Abstract
Major depressive episodes
Affective disorders represent a major health challenge and a highly significant cost to the public purse in all countries. Indeed, in Europe in 2010 the cost of affective (mood) disorders was estimated to amount to €113.4 billion, the largest cost attributed to any single group of brain-related disorders (Gustavsson et al., 2011).Affective disorders are a group of illnesses with the two principal diagnostic categories being bipolar disorders and major depressive disorder (MDD). Bipolar disorders are separated from MDD on the basis of a history of episodes of pathological elevation of mood, which may be more (mania/bipolar 1) or less severe (hypomania/bipolar II and bipolar spectrum disorders). Despite this well-enshrined delineation, the clinical presentation of these apparently separate illnesses is frequently not clear in practice. This is mainly because major depressive episodes (MDEs) are a central feature of both bipolar disorders and MDD. However, there are no pathognomonic characteristics of MDEs in bipolar disorder compared to MDD, although factors such as family history, illness course, age of onset, and so on may raise the clinical index of suspicion for a bipolar diagnosis (Mitchell et al., 2008). Diagnostic differentiation rests on a history of mania or hypomania. The diagnosis of bipolar 1 disorder, because of the hallmark state of mania, is relatively straightforward in established cases. (There is, however, much scope for confusion in first-episode mania.)
Bipolar II and bipolar spectrum disorders present much more of a diagnostic challenge principally because of the problems associated with detecting previous episodes of hypomania (Young and Macpherson, 2011). Improved detection of bipolar disorder thus depends upon better ascertainment of a history of hypomania. The more widespread use of readily available screening tools (e.g. the hypomania checklist; Angst et al., 2005) would do much to move us to this end. The aim of a more accurate diagnosis of depression (bipolar or MDD) is to guide appropriate, evidence-based treatment. This gives rise to the question as to what is the best treatment for MDEs and does this differ between bipolar disorder and MDD? The purpose of this debate paper is to briefly highlight some of the issues which arise when we ask this question of antidepressant drug treatment and to suggest a modest proposal which, if implemented, might go some way to resolving our current confusion.
The efficacy of antidepressants
Antidepressants are extremely commonly used medicines and their use would seem to be becoming more frequent. In England, the number of prescriptions for antidepressants increased by 28% from 34 million in 2007–2008 to 43.4 million in 2010–2011, according to the National Health Systems (NHS) information centre quoted in a recent article in the UK newspaper The Guardian (Batty, 2012), and similar data has been reported from other countries.
The evidence base for the use of antidepressants in MDD is very extensive and has been the subject of a number of recent attempts to synthesize and summarize the relevant data. A recent review of 234 studies broadly confirmed antidepressants’ efficacy in MDD, although individual drugs differed in onset of action, adverse events and some measures of health-related quality of life (Gartlehner et al., 2011). A similar evidence base for the treatment of MDEs in bipolar disorder is somewhat lacking, but what evidence there is does not suggest that we cannot be as confident of the efficacy of antidepressants for the treatment of MDEs in this mood disorder. Sidor and MacQueen (2011) recently reviewed and synthesized the evidence for the use of antidepressants in bipolar disorders. They conducted a meta-analysis of randomized, controlled trials of antidepressants in bipolar 1 and bipolar II depression and identified a total of 15 studies containing 2373 patients. Their findings were that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression. However, antidepressants were not associated with an increased risk of switch into pathological mood states.
Studies that employed more sensitive criteria to define manic/hypomanic switch did report elevated switch rates for antidepressants. It was notable, however, that for bipolar 2 disorder the evidence is even scarcer. Even where bipolar 2 patients are studied, separate outcome measures for this crucial group are rarely reported (Sidor and MacQueen, 2011). Sidor and MacQueen (2011) conclude that although they found antidepressants to be (relatively) safe for the acute treatment of bipolar depression, the lack of clear-cut efficacy for these medications may limit their clinical utility. This conclusion is reflected in treatment guidelines which typically do not recommend antidepressant monotherapy for the treatment of MDEs in bipolar disorder (Yatham et al., 2009), although combination treatment with some antidepressants and atypical antipsychotics or mood stabilizers is allowed.
From evidence to clinical practice
Clinical practice of the treatment of MDEs seems to differ everywhere from that recommended in guidelines.In our recent international study of over 5000 patients with MDEs in MDD or bipolar disorder, 90.5% of patients were receiving antidepressant treatment (Angst et al., 2011).Compared to those with MDD, this proportion was slightly lower among those meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for bipolar disorder (79.3%) than in those in the wider bipolar-specifier group [2246 (84.9%)]. Notwithstanding the diagnostic cut applied to bipolar symptoms in patients with depression, it seems clear that roughly between 80 and 85% of bipolar depressed patients may be treated with antidepressants.This treatment of bipolar depression with antidepressants is largely not evidence based and also means that patients are likely being denied the first-line treatments recommended in guidelines (Yatham et al., 2009).Although we must be cautious about generalizing these findings too readily, it does seem likely that many patients with major depressive episodes who have an underlying bipolar disorder receive pharmacological treatment with ineffective agents.
A modest proposal
In recent years a number of studies of the drug treatment of MDEs in bipolar depression have been published and have greatly informed our knowledge base (see Yatham et al., 2009).These studies have been most commonly carried out by pharmaceutical companies in response to regulatory authorities’ requirements for evidence necessary for drug licensing and have resulted in new treatments being licensed for the treatment of MDEs in bipolar disorder. Notably, no traditional or even newer antidepressants, e.g. selective serotonin reuptake inhibitors (SSRIs), have passed these demanding hurdles. The process of licensing pharmacological treatments for MDEs in MDD and bipolar disorder are disconnected, a surprising state of affairs given that clinicians seem to assume that a drug efficacious for MDD has clinical utility for MDEs in bipolar disorder.
A slight change in approach, reflecting clinical reality, might potentially be of great benefit to patients. If the regulatory focus were shifted to the treatment of MDEs per se, trials would have to be pursued in both MDD and bipolar disorder simultaneously. Furthermore, given the uncertain boundaries between the disorders (Angst et al., 2011), a dimensional quantification of ‘bipolarity’ (e.g. based on the hypomania checklist data) in patients with MDEs should be a requirement. Such a change would help us understand which antidepressants are efficacious for which disorder and would better guide treatment of all MDEs.
Conclusion
Major depressive episodes in both MDD and bipolar disorder are commonly treated with antidepressants.The requirements for licensing antidepressants should reflect this and require studies in all mood disorder diagnoses in which MDEs may occur.