Discussion
anhedonia, TSD, depressive symptoms, MDD, depression
TSD
This was the first study to investigate the safety and pharmacokinetics of the CNS penetrant and selective P2X7 receptor antagonist JNJ-54175446 in MDD, and to explore its potential effects on mood-related phenomena such as reward propensity and changes in peripheral cytokine production following TSD. Although healthy subjects had received single doses of JNJ-54175446 up to 600 mg [TSD was applied as a behavioral challenge to investigate whether its effects on mood and mood-related symptoms could be modulated by JNJ-54175446. TSD alleviated depressive symptoms on both self-reported and clinician rated rating instruments, which lasted until the last study day (day 10). Although this again confirms TSD as an adequate behavioral challenge paradigm to induce a rapid recovery from depressive symptoms, it conflicts with pre-existing literature reporting transient mood improvement that disappears after a single post-TSD night of recovery sleep [JNJ-54175446 demonstrated no effect on depressive symptoms when administered prior to TSD, suggesting that JNJ-54175446 does not produce rapidly-acting antidepressant effects. Furthermore, no significant effects of JNJ-54175446 were observed on mood improvement, which in all groups occurred after TSD and subsequently did not substantially change during the remainder of the study. However, the reduction in anhedonia observed (SHAPS) in the placebo group after recovery sleep was significantly attenuated by JNJ-54175446 in both the early (day 1) and late (day 4) starting groups. Since JNJ-54175446 was administered for the first time in the delayed group as a loading dose during the TSD procedure on the morning before the recovery sleep, this effect on hedonic capacity appeared to occur acutely, suggesting a stabilizing effect of JNJ-54175446 even after a single high dose on the anhedonia levels, such that they persisted during TSD. A similar pattern, although not statistically significant, was suggested by the total points lost on the PILT assessment of reward learning. This apparent mood stabilizing effect, which nevertheless blunted the beneficial effects of TSD on anhedonia, contrasts with the effects of P2X7R antagonism on stress-induced anhedonia seen in animal experiments, [Overall, there were no differences in levels of IL-1β in peripheral blood in response to JNJ-57417446 treatment as compared to placebo, which may reflect the multiple paths for releasing IL-1β that do not involve P2X7 receptors. However, JNJ-57417446 did decrease ex-vivo IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X7 receptor agonist BzATP. This provided proof of pharmacological activity in the blood, which considering the high blood-brain-barrier permeability of JNJ-57417446 is also likely to have occurred in the CNS.Several limitations were identified in this study. We observed a protracted effect of TSD on depression severity ratings in MDD patients and, as a consequence, could not determine a clear difference between and the placebo group and patients receiving a loading dose of JNJ-54175446 prior to the TSD recovery night. Although previous investigations suggested that combining TSD with bright light therapy is effective in sustaining its antidepressant effect [In conclusion, JNJ-54175446 was safe and well tolerated by MDD patients. In line with its pharmacological properties, JNJ-54175446 reduced IL-1β release from LPS-stimulated peripheral white blood cells in the presence of the P2X7R agonist BzATP. TSD (combined with light therapy) alleviated depressive symptoms on both self-reported and clinician rated rating instruments, which lasted until the end of the observation period (day 10). This is longer than previously reported in the literature, which may have prevented evaluation of any potential antidepressant effect of post-TSD administration of JNJ-54175446. However, the current study suggested that JNJ-54175446 at the relatively high exposures tested may blunt the reduction of anhedonia that occurs in MDD patients after TSD. These potential mood stabilizing effects on hedonic capacity warrant further exploration in future studies of the P2X7 antagonist mechanism.