Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting.

BACKGROUND: KRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L). METHODS: Patients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation. RESULTS: Of 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C-positive cancer. At 1L treatment start, significantly more patients with KRAS G12C-positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C-positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status. CONCLUSIONS: This real-world study showed that patients with KRAS G12C-positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C-positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.

Venetoclax and Hypomethylating Agents as First-line Treatment in Newly Diagnosed Patients with AML in a Predominately Community Setting in the US.

BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.

Real-world data prognostic model of overall survival in patients with advanced NSCLC receiving anti-PD-1/PD-L1 immune checkpoint inhibitors as second-line monotherapy.

BACKGROUND AND AIM: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model. METHODS: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. RESULTS: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort. CONCLUSIONS: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode.

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.

Electronic Ecological Momentary Assessment (EMA) in youth with bipolar disorder: Demographic and clinical predictors of electronic EMA adherence.

BACKGROUND: Ecological momentary assessment (EMA) is increasingly used to characterize patients' daily lives, monitor mood, and test efficacy of treatment interventions. However, few studies have examined patient characteristics impacting adherence with EMA protocols, and to our knowledge, no such study has been conducted in youth with bipolar disorder (BD). METHODS: As part of a larger observational study, 14- to 21-year-olds diagnosed with BD, and who were between episodes of illness (n = 39, 19.0 ±â€¯2.05 Mean ±â€¯Standard Deviation years old, 74.4% female) and psychiatrically healthy controls (n = 47, 18.3 ±â€¯2.40 years old, 66.0% female) completed baseline diagnostic and symptom severity interviews, and were instructed to complete diary assessments of mood, sleep, and behavior electronically three times per day for 21 consecutive days (i.e., in total 5418 (or 63 per person) diary entries). Multiple regression was used to examine effects of BD participants' demographic and clinical characteristics on diary completion rates. RESULTS: 53.8 ±â€¯9.3 diary entries per person were actually completed. Adherence rates were high (87.5% of healthy controls and 80.4% of adolescents with BD), but were still significantly poorer in youth with BD. Adequate adherence (≥80%) rates were also significantly poorer in youth with BD relative to healthy controls (56.4% versus 83.0%). Among youth with BD, more lifetime suicide attempts and higher current mood elevation symptom severity predicted significantly poorer adherence. LIMITATIONS: Limited sample size/generalizability. CONCLUSIONS: Findings highlight the importance of considering the impact of patient characteristics on adherence with EMA protocols among youth with severe mental illness.

Network dynamics of positive and negative affect in bipolar disorder.

BACKGROUND: The network approach to psychopathology has become increasingly popular. Little research has examined the dynamic network structure of mental disorders, and, to date, no study has investigated the network dynamics of positive affect, negative affect, and physical activity in bipolar disorder. This represents the first study to estimate the dynamic network structure of affect and physical activity in individuals with and without bipolar I disorder. METHODS: An intensive longitudinal design was used to assess positive affect, negative affect, and actigraphy-based estimates of physical activity. The overall sample consisted of 32 adults with bipolar I disorder and 36 healthy control participants. Eligible participants underwent an 8-week assessment period, in which once-per-day ratings of affect and actigraphy estimates were obtained. Participants were re-assessed on baseline measures afterwards. Dynamic network analysis was used to examine the network structure of affect and physical activity over time. Multilevel models were used to examine the relationship between autocorrelation and changes in depression symptoms among participants with bipolar disorder. LIMITATIONS: The network analyses assume stationarity. Future research should consider time-varying multilevel network models to better account for time trends. RESULTS: The results of the temporal networks indicated that the directed edges between positive and negative affect were mostly positive among individuals with bipolar I disorder. Among healthy control participants, the directed edges between positive and negative affect were mostly negative in direction. Physical activity, as assessed by daily actigraphy indices, was more densely connected in the healthy control network than the bipolar disorder network. Furthermore, the results indicated that critical slowing down predicted worsening of mood symptoms in the bipolar I disorder group. CONCLUSIONS: This study suggests that certain dynamic patterns of affect may be an underlying process that contributes to the maintenance of bipolar disorder. These results have both theoretical and practical implications.

Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder.

AIMS: Antidepressants are common in bipolar disorder (BD), but controversial due to questionable efficacy/tolerability. We assessed baseline antidepressant use/depression associations in BD. METHODS: Stanford BD Clinic outpatients, enrolled during 2000-2011, assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, were monitored up to two years with the STEP-BD Clinical Monitoring Form while receiving naturalistic expert treatment. Prevalence/correlates of baseline antidepressant use in recovered (euthymic ≥8 weeks)/depressed patients were assessed. Kaplan-Meier survival analyses assessed times to depressive recurrence/recovery in patients with/without baseline antidepressant use, and Cox Proportional Hazard regression analyses assessed covariate effects. RESULTS: Baseline antidepressant use was significantly (albeit without Bonferroni multiple comparison correction) less among 105 recovered (31.4%) versus 153 depressed (44.4%) patients, and among recovered patients (again without Bonferroni correction), associated with Caucasian race, earlier onset, worse Clinical Global Impression scores, and hastened depressive recurrence (only if mood elevation episodes were not censored), driven by lifetime anxiety disorder, and more (even with Bonferroni correction) bipolar II disorder, lifetime anxiety and eating disorders, and core psychotropics. Baseline antidepressant use among depressed patients was associated with significantly (again without Bonferroni correction) older age, female gender, and more (even with Bonferroni correction) anxiolytics/hypnotics, complex pharmacotherapy, and core psychotropics, but no other unfavorable illness characteristic/current mood symptom, and not time to depressive recovery. LIMITATIONS: Tertiary BD clinic referral sample receiving open naturalistic expert treatment. Analyses without/with Bonferroni correction. CONCLUSIONS: Additional research is required to assess the complex associations between baseline antidepressant use and longitudinal depressive burden in BD.

Double trouble: Weekend sleep changes are associated with increased impulsivity among adolescents with bipolar I disorder.

OBJECTIVES: Both sleep disruption and impulsivity are important predictors of the course of bipolar disorder (BD). Although sleep disruption has been shown to intensify impulsivity, little research has considered how these two important domains interact within BD. Adolescence is a critical period for the onset of BD, and is often associated with increases in impulsivity and substantial changes in sleep. We tested the hypothesis that disruptions in sleep would increase impulsivity among adolescents, and that this effect would be more pronounced among those with BD. METHODS: Thirteen- to nineteen-year-olds diagnosed with BD-I (n = 33, age [mean ± standard deviation (SD)] 16.2 ± 1.66 years, 54.5% female) and psychiatrically healthy controls (n = 26, age [mean ± SD] 15.5 ± 1.45 years, 55.6% female) reported their past-week bedtime, rise time, and sleep duration, separately for school days and weekends, and completed a self-report questionnaire on impulsivity. Stepwise regression was used to examine the effects of sleep on impulsivity, and the moderation of this effect by BD status. RESULTS: Adolescents with BD reported significantly higher impulsivity, later and more variable rise time, and more variable time in bed and sleep duration on school days than did controls. Greater change in sleep duration between school days and weekends was associated with significantly more impulsivity among adolescents with BD as compared to controls. CONCLUSIONS: These findings highlight the important effect of sleep on impulsivity among adolescents with BD and add to the growing evidence that establishing sleep routines may be an important therapeutic target for youth with BD.

Victimization and traumatic stress: Pathways to depressive symptoms among low-income, African-American girls.

Socioeconomic disadvantage is associated with increased exposure to victimization and traumatic stress. The present study evaluates longitudinal pathways linking victimization and trauma to depressive symptoms in a socioeconomically disadvantaged sample of African-American adolescent girls seeking mental health services (N = 177, 12-16 years old at baseline). Girls completed four assessments over the course of three years (T1-T4). Depressive symptoms were assessed at T1-T3 using clinical interviews and questionnaires. At T4, lifetime history of victimization and traumatic stressors was evaluated with in-person interviews. Separate structural equation models tested longitudinal pathways from stressor frequency, severity, and duration to depressive symptoms. In all three models, higher levels of victimization and traumatic stressors were associated with significantly higher levels of depressive symptoms. More frequent stressors prior to T1 directly predicted depressive symptoms at T1 and indirectly predicted depressive symptoms at T2, which, in turn, predicted depressive symptoms at T3. A similar pattern emerged in the stressor severity and duration models. Findings support the idea that victimization and traumatic stressors are associated with higher levels of depressive symptoms and that, among treatment-seeking low-income adolescent girls, these effects occur through both direct and indirect paths. Implications of these findings are discussed in the context of the stress-generation and stress proliferation models of psychopathology.

Daytime midpoint as a digital biomarker for chronotype in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is associated with later sleep and daily activity (evening rather than morning chronotype). Objective chronotype identification (e.g., based on actigraphs/smartphones) has potential utility, but to date, chronotype has mostly been assessed by questionnaires. Given the ubiquity of accelerometer-based devices (e.g. actigraphs/smartphones) worn/used during daytime and tendency to recharge rather than wear at night, we assessed chronotype using daytime (rather than sleep) interval midpoints. METHODS: Sixty-one participants with BD type I (BD-I) or II (BD-II) and 61 healthy controls completed 25-50 days of continuous actigraphy. The Composite Scale of Morningness (CSM) was completed by a subset of this group. Daytime activity midpoint was calculated for each daytime interval, excluding naps. Evening chronotype was defined as having a daytime interval midpoint at or after 16:15:00 (4:15:00 PM). RESULTS: BD versus controls had delayed daytime midpoint (mean ±â€¯standard deviation) (16:49:07 ±â€¯01:26:19 versus 16:12:51 ±â€¯01:02:14, p < 0.01), and greater midpoint variability (73.3 ±â€¯33.9 min versus 58.1 ±â€¯18.3 min, p < 0.01). Stratifying by gender and age, females and adolescents with BD had delayed and more variable daytime midpoints versus controls. Adults with BD had greater midpoint variability than controls. Within-person mean and standard deviations of daytime midpoints were highly correlated with sleep midpoints (r = 0.99, p < 0.01 and r = 0.86, p < 0.01, respectively). Daytime midpoint mean was also significantly correlated with the CSM (r = -0.56, p < 0.01). LIMITATIONS: Small sample size; analyses not fully accounting for daytime napping. CONCLUSIONS: Wrist actigraphy for determination of daytime midpoints is a potential tool to identify objective chronotype. Exploration of the use of consumer devices (wearables/smartphones) is needed.

Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder.

PURPOSE: To retrospectively assess lurasidone effectiveness/efficacy/tolerability in bipolar disorder (BD) patients. METHODS: Outpatients assessed with Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation received naturalistically administered (primarily adjunctive) open lurasidone while monitored at visits with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form. RESULTS: Sixty-one patients (32 type I, 26 type II, 3 type not otherwise specified; mean ± SD age, 45.1 ± 14.0 years; 63.9% were female) received lurasidone with 3.1 ± 1.4 (≥2 in 88.5%, monotherapy in only 3.3%) other nonanxiolytic/hypnotic prescription psychotropics, started during syndromal depression in 57.4%, subsyndromal depression in 23.0%, and euthymia in 19.7%. Lurasidone was taken for median 126 days, with final dose 55.6 ± 30.8 mg/d. By final visit taking lurasidone, syndromal depression rate decreased by nearly one-half to 31.1%, and euthymia rate more than doubled to 42.6%, whereas subsyndromal depression rate was unchanged at 23.0%. Clinical Global Impressions-BD-Overall Severity improved significantly only in patients with baseline syndromal depression. Seventy-seven percent of patients discontinued lurasidone after median 103 days, because of adverse events in 54.1% (most often akathisia, sedation/somnolence, nausea, and weight gain), inefficacy in 16.4%, and other reasons in 6.6%; 12.1% had equal to or greater than 7% weight gain, and 3.3% developed hypomania. Limitations to this study were the open design and demographically homogeneous (relatively affluent, predominantly white female) small sample taking complex pharmacotherapy. CONCLUSIONS: In American specialty clinic BD outpatients, adjunctive longer-term lurasidone commonly relieved syndromal depression and maintained euthymia, suggesting possible effectiveness/efficacy. However, lurasidone was discontinued in 54.1% because of adverse events, suggesting tolerability limitations in these challenging patients, nearly 90% of whom were already taking at least 2 other nonanxiolytic/hypnotic prescription psychotropics.

Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients.

AIMS: Antidepressant use is controversial in bipolar disorder (BD) due to questionable efficacy/psychiatric tolerability. We assessed demographic/clinical characteristics of baseline antidepressant use in BD patients. METHODS: Prevalence and correlates of baseline antidepressant use in 503 BD I and BD II outpatients referred to the Stanford Bipolar Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. RESULTS: Antidepressant use was 39.0%, overall, and was higher in BD II versus BD I (46.9% versus 30.5%, p = 0.0002). Both BD I and BD II antidepressant compared to non-antidepressant users had higher rates of complex pharmacotherapy (≥ 4 mood stabilizers, antipsychotics, and/or antidepressants) and use of other psychotropics. Antidepressant use in BD II versus BD I was higher during euthymia (44.0% vs. 28.0%) and subsyndromal symptoms (56.1% vs. 28.6%), but not depression or mood elevation. LIMITATIONS: American tertiary BD clinic referral sample receiving open naturalistic treatment. CONCLUSIONS: In our sample, antidepressant use was higher in BD II versus BD I patients, and was associated with markers of heightened illness severity in both BD I and BD II patients. Additional research is warranted to investigate these complex relationships.

Subjective versus objective evening chronotypes in bipolar disorder.

BACKGROUND: Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls. METHODS: We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, ¾, ⅔, and ½ SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data. RESULTS: BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of ≥ 95% with that made using the 75% of sleep intervals threshold. LIMITATIONS: Limited sample size/generalizability. CONCLUSIONS: Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls.

Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder.

BACKGROUND: Abnormal sleep duration (ASD, <6 or ≥9h) is common in bipolar disorder (BD), and often persists beyond acute mood episodes. Few longitudinal studies have examined the ASD's impact upon BD illness course. The current study examined the longitudinal impact of ASD upon bipolar depressive recurrence/recovery. METHODS: Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form at monthly follow-ups for up to two years of naturalistic treatment. Prevalence and clinical correlates of ASD in 93 recovered (euthymic ≥8 weeks) and 153 depressed BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between baseline ASD and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators. RESULTS: ASD was only half as common among recovered versus depressed BD outpatients, but was significantly associated with hastened depressive recurrence (Log-Rank p=0.007), mediated by lifetime anxiety disorder and attenuated by lifetime history of psychosis, and had only a non-significant tendency towards association with delayed depressive recovery (Log-Rank p=0.07). In both recovered and depressed BD outpatients, baseline ASD did not have significant association with any baseline BD illness characteristic. LIMITATIONS: Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample. CONCLUSIONS: Baseline ASD among recovered BD patients may be a risk marker for hastened depressive recurrence, suggesting it could be an important therapeutic target between mood episodes.

Sleep in Adolescents With Bipolar I Disorder: Stability and Relation to Symptom Change.

Sleep disturbances are common features of bipolar disorder (BD), yet little is known about trajectories of sleep disturbances in youth with BD. Using longitudinal data, this study assessed the stability of sleep disturbances and their ability to predict symptom progression in adolescents diagnosed with BD compared to controls. Thirteen- to 19-year-olds meeting diagnostic criteria for BD I (n = 19, 16.2 ± 1.75 years, 57.9 % female, 68.4% Caucasian) and psychiatrically healthy age-comparable controls (n = 21, 15.7 ± 1.48 years. 52.4% female, 57.1% Caucasian) were assessed for sleep onset latency, number of awakenings, and wake time, separately for weekdays and weekends using a self-report questionnaire. Sleep indices and symptoms of mania (Young Mania Rating Scale) and depression (Children's Depression Rating Scale) were assessed at two time points, T1 and T2, approximately 12 months apart. Correlations were used to examine stability of sleep indices across time points and regression models to examine the effects of T1 sleep on T2 symptoms. Adolescents with BD showed low stability on most sleep indices, whereas controls showed high stability on all sleep indices. After controlling for T1 depression symptoms, more T1 weekend awakenings and weekend wake time predicted significantly greater T2 depression symptoms in youth with BD but not in controls. No significant associations were found between T1 sleep and T2 mania symptoms. These findings suggest that increased awakenings and wakefulness on weekends may represent an important therapeutic target for reducing depression in adolescents with BD.

Daily Actigraphy Profiles Distinguish Depressive and Interepisode States in Bipolar Disorder.

Disruptions in activity are core features of mood states in bipolar disorder (BD). This study sought to identify activity patterns that discriminate between mood states in BD. Locomotor activity was collected using actigraphy for six weeks in participants with inter-episode BD type I (n=37) or participants with no lifetime mood disorders (n=39). The 24-hour activity pattern of each participant-day was characterized and within-person differences in activity patterns were examined across mood states. Results show that among participants with BD, depressive days are distinguished from other mood states by an overall lower activity level, and a pattern of later activity onset, a midday elevation of activity, and low evening activity. No distinct within-person activity patterns were found for hypomanic/manic days. Since activity can be monitored non-invasively for extended time periods, activity pattern identification may be leveraged to detect mood states in BD, thereby providing more immediate delivery of care.

Clinical significance of mobile health assessed sleep duration and variability in bipolar disorder.

OBJECTIVE: Sleep disturbances are prevalent, persistent, and impairing features of bipolar disorder. However, the near-term and cumulative impact of the severity and variability of sleep disturbances on symptoms and functioning remains unclear. We examined self-reported daily sleep duration and variability in relation to mood symptoms, medication adherence, cognitive functioning, and concurrent daily affect. METHODS: Forty-one outpatients diagnosed with bipolar disorder were asked to provide daily reports of sleep duration and affect collected via ecological momentary assessment with smartphones over eleven weeks. Measures of depressive and manic symptoms, medication adherence, and cognitive function were collected at baseline and concurrent assessment of affect were collected daily. Analyses examined whether sleep duration or variability were associated with baseline measures and changes in same-day or next-day affect. RESULTS: Greater sleep duration variability (but not average sleep duration) was associated with greater depressive and manic symptom severity, and lower medication adherence at baseline, and with lower and more variable ratings of positive affect and higher ratings of negative affect. Sleep durations shorter than 7-8 h were associated with lower same-day ratings of positive and higher same-day ratings of negative affect, however this did not extend to next-day affect. CONCLUSIONS: Greater cumulative day-to-day sleep duration variability, but not average sleep duration, was related to more severe mood symptoms, lower self-reported medication adherence and higher levels of negative affect. Bouts of short- or long-duration sleep had transient impact on affect. Day-to-day sleep variability may be important to incorporate into clinical assessment of sleep disturbances in bipolar disorder.

The Influence of Trauma, Life Events, and Social Relationships on Bipolar Depression.

A growing body of research suggests that the social environment exerts a powerful influence on the course of bipolar depression. This article reviews longitudinal research to suggest that trauma, negative life events, social support deficits, and family difficulties are common and predict a more severe course of depression when present among those diagnosed with bipolar disorder. The triggers of bipolar depression overlap with those documented for unipolar depression, suggesting that many of the treatment targets for unipolar depression may be applicable for bipolar depression.

Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography.

STUDY OBJECTIVES: Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups. METHODS: One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant. RESULTS: PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d). CONCLUSIONS: Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.