JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1 & beta;/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin ... Show moreJNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1 & beta;/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1 & beta; release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1 & beta; release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT). Show less
Gross, J.A.J.; Faber, N.S.; Kappes, A.; Nussberger, A.M.; Cowen, P.J.; Browning, M.; ... ; Dreu, C.K.W. de 2021
Helping other people can entail risks for the helper. For example, when treating infectious patients, medical volunteers risk their own health. In such situations, decisions to help should depend... Show moreHelping other people can entail risks for the helper. For example, when treating infectious patients, medical volunteers risk their own health. In such situations, decisions to help should depend on the individual's valuation of others' well-being (social preferences) and the degree of personal risk the individual finds acceptable (risk preferences). We investigated how these distinct preferences are psychologically and neurobiologically integrated when helping is risky. We used incentivized decision-making tasks (Study 1; N = 292 adults) and manipulated dopamine and norepinephrine levels in the brain by administering methylphenidate, atomoxetine, or a placebo (Study 2; N = 154 adults). We found that social and risk preferences are independent drivers of risky helping. Methylphenidate increased risky helping by selectively altering risk preferences rather than social preferences. Atomoxetine influenced neither risk preferences nor social preferences and did not affect risky helping. This suggests that methylphenidate-altered dopamine concentrations affect helping decisions that entail a risk to the helper. Show less
Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether... Show moreOver the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N=272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias. Show less
Over the past three decades, functional MRI (fMRI) has become key to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into... Show moreOver the past three decades, functional MRI (fMRI) has become key to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (n = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (n = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared to full in-person psychiatric screening), recruited at least partly from convenience samples (compared to community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias. Show less
