Major depressive disorder is a significant public health problem, since it affects nearly 1 in 6 individuals in their lifetime (the lifetime prevalence in the US is 17%).  Major depressive disorder is diagnosed when 5 of the following 9 symptoms are present nearly continuously for two weeks or more.

Depression should be considered a syndrome in that it involves a constellation of symptoms.  The underlying disorder probably arises from different causes in different individuals. As well, symptoms of depression are associated with other types of mental illness, notably bipolar disorder. Major depressive disorder is sometimes referred to as unipolar depression to distinguish it from bipolar disorder, which involves symptoms of depression alternating with episodes of mania (extreme elevated mood with overactivity and impaired judgment).

Depression may occur as a consequence of stressful life events, or in association with major illnesses, however, often it is idiopathic, meaning it arises from an unknown cause. It is often a chronic disorder, and even patients who are successfully treated have a high risk for future episodes of depression. Despite the fact that depression is so common, our understanding of the biological basis for depression is still limited.

Drug treatments

There are many different approved medications to treat depression. The main mechanism of action of drugs that work as antidepressants is that they increase the levels of monoamine neurotransmitters in the synaptic cleft, mainly serotonin and norepinephrine. Most of these drugs block transporter proteins involved in neurotransmitter reuptake from the synaptic cleft. One class of drugs specifically inhibits serotonin reuptake (selective serotonin reuptake inhibitors, SSRIs), but many antidepressants inhibit both serotonin and norepinephrine reuptake (for instance tricyclic antidepressants). Another class of antidepressant inhibits monoamine oxidase, an enzyme that metabolizes serotonin and norepinephrine (monamine oxidase inhibitors, MAOIs). Because of severe side affects that may result with consumption of certain foods, MAOIs are no longer used as a first line therapy. The choice of drug depends upon the individual: a patient may have a better response to a particular class of antidepressant, or even to a different drug within a class. Because of the stimulant effect of increasing norepinephrine and serotonin, antidepressants are usually taken in the morning.

Drug treatments generally take 2-3 weeks before symptoms begin to improve, and usually 6 to 8 weeks before substantial improvement in mood or remission is achieved. Remission is the primary goal of treatment, and is defined by a low score on a test that evaluates symptoms. Drug therapy usually continues for 6 months to a year to prevent relapse. Only about 30% of patients achieve remission with initial treatment, and many may need to switch to a different drug or take additional drugs that have been shown to augment the effect of antidepressants. Unfortunately, even after several trials of different drugs, a significant proportion of patients (about 30%) will not achieve remission.

Ketamine is an experimental drug treatment that has shown some promise in patients with treatment-resistant depression.  Ketamine is an NMDA receptor antagonist (although it has effects on other neurotransmitter receptors and channels), and the mechanism of its antidepressant effect is still unclear.  Medically, ketamine is used in anesthesia, however it is also a drug of abuse that can cause psychosis.  Unlike drugs that increase monoamines, treatment with ketamine is able to rapidly relieve depression (within two hours), but its antidepressant effect is usually not sustained (relapse within 1-2 weeks).  Further research is needed to develop ways to safely administer the drug to provide long-term relief.  As well, it may be possible to identify safer compounds that act similarly to ketamine.

Other treatments

Psychotherapy, by itself for mild depression, or in addition to drug treatment, is an important and effective approach to the treatment of major depressive disorder. For patients in whom psychotherapy and drug treatment is not successful, electroconvulsive shock therapy (ECT) may be used. In an ECT procedure, the patient takes an anesthetic and a muscle relaxant, and then electric current is used to induce a generalized seizure in the brain. There are usually 6-12 treatments in a course of ECT therapy. While effective for some patients, ECT is controversial because it has adverse effects on memory and possibly on cognition.

Theories about the biological basis of depression

Depression is a heterogeneous disorder, and so there is not likely one explanation for its cause. Below are just a few of the many hypotheses about the pathophysiology of depression.

Depression responds to treatments with drugs that increase the level of monoamine neurotransmitters, namely serotonin or norepinephrine. The “monoamine hypothesis” is that depression somehow results from decreased function of these neurotransmitters in the brain. Brainstem nuclei that release norepinephrine and serotonin (LC and Raphe) promote arousal, but also influence emotional processing by projecting to components of the limbic system, such as the amygdala, and the prefrontal and cingulate cortex.

Here is an important point regarding the monoamine hypothesis:  although antidepressant drugs increase serotonin and norepinephrine levels acutely (within hours), the therapeutic effect of the drugs usually takes at least two weeks. Thus, the antidepressant effect of increasing monoamine neurotransmitters must be due to long-term changes in the brain.

Long-term changes could include growth of neuronal processes, changes in synapses, and even changes in the number of neurons. The hippocampus is a site in the brain where there is substantial adult neurogenesis:  the continued generation of new neurons after the developmental period. Changes in adult neurogenesis have been linked to depression in animal models. Studies in animal models have also shown that the therapeutic effect of antidepressants requires adult neurogenesis. Other studies have indicated that neurogenesis in the hippocampus may play a role in the adaptation to stress. Alterations in the regulation of stress hormones (CRF, ACTH and cortisol) and the CNS system response to stress are also thought to underlie depression.

Functional imaging studies have suggested that dysfunctional activity in the amygdala and BA25 (a specific subregion of the cingulate gyrus) may be a key feature of depression in some individuals. These regions show overactivity in depressed subjects compared to healthy controls. Successful treatment with antidepressant medications caused the activity to revert to the pattern seen in controls. As well, deep brain stimulation of BA25 has been used to treat a small number of patients whose depression failed to respond to other treatments. Deep brain stimulation is approved to treat Parkinson’s disease, but is still very much an experimental treatment for depression. So far, around two-thirds of patients treated by deep brain stimulation have shown some improvement in symptoms. While this success rate may seem marginal, it is important to remember that these are patients whose depression was not helped by any other treatments.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. Name the term that means a lack of pleasure in previously rewarding stimuli.
2. What symptom of bipolar disorder distinguishes it from major depressive disorder?
3. Name the neurotransmitter released by neurons in the Raphe nucleus.
4. Generally, how long must a patient take an antidepressant before having some relief of symptoms? [24 hours; two weeks; 6 months]
5. What part of the brain is a major site of adult neurogenesis?
6. Name a region of the brain that has been shown (by functional imaging) to be overactive in depression.

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