biology of depression biology of depression scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (mdd), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin d, and tryptophan with situational origin but biological impact. several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms. neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (acc), orbitofrontal cortex (ofc), and striatum are frequently implicated as well. these regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity. genetic factors difficulty of gene studies historically, candidate gene studies have been a major focus of study. however, as the number of genes reduces the likelihood of choosing a correct candidate gene, type i errors (false positives) are highly likely. candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. these effects are compounded by the usual assessment of genes without regard for gene-gene interactions. these limitations are reflected in the fact that no candidate gene has reached genome-wide significance. 5-httlpr the 5-httlpr, or serotonin transporter promoter gene's short allele, has been associated with increased risk of depression; since the 1990s, however, results have been inconsistent. other genes that have been linked to a gene–environment interaction include crhr1, fkbp5 and bdnf, the first two of which are related to the stress reaction of the hpa axis, and the latter of which is involved in neurogenesis. candidate gene analysis of 5-httlpr on depression was inconclusive on its effect, either alone or in combination with life stress. a 2003 study proposed 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). this hypothesis was widely discussed in both the scientific literature and popular media, where it was dubbed the "orchid gene", but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression. bdnf bdnf polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression. sirt1 and lhpp a 2015 gwas study in han chinese women positively identified two variants in intronic regions near sirt1 and lhpp with a genome-wide significant association. norepinephrine transporter polymorphisms attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results. one review identified multiple frequently studied candidate genes. the genes encoding for the 5-htt and 5-ht2a receptor were inconsistently associated with depression and treatment response. mixed results were found for brain-derived neurotrophic factor (bdnf) val66met polymorphisms. polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behavior. a meta analysis of 182 case controlled genetic studies published in 2008 found apolipoprotein e epsilon 2 to be protective, and gnb3 825t, mthfr 677t, slc6a4 44bp insertion or deletions, and slc6a3 40 bpvntr 9/10 genotype to confer risk. circadian rhythm depression may be related to the same brain mechanisms that control the cycles of sleep and wakefulness. depression may be related to abnormalities in the circadian rhythm, or biological clock. a well synchronized circadian rhythm is critical for maintaining optimal health. adverse changes and alterations in the circadian rhythm have been associated various neurological disorders and mood disorders including depression. sleep sleep disturbance is the most prominent symptom in depressive patients. studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (rem) sleep. 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. light therapy 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 people who are hospitalized for mdd (major depressive disorder). increased and decreased sleep length appears to be a risk factor for depression. people 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 illustration of the major elements in a prototypical synapse. synapses are gaps between nerve cells. these cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells. monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine. monoamine hypothesis of depression many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of 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 depression, and even that certain neurotransmitters are linked to specific symptoms. normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. some 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. the main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. one explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-ht1a autoreceptors. the therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons. monoamine receptors affect phospholipase c and adenylyl cyclase inside of the cell. green arrows means stimulation and red arrows inhibition. serotonin receptors are blue, norepinephrine orange, and dopamine yellow. phospholipase c and adenylyl cyclase start a signaling cascade which turn on or off genes in the cell. sufficient atp from mitochondria is required for these downstream signalling events. the 5ht-3 receptor is associated with gastrointestinal adverse effects and has no relationship to the other monoamine receptors. serotonin the serotonin "chemical imbalance" theory of depression, proposed in the 1960s, is not supported by the available scientific evidence. ssris alter the balance of serotonin inside and outside of neurons: their clinical antidepressant effect (which is robust in severe depression) is likely due to more complex changes in neuronal functioning which occur as a downstream consequence of this. initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-hydroxyindoleacetic acid (5-hiaa) and platelet binding. the results were generally inconsistent, and may not generalize to the central nervous system. however evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioral and neural level. pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. these emotional processing biases may explain the therapeutic gap. dopamine while various abnormalities have been observed in dopaminergic systems, results have been inconsistent. people with mdd have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. while polymorphisms of the d4 and d3 receptor have been implicated in depression, associations have not been consistently replicated. similar inconsistency has been found in postmortem studies, but various dopamine receptor agonists show promise in treating mdd. there is some evidence that there is decreased nigrostriatal pathway activity in people 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. studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems. catecholamines a number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. furthermore, norepinephrine transporter knockout in mice models increases 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 in persons lacking the predisposition. on the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently 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 depressive symptoms in adolescents. 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 disrupted 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. not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. if significant mood improvements do occur, this is often not for at least two to four weeks. one possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks.