Introduction
neuroinflammation, unipolar and bipolar mood disorders, mood disorders, ’s mood, MDD, depression
TSD, PATHOLOGY, PATHOPHYSIOLOGY
The purine P2X7 receptor (P2X7R) is one of seven identified subtypes of adenosine triphosphate (ATP)-gated P2X ion channels present on various human cell types. The P2X7R is predominantly expressed in central nervous system (CNS) in microglial cells and peripherally in monocytes [Several lines of evidence implicate neuroimmune mechanisms in the pathophysiology of mood disorders [Because of the well-documented role of the P2X7R in IL-1β release, it is hypothesized that P2X7R antagonists may be beneficial for depression associated with neuroinflammation. Iwata and colleagues were the first to show that chronic stress in rodents results in the activation the P2X7R and NLRP3 inflammasome-related release of IL-1β in hippocampus [Currently, a number of CNS-penetrant high affinity and selective P2X7R antagonists, such as JNJ-54175446 and JNJ-55308942, are in development for the treatment of unipolar and bipolar mood disorders [In healthy human studies, JNJ-54175446 demonstrated blood-brain barrier penetration and a clear dose-receptor occupancy relationship in a range of 5–300 mg using positron emission tomography, and was safe and well tolerated [Since the P2X7R is activated under conditions of elevated neuronal activity and/or pathology, pharmacological antagonism is only expected to elicit an effect when the channels are activated by sufficiently high ATP concentrations [TSD and sleep restriction have been shown to increase ATP levels resulting in an increase of peripheral cytokine levels including IL-1β [Although data from both preclinical and healthy volunteer studies with IL-1β as peripheral pharmacological biomarker for P2X7R antagonism seem encouraging, JNJ-54175446’s mood modulating effects are yet to be established in a target patient population such as MDD. The use of TSD to produce a transient change in mood in patients with MDD conceivably may serve as a probe of the effect of a physiological stressor on mood. In this context JNJ-54175446 is expected to modulate and potentially reduce the effect of TSD on mood and mood-related phenomena. It was hypothesized that TSD-associated acute mood enhancement would be attenuated in MDD patients who had received JNJ-54175446 during the 3 days prior to the TSD challenge, as the acute effects of elevated cytokine levels would be blunted by JNJ-54175446. Conversely, if patients only received JNJ-54175446 The main objective of the current study was to investigate the safety and pharmacokinetics of JNJ-54175446 in MDD, as well as to perform a proof-of-concept exploration of its potential effects on mood-related phenomena by applying TSD in a relevant clinical population.