David Walling

Refining quality of life: validating a multidimensional factor measure in the severe mentally ill.

Quality of life measurement has historically been characterized by a focus on physical functionality, great variability in definitions and insufficient attention to psychometric properties of measures. The present study examined four core subscales of the Quality of Life Enjoyment Scale (Q-LES-Q) designed to assess subjective quality of life (i.e. physical health, subjective feelings, leisure activities and social relationships) administered to 151 male and female subjects with severe mental illness admitted to a residential community treatment center or a university psychiatric hospital. The use of factor analysis is a common approach to examining construct validity of instruments through the examination of correlated clusters of item responses. Those sets of highly correlated item responses should identify a construct or dimension of related items (i.e. a factor). Two factor approaches, exploratory (i.e. the maximum number of possible factors is unspecified) and restricted (i.e. the maximum number of factors allowed is specified), were employed to examine construct validity of the four Q-LES-Q subscales. In addition, both orthogonal (i.e. independence between factors is maximized) and oblique (i.e. correlated factors are allowed) rotations (arrangements) of factor structure were also investigated to define subscale validity further. Results supported good construct validity for each subscale with either factor approach, i.e. the four proposed subscales were clearly identifiable in the factors (groupings) of correlated item responses from the sample. In both cases, the orthogonal (independent) rotation produced the simplest structure, i.e. the clearest groupings of items. These results indicate that the Q-LES-Q does appear to measure valid dimensions matching those proposed by the subscales and, thus, may be a useful and reliable tool for clinical applications. Qual. Life Res. 8:151–160

Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

Abstract To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1–6; days, 1–5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from −4.62 to 8.05 mm Hg, −3.67 to 4.43 mm Hg, and −3.57 to 14.43 beats per minute for placebo and −3.83 to 11.25 mm Hg, −1.55 to 5.80 mm Hg, and −0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.

Scope of hypnosis education in academia : Results of a national survey

The present article examines the current status of hypnosis training and the attitudes of program chairs toward inclusion of such training in doctoral education. A brief survey on hypnosis training was sent to all psychology doctoral programs accredited by the American Psychological Association (n = 218) as well as 24 nonaccredited doctoral programs. Twenty-six percent of responding programs (n = 44/170) report offering either required or elective coursework in hypnosis. Of those programs offering a course in hypnosis, the mean semester credit hours earned was 3. Although many program directors support opportunities for hypnosis education in doctoral education, other constraints (e.g., available faculty, required coursework) limit its availability.

The Emperor's Clothes: Assessing the Validity of Scores on the Tennessee Self-Concept Scale

In 1985, Tzeng, Maxey, Fortier, and Landis conducted an extensive psychometric study of the Tennessee Self-Concept Scale (TSCS) and reported a systematic failure to validate the factor structure of either the eight clinical scales or the two global internal/external scales. Despite these findings, the TSCS has continued to be used in both clinical and research settings to investigate facets of the self-concept. One possible limitation of the Tzeng et al. study was the inherent heterogeneity in the three samples used, which could have masked factor structures. To investigate whether this was the case, the present study replicated the psychometric analyses in a homogeneous sample of female nursing and medical educators from a health science center and university in the Southwest. Results strongly mirrored the findings of Tzeng et al., challenging the proposed theoretical structure while supporting the reliable measurement of some, as yet unclear, dimension by the present instrument. Implications for the use of the TSCS as it now stands are discussed.

Effect of pomaglumetad methionil on the QT interval in subjects with schizophrenia.

OBJECTIVE This thorough QT/QTc (TQT) study assessed the effects of a supratherapeutic dose of pomaglumetad methionil, a potential treatment for schizophrenia, compared to placebo on the QT interval in subjects with schizophrenia. METHODS This double-blind, 3-period crossover study enrolled 86 subjects aged 22 - 63 years, who met Diagnostic and Statistical Manual, Fourth Edition, Test Revision (DSM-IV-TR) criteria for schizophrenia; 78 subjects completed the study. Subjects were randomly assigned to sequences of 3 treatment periods of single oral doses of pomaglumetad methionil 400 mg, moxifloxacin 400 mg, and placebo. Quadruplicate electrocardiograms (ECGs) were extracted from 2 hours predose to 12 hours postdose and were overread by a blinded central reader. Time-matched pharmacokinetic (PK) parameters were assessed. RESULTS At all-time points, the upper bound of the 90% 2-sided confidence interval (CI) for the least squares (LS) mean difference in changes from baseline in Fridericias corrected QT interval (ΔQTcF) between pomaglumetad methionil and placebo was < 10 milliseconds (msec). Sufficient assay sensitivity was not achieved, likely due to food effect; although the maximum observed drug concentration (Cmax) with moxifloxacin (1,410 ng/mL) was lower than expected, the slope of the regression line of moxifloxacin plasma concentrations versus placebo-subtracted ΔQTcF was similar to that reported in the literature. CONCLUSIONS A single supratherapeutic dose of 400 mg pomaglumetad methionil did not prolong QTcF to a clinically significant degree and, importantly, did not result in any absolute QTcF > 450 msec or increase in QTcF from predose > 30 msec.

Paliperidone palmitate once-monthly maintains improvement in functioning domains of the Personal and Social Performance scale compared with placebo in subjects with schizoaffective disorder

OBJECTIVE Evaluate the effect of paliperidone palmitate once-monthly (PP1M) injectable on the specific functioning domains of the Personal and Social Performance (PSP) scale in patients with schizoaffective disorder (SCA) participating in a long-term study. METHODS This study (NCT01193153) included both in- and outpatient subjects with SCA experiencing an acute exacerbation of psychotic and mood symptoms. Subjects were treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers during a 25-week open-label (OL) phase. Stabilized subjects were randomly assigned 1:1 (PP1M or placebo) into a 15-month double-blind (DB) relapse-prevention period. Functioning of the randomized subjects during OL and DB phases was evaluated using the PSP scale (four domains: socially useful activities, personal/social relationships, self-care, and disturbing/aggressive behaviors). Three statistical approaches were utilized to analyze PSP scores to assess robustness and consistency of findings. No adjustments were made for multiplicity. RESULTS 334 of 667 enrolled subjects were stabilized with PP1M, randomly assigned to PP1M (n=164) or placebo (n=170) in the DB phase, and included in this analysis. Improvements in all PSP domain scores were observed during the OL phase and were maintained during the DB phase with PP1M, but decreased with placebo. Differences compared to placebo were significant in all four PSP domains during the DB phase (P≤0.008). CONCLUSION The analysis in this study showed that PP1M improves functioning, as measured by the four PSP domain scores, in symptomatic subjects with SCA. Functioning was maintained compared with placebo.

Paliperidone Palmitate Once-monthly Injectable Treatment for Acute Exacerbations of Schizoaffective Disorder

Abstract The optimal treatment for schizoaffective disorder (SCA) is not well established. In this initial 6-month open-label treatment period of a large, multiphase, relapse-prevention study, the efficacy and safety of paliperidone palmitate once-monthly (PP1M) injectable were evaluated in subjects with symptomatic SCA. Subjects with acute exacerbation of SCA (ie, with psychotic and either depressive and/or manic symptoms) were enrolled and treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers (combination therapy group). After flexible-dose treatment with PP1M for 13 weeks, stabilized subjects continued into a 12-week fixed-dose PP1M treatment period. A total of 667 subjects were enrolled; 320 received monotherapy and 347 received PP1M as combination therapy; 334 subjects completed the entire 25-week treatment. Statistically significant and clinically meaningful improvements from baseline were observed for all efficacy measures in psychosis (per Positive and Negative Syndrome Scale), mood symptoms (per Young Mania Rating Scale and Hamilton Depression Rating Scale—21 items), and functioning (per Personal and Social Performance Scale) from week 1 to all time points during the 25-week treatment period (P < 0.001). Similar improvements in efficacy measures were observed between subjects receiving monotherapy or combination therapy. Efficacy benefits persisted throughout the 25-week period. The most common adverse events were akathisia (11.1%), injection-site pain (10.6%), and insomnia (10.0%). Paliperidone palmitate once-monthly administered as monotherapy or in combination with mood stabilizers or antidepressants in patients with an acute exacerbation of SCA provided rapid, broad, and persistent reduction in psychotic, depressive, and manic symptoms, as well as improved functioning.

T66. PSYCHOMETRIC VALIDATION OF A NOVEL PATIENT-REPORTED OUTCOME MEASURE FOR ASSESSING PATIENTS’ SUBJECTIVE EXPERIENCE OF COGNITIVE IMPAIRMENT OF SCHIZOPHRENIA (PRECIS)

Abstract Background We have previously described the development and content validity of a new patient-reported outcome measure (PRO) to assess patients’ subjective experience of cognitive impairment in schizophrenia: The Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS). Here we assess the psychometric properties of the PRECIS PRO in patients with schizophrenia and healthy age-matched controls with the aim of developing a revised version for use in clinical studies. Methods The PRECIS PRO is a 35-item scale comprising eight concept domains (memory, communication, control, planning, handling problems, attention, sharp thinking and overall experience), each with multiple individual items. PRECIS was administered to psychiatrically-healthy controls (single visit), and a subset of patients in a large, clinical trial assessing patients with schizophrenia on stable antipsychotic treatment (NCT02281773) at baseline and Weeks 6, 9 and 12. Analysis of the original 35-item PRECIS PRO included factor structure, factor analysis (FA), internal consistency, test-retest reliability and discriminant (known groups) validity testing. FA was performed on all pre-treatment scores in the patient group (n=410) and patients and controls combined (n=498). Individual items with less than adequate reliability or validity were then identified and eliminated or modified. Results Questionnaire responses were collected from 410 patients with schizophrenia and 88 healthy controls. The mean (standard deviation [SD]) total PRECIS score was significantly lower for healthy controls (1.39 [0.7]) compared with patients (2.06 [1.2]; p<0.0001), as was overall experience domain score (1.41 [0.7] vs 2.35 [1.3]; p<0.0001). For each domain of patient experience, PRECIS mean scores were also significantly lower for healthy controls compared to patients with schizophrenia. The mean differences between groups ranged from -0.94 (overall experience domain) to -0.52 (control domain; p<0.0001, all domains). Patients with schizophrenia had wider response distributions compared with controls, while the control group had marked “floor effects” across most items. Initial exploratory FA of the 35-item PRECIS PRO identified a 6-domain solution that accounted for 62% of total item variance, and Cronbach’s alpha (0.959) indicated an extremely high level of internal consistency. Following analyses of the 35-item PRECIS PRO, a total of 11 items were eliminated based on pre-specified criteria (poor loading onto identified factors, marked floor effects in patient groups or <50% test-retest reliability). Confirmatory FA of the revised 24-item PRECIS PRO identified 1 primary domain (attention) and 3 secondary additional domains (memory, executive function, communication). An additional domain included items related to patient distress or bother related to cognitive impairment. There was a high level of internal consistency both for the overall 24-item PRECIS PRO (Cronbach’s alpha= 0.942) and individual domains (Cronbach’s alphas: 0.743–0.873). Intraclass correlation coefficients were 0.78 for the overall 24-item PRECIS PRO and ranged from 0.49–0.74 for individual domains. Finally, discriminant validity testing confirmed there were significant differences between the patient group and the control group in each of the 5 domains of the revised 24-item PRECIS PRO (p<0.0001). Discussion This large validation study demonstrated that the revised 24-item PRECIS PRO is a valid and reliable PRO measure with good internal consistency, adequate test-retest reliability and strong discriminant validity. PRECIS may therefore serve to define key patient-based endpoints for use in future clinical studies. Funding Boehringer Ingelheim (1289.20)

S43. A PROOF-OF-MECHANISM STUDY OF THE PDE10 INHIBITOR RG7203 IN PATIENTS WITH PROBING REWARD FUNCTIONS WITH IMAGING AND BEHAVIORAL APPROACHES

Abstract Background The enzyme phosphodiesterase 10A (PDE10A) is highly expressed in the striatum where it modulates both dopamine D2 and D1 dependent signaling. Its inhibition leads to a suppression of D2 mediated signaling –similar to effects of D2 antagonists - and an enhancement of D1 dependent signaling. D1-dependent signaling has been implicated in reward based learning. Its deficient activation may be a key factor underlying deficient reward functions including reward anticipation and reward based learning that have been implicated as major drivers of negative symptoms of schizophrenia. Therefore, inhibition of PDE10 could be a way to ameliorate such deficits and consequently negative symptoms. In healthy volunteers the PDE10 inhibitor RG7203 indeed enhanced performance in tasks that probed reward functioning suggestive of its potential utility to treat negative symptoms in schizophrenia. We therefore tested the hypothesis that it should enhance imaging and behavioral markers of reward functions in patients with moderate negative symptoms in order to establish mechanistic proof of its utility as treatment of negative symptoms. Methods In a three-way cross-over study we investigated the effects of two doses of RG7203 (5 mg and 15 mg) and placebo given as adjunctive treatment to stable background antipsychotic treatment on reward functioning and reward-based effortful behavior using the monetary incentive delay (MID) task during fMRI and the effort choice task in patients with chronic schizophrenia and moderate levels of negative symptoms (PANSS negative symptom factor score ≥ 18 points). Each treatment period lasted three weeks followed by a 2 week washout period. fMRI and behavioral tasks were administered at the end of each treatment period. Key outcome measures were the differential BOLD during reward anticipation and overall BOLD activity during the MID task and the percentage of high-effort high-reward choices when the probability of reward was 100% during the effort choice task. Results Thirty-three patients with schizophrenia (30 male; 21 B, 9 W, 3 A; mean age 36.6 ± 7 y; PANSS NSFS = 22.8 (±1.4) at screening) were recruited at three study centers in the US. Twenty-four subjects finished the entire study. RG7203 at 5 mg significantly increased differential BOLD activity during reward anticipation in the MID task. However, this enhancement occurred in the context of a significant decrease of BOLD activity across all conditions during the MID task under treatment with RG7203. RG7203 significantly worsened reward-based effortful behavior in the effort choice task (the high-effort high-reward choice: 67% for both doses of RG7203 versus 73% for placebo). Multiple regression revealed that the decrease in effortful behavior was significantly related to the decrease in overall BOLD activity during the MID task and not related to the difference of BOLD activity during reward anticipation versus the control condition. Discussion In contrast to our expectation and previous results in healthy volunteers, RG7203 worsened indices of reward functions which we hypothesize may be due to a further enhancement of D2 antagonistic activity. The results do not support the utility of a PDE10 inhibitor as adjunctive treatment for negative symptoms in patients with schizophrenia. Given the previous observation that RG7203 enhanced reward functions in healthy volunteers who were not treated with D2 antagonist, the results of our study point to potentially deleterious effects of D2 blockade on reward functions and by extension on negative symptoms of schizophrenia. They raise the question if the presence of D2 antagonistic treatment curtails the potential effects of any adjunctive treatment for negative symptoms.