Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention

Objective: The staging model suggests that early stages of bipolar disorder respond better to treatments and have a more favourable prognosis. This study aims to provide empirical support for the model, and the allied construct of early intervention.

Methods: Pooled data from mania, depression, and maintenance studies of olanzapine were analyzed. Individuals were categorized as having had 0, 1–5, 6–10, or >10 prior episodes of illness, and data were analyzed across these groups.

Results: Response rates for the mania and maintenance studies ranged from 52–69% and 10–50%, respectively, for individuals with 1–5 previous episodes, and from 29–59% and 11–40% for individuals with >5 previous episodes. These rates were significantly higher for the 1–5 group on most measures of response with up to a twofold increase in the chance of responding for those with fewer previous episodes. For the depression studies, response rates were significantly higher for the 1–5 group for two measures only. In the maintenance studies, the chance of relapse to either mania or depression was reduced by 40–60% for those who had experienced 1–5 episodes or 6–10 episodes compared to the >10 episode group, respectively. This trend was statistically significant only for relapse into mania for the 1–5 episode group (p = 0.005).

Conclusion: Those individuals at the earliest stages of illness consistently had a more favourable response to treatment. This is consistent with the staging model and

Efficacy of atypical antipsychotics in bipolar disorder

Bipolar disorder is a severe and recurrent disorder. Atypical antipsychotics have emerged as both an alternative and adjunct to conventional mood stabilisers. The manic phase of the illness is the best studied, and it appears that a class effect with regards to efficacy is present in both monotherapy and augmentation studies. Evidence for efficacy of atypical antipsychotics in depression is emerging. At this stage controlled data are available for both olanzapine and quetiapine. Maintenance data demonstrating efficacy are available for olanzapine. Atypical antipsychotics have utility in treating acute agitation and aggression in manic episodes of bipolar disorder. Subgroup analyses from trials treating manic phase bipolar disorder, and an open-label study of rapid cycling, have suggested that atypical antipsychotics may be useful for the treatment of mixed states and rapid cycling. Several studies have suggested that atypical antipsychotics may be useful in treatment-refractory episodes of bipolar disorder. The current available data suggest greater efficacy of the atypical antipsychotics in mania than in depression, although the data are fairly clear that induction of depression is not an issue with the atypical antipsychotics. A number of trials are underway that will hopefully address many of the questions still pending.

The validity and internal structure of the bipolar depression rating scale (BDRS): data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder

Background: The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder.

Method: The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75).

Results: A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750).

Conclusion: The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.

Dopamine dysregulation syndrome : implications for a dopamine hypothesis of bipolar disorder

Objective: Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder.

Method: A literature search was conducted using standard search engines Embase, PyschLIT, PubMed and MEDLINE. In addition, papers and book chapters known to the authors were retrieved and examined for further relevant articles.

Results: Collectively, in excess of 100 articles were reviewed from which approximately 75% were relevant to the focus of this paper.

Conclusion: Pharmacological models suggest a role of increased dopaminergic drive in mania and the converse in depression. In Parkinson’s disease, administration of high-dose dopamine precursors can produce a ‘maniform’ picture, which switches into a depressive analogue on withdrawal. It is possible that in bipolar disorder there is a cyclical process, where increased dopaminergic transmission in mania leads to a secondary down regulation of dopaminergic receptor sensitivity over time. This may lead to a period of decreased dopaminergic transmission, corresponding with the depressive phase, and the repetition of the cycle. This model, if verified, may have implications for rational drug development.

Health-related quality of life and functioning in bipolar disorder : the impact of pharmacotherapy

Bipolar disorder has a major deleterious impact on many aspects of a patient's functioning and health-related quality of life. Although the formal measurement of these deficits has been neglected until recently, many well-designed trials now include an assessment of functioning and health-related quality of life using one or more rating scales. This review describes recent developments in the measurement of functioning and health-related quality of life in bipolar disorder, and discusses the evidence that medications that improve symptoms in bipolar disorder also offer clinically relevant benefits in functioning and health-related quality of life. Direct comparisons of the benefits of medications including atypical antipsychotics are problematic due to differences in trial populations, study durations and rating scales. Data from quetiapine trials indicate that this medication offers prompt and sustained improvement of functioning in patients with mania and enhancement of health-related quality of life in patients with bipolar depression, to accompany the significant improvements in mood episodes.

Evidence and implications for early intervention in bipolar disorder

Aims: To review the evidence that supports early intervention in the treatment of bipolar disorder.

Background: Bipolar disorder is a pleomorphic condition, with varying manifestations that are determined by a number of complex factors including the ‘‘stage’’ of illness. It is consequently a notoriously difficult illness to diagnose and as a corollary is associated with lengthy delays in recognition and the initiation of suitable treatment.

Methods: A literature search was conducted using MEDLINE augmented by a manual search.

Results: Emerging neuroimaging data suggests that, in contrast to schizophrenia, where at the time of a first-episode of illness there is already discernible volume loss, in bipolar disorder, gross brain structure is relatively preserved, and it is only with recurrences that there is a sequential, but marked loss of brain volume. Recent evidence suggests that both pharmacotherapy and psychotherapy are more effective if instituted early in the course of bipolar disorder, and that with multiple episodes and disease progression there is a noticeable decline in treatment response.

Conclusions: Such data supports the notion of clinical staging, and the tailored implementation of treatments according to the stage of illness. The progressive nature of bipolar disorder further supports the concept that the first episode is a period that requires energetic broad-based treatment, with the hope that this could alter the temporal trajectory of the illness. It also raises hope that prompt treatment may be neuroprotective and that this perhaps attenuates or even prevents the neurostructural and neurocognitive changes seen to emerge with chronicity. This highlights the need for early identification at a population level and the necessity of implementing treatments and services at a stage of the illness where prognosis is optimal.

Early intervention in bipolar disorders : clinical, biochemical and neuroimaging imperatives

In the absence of clear targets for primary prevention of many psychiatric illnesses, secondary prevention becomes the most feasible therapeutic target, and is best encompassed by the concept of early intervention. This construct encompasses the goals of minimising diagnostic delay and the prompt initiation of clinically appropriate therapy. This paper develops the rationale for early intervention in bipolar disorder. Three interrelated themes are discussed; the clinical data supporting the value of prompt diagnosis and treatment in bipolar disorder, the putative biochemical mechanisms underlying the pathophysiological processes, and the parallel concept of neuroprotection, and the developing neuroimaging data that supports early intervention. Early initiation of appropriate therapy may potentially facilitate improved clinical outcomes, and further might allow the secondary prevention of the sequelae of untreated illness, which include the deleterious impact on family relationships, psychosexual and vocational development, identity and self-concept and self-stigma.

The impact of age at onset of bipolar I disorder on functioning and clinical presentation

Objectives: Recent studies have proposed the existence of three distinct subgroups of bipolar 1 disorder based on age at onset (AAO). The present study aims to investigate potential clinical and functional differences between these subgroups in an Australian sample.

Methods: Participants (n = 239) were enrolled in the Bipolar Comprehensive Outcomes Study (BCOS), a 2-year longitudinal, observational, cross-sectional study. Assessment measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD21), Clinical Global Impressions Scale (CGI-BP), SF-36, SLICE/Life Scale, and the EuroQol (EQ-5D). Participants were also asked about their age at the first major affective episode.

Results: Three AAO groups were compared: early (AAO < 20, mean = 15.5 ± 2.72; 44.4% of the participants); intermediate (AAO 20–39, mean = 26.1 ± 4.8; 48.14% of the participants) and late (AAO > 40, mean = 50.6 ± 9.04; 7.4% of the participants). Higher rates of depression, suicidal ideation and binge drinking were reported by the early AAO group. This group also reported poorer quality of life in a number of areas. The early AAO group had a predominant depressive initial polarity and the intermediate group had a manic predominance.

Conclusion: Early AAO is associated with an adverse outcome.

Clinical characteristics and management of bipolar disorder in women across the life span

Though prevalent in both genders, specific consideration needs to be given when treating a woman suffering from bipolar disorder over her lifetime. Bipolar disorder is a serious and incapacitating illness affecting an estimated 5% of women. The first episode of illness in women is usually a depressive episode. Female gender has been associated with greater axis-one comorbidity, more depressive episodes, rapid cycling and mixed affective states. Special consideration is required for the treatment of bipolar disorder during reproductive events. More studies are required to better understand the course, outcome and gender-specific treatment strategies of this disorder.

A prospective study of the impact of subthreshold mixed states on the 24-month clinical outcomes of bipolar I disorder or schizoaffective disorder

Objectives: Subthreshold mixed states are common, yet their clinical significance is unclear. This study investigated the clinical outcomes of subthreshold mixed states in participants with bipolarI disorder or schizoaffective disorder, using the Cassidy and Benazzi criteria for manic and depressive mixed states, respectively.

Methods: The Bipolar Comprehensive Outcomes Study (BCOS) is a prospective observational study of treatment and outcomes for patients with bipolar I or schizoaffective disorder, bipolar type. Participants (N=239) were grouped based on study entry clinical presentation as having pure depression (n=63) if they satisfied DSM-IV-TR criteria for a Major Depressive Episode (MDE), depressive mixed state (DMX) if they also had at least three concurrent hypomanic symptoms (n=33), or not depressed (n=143) if they did not satisfy the criteria for MDE. Participants were similarly grouped as having pure mania (n=3) if they satisfied DSM-IV criteria for a Manic Episode, manic mixed state (MMX) if they also had at least two concurrent depressive symptoms (n=33), or not manic (n=203). Clinical data were collected by interview every 3-months over a 24-month period.

Results: Measures of quality of life, mental and physical health over the 24-month period were significantly worse for participants who were classified as having mixed states at study entry on most outcome measures compared to participants who were not in an illness episode at study entry. DMX was predictive of greater manic symptomatology over the 24 months compared to participants with pure depression.

Conclusion: In participants with a current episode of mood disorder, the presence of subthreshold symptoms of opposite polarity was associated with poorer clinical outcomes over a 24-month period.

The management of individuals with bipolar disorder : a review of the evidence and its integration into clinical practice

Bipolar disorder is a common, debilitating, chronic illness that emerges early in life and has serious consequences such as long-term unemployment and suicide. It confers considerable functional disability to the individual, their family and society as a whole and yet it is often undetected, misdiagnosed and treated poorly. In the past decade, many new treatment strategies have been trialled in the management of bipolar disorder with variable success. The emerging evidence, for pharmacological agents in particular, is promising but when considered alone does not directly translate to real-world clinical populations of bipolar disorder. Data from drug trials are largely based on findings that identify difterences between groups determined in a time-limited manner, whereas clinical management concerns the treatment of individuals over the life-long course of the illness. Considering the findings in the context of the individual and their particular needs perhaps besl bridges the gap between the evidence from research studies and their application in clinical practice. Specifically, only lithium and valproate have moderate or strong evidence for use across all three phases of bipolar disorder, Anticonvulsants, such as lamotrigine. have strong evidence in maintenance; whereas antipsychotics largely have strong evidence in acute mania, with the exception of quetiapine, which has strong evidence in bipolar depression. Maintenance data for antipsychotics is emerging but at present remains weak. Combinations have strong evidence in acute phases of illness but maintenance data is urgently needed. Conventional antidepressants only have weak evidence in bipolar depression and do not have a role in maintenance therapy. Therefore, this paper summarizes the efficacy data for treating bipolar disorder and also applies clinical considerations to these data when

Atypical mood stabilizers : a 'typical' role for atypical antipsychotics

Objective: To assess the potential role of atypical antipsychotics as mood stabilizers.

Method: A MedLine, PsychLIT, PubMed, and EMBASE literature search of papers published up to December 2004 was conducted using the names of atypical antipsychotics and a number of key terms relevant to bipolar disorder. Additional articles were retrieved by scrutinizing the bibliographies of review papers and literature known to the authors. Data pertinent to the objective was reviewed according to the various phases of bipolar disorder.

Results: The data is most substantive for the use of atypical antipsychotics in mania, to the extent that an argument for a class effect of significant efficacy can be made. This does not extend to bipolar depression, however, good data is now emerging for some agents and will need to be considered for each individual agent as it accumulates. As regards mixed states and rapid cycling the evidence is thus far sparse and too few maintenance studies have been conducted to make any firm assertions. However, with respect to long-term therapy the atypical antipsychotics do have clinically significant side-effects of which clinicians need to be aware.

Conclusion: Based on the evidence thus far it is perhaps premature to describe the atypical antipsychotics as mood stabilizers. Individual agents may eventually be able to claim this label, however, much further research is needed especially with respect to maintenance and relapse prevention.

Atypical antipsychotics for bipolar disorder : overblown or blown over?

Objective：Developments in the pharmacological treatment of bipolar disorder are of much interest, as the chronicity and disability of the disorder become better understood, and as treatment goals have shifted to emphasise early control of illness course and maintenance of euthymia in addition to acute episodic remission. Atypical antipsychotics have emerged as treatment options, and this paper aims to review the evidence for their role in bipolar disorder.

Methods：A MEDLINE search was conducted for publications up till October 2006.

Results：The search yielded a number of randomised, controlled clinical trials of various atypical antipsychotics as monotherapy or adjunctive therapy in bipolar disorder. The majority of such trials have investigated their efficacy in acute mania, with fewer studies devoted to acute bipolar depression or maintenance treatment. There are no specific trials on mixed states, which have mainly been studied together with bipolar mania. The most robust evidence supports a class effect of atypical agents in the treatment of mania.

Conclusions：There are placebo-controlled trials that support the efficacy of olanzapine and quetiapine in bipolar depression, and of olanzapine and aripiprazole as maintenance treatment. There is strong support for the role of atypical antipsychotics in bipolar disorder management despite a relatively narrow literature base, chiefly for the treatment of mania. However, these findings need to be replicated, and further investigation is warranted to clarify their spectrum of efficacy in bipolar disorder.

The utility of the Mood Disorders Questionnaire as a screening tool in a methadone maintenance treatment program

Objective. Comorbid mental illness amongst methadone maintenance therapy clients may be common and screening may be warranted. The Mood Disorders Questionnaire (MDQ) is a screening tool for bipolar disorder that has been validated in other treatment settings. Its utility for patients with substance use disorders is assessed in this study.

Methods. Clients of a methadone maintenance program were invited to complete the MDQ when they attended a public Drug and Alcohol Service for their regular scheduled appointments. Information about their history of substance use was also collected.

Results. Eighty clients (43 females, 37 males) aged 35 8.0 years (mean SD) participated in the study. Seventy-four clients completed the MDQ of which 36 (48.6%) obtained a positive screen. A check of client fi les suggested that only three of the 74 participants had a current working diagnosis of bipolar disorder. These three participants had screened positive on the MDQ.

Conclusions. There was a high prevalence of manic symptoms reported by participants, suggesting that screening for bipolar disorder in this population may be warranted. However, there is a risk of false positives with the MDQ, as it does not clearly differentiate between symptoms of mania and drug intoxication.

Psychological needs of adolescents in the early phase of bipolar disorder : implications for early intervention

Aim: This paper will describe the rationale for, and importance of, psychological interventions for young people early in the course of bipolar disorder.
Methods: Emerging literature in this field will be discussed in addition to describing specific clinical challenges and opportunities with this population.
Results: In order to be more developmentally appropriate for young people with bipolar disorder, eight aspects of clinical work which may require modification were identified.
Conclusions: The evidence base for the effectiveness of psychological interventions for people diagnosed with bipolar disorder is growing. However, some aspects relating to working with adults with bipolar disorder require modification to be effective in working with young people early in the course of the disorder.