aprepitant and Depressive-Disorder

NK1 receptor antagonists were abandoned despite antidepressant efficacy in five randomized clinical trials. The loss of confidence may be attributed to the failure of a Phase III clinical program with the NK1 receptor antagonist aprepitant in Major Depression. This review examines how PET receptor occupancy was used to select doses for aprepitant and that these may not have achieved adequate exposure.. PubMed, Google Scholar, and FDA databases were searched for articles concerning NK1 receptor antagonists, human PET receptor occupancy and clinical trials in Major Depression.. Antidepressant efficacy was initially demonstrated with three NK1 receptor antagonists, including aprepitant. A nanoparticle formulation of aprepitant was then developed to improve oral bioavailability. In PET studies, doses of 80 and 160mg achieved a high level (~ 90%) of occupancy of NK1 receptors in the human brain and were selected for Phase III. The efficacy of these doses of the nanoparticle formulation may not have been established in depressed patients prior to Phase III, and previous formulations required a dose of 300mg of aprepitant for efficacy. No antidepressant effect of 80 or 160mg of aprepitant was found, and it was concluded that the NK1 antagonist concept was flawed. However, subsequent studies with other compounds showed that a higher level of NK1 receptor occupancy (100%) was required for antidepressant efficacy.. Key data concerning the bioequivalence of different formulations of aprepitant have not been published. The importance of NK1 antagonists for pharmacotherapy of depression and other psychiatric disorders has not been established in clinical practice.. Aprepitant may have failed in Phase III because of an inadequate understanding of the relationship between brain NK1 receptor occupancy and clinical response. A validated and novel mechanistic approach to treat depression has been misperceived as ineffective and abandoned. Caution should be exercised in the appropriate use of PET occupancy data to select doses for drug development programs in neuropsychiatry. The relationship between exposure, receptor occupancy and clinical response should be established. A crisis of confidence has followed the failure of this and other programs in neuropsychiatry, with a far reaching and detrimental impact on pharmaceutical research.

Topics: Antidepressive Agents; Aprepitant; Brain; Clinical Trials, Phase III as Topic; Depressive Disorder; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Treatment Failure

Substance P (SP)-neurokinin-1 (NK1) receptor pathways have been implicated in the pathophysiology of emesis and depression. Autoradiographic studies in monkey and human brains have shown a high expression of NK1 receptors in regions important for the regulation of affective behaviors and the neurochemical response to stress. Furthermore, clinical studies demonstrated that treatment with the SP (NK1 receptor) antagonist (SPA) aprepitant (also known as MK-0869) significantly improves depression symptoms and reduces the incidence of chemotherapy-induced nausea and vomiting. An important objective of all neuroscience drug discovery and development programs is to establish the correlation between dose, receptor occupancy, and the observed clinical effect (the dose-response relationship). These goals can be achieved using radioactive receptor-specific tracers and dynamic noninvasive brain imaging modalities, such as positron emission tomography (PET). In the SPA program, a tracer [18F]SPA-RQ was chosen for PET studies on the basis of several criteria, including high affinity for the NK1 receptor, low nonspecific binding, and good blood-brain barrier penetration. PET imaging studies in rhesus monkeys and humans confirmed these tracer features and established the usefulness of this probe for in vivo NK1 receptor occupancy studies. Subsequent PET occupancy studies in humans predicted that very high levels of central NK1 receptor occupancy (> 90%) were associated with therapeutically significant antidepressant and antiemetic effects. Future PET imaging studies will focus on quantification of NK1 receptor expression in depressed patients, both before and after successful treatment with antidepressants.

Topics: Animals; Aprepitant; Autoradiography; Brain; Brain Mapping; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Guinea Pigs; Humans; Iodine Radioisotopes; Macaca mulatta; Morpholines; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Substance P; Tomography, Emission-Computed

Substance P (NK1 receptor) antagonists (SPAs) are currently the best validated and clinically most advanced novel approach to treating major depressive disorder (MDD), and several compounds are in advanced clinical development. Three years since the discovery of the antidepressant efficacy of MK-869 (Merck & Co Inc), the first in a new class of drugs that act by selectively blocking the actions of substance P, the principle that blocking the NK1 receptor can alleviate major depression has recently been replicated in a placebo-controlled, blinded study. SPAs are active in a range of preclinical assays that detect clinically used antidepressant drugs, but they have a pharmacological profile that is distinct from established drugs. There is preliminary evidence that substance P and NK1 receptor density may be altered in MDD, suggesting a possible link between substance P and depressive pathophysiology. Studies in animals indicate that the psychotherapeutic effects of SPAs may be mediated at least partly through stimulation of hippocampal neurogenesis, by direct blockade of NK1 receptors in the amygdala and its associated output projections, and also via interactions with monoamines. Additional studies are needed to explore these hypothesesfurther.

Topics: Animals; Antidepressive Agents; Aprepitant; Clinical Trials as Topic; Depressive Disorder; Drug Evaluation, Preclinical; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Stress, Physiological; Substance P; Treatment Outcome

Substance P (SP) belongs to the neurokinin (NK) family of neuropeptides and exerts its biological effects via interaction with the NK1 receptor. The SP-NK1 receptor system is one of the best-characterized neurotransmitter pathways in both the central and peripheral nervous systems. It has been postulated that this pathway may have important roles in a variety of centrally regulated pathophysiologic conditions, including depression. In animal models, central injection of SP was associated with a series of anxiety-like behaviors, and this response could be abolished by pretreatment with SP (NK1) receptor antagonists (SPAs). On the basis of these and other encouraging preclinical results, several clinical trials have examined the potential of SPAs in the treatment of depression. In phase 2 trials, therapy with the SPAs aprepitant (MK-0869) and compound A resulted in improvements in depression and anxiety symptoms that were quantitatively comparable with those seen with selective serotonin reuptake inhibitors (SSRIs) and significantly greater than those seen with placebo. These positive results have established a proof of concept that the inhibition of the SP-NK1 receptor pathway may be a potentially useful novel treatment option for management of patients with depression. The apparent lack of benefit with SPAs versus placebo in subsequent dose-finding studies with aprepitant and compound A is not surprising, considering the fact that the outcomes with an active control (SSRI) in these trials were also similar to those observed with placebo. Future trials with SPAs will focus on the identification of appropriate patients and drug regimens and will also define the role of these agents in the treatment of depression.

Topics: Antidepressive Agents; Anxiety Disorders; Aprepitant; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Ethers; Female; Humans; Hydrocarbons, Fluorinated; Male; Morpholines; Neurokinin-1 Receptor Antagonists; Paroxetine; Placebos; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Substance P; Treatment Outcome

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Topics: Adolescent; Adult; Aged; Amygdala; Animals; Antidepressive Agents, Second-Generation; Aprepitant; Behavior, Animal; Brain; Depressive Disorder; Female; Gerbillinae; Guinea Pigs; Humans; Male; Middle Aged; Morpholines; Neurokinin-1 Receptor Antagonists; Norepinephrine; Paroxetine; Receptors, Neurokinin-1; Serotonin; Stress, Psychological; Substance P; Vocalization, Animal

Topics: Antidepressive Agents, Second-Generation; Anxiety Disorders; Aprepitant; Depressive Disorder; Double-Blind Method; Humans; Morpholines; Paroxetine; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Substance P

Based upon animal experiments and early clinical trials, neurokinin-1 receptor antagonists showed promise as novel antidepressants. Subsequently, however, more extensive clinical trials did not reveal evidence of efficacy in depression. The development of novel antidepressants will require a better understanding of the neural basis of antidepressant action in humans.

Topics: Animals; Antidepressive Agents; Aprepitant; Clinical Trials as Topic; Depressive Disorder; Drug Design; Humans; Models, Animal; Morpholines; Neurokinin-1 Receptor Antagonists; Substance P

Novel antiemetic agents such as the newly approved aprepitant (Emend) target receptors for substance P, known as neurokinin-1 (NK(1)) receptors. When NK(1) receptors are blocked in the vomiting center of the brainstem, chemotherapy-induced emesis is reduced. It is possible that blocking NK(1) receptors elsewhere in the CNS will lead to therapeutic actions in depression and other stress-related disorders.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Area Postrema; Brain Stem; Depressive Disorder; Humans; Morpholines; Receptors, Neurokinin-1; Serotonin; Solitary Nucleus; Stress Disorders, Traumatic; Substance P; Vomiting

Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Aprepitant; Depressive Disorder; Double-Blind Method; Humans; Meta-Analysis as Topic; Monoamine Oxidase Inhibitors; Morpholines; Placebos; Psychopharmacology; Randomized Controlled Trials as Topic; Research Design; Selective Serotonin Reuptake Inhibitors; Substance P

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Aprepitant; Brain; Clinical Trials, Phase II as Topic; Depressive Disorder; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Substance P