short or long variants leads directly to depression, but short versions of the gene put people at a distinct disadvantage if they experience stressful life events. In tracking more than 800 young adults over a five-year period, the researchers found that 33% of those with at least one “short” gene became depressed after a series of stressful life events, such as divorce or the loss of a job. People with two copies of the short variant fared worse than those with a single copy, and their risk of depression rose steadily as their lives became more stressful. By contrast, only 17% of those with two “longs” grew depressed in similar circumstances — and their risk of depression remained unchanged as stress levels rose.

In 2008, researchers studied a gene that influences a person’s reaction to childhood abuse. This gene (CRHR1) provides the code for one of the stress hormones — corticotrophin-releasing hormone or CRH (see “How stress affects the body”). For this study, published in Archives of General Psychiatry, researchers interviewed 621 adults and tested their DNA. Among people who suffered childhood abuse, those with the relatively protective versions of the CRHR1 gene had half the symptoms of depression as participants without this genetic variation. This study not only added to knowledge about protective genes, but also lent further credence to the theory that stress hormones play an important role in depression.

Another interesting discovery is the identification of a variation in the DNA sequence named G1463A. People with this atypical DNA sequence are more likely to have major depression than those who don’t.

Perhaps the easiest way to grasp the power of genetics is to look at families. It is well known that depression and bipolar disorder run in families. The strongest evidence for this comes from the research on bipolar disorder. Half of those with bipolar disorder have a relative with a similar pattern of mood fluctuations. Studies of identical twins, who share a genetic blueprint, show that if one twin has bipolar disorder, the other has a 60% to 80% chance of developing it, too. These numbers don’t apply to fraternal twins, who — like other biological siblings — share only about half of their genes. If one fraternal twin has bipolar disorder, the other has a 20% chance of developing it.

The evidence for other types of depression is more subtle, but it is real. A person who has a first-degree relative who suffered major depression has an increase in risk for the condition of 1.5% to 3% over normal.

One important goal of genetics research — and this is true throughout medicine — is to learn the specific function of each gene. This kind of information will help us figure out how the interaction of biology and environment leads to depression in some people but not others.

Temperament shapes behavior

Genetics provides one perspective on how resilient you are in the face of difficult life events. But you don’t need to be a geneticist to understand yourself. Perhaps a more intuitive way to look at resilience is by understanding your temperament. Temperament — for example, how excitable you are or whether you tend to withdraw from or engage in social situations — is determined by your genetic inheritance and by the experiences you’ve had during the course of your life. Some people are able to make better choices in life once they appreciate their habitual reactions to people and to life events.

Cognitive psychologists point out that your view of the world and, in particular, your unacknowledged assumptions about how the world works also influence how you feel. You develop your viewpoint early on and learn to automatically fall back on it when loss, disappointment, or rejection occurs. For example, you may come to see yourself as unworthy of love, so you avoid getting involved with people rather than risk losing a relationship. Or you may be so self-critical that you can’t bear the slightest criticism from others, which can slow or block your career progress.

Yet while temperament or world view may have a hand in depression, neither is unchangeable. Therapy and medications can shift thoughts and attitudes that have developed over time.

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Understating Depression: a special report on mental health

Understanding Depression

Depression affects nearly 19 million adults each year, yet this common disease is often misunderstood or misdiagnosed. While depression can’t simply be willed away by "shaking off" your blues, there are many effective treatments that can bring joy back into your life. Reading Understanding Depression and sharing it with those closest to you might help improve your life — or the life of someone close to you!. Read more »