Family, twin, and adoption studies document a complex genetic basis of MDD [15,16,17]. MDD features a highly polygenic form of inheritance, with multiple loci of small effect size interacting with each other and with environmental triggers. The largest genome-wide association study (GWAS) of depression to date, which included over 1.2 million participants [18], identified 178 genetic risk loci and 223 independent SNPs associated with MDD. The SNP-based heritability for MDD was identified to be around 11.3%, and top biological processes included nervous system development, brain volume, and synapse assembly and function (Table 1) [18].
Increased cortisol levels, HPA overactivity, and a dysfunctional negative feedback of the HPA axis have been reported in some depressed patients, particularly in specific depression subtypes [80]. Thus, multiple drugs targeting the stress system have been tested for the treatment of depression, including corticosteroid synthesis inhibitors, GR antagonists, corticotrophin-releasing hormone receptor antagonists, tryptophan 2,3-dioxygenase inhibitors, and FK506-binding protein 51 (FKBP51) receptor antagonists [81]. Since not all patients present with alterations in the HPA axis, genetic or functional assessments at baseline for the identification of potentially responsive patients may be required [81]. Indeed, treatment with mifepristone (a GR antagonist) has shown promising results in patients with psychotic depression [82].
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The GR target gene FKBP5 emerged as a significant player in depression originally inspired by the inhibitory action of its protein FKBP51 on GR [96,97,98]. FKBP5 polymorphisms have been associated with HPA axis parameters, antidepressant treatment response, and recurrence of depressive episodes [99]. FKBP51 is intertwined with other pathways related to depression: it is a target of epigenetic programming [100, 101], but potentially also a sculptor of the epigenetic landscape through its action on DNA methyltransferase 1 [102]. Through additional protein-protein interactions that recalibrate protein phosphorylation, FKBP51 also impacts signaling of other depression-relevant pathways such as GSK3β [103], BDNF [102, 104], and nuclear factor kappa B, linking it to inflammation and the immune system [105, 106], as well as autophagy [107, 108].
Associations between mitochondrial genetic variations, cognitive function, and depression [170, 207] has prompted some authors to suggest mitochondrial dysfunction as the initiator of a chain of molecular events precipitating MDD. In fact, mitochondrial damage can ultimately cause the activation of apoptotic pathways, as previously evidenced in peripheral and brain samples of MDD patients [208, 209]. Apoptotic events may eventually contribute to the activation of the immune system and lead to the chronic low-grade inflammatory status seen in MDD [210]. However, in addition to mitochondrial damage, many other stimuli and mechanisms also excite the inflammatory phenotype of MDD, including a direct effect of oxidative and nitrosative stress, the microbiome-gut-brain axis, and many environmental factors highly prevalent in patients [136]. Other downstream mechanisms may originate from dysfunctional mitochondria or other stimuli, as well. For instance, oxidative stress can impact many pathways such as BDNF signaling, neuroplasticity, and cognition [211]. It can further cause DNA damage [212, 213], alter DNA methylation [214, 215], and induce accelerated aging [216], as reported for MDD [217].
Altered myelination is increasingly recognized as an important factor in both the etiology and treatment of MDD, and is another example of the difficulties in unequivocally proving the initial triggers [222]. Through enhancing conductivity along neuronal axons [223], myelin and myelin-producing oligodendrocytes are obvious candidates for mechanisms of brain diseases in general. Several studies found pronounced alterations in myelination and oligodendrocyte lineage cells in depression and animal models thereof [222]. Even though not typically conceptualized in pathways, myelin and oligodendrocytes are known to be affected by stress and by several other factors such as neurotransmitters, neurotrophins, cytokines, ROS, epigenetic factors, intestine microbiome, among others [222, 224]. Further, oligodendrocytes shape neuronal function in many ways beyond myelination; the importance of oligodendrocytes and myelination in MDD is corroborated by their response to antidepressant treatment [222].
One of the cardinal principles of his method was the recognition that any given symptom may appear in virtually any one of these disorders; e.g., there is almost no single symptom occurring in dementia praecox which cannot sometimes be found in manic depression. What distinguishes each disease symptomatically (as opposed to the underlying pathology) is not any particular (pathognomonic) symptom or symptoms, but a specific pattern of symptoms. In the absence of a direct physiological or genetic test or marker for each disease, it is only possible to distinguish them by their specific pattern of symptoms. Thus, Kraepelin's system is a method for pattern recognition, not grouping by common symptoms.
It has been claimed that Kraepelin also demonstrated specific patterns in the genetics of these disorders and patterns in their course and outcome,[17] but no specific biomarkers have yet been identified. Generally speaking, there tend to be more people with schizophrenia among the relatives of schizophrenic patients than in the general population, while manic depression is more frequent in the relatives of manic depressives. Though, of course, this does not demonstrate genetic linkage, as this might be a socio-environmental factor as well. 2ff7e9595c
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