Recent advances in Psychoneuroendocrinoimmunology have suggested that the serotonin deficiency associated with depression is the simple consequence of an enhanced activity of indole-2,3-dioxygenase (IDO), which transforms tryptophan into kynurenine instead of serotonin. Moreover, kynurenine, in addition to its neurotoxic action, has been shown to play an immunosuppressive activity by activating regulatory T lymphocytes (T reg). IDO expression is stimulated by IL-17, whose brain production appears to be under the regulatory control of the ACE-ACE2 system. An increased expression of ACE over ACE2 allows enhanced production of angiotensin II (Ang II) instead of angiotensin 1-7 (Ang 1-7). Ang II stimulates IL-17 secretion from glial cells, and IL-17 promotes the release of other inflammatory cytokines, including IL-1beta and IL-6, which may finally activate the pituitary-adrenal axis, resulting in enhanced cortisol secretion. On the contrary, Ang 1-7 appears to inhibit both IDO expression and IL-17 secretion, with a consequent anti-neuroinflammatory activity.
The study included 30 consecutive patients diagnosed with depression according to Hamilton’s score (severe grade: 12; moderate grade: 10; low grade: 8), who were less responsive to classical antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs). A relatively rapid improvement in mood was achieved within the first month of therapy in 26/30 (85%) patients, with complete normalization of the Hamilton score in 5/30 (20%) patients. No therapy-related toxicity occurred. On the contrary, most patients reported relief from anxiety and an improvement in sleep quality.
Furthermore, the results were compared to those observed in a historical control group of 20 depressed patients less responsive to SSRIs, who received monoamine oxidase inhibitors (MAO) as second-line therapy. A clear benefit with a decline in Hamilton’s score greater than 30% was achieved in only 5/20 (25%) patients. These results were significantly lower compared to those found in patients treated with the neuroendocrine regimen.
This preliminary study suggests the possibility of treating human depression in a new manner, different from the classical serotonin therapy, consisting of exogenous correction of the main possible depression-related neuroendocrine deficiencies involving pineal function, cannabinoid system activity, oxytocin secretion, and the ACE2-Ang 1-7 axis. Further studies, detecting MLT, oxytocin, Ang 1-7, and FAAH, will be required to establish which neuroendocrine deficiency may particularly occur in each individual depressed patient.