Clinical research diagnostic criteria for bipolar illness (CRDC-BP): rationale and validity.

BACKGROUND: In the 1970 s, scientific research on psychiatric nosology was summarized in Research Diagnostic Criteria (RDC), based solely on empirical data, an important source for the third revision of the official nomenclature of the American Psychiatric Association in 1980, the Diagnostic and Statistical Manual, Third Edition (DSM-III). The intervening years, especially with the fourth edition in 1994, saw a shift to a more overtly "pragmatic" approach to diagnostic definitions, which were constructed for many purposes, with research evidence being only one consideration. The latest editions have been criticized as failing to be useful for research. Biological and clinical research rests on the validity of diagnostic definitions that are supported by firm empirical foundations, but critics note that DSM criteria have failed to prioritize research data in favor of "pragmatic" considerations. RESULTS: Based on prior work of the International Society for Bipolar Diagnostic Guidelines Task Force, we propose here Clinical Research Diagnostic Criteria for Bipolar Illness (CRDC-BP) for use in research studies, with the hope that these criteria may lead to further refinement of diagnostic definitions for other major mental illnesses in the future. New proposals are provided for mixed states, mood temperaments, and duration of episodes. CONCLUSIONS: A new CRDC could provide guidance toward an empirically-based, scientific psychiatric nosology, and provide an alternative clinical diagnostic approach to the DSM system.

The Lithium Battery: assessing the neurocognitive profile of lithium in bipolar disorder.

OBJECTIVE: The aim of the present study was to characterize the neurocognitive effects of lithium in bipolar disorder to inform clinical and research approaches for further investigation. METHODS: Key words pertaining to neurocognition in bipolar disorder and lithium treatment were used to search recognized databases to identify relevant literature. The authors also retrieved gray literature (e.g., book chapters) known to them and examined pertinent articles from bibliographies. RESULTS: A limited number of studies have examined the effects of lithium on neurocognition in bipolar disorder and, although in some domains a consistent picture emerges, in many domains the findings are mixed. Lithium administration appears to reshape key components of neurocognition - in particular, psychomotor speed, verbal memory, and verbal fluency. Notably, it has a sophisticated neurocognitive profile, such that while lithium impairs neurocognition across some domains, it seemingly preserves others - possibly those vulnerable to the effects of bipolar disorder. Furthermore, its effects are likely to be direct and indirect (via mood, for example) and cumulative with duration of treatment. Disentangling the components of neurocognition modulated by lithium in the context of a fluctuating and complex illness such as bipolar disorder is a significant challenge but one that therefore demands a stratified and systematic approach, such as that provided by the Lithium Battery. CONCLUSIONS: In order to delineate the effects of lithium therapy on neurocognition in bipolar disorder within both research and clinical practice, a greater understanding and measurement of the relatively stable neurocognitive components is needed to examine those that indeed change with lithium treatment. In order to achieve this, we propose a Lithium Battery-Clinical and a Lithium Battery-Research that can be applied to these respective settings.

Lithiumeter: Version 2.0.

BACKGROUND: The Lithiumeter was developed as a visual and practical guide for determining lithium levels in the management of bipolar disorder (BD). It appears to have been well received, as evidenced by its increasing popularity amongst doctors as a deskside clinical aide, and adoption and reproduction of the schematic in clinical guidelines and texts. However, since its publication 5 years ago, key basic neuroscience and clinical research developments pertaining to lithium have significantly advanced our understanding, necessitating further refinement of guidance concerning the practicalities of lithium therapy. METHODS: Literature concerning the indications for, and therapeutic levels of, lithium and the associated acute and chronic risks of therapy was scrutinized as part of updating clinical practice guidelines. We have reviewed these updates and identified significant areas of change with respect to the previous Lithiumeter (version 1.0). RESULTS: Since 2011, updated clinical practice guidelines have narrowed the indicated plasma lithium concentration for maintenance therapy, suggesting that additional guidance is necessary for optimizing treatment. Relevant updated clinical guidance was integrated to constitute the Lithiumeter 2.0, which provides a more comprehensive overview of the practical aspects of lithium therapy while maintaining a focus on optimization of lithium levels, such as differential titration of lithium depending on the current mood state. CONCLUSIONS: The Lithiumeter 2.0 is an update that clinicians will find useful for their practice. By addressing some of the issues faced in clinical practice, translational clinical research will continue to inform the Lithiumeter in future updates.

The lithiumeter: a measured approach.

BACKGROUND: Lithium has long been recognised for its mood-stabilizing effects in the management of bipolar disorder (BD) but in practice its use has been limited because of real and 'imagined' concerns. This article addresses the need for lithium to be measured with respect to its clinical and functional effects. It introduces a visual scale, termed lithiumeter, which captures the optimal lithium plasma levels for the treatment of BD. METHODS: Key words pertaining to lithium's administration, dosing, and side effects as well as its efficacy in acute and long-term treatment of BD were used to conduct an electronic search of the literature. Relevant articles were identified by the authors and reviewed. RESULTS: This paper outlines the considerations necessary prior to initiating lithium therapy and provides a guide to monitoring lithium plasma levels. Current recommendations for optimal plasma lithium levels in the management of BD are then discussed with respect to indications for use in the acute phases of the illness and maintenance therapy. The risks associated with lithium treatment are also discussed. CONCLUSIONS: The lithiumeter provides a practical guide of optimal lithium levels for the clinical management of BD.

Lithium specificity in bipolar illness: a classic agent for the classic disorder.

For over half a century, lithium has been the gold standard amongst the pharmacological armamentarium used to treat bipolar disorder. Its ascendancy in this regard has been attributed partly to its primacy of discovery and clinical implementation; however, it is important to consider how it has achieved success and retained its prominence and whether this is because of its unique profile and specificity of actions. In this paper, we briefly discuss the clinical evidence in support of lithium specificity and argue for its continuing use in those patients most likely to benefit, namely, patients with 'classic' bipolar disorder. Further, we suggest that accurate characterization of 'lithium responders' through focused research is likely to yield novel treatments and assist in better understanding of the pathophysiology of the illness. In addition, the unique antisuicidal actions of lithium warrant further examination, as do its impressive properties as a prophylactic agent. This is particularly so given the high morbidity associated with bipolar disorder and its potential for suicide. Hence, in this paper, after describing the changing diagnostic backdrop against which much of the research to date has been conducted, we discuss the clinical therapeutic profile of lithium in both the acute and long-term management of bipolar disorder and its phenotypic specificity of action. We demonstrate that lithium possesses significant clinical and therapeutic efficacy that is very individual and thus remains the treatment of choice for bipolar disorder when used specifically in select patients.

Reporting outcomes in clinical trials for bipolar disorder: a commentary and suggestions for change.

OBJECTIVE: Newer outcome measures and statistical reporting that better translate efficacy data to evidence-based psychiatric care are needed when evaluating clinical trials for bipolar disorder. Using efficacy studies as illustrations, the authors review and recommend changes in the reporting of traditional clinical outcomes both in the acute and maintenance phases of bipolar disorder. METHODS: Definitions of response, remission, relapse, recovery, and recurrence are reviewed and recommendations for change are made. These suggestions include reporting the numbers needed to treat or harm (NNT or NNH), and a ratio of the two, likelihood of help or harm (LHH), as an important element of the effect size (ES). Moreover, models of prediction that conduct sensitivity or specificity analyses and utilize decision trees to help predict positive and negative outcomes of interest (for instance, excessive weight gain, or time to remission) using positive or negative predictive values (PPV or NPV) are reviewed for potential value to clinicians. Finally, functional and cognitive assessments are recommended for maintenance studies of bipolar disorder. RESULTS: The examples provided in this manuscript underscore that reporting the NNT or NNH, or alternative effect sizes, or using PPV or NPV may be of particular value to clinicians. Such reports are likely to help translate efficacy-driven clinical data to information that will more readily guide clinicians on the benefits and risks of specific interventions in bipolar disorder. CONCLUSIONS: The authors opine that reporting these newer outcomes, such as NNT or NNH, area under the receiver operating curve (AUC), or PPV or NPV will help translate the results of clinical trials into a language that is more readily understood by clinicians. Moreover, assessing and evaluating functional and cognitive outcomes will not only inform clinicians about potential differences among therapeutic options, but likely will make it easier to communicate such differences to persons with bipolar illness or to their families. Finally, we hope such scientific and research efforts will translate to optimism for recovery-based outcomes in persons with bipolar disorder.

A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type.

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.

Recovery and functional outcomes following olanzapine treatment for bipolar I mania.

BACKGROUND: Typical experimental categorizations of treatment responses in bipolar disorder (BPD) patients may have limited relationship to clinical recovery or functional status, and there is inadequate research on such clinically important outcomes. METHODS: We analyzed data from a study of open continuation of olanzapine treatment following a 3-week placebo-controlled trial involving initially hospitalized adult subjects with DSM-IV BP-I mania to estimate rates and times to symptomatic remission (low scores on standardized symptomatic assessments) and clinical recovery (remission sustained>or=8 weeks), associated clinical factors, and functional outcomes. RESULTS: During treatment with olanzapine for 27.9+/-20.1 weeks, symptomatic remission was attained by 70% of subjects, half by 8 weeks (95% CI 6-10) weeks, and later lost by 82% of remitted subjects; remitted (versus non-remitted) subjects had slightly lower baseline clinical global impression scores and greater trial-completion. Sustained clinical recovery was attained by only 40 of 113 (35%) of subjects, half by 36 (95% CI 20-40) weeks, and later lost by 45%. Subjects with above-median (>12) initial Hamilton-Depression rating scale depression scores were half as likely to recover (p=0.016) and did so much later (36 versus 12 weeks) than those with lower scores. At final assessment, self-rated well being (SF-36 psychosocial functioning scores) improved substantially more among recovered versus non-recovered subjects (mean changes: 87% versus 23%), and two-thirds of recovered subjects remained unemployed-for-pay while half received disability-compensation. CONCLUSIONS: Clinically meaningful symptomatic remission and recovery in relatively severely ill adult bipolar I manic patients were achieved slowly and sustained by only some patients within an average of 7 months of continuous treatment. These clinically relevant outcomes were worse with relatively high initial dysphoria ratings. Well-being was rated higher by recovered subjects, but their ability to work and live independently were markedly impaired. These findings underscore the emerging view that BPD can often be severe, slow to remit, and disabling, particularly in association with prominent depression-dysphoria symptoms. Improved treatments for BPD are needed, guided by longitudinal assessments of clinically meaningful measures of symptomatic recovery and functional outcome.