Biology of depression

Genetic factors

In contrast to other mental disorders such as schizophrenia, genetic factors involved in depression have been more difficult to identify. In 2003 Science published an influential study of Avshalom Caspi et al. who found that a gene-environment interaction (GxE) may 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). Soon after, the results were replicated by Kenneth Kendler's group, raising hopes in the psychiatric genetics community. By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of the largest studies were negative. Two 2009 meta-analyses were also negative; one included 14 studies, the other just five, owing to different study selection criteria. A 2010 review of studies in this area found 17 replications, 8 partial replications (interaction only in females or only with one of several types of adversity), and 9 non-replications (no interaction or an interaction in the opposite direction). It also found a systematic relationship between the method used to assess environmental adversity and the results of the studies; all studies using objective indicators or structured interviews to assess stress replicated the gene–environment interaction fully or partially, whereas all non-replications relied on brief self-report measures of adversity. This review also found that both 2009 meta-analyses were significantly biased toward negative studies.

Other hypothesized genomic influences are BDNF polymorphisms, but the replications studies have been mixed and insufficient as of 2005 for a meta-analysis. Studies also indicate an association of BDNF to suicidal behavior. However, findings from the gene-environment interactions studies suggest that the current BDNF models of depression are too simplistic. A 2008 study found interactions (biological epistasis) in the signaling pathways of the BDNF and the serotonin transporter; the BDNF Val66Met allele, which was predicted to have reduced responsitivity to serotonin, was found to exercise protective effects in individuals with the short 5-HTTLPR allele that is otherwise believed to predispose individuals to depressive episodes after stressful events. Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.

The largest genome-wide study to date failed to identify variants with genome-wide significance in over 9000 cases.

Recently, the first genetics study has been published with positively identified two variants with genome-wide association with major depressive disorder (MDD). This study, conducted in Chinese Han woman, identified two variants in intronic regions near SIRT1 and LHPP.

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.

One review identified multiple frequently studied candidate genes. The 5-HTT SLC6A4 and 5-HTR2A gene's yielded inconsistent results, however they may predict treatment results. Mixed results were found for BDNF Val66Met polymorphisms. Polymorphisms in tryptophan hydroxylase genes were found to be associated with suicidal behavior. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein verepsilon 2 to be protective, and found GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype conferred risk.

Circadian rhythm

Depression may be related to abnormalities in the circadian rhythm, or biological clock. For example, rapid eye movement (REM) sleep—the stage in which dreaming occurs—may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.

Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in hospitalized patients.

Increased and decreased sleep length appears to be a risk factor for depression. Patients with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.

Monoamines

Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine. Many antidepressant drugs increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of two other neurotransmitters, norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit 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 hypothesis recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. Anxious or irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs. Others have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms.

Consistent with the monoamine hypothesis, a longitudinal study uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow stressful life events, but even more so for people with one or two short alleles of the 5-HTT gene. Serotonin may help to regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties of this dysregulation.

Various abnormalities have been observed in dopaminergic systems however results have been inconsistent. Patients with MDD have an increased reward response to D-Amphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. Polymorphisms of the D4 and D3 receptor have been implicated in depression further suggesting a role of dopamine in MDD. Results from postmortem studies have not been consistent, but various dopamine receptor agonist show promise in treating MDD There is some evidence that there is decreased nigrostriatal activity in those with melancholic depression(psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression.

Finding indicative of decreased adrenergic activity in depression have been reported. Findings include decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 receptor density. Furthermore norepinephrine transporter knockout in mice models increase their tolerance to stress, implicating norepinephrine in depression.

One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan(the precursor of serotonin), tyrosine and phenylalanine(precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not healthy persons. Inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine did not consitenyl result in decreased mood.

Monoamine oxidase

An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with the depressive symptoms in youth. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression.

Limitations

Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression; antidepressants usually increase synaptic serotonin very quickly, but it often takes at least two to four weeks before mood improves significantly. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization rather which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There has also been inconsistency with regards to serum 5-HIAA levels, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressants properties. Furthermore, some have argued that depression may be marked by a hyperseretonergic state Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.

Receptor binding

As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be underexpressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent however it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in depressed patients. Studies on 5-HTT binding are variable but tend towards an increase. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increase MAO activity in depressed patients, and it may even be a trait marker(not changed by response to treatment). Muscarianic receptor binding appears to be increased in depression, and given ligand binding dynamics, suggests increased cholinergic activity.

Emotional processing and neural circuits

Studies of emotional processing in patients with MDD show various biases such as a tendency to rate happy faces more negatively. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. Patients also showed decreased activity in the left dorsolateral prefrontal cortex in response to negative stimuli. Depressed people have impaired recognition of happy, angry, disgusted, fearful and surprised faces, but not of sad faces. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. The observation that both acute and subchronic SSRI administration increases response to positive faces.

One proposed hypothesis for negative emotional bias comes from meta analytic findings of functional neuroimaging studies. Relative to controls, depressed patients showed hyperactivity of circuit termed "the salience network," composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex, as well as decreased activity in regulatory circuits composed of the striatum and dorsolateral prefrontal cortex. However the authors acknowledge limitations exogenous factors such as patient medication status as well as small study sample size.

A similar model termed "the limbic cortical model" has been proposed involving hyperactivity of ventral paralimbic regions and hypoactivity of dorsal limbic and prefrontal regions. This model and another termed "the cortical striatal model", consisting of abnormalities in the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, caudate, putamen and globus pallidus, has been supported by more recent literature. The authors cited study bias, and lack of specificity of inclusion criteria and limiting factors.

Depression is also characterized by decreased activation of the medial prefrontal cortex, ventral striatum, and in particular the nucleus accumbens in response to positive stimuli. These regions are important in reward processing, and dysfunction of them in depression is thought to underly anhedonia, a core symptom of depression involving decreased ability to feel pleasure. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum.

Brain regions

Research on the brains of depressed patients usually shows disturbed patterns of interaction between multiple parts of the brain. Several areas of the brain are implicated in studies seeking to more fully understand the biology of depression:

Raphe nuclei

The sole source of serotonin in the brain is the raphe nuclei, a group of small nerve cell nuclei in the upper brain stem, located directly at the mid-line of the brain. There is some evidence for neuropathological abnormalities in the rostral raphe nuclei in depression. Despite their small size, they reach very widely through their projections, and are involved in a very diverse set of functions. Most antidepressants are serotonergic.

Subgenual cingulate

Recent studies have shown that Brodmann area 25, also known as Subgenual cingulate is metabolically overactive in treatment-resistant depression. This region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem, which influences changes in appetite and sleep; the amygdala and insula, which affect the mood and anxiety; the hippocampus, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep Brain Stimulations of this area have been successful in reducing its elevated activity and thus curing depression in patients that could not be cured by anti-depressants. One meta analysis found this area to be overactive in youth with MDD compared to controls.

Ventricles

Multiple studies have found evidence of ventricular enlargement in people who have depression, particularly enlargement of the third ventricle. These observations are interpreted as indicating loss of neural tissue in brain regions adjacent to the enlarged ventricle, leading to suggestions that cytokines and related mediators of neurodegeneration may play a role in giving rise to the disease.

Prefrontal cortex

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the etiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in depressed patients. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in depressed patients. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.

Amygdala

The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.

Hippocampus

Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis.

Hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body's response to stressors of various sorts. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In depressed patients the often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in patients with depression. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes by be responsible for some of the changes such as decreased bone mineral density and increased weight found in patients with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.

Altered neuroplasticity

Recent studies have called attention to the role of altered neuroplasticity in depression. A review found convergence of three phenomena:

1. Chronic stress reduces synaptic and dendritic plasticity
2. Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees)
3. Anti-depressant medications enhance neuroplasticity at both a molecular and dendritic level.

The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.

Blood levels of BDNF in depressed patients increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in depressed patients. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.

Inflammation and oxidative stress

Various review have found that general inflammation may play a role in depression. One meta analysis of cytokines in depressed patients found increased IL-6 and TNF-a levels relative to controls. First theories came about when it was noticed that interferon therapy caused depression in a large number of patients. Meta analysis on cytokine levels in depressed patients have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10 in depressed patients. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behavior, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression.

A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms.

Increased markers of oxidative stress relative to controls have been found in patients with MDD. A marker of DNA oxidation, 8-Oxo-2'-deoxyguanosine, has been found to be increased in both the plasma and urine of depressed patients. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in depressed patients. Studies with 8-Oxo-2' Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity.

One meta analysis found decreased leukocyte telomere lengths in depressed patients.

Large-scale brain network theory

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology:

Central executive network

The executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is crucially involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.

Default mode network

The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. Individuals suffering from major depression also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get “stuck” in the negative, self-focused thoughts that often characterize depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience network

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In major depressive disorder, anxiety is often a part of the emotional state that characterizes depression.