Lithium-discontinuation-induced treatment refractoriness revisited.

BACKGROUND: Lithium is effective in the long-term treatment of bipolar disorder. Concerns have been raised about non-responsiveness after discontinuation and resuming previously effective lithium prophylaxis. We reviewed the available literature on this so-called lithium-discontinuation-induced treatment refractoriness (LDITR). RESULTS: We found 11 case reports and six cohort studies including 403 patients addressing LDITR, and one nation-wide register study providing some additional data on LDITR. Pooling all cohort studies, the percentages of non-responders during re-treatment with lithium ranged from 3.6 to 27.7%, with an average of 17.3%. Non-responsiveness was associated with longer duration of lithium treatment before discontinuation, longer duration of bipolar disorder before start of lithium, faster tapering off lithium, and longer duration of discontinuation. CONCLUSIONS: There may be a subgroup in whom lithium discontinuation-induced treatment refractoriness exists. However, the vast majority of people respond when lithium is restarted. Moreover, it may be necessary to continue lithium beyond the first relapses to restore long-term prophylactic efficacy.

Predicting which intervention works better for whom: Moderators of treatment effect of Mindfulness-Based Cognitive Therapy and Positive Psychology Intervention in patients with bipolar disorder.

BACKGROUND: This study aimed to identify moderators of treatment effect (i.e. depressive symptoms and well-being) of Mindfulness-Based Cognitive Therapy (MBCT) and Positive Psychology Intervention (PPI) in patients with bipolar disorder. METHODS: Data were drawn from two multicenter randomized controlled trials investigating effectiveness of MBCT vs treatment as usual (TAU; n = 144) and PPI vs TAU (n = 97) in bipolar disorder. Outcomes were assessed at baseline, posttreatment, and 12 months after baseline. Data were analyzed using separate linear regression models, comparing the pooled MBCT or PPI outcomes to TAU, and comparing MBCT to PPI. RESULTS: The exploratory analyses not corrected for multiple comparisons showed a number of variables that were associated with stronger response to the interventions, including higher baseline anxiety, lower well-being, and lower levels of self-focused positive rumination, well-being, and self-compassion, and variables associated with a stronger response to either MBCT (higher levels of depression and anxiety and being married) or PPI (being male). After correcting for multiple testing, depressive symptoms appeared to be the most robust variable associated with better response to MBCT than PPI. LIMITATIONS: The RCTs handled slightly different enrollment criteria and outcome measures. CONCLUSIONS: The most robust finding is that patients with more severe symptomatology seem to benefit more from MBCT than PPI. CLINICAL IMPLICATIONS: This is a first step to improve personalized assignment of third-wave CBT interventions for patients with bipolar disorder. However, before definite treatment assignment criteria can be formulated and implemented in clinical practice, these findings should be replicated.

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

Do you feel up when you go up? A pilot study of a virtual reality manic-like mood induction paradigm.

OBJECTIVES: In order to understand the working mechanisms of mania, it is necessary to perform studies during the onset of manic (-like) mood states. However, clinical mania is difficult to examine experimentally. A viable method to study manic mood like states is mood induction, but mood induction tasks thus far show variable effectiveness. METHODS: In this pilot study, a new paradigm to induce mood through virtual reality (VR) is examined. Both state characteristics, namely changes in emotion, and trait characteristics, such as high and low scores on the hypomanic personality scale (HPS), were measured in 65 students. These students participated in either a neutral VR mood induction or an activating VR mood induction in which excitement, goal directedness, and tension (being aspects of mania) were induced. All participants performed a risk-taking behavioural task, Balloon Analogue Risk Task (BART). RESULTS: The experimental VR task induced excitement and tension. In participants with higher sensitivity to hypomanic personality (HPS), irritation increased in response to activation whereas it decreased in the low HPS group, and excitement increased more steeply in the low HPS group. There were no effects on the behavioural task. CONCLUSIONS: The VR task is effective in inducing relevant state aspects of hypomania and is suitable as a paradigm for future experimental studies. Activation of dual affective states (excitement and tension) is an essential aspect in manic-like mood induction paradigms.

Feasibility and Acceptability of Group Interpersonal and Social Rhythm Therapy for Recurrent Mood Disorders: A Pilot Study.

OBJECTIVE: Interpersonal and social rhythm therapy (IPSRT) was developed to empower patients with mood disorders by stabilizing underlying disturbances in circadian rhythms and by using strategies from interpersonal psychotherapy. Group IPSRT has not been studied with a transdiagnostic sample of patients across the life span with either major depressive disorder or bipolar disorder. METHODS: Thirty-eight outpatients, ages 26-80, with major depressive disorder or bipolar disorder in any mood state were recruited from clinics in the Netherlands and were treated with 20 sessions (two per week) of group IPSRT. Recruitment results, dropout rates, and session adherence were used to assess feasibility. The modified Client Satisfaction Questionnaire (CSQ) and a feedback session were used to measure treatment acceptability. Changes in mood symptoms, quality of life, and mastery were also measured. RESULTS: Participants' mean±SD age was 65.4±10.0 years. Participants were diagnosed as having major depressive disorder (N=14, 37%) or bipolar disorder (N=24, 63%). The dropout rate was relatively low (N=9, 24%). High CSQ scores (32.3±5.2 of 44.0 points) and low dropout rates indicated the acceptability and feasibility of group IPSRT for major depressive disorder and bipolar disorder. Quality of life 3 months after completion of treatment was significantly higher than at baseline (p<0.01, Cohen's d=-0.69). No significant differences were found between pre- and postintervention depressive symptom scores. CONCLUSIONS: Twice-weekly group IPSRT for older outpatients with major depressive disorder or bipolar disorder was feasible and acceptable. Future research should evaluate the short- and long-term efficacy of group IPSRT for major depressive disorder and bipolar disorder among patients of all ages.

Accelerated brain aging as a biomarker for staging in bipolar disorder: an exploratory study.

BACKGROUND: Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. METHODS: In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. RESULTS: A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. CONCLUSIONS: These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.

Bipolarity in Older individuals Living without Drugs (BOLD): Protocol and preliminary findings.

INTRODUCTION: Although clinical guidelines regard prophylactic medication as the cornerstone of treatment, it is estimated almost half of patients with bipolar disorder (BD) live without medication. This group is underrepresented in research but can provide indispensable knowledge on natural course, resilience and self-management strategies. We aim to describe the clinical phenotype of patients diagnosed with BD who have discontinued maintenance treatment. METHODS: The mixed-methods BOLD study included 58 individuals aged 50 years and over with BD that did not use maintenance medication in the past 5 years. A preliminary, quantitative comparison of clinical characteristics between BOLD and our pre-existing cohort of >220 older BD outpatients with medication (Dutch Older Bipolars, DOBi) was performed. RESULTS: BD-I, psychiatric comorbidities, number of mood episodes and lifetime psychotic features were more prevalent in BOLD compared to DOBi. BOLD participants had a younger age at onset and reported more childhood trauma. BOLD participants reported fewer current mood symptoms and higher cognitive, social, and global functioning. LIMITATIONS: Our findings may not be generalizable to all individuals diagnosed with BD living without maintenance medication due to selection-bias. CONCLUSION: A group of individuals exists that meets diagnostic criteria of BD and is living without maintenance medication. They appear to be relatively successful in terms of psychosocial functioning, although they do not have a milder clinical course than those on maintenance medication. The high prevalence of childhood trauma warrants further investigation. Future analyses will examine differences between BOLD and DOBi per domain (e.g. cognition, physical health, psychosocial functioning, coping).

A multicomponent positive psychology intervention for euthymic patients with bipolar disorder to improve mental well-being and personal recovery: A pragmatic randomized controlled trial.

OBJECTIVE: Mental well-being and personal recovery are important treatment targets for patients with bipolar disorder (BD). The goal of this study was to evaluate the effectiveness of an 8-week group multicomponent positive psychology intervention (PPI) for euthymic patients with BD as an adjunct to treatment as usual (TAU) compared to TAU alone. METHODS: Patients with BD were randomized to receive TAU (n = 43) or the PPI in addition to TAU (n = 54). The primary outcome was well being measured with the Mental Health Continuum-Short Form. Personal recovery was measured with the Questionnaire about the Process of Recovery. Data were collected at baseline, mid-treatment, post-treatment and 6- and 12-month follow-up. Life chart interviews were conducted at 12 months to retrospectively assess recurrence of depression and mania. RESULTS: Significant group-by-time interaction effects for well-being and personal recovery were found favouring the PPI. At post-treatment, between-group differences were significant for well-being (d = 0.77) and personal recovery (d = 0.76). Between-group effects for well-being were still significant at 6-month follow-up (d = 0.72). Effects on well-being and personal recovery within the intervention group were sustained until 12-month follow-up. Survival analyses showed no significant differences in time to recurrence. CONCLUSIONS: The multicomponent PPI evaluated in this study is effective in improving mental well-being and personal recovery in euthymic patients with BD and would therefore be a valuable addition to the current treatment of euthymic BD patients. The fact that the study was carried out in a pragmatic RCT demonstrates that this intervention can be applied in a real-world clinical setting.

Development and validation of a Manic Thought Inventory.

OBJECTIVE: This article describes the development and psychometric evaluation of the Manic Thought Inventory (MTI), a patient-driven self-report inventory to assess the presence of typical (hypo)manic cognitions. METHODS: The initial item pool was generated by patients with bipolar disorder (BD) type I and assessed for suitability by five psychiatrists specialized in treating BD. Study 1 describes the item analysis and exploratory factor structure of the MTI in a sample of 251 patients with BD type I. In study 2, the factor structure was validated with confirmatory factor analysis, and convergent and divergent validity were assessed in an independent sample of 201 patients with BD type I. RESULTS: Study 1 resulted in a 50-item version of the MTI measuring one underlying factor. Study 2 confirmed the essentially unidimensional underlying construct in a 47-item version of the MTI. Internal consistency of the 47-item version of the MTI was excellent (α = 0.97). The MTI showed moderate to large positive correlations with other measures related to mania. It was not correlated with measures of depression. CONCLUSION: The MTI showed good psychometric properties and can be useful in research and clinical practice. Patients could use the MTI to select items that they recognize as being characteristic of their (hypo)manic episodes. By monitoring and challenging these items, the MTI could augment current psychological interventions for BD.

Bipolar I and bipolar II subtypes in older age: Results from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project.

OBJECTIVES: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD. METHODS: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept. RESULTS: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden. CONCLUSION: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population.

Course of subthreshold manic symptoms and related risk factors in the general population: A three-year follow-up study.

OBJECTIVES: Subthreshold manic symptoms (subM) are a risk factor for the onset and recurrence of bipolar disorder (BD). Individuals with subM may benefit from preventive interventions, however, their development is hampered by a lack of knowledge on subM prevalence and subsequent course. This study examines subM characteristics, course, and risk factors for an unfavourable course. METHODS: In a Dutch representative, population-based sample aged 18-64 (N = 4618), we assessed subM, defined as the occurrence of manic core symptoms (elation/irritability), without meeting full DSM-IV criteria for BD I or II in the past 3 years. Comparison groups had either no manic symptoms (noM) or hypomania/mania in the context of BD (mBD) in the past 3 years. Furthermore, we differentiated a mild and moderate type of subM, based on the number of manic symptoms. A subsequent three-year course was assessed prospectively. RESULTS: SubM had a three-year prevalence of 4.9%. Its prevalence, characteristics, and course were in between noM and mBD, and there were few differences between mild and moderate subM. Over the 3-year follow-up, 25.0% of individuals with subM had persistent subM and another 6.1% transitioned to mBD. Eleven significant risk factors for this unfavourable course were found. The most important were a history of depression/dysthymia (OR 3.75, p ≤ 0.001), living alone (OR 2.61, p ≤ 0.01) and elevated neuroticism score (OR 1.21, p ≤ 0.001). CONCLUSIONS: This study supports the validity and clinical relevance of subM as a BD prodrome. It demonstrates that subM symptoms often persist or increase during follow-up and identifies 11 risk factors that are associated with an unfavourable course.

Why patients diagnosed with bipolar disorder start, continue or discontinue health-related apps supporting their self-management.

WHAT IS KNOWN ABOUT THE SUBJECT?: Self-management is essential in the treatment of those who have bipolar disorder. There are many apps to support self-management, but we know that these apps only sometimes cover the users' needs. WHAT IS ADDED TO EXISTING KNOWLEDGE?: In our research, we made an inventory of apps that people with bipolar disorder use to cover their needs in self-management. We also have searched for the reasons to start, continue, switch or quit the use of those apps. We found that 44% (n = 18) of our respondents use health-related apps for self-management purposes. Apps for physical activity, planning and structure and apps for relaxation were most used. In the use of apps, the "freedom of choice" and user-friendliness are the most important in continuing the use of apps, while malfunctioning and "not fitting in individual needs" the main reasons were for quitting the use of apps. IMPLICATIONS FOR PRACTICE: Various apps can be used for self-management purposes as long as these apps meet the individual user's requirements. Clinicians and patients should have a broad view when looking for suitable apps and not limit the search to just professional apps. In developing new apps, patients, clinicians and developers should collaborate in the development process, requirements and design. ABSTRACT: INTRODUCTION: Self-management is one of the cornerstones in the treatment of bipolar disorder (BD). Complementing interventions by apps are seen as a good opportunity to support self-management. However, there is insufficient knowledge about understanding the use of health-related applications by consumers with BD for self-management purposes. AIM: The study aims to gain insight from patients diagnosed with BD about reasons to use, continue or discontinue health-related apps. METHOD: This study employed a mixed-method design in which 41 participants diagnosed with BD participated in a quantitative survey, and 11 participants also participated in an in-depth interview. RESULTS: The survey showed that 44% (n = 18) of the participants use health-related apps, and 26.8% (n = 11) use those apps consistently. Interviews revealed that adjustability, usability, trustworthiness and the guarantee of privacy were the main reasons determining whether participants used or terminated the use of a health-related app. IMPLICATIONS FOR PRACTICE: Although we found that a substantial number of patients diagnosed with BD use one or more apps to support self-management, their use is often discontinued due to content that needs more robust to address their needs. Besides appropriate content, tailoring and persuasive technologies will likely promote the continued use of an app for self-management purposes. Cooperation between those diagnosed with bipolar disorder and health professionals (like mental health nurses) in developing and designing applications that are aimed to support self-management in BD is necessary for successful implementation and adaptation.

Lower Switch Rate in Depressed Patients With Bipolar II Than Bipolar I Disorder Treated Adjunctively With Second-Generation Antidepressants.

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. Methods: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score ≥3 (mildly ill). Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.Reprinted from Am J Psychiatry 2006; 163:313-315, with permission from American Psychiatric Association Publishing. Copyright © 2006.

The course of psychiatric symptoms in older age bipolar disorder during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic gives us the unique opportunity to study the course of psychiatric symptoms and resilience in older adults with bipolar disorder (OABD) whilst experiencing a collective long lasting stressor. The aim of this study was to investigate the course of depressive, manic and anxiety symptoms in OABD during the first six months of COVID-19 and how loneliness and mastery are associated with this course. Mastery is defined as the control one experiences over one's life and environment. Resilience is defined as adaptation to challenging life conditions encompassing several aspects of personal resources. METHODS: In April 2020 (n = 81), June 2020 (n = 66) and September 2020 (n = 51), participants were included from the Dutch Older Bipolars (DOBi) cohort study. RESULTS: Depressive, manic and anxiety symptoms increased over all timepoints. Participants with a higher sense of mastery experienced a greater increase in depressive and anxiety symptoms. Loneliness did not interact with the course of these symptoms. CONCLUSIONS: OABD were resilient in the first months of COVID-19 outbreak, however depressive, manic and anxiety symptoms increased as the pandemic continued. Treatment strategies in coping with long lasting stressful events should include the focus on sense of mastery.

Illness progression in older-age bipolar disorder: Exploring the applicability, dispersion, concordance, and associated clinical markers of two staging models for bipolar disorder in an older population.

OBJECTIVES: The validity and applicability of two existing staging models reflecting illness progression have been studied in bipolar disorder (BD) in adults, but not in older adult populations. Staging model A is primarily defined by the number and recurrence of mood episodes, model B is defined by the level of inter-episodic functioning. This study aimed to explore the applicability, dispersion, and concordance of, and associations with clinical markers in these two staging models in older-age bipolar disorder (OABD). METHODS: Using cross-sectional data from the Dutch Older Bipolars study, OABD outpatients (N = 126, ≥50 years) were staged using models A and B. Dispersion over the stages and concordance between the models were assessed. Associations were explored between model stages and clinical markers (familial loading, childhood abuse, illness duration, episode density, treatment resistance, Mini-Mental State Examination, and composite cognitive score). RESULTS: Ninety subjects could be assigned to model A, 111 to model B, 80 cases to both. The majority (61%) had multiple relapses (model A, stage 3C) but were living independently (model B, stage I-III). Concordance between models was low. For model A, the markers childhood abuse, illness duration, and episode density significantly increased over subsequent stages. Model B was not associated with a significant change in any marker. CONCLUSIONS: Assigning stages to OABD subjects was possible for both models, with age-related adjustments for model B. Model B as currently operationalized may be less suitable for OABD or may measure different aspects of illness progression, reflected by its low correspondence with model A and lack of associated clinical markers.

A Web-Based Positive Psychology App for Patients With Bipolar Disorder: Development Study.

BACKGROUND: Patients with bipolar disorder (BD) report lower quality of life and lower levels of well-being than the general population. Despite the growing availability of psychotherapeutic and self-management interventions, important unmet needs remain. These unmet needs are closely linked to positive psychology domains. Although a growing number of studies have evaluated the impact of positive psychology interventions (PPIs) on patients with severe mental illness in general, only few have addressed the application of positive psychology for BD. OBJECTIVE: This study aimed to gain insight into the opinions of patients with BD and health care professionals about (web-based) PPIs for BD and to develop and pilot-test an app containing PPIs specifically designed for patients with BD. METHODS: The study was conducted in accordance with the Center for eHealth and Disease Management road map principles and incorporated cocreation and designing for implementation. Data were collected using focus group discussions, questionnaires, rapid prototyping, and web-based feedback on a prototype from the participants. In total, 3 focus groups were conducted with 62% (8/13) of patients with BD and 38% (5/13) of professionals. The collected data were used to develop a smartphone app containing short PPIs. The content was based on PPIs for which a solid base of evidence is available. Finally, a pilot test was conducted to test the app. RESULTS: Focus groups revealed that PPIs as part of the current BD treatment can potentially meet the following needs: offering hope, increasing self-esteem, expressing feelings, acceptance, and preventing social isolation. Some patients expressed concern that PPIs may provoke a manic or hypomanic episode by increasing positive affect. The pilot of the app showed that the PPIs are moderately to highly valued by the participants. There were no adverse effects such as increase in manic or hypomanic symptoms. CONCLUSIONS: With the systematic use of user involvement (patients and professionals) in all steps of the development process, we were able to create an app that can potentially fulfill some of the current unmet needs in the treatment of BD. We reached consensus among consumers and professionals about the potential benefits of PPIs to address the unmet needs of patients with BD. The use of PPI for BD is intriguing and can be usefully explored in further studies. We emphasize that more evaluation studies (quantitative and qualitative) that are focused on the effect of PPIs in the treatment of BD should be conducted. In addition, to establish the working mechanisms in BD, explorative, qualitative, designed studies are required to reveal whether PPIs can address unmet needs in BD.