Journal of Psychopharmacology

Ito, Mototsugu; Walzer, Mark; Beth Blauwet, Mary; Spence, Anna; Heo, Nakyo; Kelsh, Debra; Blahunka, Paul; Erdman, Jay; Nour Alsharif, Mohamad; Marek, Gerard J

doi: 10.1177/02698811221149657pmid: 36738100

Background:There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD.Aims:To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®).Methods:In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1–4; maintenance, Days 5–18; downward titration, Days 19–26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK.Results:Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug–drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N.Conclusions:In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine.Trial registration:Clinicaltrials.gov identifier: NCT04447287.

Matuskey, David; Gallezot, Jean-Dominique; Nabulsi, Nabeel; Henry, Shannan; Torres, Kristen; Dias, Mark; Angarita, Gustavo A; Huang, Yiyun; Shoaf, Susan E; Carson, Richard E; Mehrotra, Shailly

doi: 10.1177/02698811221140008pmid: 36515395

Background:Centanafadine is an inhibitor of reuptake transporters for norepinephrine (NET), dopamine (DAT) and serotonin (SERT).Aims:This phase 1, adaptive-design positron emission tomography study investigated the occupancy time course of NET, DAT, and SERT and the relationship to centanafadine plasma concentrations.Methods:Healthy adult males received centanafadine sustained-release 400 mg/day for 4 days (N = 6) or 800 mg in a single day (N = 4). Assessments included safety monitoring; time course of occupancy of NET, DAT, and SERT; and centanafadine plasma concentrations.Results:Transporter occupancy was numerically higher for NET versus DAT or SERT. For NET, estimated (mean ± standard error [SE]) maximal observable target occupancy (TOmax) and concentration at half maximal occupancy (IC50) were 64 ± 7% and 132 ± 65 ng/mL, respectively, for all regions and 82 ± 13% and 135 ± 97 ng/mL after excluding the thalamus, which showed high nonspecific binding. For DAT and SERT, TOmax could not be established and was assumed to be 100%; estimated IC50 (mean ± SE) values were 1580 ± 186 ng/mL and 1,760 ± 309 ng/mL, respectively. For centanafadine, the estimated in vivo affinity ratio was 11.9 ± 6.0 (mean ± SE) for NET/DAT, 13.3 ± 7.0 for NET/SERT, and 1.1 ± 0.2 for DAT/SERT. DAT and SERT occupancies at a plasma concentration of 1400 ng/mL were estimated to be 47 and 44%, respectively.Conclusions:High occupancy at NET and moderate occupancy at DAT and SERT was observed at peak concentrations achieved following 400 mg total daily doses of centanafadine.

Wingelaar-Jagt, Yara Q.; Bottenheft, Charelle; Riedel, Wim J.; Ramaekers, Johannes G.

doi: 10.1177/02698811221142568pmid: 36515156

Background:Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue’s adverse effects, with modafinil as a promising alternative to caffeine. However, the effect of a single dose of modafinil after a limited period of sleep deprivation remains unknown.Aims:This study aims to determine the effect of 200 mg modafinil on vigilance during a limited period of sleep deprivation compared to 300 mg caffeine and placebo.Methods:Thirty-two volunteers of the Royal Netherlands Air Force (RNLAF) were double-blindly administered modafinil, caffeine, and placebo on three non-consecutive trial days after being awake for median 17 h. Afterwards, subjects completed six series of the Vigilance and Tracking test (VigTrack), psychomotor vigilance task (PVT), and Stanford Sleepiness Scale (SSS), yielding six primary endpoints.Results:This study revealed statistically significant effects of caffeine and modafinil compared with placebo on all endpoints, except for VigTrack mean tracking error. PVT results were less impaired 2 h after administration, followed by VigTrack parameters and SSS scores 2 h thereafter. Compared with caffeine, modafinil significantly improved PVT and SSS scores at 8 h after administration.Conclusions:The present study demonstrates that 200 mg modafinil and 300 mg caffeine significantly decrease the effects of a limited period of sleep deprivation on vigilance compared with placebo. Although PVT parameters already improved 2 h after administration, the most notable effects occurred 2–4 h later. Modafinil seems to be effective longer than caffeine, which is consistent with its longer half-life.

Redding, Zach V; Sabol, Karen E

doi: 10.1177/02698811221149652pmid: 36648101

Background:Goal-directed attention involves the selective processing of behaviorally relevant sensory information. This selective processing is thought to be supported by glutamatergic and noradrenergic systems. Pharmacotherapies that simultaneously target these systems could therefore be effective treatments for impaired attention.Aims:We first tested an N-methyl-D-aspartate (NMDA) receptor co-agonist (D-serine) for effects on attention (processing speed and attentional lapses). NMDA receptor activation is thought to support noradrenergic effects on sensory processing; therefore, we tested a combination treatment comprising D-serine and a norepinephrine reuptake inhibitor (atomoxetine).Methods:D-serine was first tested in rats performing a two-choice visuospatial discrimination task. Combination treatments comprising relatively low doses of D-serine and atomoxetine were then tested in a separate group.Results:In experiment 1, D-serine reduced the skew of initiation time (IT) distributions (IT devmode) at the highest dose tested (300 mg/kg). In experiment 2, low-dose D-serine (125 mg/kg) had no effect, while low-dose atomoxetine (0.3 mg/kg) reduced IT devmode and slowed movement speed. Importantly, the combination of these relatively low doses of D-serine and atomoxetine reduced IT devmode more than either drug alone without further slowing movement speed.Conclusions:IT devmode is thought to reflect attentional lapses; therefore, D-serine’s effects on IT devmode suggest that NMDA receptors are involved in the preparatory deployment of attention. Greater effects following a combination of D-serine and atomoxetine suggest that preparatory attention can be facilitated by targeting glutamatergic and noradrenergic systems simultaneously. These results could inform the development of improved treatments for individuals with ADHD who experience abnormally high attentional lapses.

Hahl-Häkkinen, Lydia; Rask, Susanna Maria; Solismaa, Anssi; Ruuhonen, Sanna; Leinonen, Esa

doi: 10.1177/02698811221148611pmid: 36703576

Background:Alcohol use disorder (AUD) is a significant co-morbidity in patients with schizophrenia. Clozapine offers some benefits in treating patients with refractory schizophrenia and AUD, but co-medicating with disulfiram is also common.Procedures:We report two cases where co-medicating with disulfiram led to a significant increase in clozapine serum levels.Findings:Clozapine serum levels decreased to one-third in Patient 1 when disulfiram was discontinued and started to increase again when disulfiram was reintroduced. Patient 2 developed toxic serum levels of clozapine during disulfiram treatment combined with heavy coffee drinking and symptoms reminiscent of neuroleptic malignant syndrome.Conclusions:Clozapine and disulfiram are both metabolized by cytochrome P450 CYP1A2 and clinically relevant interaction through this shared pathway is possible.