Challenges in defining treatment-resistant mania in adults: A systematic review.

OBJECTIVES: To review the definitions of treatment-resistant mania (TRM) in the literature and propose criteria for an operationalized definition. METHODS: A systematic search of five databases (MEDLINE, EMBASE, PsychInfo, Cochrane Central, and CINAHL) and data extraction of eligible articles. RESULTS: In total, 47 articles addressing the concept of TRM were included, comprising 16 case reports, 11 case series, 3 randomized clinical trials, 8 open-label clinical trials, 1 experimental study, 7 narrative reviews, and 1 systematic review. While reviews discussed several challenges in defining TRM, definitions varied substantially based on different criteria for severity of mania, duration of mania, and use of specific therapeutic agents with minimal dosages and duration of treatment. Only a handful of the reviewed articles operationalized these criteria. CONCLUSION: While the concept of TRM has been discussed in the literature for over three decades, we could not find an agreed-upon operationalized definition based on specific criteria. We propose and discuss a possible definition that could be used by clinicians to guide their practice and by researchers to assess the prevalence of TRM and develop and test interventions targeting TRM.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project: Understanding older-age bipolar disorder by combining multiple datasets.

OBJECTIVE: There is a dearth of research about the aging process among individuals with bipolar disorder (BD). One potential strategy to overcome the challenge of interpreting findings from existing limited older-age bipolar disorder (OABD) research studies is to pool or integrate data, taking advantage of potential overlap or similarities in assessment methods and harmonizing or cross-walking measurements where different measurement tools are used to evaluate overlapping construct domains. This report describes the methods and initial start-up activities of a first-ever initiative to create an integrated OABD-focused database, the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project. METHODS: Building on preliminary work conducted by members of the International Society for Bipolar Disorders OABD taskforce, the GAGE-BD project will be operationalized in four stages intended to ready the dataset for hypothesis-driven analyses, establish a consortium of investigators to guide exploration, and set the stage for prospective investigation using a common dataset that will facilitate a high degree of generalizability. RESULTS: Initial efforts in GAGE-BD have brought together 14 international investigators representing a broad geographic distribution and data on over 1,000 OABD. Start-up efforts include communication and guidance on meeting regulatory requirements, establishing a Steering Committee to guide an incremental analysis strategy, and learning from existing multisite data collaborations and other support resources. DISCUSSION: The GAGE-BD project aims to advance understanding of associations between age, BD symptoms, medical burden, cognition and functioning across the life span and set the stage for future prospective research that can advance the understanding of OABD.

Differences in presentation and survival of Asians compared to Caucasians with ovarian cancer: An NRG Oncology/GOG Ancillary study of 7914 patients.

PURPOSE: To compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer. METHODS: Ancillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed. RESULTS: Of 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p < 0.001), and were more likely to be of clear cell (15.8% vs. 6.2%, p < 0.001) and mucinous (3.3% vs. 1.9%, p < 0.001) histology. Asians had an improved 5-year disease-specific survival of 54.1% compared to 46.1% for Caucasians, p = 0.001. In multivariate analysis, the Asian race remained a significant prognostic factor for all-cause survival (HR: 0.84; 95% CI: 0.72-0.99; p = 0.04). Other factors predictive of improved survival included younger age, better performance status, optimal cytoreduction, earlier stage, non-clear cell histology, and lower grade tumors. CONCLUSION: Asians enrolled into phase III ovarian cancer clinical trials were younger, with better performance status, earlier-stage of disease, and have a greater number of clear cell and mucinous tumors. After adjusting for these prognostic factors, Asians have a better survival compared to Caucasians.

Understanding Aging in Bipolar Disorder by Integrating Archival Clinical Research Datasets.

OBJECTIVE: Although 25% of people with bipolar disorder (BD) are over age 60, there is a dearth of research on older age bipolar disorder (OABD). This report describes an initial effort to create an integrated OABD database using the U.S. National Institute of Mental Health Data Archive (NDA). Goals were to: 1) combine data from three BD studies in the United States that included overlapping data elements; 2) investigate research questions related to aims of the original studies; and 3) take an important first step toward combining existing datasets relevant to aging and BD. METHODS: Data were prepared and uploaded to the NDA, with a focus on data elements common to all studies. As appropriate, data were harmonized to select or collapse categories suitable for cross-walk analysis. Associations between age, BD symptoms, functioning, medication load, medication adherence, and medical comorbidities were assessed. The total sample comprised 451 individuals, mean age 57.7 (standard deviation: 13.1) years. RESULTS: Medical comorbidity was not significantly associated with either age or functioning and there did not appear to be an association between medication load, comorbidity, age, and adherence. Men and African-Americans were significantly more likely to have poor adherence. Both BD mania and depression symptoms were associated with functioning, but this differed across studies. CONCLUSION: Despite limitations including heterogeneity in study design and samples and cross-sectional methodology, integrated datasets represent an opportunity to better understand how aging may impact the presentation and evolution of chronic mental health disorders across the lifespan.

Assessing bipolar disorder in the older adult: the GERI-BD toolbox.

INTRODUCTION: The evidence base regarding characteristics of older adults with bipolar disorder (BD) remains limited. The NIH-funded multicenter study Acute Pharmacotherapy of Late-Life Mania (GERI-BD) assessed various clinical domains before and during mood stabilizer treatment in older adults participating in a 9-week, double-blind randomized controlled trial. We describe the rationale for selecting these instruments. METHODS: Domains and instruments were selected on the basis of the study design and the participants. The investigators' experience in clinical trials involving young adults with BD or older adults with major depressive disorder, along with open studies of older adults with BD, contributed to the selection process. RESULTS: We identified domains and selected instruments that could be used to assess the participants given their diagnostic, treatment history, and medical and mood state characteristics. They were also intended to measure tolerability and efficacy and permit examination of potential moderating and mediating factors. CONCLUSIONS: Decisions regarding the assessment domains to be included in the clinical trial highlight the challenges facing researchers studying drug treatments for older adults with BD, or more generally, mood disorders. We suggest that the domains and instruments selected by GERI-BD investigators constitute a "toolbox" that can be customized for other investigators. Copyright © 2017 John Wiley & Sons, Ltd.

A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force.

OBJECTIVES: In the coming generation, older adults with bipolar disorder (BD) will increase in absolute numbers as well as proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older-Age Bipolar Disorder (OABD). METHODS: This task force report addresses the unique aspects of OABD including epidemiology and clinical features, neuropathology and biomarkers, physical health, cognition, and care approaches. RESULTS: The report describes an expert consensus summary on OABD that is intended to advance the care of patients, and shed light on issues of relevance to BD research across the lifespan. Although there is still a dearth of research and health efforts focused on older adults with BD, emerging data have brought some answers, innovative questions, and novel perspectives related to the notion of late onset, medical comorbidity, and the vexing issue of cognitive impairment and decline. CONCLUSIONS: Improving our understanding of the biological, clinical, and social underpinnings relevant to OABD is an indispensable step in building a complete map of BD across the lifespan.

Social support in late life mania: GERI-BD.

OBJECTIVE: Using the database of the National Institute of Mental Health-sponsored acute treatment of late life mania study (GERI-BD), we assessed the role of social support in the presentation of late life bipolar mania. METHODS: In the first 100 subjects randomized in geriatric BD, we explored the demographic, clinical, and social support characteristics (assessed using the Duke Social Support Index) and aspects of manic presentation. We selected two dependent variables: symptom severity, as determined by the Young Mania Rating Scale (YMRS) at baseline, and duration of episode. We selected nine potential independent variables on the basis of Pearson correlation coefficients. We derived two final models using multiple regression analysis employing an iterative process. RESULTS: In our severity model, being married was associated with a higher YMRS score (p = 0.05), whereas higher social interaction scores with non-family members were associated with a lower YMRS score (p = 0.011). In the episode duration model, longer duration was associated with a higher Hamilton Depression Rating Scale score (p = 0.03) and higher social interaction scores with non-family members (p = 0.0003), younger age (p = 0.04), higher number of persons in one's family social network (p = 0.017), and higher instrumental support scores (p = 0.0062). CONCLUSIONS: In late life mania, more social interaction with one's community appears to be associated with less severe symptoms at presentation for treatment, however, it can also be associated with slightly longer the duration of episode. Two aspects of the Duke Social Support Index are associated with a shorter episode duration prior to seeking treatment: being part of a larger family network and a having a higher level of instrumental support prior to treatment. The Instrumental Support Subscale measures the degree of assistance that is available for the respondent in performing daily tasks. These findings suggest that in older adults with BD, close social interactions and support are important in limiting the length of the illness episode prior to treatment. Social interactions involving non-family members may be less important in moderating the intensity of the symptoms at presentation.

Symptoms and observations: differences in time course during electroconvulsive therapy in geriatric depressed patients.

Electroconvulsive therapy is used for the management of severe and refractory depression across the age spectrum. Treatment is guided by clinical response. However, there may be differences between the time course of improvement in clinical observations and patients' self-report of improvements. We report 4 cases of depression in late life that illustrate this issue. We discuss the potential significance of such differences and the need for research.

A descriptive study of older bipolar disorder residents living in New York City's adult congregate facilities.

OBJECTIVES: Much of the research on geriatric bipolar disorder is from outpatient populations or epidemiological surveys with small samples. In contrast, in this study a descriptive analysis was conducted of geriatric and younger adult residents with bipolar disorder or mania in non-clinical adult congregate facilities (ACFs) in the greater New York City region. METHODS: A total of 2602 ACF residents were evaluated in 19 facilities, across multiple demographic and health domains. Within this sample, 200 residents had chart diagnoses of bipolar disorder or mania. Among these, 50 geriatric residents (age ≥ 60) were compared to 50 younger adult residents (age < 50) on a number of demographic and health measures. RESULTS: Based on chart diagnoses, the overall prevalence of bipolar disorder was 7.8%. Compared to other studies of outpatient, epidemiological, and census samples, both older and younger residents with bipolar disorder had higher rates of cognitive impairment, impairment in executive functioning, vision impairment, and proportion of residents who had never been married. The younger group also had higher rates of obesity and the elderly group had a greater proportion of residents without high-school education. Both age groups had rates of lithium or valproate use comparable to those found in outpatient studies. Comparing the two age groups, the elderly sample had lower overall cognitive and executive functioning, and was using a larger number of medication classes than the younger group. The elderly group also had a larger proportion of residents who were separated/divorced or widowed compared to the younger group, which had higher rates of never-married residents. CONCLUSIONS: Overall, both age groups had relatively high rates of bipolar disorder, with significant cognitive impairment, medical burden, obesity, mental health service use, and lower education levels, as compared to outpatient, epidemiological, and census samples. Of note was the significant cognitive impairment across age groups.

A patient with bipolar disorder and antiphospholipid syndrome.

Antiphospholipidsyndrome (APS) is an autoimmune disorder which causes a hyper-coagulable state characterized by recurrent thrombosis. It has a diverse range of central nervous system manifestations. We describe a case of a 61 year old man with bipolar disorder and APS, and we compare this to a previously reported case. Additionally, we reviewed literature regarding APS-related markers and the relationship of APS to other psychiatric and neurologic illnesses. We discuss possible mechanisms for an association between APS and bipolar disorder. We encourage clinicians to be aware of this possible relationship and have proposed research strategies.

Correlates of treatment response in depressed older adults with bipolar disorder.

AIMS: To identify baseline clinical factors associated with acute treatment response in depressed older adults with bipolar disorder (BD) receiving lamotrigine. METHODS: Secondary analysis of a multisite, 12-week, open-label, uncontrolled study of add-on lamotrigine in 57 adults 60 years and older with BD I or II depression. Measures included the Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Cardiometabolic risk was measured with total serum cholesterol and the Cumulative Illness Rating Scale-Geriatric (CIRS-G) item #13 (endocrine/metabolic burden). Neurocognitive (executive) function was evaluated using the Trail Making Test. RESULTS: Greater reduction in MADRS from baseline was associated with higher baseline cardiometabolic burden at 6 and 9 weeks and lower YMRS scores at 9 weeks. At 12 weeks, improvement in the MADRS from baseline was no longer significantly related to baseline cardiometabolic burden or YMRS scores. A longitudinal mixed model of MADRS scores corroborated these findings with a significant finding of time-by-baseline cholesterol level interaction. In a subset of participants, better baseline executive function was related to greater improvement in the MADRS at 9 weeks but not at 6 or 12 weeks. Among all participants, higher baseline YMRS scores were related to greater likelihood of dropout. CONCLUSIONS: Lamotrigine appears to work best in depressed elderly patients with BD who have high cardiometabolic risk and low level of mania. Agents like lamotrigine that act primarily on neuroprogressive pathways involving oxidative stress, neurotrophins, and inflammation may be particularly effective in individuals with BD who have significant cardiometabolic burden because of their effects on shared vulnerability factors in BD and medical illness.

Characteristics associated with inpatient versus outpatient status in older adults with bipolar disorder.

OBJECTIVES: This is an exploratory analysis of ambulatory and inpatient services utilization by older persons with type I bipolar disorder experiencing elevated mood. The association between type of treatment setting and the person's characteristics is explored within a framework that focuses upon predisposing, enhancing, and need characteristics. METHOD: Baseline assessments were conducted with the first 51 inpatients and 49 outpatients 60 years of age and older, meeting criteria for type I bipolar disorder, manic, hypomanic, or mixed episode enrolled in the geriatric bipolar disorder study (GERI-BD) study. We compared participants recruited from inpatient versus outpatient settings in regard to the patients' predisposing, enabling, and need characteristics. RESULTS: Being treated in an inpatient rather than an outpatient setting was associated with the predisposing characteristic of being non-Hispanic caucasian (odds ratio [OR]: 0.1; P = .005) and past history of treatment with first-generation antipsychotics (OR: 6.5; P < .001), and the need characteristic reflected in having psychotic symptoms present in the current episode (OR: 126.08; P < .001). CONCLUSION: Ethnicity, past pharmacologic treatment, and current symptom severity are closely associated with treatment in inpatient settings. Clinicians and researchers should investigate whether closer monitoring of persons with well-validated predisposing and need characteristics can lead to their being treated in less costly but equally effective ambulatory rather than inpatient settings.

ECT use in unipolar and bipolar depression.

BACKGROUND: Few studies have compared response to electroconvulsive therapy (ECT) in depressed patients with unipolar and bipolar disorder. METHODS: We reviewed the charts of inpatients with unipolar or bipolar depression who received open treatment with right unilateral ECT. We compared the number of treatments, demographics, and change in Global Assessment of Functioning scores and length of hospital stay in both groups. RESULTS: Whereas changes in Global Assessment of Functioning scores and length of stay overlapped, the number of treatments in patients with bipolar disorder (mean ± SD, 7.5 ± 1.6) was lower than that in patients with unipolar disorder (mean ± SD, 10.2 ± 1.9). CONCLUSION: Fewer ECT treatments may be required to achieve similar benefit in patients with bipolar disorder compared to patients with unipolar disorder.

Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report.

AIMS: This is a multisite, 12-week, open-label trial of lamotrigine augmentation in 57 older adults (≥ 60 years; mean ± SD age = 66.5 ± 6.7 years) with either type I or type II bipolar depression. METHODS: Primary outcome measure was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule II (WHO-DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess side effects. RESULTS: A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. CONCLUSIONS: In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression.

Depression symptom ratings in geriatric patients with bipolar mania.

OBJECTIVE: Given the paucity of information available regarding standardized ratings of depression symptoms in bipolar manic states, and in particular those in older adults, we explored depression ratings in symptomatic participants in a multicenter study of treatment of bipolar I disorder in late life. METHODS: Baseline data was obtained from the first 100 patients enrolled in an NIMH-funded, 9-week, randomized, double-blind RCT comparing treatment with lithium or valproate in patients of age 60 years and older with Type I Bipolar mania or hypomania. This multi-site study was conducted at six academic medical centers in the United States and enrolled inpatients and outpatients with a total Young Mania Rating Scale (YMRS) score of 18 or greater. Depressive symptoms were evaluated with the Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS). The criterion for at least moderate bipolar depressive symptoms was the European College of Neuropsychopharmacology (ECNP) Consensus Meeting definition of HAM-D 17 total score >20. RESULTS: Eleven percent of patients had mixed symptoms defined by depression scale severity according to ECNP criterion. In the overall sample, total scores on the two depression scales were highly correlated. Total YMRS scores of this mixed symptom group were similar to the remainder of the sample. CONCLUSIONS: These preliminary findings suggest that moderate to severe depressive symptoms occur in about one in ten bipolar manic elders. Future studies are needed to further evaluate symptom profiles, clinical correlates, and treatments for bipolar older adults with combined manic and depressive symptoms.

The relationship of bipolar disorder lifetime duration and vascular burden to cognition in older adults.

OBJECTIVES: We describe the cognitive function of older adults presenting with bipolar disorder (BD) and mania and examine whether longer lifetime duration of BD is associated with greater cognitive dysfunction. We also examine whether there are negative, synergistic effects between lifetime duration of BD and vascular disease burden on cognition. METHODS: A total of 87 nondemented individuals with bipolar I disorder, age 60 years and older, experiencing manic, hypomanic, or mixed episodes, were assessed with the Dementia Rating Scale (DRS) and the Framingham Stroke Risk Profile (FSRP) as a measure of vascular disease burden. RESULTS: Subjects had a mean (SD) age of 68.7 (7.1) years and 13.6 (3.1) years of education; 50.6% (n = 44) were females, 89.7% (n = 78) were white, and 10.3% (n = 9) were black. They presented with overall and domain-specific cognitive impairment in memory, visuospatial ability, and executive function compared to age-adjusted norms. Lifetime duration of BD was not related to DRS total score, any other subscale scores, or vascular disease burden. FSRP scores were related to the DRS memory subscale scores, but not total scores or any other domain scores. A negative interactive effect between lifetime duration of BD and FSRP was only observed with the DRS construction subscale. CONCLUSIONS: In this study, lifetime duration of BD had no significant relationship with overall cognitive function in older nondemented adults. Greater vascular disease burden was associated with worse memory function. There was no synergistic relationship between lifetime duration of BD and vascular disease burden on overall cognition function. Addressing vascular disease, especially early in the course of BD, may mitigate cognitive impairment in older age.