Vol 4 n° 4 - Drug Development
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Interaction between the serotonergic system and HPA and HPT axes in patients with major depression: implications for pathogenesis of suicidal behavior Fabrice Duval, MD; Marie-Claude Mokrani, PhD; José Monreal, MD; Thomas Weiss, MD; Said Fattah, MD; Béatrice Hamel, PhD; Jean-Paul Macher, MD etrospective  studies,  using  prolactin  (PRL) response to d-fenfluramine test (d-FEN; a presynaptic serotonin  [5-hydroxytryptamine,  5-HT]–releasing  and –uptake-inhibiting agent), have suggested that reduced serotonergic functioning may be a marker of increased sui- cide risk in patients with major depression1 and schizo- phrenia.2  The  etiology  of  this  abnormality  remains unknown, but it has been suggested3 that overactivation of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress, and the associated hypercortisolism, could directly induce changes in 5-HT pathways. Consequently, it has been hypothesized that 5-HT abnormality in patients with a history of suicidal behavior could be secondary to hyper- activity of the HPA axis. Keywords: serotonin; dopamine; d-fenfluramine test; thyrotropin-releasing hormone test; dexamethasone suppression test; depression; suicide Author  affiliations:  FORENAP,  Institute  for  Research  in  Neuroscience  and Neuropsychiatry, Rouffach, France Address   for   correspondence:   Dr   Fabrice   Duval,   FORENAP,   Institute   for Research in Neuroscience and Neuropsychiatry, BP29, 68250 Rouffach, France
(e-mail: fduval@forenap.asso.fr) B a s i c   r e s e a r c h 4 1 7 R Disturbances in the serotonin (5-hydroxytryptamine, 5-HT) system constitute the neurobiological abnormality most con- sistently associated with suicide. This abnormality could be a marker of vulnerability predisposing individuals to auto- aggressive and impulsive behavior. However, other abnormalities, such as hyperactivity of the hypothalamic-pituitary- adrenal (HPA) axis, have also been described in suicide victims. While inhibitory effects of adrenocorticosteroids on 5-HT1A receptor function have been shown in animals, HPA axis hyperactivity does not seem to be responsible for the reduced 5- HT activity found in depressed patients with a history of suicidal behavior. On the other hand, hypothalamic-pituitary- thyroid (HPT) axis dysfunction, frequently observed in depression, may represent a compensatory response to reduced central 5-HT neurotransmission. Moreover, in depressed patients with a history of suicidal behavior, the absence of a func- tional link between HPT and dopamine activity at the hypothalamic level may be implicated in the pathophysiology of suicidal behavior. Future research is needed to determine why compensatory mechanisms are not efficient in patients with suicidal behavior. Dialogues Clin Neurosci. 2002;4:417-425.