The degree of variability in the clinical presentation of major depressive disorder (MDD) has led to multiple suspected pathological mechanisms for the disease. The general consensus at this time is that interactions between genetics, neurobiology, and stress response are the basis for the disease. The strongest evidence lies in the neurobiological theory based on dysfunction of monoamine neurotransmitters. Research has shown moderate heritability of MDD, which will be covered. The third theory outlined will be dysfunction of the hypothalamic-pituitary-adrenal axis and its increased stress-like response.
Monoamine dysfunction is central to both the pathology and pharmacological treatment of MDD. Serotonin, norepinephrine, and dopamine, the monoamines of importance in MDD, have most of their receptors in the midbrain and brainstem nuclei making them central to regulation of mood, attention, reward processing, sleep, appetite, and cognition. The theory is based on a deficiency of these monoamines in the central nervous system (Hasler, 2010). Many depressive symptoms are directly related to the above mentioned brain areas and the functions they regulate, making the monoamine theory highly relatable to many MDD patients.
A genetic role in the development of MDD has been identified. The heritability is shown to be higher in females than males, and moderately significant in both genders. Multiple twin studies have shown the heritability to be approximately 41% and 29% in females and males respectively (Kendler, Gatz, Gardner, & Pederson, 2006).
The hypothalamic-pituitary-adrenal axis (HPA) is involved in the typical physiological adaptive response to stress. In MDD, HPA axis hyperactivity leads to oversecretion of corticotropin-releasing-factor, and in turn a decreased inhibitory effect of cortisol on the HPA axis. It is unclear whether HPA axis dysfunction is directly involved in the pathogenesis of MDD, but it can be confirmed that at a minimum it is involved in the creation of symptoms of the disease (Monteleone, 2001).
While the pathological mechanisms outlined above are only a small section of those that exist, they are all strongly supported by research. With the diverse range of presentation of MDD comes a diverse base of pathological theory. This is an important consideration when formulating a treatment regimen for those presenting with MDD.