Bipolar Disorder: Yatham LN

Yatham LN, Kennedy SH, O'Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S, Anonymous00162. · Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #17156158 No free full text.

Abstract: In 2005, the Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder. This update reviews new evidence since the previous publication and incorporates recommendations based on the most current evidence for treatment of various phases of bipolar disorder. It is designed to be used in conjunction with the 2005 CANMAT Guidelines. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate and several atypical antipsychotics continue to be recommended as first-line treatments for acute mania. For the management of bipolar depression, new data support quetiapine monotherapy as a first-line option. Lithium and lamotrigine monotherapy, olanzapine plus selective serotonin reuptake inhibitors (SSRI), and lithium or divalproex plus SSRI/bupropion continue to remain the other first-line options. First-line options in the maintenance treatment of bipolar disorder continue to be lithium, lamotrigine, valproate and olanzapine. There is recent evidence to support the combination of olanzapine and fluoxetine as a second-line maintenance therapy for bipolar depression. New data also support quetiapine monotherapy as a second-line option for the management of acute bipolar II depression. The importance of comorbid psychiatric and medical conditions cannot be understated, and this update provides an expanded look at the prevalence, impact and management of comorbid conditions in patients with bipolar disorder.

Yatham LN, Kennedy SH, O'Donovan C, Parikh S, MacQueen G, McIntyre R, Sharma V, Silverstone P, Alda M, Baruch P, Beaulieu S, Daigneault A, Milev R, Young LT, Ravindran A, Schaffer A, Connolly M, Gorman CP, Anonymous00076. · Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #15952957 No free full text.

Abstract: Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.

Malhi GS, Yatham LN. · Guest Editors. · Acta Psychiatr Scand Suppl. · Pubmed #17688457 No free full text.

This publication has no abstract.

Bond DJ, Noronha MM, Kauer-Sant'Anna M, Lam RW, Yatham LN. · Research and International Affairs, Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Room 2C7, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1 Canada. · J Clin Psychiatry. · Pubmed #19192442 No free full text.

Abstract: OBJECTIVE: Antidepressant-associated manic and hypomanic episodes have been reported in bipolar I disorder but are rare in major depressive disorder (MDD). Several lines of evidence suggest that bipolar II disorder is a distinct illness from bipolar I disorder and MDD. The risk of antidepressant-associated mood elevations (AAME) in bipolar II disorder relative to bipolar I disorder and MDD is unknown. DATA SOURCES: We conducted a computer-aided MEDLINE search encompassing the dates 1949 to February 2008, using the keywords antidepressant and mania, antidepressant and hypomania, antidepressant and bipolar, fluoxetine and bipolar, fluvoxamine and bipolar, sertraline and bipolar, paroxetine and bipolar, citalopram and bipolar, escitalopram and bipolar, venlafaxine and bipolar, mirtazapine and bipolar, bupropion and bipolar, monoamine oxidase inhibitor and bipolar, phenelzine and bipolar, tranylcypromine and bipolar, tricyclic and bipolar, imipramine and bipolar, amitriptyline and bipolar, nortriptyline and bipolar, and desipramine and bipolar. STUDY SELECTION: All prospective English-language studies, including randomized, controlled trials (RCTs), open-label studies, and naturalistic treatment reports, were eligible for inclusion. We located 13 studies, including 7 RCTs, that reported rates of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder, and 5, including 4 RCTs, that reported rates in bipolar II disorder versus MDD. DATA EXTRACTION: Data were combined to estimate mean switch rates and subjected to meta-analysis to determine the relative risks of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder and in bipolar II disorder versus MDD. DATA SYNTHESIS: The mean rates of antidepressant-associated mood elevations in studies comparing bipolar I disorder and bipolar II disorder were 14.2% and 7.1%, respectively, in acute trials (less than 16 weeks), and 23.4% and 13.9%, respectively, in maintenance studies. The mean rates in reports comparing bipolar II disorder and MDD were 8.1% and 1.5%, respectively, in acute trials, and 16.5% and 6.0%, respectively, in maintenance studies. The relative risk (RR) of antidepressant-associated mood elevations was greater in bipolar I disorder than bipolar II disorder (RR = 1.78, 95% CI = 1.24 to 2.58, p = .002), and higher in bipolar II disorder than MDD (RR = 2.77, 95% CI = 1.26 to 6.09, p = .01). Mood elevations occurred almost exclusively into hypomania in MDD and bipolar II disorder, while patients with bipolar I disorder experienced manias and hypomanias with similar frequencies. CONCLUSIONS: The risk of antidepressant-associated mood elevations in bipolar II disorder is intermediate between that in bipolar I disorder and MDD.

Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. · J Affect Disord. · Pubmed #18539338 No free full text.

Abstract: BACKGROUND: Oxidative stress is thought to mediate neuropathological processes of a number of neuropsychiatric disorders and recent data suggest that oxidative stress may be involved in the pathophysiology of bipolar disorder (BD). In the present investigation, we conducted a meta-analysis of studies that evaluated markers of oxidative stress in individuals with BD, as compared to healthy controls. METHODS: A Medline search was conducted to identify studies that measured peripheral markers of oxidative stress in bipolar disorder. Data were subjected to meta-analysis using a random effects model to examine the effect sizes of the pooled results. Bias assessment (Egger's test) and assessment of heterogeneity (I(2)) were also carried out. RESULTS: Thiobarbituric acidic reactive substances (TBARS) (p = 0.001) as well as NO activity (p = 0.02) were significantly increased in BD with a large effect size for TBARS and a moderate effect size for increase in NO. No significant effect sizes were observed for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase (all p>0.05). LIMITATIONS: Some caution is warranted in interpreting these results: (1) Egger's test was positive for SOD, suggesting that SOD results may have been influenced by a publication bias. (2) We analyzed the absolute values of each antioxidant enzyme separately and the literature suggests that an imbalance between the antioxidant enzymes is a better indication of the presence of oxidative stress. CONCLUSIONS: The present meta-analysis suggests that oxidative stress markers are increased in BD and that oxidative stress may play a role in the pathophysiology of BD.

Cassidy F, Yatham LN, Berk M, Grof P. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · Bipolar Disord. · Pubmed #18199232 No free full text.

Abstract: OBJECTIVE: To review issues surrounding the diagnosis and validity of bipolar manic states. METHODS: Studies of the manic syndrome and its diagnostic subtypes were reviewed emphasizing historical development, conceptualizations, formal diagnostic proposals, and validation. RESULTS: Definitions delineating mixed and pure manic states derive some validity from external measures. DSM-IV and ICD-10 diagnosis of bipolar mixed states are too rigid and less restrictive definitions can be validated. Anxiety is a symptom often overlooked in diagnosis of manic subtypes and may be relevant to the mixed manic state. The boundary for separation of mixed mania and depression remains unclear. A 'pure' non-psychotic manic state similar to Kraepelin's 'hypomania' has been observed in several independent studies. CONCLUSIONS: Issues surrounding diagnostic subtyping of manic states remain complex and the debates surrounding categorical versus dimensional approaches continue. To the extent that categorical approaches for mixed mania diagnosis are adopted, both DSM-IV and ICD-10 are too rigid. Inclusion of non-specific symptoms in definitions of mixed mania, such as psychomotor agitation, does not facilitate and may hinder the diagnostic separation of pure and mixed mania. The inclusion of a diagnostic seasonal specifier for DSM-IV, which is currently based on seasonal patterns for depression might be expanded to include seasonal patterns for mania. Boundaries between subtypes may be 'fuzzy' rather than crisp, and graded approaches could be considered. With the continued development of new tools, such as imaging and genetics, alternative approaches to diagnosis other than the purely symptom-centric paradigms might be considered.

Berk M, Conus P, Lucas N, Hallam K, Malhi GS, Dodd S, Yatham LN, Yung A, McGorry P. · Barwon Health and The Geelong Clinic, Geelong, Victoria, Australia. · Bipolar Disord. · Pubmed #17988356 No free full text.

Abstract: Bipolar disorder is common, and both difficult to detect and diagnose. Treatment is contingent on clinical needs, which differ according to phase and stage of the illness. A staging model could allow examination of the longitudinal course of the illness and the temporal impact of interventions and events. It could allow for a structured examination of the illness, which could set the stage for algorithms that are tailored to the individuals needs. A staging model could further provide as structure for assessment, gauging treatment and outcomes. The model incorporates prodromal stages and emphasizes early detection and algorithm appropriate intervention where possible. At the other end of the spectrum, the model attempts to operationalize treatment resistance. The utility of the model will need to be validated by empirical research.

Bond DJ, Pratoomsri W, Yatham LN. · Mood Disorders Clinical Research Unit, The University of British Columbia, Vancouver, BC, Canada. · Acta Psychiatr Scand Suppl. · Pubmed #17688458 No free full text.

Abstract: OBJECTIVE: To review the literature on the efficacy and safety of depot formulations of first- and second-generation antipsychotic medications (FGAs and SGAs) in patients with bipolar disorder. METHOD: We conducted a computer-aided MEDLINE search using the search terms 'depot antipsychotic', 'bipolar disorder' and 'compliance.' RESULTS: We identified eight published reports in bipolar patients regarding the use of depot FGAs, and six preliminary reports on the use of depot SGAs. These studies suggest that depots FGAs are efficacious in preventing manic episodes during the maintenance treatment of bipolar disorder. Several studies, however, indicate that depot FGAs may be associated with increased time with depressive symptoms, particularly in patients with a predominantly depressive course of illness. Preliminary data on the role of depot formulations of SGAs suggest that they reduce the frequency of both manic and depressive episodes during maintenance treatment, and are well tolerated by patients. CONCLUSION: After a careful risk-benefit analysis, depot antipsychotics may be considered for the long-term control of mood episodes in bipolar patients who have relapsed due to medication non-adherence or who have failed to respond to standard therapies. Depot FGAs should be avoided in patients with a high burden of illness from depressive symptoms and particularly in those judged to be at high risk of suicide. The available data on depot formulations of SGAs indicate that they are efficacious in the maintenance treatment of bipolar illness without increasing the burden of the depressive pole of the illness, but further systematic studies are required to definitively assess this.

Pratoomsri W, Yatham LN, Bond DJ, Lam RW, Sohn CH. · Mood Disorders Centre of Excellence, University of British Columbia, Vancouver. · Can J Psychiatry. · Pubmed #16933591 No free full text.

Abstract: OBJECTIVE: To review the data on the efficacy of oxcarbazepine (OXC) in bipolar disorder (BD) and to provide recommendations for clinicians on the use of this medication in treating BD. METHOD: Using the terms oxcarbazepine and bipolar disorder, oxcarbazepine and mania, or oxcarbazepine and bipolar depression, we conducted a computer-aided search of MEDLINE for the years 1950 to 2005. RESULTS: Case reports, retrospective chart reviews, open prospective studies, and double-blind studies reported the efficacy and effectiveness of OXC in treating BD. The data indicate that OXC has efficacy in treating acute mania and may be a useful add-on in treating acute bipolar depression and in BD prophylaxis. OXC is generally well-tolerated. CONCLUSION: We recommend using OXC as monotherapy or as add-on therapy in refractory mania, but we recommend it be used predominantly as an add-on treatment for other phases of BD in patients who have not improved with well-established treatments or in patients who have difficulty tolerating adequate dosages.

Lin D, Mok H, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, Canada. · CNS Drugs. · Pubmed #16396522 No free full text.

Abstract: Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.

Michalak EE, Yatham LN, Lam RW. · Department of Psychiatry, University of British Columbia, Vancouver, Canada. · Health Qual Life Outcomes. · Pubmed #16288650 links to  free full text

Abstract: A sizable body of research has now examined the complex relationship between quality of life (QoL) and depressive disorder. Uptake of QoL research in relation to bipolar disorder (BD) has been comparatively slow, although increasing numbers of QoL studies are now being conducted in bipolar populations. We aimed to perform a review of studies addressing the assessment of generic and health-related QoL in patients with bipolar disorder. A literature search was conducted in a comprehensive selection of databases including MEDLINE up to November 2004. Key words included: bipolar disorder or manic-depression, mania, bipolar depression, bipolar spectrum and variants AND quality of life, health-related QoL, functional status, well-being and variants. Articles were included if they were published in English and reported on an assessment of generic or health-related QoL in patients with BD. Articles were not included if they had assessed fewer than 10 patients with BD, were only published in abstract form or only assessed single dimensions of functioning. The literature search initially yielded 790 articles or abstracts. Of these, 762 did not meet our inclusion criteria, leaving a final total of 28 articles. These were sub-divided into four categories (assessment of QoL in patients with BD at different stages of the disorder, comparisons of QoL in patients with BD with that of other patient populations, QoL instrument evaluation in patients with BD and treatment studies using QoL instruments to assess outcome in Patients with BD) and described in detail. The review indicated that there is growing interest in QoL research in bipolar populations. Although the scientific quality of the research identified was variable, increasing numbers of studies of good design are being conducted. The majority of the studies we identified indicated that QoL is markedly impaired in patients with BD, even when they are considered to be clinically euthymic. We identified several important avenues for future research, including a need for more assessment of QoL in hypo/manic patients, more longitudinal research and the development of a disease-specific measure of QoL for patients with BD.

Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #15948763 No free full text.

Abstract: Bipolar disorder is associated with significant morbidity and mortality; however, many aspects of this disorder remain poorly understood. It is likely that rapid advances in molecular genetics and neuroimaging will play a major role in advancing our understanding of bipolar disorder in future. Molecular genetics studies have already identified some candidate genes; for example, the BDNF, G72 and XBP1 genes, and chromosomal 'hot spots', which may confer a predisposition to development of bipolar disorder. Such advances may facilitate earlier, easier and more accurate diagnosis and provide novel targets for the treatment of this condition. Brain imaging studies using positron emission tomography and single photon emission computed tomography have shown that reduction in brain 5-hydroxytryptamine type 2 (5-HT(2)) receptors may be associated with prevention of or relief from depressive symptoms. Similarly, other imaging studies suggest that increased dopamine levels in the synapse mediate the symptoms of bipolar mania and that reduction in dopamine transmission through reduction in dopamine synthesis or blockade of dopamine D(2) receptors may be associated with antimanic effects. The ability of atypical antipsychotics to block both 5-HT(2) and D(2) receptors and downregulate 5-HT(2) receptors may explain how these drugs treat both the depressive and manic symptoms of bipolar disorder. Although molecular genetics and imaging techniques are not yet used as clinical tools for bipolar disorder, they provide valuable data to improve the understanding of the pathophysiology of bipolar disorder and should lead to new treatments and potentially episode prevention.

Fung J, Mok H, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, Canada. · Expert Rev Neurother. · Pubmed #15853534 No free full text.

Abstract: Lamotrigine (Lamictal, GlaxoSmithKline) is a recently developed anticonvulsant which has been investigated for efficacy in bipolar disorder. Increasing evidence indicates that it may have a different therapeutic profile than more established first-line mood stabilizers such as lithium and valproate. In particular, evidence from well-designed trials suggests efficacy for acute management and prophylaxis of bipolar depression but not mania. However, clinically relevant drug interactions and side effects can occur with lamotrigine, including benign to serious rash. The objectives of this drug profile are to review the basic chemical and pharmacological characteristics of lamotrigine, critically examine the growing body of research literature on its clinical use in the treatment of bipolar disorder, and review the safety and tolerability of lamotrigine as well as drug interactions relevant to clinical practice. Practical recommendations regarding titration and the management of rash are offered.

Yatham LN. · Mood Disorders Clinical Research Unit, University of British Columbia, Room 2C7-2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. · Psychiatr Clin North Am. · Pubmed #15826735 No free full text.

Abstract: Atypical antipsychotic agents have been widely investigated for their efficacy in acute mania. The data to date suggest that olanzapine,risperidone, quetiapine, aripiprazole, and ziprasidone are effective, with no significant differences in antimanic efficacy among these agents. These agents are effective as an alternative to lithium or divalproex as monotherapy or in combination with these mood stabilizers. The data concerning their utility in acute bipolar depression and maintenance treatment of bipolar disorder are limited. The studies to date suggest that olanzapine has modest acute antidepressant properties but probably has efficacy comparable to lithium and divalproex in preventing manic and depressive episodes. Quetiapine seems to have robust antidepressant properties, but these data need to be replicated in further trials before quetiapine can be recommended as a first-line agent for acute bipolar depression. Aripiprazole has shown promise in preventing manic episodes in one 6-month study, but further studies with at least 1-year duration and larger sample sizes are needed before this agent can be recommended as a monotherapy for prophylaxis of bipolar disorder. It is currently unknown if risperidone, aripiprazole, and ziprasidone have any efficacy in treating acute bipolar depression. Similarly, long-term studies are needed to ascertain the role of risperidone, quetiapine, and ziprasidone in the maintenance treatment of bipolar disorder. Overall, the atypical antipsychotic agents as a group represent an effective and relatively safe addition to the armamentarium for the treatment of bipolar disorder.

Yatham LN. · Division of Mood Disorders, University of British Columbia, Vancouver, Canada. · J Clin Psychiatry. · Pubmed #15693747 No free full text.

Abstract: Bipolar II disorder is frequently misdiagnosed as major depressive disorder. In particular, correct diagnosis of bipolar II disorder may be delayed by years due to the predominance of depressive symptoms and the relative subtlety of hypomania, which may manifest only briefly and without elevated mood. The prevalence of bipolar II disorder varies from 0.5% to about 5% depending on the criteria used. Diagnosis can be improved by using mood disorder questionnaires, systematic probing, and prospective mood diary charting. There is a dearth of research into treatment of bipolar disorder. The limited available evidence suggests that lithium and lamotrigine may have efficacy in preventing relapse of mood episodes. Acute bipolar II depression could be treated with a combination of a mood stabilizer plus an antidepressant or pramipexole and in rare cases with antidepressant monotherapy. Hypomania will likely respond to monotherapy with antimanic agents. Adjunctive psychosocial treatments may provide additional benefit in patients with bipolar II disorder.

Hadjipavlou G, Mok H, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver. · Can J Psychiatry. · Pubmed #15679203 No free full text.

Abstract: OBJECTIVE: Recent research on the epidemiology, clinical course, diagnosis, and treatment of bipolar II disorder (BD II) stands to have a considerable impact on clinical practice. This paper reviews these developments. METHOD: We conducted a Pubmed search, focusing on the period from January 1, 1994, to August 31, 2004. Articles deemed directly relevant to the epidemiology, course, diagnosis, and management of BD II were considered. RESULTS: The prevalence of BD II is likely higher than previously suggested. Systematic probing for particular clinical features and use of screening tools allow for a more timely and accurate detection of the disorder. There is a paucity of good quality data to guide clinicians treating BD II. CONCLUSION: Significant progress has been made in clarifying diagnostic and treatment issues in BD II. Neither strong nor broad treatment recommendations can be made; a cautious interpretation of available data suggests that lithium or lamotrigine are fairly reasonable first-line choices. More well-designed studies with larger samples are needed to improve the evidence base for managing this disorder.

Malhi GS, Lagopoulos J, Owen AM, Yatham LN. · School of Psychiatry, The University of New South Wales, Australia. · Acta Psychiatr Scand Suppl. · Pubmed #15330938 No free full text.

Abstract: OBJECTIVE: To evaluate the literature pertaining to the use of functional magnetic resonance imaging (fMRI) in bipolar disorder research. METHOD: A search for papers published in English in journals from 1984 onwards was conducted using MedLine and EMBASE with the following terms: functional neuroimaging or fMRI and depression or bipolar disorder. In addition, retrieved papers and literature known to the authors was also scrutinized for further relevant reports. RESULTS: The research findings from 26 articles are tabulated and the results from 10 articles dealing specifically with bipolar disorder are discussed in detail. CONCLUSION: fMRI is a useful tool for investigating bipolar disorder. Preliminary studies point to trait and state abnormalities involving structures known to be associated with the generation and modulation of emotion. The patterns of fMRI activation are different to those found in healthy subjects and patients with major depression. FMRI studies are likely to provide valuable insights into the pathophysiology of bipolar disorder.

McIntyre RS, Konarski JZ, Yatham LN. · Mood Disorder Psychopharmacology Unit, University of Toronto, University Health Network-Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S9, Canada. · Hum Psychopharmacol. · Pubmed #15303241 No free full text.

Abstract: Bipolar disorders are heterogeneous disorders often requiring multimodality treatment. The expanding pharmacopeia for bipolar disorders invites the need for a treatment framework that both recognizes and anticipates the multidimensionality and comorbidity of the illness. No available neurotherapeutic agent is singularly efficacious for the complete mélange of bipolar symptomatology. An apparent paradox has emerged in the management of bipolar disorder; whilst results from rigorous controlled monotherapy trials suggest that a disparate assortment of neurotherapeutic agents are efficacious in distinct phases of bipolar disorder, the majority of tertiary-treated bipolar patients receive polypharmacotherapeutic regimens. The evidentiary base for polypharmacotherapy is sparse and has recently become an area of active research focus. In the interim, clinicians are encouraged to invoke an organizational schema for the treatment of bipolar disorder that considers the spectrum of effectiveness of putative and established mood stabilizers. This schema should be further informed by the treatment data for comorbid and accessory conditions. The authors propose a schema to provide the impetus for further work in the area.

Yatham LN. · Division of Mood Disorders, University of British Columbia, Vancouver, British Columbia, Canada. · J Clin Psychiatry. · Pubmed #15242330 No free full text.

Abstract: The anticonvulsants valproate and carbamazepine have efficacy in treating acute mania, but their efficacy in treating acute bipolar depression and preventing mood episodes remains uncertain. Despite this, and given their utility and widespread use, both are widely accepted as standard treatments for bipolar disorder. All the newer anticonvulsants that have become available during the last decade have been or are being assessed to determine their efficacy in the treatment of various phases of bipolar disorder. Among the newer anticonvulsants, some appear to have efficacy in treating core bipolar symptoms, while others have efficacy in treating psychiatric comorbidity such as substance abuse or an anxiety disorder. Lamotrigine is the most widely studied and is effective in treating and preventing bipolar depression, and it is the only anticonvulsant approved by the U.S. Food and Drug Administration as a maintenance treatment for bipolar disorder. Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy in treating acute mania, but their utility in bipolar depression and prevention of mood episodes has not been studied in double-blind trials. Pregabalin has utility in treating generalized anxiety disorder, but it has not been studied in bipolar disorder. Given the success of lamotrigine in treating bipolar disorder, further double-blind controlled trials of the newer anticonvulsants in treating bipolar disorder are warranted. This article summarizes current evidence from trials of anticonvulsants in bipolar disorder and makes recommendations for their clinical use.

Calabrese JR, Kasper S, Johnson G, Tajima O, Vieta E, Yatham LN, Young AH. · Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA. · J Clin Psychiatry. · Pubmed #15119923 No free full text.

This publication has no abstract.

Hadjipavlou G, Mok H, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, Canada. · Bipolar Disord. · Pubmed #14996137 No free full text.

Abstract: OBJECTIVES: There is much controversy surrounding the diagnosis and treatment of patients with bipolar II disorder (BP II). To address the growing need to find effective treatment strategies for patients with BP II, this article identifies and summarizes available published evidence specific to the pharmacotherapy of BP II. METHODS: Using the keywords, 'bipolar disorder', 'type II' or 'type 2', 'bipolar II', 'hypomania', and 'bipolar spectrum', a search of the databases Medline (via PubMed), the Cochrane Central Register of Controlled Trials (via Ovid), and PsychInfo was conducted for the period January 1994 to January 2003. Articles deemed directly relevant to the treatment of BP II were selected. Studies that included both BP I and II patients were excluded if results for BP II patients were not analyzed and reported separately. RESULTS: Fourteen articles were selected for the review period. There are no double blind, randomized controlled trials (RCT) involving only BP II patients. Most studies investigating the pharmacotherapy of BP II are methodologically limited, having observational or retrospective designs and small samples. For long-term treatment, lamotrigine has the strongest quality of evidence (double blind RCT), while lithium is the best studied. With regard to short-term treatment, there is some limited support for the use of risperidone in hypomania, and for divalproex, fluoxetine and venlafaxine in treating depression. CONCLUSIONS: There is a paucity of sound evidence to help guide clinicians treating BP II patients. Decisions about pharmacotherapy should be made on a case-by-case basis; overall, broad recommendations that are based on available evidence cannot be adequately made. More quality research is needed to delineate effective treatment strategies.

Yatham LN. · Mood Disorders Clinical Research Unit, The University of British Columbia, Vancouver, BC, V6T 2A1, Canada. · Bipolar Disord. · Pubmed #14700009 No free full text.

Abstract: Bipolar disorder is a complex condition including depression, mania, and in many cases associated with comorbid anxiety symptoms and substance abuse. Mood stabilizers including lithium and divalproex have been considered standard therapy for the treatment of patients with bipolar disorder, but remission rates remain inadequate. Conventional antipsychotics have demonstrated efficacy for acute mania, but they appear to have little role in the maintenance treatment of bipolar disorder. Despite substantial evidence of efficacy and recent guideline recommendations, atypical antipsychotics remain underused for the treatment of bipolar disorder. Data from double-blind, controlled trials are available for a number of clinically meaningful efficacy measures, including improvement in manic symptoms, onset of action, response rates, remission rates, improvement in comorbid depressive symptoms, and induction/worsening of mania or depression. Atypical antipsychotics are effective both as alternatives to lithium or divalproex as monotherapy, or in combination with these mood stabilizers, in the acute and likely the maintenance treatment of mania. The atypical antipsychotics represent an effective and relatively safe addition to our armamentarium for the treatment of bipolar disorder.

Yatham LN. · University of British Columbia, Vancouver, Canada. · J Clin Psychopharmacol. · Pubmed #12832944 No free full text.

Abstract: Lithium and valproate are well recognized as mood-stabilizing medications. However, a significant number of patients with bipolar disorder do not respond to or cannot tolerate the side effects of these drugs. As a result, a search for safer and more effective mood stabilizers for the treatment of bipolar disorder is ongoing. Antipsychotic medications have long been used as adjunctive therapy in combination with mood-stabilizing medications. Although conventional neuroleptics (also known as typical antipsychotics) such as haloperidol or chlorpromazine are effective antimanic agents, they do not appear to have any efficacy in treating comorbid depressive symptoms. Furthermore, typical antipsychotics are associated with a number of well-known side effects, such as extrapyramidal symptoms and tardive dyskinesia. Mood-stabilizing effects have recently been reported for a number of newer "atypical" antipsychotics that have a broader spectrum of efficacy and better safety profiles than the typical antipsychotics. The results of several clinical trials suggest that atypical antipsychotics, including risperidone, olanzapine, ziprasidone, and quetiapine, are effective for the treatment of acute mania, and open-label studies suggest that atypical antipsychotics may have long-term mood-stabilizing effects.

Yatham LN, Calabrese JR, Kusumakar V. · Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada. · Bipolar Disord. · Pubmed #12680897 No free full text.

Abstract: OBJECTIVE: This paper reviews controlled studies of bipolar depression, outlines criteria for choosing treatment, defines refractoriness in bipolar depression, and provides options for treatment of refractory bipolar depression. METHODS: Controlled studies that examined the efficacy of treatments for acute and long-term treatment of bipolar depression were located through electronic searches of several databases and by manual crosssearch of references and proceedings of international meetings. RESULTS: Lithium comes close to fulfilling the proposed criteria for first-line treatment for bipolar depression, and those not responding to lithium should be considered to have refractory bipolar depression. Options for such patients include addition of lamotrigine or a second mood stabilizer, or a newer-generation antidepressant such as a serotonin re-uptake inhibitor or bupropion, or the atypical antipsychotic olanzapine. CONCLUSIONS: Although there is a paucity of research in the treatment of refractory bipolar depression, available data could be used for providing rational treatment options for such patients. However, further studies are urgently needed to determine which options are most appropriate for which type of patients.

Yatham LN. · Mood Disorders Clinical Research Unit, Department of Psychiatry, University of British Columbia, Vancouver, Canada. · Int Clin Psychopharmacol. · Pubmed #12570068 No free full text.

Abstract: The pharmacological management of bipolar disorder is complex as a result of the cyclic nature of the condition. Long-term treatment is, however, essential to control the symptoms of depression and mania and to stabilize the cyclical mood changes. In particular the use of mood stabilizers in all phases of treatment has been acknowledged. The atypical antipsychotics are being increasingly used to control acute manic episodes, and data are emerging to support their mood-stabilizing and antidepressant properties. This article will review the results from open and double-blind studies with quetiapine, ziprasidone, risperidone and olanzapine in the management of bipolar disorder.