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). Muscarinic receptor binding appears to be increased in depression, and given ligand binding dynamics, suggests increased cholinergic activity. 55 four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-htt one on 5-HT1a, and another on dopamine transporter (DAT).
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48 For one thing, serotonin system dysfunction cannot be the sole cause of der 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. 49 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. 50 Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. 51 52 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 hyperserotonergic state 53 Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. 54 Receptor binding edit 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.
On the with other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood. 42 Monoamine oxidase edit 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. 43 In genetic studies, the alterations of mao-a-related genes have not been consistently associated with depression. 44 45 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. 46 In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression. 47 Limitations edit since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community.
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 agonist show promise in treating mdd 36 There is some evidence that there is decreased nigrostriatal activity in those with melancholic depression(psychomotor retardation). 37 Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, 38 as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. 39 Studies in rodents have supported a potential mechanism involving stress induced dysfunction of dopaminergic parts systems. 40 A number of lines of evidence 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. 38 Furthermore, norepinephrine transporter knockout in mice models reviews increase their tolerance to stress, implicating norepinephrine in depression. 41 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.
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. 34 Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioral and neural level. 35 34 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, 35 While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. Patients 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.
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30 Many antidepressant drugs acutely 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 for of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. 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. 31 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.
32 One explanation for the 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. 33 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. The 5HT-3 receptor is associated with gastrointestinal adverse effects and has no relationship to the other monoamine receptors.
24 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. 25 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. 26 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. 25 Increased and decreased sleep length appears to be a risk factor for depression.
27 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. 28 daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression. 29 Monoamines edit 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.
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22 Circadian rhythm edit 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, 23 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, 24 and is impaired by compounds, such as father's antidepressants, that increase serotonergic tone in brain stem structures. 24 overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation 23 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.
15 The largest genome meta analysis to date failed to identify variants with genome-wide significance, with a study size of 18,000 participants of European ancestry. 17 Recently, a genetics study positively identified two variants with genome-wide association with major depressive disorder (MDD). 18 This study, conducted in Chinese han women, identified two variants in intronic regions near sirt1 and lhpp. 19 Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results. 20 One review identified multiple frequently dislikes studied candidate genes. The genes encoding for the 5-htt and 5-HT2A receptor was inconsistently associated with depression, but may predict treatment response. Mixed results were found for brain-derived neurotrophic factor (bdnf) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be associated with suicidal behavior. 21 A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein verepsilon 2 to be protective, and gnb3 825t, mthfr 677t, slc6A4 44bp insertion or deletions, and slc6A3 40 bpvntr 9/10 genotype to conferre risk.
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 that all studies using objective indicators or structured interviews to assess stress replicated the geneenvironment interaction fully or partially, whereas all non-replications relied on self-reported measures of adversity. This review also argued that both 2009 meta-analyses were significantly biased toward negative studies. 12 bdnf polymorphisms have also been hypothesized to have a genetic influence, but replication results have been mixed and, as of 2005, were insufficient for a meta-analysis. 13 Studies also indicate an association of decreased bdnf production with suicidal behavior. 14 However, findings from gene-environment interactions studies suggest that the current bdnf models of depression are too simplistic. 15 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. 16 Thus, the bdnf-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.
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. 3, a 2003 study 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 ). 4 5, soon after, the results were replicated. Kenneth Kendler 's essays group, raising hopes in the psychiatric genetics community. 6, by 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE.
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Scientific studies have found that numerous brain areas show altered activity in patients suffering from depression, 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. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, inflammation and the circadian rhythm. Neural circuits implicated in depression include those write 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. 1 2, contents, genetic factors edit, genetic factors involved in depression have been difficult to identify. 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.