Innovative approaches to bipolar disorder and its treatment
Paul J. HarrisonAndrea CiprianiCatherine J. HarmerAnna C. NobreKate SaundersGuy M. GoodwinJohn Geddes
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Abstract:
All psychiatric disorders have suffered from a dearth of truly novel pharmacological interventions. In bipolar disorder, lithium remains a mainstay of treatment, six decades since its effects were serendipitously discovered. The lack of progress reflects several factors, including ignorance of the disorder's pathophysiology and the complexities of the clinical phenotype. After reviewing the current status, we discuss some ways forward. First, we highlight the need for a richer characterization of the clinical profile, facilitated by novel devices and new forms of data capture and analysis; such data are already promoting a reevaluation of the phenotype, with an emphasis on mood instability rather than on discrete clinical episodes. Second, experimental medicine can provide early indications of target engagement and therapeutic response, reducing the time, cost, and risk involved in evaluating potential mood stabilizers. Third, genomic data can inform target identification and validation, such as the increasing evidence for involvement of calcium channel genes in bipolar disorder. Finally, new methods and models relevant to bipolar disorder, including stem cells and genetically modified mice, are being used to study key pathways and drug effects. A combination of these approaches has real potential to break the impasse and deliver genuinely new treatments.Keywords:
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In this article, we investigate the range of treatments prescribed for bipolar disorder. Our analysis shows that, while a large portion of patients is treated by a single mechanism of action (44%), an equally sizable group of patients receives two or more drug classes (56%) to treat the disorder. From a therapeutic class perspective, 71 percent of patients with bipolar disorder receive an atypical antipsychotic, 53 percent receive a mood stabilizer, and 30 percent receive an antidepressant. While antipsychotics and mood stabilizers represent the vast majority of bipolar disorder monotherapy (90%), antidepressants are more commonly seen as part of a combination treatment.
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Maj M. The effect of lithium in bipolar disorder: a review of recent research evidence. Bipolar Disord 2003: 5: 180–188. © Blackwell Munksgaard, 2003 Recently published clinical research on lithium is briefly reviewed. The antimanic effect of lithium is supported by recent evidence. It is confirmed that a drastic reduction of affective morbidity is very frequent in bipolar patients receiving lithium prophylaxis regularly for several years, but that the impact of prophylaxis on the course of bipolar disorder is significantly limited by the high drop‐out rate. Lithium does seem to be efficacious also in bipolar disorder with mood‐incongruent psychotic features or with rapid cycling. The effect of lithium prophylaxis does not seem to decrease over time, at least in the large majority of patients. The recurrence risk is increased in the months following lithium discontinuation. Lithium seems to exert an antisuicidal effect in bipolar patients.
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There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder (BD). This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence.We conducted a MEDLINE search, using the MeSH Terms 'bipolar disorder' and 'lithium' together with 'randomized controlled trial' or 'controlled clinical trial' covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with BD were examined as a separate group and were assigned to precisely specified target ranges of lithium level.The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4 mmol/L with optimal response achieved at serum levels between 0.6-0.75 mmol/L. Lithium levels >0.75 mmol/L may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2 mmol/L was associated with increased risk of relapse.In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6-0.75 mmol/L, while higher levels may benefit patients with predominantly manic symptoms.
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Objective: A recent study reported an 8% increase in bipolar diagnoses in public and community mental health services in New South Wales from 2003 to 2014, an increase interpreted by the authors as reflecting increasing diagnostic boundaries of bipolar disorder, and bipolar II in particular. If valid, we would expect an increase in hospital admissions for hypomania as well as for mania and so analysed a relevant dataset to test that hypothesis. Methods: Data were examined for 27,255 individuals hospitalised in NSW psychiatric hospitals over a 14-year period (2000–2014) for ICD-10 diagnosed mania or hypomania and with analyses examining rates of hospitalisation/per year for both mania and for hypomania. Results: While overall admissions for mania and hypomania increased over the study period by 16.4%, admissions for mania increased by 31.0% and admissions for hypomania actually decreased by 32.1%. Conclusion: The increased rate in admissions of those with a bipolar disorder appears to reflect a trend over more than four decades. The hypothesis that any increase in the diagnostic boundaries of bipolar II disorder would be associated with an increase in hospitalisation rates was rejected, with the converse trend being identified.
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Effective treatment of bipolar disorder involves prophylaxis and treatment of both mania/hypomania and depression. Lithium is an effective treatment of all phases of bipolar disorder. Certain clinical presentations appear to respond better to valproate. Newer anticonvulsants (eg lamotrigine) have an emerging role in bipolar disorder. Atypical antipsychotics may be useful in the treatment of mania. (author abstract)
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Bipolar depression is as debilitating as mania in bipolar disorder, but the treatment of bipolar depression has historically received less attention. To date, there is no mood stabilizer (liberally defined as a medication that decreases episode severity, duration, or frequency in one phase of bipolar illness without producing a negative effect in other phases) that demonstrates similar efficacy in both the depressive and the manic phases of bipolar disorder. However, bipolar depression--which is prevalent, sometimes chronic, and associated with a low quality of life and a high risk of suicide--must be addressed as energetically as mania. Recent research into the long-term treatment of bipolar disorder has raised several questions about the generalizability of early lithium studies, as a result of these studies' designs. Researchers conducting more recent studies of mood stabilizers in the long-term treatment of bipolar disorder have attempted to clarify their results by, for example, performing survival analyses of the data. Until pharmacotherapy has been found that is equally efficacious in the treatment of both manic and depressive episodes in bipolar disorder, the use of combination therapy to manage bipolar disorder is advised. Lithium and divalproex sodium remain the first-line treatments for mania. Lamotrigine has been found to have acute efficacy in treating episodes of bipolar depression without increasing cycling or provoking a switch into mania, as well as a long-term role in delaying relapse and recurrence of depressive episodes.
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Objectives: There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder. This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence. Methods: We conducted a Medline search, using the MeSH Terms “bipolar disorder“ AND “lithium“ AND (“Randomized Controlled Trial“ OR “Controlled Clinical Trial“) covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with bipolar disorder were examined as a separate group and were assigned to precisely specified target ranges of lithium level. Results: The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4mmol/l with optimal response achieved at serum levels between 0.6–0.75mmol/l. Lithium levels >0.75mmol/l may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2mmol/l was associated with increased risk of relapse. Conclusions: In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6–0.75mmol/l while higher levels may benefit patients with predominantly manic symptoms.
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Adequacy of Treatment Received by Diagnosed and Undiagnosed Patients With Bipolar I and II Disorders
Article AbstractObjective: To investigate the adequacy of pharmacotherapy received by psychiatric inpatients and outpatients with a research diagnosis of bipolar I or II disorder, including patients both with and without a clinical diagnosis of bipolar disorder. Method: In the Jorvi Bipolar Study (JoBS), 1630 psychiatric inpatients and outpatients in 3 Finnish cities were systematically screened between January 1, 2002, and February 28, 2003, for bipolar I and II disorders using the Mood Disorder Questionnaire. By using SCID-I and -II interviews, 191 patients were diagnosed with bipolar disorder (90 bipolar I and 101 bipolar II). Information was collected on clinical history, diagnosis, and treatment. The adequacy of treatment received was evaluated. Results: Of the 162 patients with previous bipolar disorder episodes, only 34 (20.9%) of all and 30 (55.5%) of those with a clinical diagnosis of bipolar disorder were using a mood stabilizer at onset of the index episode. Only 81 (42.4%) of all 191 patients and 76 (65.0%) of those diagnosed with bipolar disorder received adequate treatment for the acute index phase. The factor most strongly independently associated with adequate treatment was clinical diagnosis of bipolar disorder (OR = 25.34). In addition, rapid cycling (OR = 2.45), polyphasic index episode (OR = 2.41), or depressive index phase (OR = 3.36) independently predicted inadequate treatment.Outpatients received adequate treatment markedly less often than inpatients.Conclusions: Clinical diagnosis of bipolar disorder is by far the most important prerequisite for adequate treatment. Problems in treatment are associated mostly with outpatient settings, where adequacy of treatment of bipolar depression is a major concern. Lack of attention to the longitudinal course of illness is another major problem area.
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