Biology of Depression

Biology of depression
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.
Contents
Genetic factors
Circadian rhythm
Monoamines
Monoamine oxidase
Limitations
Receptor binding
Emotional processing and neural circuits
Structural Neuroimaging
Brain regions
Raphe nuclei
Subgenual cingulate
Ventricles
Prefrontal cortex
Amygdala
Hippocampus
Altered neuroplasticity
Inflammation and oxidative stress
Large-scale brain network theory
Central executive network
Default mode network
Salience network
See also
References
Further reading
Genetic factors
Genetic factors involved in depression have been difficult to identify. In 2003 Science published an influential[1] study of Avshalom
Caspi et al. who found that agene-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).[2] Soon after, the results were replicated by Kenneth Kendler's group, raising hopes in the psychiatric genetics
community.[3] By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of
the largest studies[4][5] were negative.[6] Two 2009 meta-analyses were also negative; one included 14 studies,[7] and the other five,
owing to different study selection criteria.[8] A 2010 review 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 that 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 self-reported measures of adversity. This review also argued that
[9]
both 2009 meta-analyses were significantly biased toward negative studies.
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.[10] Studies also indicate an association of decreased BDNF production with suicidal
behavior.[11] However, findings from gene-environment interactions studies suggest that the current BDNF models of depression are
too simplistic.[12] 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.[13] Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and
[12]
antidepressants is influenced by other genetic and environmental modifiers.
[14]
The largest genome-wide study to date failed to identify variants with genome-wide significance in over 9000 cases.
Recently, a genetics study positively identified two variants with genome-wide association with major depressive disorder
(MDD).[15] This study, conducted in Chinese Han women, identified two variants in intronic regions near
SIRT1 and LHPP.[16]
[17]
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.[18] 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,
[19]
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,[20] 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,[21] and is impaired by compounds, such
as antidepressants, that increase serotonergic tone in brain
stem structures.[21] Overall, the serotonergic system is least
active during sleep and most active during wakefulness.
Prolonged wakefulness due to sleep deprivation[20]
Depression may be related to the same brain mechanisms
activates serotonergic neurons, leading to processes similar that control the cycles of sleep and wakefulness.
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
[21]
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.[22] 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.[23] Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in
[22]
combination quickly to interrupt a deep depression in hospitalized patients.
Increased and decreased sleep length appears to be a risk factor for depression.[24] 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.[25]
Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some
depression.[26]
Monoamines
Monoamines are neurotransmitters that include serotonin, dopamine,
norepinephrine, and epinephrine.[27] 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
Illustration of the major elements in a corresponding features of depression: "Norepinephrine may be related to alertness
prototypical synapse. Synapses are and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to
gaps between nerve cells. These anxiety, obsessions, and compulsions; and dopamine to attention, motivation,
cells convert their electrical impulses pleasure, and reward, as well as interest in life." The proponents of this hypothesis
into bursts of chemical relayers,
recommend choosing the antidepressant with the mechanism of action impacting the
called neurotransmitters, which travel
most prominent symptoms. Anxious or irritable patients should be treated with
across the synapses toreceptors on
adjacent cells, triggering electrical SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy
impulses to travel down the latter and enjoyment of life—with norepinephrine and dopamine enhancing drugs.[28]
cells. 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.[29]
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.[2] 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.[31]
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[32] There is some evidence that there is decreased nigrostriatal
activity in those with melancholic depression(psychomotor retardation).[33] Further supporting the role of dopamine in depression is
the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine,[34] as well as post mortem findings of
altered Dopamine receptor D3 and dopamine transporter expression.[35] Hyperactivity of catecholamine release during stress,
[36]
followed by desensitization has been proposed as a mechanism for depression.
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.[34] Furthermore, norepinephrine transporter knockout in mice models increase their tolerance to stress, implicating
norepinephrine in depression.[37]
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 consistently result
in decreased mood.[38]
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 Monoamine receptors affect
hypothesis received support from a PET study, which found significantly elevated phospholipase C and adenylyl
activity of MAO-A in the brain of some depressed people.[39] In genetic studies, the cyclase inside of the cell. Green
arrows means stimulation and red
alterations of MAO-A-related genes have not been consistently associated with
arrows inhibition. Serotonin receptors
depression.[40][41] Contrary to the assumptions of the monoamine hypothesis, are blue, norepinephrine orange, and
lowered but not heightened activity of MAO-A was associated with the depressive dopamine yellow. Phospholipase C
symptoms in youth. This association was observed only in maltreated youth, and adenylyl cyclase start asignaling
indicating that both biological (MAO genes) and psychological (maltreatment) cascade which turn on or off genes in
factors are important in the development of depressive disorders.[42] In addition, the cell. Many variations of the
monoamine hypothesis involve the
some evidence indicates that problems in information processing within neural
neurotransmitter, serotonin,
[43]
networks, rather than changes in chemical balance, might underlie depression. regulated by the serotonin
transporter, which assists the
modulation of feelings and behavior
Limitations such as anxiety, anger, appetite,
Since the 1990s, research has uncovered multiple limitations of the monoamine sexuality, sleep, mood, etc. People
with depression may have
hypothesis, and its inadequacy has been criticized within the psychiatric
differences in serotonin transporter
community.[44] For one thing, serotonin system dysfunction cannot be the sole cause
gene length.[30] People with both
of depression; antidepressants usually increase synaptic serotonin very quickly
, but it alleles that are long are less likely to
often takes at least two to four weeks before mood improves significantly. One become depressed, while people
possible explanation for this lag is that the neurotransmitter activity enhancement is with one short and one long or two
the result of auto receptor desensitization rather which can take weeks.[45] Intensive short alleles are more likely to
investigation has failed to find convincing evidence of a primary dysfunction of a develop depression.[2] The 5HT-3
receptor is associated with
specific monoamine system in patients with major depressive disorders. The
gastrointestinal adverse effects and
antidepressants that do not act through the monoamine system, such as tianeptine has no relationship to the other
and opipramol, have been known for a long time. There has also been inconsistency monoamine receptors.
with regards to serum 5-HIAA levels, a metabolite of serotonin.[46] Experiments
with pharmacological agents that cause depletion of monoamines have shown that
this depletion does not cause depression in healthy people.[47][48] 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[49] Already limited, the monoamine hypothesis has been further oversimplified when presented to the general
public.[50]
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
gic activity.[51]
increased in depression, and given ligand binding dynamics, suggests increased choliner
Two meta analyses on receptor binding in depression have been performed, one on serotonin transporter(5-HTT), and the other on 5-
HT1A. Serotonin transporter binding was reported to be reduced in the midbrain and amygdala, with the former correlating with
greater age, and the latter correlating with depression severity.[52] 5-HT1A was found to be reduced in the anterior cingulate cortex,
[53]
mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe.
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.[54] 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.[55] Depressed people have impaired recognition of happy, angry, disgusted, fearful and
surprised faces, but not of sad faces.[56] 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.[57]
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.[58]
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.[59] 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.[60] The authors cited study bias, and lack of specificity of inclusion criteria and limiting factors.
Depression is also characterized by decreased activation of themedial 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.[61]
Structural Neuroimaging
Meta analysis performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. One meta
analysis of early onset general depression reported grey matter reductions in the bilteral anterior cingulate cortex (ACC) and
dorsomedial prefrontal cortex (dmPFC).[62] One study in medication free depression found reductions in the left middle frontal
gyrus, right superior frontal gyrus, and left insula, while reporting increases in the thalamus and cuneus.[63] One meta analysis on
first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations;
medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right
inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula,
right supplementary motor area, and right middle temporal gyrus.[64] Another study distinguishing medicated and medication free
populations, albeit not restricted to first episode patients, observed reductions in the combined population in the bilateral superior,
right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. Increases in thalamic and ACC grey matter
.[65]
was reported in the medication free and medicated populations respectively
[66]
An "Activation Likelihood Estimate" meta analysis reported reductions in the paracingulate cortex, dACC and amygdala.
Using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the ACC, medial
prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in orbitofrontal cortex and ventromedial
prefrontal cortex grey matter were also reported.[67]
Two studies on depression from the ENIGMA consortium have been published, one on cortical thickness, and the other on
subcortical volume. Reduced cortical thickness was reported in the bilateral orbitofrontal cortex, ACC, insula, middle temporal gyri,
fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal,
orbitofrontal and precentral regions.[68] Subcortical abnormalities, including reductions in hippocampus and amygdala volumes,
[69]
which were especially pronounced in early onset depression.
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 areserotonergic.[70]
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 stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant
depression.[71]:576–578 [72]
Ventricles
Multiple studies have found evidence of ventricular enlargement in people who have depression, particularly enlargement of the third
ventricle.[73][74][75] 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.[76][77][78]
Prefrontal cortex
One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls.[79] 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.[80] One meta
analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in depressed
patients.[81] 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.
[82]
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.[72]
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.[83] 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.[84] One study, however, found no difference in amygdala activity during emotional processing tasks.[85]
Hippocampus
[86][87]
Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis.
Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as
suppression in hippocampal neurogenesis.[88] This leads to alteration in emotion and cognition related brain regions as well as HPA
axis dysfunction. Through the dysfunction, the effects of stress can be exacerbated including its effects on 5-HT. Furthermore, some
of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis. This leads to a
restoration in HPA activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-HT.[89]
The hypothalamic-pituitary-adrenal axisis 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.[90] Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in patients
with depression.[91] Early life stress has been hypothesized as a potential cause of HPA dysfunction.[92][93] 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.[94] 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
[95]
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 may enhance neuroplasticity at both a molecular and dendritic level.
[96]
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.[97] 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.[98]
Inflammation and oxidative stress

Various review have found that general inflammation may play a role in depression.[99][100] One meta analysis of cytokines in
depressed patients found increased IL-6 and TNF-a levels relative to controls.[101] First theories came about when it was noticed that
interferon therapy caused depression in a large number of patients.[102] Meta analysis on cytokine levels in depressed patients have
demonstrated increased levels ofIL-1, IL-6, C-reactive protein, but not IL-10 in depressed patients.[103][104] Increased numbers of T-
Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in
depression.[105] Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems,
diet, smoking and obesity.[106] 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.[107] One review found normalization of cytokine levels
after successful treatment of depression.[108]
A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors
reduced depressive symptoms.[109]
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.[110] Another meta-analysis found similar results with regards to
.[111]
oxidative damage products as well as decreased oxidative capacity
[112]
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,[113] 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:[113]
Central executive network

The executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal
cortex.[114][115] This network is crucially involved in high level cognitive functions such as maintaining and using information in
working memory, problem solving, and decision making.[113][116][117][118][119] Deficiencies in this network are common in most
major psychiatric and neurological disorders, including depression.[120][121] Because this network is crucial for everyday life
[122]
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.[113] 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.[123][124] 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.[125] 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.[126] 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.[127] 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.[114] 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.[113] 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.[128] This atypically high activity in the right anterior insula is thought to contribute to the experience of negative
and worrisome feelings.[129] In major depressive disorder, anxiety is often a part of the emotional state that characterizes
depression.[130]
See also
Biological psychiatry
Biology of bipolar disorder
References
1. Nierenberg, AA (2009)."The long tale of the short arm of the promoter region for the gene that encodes the
serotonin uptake protein"(http://www.cnsspectrums.com/UserDocs/ArticleImages/174/0909CNS_Nierenberg.pdf)
(PDF). CNS spectrums. 14 (9): 462–3. doi:10.1017/s1092852900023506(https://doi.org/10.1017%2Fs10928529000
23506). PMID 19890228 (https://www.ncbi.nlm.nih.gov/pubmed/19890228).
2. Caspi, Avshalom; Sugden, Karen; Moffitt, Terrie E.; Taylor, Alan; Craig, Ian W.; Harrington, HonaLee; McClay,
Joseph; Mill, Jonathan; Martin, Judy; Braithwaite, Antony; Poulton, Richie (July 2003). "Influence of Life Stress on
Depression: Moderation by a Polymorphism in the 5-HTT Gene"(https://www.sciencemag.org/content/301/5631/386.
abstract). Science. 301 (5631): 386–89. Bibcode:2003Sci...301..386C (http://adsabs.harvard.edu/abs/2003Sci...301..
386C). doi:10.1126/science.1083968(https://doi.org/10.1126%2Fscience.1083968) . PMID 12869766 (https://www.n
cbi.nlm.nih.gov/pubmed/12869766).
3. Kendler, K.; Kuhn, J.; Vittum, J.; Prescott, C.; Riley, B. (2005). "The interaction of stressful life events and a serotonin
transporter polymorphism in the prediction of episodes of major depression: a replication". Archives of General
Psychiatry. 62 (5): 529–535. doi:10.1001/archpsyc.62.5.529(https://doi.org/10.1001%2Farchpsyc.62.5.529) .
PMID 15867106 (https://www.ncbi.nlm.nih.gov/pubmed/15867106). Lay summary (http://www.esi-topics.com/nhp/20
06/september-06-KennethSKendler.html) – New Hot Paper Comments(6 September 2006).
4. Gillespie, N. A.; Whitfield, J. B.; Williams, B.; Heath, A. C.; Martin, N. G. (2005). "The relationship between stressful
life events, the serotonin transporter (5-HTTLPR) genotype and major depression". Psychological Medicine. 35 (1):
101–111. doi:10.1017/S0033291704002727(https://doi.org/10.1017%2FS0033291704002727) . PMID 15842033 (htt
ps://www.ncbi.nlm.nih.gov/pubmed/15842033).
5. Surtees, P.; Wainwright, N.; Willis-Owen, S.;Luben, R.; Day, N.; Flint, J. (2006). "Social adversity, the serotonin
transporter (5-HTTLPR) polymorphism and major depressive disorder". Biological Psychiatry. 59 (3): 224–229.
doi:10.1016/j.biopsych.2005.07.014(https://doi.org/10.1016%2Fj.biopsych.2005.07.014) . PMID 16154545 (https://w
ww.ncbi.nlm.nih.gov/pubmed/16154545).
6. Uher, R.; McGuffin, P. (2008). "The moderation by the serotonin transporter gene of environmental adversity in the
aetiology of mental illness: review and methodological analysis".Molecular Psychiatry. 13 (2): 131–146.
doi:10.1038/sj.mp.4002067(https://doi.org/10.1038%2Fsj.mp.4002067). PMID 17700575 (https://www.ncbi.nlm.nih.g
ov/pubmed/17700575).
7. Risch, N.; Herrell, R.; Lehner, T.; Liang, K.; Eaves, L.; Hoh, J.; Griem, A.; Kovacs, M.; Ott,J.; Merikangas, K. R.
(2009). "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression:
a meta-analysis" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938776). Journal of the American Medical
Association. 301 (23): 2462–2471. doi:10.1001/jama.2009.878(https://doi.org/10.1001%2Fjama.2009.878).
PMC 2938776 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938776) . PMID 19531786 (https://www.ncbi.nlm.ni
h.gov/pubmed/19531786).
8. Munafo, M.; Durrant, C.; Lewis, G.; Flint, J. (2009). "Gene × Environment Interactions at the Serotoninransporter
T
Locus". Biological Psychiatry. 65 (3): 211–219. doi:10.1016/j.biopsych.2008.06.009(https://doi.org/10.1016%2Fj.bio
psych.2008.06.009). PMID 18691701 (https://www.ncbi.nlm.nih.gov/pubmed/18691701).
9. Uher, R.; McGuffin, P. (2010). "The moderation by the serotonin transporter gene of environmental adversity in the
etiology of depression: 2009 update".Molecular Psychiatry. 15 (1): 18–22. doi:10.1038/mp.2009.123 (https://doi.org/
10.1038%2Fmp.2009.123). PMID 20029411 (https://www.ncbi.nlm.nih.gov/pubmed/20029411).
10. Levinson, D. (2006). "The genetics of depression: a review".Biological Psychiatry. 60 (2): 84–92.
11. Dwivedi Y (2009). "Brain-derived neurotrophic factor: role in depression and suicide"(https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC2732010). Neuropsychiatr Dis Treat. 5: 433–49. doi:10.2147/NDT.S5700 (https://doi.org/10.2147%2
FNDT.S5700). PMC 2732010 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732010) . PMID 19721723 (https://w
12. Krishnan, V.; Nestler, E. (2008). "The molecular neurobiology of depression"(https://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC2721780). Nature. 455 (7215): 894–902. Bibcode:2008Natur.455..894K (http://adsabs.harvard.edu/abs/2008
Natur.455..894K). doi:10.1038/nature07455 (https://doi.org/10.1038%2Fnature07455). PMC 2721780 (https://www.n
cbi.nlm.nih.gov/pmc/articles/PMC2721780) . PMID 18923511 (https://www.ncbi.nlm.nih.gov/pubmed/18923511).
13. Pezawas, L.; Meyer-Lindenberg, A.; Goldman, A. L.; V erchinski, B. A.; Chen, G.; Kolachana, B. S.; Egan, M. .;F
Mattay, V. S.; Hariri, A. R.; Weinberger, D. R. (2008). "Evidence of biologic epistasis betwe
en BDNF and SLC6A4
and implications for depression".Molecular Psychiatry. 13 (7): 709–716. doi:10.1038/mp.2008.32 (https://doi.org/10.
1038%2Fmp.2008.32). PMID 18347599 (https://www.ncbi.nlm.nih.gov/pubmed/18347599).
14. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium; Ripke, S; Wray, N. R.; Lewis, C.
M.; Hamilton, S. P.; Weissman, M. M.; Breen,G; Byrne, E. M.; Blackwood, D. H.; Boomsma, D. I.; Cichon, S; Heath,
A. C.; Holsboer, F; Lucae, S; Madden, P. A.; Martin, N. G.; McGuffin, P; Muglia, P; Noethen, M. M.; Penninx, B. P
.;
Pergadia, M. L.; Potash, J. B.; Rietschel, M; Lin, D; Müller-Myhsok, B; Shi, J; Steinberg, S; Grabe, H. J.;
Lichtenstein, P; et al. (2013)."A mega-analysis of genome-wide association studies for major depressive disorder" (h
ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837431). Molecular Psychiatry. 18 (4): 497–511.
doi:10.1038/mp.2012.21 (https://doi.org/10.1038%2Fmp.2012.21). PMC 3837431 (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3837431) . PMID 22472876 (https://www.ncbi.nlm.nih.gov/pubmed/22472876).
15. Converge Consortium; Bigdeli, Tim B.; Kretzschmar, Warren; Li, Yihan; Liang, Jieqin; Song, Li; Hu, Jingchu; Li,
Qibin; Jin, Wei; Hu, Zhenfei; Wang, Guangbiao; Wang, Linmao; Qian, Puyi; Liu, Yuan; Jiang, Tao; Lu, Yao; Zhang,
Xiuqing; Yin, Ye; Li, Yingrui; Xu, Xun; Gao, Jingfang; Reimers, Mark; Webb, Todd; Riley, Brien; Bacanu, Silviu;
Peterson, Roseann E.; Chen, Yiping; Zhong, Hui; Liu, Zhengrong; et al. (2015)."Sparse whole-genome sequencing
identifies two loci for major depressive disorder"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522619). Nature.
523 (7562): 588–91. doi:10.1038/nature14659 (https://doi.org/10.1038%2Fnature14659). PMC 4522619 (https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC4522619) . PMID 26176920 (https://www.ncbi.nlm.nih.gov/pubmed/26176920).
16. Smoller, Jordan W (2015). "The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders"
(h
ttps://doi.org/10.1038%2Fnpp.2015.266). Neuropsychopharmacology. Springer Nature. 41 (1): 297–319.
doi:10.1038/npp.2015.266(https://doi.org/10.1038%2Fnpp.2015.266). Retrieved 24 March 2017.
17. Zhao, Xiaofeng; Huang, Yinglin; Ma, Hui; Jin, Qiu; Wang, Yuan; Zhu, Gang (15 August 2013). "Association between
major depressive disorder and the norepinephrine transporter polymorphisms-182C T and G1287A: a meta-
analysis". Journal of Affective Disorders. 150 (1): 23–28. doi:10.1016/j.jad.2013.03.016(https://doi.org/10.1016%2Fj.
jad.2013.03.016). ISSN 1573-2517 (https://www.worldcat.org/issn/1573-2517). PMID 23648227 (https://www.ncbi.nl
m.nih.gov/pubmed/23648227).
18. Lohoff, Falk W. (6 December 2016). "Overview of the Genetics of Major Depressive Disorder"(https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3077049). Current psychiatry reports. 12 (6): 539–546. doi:10.1007/s11920-010-0150-6(ht
tps://doi.org/10.1007%2Fs11920-010-0150-6) . ISSN 1523-3812 (https://www.worldcat.org/issn/1523-3812).
19. López-León, S.; Janssens, A. C. J. W.; González-Zuloeta Ladd, A. M.; Del-Favero, J.; Claes, S. J.; Oostra, B. A.; van
Duijn, C. M. (1 August 2008). "Meta-analyses of genetic studies on major depressive disorder".
Molecular
Psychiatry. 13 (8): 772–785. doi:10.1038/sj.mp.4002088(https://doi.org/10.1038%2Fsj.mp.4002088). ISSN 1476-
5578 (https://www.worldcat.org/issn/1476-5578). PMID 17938638 (https://www.ncbi.nlm.nih.gov/pubmed/17938638).
20. Carlson, Neil R. (2013).Physiology of behavior(11th ed.). Boston: Pearson. pp. 578–582.ISBN 978-0-205-23939-9.
OCLC 769818904 (https://www.worldcat.org/oclc/769818904).
21. Adrien J.. Neurobiological bases for the relation between sleep and depression.Sleep Medicine Review.
2003;6(5):341–51. doi:10.1053/smrv.2001.0200 (https://doi.org/10.1053%2Fsmrv.2001.0200). PMID 12531125 (http
s://www.ncbi.nlm.nih.gov/pubmed/12531125).
22. Terman M. Evolving applications of light therapy. Sleep Medicine Review. 2007;11(6):497–507.
doi:10.1016/j.smrv.2007.06.003 (https://doi.org/10.1016%2Fj.smrv.2007.06.003). PMID 17964200 (https://www.ncbi.
nlm.nih.gov/pubmed/17964200).
23. Benedetti F, Barbini B, Colombo C, SmeraldiE. Chronotherapeutics in a psychiatric ward.Sleep Medicine Review.
2007;11(6):509–22. doi:10.1016/j.smrv.2007.06.004 (https://doi.org/10.1016%2Fj.smrv.2007.06.004).
PMID 17689120 (https://www.ncbi.nlm.nih.gov/pubmed/17689120).
24. Zhai, Long; Zhang, Hua; Zhang, Dongfeng (1 September 2015). "SLEEP DURA TION AND DEPRESSION AMONG
ADULTS: A META-ANALYSIS OF PROSPECTIVE STUDIES". Depression and Anxiety. 32 (9): 664–670.
doi:10.1002/da.22386 (https://doi.org/10.1002%2Fda.22386). ISSN 1520-6394 (https://www.worldcat.org/issn/1520-6
25. Germain, Anne; Kupfer, David J. (6 December 2016). "CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612129). Human psychopharmacology. 23 (7): 571–585.
doi:10.1002/hup.964 (https://doi.org/10.1002%2Fhup.964). ISSN 0885-6222 (https://www.worldcat.org/issn/0885-62
22). PMC 2612129 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612129) . PMID 18680211 (https://www.ncbi.nl
26. Savitz, Jonathan B.; Drevets, Wayne C. (1 April 2013). "Neuroreceptor imaging in depression".Neurobiology of
Disease. 52: 49–65. doi:10.1016/j.nbd.2012.06.001(https://doi.org/10.1016%2Fj.nbd.2012.06.001) . ISSN 1095-
953X (https://www.worldcat.org/issn/1095-953X). PMID 22691454 (https://www.ncbi.nlm.nih.gov/pubmed/22691454).
27. Carlson, Neil R. (2005).Foundations of Physiological Psychology(6th ed.). Boston: Pearson A and B. p. 108.
ISBN 0-205-42723-5. OCLC 60880502 (https://www.worldcat.org/oclc/60880502).
28. Nutt DJ (2008). "Relationship of neurotransmitters to the symptoms of major depressive disorder".
Journal of Clinical
Psychiatry. 69 Suppl E1: 4–7. PMID 18494537 (https://www.ncbi.nlm.nih.gov/pubmed/18494537).
29. Marchand; Valentina; Jensen. "Neurobiologyof Mood disorders". Hospital physician: 17–26.
30. Carlson, N. (2013). Physiology of behavior
. (11 ed., pp. 575–576). United States of America: Pearson.
31. Mandell AJ, Knapp S (1979). "Asymmetry and mood, emergent properties of serotonin regulation: A proposed
mechanism of action of lithium".Archives of General Psychiatry. 36 (8): 909–16.
doi:10.1001/archpsyc.1979.01780080083019(https://doi.org/10.1001%2Farchpsyc.1979.01780080083019) .
32. Dunlop, Boadie W.; Nemeroff, Charles B. (1 April 2007)."The Role of Dopamine in the Pathophysiology of
Depression" (https://www.researchgate.net/publication/6466257_The_Role_of_Dopamine_in_the_Pathophysiology_
of_Depression?enrichId=rgreq-a678e8806e51f3776fd6cdce3da0468e-XXX&enrichSource=Y292ZXJQYWdlOzY0Nj
YyNTc7QVM6MTAzMzg3OTg3MTg1NjY3QDE0MDE2NjEwMjU0OTY%3D&el=1_x_3) . Archives of General
Psychiatry. 64 (3): 327–37. doi:10.1001/archpsyc.64.3.327(https://doi.org/10.1001%2Farchpsyc.64.3.327) .
ISSN 0003-990X (https://www.worldcat.org/issn/0003-990X). PMID 17339521 (https://www.ncbi.nlm.nih.gov/pubme
d/17339521).
33. Willner, Paul (1 December 1983)."Dopamine and depression: A review of recent evidence. I. Empirical studies"
(htt
p://www.sciencedirect.com/science/article/pii/016501738390005X). Brain Research Reviews. 6 (3): 211–224.
doi:10.1016/0165-0173(83)90005-X(https://doi.org/10.1016%2F0165-0173%2883%2990005-X) .
34. HASLER, GREGOR (4 December 2016)."PATHOPHYSIOLOGY OF DEPRESSION: DO WE HA VE ANY SOLID
EVIDENCEOF INTEREST TO CLINICIANS?" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950973). World
Psychiatry. 9 (3): 155–161. ISSN 1723-8617 (https://www.worldcat.org/issn/1723-8617). PMC 2950973 (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC2950973) . PMID 20975857 (https://www.ncbi.nlm.nih.gov/pubmed/20975857).
35. Kunugi, Hiroshi; Hori, Hiroaki; Ogawa, Shintaro (1 October 2015). "Biochemical markers subtyping major depressive
disorder". Psychiatry and Clinical Neurosciences. 69 (10): 597–608. doi:10.1111/pcn.12299 (https://doi.org/10.111
1%2Fpcn.12299). ISSN 1440-1819 (https://www.worldcat.org/issn/1440-1819). PMID 25825158 (https://www.ncbi.nl
36. Lammel, S.; Tye, K. M.; Warden, M. R. (1 January 2014)."Progress in understanding mood disorders: optogenetic
dissection of neural circuits"(http://onlinelibrary.wiley.com/doi/10.1111/gbb.12049/epdf). Genes, Brain and Behavior.
13 (1): 38–51. doi:10.1111/gbb.12049 (https://doi.org/10.1111%2Fgbb.12049). ISSN 1601-183X (https://www.worldc
at.org/issn/1601-183X).
37. Delgado PL, Moreno FA (2000). "Role of norepinephrine in depression".J Clin Psychiatry. 61 Suppl 1: 5–12.
38. Ruhe, HG; Mason, NS; Schene, AH (2007). "Mood is indirectly related to serotonin, norepinephrine and dopamine
levels in humans: a meta-analysis of monoamine depletion studies".Molecular Psychiatry. 12: 331–359.
doi:10.1038/sj.mp.4001949(https://doi.org/10.1038%2Fsj.mp.4001949). PMID 17389902 (https://www.ncbi.nlm.nih.g
ov/pubmed/17389902).
39. Meyer JH, Ginovart N, Boovariwala A, et al. (November 2006)."Elevated monoamine oxidase a levels in the brain:
An explanation for the monoamine imbalance of major depression"(http://archpsyc.ama-assn.org/cgi/content/full/63/
11/1209). Archives of General Psychiatry. 63 (11): 1209–16. doi:10.1001/archpsyc.63.11.1209(https://doi.org/10.10
01%2Farchpsyc.63.11.1209). PMID 17088501 (https://www.ncbi.nlm.nih.gov/pubmed/17088501).
40. Huang SY, Lin MT, Lin WW, Huang CC, Shy MJ, Lu RB (2007-12-19)."Association of monoamine oxidase A (MAOA)
polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population" (http://www.info
rmaworld.com/10.1080/15622970701816506) . World Journal of Biological Psychiatry. Informa Healthcare. 10 (4 Pt
2): 544–51. doi:10.1080/15622970701816506(https://doi.org/10.1080%2F15622970701816506) . PMID 19224413
(https://www.ncbi.nlm.nih.gov/pubmed/19224413). Retrieved 2008-09-20.
41. Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW (September 2005). "Association study of a monoamine
oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response".
Neuropsychopharmacology. 30 (9): 1719–23. doi:10.1038/sj.npp.1300785(https://doi.org/10.1038%2Fsj.npp.130078
42. Cicchetti D, Rogosch FA, Sturge-Apple ML (2007). "Interactions of child maltreatment and serotonin transporter and
monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic
status backgrounds". Dev. Psychopathol. 19 (4): 1161–80. doi:10.1017/S0954579407000600(https://doi.org/10.101
7%2FS0954579407000600). PMID 17931441 (https://www.ncbi.nlm.nih.gov/pubmed/17931441).
43. Castrén, E (2005). "Is mood chemistry?".Nature Reviews Neuroscience. 6 (3): 241–46. doi:10.1038/nrn1629 (http
s://doi.org/10.1038%2Fnrn1629). PMID 15738959 (https://www.ncbi.nlm.nih.gov/pubmed/15738959).
44. Hirschfeld RM (2000). "History and evolution of the monoamine hypothesis of depression".
Journal of Clinical
Psychiatry. 61 Suppl 6: 4–6. PMID 10775017 (https://www.ncbi.nlm.nih.gov/pubmed/10775017).
45. al.], editors, Kenneth L. Davis ... [et (2002).Neuropsychopharmacology : the fifth generation of progress : an official
publication of the American College of Neuropsychopharmacology(5th ed.). Philadelphia, Pa.: Lippincott Williams &
Wilkins. pp. 1139–1163.ISBN 9780781728379.
46. Jacobsen, Jacob P. R.; Medvedev, Ivan O.; Caron, Marc G. (5 September 2012)."The 5-HT deficiency theory of
depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin
mouse" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405680). Philosophical Transactions of the Royal Society
B: Biological Sciences. 367 (1601): 2444–2459. doi:10.1098/rstb.2012.0109(https://doi.org/10.1098%2Frstb.2012.0
109). ISSN 0962-8436 (https://www.worldcat.org/issn/0962-8436). PMC 3405680 (https://www.ncbi.nlm.nih.gov/pmc/
47. Delgado PL, Moreno FA (2000). "Role of norepinephrine in depression".J Clin Psychiatry. 61 Suppl 1: 5–12.
48. Delgado PL (2000). "Depression: the case for a monoamine deficiency".
Journal of Clinical Psychiatry. 61 Suppl 6:
7–11. PMID 10775018 (https://www.ncbi.nlm.nih.gov/pubmed/10775018).
49. Andrews, Paul W.; Bharwani, Aadil; Lee, Kyuwon R.; Fox, Molly; Thomson, J. Anderson (1 April 2015). "Is serotonin
an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant
response". Neuroscience and Biobehavioral Reviews. 51: 164–188. doi:10.1016/j.neubiorev.2015.01.018 (https://doi.
org/10.1016%2Fj.neubiorev.2015.01.018). ISSN 1873-7528 (https://www.worldcat.org/issn/1873-7528).
50. Lacasse, Jeffrey R.; Leo, Jonathan (8 November 2005). "Serotonin and Depression: A Disconnect between the
Advertisements and the Scientific Literature"(http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0
020392). PLoS Medicine. 2 (12): e392. doi:10.1371/journal.pmed.0020392(https://doi.org/10.1371%2Fjournal.pmed.
0020392). PMC 1277931 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931) . PMID 16268734 (https://www.
ncbi.nlm.nih.gov/pubmed/16268734).
51. Savitz, Jonathan; Drevets, Wayne (2013). "Neuroreceptor imaging in depression".Neurobiology of Disease. 52: 49–
65. doi:10.1016/j.nbd.2012.06.001(https://doi.org/10.1016%2Fj.nbd.2012.06.001). PMID 22691454 (https://www.ncb
i.nlm.nih.gov/pubmed/22691454).
52. Gryglewski, G; Lanzenberger, R; Kranz, GS; Cumming, P (July 2014)."Meta-analysis of molecular imaging of
serotonin transporters in major depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083395). Journal of
cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and
Metabolism. 34 (7): 1096–103. doi:10.1038/jcbfm.2014.82(https://doi.org/10.1038%2Fjcbfm.2014.82).
53. Wang, L; Zhou, C; Zhu, D; Wang, X; Fang, L; Zhong, J; Mao, Q; Sun, L; Gong, X; Xia, J; ian,
L B; Xie, P (13
September 2016). "Serotonin-1A receptor alterations in depression: a meta-analysis of molecular imaging studies"
(h
ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022168). BMC Psychiatry. 16 (1): 319. doi:10.1186/s12888-016-
1025-0 (https://doi.org/10.1186%2Fs12888-016-1025-0) . PMC 5022168 (https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC5022168) . PMID 27623971 (https://www.ncbi.nlm.nih.gov/pubmed/27623971).
54. Bourke, Cecilia; Douglas, Katie; Porter, Richard (1 August 2010). "Processing of facial emotion expression in major
depression: a review".The Australian and New Zealand Journal of Psychiatry . 44 (8): 681–696.
doi:10.3109/00048674.2010.496359(https://doi.org/10.3109%2F00048674.2010.496359) . ISSN 1440-1614 (https://
www.worldcat.org/issn/1440-1614). PMID 20636189 (https://www.ncbi.nlm.nih.gov/pubmed/20636189).
55. Groenewold, Nynke A.; Opmeer, Esther M.; de Jonge, Peter; Aleman, André; Costafreda, Sergi G. (1 February
2013). "Emotional valence modulates brain functional abnormalities in depression: evidence from a meta-analysis of
fMRI studies". Neuroscience and Biobehavioral Reviews. 37 (2): 152–163. doi:10.1016/j.neubiorev.2012.11.015 (http
s://doi.org/10.1016%2Fj.neubiorev.2012.11.015). ISSN 1873-7528 (https://www.worldcat.org/issn/1873-7528).
56. Dalili, M. N.; Penton-Voak, I. S.; Harmer, C. J.; Munafò, M. R. (7 December 2016)."Meta-analysis of emotion
recognition deficits in major depressive disorder"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712476).
Psychological Medicine. 45 (6): 1135–1144. doi:10.1017/S0033291714002591(https://doi.org/10.1017%2FS003329
1714002591). ISSN 0033-2917 (https://www.worldcat.org/issn/0033-2917). PMC 4712476 (https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC4712476) . PMID 25395075 (https://www.ncbi.nlm.nih.gov/pubmed/25395075).
57. Harmer, C. J.; Goodwin, G. M.; Cowen, P. J. (31 July 2009). "Why do antidepressants take so long to work? A
cognitive neuropsychological model of antidepressant drug action".The British Journal of Psychiatry. 195 (2): 102–
108. doi:10.1192/bjp.bp.108.051193(https://doi.org/10.1192%2Fbjp.bp.108.051193) .
58. Hamilton, J. Paul; Etkin, Amit; Furman, Daniella J.; Lemus, Maria G.; Johnson, Rebecca.;FGotlib, Ian H. (1 July
2012). "Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line
activation and neural response data".The American Journal of Psychiatry. 169 (7): 693–703.
doi:10.1176/appi.ajp.2012.11071105(https://doi.org/10.1176%2Fappi.ajp.2012.11071105) . ISSN 1535-7228 (https://
59. Mayberg, Helen (1 August 1997)."Limbic-cortical dysregulation: a proposed model of depression"(http://neuro.psyc
hiatryonline.org/doi/abs/10.1176/jnp.9.3.471). The Journal of Neuropsychiatry and Clinical Neurosciences
. 9 (3):
471–481. doi:10.1176/jnp.9.3.471 (https://doi.org/10.1176%2Fjnp.9.3.471). ISSN 0895-0172 (https://www.worldcat.o
rg/issn/0895-0172).
60. Graham, Julia; Salimi-Khorshidi, Gholamreza; Hagan, Cindy; W alsh, Nicholas; Goodyer, Ian; Lennox, Belinda;
Suckling, John (1 November 2013)."Meta-analytic evidence for neuroimaging models of depression: State or trait?"
(http://www.sciencedirect.com/science/article/pii/S0165032713005491#bib17). Journal of Affective Disorders. 151
(2): 423–431. doi:10.1016/j.jad.2013.07.002(https://doi.org/10.1016%2Fj.jad.2013.07.002) .
61. Sternat T, Katzman MA (1 January 2016)."Neurobiology of hedonic tone: the relationship between treatment-
resistant depression, attention-deficit hyperactivity disorder
, and substance abuse"(https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC5003599). Neuropsychiatric Disease and Treatment. 12: 2149–64. doi:10.2147/NDT.S111818 (https://
doi.org/10.2147%2FNDT.S111818). PMC 5003599 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003599) .
62. Bora, E; Fornito, A; Pantelis, C; Yücel, M (April 2012). "Gray matter abnormalities in Major Depressive Disorder: a
meta-analysis of voxel based morphometry studies".Journal of Affective Disorders. 138 (1–2): 9–18.
doi:10.1016/j.jad.2011.03.049(https://doi.org/10.1016%2Fj.jad.2011.03.049) . PMID 21511342 (https://www.ncbi.nlm.
nih.gov/pubmed/21511342).
63. Peng, W; Chen, Z; Yin, L; Jia, Z; Gong, Q (15 July 2016). "Essential brain structural altera
tions in major depressive
disorder: A voxel-wise meta-analysis on first episode, medication-naive patients".Journal of Affective Disorders.
199: 114–23. doi:10.1016/j.jad.2016.04.001(https://doi.org/10.1016%2Fj.jad.2016.04.001) . PMID 27100056 (https://
www.ncbi.nlm.nih.gov/pubmed/27100056).
64. Zhang, H; Li, L; Wu, M; Chen, Z; Hu, X; Chen, Y; Zhu, H; Jia, Z; Gong, Q (January 2016). "Brain gray matter
alterations in first episodes of depression: A meta-analysis of whole-brain studies".
Neuroscience and Biobehavioral
Reviews. 60: 43–50. doi:10.1016/j.neubiorev.2015.10.011 (https://doi.org/10.1016%2Fj.neubiorev .2015.10.011).
65. Zhao, YJ; Du, MY; Huang, XQ; Lui, S; Chen, ZQ; Liu, J; Luo, Y ; Wang, XL; Kemp, GJ; Gong, QY (October 2014).
"Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis".
Psychological Medicine. 44 (14): 2927–37. doi:10.1017/S0033291714000518(https://doi.org/10.1017%2FS0033291
66. Sacher, J; Neumann, J; Fünfstück, T; Soliman, A; Villringer, A; Schroeter, ML (October 2012). "Mapping the
depressed brain: a meta-analysis of structural and functional alterations in major depressive disorder".
Journal of
Affective Disorders. 140 (2): 142–8. doi:10.1016/j.jad.2011.08.001(https://doi.org/10.1016%2Fj.jad.2011.08.001).
67. Arnone, D; Job, D; Selvaraj, S; Abe, O; Amico, F; Cheng, ;YColloby, SJ; O'Brien, JT; Frodl, T; Gotlib, IH; Ham, BJ;
Kim, MJ; Koolschijn, PC; Périco, CA; Salvadore, G; Thomas, AJ; anV Tol, MJ; van der Wee, NJ; Veltman, DJ;
Wagner, G; McIntosh, AM (April 2016). "Computational meta-analysis of statistical parametric maps in major
depression". Human brain mapping. 37 (4): 1393–404. doi:10.1002/hbm.23108 (https://doi.org/10.1002%2Fhbm.231
68. Schmaal, L; Hibar, DP; Sämann, PG; Hall, GB; Baune, BT; Jahanshad, N; Cheung, JW; van Erp, TGM; Bos, D;
Ikram, MA; Vernooij, MW; Niessen, WJ; Tiemeier, H; Hofman, A; Wittfeld, K; Grabe, HJ; Janowitz, D; Bülow , R;
Selonke, M; Völzke, H; Grotegerd, D; Dannlowski, U; Arolt, ;VOpel, N; Heindel, W; Kugel, H; Hoehn, D; Czisch, M;
Couvy-Duchesne, B; Rentería, ME; Strike, T L; Wright, MJ; Mills, NT; de Zubicaray, GI; McMahon, KL; Medland, SE;
Martin, NG; Gillespie, NA; Goya-Maldonado, R; Gruber , O; Krämer, B; Hatton, SN; Lagopoulos, J; Hickie, IB; Frodl,
T; Carballedo, A; Frey, EM; van Velzen, LS; Penninx, BWJH; van Tol, MJ; van der Wee, NJ; Davey, CG; Harrison,
BJ; Mwangi, B; Cao, B; Soares, JC; Veer, IM; Walter, H; Schoepf, D; Zurowski, B; Konrad, C; Schramm, E;
Normann, C; Schnell, K; Sacchet, MD; Gotlib, IH; MacQueen, GM; Godlewska, BR; Nickson,; T McIntosh, AM;
Papmeyer, M; Whalley, HC; Hall, J; Sussmann, JE; Li, M; Walter, M; Aftanas, L; Brack, I; Bokhan, NA; Thompson,
PM; Veltman, DJ (June 2017)."Cortical abnormalities in adults and adolescents with major depression based on
brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder W orking Group" (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC5444023). Molecular Psychiatry. 22 (6): 900–909. doi:10.1038/mp.2016.60 (https://doi.
org/10.1038%2Fmp.2016.60). PMC 5444023 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444023) .
69. Schmaal, L; Veltman, DJ; van Erp, TG; Sämann, PG; Frodl, T; Jahanshad, N; Loehrer, E; Tiemeier, H; Hofman, A;
Niessen, WJ; Vernooij, MW; Ikram, MA; Wittfeld, K; Grabe, HJ; Block, A; Hegenscheid, K; Völzke, H; Hoehn, D;
Czisch, M; Lagopoulos, J; Hatton, SN; Hickie, IB; Goya-Maldonado, R; Krämer , B; Gruber, O; Couvy-Duchesne, B;
Rentería, ME; Strike, LT; Mills, NT; de Zubicaray, GI; McMahon, KL; Medland, SE; Martin, NG; Gillespie, NA; Wright,
MJ; Hall, GB; MacQueen, GM; Frey, EM; Carballedo, A; van Velzen, LS; van Tol, MJ; van der Wee, NJ; Veer, IM;
Walter, H; Schnell, K; Schramm, E; Normann, C; Schoepf, D; Konrad, C; Zurowski, B; Nickson,; T McIntosh, AM;
Papmeyer, M; Whalley, HC; Sussmann, JE; Godlewska, BR; Cowen, PJ; Fischer , FH; Rose, M; Penninx, BW;
Thompson, PM; Hibar, DP (June 2016). "Subcortical brain alterations in major depressive disorder: findings from the
ENIGMA Major Depressive Disorder working group"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879183).
Molecular Psychiatry. 21 (6): 806–12. doi:10.1038/mp.2015.69 (https://doi.org/10.1038%2Fmp.2015.69).
70. Salomon, RM; Cowan, RL (November 2013)."Oscillatory serotonin function in depression"(https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC3786873). Synapse (New York, N.Y.). 67 (11): 801–20. doi:10.1002/syn.21675 (https://doi.org/
10.1002%2Fsyn.21675). PMC 3786873 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786873) .
71. Carlson, Neil R. (2012).Physiology of Behavior Books a La Carte Edition(11th ed.). Boston: Pearson College Div
.
ISBN 978-0-205-23981-8.
72. Miller, Chris H.; Hamilton, J. Paul; Sacchet, Matthew D.; Gotlib, Ian H. (1 October 2015). "Meta-analysis of
Functional Neuroimaging of Major Depressive Disorder in oYuth". JAMA Psychiatry. 72 (10): 1045–1053.
doi:10.1001/jamapsychiatry.2015.1376 (https://doi.org/10.1001%2Fjamapsychiatry .2015.1376). ISSN 2168-6238 (htt
ps://www.worldcat.org/issn/2168-6238). PMID 26332700 (https://www.ncbi.nlm.nih.gov/pubmed/26332700).
73. Hendrie, C.A.; Pickles, A.R. (2009)."Depression as an evolutionary adaptation: Implications for the development of
preclinical models" (https://www.academia.edu/1145742/Depression_as_an_evolutionary_adaptation_Implications_f
or_the_development_of_preclinical_models). Medical Hypotheses. 72 (3): 342–347. doi:10.1016/j.mehy.2008.09.053
(https://doi.org/10.1016%2Fj.mehy.2008.09.053). PMID 19153014 (https://www.ncbi.nlm.nih.gov/pubmed/19153014).
Retrieved September 25, 2013.
74. Hendrie, C.A.; Pickles, A.R. (2010)."Depression as an evolutionary adaptation: Anatomical organisation around the
third ventricle" (https://www.academia.edu/1145735/Depression_An_Evolutionary_Adaptation_Organised_Around_th
e_Third_Ventricle). Medical Hypotheses. 74 (4): 735–740. doi:10.1016/j.mehy.2009.10.026 (https://doi.org/10.1016%
2Fj.mehy.2009.10.026). PMID 19931308 (https://www.ncbi.nlm.nih.gov/pubmed/19931308). Retrieved
September 25, 2013.
75. Sheline, Yvette (August 2003). "Neuroimaging studies of mood disorder effects on the brain" (http://www.biologicalps
ychiatryjournal.com/article/S0006-3223%2803%2900347-0/abstract) . Biological Psychiatry. 54 (3): 338–352.
doi:10.1016/s0006-3223(03)00347-0(https://doi.org/10.1016%2Fs0006-3223%2803%2900347-0) . PMID 12893109
(https://www.ncbi.nlm.nih.gov/pubmed/12893109). Retrieved September 25, 2013.
76. Manji, Husseini K.; Quiroz, Jorge A.; Sporn, Jonathan; Payne, Jennifer L.; Denicof f, Kirk; Gray, Neil A.; Zarate Jr.,
Carlos A.; Charney, Dennis S. (April 2003)."Enhancing neuronal plasticity and cellular resilience to develop novel,
improved therapeutics for difficult-to-treat depression" (http://www.biologicalpsychiatryjournal.com/article/S0006-322
3%2803%2900117-3/abstract). Biological Psychiatry. 53: 707–742. doi:10.1016/s0006-3223(03)00117-3(https://doi.
org/10.1016%2Fs0006-3223%2803%2900117-3) . Retrieved September 25, 2013.
77. Miller, A. H.; Maletic, V.; Raison, C. L. (2009)."Inflammation and its discontents: the role of cytokines in the
pathophysiology of major depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680424). Biological
Psychiatry. 65 (9): 732–741. doi:10.1016/j.biopsych.2008.11.029(https://doi.org/10.1016%2Fj.biopsych.2008.11.02
9). PMC 2680424 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680424) . PMID 19150053 (https://www.ncbi.nl
78. Raison, C. L.; Capuron, L.; Miller, A. H. (2006). "Cytokines sing the blues: inflammation and the pathogenesis of
depression" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392963). Trends in Immunology. 27 (1): 24–31.
doi:10.1016/j.it.2005.11.006(https://doi.org/10.1016%2Fj.it.2005.11.006). PMC 3392963 (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC3392963) . PMID 16316783 (https://www.ncbi.nlm.nih.gov/pubmed/16316783).
79. Wessa, Michèle; Lois, Giannis (30 November2016). "Brain Functional Effects of Psychopharmacological Treatment
in Major Depression: A Focus on Neural Circuitry of Affective Processing" (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC4790403). Current Neuropharmacology. 13 (4): 466–479. doi:10.2174/1570159X13666150416224801(https://d
oi.org/10.2174%2F1570159X13666150416224801) . ISSN 1570-159X (https://www.worldcat.org/issn/1570-159X).
80. Outhred, Tim; Hawkshead, Brittany E.; Wager, Tor D.; Das, Pritha; Malhi, Gin S.; Kemp, Andrew H. (1 September
2013). "Acute neural effects of selective serotonin reuptake inhibitors versus noradrenaline reuptake inhibitors on
emotion processing: Implications for differential treatment efficacy". Neuroscience and Biobehavioral Reviews. 37
(8): 1786–1800. doi:10.1016/j.neubiorev.2013.07.010 (https://doi.org/10.1016%2Fj.neubiorev .2013.07.010).
ISSN 1873-7528 (https://www.worldcat.org/issn/1873-7528). PMID 23886514 (https://www.ncbi.nlm.nih.gov/pubmed/
23886514).
81. Hamilton, J. Paul; Etkin, Amit; Furman, Daniella J.; Lemus, Maria G.; Johnson, Rebecca.;FGotlib, Ian H. (2012).
"Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation
and Neural Response Data"(http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2012.11071105) . American
Journal of Psychiatry. 169 (7): 693–703. doi:10.1176/appi.ajp.2012.11071105(https://doi.org/10.1176%2Fappi.ajp.2
012.11071105). PMID 22535198 (https://www.ncbi.nlm.nih.gov/pubmed/22535198).
82. Fitzgerald, Paul B.; Laird, Angela R.; Maller
, Jerome; Daskalakis, Zafiris J. (20 May 2010)."A Meta-Analytic Study of
Changes in Brain Activation in Depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873772). Human brain
mapping. 29 (6): 683–695. doi:10.1002/hbm.20426 (https://doi.org/10.1002%2Fhbm.20426). ISSN 1065-9471 (http
s://www.worldcat.org/issn/1065-9471). PMC 2873772 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873772) .
83. Hamilton, J. Paul; Siemer, Matthias; Gotlib, Ian H. (8 Sep 2009). "Amygdala volume in Major Depressive Disorder: A
meta-analysis of magnetic resonance imaging studies"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739676).
Molecular Psychiatry. 13 (11): 993–1000. doi:10.1038/mp.2008.57 (https://doi.org/10.1038%2Fmp.2008.57).
ISSN 1359-4184 (https://www.worldcat.org/issn/1359-4184). PMC 2739676 (https://www.ncbi.nlm.nih.gov/pmc/article
s/PMC2739676) . PMID 18504424 (https://www.ncbi.nlm.nih.gov/pubmed/18504424).
84. Palmer, Susan M.; Crewther, Sheila G.; Carey, Leeanne M. (14 January 2015)."A Meta-Analysis of Changes in
Brain Activity in Clinical Depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294131). Frontiers in Human
Neuroscience. 8. doi:10.3389/fnhum.2014.01045(https://doi.org/10.3389%2Ffnhum.2014.01045) . ISSN 1662-5161
(https://www.worldcat.org/issn/1662-5161). PMC 4294131 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294131)
. PMID 25642179 (https://www.ncbi.nlm.nih.gov/pubmed/25642179).
85. Fitzgerald, Paul B.; Laird, Angela R.; Maller
, Jerome; Daskalakis, Zafiris J. (5 December 2016)."A Meta-Analytic
Study of Changes in Brain Activation in Depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873772).
Human brain mapping. 29 (6): 683–695. doi:10.1002/hbm.20426 (https://doi.org/10.1002%2Fhbm.20426).
ISSN 1065-9471 (https://www.worldcat.org/issn/1065-9471). PMC 2873772 (https://www.ncbi.nlm.nih.gov/pmc/article
s/PMC2873772) . PMID 17598168 (https://www.ncbi.nlm.nih.gov/pubmed/17598168).
86. Cole, James; Costafreda, Sergi G.; McGuffin, Peter; Fu, Cynthia H. Y. (1 November 2011). "Hippocampal atrophy in
first episode depression: a meta-analysis of magnetic resonance imaging studies".
Journal of Affective Disorders.
134 (1–3): 483–487. doi:10.1016/j.jad.2011.05.057(https://doi.org/10.1016%2Fj.jad.2011.05.057) . ISSN 1573-2517
(https://www.worldcat.org/issn/1573-2517). PMID 21745692 (https://www.ncbi.nlm.nih.gov/pubmed/21745692).
87. Videbech, Poul; Ravnkilde, Barbara (1 November 2004). "Hippocampal volume and depression: a meta-analysis of
MRI studies". The American Journal of Psychiatry. 161 (11): 1957–1966. doi:10.1176/appi.ajp.161.11.1957(https://d
oi.org/10.1176%2Fappi.ajp.161.11.1957). ISSN 0002-953X (https://www.worldcat.org/issn/0002-953X).
88. Mahar, I; Bambico, FR; Mechawar, N; Nobrega, JN (January 2014). "Stress, serotonin, an d hippocampal
neurogenesis in relation to depression and antidepressant effects". Neuroscience and Biobehavioral Reviews. 38:
173–92. doi:10.1016/j.neubiorev.2013.11.009 (https://doi.org/10.1016%2Fj.neubiorev .2013.11.009). PMID 24300695
(https://www.ncbi.nlm.nih.gov/pubmed/24300695).
89. Willner, P; Scheel-Krüger, J; Belzung, C (December 2013). "The neurobiology of depression and antidepressant
action". Neuroscience and Biobehavioral Reviews. 37 (10 Pt 1): 2331–71. doi:10.1016/j.neubiorev.2012.12.007 (http
s://doi.org/10.1016%2Fj.neubiorev.2012.12.007). PMID 23261405 (https://www.ncbi.nlm.nih.gov/pubmed/23261405).
90. Pariante CM, Lightman SL (September 2008). "The HP A axis in major depression: classical theories and new
developments". Trends Neurosci. 31 (9): :464–468. doi:10.1016/j.tins.2008.06.006(https://doi.org/10.1016%2Fj.tins.
2008.06.006). PMID 18675469 (https://www.ncbi.nlm.nih.gov/pubmed/18675469).
91. Belvederi Murri, Martino;Pariante, Carmine; Mondelli, Valeria; Masotti, Mattia; Atti, AnnaRita; Mellacqua, Zefiro;
Antonioli, Marco; Ghio, Lucio; Menchetti, Marco; Zanetidou, Stamatula; Innamorati, Marco; Amore, Mario (1 March
2014). "HPA axis and aging in depression: systematic review and meta-analysis".Psychoneuroendocrinology. 41:
46–62. doi:10.1016/j.psyneuen.2013.12.004(https://doi.org/10.1016%2Fj.psyneuen.2013.12.004) . ISSN 1873-3360
(https://www.worldcat.org/issn/1873-3360). PMID 24495607 (https://www.ncbi.nlm.nih.gov/pubmed/24495607).
92. Juruena, Mario F. (1 September 2014). "Early-life stress and HPA axis trigger recurrent adulthood depression".
Epilepsy & Behavior: E&B. 38: 148–159. doi:10.1016/j.yebeh.2013.10.020(https://doi.org/10.1016%2Fj.yebeh.2013.
10.020). ISSN 1525-5069 (https://www.worldcat.org/issn/1525-5069). PMID 24269030 (https://www.ncbi.nlm.nih.gov/
pubmed/24269030).
93. Heim, Christine; Newport, D. Jeffrey; Mletzko, Tanja; Miller, Andrew H.; Nemeroff, Charles B. (1 August 2008)."The
link between childhood trauma and depression: Insights from HP A axis studies in humans"(https://www.researchgat
e.net/publication/5249983_The_link_between_childhood_trauma_and_depression_Insights_from_HP A_axis_studies
_in_humans?enrichId=rgreq-f3e8a4abd1dad89dc860493084d6fa67-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk
5ODM7QVM6OTk0NjQxMjM1MTg5ODZAMTQwMDcyNTUwMzQyNA%3D%3D&el=1_x_3&_esc=publicationCoverP
df). Psychoneuroendocrinology. 33 (6): 693–710. doi:10.1016/j.psyneuen.2008.03.008(https://doi.org/10.1016%2Fj.
psyneuen.2008.03.008). ISSN 0306-4530 (https://www.worldcat.org/issn/0306-4530). PMID 18602762 (https://www.
ncbi.nlm.nih.gov/pubmed/18602762).
94. Arana, G. W.; Baldessarini, R. J.; Ornsteen, M. (1 December 1985). "The dexamethasone suppression test for
diagnosis and prognosis in psychiatry. Commentary and review". Archives of General Psychiatry. 42 (12): 1193–
1204. doi:10.1001/archpsyc.1985.01790350067012(https://doi.org/10.1001%2Farchpsyc.1985.01790350067012) .
ISSN 0003-990X (https://www.worldcat.org/issn/0003-990X). PMID 3000317 (https://www.ncbi.nlm.nih.gov/pubmed/
3000317).
95. Varghese, Femina P.; Brown, E. Sherwood (1January 2001). "The Hypothalamic-Pituitary-Adrenal Axis in Major
Depressive Disorder: A Brief Primer for Primary Care Physicians"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC18
1180). Primary Care Companion to The Journal of Clinical Psychiatry . 3 (4): 151–155. doi:10.4088/pcc.v03n0401(htt
ps://doi.org/10.4088%2Fpcc.v03n0401). ISSN 1523-5998 (https://www.worldcat.org/issn/1523-5998). PMC 181180
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181180) . PMID 15014598 (https://www.ncbi.nlm.nih.gov/pubmed/1
5014598).
96. Christopher Pittenger; Ronald S Duman (2008)."Stress, Depression, and Neuroplasticity: A Convergence of
Mechanisms" (http://www.nature.com/npp/journal/v33/n1/full/1301574a.html). Neuropsychopharmacology. 33 (1):
88–109. doi:10.1038/sj.npp.1301574(https://doi.org/10.1038%2Fsj.npp.1301574). PMID 17851537 (https://www.ncb
i.nlm.nih.gov/pubmed/17851537)
97. Brunoni, André Russowsky; Lopes, Mariana; Fregni, Felipe (1 December 2008). "A systematic review and meta-
analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in
depression" (http://ijnp.oxfordjournals.org/content/11/8/1169.full)
. International Journal of
Neuropsychopharmacology. 11 (8): 1169–1180. doi:10.1017/S1461145708009309(https://doi.org/10.1017%2FS146
1145708009309). ISSN 1461-1457 (https://www.worldcat.org/issn/1461-1457). PMID 18752720 (https://www.ncbi.nl
98. Serafini, Gianluca (22 June 2012)."Neuroplasticity and major depression, the role of modern antidepressant drugs"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782176). World Journal of Psychiatry. 2 (3): 49–57.
doi:10.5498/wjp.v2.i3.49 (https://doi.org/10.5498%2Fwjp.v2.i3.49). ISSN 2220-3206 (https://www.worldcat.org/issn/2
220-3206). PMC 3782176 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782176) . PMID 24175168 (https://ww
w.ncbi.nlm.nih.gov/pubmed/24175168).
99. Krishnadas, Rajeev; Cavanagh, Jonathan (1 May 2012). "Depression: an inflammatory illness?".Journal of
Neurology, Neurosurgery, and Psychiatry. 83 (5): 495–502. doi:10.1136/jnnp-2011-301779(https://doi.org/10.1136%
2Fjnnp-2011-301779). ISSN 1468-330X (https://www.worldcat.org/issn/1468-330X). PMID 22423117 (https://www.nc
bi.nlm.nih.gov/pubmed/22423117).
100. Patel, Amisha (1 September 2013). "Review: the role of inflammation in depression".
Psychiatria Danubina. 25 Suppl
2: S216–223. ISSN 0353-5053 (https://www.worldcat.org/issn/0353-5053). PMID 23995180 (https://www.ncbi.nlm.ni
101. Dowlati, Yekta; Herrmann, Nathan; Swardfager, Walter; Liu, Helena; Sham, Lauren; Reim, Elyse K.; Lanctôt, Krista
L. (1 March 2010). "A meta-analysis of cytokines in major depression".Biological Psychiatry. 67 (5): 446–457.
doi:10.1016/j.biopsych.2009.09.033(https://doi.org/10.1016%2Fj.biopsych.2009.09.033) . ISSN 1873-2402 (https://w
ww.worldcat.org/issn/1873-2402). PMID 20015486 (https://www.ncbi.nlm.nih.gov/pubmed/20015486).
102. Dantzer, Robert; O’Connor, Jason C.; Freund, Gregory G.; Johnson, Rodney W .; Kelley, Keith W. (3 December
2016). "From inflammation to sickness and depression: when the immune system subjugates the brain" (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC2919277). Nature Reviews Neuroscience. 9 (1): 46–56. doi:10.1038/nrn2297 (http
s://doi.org/10.1038%2Fnrn2297). ISSN 1471-003X (https://www.worldcat.org/issn/1471-003X). PMC 2919277 (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919277) . PMID 18073775 (https://www.ncbi.nlm.nih.gov/pubmed/1807
3775).
103. Hiles, Sarah A.; Baker, Amanda L.; de Malmanche, Theo; Attia, John (1 October 2012). "A meta-analysis of
differences in IL-6 and IL-10 between peoplewith and without depression: exploring the causes of heterogeneity".
Brain, Behavior, and Immunity. 26 (7): 1180–1188. doi:10.1016/j.bbi.2012.06.001(https://doi.org/10.1016%2Fj.bbi.2
012.06.001). ISSN 1090-2139 (https://www.worldcat.org/issn/1090-2139). PMID 22687336 (https://www.ncbi.nlm.nih.
gov/pubmed/22687336).
104. Howren, M. Bryant; Lamkin, Donald M.; Suls, Jerry (1 February 2009). "Associations of depression with C-reactive
protein, IL-1, and IL-6: a meta-analysis".Psychosomatic Medicine. 71 (2): 171–186.
doi:10.1097/PSY.0b013e3181907c1b (https://doi.org/10.1097%2FPSY.0b013e3181907c1b). ISSN 1534-7796 (http
s://www.worldcat.org/issn/1534-7796). PMID 19188531 (https://www.ncbi.nlm.nih.gov/pubmed/19188531).
105. Maes, Michael (29 April 2011). "Depression is an inflammatory disease, but cell-mediated immune activation is the
key component of depression".Progress in Neuro-Psychopharmacology & Biological Psychiatry . 35 (3): 664–675.
doi:10.1016/j.pnpbp.2010.06.014(https://doi.org/10.1016%2Fj.pnpbp.2010.06.014) . ISSN 1878-4216 (https://www.w
orldcat.org/issn/1878-4216). PMID 20599581 (https://www.ncbi.nlm.nih.gov/pubmed/20599581).
106. Berk, Michael; Williams, Lana J; Jacka, Felice N; O’Neil, Adrienne; Pasco, Julie A; Moylan, Steven; Allen, Nicholas
B; Stuart, Amanda L; Hayley, Amie C; Byrne, Michelle L; Maes, Michael (12 September 2013)."So depression is an
inflammatory disease, but where does the inflammation come from?"(https://www.ncbi.nlm.nih.gov/pmc/articles/PM
C3846682). BMC Medicine. 11: 200. doi:10.1186/1741-7015-11-200(https://doi.org/10.1186%2F1741-7015-11-
200). ISSN 1741-7015 (https://www.worldcat.org/issn/1741-7015). PMC 3846682 (https://www.ncbi.nlm.nih.gov/pmc/
107. Leonard, Brian; Maes, Michael (1 February 2012). "Mechanistic explanations how cell-mediated immune activation,
inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the
pathophysiology of unipolar depression".Neuroscience and Biobehavioral Reviews. 36 (2): 764–785.
doi:10.1016/j.neubiorev.2011.12.005 (https://doi.org/10.1016%2Fj.neubiorev
.2011.12.005). ISSN 1873-7528 (https://
108. Raedler, Thomas J. (1 November 2011). "Inflammatory mechanisms in major depressive disorder".Current Opinion
in Psychiatry. 24 (6): 519–525. doi:10.1097/YCO.0b013e32834b9db6(https://doi.org/10.1097%2FYCO.0b013e3283
4b9db6). ISSN 1473-6578 (https://www.worldcat.org/issn/1473-6578). PMID 21897249 (https://www.ncbi.nlm.nih.go
v/pubmed/21897249).
109. Köhler, Ole; Benros, Michael E.; Nordentoft, Merete; Farkouh, Michael E.; Iyengar, Rupa L.; Mors, Ole; Krogh,
Jesper (1 December 2014). "Effect of anti-inflammatory treatment on depression, depressive symptoms, and
adverse effects: a systematic review and meta-analysis of randomized clinical trials".JAMA Psychiatry. 71 (12):
1381–1391. doi:10.1001/jamapsychiatry.2014.1611 (https://doi.org/10.1001%2Fjamapsychiatry .2014.1611).
ISSN 2168-6238 (https://www.worldcat.org/issn/2168-6238). PMID 25322082 (https://www.ncbi.nlm.nih.gov/pubmed/
25322082).
110. Black, Catherine N.; Bot, Mariska; Scheffer, Peter G.; Cuijpers, Pim; Penninx, Brenda W
. J. H. (1 January 2015). "Is
depression associated with increased oxidative stress? A systematic review and meta-analysis".
Psychoneuroendocrinology. 51: 164–175. doi:10.1016/j.psyneuen.2014.09.025(https://doi.org/10.1016%2Fj.psyneu
en.2014.09.025). ISSN 1873-3360 (https://www.worldcat.org/issn/1873-3360). PMID 25462890 (https://www.ncbi.nl
111. Liu, Tao; Zhong, Shuming; Liao, Xiaoxiao; Chen, Jian; He, Tingting; Lai, Shunkai; Jia, Yanbin (1 January 2015)."A
Meta-Analysis of Oxidative Stress Markers in Depression"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596519).
PLOS ONE. 10 (10): e0138904. doi:10.1371/journal.pone.0138904(https://doi.org/10.1371%2Fjournal.pone.013890
4). ISSN 1932-6203 (https://www.worldcat.org/issn/1932-6203). PMC 4596519 (https://www.ncbi.nlm.nih.gov/pmc/art
icles/PMC4596519) . PMID 26445247 (https://www.ncbi.nlm.nih.gov/pubmed/26445247).
112. Schutte, Nicola S.; Malouff, John M. (1 April 2015). "The association between depression and leukocyte telomere
length: a meta-analysis".Depression and Anxiety. 32 (4): 229–238. doi:10.1002/da.22351 (https://doi.org/10.1002%2
Fda.22351). ISSN 1520-6394 (https://www.worldcat.org/issn/1520-6394). PMID 25709105 (https://www.ncbi.nlm.nih.
gov/pubmed/25709105).
113. Menon, Vinod (October 2011). "Large-scale brain networks and psychopathology: a unifying triple network model".
Trends in Cognitive Sciences. 15 (10): 483–506. doi:10.1016/j.tics.2011.08.003(https://doi.org/10.1016%2Fj.tics.201
1.08.003). PMID 21908230 (https://www.ncbi.nlm.nih.gov/pubmed/21908230).
114. Seeley, W.W; et al. (February 2007). "Dissociable intrinsic connectivity networks for salience processing and
executive control". The Journal of Neuroscience. 27.
115. Habas, C; et al. (1 July 2009). "Distinct cerebellar contributions to intrinsic connectivity networks".
The Journal of
Neuroscience. 29.
116. Petrides, M (2005). "Lateral prefrontal cortex: architecture and functional organization".
Philosophical Transactions of
the Royal Society B. 360 (1456): 781–795. doi:10.1098/rstb.2005.1631(https://doi.org/10.1098%2Frstb.2005.1631).
117. Koechlin, E; Summerfield, C (2007). "An information theoretical approach to prefrontal executive function".
Trends in
Cognitive Sciences. 11 (6): 229–235. doi:10.1016/j.tics.2007.04.005(https://doi.org/10.1016%2Fj.tics.2007.04.005).
118. Miller, E.K.; Cohen, J.D. (2001). "An integrative theory of prefrontal cortex function".Annual Review of Neuroscience.
24: 167–202. doi:10.1146/annurev.neuro.24.1.167 (https://doi.org/10.1146%2Fannurev.neuro.24.1.167).
119. Muller, N.G.; Knight, R.T. (2006). "The functional neuroanatomy of working memory: contr
ibutions of human brain
lesion studies". Neuroscience. 139 (1): 51–58. doi:10.1016/j.neuroscience.2005.09.018(https://doi.org/10.1016%2Fj.
neuroscience.2005.09.018). PMID 16352402 (https://www.ncbi.nlm.nih.gov/pubmed/16352402).
120. Woodward, N.D.; et al. (2011)."Functional resting-state networks are differentially affected in schizophrenia"(https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC3139756). Schizophrenia Research. 130 (1–3): 86–93.
doi:10.1016/j.schres.2011.03.010(https://doi.org/10.1016%2Fj.schres.2011.03.010) . PMC 3139756 (https://www.ncb
i.nlm.nih.gov/pmc/articles/PMC3139756) . PMID 21458238 (https://www.ncbi.nlm.nih.gov/pubmed/21458238).
121. Menon, Vinod; et al. (2001). "Functional neuroanatomy of auditory working memory in schizophrenia: relation to
positive and negative symptoms".NeuroImage. 13 (3): 433–446. doi:10.1006/nimg.2000.0699(https://doi.org/10.100
6%2Fnimg.2000.0699). PMID 11170809 (https://www.ncbi.nlm.nih.gov/pubmed/11170809).
122. Levin, R.L.; et al. (2007). "Cognitive deficits in depression and functional specificity of regional brain activity".
Cognitive Therapy and Research. 31 (2): 211–233. doi:10.1007/s10608-007-9128-z(https://doi.org/10.1007%2Fs10
608-007-9128-z).
123. Qin, P; Northoff, G (2011). "How is our self related to midline regions and the default mode network?".NeuroImage.
57 (3): 1221–1233. doi:10.1016/j.neuroimage.2011.05.028(https://doi.org/10.1016%2Fj.neuroimage.2011.05.028) .
124. Raichle, M.E.; et al. (2001)."A default mode of brain function"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464
7). Proceedings of the National Academy of Sciences of the United States of America . 98 (2): 676–682.
doi:10.1073/pnas.98.2.676(https://doi.org/10.1073%2Fpnas.98.2.676). PMC 14647 (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC14647) . PMID 11209064 (https://www.ncbi.nlm.nih.gov/pubmed/11209064).
125. Cooney, R.E.; et al. (2010). "Neural correlates of rumination in depression".Cognitive Affective and Behavioral
Neuroscience. 10 (4): 470–478. doi:10.3758/cabn.10.4.470(https://doi.org/10.3758%2Fcabn.10.4.470).
126. Broyd, S.J.; et al. (2009). "Default mode brain dysfunction in mental disorders: a systematic review".
Neuroscience &
Biobehavioral Reviews. 33 (3): 279–296. doi:10.1016/j.neubiorev.2008.09.002 (https://doi.org/10.1016%2Fj.neubiore
v.2008.09.002). PMID 18824195 (https://www.ncbi.nlm.nih.gov/pubmed/18824195).
127. Hamani, C; et al. (15 February 2011). "The subcallosal cingulate gyrus in the context of major depression".
Biological
Psychiatry. 69 (4): 301–8. doi:10.1016/j.biopsych.2010.09.034(https://doi.org/10.1016%2Fj.biopsych.2010.09.034) .
128. Feinstein, J.S.; et al. (September 2006). "Anterior insula reactivity during certain decisions is associated with
neuroticism". Social Cognition and Affective Neuroscience. 1 (2): 136–142. doi:10.1093/scan/nsl016 (https://doi.org/
10.1093%2Fscan%2Fnsl016).
129. Paulus, M.P; Stein, M.B. (2006). "An insular view of anxiety".Biological Psychiatry. 60 (4): 383–387.
130. Antony, M.M. (2009). Oxford Handbook of Anxiety and Related Disorders
. Oxford University Press.
Further reading
Szafran, K; Faron-Górecka, A; Kolasa, M; Kuśmider , M; Solich, J; Zurawek, D; Dziedzicka-Wasylewska, M (2013).
"Potential role of G protein-coupled receptor (GPCR) heterodimerization in neuropsychiatric disorders: a focus on
depression" (PDF). Pharmacol Rep. 65 (6): 1498–505. doi:10.1016/s1734-1140(13)71510-x. PMID 24552997.
Naumenko, VS; Popova, NK; Lacivita, E; Leopoldo, M; Ponimaskin, EG (July 2014). "Interplay between serotonin 5-
HT1A and 5-HT7 receptors in depressive disorders" . CNS Neurosci Ther. 20 (7): 582–90. doi:10.1111/cns.12247.
PMID 24935787.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Biology_of_depression&oldid=829681657

"
This page was last edited on 10 March 2018, at 03:20.
Text is available under theCreative Commons Attribution-ShareAlike License ; additional terms may apply. By using this
site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of theWikimedia
Foundation, Inc., a non-profit organization.

Biology of Depression

Загружено:

Сведения о документе

Авторское право

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Biology of Depression

Загружено:

Авторское право:

Biology of depression

Emotional processing and neural circuits

1. Chronic stress reduces synaptic and dendritic plasticity

Inflammation and oxidative stress

Large-scale brain network theory

Central executive network

Default mode network

Retrieved from "https://en.wikipedia.org/w/index.php?title=Biology_of_depression&oldid=829681657

This page was last edited on 10 March 2018, at 03:20.

Вам также может понравиться