Article

Substance P receptor antagonists in psychiatry: Rationale for development and therapeutic potential

Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, Germany.
CNS Drugs (Impact Factor: 4.38). 02/2005; 19(4):275-93.
Source: PubMed

ABSTRACT Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects. Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are--at least partially--distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant. There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

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    • "Neurokinin (NK)1 receptors as target for anxiety disorders (Ebner et al., 2009; Griebel and Holmes, 2013; Herpfer and Lieb, 2005; Kwako et al., 2015; Mathew et al., 2011; Tauscher et al., 2010). "
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    • "Isolation-induced emotional stress and acute stress of foot shock both result in higher levels of SP in specific brain tissues (Mello et al., 2007; Ebner and Singewald, 2006; Hasen√∂hrl et al., 2000). In addition, the central administration of SP produces a range of fear-related behavior in rats (Herpfer and Lieb, 2005). In cerebrospinal fluid of the patients with depression, SP levels are significantly higher compared to healthy people (Geracioti et al., 2006). "
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    • "The initial interest in this neuropeptide and receptor family for mood and anxiety conditions reflected its extensive colocalization with monoamine neurotransmitters (Ebner et al, 2004) and abundant expression in stress neural circuitry. Genetic or pharmacologic blockade of NK-1 receptors were observed to induce many of the same long-term neural effects as standard antidepressants on cell signaling molecules such as BDNF and hippocampal neurogenesis (Blier et al, 2004; van der Hart et al, 2005), providing the rationale for experimental therapeutic trials in mood and anxiety disorders (Herpfer and Lieb, 2005). Despite the promising preclinical data, a recent pooled analysis of five 8-week randomized, doubleblind , placebo-controlled, multicenter studies of the NK-1 receptor antagonist aprepitant in over 2500 patients with major depression failed to demonstrate efficacy (Keller et al, 2006). "
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