A novel peripheral biomarker for depression and antidepressant response.

In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

Use of video-recordings of site-based interviews for quality assurance in a study of subjects with schizophrenia and persistent negative symptoms.

Site-independent ratings derived from audio-digital recordings of site-based interviews are often used for quality assurance monitoring to affirm ratings reliability in CNS clinical trials. The present study of subjects with schizophrenia and persistent negative symptoms used video instead of audio recordings of site-based interviews and thereby facilitated visual observation of the subject by the remote rater. "Paired" site-independent scores of the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS) were obtained from video-recordings of site-based interviews. The intraclass correlation between site-based and paired site-independent ratings was r = 0.839 for the total PANSS scores (n = 1006) and r = 0.871 for the total BNSS scores (n = 892); <5 % of paired scores deviated outside the acceptable confidence intervals. Ratings "outliers" were identified and remediated. We examined the pattern of paired scoring deviations for the BNSS, total PANSS, PANSS symptom subscales, and the Marder negative symptom factor. Each metric revealed a bidirectional pattern of scoring deviations such that mean site-based ratings were higher than site-independent ratings when symptom severity was high but lower than site-independent ratings when symptom severity was low. The pattern of bidirectional paired scoring deviations observed in this analysis has previously been noted in paired ratings analyses of subjects experiencing an acute exacerbation of psychosis in schizophrenia and major depressive disorder as well. The bidirectional pattern may reflect inherent differences between live ratings and remotely scored recorded ratings. This analysis affirms the utility of video-recordings of site-based ratings for surveillance in trials with subjects with schizophrenia and persistent negative symptoms.

Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials.

BACKGROUND: Currently approved antipsychotics do not adequately treat negative symptoms (NS), which are a major determinant of functional disability in schizophrenia. KarXT, an M1 /M4 preferring muscarinic receptor agonist, has shown efficacy as a broad-spectrum monotherapy for the treatment of schizophrenia in participants with acute psychosis. Post hoc analyses evaluated the possibility that NS improve independently of positive symptoms with KarXT in a subgroup of participants with moderate-to-severe NS and no predominance of positive symptoms. METHODS: Data were pooled from the three pivotal trials of KarXT monotherapy in people with schizophrenia with an acute exacerbation of psychosis. All 3 studies used similar 5-week randomized, double-blind, placebo-controlled designs (modified intention-to-treat sample N = 640). PANSS criteria proposed in the literature identified a subset of study participants (n = 64) with prominent NS. RESULTS: KarXT was significantly better than placebo on PANSS Marder Negative Factor Scores in the full sample (p < .001; Cohen's d = 0.42) and more so in the prominent NS subgroup (p < .001; Cohen's d = 1.18). Further, the KarXT effect in the NS subgroup remained significant after accounting for changes in positive symptoms, depression/anxiety, disorganization, and hostility. CONCLUSIONS: Participants with prominent NS revealed greater improvement of NS following KarXT therapy than the full sample that persisted after accounting for positive and other symptoms. While these findings must be interpreted with caution, they are consistent with the possibility that NS improvements associated with KarXT are not secondary to improvements in other symptom domains and support further investigation in larger, stable outpatient studies.

A cross-cultural comparison study of depression assessments conducted in Japan.

BACKGROUND: The advent of global clinical trials has necessitated the use of English-based rating instruments in diverse cultures where English is clearly not the primary language. The cross-cultural applicability of rating instruments developed in one language with only one cultural group is an important issue in both research and clinical settings where these instruments might be used. We examined the cross-cultural applicability of the Montgomery-Asberg Depression Rating Scale (MADRS) in Japan. METHODS: As part of a rater-training program for a clinical trial in Japan, we assessed inter-rater agreement using two videotaped MADRS interviews administered in Japanese and produced with English subtitles. We looked for possible interpretational variance that might have been generated by cultural differences between Japanese raters in Japan and English-speaking raters in the USA scoring the same interviews. RESULTS: The US and Japanese raters demonstrated high inter-rater agreement and no significant scoring difference on the total MADRS score. The subtitles in English did not adversely affect the overall scoring.We separately analyzed the 10 individual items from each of the two MADRS interviews used for rater training. Of the 20 items, 18 were concordant between the US and Japanese raters. In one interview, the US raters scored lassitude significantly higher (p = 0.013) and the inability to feel significantly lower (p = 0.037) than the Japanese raters, reflecting a possible interpretational difference on these items. CONCLUSION: Although developed in Europe, these findings support the general applicability of the MADRS to assess the severity of depressive symptoms in Japan. We did note significant scoring differences on 2 of the 20 individual items, suggesting a possible cultural difference. It is possible that more interviews might have revealed more interpretational differences. These findings highlight the need for cultural familiarity when assessing psychiatric patients.

A structured interview guide for global impressions: increasing reliability and scoring accuracy for CNS trials.

BACKGROUND: The clinical global impression of severity (CGI-S) scale is a frequently used rating instrument for the assessment of global severity of illness in Central Nervous System (CNS) trials. Although scoring guidelines have been proposed to anchor these scores, the collection of sufficient documentation to support the derived score is not part of any standardized interview procedure. It is self evident that the absence of a standardized, documentary format can affect inter-rater reliability and may adversely affect the accuracy of the resulting data. METHOD: We developed a structured interview guide for global impressions (SIGGI) and evaluated the instrument in a 2-visit study of ambulatory patients with Major Depressive Disorder (MDD) or schizophrenia. Blinded, site-independent raters listened to audio recorded SIGGI interviews administered by site-based CGI raters. We compared SIGGI-derived CGI-S scores between the two separate site-based raters and the site-independent raters. RESULTS: We found significant intraclass correlations (p = 0.001) on all SIGGI-derived CGI-S scores between two separate site-based CGI raters with each other (r = 0.768) and with a blinded, site-independent rater (r = 0.748 and r = 0.706 respectively) and significant Pearson's correlations between CGI-S scores with all MADRS validity comparisons for MDD and PANSS comparisons for schizophrenia (p- 0.001 in all cases). Compared to site-based raters, the site-independent raters gave identical "dual" CGI-S scores to 67.6% and 68.2% of subjects at visit 1 and 77.1% at visit 2. CONCLUSION: We suggest that the SIGGI may improve the inter-rater reliability and scoring precision of the CGI-S and have broad applicability in CNS clinical trials.

Recommendations for selection and adaptation of rating scales for clinical studies of rapid-acting antidepressants.

The novel mechanisms of action (MOA) derived from some recently introduced molecular targets have led to regulatory approvals for rapid acting antidepressants (RAADs) that can generate responses within hours or days, rather than weeks or months. These novel targets include the N-methyl-D-glutamate receptor antagonist ketamine, along with its enantiomers and various derivatives, and the allosteric modulators of gamma-aminobutyric acid (GABA) receptors. There has also been a strong resurgence in interest in psychedelic compounds that impact a range of receptor sites including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF. The RAADs developed from these novel targets have enabled successful treatment for difficult to treat depressed individuals and has generated a new wave of innovation in research and treatment. Despite the advances in the neurobiology and clinical treatment of mood disorders, we are still using rating instruments that were created decades ago for drugs from a different era (e.g., The Hamilton and Montgomery-Åsberg depression rating scales, HDRS, and MADRS) continue to be used. These rating instruments were designed to assess mood symptoms over a 7-day time frame. Consequently, the use of these rating instruments often requires modifications to address items that cannot be assessed in short time frames, such as the sleep and appetite items. This review describes the adaptative approaches that have been made with the existing scales to meet this need and examines additional domains such as daily activities, side effects, suicidal ideation and behavior, and role functioning. Recommendations for future studies are described, including the challenges related to implementation of these adapted measures and approaches to mitigation.

A global measure to assess switching antipsychotic medications in the treatment of schizophrenia.

OBJECTIVES: It is common practice to switch antipsychotic medications in the treatment of patients with schizophrenia to enhance clinical efficacy and/or reduce drug-related side effects. The conventional Clinical Global Impression (CGI) of severity scale is a well-understood measure to track switching effects but does not differentiate between the severity of clinical symptoms and the impact of side effects.. METHODS: We developed a CGI-switch instrument that contains distinct global severity scales for clinical efficacy, safety and/or tolerability, and a third unified (integrated) CGI severity score to assess these interrelated assessments. An integrated Clinical Global Impression of Change was also created to assess global clinical change relative to the initiation of treatment. RESULTS: Interrater reliability conducted as part of a rater-training program for a clinical study (Novartis protocol CIL0522D; clinitrials.gov identifier: CT01207414) revealed high interrater agreement (Cronbach's alpha = 0.945). Data were collected from 1066 CGI assessments during the course of the trial. CGI raters easily grasped the utility of the instrument. The distinction made between efficacy and safety/tolerability facilitated serial tracking of each condition during the course of treatment. CONCLUSION: The modified CGI-switch instrument is a simple, reliable, and practical metric to assess the benefits, if any of switching antipsychotic medications in patients with schizophrenia.

Audio-digital recordings to assess ratings reliability in clinical trials of schizophrenia.

We examined ratings reliability in 5 clinical trials of subjects with schizophrenia experiencing an acute exacerbation of psychosis. Audio-digital recordings of site-based interviews of the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) were used to obtain blinded, site-independent scores to evaluate paired scoring concordance. High intraclass correlations were noted between 1810 paired site-based and site-independent PANSS scores (r = 0.801) and 1837 paired BPRS scores (r = 0.897) with high limits of agreement such that 93.9% of paired scores were within the calculated 95% confidence intervals. In 2 studies where sufficient PANSS data was available at baseline and endpoint, blinded site-independent ratings yielded a predictive value of 84.2% for replicating site-based response/nonresponse treatment outcomes. There was a significant positive correlation between site-based scores and paired scoring deviations (PANSS: r = 0.246; p < 0.0001; BPRS: r = 0.176; p < 0.0001). The magnitude (symptom severity) of PANSS or BPRS scores affected the directionality of paired scoring deviations in each study. Site-based raters scored the most symptomatic subjects higher and less symptomatic subjects lower than the paired site-independent raters on either instrument. This analysis affirms the utility of paired audio-digital scoring of site-based interviews as a surveillance strategy for schizophrenia studies. We noted a high predictive value of blinded site-independent raters to replicate site-based treatment outcomes. The bi-directionality of paired scoring deviations observed for both the PANSS and BPRS is consistent with findings found for depression rating instruments.

Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial.

Blinded, site-independent (remote) ratings from audio-digital recordings of site-based Positive and Negative Syndrome Scale (PANSS) interviews were obtained in a 5-week, randomized, double-blinded study assessing the safety, tolerability, and efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) in hospitalized adults with schizophrenia experiencing an acute exacerbation of psychosis (EMERGENT-1; ClinicalTrials.gov identifier: NCT3697252). The blinded site-independent raters had no knowledge of site location, study visit, drug vs. placebo assignment, or any treatment emergent adverse events (TEAEs). Concordance analyses of 561 paired site-based and site-independent PANSS ratings across all visits revealed a high correlation (ICC = 0.775). Paired scoring differences were positively correlated with the PANSS total score (Spearman's rho = 0.37, p < 0.0001). Paired PANSS scores were available from 148 subjects at both the baseline and end of study visits (KarXT = 72, Placebo = 76). Site-based PANSS total scores (primary aim) revealed a significantly greater improvement from baseline in the KarXT group compared to the placebo group (p < 0.0001). The blinded site-independent PANSS total scores derived from listening to and scoring the recorded site-based PANSS interviews replicated this finding (p < 0.001) and yielded an overall predictive value of 85.1% for matching the site-based response/non-response outcomes. TEAE's have the potential to "unblind" site-based ratings. In this study, the site-independent raters were blinded to TEAEs, affirmed the site-based PANSS ratings, and mitigated concerns about possible functional unblinding of site-based raters. This method of blinded assessment via audio-digital recordings may have utility for other studies concerned with ratings precision and/or functional unblinding.

Ecological momentary assessment as a measurement tool in depression trials.

We used ecological momentary assessment (EMA) to track symptoms during a clinical trial. Thirty-six participants with major depressive disorder (MDD) and MADRS scores ≥20 were enrolled in a nonrandomized 6-week open-label trial of commercially available antidepressants. Twice daily, a mobile device prompted participants to self-report the 6 items of the HamD6 sub-scale derived from the Hamilton rating scale for depression (HamD17). Morning EMA reports asked "how do you feel now" whereas evening reports gathered a full-day impression. Clinicians who were blinded to the EMA data rated the MADRS, HamD17 and HamD6 at screen, baseline and weeks 2,4, and 6. Hierarchical linear modeling (HLM) examined the course of the EMA assessments and convergence between EMA scores and clinician ratings. HLM analyses revealed strong correlations between AM and PM EMA derived HamD6 scores and revealed significant improvements over time. EMA improvements were significantly correlated with the clinician rated HamD6 scores at endpoint and predicted clinician rated HamD6 score changes from baseline to endpoint (p < .001). There was a large correlation between EMA and clinician derived HamD6 scores at each in-person assessment after baseline. Treatment response defined by EMA matched the clinician rated HamD6 treatment responses in 33 of 36 cases (91.7%). EMA derived symptom scores appear to be efficient and valid measures to track daily symptomatic change in clinical trials and may provide more accurate measures of symptom severity than the episodic "snapshots" that are currently used as clinical outcomes. These findings support further investigation of EMA for assessment in clinical trials.

Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease.

BACKGROUND: Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD). OBJECTIVE: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. METHODS: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation ("on") or sham DBS-f ("off") for 12 months. RESULTS: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the "on" and "off" groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer's Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f "off" versus "on" over 12 months in the < 65 age group but favored DBS-f "on" versus "off" in the≥65 age group on all clinical metrics. On the integrated Alzheimer's Disease rating scale (iADRS), the effect size contrasting DBS-f "on" versus "off" changed from +0.2 (favoring "off") in the < 65 group to -0.52 (favoring "on") in the≥65 age group. CONCLUSION: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.

Early score fluctuation and placebo response in a study of major depressive disorder.

Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints. We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404. A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.

The Clinical Global Impressions scale: errors in understanding and use.

OBJECTIVE: The Clinical Global Impressions Severity and Improvement scales (CGI-S and CGI-I) are widely included as efficacy data in psychopharmacology new drug application submissions. This study was conducted to determine the extent to which clinical trials investigators included information unrelated to efficacy in their CGI ratings. METHOD: Forty-five principal investigators provided CGI-S and CGI-I ratings of narratives of patients with major depressive disorder or generalized anxiety disorder. Investigators were blindly randomized to receive narratives that either did (experimental) or did not (control) contain indication-unrelated medical or psychiatric adverse events. Investigators then completed a survey assessing CGI-S and CGI-I rating patterns. RESULTS: CGI-S and CGI-I ratings were significantly more severe and less improved when the narratives contained medical and psychiatric adverse events unrelated to the diseases under study (major depressive disorder and generalized anxiety disorder) than when the narratives did not (Ps < .04). In response to the survey, 46% and 56% of investigators reported that a psychiatric adverse event unrelated to the disease under study would not affect their CGI-S and CGI-I ratings, respectively. Although 87% of investigators reported that their CGI-S and CGI-I ratings would not be affected by a medical adverse event, actual CGI-S ratings were significantly more severe when an unrelated medical adverse event was described as occurring than when it was not (P < .03). CONCLUSION: Clinical trials investigators' inclusion of indication-irrelevant adverse events threatens the validity of the CGI as an efficacy measure and may contribute to failure to detect efficacy signals in psychopharmacology clinical trials.

Audio-digital recordings for surveillance in clinical trials of major depressive disorder.

Ratings surveillance is used in clinical trials to assure ratings reliability of site-based scores. One surveillance method employs audio-digital recordings of site-based clinician interviews to obtain remote, site-independent scores for assessment of paired scoring concordance and interview quality. We examined the utility of this surveillance strategy using paired site-independent scores derived from recorded site-based Montgomery-Asberg depression rating scale (MADRS) interviews obtained from patients with major depressive disorder (MDD) participating in 5 clinical trials. High correlations were noted between the 3736 paired site-based and site-independent scores across all visits. Some rater "outliers" were identified whose ratings performance improved following remediation. In 3 studies with available outcome data, the blinded remote ratings yielded a high predictive value (91.2%) for replicating treatment response rates. The magnitude of the total MADRS scores affected the directionality of paired scoring deviations in each of the 5 studies. Across all visits, site-based raters scored the more severe MADRS scores (≥30) higher than site-independent raters and the less severe MADRS scores (<20) lower than site-independent raters. Individual MADRS items were similarly affected by the directionality of symptom severity. This analysis affirms the utility of audio-digital recording of site-based interviews as a surveillance strategy for quality assurance (monitoring and remediation). In addition, the high predictive value of blinded remote ratings to replicate site-based treatment outcomes may be useful to affirm primary site-based results when there is a potential of functional unblinding. The use of remote ratings as a primary measure beyond its utility for quality assurance needs further exploration.

The Effect of Early Life Stress on Adult Psychiatric Disorders.

There is a crisis of early childhood maltreatment in the United States. In 2012, the United States Department of Health and Human Services noted 3.4 million referrals to childhood protective services, of which the majority related to child abuse or neglect. Early life stress (ELS) due to childhood abuse and/or neglect can generate life-long consequences. ELS has been associated with disrupted neurodevelopment that can yield social, emotional, and cognitive impairment; adult medical and psychiatric disorders; disability; and even earlier death. Some studies have shown that adults with major depression and ELS respond less well to conventional treatments than adults who did not experience early life stress. In this article, we review some of the neurobiological and epigenetic studies that explore this association.

D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer's Disease Patients with Dementia.

Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer's disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.

Targeted scoring criteria reduce variance in global impressions.

OBJECTIVE: This study examined the confounding effect of treatment emergent physical or psychic symptoms on clinical global impression (CGI) ratings in CNS trials and examined the benefit of targeted scoring criteria on clarifying ratings and reducing scoring variance. METHODS: Twenty-four raters participating in an investigator meeting training session scored a series of scripted CGI scenarios that included treatment emergent symptoms. RESULTS: The addition of treatment emergent gastrointestinal (GI) symptoms or anxiety symptoms significantly changed the rating of clinical global improvement and caused a broad CGI-improvement (CGI-I) scoring variance reflecting scoring ambiguity amongst these raters. Re-rating after a presentation of well-defined criteria that addressed these scoring issues narrowed the variance and significantly improved inter-rater reliability. CONCLUSIONS: It is clear that CNS trials must define scoring criteria for global ratings prior to the initiation of a study to assure ratings consistency. The actual definition of global must be study-specific and may depend upon the targeted symptoms of interest and mechanism of drug action. The targeted criteria that define global must be included in all published reports about the trial.

Cognitive Impairment Associated with Cancer: A Brief Review.

This brief review explores the areas of cognitive impairment that have been observed in cancer patients and survivors, the cognitive assessment tools used, and the management of the observed cognitive changes. Cognitive changes and impairment observed in patients with cancer and those in remission can be related to the direct effects of cancer itself, nonspecific factors or comorbid conditions that are independent of the actual disease, and/or the treatments or combination of treatments administered. Attention, memory, and executive functioning are the most frequently identified cognitive domains impacted by cancer. However, the prevalence and extent of impairment remains largely unknown due to marked differences in methodology, definitions of cognitive impairment, and the assessment measures used. Assessment of cognitive functioning is an important and necessary part of a comprehensive oncological care plan. Research is needed to establish a better understanding of cognitive changes and impairments associated with cancer so that optimal patient outcomes can be achieved.

An augmentation study of MSI-195 (S-adenosylmethionine) in Major Depressive Disorder.

We conducted a 6-week double-blind, placebo-controlled, augmentation study comparing the efficacy and safety of MSI-195 800 mg (a proprietary formulation of S-adenosylmethionine) or placebo added to ongoing antidepressant medication (ADT) in acutely depressed subjects with Major Depressive Disorder (MDD) who had experienced an inadequate response to their ongoing ADT (The Horizon Study, ClinicalTrials.gov NCT01912196). There were 234 eligible subjects randomized to either MSI-195 (n = 118) or placebo (n = 116). There were no overall statistically significant differences found between MSI-195 added to ongoing ADT compared to placebo on any of 3 depression-rating instruments (HamD17, MADRS, IDS-SR30) in the ITT set. MSI-195 was generally safe and well tolerated with predominantly mild gastrointestinal side effects. Post-hoc analyses examined factors that might have affected study outcome. The ITT set was divided into subjects enrolled during the 1st half (first nine months) and 2nd half of the study. MSI-195 added to ongoing ADT was significantly better than placebo on both the HamD17 and MADRS in the 1st half (p = 0.03 and 0.02 respectively), but not in the 2nd half of the study. Several demographic and clinical characteristics were significantly different between the two study segments including body mass index, pre-randomization symptom severity fluctuation, number of lifetime depressive episodes, and anxious depression sub-type. Thus, the characteristics of the enrolled subjects changed between the 1st and 2nd half of the study. These post-hoc findings highlight the inherent challenges encountered for subject selection in double-blind, placebo controlled trials and compel further investigation of enrollment criteria and moderating factors that affect treatment. The favorable safety profile and clinical benefit observed with MSI-195 in the 1st half of this study warrant further investigation in MDD.

Ratings surveillance and reliability in a study of major depressive disorder with subthreshold hypomania (mixed features).

OBJECTIVES: Site-independent ratings surveillance assessed ratings reliability in a clinical trial. METHODS: Inter-rater reliability was assessed at the screen visit in a 6-week, double-blind, placebo-controlled study of lurasidone for the treatment of major depressive disorder (MDD) with subthreshold hypomanic ("mixed") symptoms (clinicaltrials.gov NCT01421134). Site-based Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) interviews were paired with 184 site-independent ratings derived from audio-digital recordings. RESULTS: The paired MADRS and YMRS scores were highly correlated (r = 0.708 and 0.885, respectively) and generated minimal scoring discordance. The surveillance program identified 14 MADRS scores (7.6% of this sample) that were below the study entry criterion (MADRS ≥26) and resulted in screen failure. When present, paired scoring discordance was associated with symptom severity, interview length, interview quality, and the level of patient cooperation. Higher severity scores (MADRS ≥40 and YMRS ≥15) were associated with greater paired scoring discordance. Further, MADRS scores <30 and short MADRS interviews conducted in ≤12 min revealed significantly more pairs of discordant outliers (p = 0.04 and 0.009, respectively). CONCLUSIONS: The findings suggest that MDD patients with mixed features can be reliably assessed, that paired site-based and site-independent assessments were generally concordant, and that ratings surveillance may reinforce ratings precision.