Question: Does major depressive disorder (MDD) have a clear biological basis?
Takeaway: This 2011 review surveys a variety of biomarkers closely associated with MDD. These markers may describe a biological basis for MDD; at minimum, they illustrate various pathways linking MDD to its comorbidities. Directly addressing these biomarkers — which often can be done through changes to diet, exercise, and lifestyle alone — may be an effective means to manage depression and reduce its associated disease burden.
This 2011 review summarizes many of the biological correlates of major depressive disorder (MDD). The majority of the data presented illustrates associations between depression (and/or depression severity) and various biochemical markers. It therefore cannot determine whether depression causes the observed elevations and suppressions or is caused by them. Taken together, however, these data illustrate a clear biochemical basis for depression. They also suggest depression and its comorbidities — which include elevated risk of a variety of conditions, including heart disease, diabetes, and impaired immune function (1) — may be mediated by direct treatment of the relevant biomarkers.
The authors propose a comprehensive disease model, illustrated in the figure below. This model links MDD to elevation or suppression of a variety of biochemical systems and outlines the extensive downstream effects of the chronic stress increase associated with MDD. As such, this model, which has been explored in previous publications, explains both how these biological factors can directly contribute to MDD and how MDD, via its biological effects, leads to its various comorbidities (2).
The top of the figure represents hyperactivity of the LHPA axis, one of the two major moderators of the biological stress response (3). Psychological stress can clearly trigger a depressive episode (4), specifically when the psychological impact of a stressor exceeds the coping ability of the individual (5). Coping ability may itself have a biological basis, which was reviewed in previous literature (6). Early-life adversity may predispose an individual to LHPA axis hyperactivity and so increase sensitivity to initiation of this cascade (7). This model thus explains why childhood adversity has been frequently linked to a variety of conditions associated with impaired metabolism and aging (8). By increasing the sensitivity of the individual to stress, these experiences increase risk of exposure to the various metabolic defects described in this model.
A major downstream consequence of MDD is elevated glucocorticoid (the most important of these being cortisol) levels, which are present in the majority of depressed individuals but not all (9). High cortisol levels may be particularly harmful alongside elevated levels of inflammatory cytokines, which inhibit the action of cortisol by downregulating cortisol receptor activity (10). High cortisol levels may directly contribute to cell damage and death in a variety of cell types, including hippocampal cells, in part by impairing effective regulation of cellular glutamate (11).
Unmedicated depressives display low levels of neurosteroids, including GABA-A, DHEA, and allopregnanolone; treatment and remission of depression restores normal levels (12). Neurosteroids, in addition to directly modulating the LHPA axis, support healthy immune system activity and have antioxidant and neuroprotective effects (13). Under chronic stress, low levels of these neurosteroids could increase the vulnerability of the LHPA axis to dysregulation and increase individual sensitivity to external stressors (14). This is acutely apparent in the context of premenstrual dysphoric disorder (PMDD), which includes severe physical and emotional symptoms correlated with a failure to elevate neurosteroid levels effectively in response to external stressors (15).
Insulin resistance and impaired glucose tolerance are frequently seen in individuals with MDD, especially those who are hypercortisolemic (16). These effects may be directly related to the effect of cortisol on glucose levels and glucose utilization; for example, one PET scan study showed cortisol directly inhibited hippocampal glucose utilization in otherwise healthy individuals (17). This suggests a major mechanism by which depression-induced hypercortisolemia leads to many of the comorbidities of MDD, including metabolic and neurodegenerative disease (18).
MDD is also associated with the elevation of a variety of inflammatory cytokines and elevated net inflammatory burden. These chronically elevated levels of inflammation can impair immune function and increase risk of serious comorbidities (19). Similarly, these elevated levels of inflammation may directly impair hippocampal function, as the hippocampus is rich in IL-6 receptors (20). Similarly, chronically elevated LHPA axis activity, as seen in MDD, increases oxidative stress, which, particularly alongside elevated inflammation, contributes to PTSD, stroke, neurodegenerative conditions, and other conditions typically associated with aging (21). Interestingly, many antidepressants have antioxidant effects (22).
Finally, according to the so-called “neurotrophic model,” depression results from impaired neurogenesis and neuroplasticity, itself the result of low hippocampal brain-derived neurotrophic factor (BDNF) activity. Low serum BDNF levels are consistently observed in unmedicated depressives, and this theory is central to the mechanism of action of multiple prominent antidepressants (23). Similarly, direct BDNF administration acutely reverses depressive behaviors in mice, suggesting it has direct biological effects and is not merely a marker of disease (24). More recent research has begun to establish BDNF as a metabotrophin, with significant effects in the periphery; low BDNF levels, for example, are correlated with insulin resistance and impaired glucose tolerance (25). The low BDNF levels seen in MDD, therefore, may play a major role in moderating the relationship between MDD and Alzheimer’s disease, diabetes, and other metabolically influenced conditions (26).
The authors of this review conclude by noting the implications of these findings. The majority of the relationships described are associations, and thus it is not clear to what extent MDD is the cause of these biochemical distortions and to what extent they contribute to the genesis, perpetuation, and/or exacerbation of MDD. The existence of these biochemical mediators, however, and the consistent links between them, depression, and its comorbidities suggest there is a clear biological basis for depression; furthermore, these findings suggest direct treatment of these biochemical distortions is a potential avenue to treat, manage, or even reverse MDD. As shown in the table below, many of the existing tools used to manage these mediators are lifestyle interventions related to diet, exercise, and general health and well-being. This biological framework suggests these and similar treatments have the potential to prevent and treat major depressive disorder and, at minimum, to reduce the comorbidity risks associated with depression.
- Depression, endocrinologically a syndrome of premature aging?; Should depressive syndromes be reclassified as “metabolic syndrome type II?”; Mood disorders in the medically ill: Scientific review and recommendations; Association between depression and mortality in older adults: the Cardiovascular Health Study
- Stress hormone-related psychopathology: Pathophysiological and treatment implications; The stress of life; Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging; Allostasis and allostatic load: Implications for neuropsychopharmacology
- Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: Relation to hypercortisolism and corticotropin-releasing hormone
- Psychological and metabolic stress: A recipe for accelerated cellular aging?; Accelerated telomere shortening in response to life stress; The possibility of neurotoxicity in the neurocampus in major depression: A primer on neuron death; Causal relationship between stressful life events and the onset of major depression; When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders
- Dynamics of a stressful encounter: Cognitive appraisal, coping and encounter outcomes; Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women; Cognitive appraisals and emotions predict cortisol and immune responses: A meta-analysis of acute laboratory social stressors and emotion inductions
- Psychobiology and molecular genetics of resilience
- Early parental loss and development of adult psychopathology; Adverse childhood experiences and risk of depressive disorders in adulthood; Importance of studying the contributions of early adverse experience to neurobiological findings in depression; Psychobiology of childhood maltreatment: Effects of allostatic load?; Childhood trauma associated with smaller hippocampal volume in women with major depression; Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder; The enduring effects of abuse and related adverse experiences in childhood: A convergence of evidence from neurobiology and epidemiology
- Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress; Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation; Pathways linking the early environment to long-term health and lifespan; Lasting epigenetic influence of early-life adversity on the BDNF gene; Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex; Obesity and type 2 diabetes risk in midadult life: The role of childhood adversity
- A new view on hypocortisolism; Major depression in late life is associated with both hypo- and hypercortisolemia
- Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide
- Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine; Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes; Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain allopregnanolone availability?; Concentrations of 3a-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery
- Neurobiological and neuropsychiatric effects of DHEA and DHEAS; The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus; Chronic stress and immunosenescence: A review; Oxidative stress in NPC1 deficient cells: Protective effect of allopregnanolone; Regenerating in a degenerating brain: potential of allopregnanolone as a neuroregenerative agent
- Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events; Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation
- Histories of depression, allopregnanolone responses to stress, and premenstrual symptoms in women; Progesterone metabolite allopregnanolone in women with premenstrual syndrome; Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects
- Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls; Lipid metabolism and insulin resistance in depressed patients: significance of weight, hypercortisolism, and antidepressant treatment; Hypercortisolemic depression is associated with increased intra-abdominal fat; Hypercortisolemic depression is associated with the metabolic syndrome in late-life
- Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer’s disease
- Managing psychiatric disorders with antidiabetic agents: Translational research and treatment opportunities; Insulin resistance in depressive disorders and Alzheimer’s disease: Revisiting the missing link hypothesis; Insulin signaling and life span
- The role of stress factors during aging of the immune system; Depression and immune function: Central pathways to morbidity and mortality; Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression; A meta-analysis of cytokines in major depression
- Pro-inflammatory cytokines and their effects in the dentate gyrus; Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression; Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults
- Depression and possible cancer risk due to oxidative DNA damage; Oxidative stress and inflammation in brain aging: nutritional considerations
- Total antioxidant capacity and total oxidant status in patients with major depression: Impact of antidepressant treatment
- Is it time to reassess the BDNF hypothesis of depression?; Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication; Serum and plasma BDNF levels in major depression: a replication study and meta-analyses
- Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models
- Comment on: Brain-derived neurotrophic factor (BDNF) and type 2 diabetes
- Brain-derived neurotrophic factor (BDNF) and type 2 diabetes