Functioning and Cognition in Patients with Schizophrenia After Initiating Treatment with Aripiprazole Lauroxil: Secondary Outcomes and Post Hoc Analysis.

Background: Clinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between clinicians, patients with schizophrenia, and their caregivers have been associated with impaired functional abilities in patients; medication side effects might worsen both cognition and daily functioning. We assessed daily/social functioning and cognition in stable patients with schizophrenia who switched to the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL). Methods: Clinically stable adults with residual symptoms of schizophrenia or intolerance following three or more doses of paliperidone palmitate or risperidone LAI were switched to flexibly dosed open-label AL treatment (441mg, 662mg, or 882mg every 4 weeks or 882mg every 6 weeks) for six months (ClinicalTrials.gov identifier: NCT02634320). Daily/social functioning was assessed using the Personal and Social Performance Scale (PSP); total and subscale scores were summarized using descriptive statistics. The cognitive status of patients was assessed using the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) at baseline and Month 6 or early termination, providing patient, caregiver, and clinician perspectives. A post hoc analysis assessed level of agreement in ratings of cognitive status among respondents, evaluated at baseline and last assessment, using weighted kappa coefficients (0.01-0.20, slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement.). Results: All 51 enrolled patients received one or more AL doses; 35 completed the study, and 45 contributed data at last assessment. Mean age was 40.6 years; 72.5 percent of patients were male. Based on PSP total score, functioning was maintained from baseline (mean [standard deviation (SD)]: 55.1 [10.5]) through six months of AL treatment (mean [SD]: 57.7 [13.2]). Proportions of patients rating personal and social functioning issues as "not present" or "mild" remained stable between baseline and Month 6 for each PSP subscale. At baseline (n=50), cognitive difficulties were most commonly rated "not present" or "mild" in all NY-AACENT domains by patients (58-86% across domains), clinicians (62-94%), and caregivers (50-92%), and these rates were maintained or increased at last assessment for all reporters. Weighted kappa coefficients indicated fair-to-substantial agreement between patients and clinicians across domains at last assessment (0.32-0.64; baseline: 0.14-0.55); patient-caregiver agreement ranged from 0.07 to 0.50 at last assessment (baseline: 0.25-0.60). Conclusion: In clinically stable patients with schizophrenia who initiated AL, self-reported functioning was maintained over six months of treatment. Clinician-, caregiver-, and patient-reported cognitive function was stable at baseline and maintained in all NY-AACENT domains; patient-clinician agreement on level of cognitive impairment increased over six months of treatment with AL.

Design of a real-world, prospective, longitudinal, observational study to compare vortioxetine with other standard of care antidepressant treatments in patients with major depressive disorder: a PatientsLikeMe survey.

BACKGROUND: Major depressive disorder (MDD) is a recurrent psychiatric condition that presents challenges in responding to treatment and achieving long-term remission. To improve outcomes, a shared decision-making treatment approach with patient and healthcare practitioner (HCP) engagement is vital. PatientsLikeMe (PLM), a peer community of patients, provides information on MDD, symptoms, and treatment through forums and resources, helping patients stay engaged in their treatment journey. Data on PLM can be harnessed to gain insights into patient perspectives on MDD symptom management, medication switches, and treatment goals and measures. METHODS: This ongoing, decentralized, longitudinal, observational, prospective study is being conducted using the PLM platform in two parts, enrolling up to 500 patients with MDD in the United States aged ≥ 18 years to compare vortioxetine with other monotherapy antidepressants. The first qualitative component consists of a webinar and discussion forum with PLM community members with MDD, followed by a pilot for functionality testing to improve the study flow and questions in the quantitative survey. The quantitative component follows on the PLM platform, utilizing patient-reported assessments, over a 24-week period. Three surveys will be conducted at baseline and weeks 12 and 24 to collect data on patient global impression of improvement, depression severity, cognitive function, quality of life (QoL) and well-being, medication satisfaction, emotional blunting, symptoms of anhedonia and resilience, as well as goal attainment. Quantitative results will be compared between groups. The qualitative component is complete; patient recruitment is underway for the quantitative component, with results expected in late 2023. DISCUSSION: These results will help HCPs understand patient perspectives on the effectiveness of vortioxetine versus other monotherapy antidepressants in alleviating symptoms of MDD and improvements in QoL. Data from the PLM platform will support a patient goal-based treatment approach, as results can be shared by patients with their HCPs, providing them with insights on patient-centric goals, treatment management and adherence, as well as allowing them to observe changes in patient-related outcomes scores. Findings from the study will also help to optimize the PLM platform to build scalable solutions and connectivity within the community to better serve patients with MDD.

Bridging the Measurement Gap Between Research and Clinical Care in Schizophrenia: Positive and Negative Syndrome Scale-6 (PANSS-6) and Other Assessments Based on the Simplified Negative and Positive Symptoms Interview (SNAPSI).

There is currently a "measurement gap" between research and clinical care in schizophrenia. The main reason behind this gap is that the most widely used rating scale in schizophrenia research, the 30-item Positive and Negative Syndrome Scale (PANSS), takes so long to administer that it is rarely used in clinical practice. This compromises the translation of research findings into clinical care and vice versa. The aim of this paper is to discuss how this measurement gap can be closed. Specifically, the main points of discussion are 1) the practical problems associated with using the full 30-item PANSS in clinical practice; 2) how the brief, six-item version of the Positive and Negative Syndrome Scale (PANSS-6) was derived empirically from the full 30-item PANSS and what the initial results obtained with PANSS-6 entail; and 3) how PANSS-6 ratings, guided by the newly developed, 15-25-minute, stand-alone Simplified Negative and Positive Symptoms Interview (SNAPSI), might help bridge the measurement gap between research and clinical care in schizophrenia. The full 30-item PANSS is often used in research studies, but is too time consuming to allow for routine clinical use. Recent studies suggest that the much briefer PANSS-6 is a psychometrically valid measure of core positive and negative symptoms of schizophrenia and that the scale is sensitive to symptom improvement following pharmacological treatment. SNAPSI is a brief interview that yields the information needed to rate PANSS-6 (and other brief rating scales). We believe that PANSS-6 ratings guided by SNAPSI will help bridge the measurement gap between research and clinical care in schizophrenia.

Positive and Negative Syndrome Scale (PANSS) Training: Challenges, Solutions, and Future Directions.

Rater training and the maintenance of the consistency of ratings are critical to ensuring reliability of study measures and sensitivity to changes in the course of a clinical trial. The Positive and Negative Syndrome Scale (PANSS) has been widely used in clinical trials of schizophrenia and other disorders and is considered the "gold standard" for assessment of antipsychotic treatment efficacy. The various features associated with training and calibration of this scale are complex, reflecting the intricacy and heterogeneity of the disorders that the PANSS is used to evaluate. In this article, the authors review the methods for ensuring reliability of the PANSS as well as a proposed trajectory for its use in the future. An overview of the current principles, implementation, technologies, and strategies for the best use of the PANSS; tips for how to achieve consistency among raters; and optimal training practices of this instrument are presented.

Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

The Symptoms of Trauma Scale (SOTS): An Initial Psychometric Study.

The Symptoms of Trauma Scale (SOTS) is a 12-item, interview-based, clinician-rated measure that assesses the severity of a range of trauma-related symptoms. This pilot study evaluated its use and psychometric properties in an outpatient setting that provides treatment to survivors of chronic interpersonal trauma. Thirty participants completed self-report measures of posttraumatic stress symptoms, depression, dissociation, self-esteem, and affect dysregulation; the participants also participated separately in a semistructured interview based on the SOTS conducted by 2 trained interviewers. SOTS composite severity scores for DSM-IV posttraumatic stress disorder (PTSD) and complex PTSD (cPTSD), DSM-5 PTSD, and PTSD dissociative subtype, and total traumatic stress symptoms generally had acceptable internal consistency and interrater reliability. Evidence of convergent, discriminant, criterion, and construct validity was found for the SOTS composite PTSD scores, although potential limitations to validity that require further research and refinement of the measure were identified for the SOTS total and DSM-IV cPTSD scores and the hyperarousal, affect dysregulation, and dissociation items. Interviewers and interviewees described the interview as efficient, informative, and well tolerated. Implications for clinical practice and research to refine the SOTS are discussed.

Brain tumor location and psychiatric symptoms: is there any association? A meta-analysis of published case studies.

A meta-analytic study of reports of brain tumors and psychiatric symptoms for the past 50 years was conducted to examine potential associations between tumor location and psychiatric symptoms. Results demonstrated that there is a statistically significant association between anorexia symptoms and hypothalamic tumors. For the rest of the brain regions a statistically significant association could not be definitively determined. However, several of the regions demonstrated an increased likelihood of associated symptoms when compared with other regions. The methodological limitations of this analysis are discussed.

Time-to-pregnancy and risk of schizophrenia.

Schizophrenia has been linked to advanced paternal age, but the explanation is unknown. We questioned whether the incidence of schizophrenia would be related to male reproductive capacity, as reflected in the time taken to conceive. We measured the incidence of schizophrenia in relation to time to conception in a sub-group of 12,269 in the Jerusalem cohort whose mothers, interviewed post-partum, reported that the pregnancy had been intended. Compared with those conceived in less than 3 months, the unadjusted relative risks (RR) of schizophrenia associated with conception-waits of 3-5, 6-11 and 12+ months were 1.10 (95% confidence interval, 0.62-1.94), 1.41 (0.79-2.52) and 1.88 (1.05-3.37) with p for trend=0.035. This trend was attenuated somewhat by adjusting for paternal age, and was observed more strongly in offspring of fathers aged 30+ (p=.010). These findings suggest that factors associated with fecundability, either male or female, may contribute to the risk of schizophrenia.

Prenatal exposure to lead, delta-aminolevulinic acid, and schizophrenia: further evidence.

BACKGROUND: A previously conducted study of prenatal lead exposure and schizophrenia using delta-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959-1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life. OBJECTIVES: In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959-1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort. METHODS: We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education. RESULTS: The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 microg/dL of blood Pb was 1.92 (95% confidence interval, 1.05-3.87; p = 0.03). CONCLUSION: Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.

Statistical validation of the criteria for symptom remission in schizophrenia: preliminary findings.

BACKGROUND: Published methods for assessing remission in schizophrenia are variable and none have been definitively validated or standardized. Andreasen et al (2005) suggest systematic operational criteria using eight PANSS items for which patients must score < or = 3 (mild) for at least six months. METHODS: Using data from a one year, multi-site clinical trial (n = 675) remission criteria were compared to total PANSS scores and other endpoints and demonstrate excellent agreement with overall clinical status. RESULTS: Compared to total PANSS score of 60 points and other criteria, at time points > 6 months (8 and 12 months) the specificity of the remission criteria was 85%, i.e. of the patients who had a total score >60, 85% were classified as "not in remission." Sensitivity was also very high; 75% of patients with scores of <60 were classified as "in remission."Patients who dropped out of the trial were more likely not to be in remission prior to dropping out. CONCLUSION: These findings indicate that the remission criteria are both sensitive and specific indicators of clinical status. Additional analyses are required to determine if remission status predicts other outcomes, such as employment, independent living, and prognosis.

PANSS rater training using Internet and videoconference: results from a pilot study.

Problems associated with the clinician-administered rating scales have led to new approaches to improve rater training. These include interactive, on-line didactic tutorials and live, remote evaluation of raters' clinical skills through the use of videoconferencing. The purpose of this study was to evaluate this approach in training novice raters on the administration of the Positive and Negative Symptom Scale (PANSS). Twelve trainees with no prior PANSS experience completed didactic training via CD-ROM and two remote training sessions where they interviewed a standardized patient-actor while being remotely observed in real time and given feedback. Results found a significant improvement in trainees' conceptual knowledge and an improvement in trainees' clinical skills. The use of these technologies allows for training to be more effectively delivered to diverse sites in multi-center trials, and for evaluation of raters' applied clinical skills, an area that has previously been overlooked.

Fetal environment and schizophrenia.

Schizophrenia and related disorders are adult-onset illnesses with no definitively established risk factors. Several studies report that exposures to infection and nutritional deprivation during early development may elevate the risk of later developing schizophrenia, specifically during the prenatal period. Preliminary evidence implicates lead exposure as well, suggesting that chemical exposures during early development may constitute a new class of risk factors for schizophrenia that has not been adequately investigated. Exposure to lead is given as an example of a chemical agent for which some effects have been described throughout the life course on both general neurodevelopmental outcomes and now on a specific psychiatric diagnosis. Findings from prospectively collected birth cohorts are offered as examples of both innovations in methodology and opportunities for future generations of investigators.

Prenatal lead exposure, delta-aminolevulinic acid, and schizophrenia.

Schizophrenia is a severe mental disorder of unknown etiology. Recent reports suggest that a number of environmental factors during prenatal development may be associated with schizophrenia. We tested the hypothesis that environmental lead exposure may be associated with schizophrenia using archived serum samples from a cohort of live births enrolled between 1959 and 1966 in Oakland, California. Cases of schizophrenia spectrum disorder were identified and matched to controls. A biologic marker of lead exposure, delta-aminolevulinic acid (delta-ALA), was determined in second-trimester serum samples of 44 cases and 75 controls. delta-ALA was stratified into high and low categories, yielding 66 subjects in the high category, corresponding to a blood lead level (BPb) greater than or equal to 15 micro g/dL, and 53 in the low category, corresponding to BPb less than 15 micro g/dL. Using logistic regression, the odds ratio (OR) for schizophrenia associated with higher delta-ALA was 1.83 [95% confidence interval (CI), 0.87-3.87; p = 0.1]. Adjusting for covariates gave an OR of 2.43 (95% CI, 0.99-5.96; p = 0.051). This finding suggests that the effects of prenatal exposure to lead and/or elevated delta-ALA may extend into later life and must be further investigated as risk factors for adult psychiatric diseases.