Biological causes of depression

In: Causes

Monoamine hypothesis

Most antidepressant medications increase the levels of one or more of the monoamines—the neurotransmitters serotonin, norepinephrine and dopamine—in the synaptic cleft between neurons in the brain. Some medications affect the monoamine receptors directly.
 
Schematic of a synapse between an axon of one neuron and a dendrite of another. Synapses are specialized gaps between neurons. Electrical impulses arriving at the axon terminal trigger release of packets of chemical messengers (neurotransmitters), which diffuse across the synaptic cleft to receptors on the adjacent dendrite temporarily affecting the likelihood that an electrical impulse will be triggered in the latter neuron. Once released the neurotransmitter is rapidly metabolized or pumped back into a neuron. Antidepressants influence the overall balance of these processes.

Serotonin is hypothesized to regulate other neurotransmitter systems; decreased serotonin activity may allow these systems to act in unusual and erratic ways. According to this "permissive hypothesis", depression arises when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter. Some antidepressants enhance the levels of norepinephrine directly, whereas others raise the levels of dopamine, a third monoamine neurotransmitter. These observations gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that a deficiency of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." The proponents of this theory recommend the choice of an antidepressant with mechanism of action that impacts the most prominent symptoms. Anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and those experiencing a loss of energy and enjoyment of life with norepinephrine- and dopamine-enhancing drugs.

Besides the clinical observations that drugs which increase the amount of available monoamines are effective antidepressants, recent advances in psychiatric genetics indicate that phenotypic variation in central monoamine function may be marginally associated with vulnerability to depression. Despite these findings, the cause of depression is not simply monoamine deficiency. In the past two decades, research has revealed multiple limitations of the monoamine hypothesis, and its explanatory inadequacy has been highlighted within the psychiatric community. A counterargument is that the mood-enhancing effect of MAO inhibitors and SSRIs takes weeks of treatment to develop, even though the boost in available monoamines occurs within hours. Another counterargument is based on experiments with pharmacological agents that cause depletion of monoamines; while deliberate reduction in the concentration of centrally available monoamines may slightly lower the mood of unmedicated depressed patients, this reduction does not affect the mood of healthy people. An intact[clarification needed] monoamine system is necessary for antidepressants to achieve therapeutic effectiveness, but some medications like tianeptine and opipramol have antidepressant properties despite the fact that the former is a serotonin reuptake enhancer and the latter has no effect on the monoamine system.[citation needed] The monoamine hypothesis, already limited, has been further oversimplified when presented to the general public as a mass marketing tool, usually phrased as a "chemical imbalance".

In 2003 a gene-environment interaction (GxE) was hypothesized to explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR); a 2009 meta-analysis showed stressful life events was associated with depression, but found no evidence for an association with the 5-HTTLPR genotype. Another 2009 meta-analysis agreed with the latter finding. A 2010 review of studies in this area found a systematic relationship between the method used to assess environmental adversity and the results of the studies; this review also found that both 2009 meta-analyses were significantly biased toward negative studies, which used self-report measures of adversity.

Other theories

MRI scans of patients with depression have revealed a number of differences in brain structure compared to those who are not depressed. Although there is some inconsistency in the results, meta-analyses have shown there is evidence for smaller hippocampal volumes and increased numbers of hyperintensive lesions. Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.

There may be a link between depression and neurogenesis of the hippocampus, a center for both mood and memory. Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood. Drugs may increase serotonin levels in the brain, stimulating neurogenesis and thus increasing the total mass of the hippocampus. This increase may help to restore mood and memory. Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior. One of the neurotrophins responsible for neurogenesis is brain-derived neurotrophic factor (BDNF). The level of BDNF in the blood plasma of depressed subjects is drastically reduced (more than threefold) as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although decreased plasma BDNF levels have been found in many other disorders, there is some evidence that BDNF is involved in the cause of depression and the mechanism of action of antidepressants.

There is some evidence that major depression may be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that results in an effect similar to the neuro-endocrine response to stress. Investigations reveal increased levels of the hormone cortisol and enlarged pituitary and adrenal glands, suggesting disturbances of the endocrine system may play a role in some psychiatric disorders, including major depression. Oversecretion of corticotropin-releasing hormone from the hypothalamus is thought to drive this, and is implicated in the cognitive and arousal symptoms.

The hormone estrogen has been implicated in depressive disorders due to the increase in risk of depressive episodes after puberty, the antenatal period, and reduced rates after menopause. Conversely, the premenstrual and postpartum periods of low estrogen levels are also associated with increased risk. Sudden withdrawal of, fluctuations in or periods of sustained low levels of estrogen have been linked to significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized or restored.

Other research has explored potential roles of molecules necessary for overall cellular functioning: cytokines. The symptoms of major depressive disorder are nearly identical to those of sickness behavior, the response of the body when the immune system is fighting an infection. This raises the possibility that depression can result from a maladaptive manifestation of sickness behavior as a result of abnormalities in circulating cytokines. The involvement of pro-inflammatory cytokines in depression is strongly suggested by a meta-analysis of the clinical literature showing higher blood concentrations of IL-6 and TNF-? in depressed subjects compared to controls.