Serotonin activity with short 5-HTT promotor region and depression

So after reading a few studies (1,2) it seems that a shorter promotor region for the serotonin transport protein may be associated with increased likelihood of developing depression after stressful life events.

I'm still an undergrad but this would seem like it would lead to less transcription of the protein leading to more serotonin at the synapse. My understanding is that this should then lead to some sort protection against mood disorders not the increased likelihood of them like the studies suggest. Is someone able to explain what I'm missing here?



A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038 allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.

Although the impact of seasons on the incidence of mood disorders has been known since ancient times, only in the 1980s of our century seasonal affective disorder (SAD) has been described as a distinct nosologic entity. 1 Typically, patients with SAD, winter type, fulfill the diagnostic criteria for recurrent major depressive or bipolar disorder according to DSM-IV criteria and suffer from depressive episodes during fall and winter, alternating with remission or hypomania/mania in spring and summer. Common symptoms in SAD include depressed mood and the so-called atypical or reverse neurovegetative symptoms, such as hypersomnia, hyperphagia, fatigue, carbohydrate craving, and subsequent weight gain. The tendency to experience seasonal variations in mood, feeding behavior, energy, and social activity has been termed seasonality and can be measured using the global seasonality score (GSS). Although the etiology of SAD is still unclear, a substantial heritable component in seasonality has been shown in twin studies. 2,3 A solid body of literature suggests involvement of serotonin (5-HT) in the pathogenesis of SAD. 4 Serotonergic parameters, including central 5-HTT availability, 5 hypothalamic 5-HT concentrations, and peripheral serotonergic parameters 6 show seasonal fluctuations. A variety of research parameters, such as the tryptophan depletion paradigm, 7 hormonal challenge studies, 8 and in vivo imaging of central 5-HTT availability 9 have shown alterations in serotonergic parameters in depressed patients with SAD. Some studies also suggest that serotonergic alterations may be trait markers in SAD. 7 Genes involved in serotonergic neurotransmission are thus good candidates in the genetic research of SAD.

The 5-HTT is a member of the family of the Na + /Cl − -dependent membrane transporters and controls the spread of the serotonergic signal in time and space by reuptake of 5-HT from the synaptic cleft immediately after its release. A polymorphism in the 5-HTT promoter gene region (5-HTTLPR) 10 with two common alleles, consisting of a 44-bp insertion (l-allele) or deletion (s-allele), has been shown to regulate 5-HTT expression in vitro. The presence of one or two copies of the s-allele led to a significant reduction in the amount of 5-HTT mRNA and 5-HTT expressed by human cell lines. 11 Besides anxiety-related personality traits, 11 affective disorder, 12 and violent suicide, 13 the 5-HTTLPR s-allele has been associated with SAD and seasonality. 14 In view of these findings, 138 unrelated patients (82.6% females, 17.4% males mean age: 37.5±11.3 years) from our outpatient unit for SAD and 146 unrelated healthy volunteers with low seasonality levels (85.6% females, 14.4% males mean age: 28.2±10.5 years) were studied and genotyped for 5-HTTLPR from autumn 1997 to spring 2000. Serotonin is known to play a key role in the regulation of food intake 15 and sleep. 16 Since feeding behavior and sleep are altered in opposite directions in melancholic and atypical depression, data were analyzed for differences in 5-HTTLPR genotype distribution between melancholic and atypical depression subtypes according to DSM-IV.

Genotype and allele distributions did not differ significantly between patients and controls (two-sided Fisher's exact test: genotype: P=0.499 allele distribution: P=0.933 see Table 1) and were within the Hardy–Weinberg equilibrium in both groups. In contrast to the Rosenthal et al 14 study, our data did not show an association between 5-HTTPLR and seasonality measured using the GSS in patients (one-way ANOVA: F=0.221, df=2, P=0.802 Kruskal–Wallis χ 2 =0.371, df=2, P=0.831). The effect of 5-HTTLPR on the GSS in healthy controls was not analyzed, since a score of 6 or less was requested for control subjects to take part in the study. Power calculations for a χ 2 test assuming the genotype frequencies published by Rosenthal et al 14 as true population frequencies showed a probability of 0.81 to observe a P-value of 0.01 (or less) and 0.93 for a P-value of 0.05 for a sample size of n=140 in each group (as in our study). The probability to observe a P-value of 0.58 or larger (as in our study sample when using χ 2 statistics) was <0.0015 when assuming the Rosenthal et al data as true population frequencies. Hence, the hypothesis of an association between 5-HTTLPR and SAD, as strong or stronger than the association found by Rosenthal et al, should be rejected for our sample. A limitation of our study is the age difference between SAD patients and healthy controls (two-tailed t=7.17 df=282 P<0.001). However, this shortcoming is considerably offset by the fact that the age of illness onset in patients did not differ from the mean age of the control subjects (age of SAD onset: 28.4±11.9 years age controls: 28.2±10.5 years two-tailed t=0.159 df=276 P=0.874). Stratification effects due to ethnical inhomogeneity of the study subjects or their ancestors may in part be responsible for the divergent findings of the Rosenthal et al study and the present one, as 5-HTTLPR genotypes frequencies have been shown to vary considerably across different ethnic groups. In the present study, substantial effort has been made to avoid ethnical stratification by including only Caucasian subjects with central European origin. Adding external validity to our data, a recently conducted meta-analysis in samples from various nationalities provides no evidence for an association between 5-HTTLPR and SAD. 17

While no significant differences in 5-HTTLPR genotype distribution were found between bipolar and unipolar depression (two-sided Fisher's exact test: P=0.581), a marked difference in 5-HTTLPR genotype (two-sided Fisher's exact test: P=0.0038) and allelic distribution (two-sided Fisher's exact test: P=0.007) was found between patients with SAD suffering from the atypical depression subtype according to DSM-IV 18 and patients suffering from the melancholic subtype (see Table 2). Carriers of the s-allele were significantly more likely to suffer from atypical depression, while patients homozygous for the 5-HTTLPR l-allele were more likely to suffer from melancholic depression (odds ratio: 3.956, 95% CI 1.640–9.774). There was no difference in age (one-way ANOVA F=0.697, df=2, P=0.50) and gender distribution (two-sided Fisher's exact test: P=0.792) between the respective genotype groups. The association of 5-HTTLPR with DSM-IV depression subtypes is of interest insofar as larger scale twin studies provided substantial evidence for hereditability and familiality of depressive subtypes. 19 Melancholic depression has been shown to reliably identify a subset of severely depressed individuals with distinct clinical features. 20 Moreover, biological research paradigms allow to differentiate between melancholic and nonmelancholic depression, 21 and, interestingly, lower plasma tryptophan levels have been shown for melancholic depression. 21 Of course, future studies will have to prove whether the association between 5-HTTLPR and depression subtypes in SAD found in our study can be generalized to nonseasonal depression.

The overall pattern of results derived by studies on 5-HTTLPR and its effects on brain 5-HTT availability, 22 5-HT uptake in human platelets, 23 seasonal variations in blood 5-HT levels 6 and on the therapeutic response to serotonin reuptake inhibitors (SSRIs), 24 and to sleep deprivation 25 is most suggestive for a functional dominance of the s-allele. We therefore analyzed I/s heterozygous patients grouped with both, s/s and I/I homozygous patients (ie I/I vs Is+ss and II+Is vs ss). The analysis of s-carriers vs I/I homozygous patients revealed a strong effect on DSM-IV depression subtypes (I/I vs Is+ss: two-sided Fisher's exact test: P=0.0012), while this was not the case when all I-carrying patients were grouped together (ss vs II+Is: two-sided Fisher's exact test: P=0.44). Our data are so far in line with the original in vitro findings, 11 as they are compatible with a functional dominance of the 5-HTTLPR s-allele.

The presence of reverse vegetative symptoms in SAD patients with atypical depression is suggestive for a reduced central 5-HT neurotransmission, 15 at least in key areas involved in the regulation of feeding behavior and sleep. Our own group reported a reduction in hypothalamic 5-HTT availability in patients with SAD. 9 Although the data in this study were not evaluated separately for patients with melancholic and atypical depression, by far the greater part of the patients in this study suffered from atypical depression. However, results on in vivo effects of 5-HTTLPR are controversial, 22,26,27 and the complex interaction of pre- and postsynaptic elements renders simple quantitative conclusions on 5-HT neurotransmission impossible. However, high-resolution imaging techniques using selective 5-HTT ligands will give the opportunity to measure possible differences in 5-HTT availability between depression subtypes in vivo. These studies may furthermore help to answer the question, whether the association of 5-HTTLPR with depression subtypes, as found in the present study, is due to functional effects of this polymorphism itself, or whether linkage disequilibrium may be held responsible for the present finding.

Studies investigating the relationship between 5-HTTLPR and response to selective serotonin inhibitors, 24 therapeutic sleep deprivation, 25 and the combination of sleep deprivation and bright light therapy (BLT), 28 found the I-allele to be associated with better treatment outcome. The favorable response to BLT predicted by the presence of atypical depressive symptoms in SAD 29 raises the question, whether 5-HTTLPR may serve as a treatment predictor to bright light as well. As a nonpharmacological treatment modality, BLT offers ideal imaging possibilities to study the in vivo dynamics of 5-HTT regulation from the depressed state to symptom remission in patients with SAD. In conclusion, our data do not support a direct role of 5-HTTLPR in the etiology of SAD. However, they are compatible with a disease process that involves 5-HTTLPR, possibly via 5-HT uptake, somewhere on its way to the phenotypic disease expression. Our results furthermore suggest that studies beyond the unitary depression model could be a promising strategy in the future biological research of affective disorders.


Postpartum depression (PPD) is a mood disorder in females that usually presents within the first 4𠄶 weeks after childbirth the condition is clinically characterized by depression, sadness, frustration, crying, irritability, restlessness and even suicidal tendencies (1). According to a previous meta-analysis, PPD is prevalent worldwide, and 10�% of females may be affected (2). In addition to the general symptoms of depression, PPD can, in certain cases, be associated with a disturbance of consciousness, psychotic symptoms and Schneider’s symptoms, which can only be alleviated by regular treatments (3,4). It has been acknowledged that PPD is induced by biological, psychological and/or social factors bio-genetics in particular is closely linked with the mental illnesses (5,6).

Recent genetic studies have shown that dysfunction of the 5-hydroxytryptamine (5-HT) system is the key factor in the development of depression (7,8). Accordingly, genes associated with the synthesis, release, uptake and metabolism of 5-HT could become candidates for studies on the pathogenesis of depression. The serotonin transporter (5-HTT) plays an important role in the re-uptake of 5-HT following release, and therefore is the target for the majority of antidepressants (9,10). A recent study indicated that the transcriptional activity of the human 5-HTT gene is regulated by the 5-HTT gene-linked polymorphic region (5-HTTLPR) (11), with long (L) and short (S) alleles. The L allele in 5-HTTLPR is associated with higher transcriptional efficiency of the promoter compared with the S allele. The mRNA transcription and protein expression levels of 5-HTT are higher in individuals with a homozygous L/L genotype than those with S/S genotypes (12).

To date, the association between 5-HTTLPR gene polymorphism and PPD has not been fully established, and there are few studies focusing on the association between the genetic polymorphism and the clinical characteristics. In the present study, the 5-HTTLPR status in the 5-HTT gene was evaluated in order to establish whether it had an association with PPD pathogenesis in Han female patients.


The polymorphism occurs in the promoter region of the gene. Researchers commonly report it with two variations in humans: A short ("s") and a long ("l"), but it can be subdivided further. [4] The short (s)- and long (l)- alleles have been thought to be related to stress and psychiatric disorders. [5] In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532. [6]

One study published in 2000 found 14 allelic variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese and Europeans. [4] The difference between 16-A and 16-D is the rs25531 SNP. It is also the difference between 14-A and 14-D. [3]

Some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines. The higher level may be due to the A-allele of rs25531, such that subjects with the long-rs25531(A) allelic combination (sometimes written LA) have higher levels while long-rs25531(G) carriers have levels more similar to short-allele carriers. Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes. [7] The allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. [8] It is argued that the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection. [8]

In the 1990s it has been speculated that the polymorphism might be related to affective disorders, and an initial study found such a link. [9] However, another large European study found no such link. [10] A decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress an example of gene-environment interaction (GxE) not considered in the previous studies. [11] [12] [13] However, a 2017 meta-analysis found no such association. [14] Earlier, two 2009 meta-analyses found no overall GxE effect, [15] [16] while a 2011 meta-analysis, demonstrated a positive result. [17] In turn, the 2011 meta-analysis has been criticized as being overly inclusive (e.g. including hip fractures as outcomes), for deeming a study supportive of the GxE interaction which is actually in the opposite direction, and because of substantial evidence of publication bias and data mining in the literature. [18] This criticism points out that if the original finding were real, and not the result of publication bias, we would expect that those replication studies which are closest in design to the original are the most likely to replicate—instead we find the opposite. This suggests that authors may be data dredging for measures and analytic strategies which yield the results they want.

Treatment response Edit

With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants. [19] Another antidepressant treatment response study did, however, rather point to the rs25531 SNP, [20] and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus". [21]

One study could find a treatment response effect for repetitive transcranial magnetic stimulation to drug-resistant depression with long/long homozygotes benefitting more than short-allele carriers. The researchers found a similar effect for the Val66Met polymorphism in the BDNF gene. [22]

Amygdala Edit

The 5-HTTLPR has been thought to predispose individuals to affective disorders such as anxiety and depression. There have been some studies that test whether this association is due to the effects of variation in 5-HTTLPR on the reactivity of the human amygdala. In order to test this, researchers gathered a group of subjects and administered a harm avoidance (HA) subset of the Tridimensional Personality Questionnaire as an initial mood and personality assessment. [23] Subjects also had their DNA isolated and analyzed in order to be genotyped. Next, the amygdala was then engaged by having the subject match fearful facial expressions during an fMRI scan (by the 3-T GE Signa scanner). [23] The results of the study showed that there was bilateral activity in the amygdala for every subject when processing the fearful images, as expected. However, the activity in the right amygdala was much higher for subjects with the s-allele, which shows that the 5-HTTLPR has an effect on amygdala activity. It is also important to note that there did not seem to be the same effect on the left amygdala.

There has been speculation that the 5-HTTLPR gene is associated with insomnia and sleep quality. Primary insomnia is one of the most common sleep disorders and is defined as having trouble falling or staying asleep, enough to cause distress in one's life. Serotonin (5-HT) has been associated with the regulation of sleep for a very long time now. [5] The 5-HT transporter (5-HTT) is the main regulator of serotonin and serotonergic energy and is therefore targeted by many antidepressants. [5] There also have been several family and twin studies that suggest that insomnia is heavily genetically influenced. Many of these studies have found that there is a genetic and environment dual-factor that influences insomnia. It has been hypothesized that the short 5-HTTLPR genotype is related to poor sleep quality and, therefore, also primary insomnia. It is important to note that research studies have found that this variation does not cause insomnia, but rather may predispose an individual to experience worse quality of sleep when faced with a stressful life event.

Brummett Edit

The effect that the 5-HTTLPR gene had on sleep quality was tested by Brummett in a study conducted at Duke University Medical Center from 2001 to 2004. The sleep quality of 344 participants was measured using The Pittsburgh Sleep Quality Index. The study found that caregivers with the homozygous s-allele had poorer sleep quality, which shows that the stress of caregiving combined with the allele gave way to worse sleep quality. Although the study found that the 5-HTTLPR genotype did not directly affect sleep quality, the 5-HTTLPR polymorphism's effect on sleep quality was magnified by one's environmental stress. [24] It supports the notion that the 5-HTTLPR s-allele is what leads to hyperarousal when exposed to stress hyperarousability is commonly associated with insomnia.

Deuschle Edit

However, in a 2007 study conducted by a sleep laboratory in Germany, it was found that the 5-HTTLPR gene did have a strong association with both insomnia and depression both in participants with and without lifetime affective disorders. This study included 157 insomnia patients and a control group of 836 individuals that had no psychiatric disorders. The subjects were then genotyped through polymerase chain reaction (PCR) techniques. [5] The researchers found that the s-allele was greater represented in the vast majority of patients with insomnia compared to those who had no disorder. [5] This shows that there is an association between the 5-HTTPLR genotype and primary insomnia. However, it is important to consider the fact that there was a very limited number of subjects with insomnia tested in this study.

5-HTTLPR may be related to personality traits: Two 2004 meta-analyses found 26 research studies investigating the polymorphism in relation to anxiety-related traits. [25] [26] The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism score with the NEO PI-R personality questionnaire, [27] and this result was replicated by the group with new data. [28] Some other studies have, however, failed to find this association, [29] nor with peer-rated neuroticism, [30] and a 2006 review noted the "erratic success in replication" of the first finding. [31] A meta-analysis published in 2004 stated that the lack of replicability was "largely due to small sample size and the use of different inventories". [25] They found that neuroticism as measured with the NEO-family of personality inventories had quite significant association with 5-HTTLPR while the trait harm avoidance from the Temperament and Character Inventory family did not have any significant association. A similar conclusion was reached in an updated 2008 meta-analysis. [32] However, based on over 4000 subjects, the largest study that used the NEO PI-R found no association between variants of the serotonin transporter gene (including 5-HTTLPR) and neuroticism, or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). [33]

In a study published in 2009, authors found that individuals homozygous for the long allele of 5-HTTLPR paid more attention on average to positive affective pictures while selectively avoiding negative affective pictures presented alongside the positive pictures compared to their heterozygous and short-allele-homozygous peers. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic. [34] Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. [35] Another study published in 2009 using an eye tracking assessment of information processing found that short 5-HTTLPR allele carriers displayed an eye gaze bias to view positive scenes and avoid negative scenes, while long allele homozygotes viewed the emotion scenes in a more even-handed fashion. [36] This research suggests that short 5-HTTLPR allele carriers may be more sensitive to emotional information in the environment than long allele homozygotes.

Another research group have given evidence for a modest association between shyness and the long form in grade school children. [37] This is, however, just a single report and the link is not investigated as intensively as for the anxiety-related traits.

Molecular neuroimaging studies have examined the association between genotype and serotonin transporter binding with positron emission tomography (PET) and SPECT brain scanners. Such studies use a radioligand that binds—preferably selectively—to the serotonin transporter so an image can be formed that quantifies the distribution of the serotonin transporter in the brain. One study could see no difference in serotonin transporter availability between long/long and short/short homozygotes subjects among 96 subjects scanned with SPECT using the iodine-123 β-CIT radioligand. [38] Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups. [39] Newer studies have used the radioligand carbon-11-labeled DASB with one study finding higher serotonin transporter binding in the putamen of LA homozygotes compared to other genotypes. [7] Another study with similar radioligand and genotype comparison found higher binding in the midbrain. [40]

Associations between the polymorphism and the grey matter in parts of the anterior cingulate brain region have also been reported based on magnetic resonance imaging brain scannings and voxel-based morphometry analysis. [41] 5-HTTLPR short allele–driven amygdala hyperreactivity was confirmed in a large (by MRI study standards) cohort of healthy subjects with no history of psychiatric illness or treatment. [23] Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. [42] The glucose metabolism in the brain has also been investigated with respect to the polymorphism, [43] and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism. [44] [45]

Especially the amygdala brain structure has been the focus of the functional neuroimaging studies.

The relationship between the Event Related Potentials P3a and P3b and the genetic variants of 5-HTTLPR were investigated using an auditory oddball paradigm and revealed short allele homozygotes mimicked those of COMT met/met homozygotes with an enhancement of the frontal, but not parietal P3a and P3b. This suggests a frontal-cortical dopaminergic and serotoninergic mechanism in bottom-up attentional capture. [46]

Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice

Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress.

Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing

Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning.


The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for.


Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities.


The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.

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Serotonin (5-hydroxytryptamine) has been implicated in various central physiological functions including sleep, appetite, memory, sexual behavior, neuroendocrine function, and mood ( (1) ). A possible physiological role of endogenous serotonin in controlling natural patterns of eating and nutrient selection has also been reported ( (2) ). Furthermore, several lines of evidence implicate a role for the serotonergic system in body weight regulation and eating disorders ( (3) ). One important component of the serotonergic system, the serotonin transporter (5-HTT) 1 1 Nonstandard abbreviations: 5-HTT, serotonin transporter L, long S, short 5-HTTLPR, 5-HTT gene-linked polymorphic region OR, odds ratio CI, confidence interval.
recycles serotonin after its release, thereby determining the magnitude and duration of serotonergic responses ( (4) ). The human 5-HTT is encoded by a single gene (SLC6A4) on chromosome 17q11.1–17q12 ( (5) ), and a polymorphic region was identified: a 44-bp insertion (long: L)/deletion (short: S) in the promoter region [5-HTT gene-linked polymorphic region (5-HTTLPR)] ( (6) ). Transfection studies showed that the L and S variants of the promoter polymorphism differentially modulate transcription of SLC6A4, the S variant being less efficient ( (6) ), suggesting that 5-HTTLPR is associated with an altered functional response of the serotonin system.

Because individuals who are carriers for the S variant of the 5-HTT gene are known to be at risk for higher levels of anxiety ( (7) ), and rates of anxiety and depression are three to four times higher among obese individuals than among their leaner peers ( (8) ), we hypothesized that S variant may be associated with overweight. Thus, the aim of this study is to explore the effect of the S variant of the serotonin transporter gene promoter on obesity in Argentinean adolescents. Hence, we looked for the association of the S/L variant of the SLC6A4 with clinical and laboratory characteristics of adolescents harboring features of metabolic syndrome from a population-based study performed in a rural town. To replicate the findings, we also studied a group of outpatients from a Children's County Hospital located in a different geographic area (Buenos Aires, metropolitan area).

In the first population, genotypes for the SLC6A4 promoter were in Hardy-Weinberg equilibrium and were similar to that reported in other populations ( (7) ) (LL: 29%, LS: 45%, SS: 26%) the observed allele frequencies were 52% for the L allele and 48% for the S allele.

Because human SLC6A4 transcription is differentially modulated by the allelic variants of the SLC6A4 promoter, showing that LL homozygous have higher rate of 5-HTT mRNA transcription and higher 5-HT uptake than individuals carrying at least one copy of the S allele ( (7) ), we grouped LS and homozygous SS individuals in a dominant model as carriers of the S allele for further analysis.

As shown in Table 1, in univariate analysis, we found that there was no difference between S allele carriers and noncarriers in most of the clinical characteristics of the metabolic syndrome. In contrast, using a two-way ANOVA, we found a significant (p < 0.03) higher age- and sex-adjusted BMI (BMI z-score) in the S allele carriers independently of the effect of hypertension. To make the difference clearer, absolute BMI values were compared between genotypes in both sexes using age as a covariate (Figure 1).

Features LL LS + SS
Number of subjects 44 128
Age (years) 16 ± 2 16 ± 2
Sex (F/M) 27/17 77/51
SABP z-score 0.34 ± 1.55 0.67 ± 1.69
DABP z-score −0.13 ± 0.81 −0.07 ± 0.89
Homocysteine (μM) 8.6 ± 4.9 7.5 ± 3.6
Total cholesterol (mg/dL) 154.7 ± 24.5 159.8 ± 28.1
Triacylglycerol (mg/dL) 86.4 ± 38.9 91.8 ± 52
HDL-cholesterol (mg/dL) 47.7 ± 7.8 49.3 ± 10.5
LDL-cholesterol (mg/dL) 89.8 ± 20.4 92.5 ± 24
Uric acid (mg/dL) 4.1 ± 1.1 4.1 ± 1
Glucose (mg/dL) 88.6 ± 7 88 ± 6.9
Insulin (uU/mL) 10.4 ± 3.8 12.4 ± 7.1
HOMA 2.28 ± 0.86 2.73 ± 1.65
BMI z-score 0.17 ± 0.91 0.49 ± 1.14*
Waist circunference (cm) 73.0 ± 7.4 74.7 ± 10.2
Smoking (smokers/ nonsmokers) 4/40 17/111†
  • Results are expressed as mean ± SD. z-scores stand for sex- and age-adjusted values.
  • * p< 0.03 vs. LL.
  • † After adjustment for age and sex, OR: 2.1 95% CI: 1.05, 4.53 p < 0.04.
  • SABP, systolic arterial blood pressure DABP, diastolic arterial blood pressure HOMA, homeostasis model assessment of insulin resistance.

BMI of adolescents from the population-based study (top) and the outpatient-based study (bottom) according to sex and genotype of the long (L) and short (S) allele of the SLC6A4 promoter (homozygotes LL, white bars, vs. heterozygous LS plus homozygous SS, black bars). In both populations, BMIs of homozygous LL were significantly (p < 0.02) lower than those of the other group (analysis of covariance with age as a covariate). Results are expressed as mean ± SD.

In addition, the S allele was associated with overweight (BMI > 85th percentile χ 2 , p < 0.02) because the S allele was more frequent in the overweight group (LL: 14.0%, n = 7 LS + SS: 86.0%, n = 43) in comparison with lean adolescents (LL: 30.3%, n = 37 LS + SS: 69.7%, n = 85). Logistic regression analysis indicated that the S allele is a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85 95% confidence interval (CI): 1.13, 3.05 p < 0.02]. Data concerning BMI z-score in the three genotypes are as follows: LL, 0.17 ± 0.91, n = 44 LS, 0.47 ± 1.18, n = 76 SS, 0.51 ± 1.08, n = 52. This indicates that LS and SS groups are phenotypically similar.

Table 2 shows differences in anthropometric variables and laboratory findings in the outpatient sample of children according to SLC6A4 promoter genotypes. Compared with the homozygous LL allele carriers, the S allele carriers showed a greater BMI z-score and higher other estimates of obesity and fat distribution, such as waist circumference, subscapular, and triceps skinfold thickness (Figure 2). Differences in absolute BMI values are depicted in Figure 1. Again, the S allele was associated with overweight (BMI > 85th percentile χ 2 , p < 0.01) because the S allele was more frequent in the overweight group (LL: 8.2%, n = 7 LS + SS: 91.2%, n = 75) in comparison with the lean group (LL: 26.3%, n = 10 LS + SS: 73.7%, n = 27). Logistic regression analysis indicated that the S allele is a risk factor for overweight independently of sex and age and arterial blood pressure (OR: 3.98 95% CI: 1.31, 12.18 p < 0.02). Moreover, a similar result was found with obesity as defined by BMI >95th percentile (OR: 3.95 95% CI: 1.18, 13.38 p < 0.03). Data concerning the three genotypes and BMI z-score were as follows: LL, 0.50 ± 1.39, n = 18 LS, 1.55 ± 1.02, n = 70 SS, 1.24 ± 1.21, n = 31.

Features LL LS + SS
Number of subjects 18 101
Age (years) 12 ± 2 12 ± 2
Sex (F/M) 5/13 47/54
SABP z-score −0.32 ± 0.84 −0.14 ± 1.01
DABP z-score 0.5 ± 0.63 0.4 ± 0.75
Homocysteine (μM) 5.9 ± 1.6 6.7 ± 2.7
Total cholesterol (mg/dL) 171.3 ± 33.3 168.8 ± 32.7
HDL-cholesterol (mg/dL) 45 ± 10.6 46 ± 11.2
Triacylglycerol (mg/dL) 86.9 ± 30.1 101.2 ± 56.7
LDL-cholesterol (mg/dL) 105.8 ± 29.2 110.7 ± 29.6
Uric acid (mg/dL) 4.6 ± 1.1 4.6 ± 1.2
Glucosa (mg/dL) 87.5 ± 9 86.9 ± 7.1
Insulin (μU/mL) 13.3 ± 7.8 15.1 ± 9
HOMA 2.89 ± 1.72 3.22 ± 1.89
  • Results are expressed as mean ± SD. z-scores stand for sex- and age-adjusted values.
  • SABP, systolic arterial blood pressure DABP, diastolic arterial blood pressure HOMA, homeostasis model assessment of insulin resistance.

Sex- and age-adjusted BMI (z-score), waist circumference, subscapular skinfold thickness (SSFT), and triceps skinfold thickness (TSFT) of the adolescents in the outpatient hospital-based study according to SLC6A4 promoter genotypes: homozygous LL was compared with S allele carriers (LS + SS). Results are expressed as mean ± SD (* p < 0.003, † p < 0.01, ‡ p < 0.004, and # p < 0.001).

By pooling the two samples by means of Mantel-Haenszel's fixed and random models, we observed that both groups were homogeneous, obtaining a very similar but more robust result regarding BMI differences between genotypes (OR, 3.36 95% CI, 1.68 to 6.72 p < 0.001).

Consequently, the main finding of our study is a significant association between the short variant of the SLC6A4 promoter and overweight in a population-based sample of adolescents. Accordingly, S allele carriers are almost twice as likely to be overweight than homozygous LL, independently of sex, age, and hypertension. This result was replicated, even with a greater OR, in an independent sample of children outpatients of a hospital-based study from a different geographic location.

Although association does not necessarily mean a causal relationship, in this case, several lines of evidence support the association between the S/L SLC6A4 promoter variant and overweight: the biological plausibility of this relationship, the proven effect of the L/S SLC6A4 variant on serotonin transporter activity ( (7) ), and our findings were replicated in two different samples of adolescents from two distant geographic regions of our country. In this regard, we wish to note that we selected the 5-HTTLPR variant because it was previously reported that serotonin uptake is genetically controlled, and the polymorphism mentioned contributes to the interindividual differences in 5-HTT expression and regulation. Moreover, it was shown that the polymorphism influences a constellation of traits related to anxiety and depression, features that were the background we used to formulate the hypothesis about the putative relationship between 5-HTT and obesity ( (6) , (7) ). Furthermore, it was recently published that, using high-resolution structural images and automated processes to test for brain volume and gray matter density, there are not only functional differences in the 5HTT genotypes but also structural ones ( (9) ). Finally, most of the studies that look for genetic relationships between the gene variants at the SLC6A4 and quantitative traits show significant associations only with the 5-HTTLPR but not the 5-HTTVNTR or the other single nucleotide polymorphisms. These results are shown, for instance, in the study of Curran et al. ( (10) ) that searches for differences at 5-HTTLPR, 5-HTTVNTR in the second intron, a single nucleotide polymorphism in the 3′-untranslated region, and 10 single nucleotide polymorphisms spread across the gene in a large epidemiological study of attention-deficit/hyperactivity disorder.

Although novel, these results are consistent with several independent observations. On one hand, the above-mentioned cumulative body of experimental evidence on the role of serotonin as a key regulator of energy homeostasis includes an important interaction with leptin-responsive central neuropeptide systems ( (11) ).

On the other hand, Rosmond et al. ( (12) ) found that a polymorphism in the 5-HT2a receptor gene promoter is strongly related with increased BMI and abdominal fat distribution, suggesting a relative deficiency of serotonergic effects in the carriers of the mutant allele.

More recently, Muldoon et al. ( (13) ) revealed an association between reduced central serotonergic response and the metabolic syndrome because the prolactin response evoked by a serotonin-releasing agent was blunted in overweight, insulin-resistant, and dyslipidemic individuals.

Conversely, Hinney et al. ( (14) ) did not find any association between the 5-HTT variant and body weight, although the study was focused on the allele distribution in relation to anorexia nervosa patients and extremely obese individuals in whom other factors and candidate genes seem to be involved.

Otherwise, obesity is a biologically heterogeneous disorder. The increasing prevalence of obesity in adolescents justifies a widespread effort and attention of physicians looking for depressive symptoms, anxiety, and loss of self-esteem in their patients.

In the light of the association between obesity and the SLC6A4 short variant we found, along with previous reports suggesting a strong association between the variant and anxiety and major depression, one may speculate that individuals who carry the S allele may be at risk of being overweight/obese as a result of a genetic predisposition, leading them to eat more.

For instance, Pine et al. ( (15) ) showed that childhood depression was associated with an increased BMI in adulthood, a finding that was recently replicated by a large community-based cohort study ( (16) ). Also, Goodman and Whitaker ( (17) ) reported that depressed adolescents are at increased risk for the development of obesity during adolescence, reinforcing the previous-mentioned evidence of common neurobiological mechanisms between obesity and depression.

Last, considering that dysfunction of serotonergic neurotransmission may result in a clinical picture of carbohydrate-craving obesity ( (18) ), it is reasonable to speculate that this may be an alternative explanation to our results as a potential mechanism affecting food intake. In this regard, obesity can be seen as a food addiction. In fact, it has been proposed to treat obese patients with similar therapeutic schemes than those used in patients who are addicted to drugs ( (19) ). It is tempting to speculate that 5-HTT plays a similar role in obesity as in drug and alcohol consumers or smokers ( (20) , (21) ).

To summarize, in Argentinean children and adolescents, the S allele of the SLC6A4 promoter is associated with overweight being an independent genetic risk factor for overweight/obesity.

In other words, by using the BMI cut-off values reported by Cole et al. ( (22) ), it can be predicted that, after reaching 18 years of age, 1.6-fold more S allele carriers than LL homozygous persons would be overweight or obese in our adolescent population.

This is, to our knowledge, the first report about the association between an SLC6A4 promoter variant and obesity in adolescents harboring features of the metabolic syndrome. We hope our study can serve as a primer, because further research is needed to confirm and extend these findings, improving the power of the study by increasing the number of subjects and revealing the intimate mechanism by which the putative decrease in the 5-HTT activity related to the SLC6A4 S variant may lead to a central serotonergic system dysfunction.


Of the 557 participants, 96 (17%) were homozygous for the s allele (s/s genotype), 287 (52%) were heterozygous (s/l genotype), and 174 (31%) were homozygous for the l allele (l/l genotype). The allele frequencies were almost identical to previously reported frequencies in white populations (4 , 14) . The three groups were in Hardy-Weinberg equilibrium (χ 2 =0.12, df=2, n.s.). No differences in age, sex, medical illness, medication use, body mass index, alcohol use, and cardiac function were observed between s allele carriers and l/l individuals. Characteristics stratified according to s allele status are shown in Table 1 .

5-HTTLPR and Depression

Of the 557 participants, 126 (23%) were currently depressed. The proportions of participants with current depression, our primary outcome variable, were identical in individuals with the s/s genotype (24 of 96, 25%) and s/l genotype (73 of 287, 25%), confirming a dominant effect of the s allele. Therefore, we designated the individuals with the s/s and s/l genotypes as s allele carriers. Current depression was diagnosed in 25% of the individuals carrying an s allele (97 of 383), compared with 17% of the l/l carriers (29 of 174) ( Figure 1 ) the odds ratio for depression in s allele carriers, therefore, was 1.6, as shown in Table 2 . After adjustment for age and gender, this association remained but was not significant at the traditional p<0.05 cutoff point.

Figure 1. Depression, Stress, and Norepinephrine Excretion in Patients With Coronary Disease, by Genotype for the 5-HTTLPR Serotonin Transporter Polymorphism

a Depression was assessed for the past month. Significant difference between groups (χ 2 =4.3, df=1, p=0.04).

b Significant difference between groups (ANCOVA: F=4.7, df=1, 556, p=0.02).

c Significant difference between groups (ANCOVA: F=3.6, df=1, 556, p=0.04).

5-HTTLPR and Perceived Stress

Carriers of the s allele had a higher mean score on the Perceived Stress Scale (mean=5.4, SD=3.4) than the l/l homozygotes (mean=4.7, SD=2.9) ( Figure 1 ). In a logistic regression analysis, s allele carriers had an increased odds of having moderate to high scores for perceived stress ( Table 2 ). This association remained strong after adjustment for age and gender.

5-HTTLPR and 24-Hour Norepinephrine Excretion

Urinary 24-hour excretion of norepinephrine was higher in s allele carriers (mean=55.6 mg, SD=24.0) than in l/l homozygotes (mean=50.2, SD=23.8) ( Figure 1 ). In a logistic regression analysis, s allele carriers had higher odds of having norepinephrine values in the highest quartile ( Table 2 ).

Potential Moderating Variables

We did not find any significant effects of interactions between 5-HTTLPR and measures of cardiac disease severity, including exercise capacity (metabolic equivalents achieved), history of myocardial infarction, history of coronary artery bypass graft, or overall perceived health status in predicting depression, perceived stress, or norepinephrine excretion (all p values for interactions were >0.20).


Difficulty of gene studies Edit

Historically, candidate gene studies have been a major focus of study. However, as the number of genes reduces the likelihood of choosing a correct candidate gene, Type I errors (false positives) are highly likely. Candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. These effects are compounded by the usual assessment of genes without regard for gene-gene interactions. These limitations are reflected in the fact that no candidate gene has reached genome-wide significance. [5]

Gene candidates Edit


A 2003 study proposed that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). [6] This hypothesis was widely-discussed in both the scientific literature and popular media, where it was dubbed the "Orchid gene," but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression. [7]


BDNF polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression. [8]

SIRT1 and LHPP Edit

A 2015 GWAS study in Han Chinese women positively identified two variants in intronic regions near SIRT1 and LHPP with a genome-wide significant association. [9] [10]

Norepinephrine transporter polymorphisms Edit

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results. [11]

One review identified multiple frequently studied candidate genes. The genes encoding for the 5-HTT and 5-HT2A receptor were inconsistently associated with depression and treatment response. Mixed results were found for brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behavior. [12] A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E verepsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk. [13]

Sleep Edit

Depression may be related to abnormalities in the circadian rhythm, [14] 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, [15] and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. [15] Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation [14] activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness. [15]

Light therapy Edit

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. [16] 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. [17] Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in people who are hospitalized for MDD (Major Depressive Disorder). [16]

Increased and decreased sleep length appears to be a risk factor for depression. [18] People with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift. [19]

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression. [20]

Monoamine hypothesis of depression Edit

Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and serotonin. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. Normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion norepinephrine to the fight-or-flight response and dopamine to movement, pleasure, and motivation. Some have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms. [22] The main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. One explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-HT1A autoreceptors. The therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons. [23]

Serotonin Edit

Initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-Hydroxyindoleacetic acid (5-HIAA) and platelet binding. The results were generally inconsistent, and may not generalize to the central nervous system. However evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. [24] Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioral and neural level. [25] [24] Pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. These emotional processing biases may explain the therapeutic gap. [25]

Dopamine Edit

While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. People with MDD have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. While polymorphisms of the D4 and D3 receptor have been implicated in depression, associations have not been consistently replicated. Similar inconsistency has been found in postmortem studies, but various dopamine receptor agonists show promise in treating MDD. [26] There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). [27] Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, [28] as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. [29] Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems. [30]

Catecholamines Edit

A number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. Findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. [28] Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression. [31]

One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan (the precursor of serotonin), tyrosine and phenylalanine (precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not in persons lacking the predisposition. On the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood. [32]

Monoamine oxidase Edit

An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. [33] In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. [34] [35] Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with depressive symptoms in adolescents. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. [36] In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression. [37]

Limitations Edit

Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. [38] For one thing, serotonin system dysfunction cannot be the sole cause of depression. Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks. [39] Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There have also been inconsistent findings with regard to levels of serum 5-HIAA, a metabolite of serotonin. [40] Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. [41] [42] Another problem that presents is that drugs that deplete monoamines may actually have antidepressants properties. Further, some have argued that depression may be marked by a hyperserotonergic state. [43] Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. [44]

Receptor binding Edit

As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be underexpressed in the striatum of people with MDD. 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 people with MDD. Results from studies on 5-HTT binding are variable, but tend to indicate higher levels in people with MDD. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increased MAO activity in people with MDD, and it may even be a trait marker (not changed by response to treatment). Muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity. [45]

Four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-HTT), one on 5-HT1A, and another on dopamine transporter (DAT). One meta analysis on 5-HTT reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. [46] Another meta-analysis on 5-HTT including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-HTT in the striatum, amygdala and midbrain, post mortem studies found no significant associations. [47] 5-HT1A was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. The most commonly used 5-HT1A ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. [48] Dopamine transporter binding is not changed in depression. [49]

Emotional Bias Edit

People with MDD show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. [50] Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. [51] Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. One meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. [52] Another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naive, not elderly, and had no comorbidities. [53] The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. This is supported by the observation that both acute and subchronic SSRI administration increases response to positive faces. [54] Antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlPFC response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. The fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias. [55] These effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation. [56]

Neural circuits Edit

One meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias. Relative to controls, people with MDD showed hyperactivity of circuits in the salience network (SN), composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex (dACC), as well as decreased activity in regulatory circuits composed of the striatum and dlPFC. [57]

A neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. The model attempts to relate specific symptoms of depression to neurological abnormalities. Elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories. The ACC was divided into pregenual (pgACC) and subgenual regions (sgACC), with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. Hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning. [59] [60] This model and another termed "the cortical striatal model", which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. Reduced striatal activity, elevated OFC activity, and elevated sgACC activity were all findings consistent with the proposed models. However, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. Furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers (i.e. dependent upon mood), while subcortical abnormalities are trait markers (i.e., reflect a susceptibility). [61]

Reward Edit

While depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system. [62] The study of reward in depression is limited by heterogeneity in the definition and conceptualizations of reward and anhedonia. Anhedonia is broadly defined as a reduced ability to feel pleasure, but questionnaires and clinical assessments rarely distinguish between motivational "wanting" and consummatory "liking". While a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. Furthermore, response to natural rewards such as sucrose does not appear to be attenuated. General affective blunting may explain "anhedonic" symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. [63] [64] As anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgACC), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (NAcc) in response to positive stimuli. [65] Although the finding of reduced NAcc activity during reward paradigms is fairly consistent, the NAcc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (BOLD) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. [66] Nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. 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. [65] The response to reward in the medial orbitofrontal cortex (OFC) is attenuated in depression, while lateral OFC response is enhanced to punishment. The lateral OFC shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behavior in response to changing contingencies. Hypersensitivity in the lOFC may lead to depression by producing a similar effect to learned helplessness in animals. [67]

Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. [65] [68] [69] Treatment is also associated with attenuated activity in the sgACC, [70] and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. [71] Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. [72] Contrary to studies of functional magnetic resonance imaging response in the sgACC during tasks, resting metabolism is reduced in the sgACC. However, this is only apparent when correcting for the prominent reduction in sgACC volume associated with depression structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgACC cell markers. The model of depression proposed from these findings by Drevets et al. suggests that reduced sgACC activity results in enhanced sympathetic nervous system activity and blunted HPA axis feedback. [73] Activity in the sgACC may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgACC activity reflected increased need to modulate automatic emotional responses in depression. More extensive sgACC and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. This was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex. [74]

While a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. For example, averaging across populations may hide certain subgroup related findings while reduced dlPFC activity is reported in depression, a subgroup may present with elevated dlPFC activity. Averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of subjects. [75] Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression. [61]

Structural neuroimaging Edit

Meta analyses 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 bilateral anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (dmPFC). [77] 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. [78] Another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of MDD, found 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 was reported in the medication free and medicated populations respectively. [79] A meta analysis performed using "activation likelihood estimate" reported reductions in the paracingulate cortex, dACC and amygdala. [80]

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 the OFC and ventromedial prefrontal cortex grey matter were also reported. [81]

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 OFC, 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. [82] Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression. [83]

Multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy (FA). Reduced FA has been reported in the corpus callosum (CC) in both first episode medication naive, [85] [86] and general major depressive populations. [84] [87] The extent of CC reductions differs from study to study. People with MDD who have not taken antidepressants before have been reported to have reductions only in the body of the CC [85] and only in the genu of the CC. [86] On the other hand, general MDD samples have been reported to have reductions in the body of the CC, [86] the body and genu of the CC, [84] and only the genu of the CC. [87] Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) [85] [84] and superior longitudinal fasciculus. [85] [86]

Functional neuroimaging Edit

Studies of resting state activity have utilized a number of indicators of resting state activity, including regional homogeneity (ReHO), amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF), arterial spin labeling (ASL), and positron emission tomography measures of regional cerebral blood flow or metabolism.

Studies using ALFF and fALFF have reported elevations in ACC activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. [88] A conjunction analysis of ALFF and CBF studies converged on the left insula, with previously untreated people having increased insula activity. Elevated caudate CBF was also reported [89] A meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. [90] An activation likelihood estimate (ALE) meta analysis of PET/SPECT resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. [91] Compared to the ALE meta analysis of PET/SPECT studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus. [57]

Brain regions Edit

Research on the brains of people with MDD 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:

Subgenual cingulate Edit

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. [92] : 576–578 [93]

Prefrontal cortex Edit

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. [94] 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. [95] One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. [57] 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 people with MDD. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results. [91]

Amygdala Edit

The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. [93] 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. [96] 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. [97] One study, however, found no difference in amygdala activity during emotional processing tasks. [98]

Hippocampus Edit

Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis. [99] [100]

Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. [101] 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. [102]

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 people with MDD the often shows increased activation in depressed people, but the mechanism behind this is not yet known. [103] Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. [104] Early life stress has been hypothesized as a potential cause of HPA dysfunction. [105] [106] 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. [107] HPA axis changes by be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD. [108]

Hippocampal Neurogenesis

Reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. A genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. [109] Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction. [110]

A number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. However, some of these changes are reflected in physiology and behavior, the latter of which is the target of many animal models. These models are generally assessed according to four facets of validity the reflection of the core symptoms in the model the predictive validity of the model the validity of the model with regard to human characteristics of etiology [111] and the biological plausibility. [112] [113]

Different models for inducing depressive behaviors have been utilized neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics genetic models such as 5-HT1A knockout or selectively bred animals [111] models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. [114] The validity of these models in producing depressive behaviors may be assessed with a number of behavioral tests. Anhedonia and motivational deficits may, for example, be assessed via examining an animal's level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. Anxious and irritable symptoms may be assessed with exploratory behavior in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus-maze. Fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests.

Animal models possess a number of limitations due to the nature of depression. Some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. [113] From an evolutionary standpoint, the behavior correlates of defeats of loss are thought to be an adaptive response to prevent further loss. Therefore, attempts to model depression that seeks to induce defeat or despair may actually reflect adaption and not disease. Furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve. [111] Pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans. [115]

Neurocircuits Edit

Regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral pallidum (VP), lateral habenula (LHb) and medial prefrontal cortex (mPFC). Tentative fMRI studies in humans demonstrate elevated LHb activity in depression. [116] The lateral habenula projects to the RMTg to drive inhibition of dopamine neurons in the VTA during omission of reward. In animal models of depression, elevated activity has been reported in LHb neurons that project to the ventral tegmental area (ostensibly reducing dopamine release). The LHb also projects to aversion reactive mPFC neurons, which may provide an indirect mechanism for producing depressive behaviors. [117] Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. [116] A number of inputs to the LHb have been implicated in producing depressive behaviors. Silencing GABAergic projections from the NAc to the LHb reduces conditioned place preference induced in social aggression, and activation of these terminals induces CPP. Ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioral correlates of depression. [116] Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. [118] This led to early studies investigating VTA activity and manipulations in animal models of depression. Massive destruction of VTA neurons enhances depressive behaviors, while VTA neurons reduce firing in response to chronic stress. However, more recent specific manipulations of the VTA produce varying results, with the specific animal model, duration of VTA manipulation, method of VTA manipulation, and subregion of VTA manipulation all potentially leading to differential outcomes. [119] Stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to Dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) and depression of excitatory inputs to Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs). Optogenetic excitation of D1-MSNs alleviates depressive symptoms and is rewarding, while the same with D2-MSNs enhances depressive symptoms. Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. [119] Manipulations of different regions of the mPFC can produce and attenuate depressive behaviors. For example, inhibiting mPFC neurons specifically in the intralimbic cortex attenuates depressive behaviors. The conflicting findings associated with mPFC stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects. [71] mPFC projections to the raphe nuclei are largely GABAergic and inhibit the firing of serotonergic neurons. Specific activation of these regions reduce immobility in the forced swim test but do not affect open field or forced swim behavior. Inhibition of the raphe shifts the behavioral phenotype of uncontrolled stress to a phenotype closer to that of controlled stress. [120]

Recent studies have called attention to the role of altered neuroplasticity in depression. A review found a 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.

The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants. [121]

Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. [122] Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with MDD. 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. [123]

Various review have found that general inflammation may play a role in depression. [124] [125] One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. [126] The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. [127] Meta analysis on cytokine levels in people with MDD have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10. [128] [129] Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. [130] Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. [131] 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. [132] One review found normalization of cytokine levels after successful treatment of depression. [133] A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. [134] Exercise can act as a stressor, decreasing the levels of IL-6 and TNF-a and increasing those of IL-10, an anti-inflammatory cytokine. [135]

Inflammation is also intimately linked with metabolic processes in humans. For example, low levels of Vitamin D have been associated with greater risk for depression. [136] The role of metabolic biomarkers in depression is an active research area. Recent work has explored the potential relationship between plasma sterols and depressive symptom severity. [137]

A marker of DNA oxidation, 8-Oxo-2'-deoxyguanosine, has been found to be increased in both the plasma and urine of people with MDD. 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 people with MDD. 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. [138] Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. [139] Oxidative DNA damage may play a role in MDD. [140]

Mitochondrial Dysfunction:

Increased markers of oxidative stress relative to controls have been found in people with MDD. [141] These markers include high levels of RNS and ROS which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. This lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. [142] The brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. Mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains. [143]

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, [144] 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: [144]

Central executive network Edit

The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. [145] [146] This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. [144] [147] Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. [148] [149] 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. [150]

Default mode network Edit

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. [144] 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. [151] [152] 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. [153] People with MDD 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. [154] 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. [155] However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience network Edit

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. [145] 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. [144] 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. [156] This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. [157] In major depressive disorder, anxiety is often a part of the emotional state that characterizes depression. [158]