Commentary: Building the developmental foundations of developmental computational psychiatry: reflections on Hauser et al. (2019).

There is a growing interest in applying the conceptual and analytical frameworks of computational psychiatry to developmental populations. This is motivated by appreciation that psychiatric illness needs to be understood from a neurodevelopmental perspective. The target article by Hauser and colleagues highlights progress in applying the computational psychiatry perspectives to identifying the developmental mechanisms of mental illness. We share the enthusiasm and optimism for this venture, while recognizing the substantial theoretical and pragmatic challenges associated with applying computational frameworks to developing populations. In this commentary, we highlight the ways that taking a developmental perspective in this arena stretches beyond merely identifying age differences in a computational parameter of interest. These include the need for experimental and computational frameworks to recognize that developmental changes can be quantitative or qualitative in nature, the need to consider developmental stage beyond age groupings or even numerical age, and the need for large quantities of data to model age-related changes in a reproducible manner. In doing so, we hope to stimulate progress in uncovering the mechanisms of psychiatric illness in a way that is developmentally informed.

Relaxation with Immersive Natural Scenes Presented Using Virtual Reality.

INTRODUCTION: Virtual reality (VR) can provide exposure to nature for those living in isolated confined environments. We evaluated VR-presented natural settings for reducing stress and improving mood. METHODS: There were 18 participants (9 men, 9 women), ages 32 ± 12 yr, who viewed three 15-min 360° scenes (an indoor control, rural Ireland, and remote beaches). Subjects were mentally stressed with arithmetic before scenes. Electrodermal activity (EDA) and heart rate variability measured psycho-physiological arousal. The Positive and Negative Affect Schedule and the 15-question Modified Reality Judgment and Presence Questionnaire (MRJPQ) measured mood and scene quality. RESULTS: Reductions in EDA from baseline were greater at the end of the natural scenes compared to the control scene (-0.59, -0.52, and 0.32 µS, respectively). The natural scenes reduced negative affect from baseline ( 1.2 and 1.1 points), but the control scene did not ( 0.4 points). MRJPQ scores for the control scene were lower than both natural scenes (4.9, 6.7, and 6.5 points, respectively). Within the two natural scenes, the preferred scene reduced negative affect ( 2.4 points) more than the second choice scene ( 1.8 points) and scored higher on the MRJPQ (6.8 vs. 6.4 points). DISCUSSION: Natural scene VR provided relaxation both objectively and subjectively, and scene preference had a significant effect on mood and perception of scene quality. VR may enable relaxation for people living in isolated confined environments, particularly when matched to personal preferences.Anderson AP, Mayer MD, Fellows AM, Cowan DR, Hegel MT, Buckey JC. Relaxation with immersive natural scenes presented using virtual reality. Aerosp Med Hum Perform. 2017; 88(6):520526.

The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase.

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once-daily 80-mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil.

BACKGROUND: Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinemia. To evaluate the effect of pivalate prodrug treatment on carnitine homeostasis, we administered a pivalate prodrug, cefditoren pivoxil, to healthy subjects and performed carnitine balance studies. METHODS: Cefditoren pivoxil was administered in one of two dosing regimens (200 mg cefditoren twice daily for 10 days or 400 mg cefditoren twice daily for 14 days) to gender-balanced groups of 15 subjects. Plasma and urine concentrations of carnitine, acetylcarnitine, pivaloylcarnitine, and total carnitine were quantified before, during, and after treatment. RESULTS: Plasma carnitine concentrations fell during cefditoren pivoxil dosing. The nadir in carnitine concentration was dependent on the dose of cefditoren and subject gender (decrease from 44.8 +/- 10.9 micromol/L to 9.2 +/- 1.9 micromol/L in male patients and from 32.5 +/- 5.4 micromol/L to 6.3 +/- 1.7 micromol/L in female patients after 14 days of 400 mg cefditoren twice daily). Urinary elimination of pivaloylcarnitine resulted in a marked increase in total carnitine excretion, as well as net losses of total carnitine of approximately 4.6 mmol with the 200-mg, 10-day regimen and up to 14.9 mmol with the 400-mg, 14-day regimen. Pivaloylcarnitine was the dominant form of excreted pivalate. DISCUSSION: Short-term administration of cefditoren pivoxil results in hypocarnitinemia and increased net losses of total carnitine. It is estimated that net carnitine losses were only 10% of body stores, even with the highest dose regimen tested. Losses of this magnitude would not be anticipated to result in adverse clinical effects.

Assay of TNP-470 and its two major metabolites in human plasma by high-performance liquid chromatography-mass spectrometry.

In this study, a sensitive, specific assay for the determination of TNP-470 and its two major metabolites M-IV (also know as AGM-1883) and M-II in human plasma is reported. The assay involves liquid-liquid extraction of acidified plasma followed by reversed-phase high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. A liquid-liquid extraction using an organic solvent mixture (methyl-tert-butyl-ether-hexane, 1:1, v/v) is used in place of solid-phase extraction because it provides consistent recoveries for all analytes, including the internal standard. Retention times for the analytes and internal standard are less than 7 min. Within- and between-day precision is < or = 6.5% and < or = 13.3% relative standard deviation, respectively, for the three analytes. The lower limits of quantitation are 0.25, 0.5, and 1.0 ng/mL for TNP-470, M-IV, and M-II, respectively.

Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment.

To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.73 m), or severe renal impairment (n = 7, CLcr 10-29 mL/min/1.73 m). The pharmacokinetics of febuxostat and its active quantifiable metabolites 67M-1, 67M-2, and 67M-4 as well as the pharmacodynamics of uric acid, xanthine, and hypoxanthine were determined in plasma (or serum) and urine. Febuxostat was safe and well tolerated. Regression analyses indicated that febuxostat tmax and Cmax,u values were not affected by CLcr. However, for AUC24,u, CLu/F, and t1/2z, regression analyses indicated a statistically significant relationship with CLcr. With the exception of 67M-1 Cmax, regression analyses for 67M-2 and 67M-4 Cmax, and for AUC24 for all 3 metabolites indicated a statistically significant linear relationship with CLcr. Irrespective of renal function group, the mean serum uric acid concentrations decreased by 55% to 64% by day 7. Although plasma exposure to febuxostat and its metabolites was generally higher in subjects with increasing degrees of renal impairment, the percentages of decrease in serum uric acid were comparable regardless of the renal function group. A once-daily 80-mg dose of febuxostat appears to be safe and well tolerated in different renal function groups and does not appear to require any dose adjustment based on differences in renal function.