Associations Among Monoamine Neurotransmitter Pathways, Personality Traits, and Major Depressive Disorder

Major depressive disorder (MDD) is a complex psychiatric disease requiring multidisciplinary approaches to identify specific risk factors and establish more efficacious treatment strategies. Although the etiology and pathophysiology of MDD are not clear until these days, it is acknowledged that they are almost certainly multifactorial and comprehensive. Monoamine neurotransmitter system dysfunction and specific personality traits are independent risk factors for depression and suicide. These factors also demonstrate complex interactions that influence MDD pathogenesis and symptom expression. In this review, we assess these relationships with the aim of providing a reference for the development of precision medicine.


INTRODUCTION
Major depressive disorder (MDD) is the most prevalent mood disorder and the most common disabling psychiatric disease across the globe. In the United States, the lifetime prevalence of MDD is 20.6% (1), and the associated healthcare and economic burdens are surpassed only by cardiomyopathy (2). The most clinically significant symptom of MDD is suicidality (3,4). Over the years, MDD has been explained in genetic, biological, psychosocial, personality and other terms. No definite explanation accounts for the mechanism of MDD, however. Reducing the morbidity and mortality associated with MDD requires a more complete understanding of disease pathophysiology. Evidence accrued over many decades strongly implicates dysregulation of monoamine neurotransmitter systems in MDD development. Further, there is compelling evidence that MDD risk is strongly associated with certain personality traits. In this review, we expound the underlying relationships among monoamine neurotransmitter systems, personality traits, and MDD.
A biological basis for MDD risk is strongly supported by genetic studies demonstrating moderate heritability (ranging from about 37% and 45%) (5-9). Thus, gene-environment interactions are likely crucial to disease etiology, such as stressful life events (10, 11), childhood maltreatment (including emotional abuse, sexual abuse, emotional neglect, and physical neglect) (12, 13), and in fact these interactions result in an underestimation of the overall genetic influence (14). Kendler et al. reported a genetic correlation for liability to major depression of 0.63 in both males and females (9), and a similar estimate was reported in a populationbased twin study (0.55) (15), consistent with several earlier studies suggesting that genetic risk factors are not sex-specific (16)(17)(18)(19). However, the largest-sample twin study reported greater heritability in females (0.49, 95%CI = 0.31─0.56 vs. 0.41, 95% CI = 0.21─0.49), as well as 0.36 (95%CI = 0.31─0.38) in full siblings and 0.51 (95%CI = 0.51─0.53) in half-siblings (20). Several other studies have found a similarly elevated genetic propensity in females (9, 21, 22). These observed differences in MDD heritability between males and females are particularly interesting because recent neuroimaging and molecular genetic studies have also shown potential biological differences in MDD etiology between men and women. Edvardsen et al. reported a higher monozygotic/dizygotic ratio among male twins compared to female twins (8). Alternatively, a sex-limitation model suggested that the same genes influence MDD in males and females (19), although others have found that different genes impacted depressive illness (23). Thus, there is still no consensus on sex differences in the genetics of MDD. Raphe serotonergic neurons project to the caudate, putamen, pallidus, amygdala, limbic forebrain, and neocortex, where 5-HT signaling contributes to motivation, emotion stress processing (26), and regulation of other limbic functions (27). Acute depletion of the 5-HT precursor tryptophan (acute tryptophan depletion, ATD) markedly influences affective experience and emotional regulation in subjects with a family history of MDD (28). Challis et al. reported sensitization of inhibitory GABAergic neurons within the dorsal raphe nuclei and concomitant inhibition of serotonergic activity following social defeat in mice (29). Collectively, human and animal studies of tryptophan depletion (30) and associated serotonergic signaling deficiency strongly implicate 5-HT in mood regulation and MDD pathogenesis. Such insufficient 5-HT signaling may result from both reduced release and lower postsynaptic sensitivity as MDD patients demonstrate both decreased plasma and platelet levels of 5-HT, as well as blunted prefrontal cortical responses to 5-HT (31). Barton et al. reported elevated brain serotonin turnover before antidepressant therapy and markedly reduced turnover after antidepressant therapy and condition improvement, suggesting brain serotonin turnover as a potential biomarker for MDD (32). Further, a recent positron emission tomography (PET) study found reduced binding potential of the 5-HT 1A receptor subtype in MDD patients relative to controls, and the authors suggested that lower 5-HT 1A activity may result in "decreased engagement of the cognitive control network and impaired resolution of interfering cognitive stimuli" (33). Also consistent with a major contribution of 5-HT signaling dysfunction to MDD, elevated brain turnover of 5-HT is strongly influenced by 5-HT transporter (5-HTT) genotype (32), which in turn is associated with MDD risk. The urine serotonin/dopamine ratio may also be a useful diagnostic indicator for patients with MDD (34). Alternatively, selective serotonergic reuptake inhibitors (SSRIs) like fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram can enhance brain serotonin levels and are considered the first-line therapies for MDD patients based on demonstrated efficacy in the majority of placebo-controlled clinical studies (35). Growing evidence supports the hypothesis that epigenetic mechanisms, such as DNA methylation, play an important role in psychiatric diseases (36) such as MDD and personality disorders (37, 38), where epigenetic factors bridge the environmental and genetic mechanisms. A multitude of reports have considered the DNA methylation of the serotonin transporter gene (SLC6A4), located on chromosome 17 (39), as the major research target in investigation and evaluation in depression ( Table 1). In summary, 5-HT is the biogenic amine most strongly associated with depression, as evidenced by the negative influence of 5-HT depletion on mood, the antidepressant efficacy of SSRIs, the perturbed 5-HT turnover and neuronal sensitivity in MDD patients and animal models, and the numerous associations between 5-HT pathway gene polymorphisms and MDD (Table 1).

MONOAMINE NEUROTRANSMITTERS AND MDD
Changes in 5-HT signaling may also predict suicidality. Patients with suicidal impulses exhibited lower cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIIA) and fewer 5-HT uptake sites on platelets (92,93). Weissmann et al. reported increased editing of the 5-HT 2C receptor (5-HT 2C R) mRNA in cortical areas of depressed suicides compared to non-psychiatric controls, suggesting that regionspecific changes in 5-HT 2C R function may contribute to MDD etiology (94). Further, altered activities of the major 5-HT biosynthetic enzymes tryptophan hydroxylase 1 and 2 (TPH 1 and TPH 2) (95), of 5-HTT (96), and of serotonin receptors, especially HTR 1A (97), HTR 2A (98), and HTR 2C (99), are associated with suicidal impulses and violent suicidal behavior. However, contradictory findings have been reported (98,100,101), possibly due to low statistical power or heterogeneity of study populations. Larger-scale studies of different clinical and ethnic populations may resolve these controversies.
In animal models, genetic and pharmacological manipulation of serotonergic signaling can induce acute depressionand anxiety-like behaviors (102). Further, manipulating serotonergic and dopaminergic signaling during development can affect later-life somatosensory, anxiety/depression-like, and aggressive behavior (103). A recent study found generally lower levels of all three monoamines in a Wistar-Kyoto (WKY) animal model of maternal depression compared to matched control Sprague-Dawley (SD) rats (104).
Norepinephrine (NE) secreted from the locus coeruleus (LC) is a critical modulator of neural circuits involved in learning and  (108). Moreover, the antidepressant actions of monoamine oxidase (MAO) inhibitors and non-selective monoamine reuptake blockers suggest that NE plays a major role in the neurobiology of MDD (109). One potential pathogenic mechanism is elevated NE sensitivity of a 2adrenoceptors, which can inhibit NE release from the LC via negative feedback (110,111). Indeed, elevated density and enhanced activity of a 2 -adrenoceptors have been reported in the brain tissues and platelets of MDD patients (112,113). Elevated a 2 -adrenoceptor density has also been found in the frontal cortex and hippocampus of depressed suicides (114,115). Moreover, Rivero and co-workers found that the elevated a 2adrenoceptors density in the prefrontal cortex of suicidal depressed subjects was resistant to antidepressant therapy, whereas elevated b 1 -adrenoceptor density was reduced by such therapy (116). The efficacy of selective norepinephrine reuptake inhibitors (SNRIs) provides the strongest evidence for a direct contribution of deficient NE transmission to depression. A recent systematic review concluded that the SNRI duloxetine hydrochloride was effective against MDD as well as panic disorder, obsessivecompulsive disorder, and other psychiatric disorders (117), indicating broad involvement of NE in psychopathology. Another review suggested that duloxetine may be safe for older adults with MDD (118), although this agent has not been suggested for use as first-line acute therapy for MDD (119). Nonetheless, the norepinephrine transporter (NET) is well documented therapeutic target for MDD and like SSRIs (120), nonselective 5-HT/NE reuptake inhibitors such as venlafaxine (121) are widely used for MDD treatment. Many studies have also implicated NET gene polymorphism in MDD pathogenesis ( Table 2). Abnormalities of noradrenergic function may also be involved in the pathogenesis of suicide (148). Several earlier studies reported upregulation of b-adrenoceptors in the brains of suicides (114,149,150), although several others reported the opposite (150,151). Aside for receptor abnormalities, excessive stress could trigger depletion of NE and the onset of MDD (152).
While 5-HT and NE are the biogenic amines most consistently associated with MDD, abnormalities in DA signaling have also been implicated. For instance, depletion of DA has also been reported in MDD patients (153). The medial part of the VTA projects mainly to the nucleus accumbens and ventral striatum, which are central hubs of the brain reward system (154,155). Allelic variation of DA-related genes modulate brain circuitry involved in the regulation of negative emotional stimuli (156), and DA system dysfunction has been associated with many symptoms of MDD such as anhedonia and low motivation (157,158), as well as with cognitive symptoms such as impaired concentration (159,160). A dopamine deficiency has also been reported in MDD. One study measuring monoamine neurotransmitters and related metabolites in the cortex of rats detected DA only in the control group (161). A multi-data source-based prioritization (MDSP) study by Liu et al. identified 143 depression-related genes, including the DA receptor 4 (DRD4), as well 16 significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including the 'dopaminergic synapse' as well as the 'serotonergic synapse' and 'glutamatergic synapse'. The neuroactive ligand-receptor interaction list from KEGG pathway analysis also included the dopaminergic synapse (162). Further, a number of dopaminergic gene polymorphisms are associated with MDD ( Table 2).
Reduced NE, 5-HT, and DA have been identified as significant biomarkers for depression in animal studies (163,164). Advances in imaging techniques, including PET and singlephoton emission computed tomography (SPECT), have also provided valuable insights into the contributions of DA to MDD. For instance, a recent study reported significantly reduced DA transporter (DAT) availability in the bilateral putamen and VTA of patients compared to healthy controls (Cohen d range, −0.62 to −0.71) (158). Moreover, this same study found lowest DAT availability in the VTA of patients reporting the greatest stress-related fatigue (165). While this relationship was replicated (166), the findings of a meta-analysis were contradictory (167).
In summary, the evidence is very strong that dysregulation of NE, DA, and 5-HT signaling contributes to MDD development and symptom expression. However, prospective studies are required to establish causal relationships between these deficiencies and MDD. A large-scale longitudinal cohort study using baseline and 2year follow-up data found that increased neuroticism scores on the NEO-FFI were associated with both anxiety and depressive disorders. Higher agreeableness has also been associated with the occurrence of MDD, while openness demonstrated no association with the occurrence of, or recovery from, any depressive or anxiety disorder (168). In contrast, extraversion trait scores were associated with lower depressive disorder incidence and increased rate of recovery (169). Pair-wise genome-wide association studies (GWASs) have also found that numerous genetic variants overlap between depression and trait neuroticism (170). Further, high trait neuroticism has been confirmed as a dominant risk factor for depression (104). Also, low extraversion scores were a predictor of depression during the remission period of bipolar disorder (BP), the other main subtype of mood disorder (171). A recent resting-state dynamic functional network connectivity analysis found that state 4 was positively correlated with trait extraversion and negatively correlated with neuroticism, as measured by the EPQ, and that MDD patients showed significantly reduced dwell time and fractional time in state 4 compared to healthy controls, with lowest centrality degree in hippocampus and ventral striatum (172).
Neuroticism can improve the ability to cope with negative emotional stimuli (173) and has been linked to panic disorder (174), schizophrenia (175), and obsessive-compulsive disorder (OCD) (176) as well as to MDD. According to twin studies, the heritability of trait neuroticism is approximately 40%, with 15% to 37% caused by single-nucleotide polymorphism (SNP) variations (177). High trait neuroticism is associated with sensitivity to stress and negative emotional experiences, as well as with excessive worry, emotional vulnerability, and increased emotional exhaustion (178), all of which can impact an individual's physical activity (179), perception (180,181), and emotion (182). An early meta-analysis of GWASs analyzing over 106,000 individuals identified nine neuroticism-associated loci (including the ionotropic kainate 3 glutamate receptor, Kelchlike protein 2, and corticotropin-releasing hormone receptor 1). This same study also found a strong association between neuroticism and MDD (genetic correlation = 0.64), but no sex difference in the heredity of neuroticism (177). Another metaanalysis of GWASs identified the Membrane-associated guanylate kinase inverted repeat member 1 (MAGI1) gene as a novel locus for neuroticism, both among the entire cohort of 63,661 individuals as well as in the combined Netherlands Twin Registry (NTR)/Netherlands Study of Depression and Anxiety (NESDA) cohort, with significant polygenic risk scores associated with MDD for SNP sets at P-value thresholds of 0.01 and 0.05, again providing compelling evidence that higher neuroticism is strongly correlated with MDD (183).
Harm avoidance (HA), a core personality trait defined by Cloninger, reflects a tendency to avoid potential danger, and like neuroticism, is related to traits such as pessimism, anxiousness, insecurity, bashfulness, and unusual susceptibility to fatigue (184). Trait HA has a high degree of stability throughout life (185), and is strongly associated with OCD (186), eating disorders (187), and other psychiatric disorders. High HA scores are also considered predictive of MDD (188). Bipolar disease patients demonstrating high HA scores on the TCI also showed a strong tendency for poor antidepressant treatment response during depressive episodes (189). A meta-analysis focusing on the associations between personality traits and MDD recovery found that patients with high novelty seeking (NS), high self-directedness (SD), and low HA exhibited better antidepressant responses (190). Alternatively, higher HA scores and lower SD scores were significantly correlated with nonremission in MDD patients (191), these findings have been replicated (192)(193)(194). Interestingly, a meta-analysis from Zaninotto et al. not only found such correlations, but the team reported the influence of HA in MDD vs healthy subjects was significantly greater than that found in BP vs healthy subjects (195), although there was marked heterogeneity among the included studies. Additional longitudinal studies are needed to confirm the association between HA and MDD.
Personality traits are also the major focus of suicide research. Garcia Herrero et al. concluded that high neuroticism can predict suicidal ideation (196). Similarly, Peters and his colleagues followed a large sample population in the United Kingdom for 10 years and found that neuroticism was related to suicide risk in both males and females and that neuroticism was a major predictor of suicide in females with mood disorders (197). An earlier study also found that neuroticism and openness were risk factors for suicide specifically in females, while extraversion and conscientiousness reduced the risk in males (198).
A recent study using the TCI to assess personality traits found that higher HA increased the risk of suicidal ideation in depression (199). Eric et al. also reported significantly higher HA scores, as well as low SD scores in subjects with suicidal ideation (192). Further, several studies have found that higher HA and NS scores are significant risk factors for suicidal behavior (200)(201)(202), while others have linked lower SD and higher self-transcendence (ST) to suicidality (203,204).
Mood state may also impact personality traits, at least as measured at specific times, which complicates these association results. Nonetheless, the relatively consistent relationships between specific traits and MDD, including suicidal MDD, and the overlap between several trait-related and MDD-related genes suggest that investigations of the genetic and physiological attributes underlying specific traits may provide additional clues to the pathophysiology of MDD.
Extraversion, a higher-order personality trait, has been linked to reward system function in several studies (213)(214)(215). Furthermore, evidence strongly suggests that DA modulation is involved in both reward system function and extroversion (216). Smillie et al. (208) and co-workers reported that subjects with the DA receptor 2 (DRD2) gene A1-allele had significantly higher extroversion scores. In contrast, however, a functional magnetic resonance imaging (fMRI) study reported that A1-allele carriers exhibited lower extraversion scores, although the difference between carriers and non-carriers was not significant (217). A cross-national study of personality differences by Fischer et al. found a positive correlation between dopaminergic brain function index score and extraversion as well as a negative association between dopaminergic function and neuroticism score in those under high stress (218). A meta-analysis also found a relationship between self-consciousness (one facet of neuroticism) and the domain receptor 1 (DDR1) gene (219). Again, these relationships may be complicated by covariables. For instance, a previous study reported a negative correlation between neuroticism scores and quality of life in schizophrenia (175).
The opponent interactions between serotonin and DA makes the relationship between serotonin and personality traits was interesting and complex (220). Several studies have looked at the relationship, but the results have been inconsistent ( Table 3). For example, most evidence to date support a link between the serotonin-transporter-linked polymorphic region (5-HTTLPR) and neuroticism (252,286), meanwhile the different result were obtained using NEO-FFI (225). Interesting, in Swedish cohort study, they observed openness was significantly associated with 5-HTTLPR, while they also found that the positive association between openness and childhood adversity in the geneenvironment model regardless of 5-HTTLPR genotype (225). Paaver et al. demonstrated S allele carriers with adverse family relations were related to higher thoughtlessness, disinhibition and impulsivity using the Barratt Impulsiveness Scale 11 (BIS-11) solely among girls (254), they also indicated that, in agreement with other studies, the influence of 5-HTTLPR genotype on affect is related to environmental adversity (61, 66). Indeed, environmental adversity, such as childhood adversity, can have a negative effect on child's expectations and present strained interpersonal relationships, which can affect personality or temperature (295), as well as associate with a range of psychopathology, including MDD (11). This factor has not been considered in some studies, which might be one of the fundamental reasons for the inconsistent results. Some studies on children have demonstrated significant association between 5-HTTLPR short (S) allele and higher NS scores (253), and S allele closely related to higher prevalence of substance use (296). In addition, the study of the relationship between personality trait and NE is rather little.
Undoubtedly, it is important that any assessment of the role of monoamines in personality traits should involve precise neural circuits associated with the relevant behavioral processes from the examples provided above (298). However, in many studies, there are some limitations, such as the small sample size with low statistical power, still need more participants to provide high quality evidence in further analysis.

CONCLUSIONS
MDD, therapeutic strategy still remain unclear, is one of the most prevalent medical disorder which causes life-threatening conditions, like suicides tend and suicidal behaviors. Although the precise etiology is not known, several studies support the fact that MDD is the severe mental disease that involves disturbance of chemical neurotransmitters, psychosocial factors, genetic factors, personality traits and other formulations. In our study, numerous strong associations have been identified among monoamine signaling deficits, detrimental personality traits, and major depressive disorder, providing potential clues to disease pathogenesis. And through incredible advancements in medical technology, these independent and interactive dimensions may be promising targets for precision medicine. Suicide is a massive public problem in depressed patients, thus research regarding the prevention and intervenient countermeasures of suicide should be thoroughly investigated in the field of biogenic amines changes and personality traits. Moreover, such studies have identified potential biomarkers for MDD risk that could aid in the early identification of at-risk individuals (299). Clinical programs should focus on early identification and intervention for emotional problems and high-risk behaviors among children and adolescents. Notably, the evidences for the relationship between monoamines, MDD and personality traits are confused and contradictory. Small sample size (significantly drop the accuracy rate and lead bias), unified analyzing methods, differences in tissues, depressive  Dutch personality questionnaire (DPQ) 5-HTTLPR S-allele increases affective reactivity to examination stress independent of trait Neuroticism. (253) 216 (129 males and 87  females) TPQ and Buss-Durkee Hostility Inventory S allele of 5-HTTLPR was related to higher NS scores.  phenotypes, ethnicities, and others may lead to these inconsistent data. These factors should be considered in future studies.

AUTHOR CONTRIBUTIONS
GZ planned and directed the paper, and XS wrote it.