Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations

Based upon animal experiments and early clinical trials, neurokinin-1 receptor antagonists showed promise as novel antidepressants.Subsequently, however, more extensive clinical trials did notreveal evidence of efficacy in depression. The developmentof novel antidepressants will require a better understandingof the neural basis of antidepressant action in humans.

INTRODUCTION

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INTRODUCTION

For the past 50 years the pharmacological treatment of depressionhas rested on the use of drugs that potentiate the activityof monoamines, particularly serotonin (5-hydroxytryptamine;5-HT) and noradrenaline. Both the tolerability and efficacyof current treatment is limited and there has been much effortto invent antidepressant agents with different modes of actionand improved therapeutic profile. The difficulties confrontingthose engaged in this task are well illustrated by the clinicaldevelopment of neurokinin-1 (NK₁) receptor antagonists.

SUBSTANCE P AND NK₁ RECEPTORS

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SUBSTANCE P AND NK1...

Substance P is a neuropeptide that acts as a neurotransmitteror neuromodulator within both the central and peripheral nervoussystems by preferentially binding to the NK₁ receptor. In manybrain regions it acts as a co-transmitter with ‘classical’monoamine neurotransmitters such as 5-HT and noradrenaline.A number of findings from animal studies are consistent withthe notion that substance P and NK₁ receptors might be implicatedin the pathophysiology of depression (Kramer et al, 1998).First, NK₁ receptors are found in brain regions that are implicatedin the regulation and expression of emotion, including the hippocampus,amygdala, prefrontal cortex and ventral striatum. Second, a variety of emotionally unpleasant stimuli, including foot-shock,pain, immobilisation and maternal separation increase substanceP concentrations in limbic regions. Third, central administrationof substance P produces behavioural and cardiovascular responsesthat resemble those seen following stressful stimuli. Fourth,there is significant overlap between 5-HT and noradrenalinepathways and substance P in limbic brain areas, and repeated administration of traditional antidepressants leads to decreasedsynthesis of substance P in certain brain regions. Fifth, micein whom the NK₁ receptor has been knocked out are less anxious;for example, these mice exhibit greater exploration in theopen field test. In addition, NK₁ receptor knockout mice aremore active in the forced swim test, an effect similar to thatproduced by antidepressant treatment in wild-type mice (Santarelli et al, 2002).

There is little direct evidence in humans implicating substanceP in depression, but substance P levels may be increased incerebrospinal fluid in people with depression who are not onmedication (Geracioti et al, 2006). A post-mortem study of12 depression patients, 6 of whom had died by suicide, foundlowered NK₁ receptor numbers in the orbitofrontal cortex comparedwith controls (Stockmeier et al, 2002). This could be consistentwith increased release of substance P.

PRECLINICAL STUDIES OF NK₁ RECEPTOR ANTAGONISTS

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PRECLINICAL STUDIES OF NK1...

Non-peptide antagonists for the NK₁ receptor were discovered about 15 years ago and several highly specific ligands havebeen developed since. As expected, these drugs block the behaviouraleffects of centrally administered substance P as well as certainstress-related behaviours in which substance P has been implicated,for example, vocalisations by guinea pig pups separated fromtheir mothers (Kramer et al, 1998).

NK₁ receptor antagonists are active in several animal models designed to detect anxiolytic and antidepressant effects. Someanimal models of anxiety are based on unconditioned fear responses;these include the elevated plus maze or open field test, whichmeasure aversion of rodents to novel, brightly lit environments.Similar models examine anxiety produced by social interactionwith unfamiliar conspecifics or maternal separation. Other testsuse conditioned anxiety responses where a stimulus (for example,a light) becomes aversive through being paired with a mildelectric foot-shock. Conditioned anxiety models detect theeffects of standard anxiolytics such as benzodiazepines. NK₁receptor antagonists have been shown to have anxiolytic propertiesin the rodent elevated plus maze, rat social interaction testand fear-conditioning paradigms (see Ebner & Singewald, 2006).

Animal models are also used to detect potential antidepressantdrugs. Some of these tests (for example, tail suspension ofmice or the forced swim test in mice and rats) are used asassays which have proved sensitive to clinically establishedantidepressant drugs. Others, employing chronic environmental stressors, attempt to provide models of depression that havesome face validity for the human disorder and which shouldtherefore be sensitive to both established and novel antidepressantagents. For example, the chronic mild stress model in ratsuses a variety of modestly unpleasant environmental manipulations,including changes of temperature and periods of food and water deprivation, to produce a decrease in the consumption of sucrosesolution; this symptom is taken as an analogue of anhedoniaand is reversed by chronic treatment with antidepressant drugs.Social stress and setbacks are known to be associated withdepression in humans; therefore other animal models use stressfulsocial manipulations to produce behavioural deficits (for example, decreased scent marking by tree shrews) that are sensitiveto antidepressant administration. NK₁ receptor antagonistshave antidepressant properties in the chronic mild stress andsocial stress model as well as the forced swim and tail suspensiontests (Ebner & Singewald, 2006).

CLINICAL STUDIES OF NK₁ RECEPTOR ANTAGONISTS IN DEPRESSION

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CLINICAL STUDIES OF NK1...

Kramer et al (1998) studied the effect of an NK₁ receptor antagonist,MK-869 (aprepitant), in a 6-week trial in about 200 peoplewith major depression. Participants were randomly allocatedunder masked conditions to one of three treatments: aprepitant300 mg daily, paroxetine 20 mg daily and placebo. Both aprepitantand paroxetine were significantly superior to placebo in lowering scores on the Hamilton Rating Scale for Depression (HRSD) andthe Hamilton Rating Scale for Anxiety. Both active treatmentswere of equal efficacy but aprepitant was better toleratedthan paroxetine, with increased levels of somnolence the onlyside-effect compared with placebo. In a further double-blindstudy of about 130 out-patients with melancholic depression, Kramer et al (2004) found that another NK₁ receptor antagonist(L-759274) also produced a significantly greater improvementin HRSD scores than placebo.

However, these compelling early findings were not supportedby subsequent investigations. Keller et al (2006) reportedresults from five randomised, double-blind, controlled studiesin over 2500 people with depression. They found that 8 weeksof treatment with aprepitant at doses of 80 mg and 160 mg showedno benefit over placebo. In contrast, paroxetine 20 mg daily,which was used as an active comparator in three of the fivestudies, was significantly better than placebo in each one.Positron emission tomography carried out at the same time indicatedthat both doses of aprepitant used in the trials would haveproduced high levels of central NK₁ receptor blockade withoccupancy with the 160 mg dose regime being over 95% (Keller et al, 2006).Given together with dexamethasone and a 5-HT₃ receptor antagonist,aprepitant is licensed at daily doses of 80–125 mg forthe prevention of chemotherapy-induced nausea and vomiting;this suggests that the doses employed in the clinical trialsof people with depression would have been pharmacologicallyactive.

CONCLUSIONS

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CONCLUSIONS

More effective and better tolerated antidepressant medicationsare badly needed for the management of major depression; however,the development of the NK₁ receptor antagonists as antidepressantsshows how formidable this task is. The NK₁ receptor antagonistaprepitant survived many hurdles at which candidate antidepressantdrugs may fall. Aprepitant appears safe and well toleratedand has suitable oral pharmacokinetics for the treatment ofdepression. Two early clinical trials suggested efficacy.

A somewhat later, but major problem in the development of antidepressant drugs is the high frequency of failed trials in major depression;that is studies where both an active comparator as well asthe compounds under investigation fail to show therapeuticbenefits over placebo. However, this was not the case in thestudies summarised by Keller et al (2006) in which the comparator drug paroxetine was indeed more effective than placebo. However,the problem seems to have been rather that the underlying conceptof NK₁ receptor antagonism as an antidepressant mechanism mayhave been mistaken.

A major underlying problem in the development of new antidepressantdrugs is the reliance on animal models to provide proof ofconcept because we lack valid animal models of depression.However, even with conditions such as head injury or neonatalrespiratory distress syndrome, which can be more closely modelledin animal studies, clear concordance between beneficial effectsof treatment in animals and patients is often lacking (Perel et al, 2007). We suggest that there is a need to develop new human modelsin which effects of potential antidepressants can be detected.This work requires a much better understanding of the interactionof antidepressant drugs with the neural circuitry involvedin emotional regulation, work which modern methods of brain imaging is beginning to make possible (see Norbury et al, 2007). In addition, with appropriate ethical safeguards it shouldbe possible to carry out proof of concept studies of potentialantidepressant agents in the most relevant participant groups;that is patients with depression or those at high risk (Bhagwagar et al, 2004).

The possible role of NK₁ receptor antagonists in the treatment of emotional disorders is still an area of active enquiry.The early clinical studies suggest that some people with depressionmay benefit, but identification of potential responders onclinical grounds alone seems unlikely to be successful. NK₁receptors have pharmacological interactions with 5-HT pathways,hence it is conceivable that NK₁ receptor antagonists mightaugment the therapeutic effects of selective serotonin reuptakeinhibitors in depressive and anxiety disorders (Ebner & Singewald, 2006). Finally it is probably easier to model anxiety than depressionin animals, albeit normal anxiety responses to stressors ratherthan true pathological states. As noted above there is muchevidence from animal studies that NK₁ receptor antagonistscould have anxiolytic effects and there are now clinical datasuggesting potential efficacy of another NK₁ receptor antagonist,GR205171, in patients with social phobia (Furmark et al, 2005). A number of other NK₁ receptor antagonists are still being investigated for their psychotropic potential.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

S.H. was an MRC Clinical Research Training Fellow and P.J.C.is an MRC Clinical Scientist.

REFERENCES

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