Practices, knowledge, and attitudes about lithium treatment: Results of online surveys completed by clinicians and lithium-treated patients.

BACKGROUND: Lithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients' experiences, knowledge and attitudes about lithium may improve its clinical use. METHODS: Online anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). RESULTS: Among 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients' survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium. LIMITATIONS: Cross-sectional design with predominantly English-speaking participants from Brazil and North America. CONCLUSIONS: There is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use.

The clinical characterization of the adult patient with bipolar disorder aimed at personalization of management.

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.

Are personality disorders in bipolar patients more frequent in the US than Europe?

OBJECTIVE: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as "Europe") have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs). METHODS: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors. RESULTS: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe. CONCLUSIONS: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study.

The course of bipolar disorder in pregnant versus non-pregnant women.

BACKGROUND AND RATIONALE: Although it has been suggested that pregnancy may influence the course of bipolar disorder (BD), studies show contradictory results. Until now, no studies included a finegrained validated method to report mood symptoms on a daily basis, such as the lifechart method (LCM). The aim of the present study is to investigate the course of BD during pregnancy by comparing LCM scores of pregnant and non-pregnant women. METHODS: Study design: Comparison of LCM scores of two prospective observational BD cohort studies, a cohort of pregnant women (n = 34) and a cohort of non-pregnant women of childbearing age (n = 52). Main study parameters are: (1) proportions of symptomatic and non-symptomatic days; (2) symptom severity, frequency, and duration of episodes; (3) state sequences, longitudinal variation of symptom severity scores. RESULTS: No differences in clinical course variables (symptomatic days, average severity scores, frequency, and duration of episodes in BD were found between pregnant and non-pregnant women. With a combination of State Sequence Analysis (SSA) and cluster analysis on the sequences of daily mood scores three comparable clusters were found in both samples: euthymic, moderately ill and severely ill. The distribution differences between pregnant and non-pregnant women were significant, with a majority of the pregnant women (68%) belonging to the moderately ill cluster and a majority of the non-pregnant women (46%) to the euthymic cluster. In pregnant women the average daily variation in mood symptoms as assessed with Shannon's entropy was less than in non-pregnant women (respectively 0.43 versus 0.56). CONCLUSIONS: Although the use of daily mood scores revealed no difference in overall course of BD in pregnant versus non-pregnant women, more pregnant than non-pregnant women belonged to the moderately ill cluster, and during pregnancy the variation in mood state was less than in non-pregnant women. Further research is necessary to clarify these findings.

Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes.

BACKGROUND: Depending on the classification system used, 5-40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. METHODS: Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. RESULTS: Mean age of participants was 40 ± 12 years (range 18-81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria. CONCLUSION: Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.

The Challenges of Children with Bipolar Disorder.

Childhood onset bipolar disorder (CO-BD) presents a panoply of difficulties associated with early recognition and treatment. CO-BD is associated with a variety of precursors and comorbidities that have been inadequately studied, so treatment remains obscure. The earlier the onset, the longer is the delay to first treatment, and both early onset and treatment delay are associated with more depressive episodes and a poor prognosis in adulthood. Ultra-rapid and ultradian cycling, consistent with a diagnosis of BP-NOS, are highly prevalent in the youngest children and take long periods of time and complex treatment regimens to achieve euthymia. Lithium and atypical antipsychotics are effective in mania, but treatment of depression remains obscure, with the exception of lurasidone, for children ages 10-17. Treatment of the common comorbid anxiety disorders, oppositional defiant disorders, pathological habits, and substance abuse are all poorly studied and are off-label. Cognitive dysfunction after a first manic hospitalization improves over the next year only on the condition that no further episodes occur. Yet comprehensive expert treatment after an initial manic hospitalization results in many fewer relapses than traditional treatment as usual, emphasizing the need for combined pharmacological, psychosocial, and psycho-educational approaches to this difficult and highly recurrent illness.

25 Years of the International Bipolar Collaborative Network (BCN).

BACKGROUND: The Stanley Foundation Bipolar Treatment Outcome Network (SFBN) recruited more than 900 outpatients from 1995 to 2002 from 4 sites in the United States (US) and 3 in the Netherlands and Germany (abbreviated as Europe). When funding was discontinued, the international group of investigators continued to work together as the Bipolar Collaborative Network (BCN), publishing so far 87 peer-reviewed manuscripts. On the 25th year anniversary of its founding, publication of a brief summary of some of the major findings appeared appropriate. Important insights into the course and treatment of adult outpatients with bipolar disorder were revealed and some methodological issues and lessons learned will be discussed. RESULTS: The illness is recurrent and pernicious and difficult to bring to a long-term remission. Virtually all aspects of the illness were more prevalent in the US compared to Europe. This included vastly more patients with early onset illness and those with more psychosocial adversity in childhood; more genetic vulnerability; more anxiety and substance abuse comorbidity; more episodes and rapid cycling; and more treatment non-responsiveness. CONCLUSIONS: The findings provide a road map for a new round of much needed clinical treatment research studies. They also emphasize the need for the formation of a new network focusing on child and youth onset of mood disorders with a goal to achieve early precision diagnostics for intervention and prevention in attempting to make the course of bipolar illness more benign.

The Kindling/Sensitization Model and Early Life Stress.

INTRODUCTION: Few animal models address the characteristics of the longitudinal course of bipolar disorder. However, behavioral sensitization (to recurrent stressors and psychomotor stimulants) and kindling of seizures both provide clues to mechanisms in the progressive course of bipolar disorder. METHODS: We describe aspects of bipolar illness that show sensitization and kindling-like increases reactivity to the recurrence of stressors, mood episodes, and bouts of substance abuse. Mechanisms of these events and clinical implications for treatment are discussed. RESULTS: Early life stress is a risk factor for the development of episodes of unipolar depression and bipolar disorder and the acquisition of substance abuse. Initial affective episodes are often triggered by the recurrence of psychosocial stressors in adulthood, but after many episodes have occurred, episodes may also begin to emerge spontaneously in a kindling-like progression. More prior episodes are associated with faster recurrences, dysfunction, disability, frontal cortical abnormalities, cognitive impairment, shorter telomeres, treatment refractoriness, and an increased risk of a diagnosis of dementia in old age. Sensitization to stressors, episodes, and substances of abuse each appear driven by epigenetic mechanisms and their accumulation on DNA, histones, and microRNA. Patients with bipolar illness in the USA are more ill than those from Europe and experience more sensitization to stressors, episodes, substance abuse, as well as more genetic vulnerability across four generations. DISCUSSION: The sensitization and kindling models highlight the importance of early intervention and prevention in order to limit or halt the downhill progression of bipolar disorder and its multiple comorbidities toward treatment refractoriness. Clinical data support this conclusion as well but have not been sufficient to change practice in the direction of early intervention. It is hoped that a better understanding of sensitization and kindling-like mechanisms will add neurobiological rationales for the importance of prevention and sustained prophylactic intervention in rendering bipolar disorder a more benign illness.

How to prevent the malignant progression of bipolar disorder

There is increasing recognition that, in a high percentage of cases, bipolar disorder is a progressive illness. Multiple types of sensitization (or increased reactivity to repetition of the same stimulus) drive illness progression. One of the clearest is that of episode sensitization, where increased numbers of prior episodes are associated with: faster recurrences; more dysfunction; disability; social, educational, and employment deficits; suicide; medical comorbidities; cognitive dysfunction; and an increased incidence of dementia in old age. Repetition of stressors and bouts of substance abuse can also result in sensitization. Each type of sensitization appears to have an epigenetic basis, such that preventing sensitization should minimize the accumulation of adverse epigenetic chemical marks on DNA, histones, and microRNA. New data emphasize the importance of early, consistent intervention after an initial manic episode. The cognitive dysfunction associated with a first episode improves only if there are no further episode recurrences during the next year. A randomized study has also shown that comprehensive multimodal prophylactic intervention for 2 years leads to improvements in illness course extending over a total of 6 years. Intensive treatment of the earliest stages of bipolar disorder can thus exert lasting positive effects on the course of illness.

Little Agreement on Treating Residual Bipolar Disorder Symptoms in a Child.

BACKGROUND: There is a paucity of studies on treatment of childhood-onset bipolar disorder and its associated comorbidities, which leads to a wide diversity of opinion on choice and sequencing of treatment options. METHODS: From December 2018 to January 2019, a graphic depiction of medications and weekly ratings of symptoms of mania, depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), and oppositional behavior that parents had rated on their 9-year-old child over a period of several years was sent to experts in child and adult bipolar disorder. These responding medical doctors (MDs, 8 child and 18 adult psychiatrists) rated a comprehensive list of medications that they would choose (and with what priority) to treat the child's now improved mood (mania and depression) but continued mild to moderate symptoms of anxiety, ADHD, and oppositional behavior. RESULTS: In the whole group, the drugs most highly endorsed were lamotrigine: 69%, lithium: 62%, lurasidone: 62%, quetiapine: 54%, aripiprazole: 46%, and valproate: 42%. Among the antidepressants, 38% endorsed a selective serotonin reuptake inhibitor, 12% a serotonin-norepinephrine reuptake inhibitor, and 27% bupropion. Of the child MDs, 75% suggested increasing the 1-mg dose of risperidone, while few adult MDs suggested this. Conversely, 56% of the adult MDs suggested using valproate, while only 1 child MD did so. There was little consensus on how to manage ADHD symptoms unresponsive to methylphenidate 36 mg/d. How these treatment options were sequenced also varied widely. CONCLUSIONS: There was wide variation in suggestions on to how to treat persistent symptoms of anxiety, ADHD, and oppositional behavior in a child whose mania and depression had been brought under good control. We surmise that this great diversity in recommendations among experts in child and adult bipolar disorder stems at least partially from inadequate literature on treatment and that a new emphasis on funding and conducting studies on efficacy and effectiveness is needed.

Relationship of comorbid personality disorders to prospective outcome in bipolar disorder.

Introduction There is a high incidence of Axis II personality disorders (PDs) in patients with bipolar illness, but their influence on the prospectively measured course of bipolar disorder has been less well explicated. Methods 392 outpatients with bipolar disorder gave informed consent, completed the PDQ4 99 item personality disorder rating, and where clinically rated during at least one year of prospective naturalistic treatment. They were classified as Well on admission (N = 64) or Responders (N = 146) or Non-responders (N = 182) to treatment for at least six months. Results Patients who were positive for PDs were very infrequently represented in the category of Well on admission. In addition, patients with borderline, depressive, and schizoid PDs were significantly more likely to be Non-responders compared to Responders upon prospective naturalistic treatment in the network. Conclusions Patients with bipolar disorder and comorbid PDs were in general less likely to be Well from treatment in the community at network entry or to be a Responder to prospective treatment in the network. Therapeutic approaches to patients with PDs deserve specific study in an attempt to achieve a better long-term course of bipolar disorder.

Double jeopardy in the United States: Early onset bipolar disorder and treatment delay.

BACKGROUND: Evidence is emerging that early onset bipolar disorder and the duration of the delay to first treatment are both risk factors for poor treatment outcome. We report on the incidence and implications of these two risk factors in patients from the United States (US) versus Europe. METHODS: Age of onset and age at first treatment for depression or mania was assessed in 967 outpatients with bipolar disorder who gave informed consent for participation and filling out a detailed questionnaire. Age at onset and treatment delay were compared in the 675 patients from the US and 292 from the Netherlands and Germany (abbreviated as Europe). Both were then graphed and analyzed. RESULTS: Age of onset of bipolar disorder was earlier in the US than in Europeans by an average of 6-7 years with similar results in those with first onsets of depression or of mania. Delay to first treatment was strongly inversely related to age of onset and was twice as long in the US than in Europe, and especially different for mania in adolescents. The longer delay to treatment in the US was not solely due to earlier age of onset. CONCLUSIONS: Treatment delay is a remedial risk factor and could be shortened with better recognition of the higher incidence of early onset bipolar disorder in the US, which also associated with more genetic and environmental vulnerability factors compared to Europe. New treatment and research initiatives are needed to address these liabilities so that children with bipolar achieve more positive long-term outcomes.