Vol 4 n° 1 - Pathophysiology of Depression
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Substance   P   (for   “powder”),   identified   as   a   gut tachykinin in 1931 and involved in the control of multiple other autonomic functions, notably pain transmission, is the focus of intense fundamental and clinical psychiatric research as a central neurotransmitter, neuromodulator, and immunomodulator, along with sister neurokinins A and B (NKA and NKB), discovered in 1984. Substance P is widely  distributed  throughout  the  central  nervous  sys- tem,  where  it  is  often  colocalized  with  serotonin,  nor- epinephrine,  and  dopamine.  Many  neurokinin  (NK) receptor antagonists and agonists have been synthesized and  some  clinically  tested.  A  double-blind  study  of MK869, a selective NK1 receptor antagonist that blocks the action of substance P, showed significant activity ver- sus placebo and fewer sexual side effects than paroxetine in outpatients with major depression and moderate anx- iety. Substance P, which is degraded by the angiotensin- converting  enzyme  (ACE),  may  mediate  modulation  of therapeutic outcome in affective disorders by functional polymorphism within the ACE gene: the D allele is asso- ciated  with  higher  ACE  levels  and  increased  neuropep- tide  degradation,  with  the  result  that  patients  with major  depression  who  carry  the  D  allele  have  lower depression scores and shorter hospitalization. ACE poly- morphism genotyping might thus identify those patients with major depression likely to benefit from NK1 recep- tor antagonist therapy. n the 1960s, the first tricyclic antidepressant drugs were found to act by blocking the reuptake of the classical neurotransmitters serotonin (5-hydroxytrypt- amine [5-HT]) and norepinephrine (NE).1  Since then, these two monoamine neurotransmitters have been the focus of antidepressant drug research and the most com- mon pathophysiological concepts of major depression are  based  on  this  profile  of  antidepressant  action. Increasing knowledge has indicated that the modula- tion of monoamines is not the only mechanism for anti- depressant actions. Neuropeptides, which are colocal- ized with monoamines, could also be involved in the pathophysiology of depression. Substance P (SP), which was first detected 70 years ago, came into play in recent years. In 1998, there was an exciting report in the journal Science  by  Kramer  et  al  showing  the  antidepressant activity of an SP receptor antagonist.2 In the following, we will give a comprehensive overview of the nature of SP, the neuropeptide family it belongs to, and current data regarding the activity of SP receptor antagonists as psychotropic drugs. Substance P and the tachykinin family SP was the first known neuropeptide. Von Euler and Gaddum isolated SP from extracts of intestine and from brain as one of many substances. As it was in the pow- dered form, they named it substance P. In the first exper- iments, SP stimulated contractions of rabbit-ileum in an atropine-resistant manner. This first report on SP was published in 1931.3 In 1953, SP was recognized as a sen- sory neurotransmitter by Lembeck et al.4 It was more than 10 years later that SP was isolated from bovine Keywords: antidepressant drug; anxiolytic drug; neuropeptide; NK1 receptor antagonist; substance P; tachykinin Author affiliations: Department of Neurochemistry, Psychiatric Hospital, University of Munich, Germany
Address for correspondence:  M. Ackenheil, MD, Department of Neurochemistry, Psychiatric Hospital, University of Munich, Nussbaumstrasse 7, D-80336 Munich, Germany
(e-mail: ac@psy.med.uni-muenchen.de) 2 1 B a s i c   r e s e a r c h I The role of substance P in depression: therapeutic implications Markus J. Schwarz, MD; Manfred Ackenheil, MD Dialogues Clin Neurosci.  2002;4:21-29.