During the past decade, tremendous insights have been gathered regarding putative pathogenesis in individuals with mood disorders. The availability and advances in cellular and molecular biology, as well as other platforms such as bioinformatics capabilities, have positioned neuroscience to not only refine disease models but also to consider novel treatment and preventive approaches. The anachronistic notion that mood disorders are recurrent, adult-onset conditions has been supplanted by a different conceptualization: that these are brain-based conditions that have both neurodevelopmental and neurodegenerative aspects.1 In addition, it is also now conjectured that a subgroup of individuals with mood disorders exhibit what appears to be evidence of premature aging.2
Individuals with mood disorders (both major depressive disorders and bipolar disorders) are differentially affected by age-related diseases much earlier in life. For example, it has been reported that adolescents with mood disorders have higher rates of cardiovascular disease, in addition to traditional and emerging risk factors for cardiovascular disease.3
In adults with mood disorders, a significant hazard exists for early-onset type 2 diabetes, cardiovascular disease (eg, hypertension), as well as dementing disorders. Replicated evidence from European epidemiologic studies indicates that the elevated risk for dementing disorders in adults with pre-existing mood disorders may be influenced by the number of prior affective episodes, speaking to both mechanisms, and translation (eg, preventive opportunity).1
If in fact we shift our gaze to below the surface and look at separate units of analysis, convergent evidence across protein, cellular, and circuit-based studies also hint at premature aging processes.4 For example, multiple studies and meta-analyses indicate that individuals with mood disorders exhibit telomere shortening.5 Telomeres are protein-nucleic complexes that shorten as a function of cellular division. This has been interpreted as molecular evidence of cellular aging and premature senescence.
Moreover, it has also been shown that a substantial percentage of individuals with mood disorders (particularly mid- to late-trajectory illness) evince alterations in the immuno-inflammatory-homeostatic network.6 For example, increased peripheral levels of acute phase reactants (eg, high-sensitivity C-reactive protein) and proinflammatory cytokines (interleukin-1, interleukin-6)7 have been reported. In the general population, a homeostatic imbalance toward proinflammatory cytokine elevation as an apparent function of age has also been observed.
Separate lines of evidence commensurate with telomere and inflammatory reports recognize that mood disorders are highly associated with insulin resistance. Indeed, there are disparate contributory/causative factors, including but not limited to iatrogenic (medication-induced) factors. The preponderance of evidence indicates that insulin resistance in mood disorders is intrinsic to the disease process and is seen in individuals independent of exposure to psychotropic medications and other established social determinants and mediational factors.8-9
Insulin resistance is also a feature of normal aging and is particularly common in individuals with dementing disorders. For example, it is reported that up to 80% of individuals with a clinical diagnosis of Alzheimer’s disease (AD) have insulin resistance.10 It is tempting to speculate, although it is not known at this time, that the insulin resistance seen in middle-aged adults with mood disorders represents a biomarker that predicts potential risk for dementing disorders and other age-related conditions.
On a related note, many research groups employing different methodologies across different centers have reported a common finding that many individuals with mood disorders exhibit age-inappropriate elevations of amyloid within the brain parenchyma.11 The ability to detect amyloid in vivo in brain is facilitated by the availability of radiopharmaceutical tagging. Notwithstanding debates concerning the mechanistic role of amyloid in the AD disease process, it is generally accepted that amyloid deposition and accumulation activate a host of intra- and extracellular mechanisms that result in neuronal endangerment and structural changes.
Sirtuins, a relatively new class of proteins, have been identified and implicated as possibly abnormal in individuals with mood disorders.12-14 Sirtuins have pleotropic cellular activity and are known to affect aspects of epigenetics (via histone deacetylation activity), metabolism, and cellular aging. In animal models of chronic stress, it is reported that there are reductions in sirtuin expression. Seven isoforms of sirtuins have been identified, of which select isoforms may be particularly pertinent to mood disorders (sirtuin-1).