New International Consensus Statement on Bipolar Depression

Marlene Busko

September 05, 2008

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September 5, 2008 — A new international consensus statement on bipolar depression summarizes the most recent knowledge about this condition in children and adults, from epidemiology to treatment challenges and research design.

The statement, presented at the 21st European College of Neuropsychopharmacology (ECNP) Congress, in Barcelona, Spain, is based on discussions held in March 2007 including some 60 experts in bipolar disorder. The document was published in the July issue of European Neuropsychopharmacology and is available on the ENCP Web site.

"The profile of bipolar depression has assumed increasing importance," lead author, Guy M. Goodwin, BM, BCh, from the department of psychiatry at Warneford Hospital, in Oxford, the United Kingdom, told Medscape Psychiatry. "We hope to achieve awareness into how and why bipolar depression develops in young people and stimulate research into treatment."

The writing group includes participants from Australia, France, Germany, the Netherlands, Spain, the United Kingdom, and the United States and builds on an earlier document issued in 2001.

Diagnosis and Epidemiology

European surveys and a recent American survey estimate that, at some point in their lives, almost 2% of the population is affected by bipolar disorder and up to 6% by bipolar spectrum disorder.

Converging evidence suggests that the first onset of bipolar mood disorder occurs in the mid-teens to 20s until the 30s, when it usually manifests as a major depressive episode or hypomania. The onset of major depressive disorder tends to be later, and the risk continues into old age, which may reflect different causation for the 2 disorders.

"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 depression," the group emphasizes. Patients experience a debilitating decrease in functioning not only during their acute stages of illness, but increasingly also between episodes.

Bipolar disorder without depressive disorder is very rare, and the long-term course of bipolar disorder is dominated by depression rather than manic symptoms.

Since reliable criteria for delineating unipolar and bipolar depression are currently lacking, there is a considerable risk — probably over 10% — that patients initially diagnosed as having unipolar depression turn out have bipolar depression in the long run, the group stresses.

Bipolar Depression in Children

It is widely accepted that bipolar disorder exists in children and adolescents, but the age at which it can be first diagnosed remains controversial. Although bipolarlike symptoms may be quite frequent, reliably defined bipolar I disorder is rare in prepubertal children. Bipolar I disorder is characterized by a history of at least 1 manic episode, with or without depressive symptoms, whereas bipolar II disorder includes the presence of both depressive symptoms and a less severe form of mania, hypomania.

Early-onset bipolar disorder is increasingly recognized when patients are in their late teens. Since early intervention may improve patients' prognosis, trials of treatments for children and adolescents are important, the consensus document notes. To determine the best treatments, rather than extrapolate findings from clinical trials in adult patients, clinical trials are needed for young patients. It remains a challenge to find ways to collaborate and recruit patients for such research studies.

"The ECNP supports collaborating networks of clinicians in Europe who seek to improve treatment and research in children" with bipolar disorder," the group writes.

Bipolar Depression vs Unipolar Depression in Adults

Currently, the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) criteria for a major depressive episode in bipolar depression (or unipolar depression) do not take into consideration the overall course of the disorder. The next edition of the DSM is likely to use a probabilistic definition, as recommended by the International Society for Bipolar Disorders, to distinguish bipolar from unipolar depression, and this type of definition should be used in future research studies, they write.

Since anxiety is commonly present in bipolar populations, randomized controlled trials should accept patients with comorbid anxiety. Rapid cycling patients, defined as suffering from 4 or more episodes a year, can also be recruited into these trials without impairing the outcomes.

Treatment Studies

Monotherapy trials comparing a drug vs placebo remain the gold-standard clinical-trial design for determining efficacy in bipolar depression. If efficacy is proven for a new drug vs placebo, the drug can then be tested in a placebo-controlled trial with adjunctive medication, the authors write. Younger adults, without an established need for long-term medication, may be particularly suited to placebo-controlled clinical trials.

The minimum scores for entry into bipolar-depression trials should be > 20 on the Hamilton-Depression (HAM-D) 17-item rating scale, and efficacy is best detected in patients with a HAM-D rating > 24 at baseline, they recommend.

In addition to basing trial outcomes on ratings in the traditional symptom-severity scales, it would be advisable to include secondary measures of functionality, such as quality-of-life measures and neuropsychological tests of attention, memory, and executive function.

Preventing Switch to Mania

"Switching from bipolar depression to mania or hypomania is a particular risk that requires a different approach to treatment from unipolar depression," the group cautions.

Some medications, such as the tricyclic antidepressants and venlafaxine, may be more likely than other medications to provoke this switch, but this effect might not be seen until 10 weeks of treatment. Thus, 12-week trials of drug vs placebo are needed to determine the risk for switch and to establish continuing effects, they write.

Study subjects need to be assessed carefully at 6 to 8 weeks to ensure nonresponsive patients do not remain in the study for an unacceptable length of time.

Preventing Relapse

"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 treatments," the group notes.

Trials that aim to detect a maintenance effect or a continued response should follow a relapse-prevention design. That is, patients who are experiencing an episode of bipolar disorder are treated with a study drug and are then randomized to continue active treatment with the drug or to receive placebo. However, acute withdrawal of active medication after treatment response might artificially enhance the effect of the study drug, they note.

A short tapering-off period is usually desirable. In addition, mood stabilization for up to 3-month periods is desirable, but protocol compliance for these longer periods may be difficult to achieve, making these studies more expensive and more difficult to conduct.

Clinical trials that include the addition of a drug to other agents during or after the resolution of a depressive or manic episode and then investigate the effect of this drug vs placebo to prevent relapse would be clinically informative.

Clinical Challenge

In the UnitedStates, as compared with Europe, "there are no differences in the clinical challenge — it's the same disease — but healthcare systems are different, and this affects patient access," said Dr. Goodwin. "The United States has gone much further in trying to diagnose children before an adult pattern of illness is present. This is a hazardous project, and the European approach is more cautious."

The study authors report no financial disclosures.

Eur Neuropsychopharmacol 2008; 8:535-549. Abstract


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