ECNP releases consensus statement on bipolar depression
Bipolar disorder is one of the most important psychiatric diseases, often associated with considerable treatment needs and tremendous social and occupational burden for both the individual and family (Pini et al., 2005). Previously also labelled manic-depressive illness, bipolar disorder is typically referred to as an episodic, yet lifelong and clinically severe mood (or affective) disorder.
Mood in bipolar disorder may swing from euphoria and/or extreme irritability (defined as ´mania´) to depressed mood or loss of interest or pleasure (´bipolar depression´). Less severe mood elevation (hypomanic episodes) characterise so-called Bipolar II disorder. Thus bipolar disorder may be divided into two major subtypes – Bipolar I and Bipolar II – although emerging data reveal that further extension of the bipolar spectrum (at the expense of unipolar depression) may be of broad clinical relevance.
* Bipolar I disorder is characterized by a history of at least one manic episode, with or without depressive symptoms.
* Bipolar II disorder is characterized by the presence of both depressive symptoms and a less severe form of mania (´hypomania´).
Acute episodes may vary in duration as well as intensity over time. Early in the course of the disease, for example, the periods between acute episodes may last months or even years, but later these symptom-free periods tend to decrease. ´Rapid cycling´ a not infrequent course variant is defined as suffering from 4 or more episodes per year. Clinical decisions pertaining to the treatment of bipolar disorder essentially are grouped around the topics of depression, mania, and rapid cycling/mixed states.
Recent studies have suggested that bipolar disorders are much more frequent than previously thought. Almost 2% of the EU-population is or will be suffering from bipolar disorders in the course of their lives. When the wider range of the bipolar spectrum conditions is considered, estimates might be increase to as much as 6% (Pini et al., 2005). The estimates of the frequency of bipolar disorder are relatively stable: they show little indication of substantial variation by culture and region, there is convergent evidence for relatively early onset of illness in the mid-teenage years and twenties, and there is little evidence that the disorder is increasing substantially over time.
The first onset of bipolar disorders tends to be earlier than that of unipolar major depression in population samples, which may indicate that bipolar disorder have partly different causal factors promoting the illness. The risk for this illness is highest in the time period between late adolescence and the third decade and is substantially decreased after this age; conversely, the overall the risk of unipolar major depression continues to grow further on into the old age (Wittchen et al., 2003). A consequence of the symptoms of bipolar disorder is that patients experience a debilitating decrease in functioning not only during their acute stages of illness, but increasingly also inbetween episodes. Typically they have for example difficulty in maintaining long-term relationships and they perform poorly at school or work, which impacts on opportunities for employment and finances.
The early onset of bipolar disorder potentially implies a severe burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to the acute depression episodes.
Bipolar depression: a major treatment challenge
Bipolar disorder may be defined by the existence of depression and (hypo-)mania, but its long-term course is almost always dominated by depressive rather than (hypo)manic symptoms. Patients with bipolar disorders are at a substantially increased risk of suicide, particularly during depressive episodes. Furthermore, in bipolar patients a high degree of concurrent and sequential comorbidity with other mental disorders and physical illnesses is common. Unfortunately, all too often patients with bipolar disorders remain unrecognized by health professionals, untreated or improperly treated, which clearly is associated with a lower life expectancy, a more malignant course and an altogether lower quality of life. In particular bipolar II disorder has been under-recognized until recently, in part owing to difficulties in distinguishing bipolar from unipolar depression (Berk et al., 2005). Thus, a major challenge in the treatment of patients with mood disorders is the distinction between bipolar and unipolar depression, since these mood disorders require different approaches to treatments.
There is a considerable longitudinal risk – probably over 10% – that initial unipolar depressive patients ultimately turn out as bipolar patients in the longer run.
Bipolar depression in children
Bipolar disorder exists in children and adolescents, but the age at which bipolar disorder can first be diagnosed remains controversial. Although bipolar-like symptoms may be quite frequent, reliably defined bipolar I disorder is rare in prepubertal children. Since early intervention may improve diagnosis, treatment studies are an important objective for future research. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions via clinical networks. ECNP will aspire to facilitate such developments.
ECNP supports collaborating networks of clinicians in Europe who seek to improve treatment and research in children and in bipolar disorder.
Treatment studies in bipolar depression
Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled trials. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo-controls. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medications such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Thus, 12-week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessments at 6-8 weeks are required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time.
Switching from bipolar depression to mania or hypomania is the particular risk that requires a different approach to treatment from unipolar depression.
Long-term treatment of bipolar disorder
Long-term treatment is commonly required in bipolar disorder. Thus, trials to detect maintenance of effect or continued response in bipolar depression should follow a relapse prevention design: i.e. patients are treated in an episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. Thus, long periods of mood stabilization for up to 3 months may appear desirable, but protocol compliance may then be difficult to achieve in practice and certainly will make studies more difficult and expensive to conduct.
The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse also is clinically informative. Finally, besides the traditional measures of outcome based on symptom severity rating scales, it would be advisable to include measures addressing functionality such as neuropsychological tests of attention, memory and executive function, and quality of life.
Long term prevention of relapse is the major challenge in bipolar disorder. Success requires a mature therapeutic alliance between doctor and patient, effective self-management by the patients and their families and effective well tolerated bipolar disorder treatments.
Goodwin GM, Anderson I, Arango C, et al. ECNP consensus meeting. Bipolar depression. Nice, March 2007. European Neuropsychopharmacology 2008;18:535-549 –
The full paper of the ECNP Consensus document on bipolar depression is available through the ECNP website: www.ecnp.eu
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2. Berk M, Hallam K, Lucas N, et al. Health-related quality of life and functioning in bipolar disorder: the impact of pharmacotherapy. Expert Rev Pharmacoeconomics Outcomes Res 2006;6:509-523
3. Wittchen HU, Mhlig S, Pezawas L. Natural course and burden of bipolar disorders. Int J Neuropsychopharmacol 2003;6:145-154