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.
- 1 Genetic factors
- 2 Circadian rhythm
- 3 Monoamines
- 4 Emotional processing and neural circuits
- 5 Brain regions
- 6 Altered neuroplasticity
- 7 Inflammation and oxidative stress
- 8 Large-scale brain network theory
- 9 See also
- 10 References
- 11 Further reading
Genetic factors involved in depression have been difficult to identify. In 2003 Science published an influential study of Avshalom Caspi et al. who found that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). Soon after, the results were replicated by Kenneth Kendler's group, raising hopes in the psychiatric genetics community. By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of the largest studies were negative. Two 2009 meta-analyses were also negative; one included 14 studies, and the other five, owing to different study selection criteria. 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 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. Studies also indicate an association of decreased BDNF production with suicidal behavior. However, findings from gene-environment interactions studies suggest that the current BDNF models of depression are too simplistic. A 2008 study found interactions (biological epistasis) in the signaling pathways of the BDNF and the serotonin transporter; the BDNF Val66Met allele, which was predicted to have reduced responsitivity to serotonin, was found to exercise protective effects in individuals with the short 5-HTTLPR allele that is otherwise believed to predispose individuals to depressive episodes after stressful events. Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.
The largest genome-wide study to date failed to identify variants with genome-wide significance in over 9000 cases.
Recently, a genetics study positively identified two variants with genome-wide association with major depressive disorder (MDD). This study, conducted in Chinese Han women, identified two variants in intronic regions near SIRT1 and LHPP.
Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.
One review identified multiple frequently studied candidate genes. The 5-HTT SLC6A4 and 5-HTR2A gene's yielded inconsistent results, however they may predict treatment results. Mixed results were found for BDNF Val66Met polymorphisms. Polymorphisms in tryptophan hydroxylase genes were found to be associated with suicidal behavior. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein verepsilon 2 to be protective, and found GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype conferred risk.
Depression may be related to abnormalities in the circadian rhythm, or biological clock. For example, rapid eye movement (REM) sleep—the stage in which dreaming occurs—may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.
Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in hospitalized patients.
Increased and decreased sleep length appears to be a risk factor for depression. Patients with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.
Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.
Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine. Many antidepressant drugs increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of two other neurotransmitters, norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." The proponents of this hypothesis recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. Anxious or irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs. Others have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms.
Consistent with the monoamine hypothesis, a longitudinal study uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow stressful life events, but even more so for people with one or two short alleles of the 5-HTT gene. Serotonin may help to regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties of this dysregulation.
Various abnormalities have been observed in dopaminergic systems however results have been inconsistent. Patients with MDD have an increased reward response to D-Amphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. Polymorphisms of the D4 and D3 receptor have been implicated in depression further suggesting a role of dopamine in MDD. Results from postmortem studies have not been consistent, but various dopamine receptor agonist show promise in treating MDD There is some evidence that there is decreased nigrostriatal activity in those with melancholic depression(psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. Hyperactivity of catecholamine release during stress, 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. Furthermore, norepinephrine transporter knockout in mice models increase their tolerance to stress, implicating norepinephrine in depression.
One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan(the precursor of serotonin), tyrosine and phenylalanine(precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not healthy persons. Inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine did not consistently result in decreased mood.
An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with the depressive symptoms in youth. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression.
Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression; antidepressants usually increase synaptic serotonin very quickly, but it often takes at least two to four weeks before mood improves significantly. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization rather which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There has also been inconsistency with regards to serum 5-HIAA levels, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressants properties. Furthermore, some have argued that depression may be marked by a hyperserotonergic state Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.
As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be underexpressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent however it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in depressed patients. Studies on 5-HTT binding are variable but tend towards an increase. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increase MAO activity in depressed patients, and it may even be a trait marker(not changed by response to treatment). Muscarianic receptor binding appears to be increased in depression, and given ligand binding dynamics, suggests increased cholinergic activity.
Emotional processing and neural circuits
Studies of emotional processing in patients with MDD show various biases such as a tendency to rate happy faces more negatively. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. Patients also showed decreased activity in the left dorsolateral prefrontal cortex in response to negative stimuli. Depressed people have impaired recognition of happy, angry, disgusted, fearful and surprised faces, but not of sad faces. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. The observation that both acute and subchronic SSRI administration increases response to positive faces.
One proposed hypothesis for negative emotional bias comes from meta analytic findings of functional neuroimaging studies. Relative to controls, depressed patients showed hyperactivity of circuit termed "the salience network," composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex, as well as decreased activity in regulatory circuits composed of the striatum and dorsolateral prefrontal cortex. However the authors acknowledge limitations exogenous factors such as patient medication status as well as small study sample size.
A similar model termed "the limbic cortical model" has been proposed involving hyperactivity of ventral paralimbic regions and hypoactivity of dorsal limbic and prefrontal regions. This model and another termed "the cortical striatal model", consisting of abnormalities in the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, caudate, putamen and globus pallidus, has been supported by more recent literature. The authors cited study bias, and lack of specificity of inclusion criteria and limiting factors.
Depression is also characterized by decreased activation of the medial prefrontal cortex, ventral striatum, and in particular the nucleus accumbens in response to positive stimuli. These regions are important in reward processing, and dysfunction of them in depression is thought to underly anhedonia, a core symptom of depression involving decreased ability to feel pleasure. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum.
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:
The sole source of serotonin in the brain is the raphe nuclei, a group of small nerve cell nuclei in the upper brain stem, located directly at the mid-line of the brain. There is some evidence for neuropathological abnormalities in the rostral raphe nuclei in depression. Despite their small size, they reach very widely through their projections, and are involved in a very diverse set of functions. Most antidepressants are serotonergic.
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.:576–578
Multiple studies have found evidence of ventricular enlargement in people who have depression, particularly enlargement of the third ventricle. These observations are interpreted as indicating loss of neural tissue in brain regions adjacent to the enlarged ventricle, leading to suggestions that cytokines and related mediators of neurodegeneration may play a role in giving rise to the disease.
One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the etiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in depressed patients. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in depressed patients. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.
The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.
Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. 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.
The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body's response to stressors of various sorts. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In depressed patients the often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in patients with depression. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes by be responsible for some of the changes such as decreased bone mineral density and increased weight found in patients with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.
Recent studies have called attention to the role of altered neuroplasticity in depression. A review found convergence of three phenomena:
- Chronic stress reduces synaptic and dendritic plasticity
- Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees)
- Anti-depressant medications enhance neuroplasticity at both a molecular and dendritic level.
The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.
Blood levels of BDNF in depressed patients increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in depressed patients. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.
Inflammation and oxidative stress
Various review have found that general inflammation may play a role in depression. One meta analysis of cytokines in depressed patients found increased IL-6 and TNF-a levels relative to controls. First theories came about when it was noticed that interferon therapy caused depression in a large number of patients. Meta analysis on cytokine levels in depressed patients have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10 in depressed patients. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behavior, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression.
A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms.
Increased markers of oxidative stress relative to controls have been found in patients with MDD. A marker of DNA oxidation, 8-Oxo-2'-deoxyguanosine, has been found to be increased in both the plasma and urine of depressed patients. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in depressed patients. Studies with 8-Oxo-2' Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity.
One meta analysis found decreased leukocyte telomere lengths in depressed patients.
Large-scale brain network theory
Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology:
Central executive network
The executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is crucially involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.
Default mode network
The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. Individuals suffering from major depression also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get “stuck” in the negative, self-focused thoughts that often characterize depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.
The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In major depressive disorder, anxiety is often a part of the emotional state that characterizes depression.
- Nierenberg, AA (2009). "The long tale of the short arm of the promoter region for the gene that encodes the serotonin uptake protein" (PDF). CNS spectrums. 14 (9): 462–3. PMID 19890228. doi:10.1017/s1092852900023506.
- 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". Science. 301 (5631): 386–89. Bibcode:2003Sci...301..386C. PMID 12869766. doi:10.1126/science.1083968.
- 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. PMID 15867106. doi:10.1001/archpsyc.62.5.529. Lay summary – New Hot Paper Comments (6 September 2006).
- 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. PMID 15842033. doi:10.1017/S0033291704002727.
- 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. PMID 16154545. doi:10.1016/j.biopsych.2005.07.014.
- 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. PMID 17700575. doi:10.1038/sj.mp.4002067.
- 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". Journal of the American Medical Association. 301 (23): 2462–2471. PMC . PMID 19531786. doi:10.1001/jama.2009.878.
- Munafo, M.; Durrant, C.; Lewis, G.; Flint, J. (2009). "Gene × Environment Interactions at the Serotonin Transporter Locus". Biological Psychiatry. 65 (3): 211–219. PMID 18691701. doi:10.1016/j.biopsych.2008.06.009.
- 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. PMID 20029411. doi:10.1038/mp.2009.123.
- Levinson, D. (2006). "The genetics of depression: a review". Biological Psychiatry. 60 (2): 84–92. PMID 16300747. doi:10.1016/j.biopsych.2005.08.024.
- Dwivedi Y (2009). "Brain-derived neurotrophic factor: role in depression and suicide". Neuropsychiatr Dis Treat. 5: 433–49. PMC . PMID 19721723. doi:10.2147/NDT.S5700.
- Krishnan, V.; Nestler, E. (2008). "The molecular neurobiology of depression". Nature. 455 (7215): 894–902. Bibcode:2008Natur.455..894K. PMC . PMID 18923511. doi:10.1038/nature07455.
- Pezawas, L.; Meyer-Lindenberg, A.; Goldman, A. L.; Verchinski, B. A.; Chen, G.; Kolachana, B. S.; Egan, M. F.; Mattay, V. S.; Hariri, A. R.; Weinberger, D. R. (2008). "Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression". Molecular Psychiatry. 13 (7): 709–716. PMID 18347599. doi:10.1038/mp.2008.32.
- 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". Molecular Psychiatry. 18 (4): 497–511. PMC . PMID 22472876. doi:10.1038/mp.2012.21.
- 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". Nature. 523 (7562): 588–91. PMC . PMID 26176920. doi:10.1038/nature14659.
- Smoller, Jordan W (2015). "The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders". Neuropsychopharmacology. Springer Nature. 41 (1): 297–319. doi:10.1038/npp.2015.266. Retrieved 24 March 2017.
- 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 T-182C and G1287A: a meta-analysis". Journal of Affective Disorders. 150 (1): 23–28. ISSN 1573-2517. PMID 23648227. doi:10.1016/j.jad.2013.03.016.
- Lohoff, Falk W. (6 December 2016). "Overview of the Genetics of Major Depressive Disorder". Current psychiatry reports. 12 (6): 539–546. ISSN 1523-3812. PMC . PMID 20848240. doi:10.1007/s11920-010-0150-6.
- 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. ISSN 1476-5578. PMID 17938638. doi:10.1038/sj.mp.4002088.
- Carlson, Neil R. (2013). Physiology of behavior (11th ed.). Boston: Pearson. pp. 578–582. ISBN 978-0-205-23939-9. OCLC 769818904.
- 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. PMID 12531125.
- Terman M. Evolving applications of light therapy. Sleep Medicine Review. 2007;11(6):497–507. doi:10.1016/j.smrv.2007.06.003. PMID 17964200.
- Benedetti F, Barbini B, Colombo C, Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Medicine Review. 2007;11(6):509–22. doi:10.1016/j.smrv.2007.06.004. PMID 17689120.
- Zhai, Long; Zhang, Hua; Zhang, Dongfeng (1 September 2015). "SLEEP DURATION AND DEPRESSION AMONG ADULTS: A META-ANALYSIS OF PROSPECTIVE STUDIES". Depression and Anxiety. 32 (9): 664–670. ISSN 1520-6394. PMID 26047492. doi:10.1002/da.22386.
- Germain, Anne; Kupfer, David J. (6 December 2016). "CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION". Human psychopharmacology. 23 (7): 571–585. ISSN 0885-6222. PMC . PMID 18680211. doi:10.1002/hup.964.
- Savitz, Jonathan B.; Drevets, Wayne C. (1 April 2013). "Neuroreceptor imaging in depression". Neurobiology of Disease. 52: 49–65. ISSN 1095-953X. PMID 22691454. doi:10.1016/j.nbd.2012.06.001.
- Carlson, Neil R. (2005). Foundations of Physiological Psychology (6th ed.). Boston: Pearson A and B. p. 108. ISBN 0-205-42723-5. OCLC 60880502.
- Nutt DJ (2008). "Relationship of neurotransmitters to the symptoms of major depressive disorder". Journal of Clinical Psychiatry. 69 Suppl E1: 4–7. PMID 18494537.
- Marchand; Valentina; Jensen. "Neurobiology of Mood disorders". Hospital physician: 17–26.
- Carlson, N. (2013). Physiology of behavior. (11 ed., pp. 575–576). United States of America: Pearson.
- 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. PMID 454111. doi:10.1001/archpsyc.1979.01780080083019.
- Dunlop, Boadie W.; Nemeroff, Charles B. (1 April 2007). "The Role of Dopamine in the Pathophysiology of Depression". Archives of General Psychiatry. 64 (3): 327–37. ISSN 0003-990X. PMID 17339521. doi:10.1001/archpsyc.64.3.327.
- Willner, Paul (1 December 1983). "Dopamine and depression: A review of recent evidence. I. Empirical studies". Brain Research Reviews. 6 (3): 211–224. doi:10.1016/0165-0173(83)90005-X.
- HASLER, GREGOR (4 December 2016). "PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCEOF INTEREST TO CLINICIANS?". World Psychiatry. 9 (3): 155–161. ISSN 1723-8617. PMC . PMID 20975857.
- Kunugi, Hiroshi; Hori, Hiroaki; Ogawa, Shintaro (1 October 2015). "Biochemical markers subtyping major depressive disorder". Psychiatry and Clinical Neurosciences. 69 (10): 597–608. ISSN 1440-1819. PMID 25825158. doi:10.1111/pcn.12299.
- Lammel, S.; Tye, K. M.; Warden, M. R. (1 January 2014). "Progress in understanding mood disorders: optogenetic dissection of neural circuits". Genes, Brain and Behavior. 13 (1): 38–51. ISSN 1601-183X. doi:10.1111/gbb.12049.
- Delgado PL, Moreno FA (2000). "Role of norepinephrine in depression". J Clin Psychiatry. 61 Suppl 1: 5–12. PMID 10703757.
- 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. PMID 17389902. doi:10.1038/sj.mp.4001949.
- 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". Archives of General Psychiatry. 63 (11): 1209–16. PMID 17088501. doi:10.1001/archpsyc.63.11.1209.
- 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". World Journal of Biological Psychiatry. Informa Healthcare. 10 (4 Pt 2): 544–51. PMID 19224413. doi:10.1080/15622970701816506. Retrieved 2008-09-20.
- 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. PMID 15956990. doi:10.1038/sj.npp.1300785.
- 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. PMID 17931441. doi:10.1017/S0954579407000600.
- Castrén, E (2005). "Is mood chemistry?". Nature Reviews Neuroscience. 6 (3): 241–46. PMID 15738959. doi:10.1038/nrn1629.
- Hirschfeld RM (2000). "History and evolution of the monoamine hypothesis of depression". Journal of Clinical Psychiatry. 61 Suppl 6: 4–6. PMID 10775017.
- 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.
- 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". Philosophical Transactions of the Royal Society B: Biological Sciences. 367 (1601): 2444–2459. ISSN 0962-8436. PMC . PMID 22826344. doi:10.1098/rstb.2012.0109.
- Delgado PL, Moreno FA (2000). "Role of norepinephrine in depression". J Clin Psychiatry. 61 Suppl 1: 5–12. PMID 10703757.
- Delgado PL (2000). "Depression: the case for a monoamine deficiency". Journal of Clinical Psychiatry. 61 Suppl 6: 7–11. PMID 10775018.
- 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. ISSN 1873-7528. PMID 25625874. doi:10.1016/j.neubiorev.2015.01.018.
- Lacasse, Jeffrey R.; Leo, Jonathan (8 November 2005). "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature". PLoS Medicine. 2 (12): e392. PMC . PMID 16268734. doi:10.1371/journal.pmed.0020392.
- Savitz, Jonathan; Drevets, Wayne (2013). "Neuroreceptor imaging in depression". Neurobiology of Disease. 52: 49–65. PMID 22691454. doi:10.1016/j.nbd.2012.06.001.
- 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. ISSN 1440-1614. PMID 20636189. doi:10.3109/00048674.2010.496359.
- 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. ISSN 1873-7528. PMID 23206667. doi:10.1016/j.neubiorev.2012.11.015.
- 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". Psychological Medicine. 45 (6): 1135–1144. ISSN 0033-2917. PMC . PMID 25395075. doi:10.1017/S0033291714002591.
- 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.
- Hamilton, J. Paul; Etkin, Amit; Furman, Daniella J.; Lemus, Maria G.; Johnson, Rebecca F.; Gotlib, 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. ISSN 1535-7228. PMID 22535198. doi:10.1176/appi.ajp.2012.11071105.
- Mayberg, Helen (1 August 1997). "Limbic-cortical dysregulation: a proposed model of depression". The Journal of Neuropsychiatry and Clinical Neurosciences. 9 (3): 471–481. ISSN 0895-0172. doi:10.1176/jnp.9.3.471.
- Graham, Julia; Salimi-Khorshidi, Gholamreza; Hagan, Cindy; Walsh, Nicholas; Goodyer, Ian; Lennox, Belinda; Suckling, John (1 November 2013). "Meta-analytic evidence for neuroimaging models of depression: State or trait?". Journal of Affective Disorders. 151 (2): 423–431. doi:10.1016/j.jad.2013.07.002.
- Sternat T, Katzman MA (1 January 2016). "Neurobiology of hedonic tone: the relationship between treatment-resistant depression, attention-deficit hyperactivity disorder, and substance abuse". Neuropsychiatric Disease and Treatment. 12: 2149–64. PMC . PMID 27601909. doi:10.2147/NDT.S111818.
- Salomon, RM; Cowan, RL (November 2013). "Oscillatory serotonin function in depression.". Synapse (New York, N.Y.). 67 (11): 801–20. PMC . PMID 23592367.
- Carlson, Neil R. (2012). Physiology of Behavior Books a La Carte Edition. (11th ed. ed.). Boston: Pearson College Div. ISBN 978-0-205-23981-8.
- 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 Youth". JAMA Psychiatry. 72 (10): 1045–1053. ISSN 2168-6238. PMID 26332700. doi:10.1001/jamapsychiatry.2015.1376.
- Hendrie, C.A.; Pickles, A.R. (2009). "Depression as an evolutionary adaptation: Implications for the development of preclinical models". Medical Hypotheses. 72 (3): 342–347. PMID 19153014. doi:10.1016/j.mehy.2008.09.053. Retrieved September 25, 2013.
- Hendrie, C.A.; Pickles, A.R. (2010). "Depression as an evolutionary adaptation: Anatomical organisation around the third ventricle". Medical Hypotheses. 74 (4): 735–740. PMID 19931308. doi:10.1016/j.mehy.2009.10.026. Retrieved September 25, 2013.
- Sheline, Yvette (August 2003). "Neuroimaging studies of mood disorder effects on the brain". Biological Psychiatry. 54 (3): 338–352. PMID 12893109. doi:10.1016/s0006-3223(03)00347-0. Retrieved September 25, 2013.
- Manji, Husseini K.; Quiroz, Jorge A.; Sporn, Jonathan; Payne, Jennifer L.; Denicoff, 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". Biological Psychiatry. 53: 707–742. doi:10.1016/s0006-3223(03)00117-3. Retrieved September 25, 2013.
- Miller, A. H.; Maletic, V.; Raison, C. L. (2009). "Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression". Biological Psychiatry. 65 (9): 732–741. PMC . PMID 19150053. doi:10.1016/j.biopsych.2008.11.029.
- Raison, C. L.; Capuron, L.; Miller, A. H. (2006). "Cytokines sing the blues: inflammation and the pathogenesis of depression". Trends in Immunology. 27 (1): 24–31. PMC . PMID 16316783. doi:10.1016/j.it.2005.11.006.
- Wessa, Michèle; Lois, Giannis (30 November 2016). "Brain Functional Effects of Psychopharmacological Treatment in Major Depression: A Focus on Neural Circuitry of Affective Processing". Current Neuropharmacology. 13 (4): 466–479. ISSN 1570-159X. PMC . PMID 26412066. doi:10.2174/1570159X13666150416224801.
- 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. ISSN 1873-7528. PMID 23886514. doi:10.1016/j.neubiorev.2013.07.010.
- Hamilton, J. Paul; Etkin, Amit; Furman, Daniella J.; Lemus, Maria G.; Johnson, Rebecca F.; Gotlib, Ian H. "Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data". American Journal of Psychiatry. 169 (7): 693–703. PMID 22535198. doi:10.1176/appi.ajp.2012.11071105.
- 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". Human brain mapping. 29 (6): 683–695. ISSN 1065-9471. PMC . PMID 17598168. doi:10.1002/hbm.20426.
- Hamilton, J. Paul; Siemer, Matthias; Gotlib, Ian H. (8 Sept 2009). "Amygdala volume in Major Depressive Disorder: A meta-analysis of magnetic resonance imaging studies". Molecular Psychiatry. 13 (11): 993–1000. ISSN 1359-4184. PMC . PMID 18504424. doi:10.1038/mp.2008.57. Check date values in:
- Palmer, Susan M.; Crewther, Sheila G.; Carey, Leeanne M. (14 January 2015). "A Meta-Analysis of Changes in Brain Activity in Clinical Depression". Frontiers in Human Neuroscience. 8. ISSN 1662-5161. PMC . PMID 25642179. doi:10.3389/fnhum.2014.01045.
- 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". Human brain mapping. 29 (6): 683–695. ISSN 1065-9471. PMC . PMID 17598168. doi:10.1002/hbm.20426.
- 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. ISSN 1573-2517. PMID 21745692. doi:10.1016/j.jad.2011.05.057.
- 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. ISSN 0002-953X. PMID 15514393. doi:10.1176/appi.ajp.161.11.1957.
- Mahar, I; Bambico, FR; Mechawar, N; Nobrega, JN (January 2014). "Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects.". Neuroscience and biobehavioral reviews. 38: 173–92. PMID 24300695. doi:10.1016/j.neubiorev.2013.11.009.
- 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. PMID 23261405. doi:10.1016/j.neubiorev.2012.12.007.
- Pariante CM, Lightman SL (September 2008). "The HPA axis in major depression: classical theories and new developments.". Trends Neurosci. 31 (9): :464–468. PMID 18675469. doi:10.1016/j.tins.2008.06.006.
- Belvederi Murri, Martino; Pariante, Carmine; Mondelli, Valeria; Masotti, Mattia; Atti, Anna Rita; 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. ISSN 1873-3360. PMID 24495607. doi:10.1016/j.psyneuen.2013.12.004.
- Juruena, Mario F. (1 September 2014). "Early-life stress and HPA axis trigger recurrent adulthood depression". Epilepsy & Behavior: E&B. 38: 148–159. ISSN 1525-5069. PMID 24269030. doi:10.1016/j.yebeh.2013.10.020.
- 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 HPA axis studies in humans". Psychoneuroendocrinology. 33 (6): 693–710. ISSN 0306-4530. PMID 18602762. doi:10.1016/j.psyneuen.2008.03.008.
- 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. ISSN 0003-990X. PMID 3000317. doi:10.1001/archpsyc.1985.01790350067012.
- Varghese, Femina P.; Brown, E. Sherwood (1 January 2001). "The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians". Primary Care Companion to The Journal of Clinical Psychiatry. 3 (4): 151–155. ISSN 1523-5998. PMC . PMID 15014598. doi:10.4088/pcc.v03n0401.
- Christopher Pittenger; Ronald S Duman (2008). "Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms". Neuropsychopharmacology. 33 (1): 88–109. PMID 17851537. doi:10.1038/sj.npp.1301574
- 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". International Journal of Neuropsychopharmacology. 11 (8): 1169–1180. ISSN 1461-1457. PMID 18752720. doi:10.1017/S1461145708009309.
- Serafini, Gianluca (22 June 2012). "Neuroplasticity and major depression, the role of modern antidepressant drugs". World Journal of Psychiatry. 2 (3): 49–57. ISSN 2220-3206. PMC . PMID 24175168. doi:10.5498/wjp.v2.i3.49.
- Krishnadas, Rajeev; Cavanagh, Jonathan (1 May 2012). "Depression: an inflammatory illness?". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (5): 495–502. ISSN 1468-330X. PMID 22423117. doi:10.1136/jnnp-2011-301779.
- Patel, Amisha (1 September 2013). "Review: the role of inflammation in depression". Psychiatria Danubina. 25 Suppl 2: S216–223. ISSN 0353-5053. PMID 23995180.
- 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. ISSN 1873-2402. PMID 20015486. doi:10.1016/j.biopsych.2009.09.033.
- 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". Nature Reviews Neuroscience. 9 (1): 46–56. ISSN 1471-003X. PMC . PMID 18073775. doi:10.1038/nrn2297.
- 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 people with and without depression: exploring the causes of heterogeneity". Brain, Behavior, and Immunity. 26 (7): 1180–1188. ISSN 1090-2139. PMID 22687336. doi:10.1016/j.bbi.2012.06.001.
- 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. ISSN 1534-7796. PMID 19188531. doi:10.1097/PSY.0b013e3181907c1b.
- 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. ISSN 1878-4216. PMID 20599581. doi:10.1016/j.pnpbp.2010.06.014.
- 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?". BMC Medicine. 11: 200. ISSN 1741-7015. PMC . PMID 24228900. doi:10.1186/1741-7015-11-200.
- 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. ISSN 1873-7528. PMID 22197082. doi:10.1016/j.neubiorev.2011.12.005.
- Raedler, Thomas J. (1 November 2011). "Inflammatory mechanisms in major depressive disorder". Current Opinion in Psychiatry. 24 (6): 519–525. ISSN 1473-6578. PMID 21897249. doi:10.1097/YCO.0b013e32834b9db6.
- 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. ISSN 2168-6238. PMID 25322082. doi:10.1001/jamapsychiatry.2014.1611.
- 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. ISSN 1873-3360. PMID 25462890. doi:10.1016/j.psyneuen.2014.09.025.
- 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". PloS One. 10 (10): e0138904. ISSN 1932-6203. PMC . PMID 26445247. doi:10.1371/journal.pone.0138904.
- 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. ISSN 1520-6394. PMID 25709105. doi:10.1002/da.22351.
- Menon, Vinod (October 2011). "Large-scale brain networks and psychopathology: a unifying triple network model". Trends in Cognitive Sciences. 15 (10): 483–506. PMID 21908230. doi:10.1016/j.tics.2011.08.003.
- Seeley, W.W; et al. (February 2007). "Dissociable intrinsic connectivity networks for salience processing and executive control". The Journal of Neuroscience. 27.
- Habas, C; et al. (1 July 2009). "Distinct cerebellar contributions to intrinsic connectivity networks". The Journal of Neuroscience. 29.
- 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.
- Koechlin, E; Summerfield, C (2007). "An information theoretical approach to prefrontal executive function". Trends in Cognitive Sciences. 11 (6): 229–235. PMID 17475536. doi:10.1016/j.tics.2007.04.005.
- Miller, E.K.; Cohen, J.D. (2001). "An integrative theory of prefrontal cortex function". Annual Review of Neuroscience. 24: 167–202. PMID 11283309. doi:10.1146/annurev.neuro.24.1.167.
- Muller, N.G.; Knight, R.T. (2006). "The functional neuroanatomy of working memory: contributions of human brain lesion studies". Neuroscience. 139 (1): 51–58. PMID 16352402. doi:10.1016/j.neuroscience.2005.09.018.
- Woodward, N.D.; et al. (2011). "Functional resting-state networks are differentially affected in schizophrenia". Schizophrenia Research. 130 (1–3): 86–93. PMC . PMID 21458238. doi:10.1016/j.schres.2011.03.010.
- Menon, Vinod; et al. (2001). "Functional neuroanatomy of auditory working memory in schizophrenia: relation to positive and negative symptoms". NeuroImage. 13 (3): 433–446. PMID 11170809. doi:10.1006/nimg.2000.0699.
- 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.
- Qin, P; Northoff, G (2011). "How is our self related to midline regions and the default mode network?". NeuroImage. 57 (3): 1221–1233. PMID 21609772. doi:10.1016/j.neuroimage.2011.05.028.
- Raichle, M.E.; et al. (2001). "A default mode of brain function". Proceedings of the National Academy of Sciences of the United States of America. 98 (2): 676–682. PMC . PMID 11209064. doi:10.1073/pnas.98.2.676.
- 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.
- Broyd, S.J.; et al. (2009). "Default mode brain dysfunction in mental disorders: a systematic review". Neuroscience & Biobehavioral Reviews. 33 (3): 279–296. PMID 18824195. doi:10.1016/j.neubiorev.2008.09.002.
- Hamani, C; et al. (15 February 2011). "The subcallosal cingulate gyrus in the context of major depression". Biological Psychiatry. 69 (4): 301–8. PMID 21145043. doi:10.1016/j.biopsych.2010.09.034.
- 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.
- Paulus, M.P; Stein, M.B. (2006). "An insular view of anxiety". Biological Psychiatry. 60 (4): 383–387. PMID 16780813. doi:10.1016/j.biopsych.2006.03.042.
- Antony, M.M. (2009). Oxford Handbook of Anxiety and Related Disorders. Oxford University Press.
- 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. PMID 24552997. doi:10.1016/s1734-1140(13)71510-x.
- 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. PMID 24935787. doi:10.1111/cns.12247.