Course and outcome patterns of depression: of depression: from unipolar episode to bipolar disorder

Eduard Vieta, MD, PhD

Bipolar Disorders Program
Institute of Neuroscience
Hospital Clinic
University of Barcelona
Barcelona, SPAIN

Course and outcome patterns of depression: from unipolar episode to bipolar disorder

by M. Reinares and E. Vieta, Spain

Depression is the most frequent presentation of bipolar disorder. Several studies have reported that the long-term course of the illness is dominated by depressive rather than manic symptoms, with a direct negative impact on patient functioning. Despite its high morbidity and mortality, it is a field of research that has been neglected until recent years. A high percentage of bipolar patients are initially misdiagnosed as having unipolar depressive disorder. This mistake carries significant negative consequences for the treatment of this population and for outcomes. Therefore, it is essential to establish an accurate distinction between bipolar and unipolar depression in order to make an accurate and early diagnosis, leading to improvements in treatment and course of illness. This could also help clarify whether bipolar depression and major depressive disorder are separate diagnostic entities or belong to the same illness spectrum. This review aims to analyze the differences between unipolar and bipolar depression and identify possible predictors that may influence the “conversion” from unipolar depression to bipolar disorder. New proposals and future challenges in this area will also be discussed.

Medicographia. 2011;33:145-150 (see French abstract on page 150)

Bipolar disorder is a high prevalent, chronic, recurrent illness with devastating consequences when untreated because of high rates of morbidity and mortality. About 15% of severe bipolar patients die by suicide1 and the percentage of patients who attempt suicide more than once is even higher. These attempts mostly occur during depressive phases. The long-term course of the illness is dominated by depressive rather than manic symptoms.2-5 Recent studies suggest that depression has a direct and negative impact on functioning and these deficits appear to persist even during remission.6 Furthermore, subsyndromal symptoms can not only impair psychosocial functioning,7 but can also lead to a recurrence.8 In spite of the deleterious consequences of bipolar depression, it has been a neglected field of research for a long time. All the risks mentioned could be lowered by means of an early diagnosis and prophylactic treatment.

To be able to distinguish between bipolar and unipolar depression is crucial, as the treatment of both conditions differs considerably. This distinction is necessary in order to ensure accurate and early diagnosis, and to improve the pharmacological treatment of depression and understand the biology involved in each condition. It would reduce the economic burden and improve the health and quality of life of these patients. It also could help clarify whether bipolar depression and major depressive disorder are separate diagnostic entities or whether they belong to the same illness spectrum as different manifestations of the same underlying disorder.

Diagnostic issues

Unipolar and bipolar depression were first described by Leonhard9 and this distinction was validated by Angst,10 Perris,11 and Winokur and coworkers12 who showed that clinical, familial, and course features supported the nosological differentiation between both forms. Officially recognized in 1980 by DSM-III (Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition), this subtyping of unipolar/bipolar was further established in DSM-IV (4th Edition) and DSM-IV-R (4th Edition, Text Revision), both of which distinguish between bipolar type I and type II. Although major depressive disorder is classified separately from bipolar disorder, the criteria for unipolar and bipolar depression are identical, and emphasis is placed upon the euphoric condition and not upon differences in the depressive episodes.13 However, the impact of antidepressant treatment is different, clear for unipolar patients, unclear and sometimes self-defeating for bipolar patients, increasing the risks of (hypo)manic switch or rapid cycling. Due tomisdiagnosis,many bipolar patients are less likely to receive mood stabilizer medications.14 Furthermore, some of the illness treatments might be less effective when they are introduced in patients who have had many previous episodes15,16 and the impact of a late introduction of mood stabilizers on top of antidepressants may carry high switch rates and increased suicidality.17

It has been reported that about 7.5 years elapse from the first time the patients ask for medical help and the time an accurate diagnosis of bipolar disorder is made.18 A survey of bipolar patients involved with National Depressive and Manic-Depressive Association support groups pointed out that 69% of patients were initially misdiagnosed, on average four psychiatrists were consulted before an accurate diagnosis was made, and unipolar depression was the most frequent misdiagnosis.19 As suggested by Goodwin and Jamison,1 there are five primary causes for misdiagnosis: (i) patients’ lack of insight with regard to manic as opposed to depressive symptoms; (ii) clinicians’ neglect of information available from family members or other third parties; (iii) clinicians’ relative focus on euphoric rather than dysphoric or irritable mood as a criterion for hypomania; (iv) the structure of DSM-IV, which by separating bipolar from all depressive disorders has obscured the close relationship between early-onset recurrent depression and bipolar disorder; and (v) widespread interest in and use of “second-generation” antidepressants.

It is difficult to establish a correct differential diagnosis based on cross-sectional information, without obtaining data about the patient’s course of illness. By definition, (hypo)mania plays an essential role in the understanding of the bipolar condition of a mood disorder. Sometimes, especially when dealing with a bipolar disorder type II, diagnosis can be difficult when hypomanic episodes are not clearly detected. Furthermore, some subjects have a hyperthymic or cyclothymic temperament with mood disturbances that can sometimes be seen as borderline personality traits. Hence, the bipolar nature of a depressive episode could be difficult to establish. In fact, it has been pointed out that depressive polarity was strongly associated with a higher number of years undiagnosed.20 A recent study found that the delay to first treatment was associated with being depressed for longer, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic.21 Another confusion factor to take into account is comorbidity with other psychiatric disorders. The high prevalence of comorbidities in bipolar patients has a negative impact on prognosis and sometimes also makes an accurate diagnosis more difficult to establish. The most frequent misdiagnosis includes substance-use disorders, anxiety disorders, personality disorders, and attention deficit hyperactivity disorder.22,23 To sum up, bipolar depression, which is often related to comorbidity, disability and mortality, is still largely unknown and frequently underestimated, which may engender a more severe course of the illness.

Clinical features of unipolar and bipolar depression

Several authors have tried to define the clinical specificity of bipolar depression. Unfortunately, some studies do not consider the distinction between bipolar subtypes. Although there are no pathognomonic characteristics specific to bipolar depression compared with unipolar depressive disorder, when both conditions have been analyzed, some clinical and epidemiological differences can be described (Table I).

Table I
Table I. Differences between bipolar and unipolar depression.

The age of onset of the first depressive episode in bipolar disorder has been found to be earlier than that observed in unipolar depression.24,25 Regarding the course of the illness, it has been reported that bipolar depressed subjects are more likely to report more prior episodes26 and shorter episode duration.27 Other typical characteristics of bipolar depression are lability of mood and hypomanic symptoms during depression.28,29 Goldberg et al30 found that two thirds of the subjects with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation. They observed that manic symptoms during depression demarcated a more severe and psychopathologically complex clinical state. It has also been reported that the stronger the manic component, the higher the mean values for novelty seeking and reward dependence, but the lower they are for harm avoidance.31 Bipolar depression is more often related to a higher risk of psychotic symptoms,32 suicidal ideation,33 postpartum episodes,34 seasonal pattern,35 fewer somatic symptoms,26 less appetite loss,36 hypersomnia,27 and atypical depressive symptoms.37 Most, but not all, investigations have reported higher levels of psychomotor retardation in bipolar patients.38,39 Comorbid conditions such as anxiety disorders and substance abuse are also more frequent in bipolar depression than in unipolar depression.40 Bipolar depression has also been more frequently related to a family history of bipolar disorder,26,41 and with manic symptoms associated with antidepressants (Table I).42 A potential limitation of many cross-sectional studies is that some people diagnosed with major depressive disorder could develop bipolar disorder.

Predictors of bipolar outcome in depression

The percentage of patients initially identified with “unipolar” depression who experience manic episodes varies widely across studies, but may be as high as 50%.43 To identify those unipolar patients who, in the long-term, “become” bipolar patients is another way of obtaining more information about bipolar depression. When the predictors are analyzed, they are quite similar to those aspects described in cross-sectional comparative studies between unipolar and bipolar depression. In a retrospective study published in 1976, Dunner and colleagues44 found that up to 21% of type I and type II bipolar patients had previously been hospitalized due to “unipolar depression.” Akiskal et al45 proposed eight criteria predictive of the “bipolarization” of a depression, and suggested calling “pseudounipolar depression” the episodes that will show its bipolarity afterwards. They found the following predictors: treatment-induced hypomania, family history of bipolar disorder, strong inheritability, depression with hypersomnia and motor retardation, psychotic depression, continuous multigenerational familial transmission, postpartum onset and early onset (before age 25). Long-term studies have shown that those patients who became bipolar were more likely to show psychosis at the index depressive episode.32,46 Younger age at onset, chronicity of the index episode, and family history of mania have also been reported.46 Some of these aspects have been included by Solomon et al47 who suggested using three items of the Screening Assessment of Depression-Polarity (SAD-P) as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression: presence of delusions during the current episode of major depression, number of prior episodes of major depression, and family history of major depression or mania.

In an 11-year follow-up study composed of 559 subjects with a major depressive episode, Akiskal and coworkers28 found that up to 12.5% later developed a manic or hypomanic episode, which confirms its inclusion in the so-called “bipolar spectrum.” Twenty-two patients (3.9%) had a full-blown manic episode, becoming bipolar type I, and 48 (8.6%) had at least one episode of hypomania, confirming its status as belonging to the bipolar II disorder. Except for greater acuteness, severity, and psychotic symptomatology, bipolar I converters were similar to major depressive disorder nonconverters. In contrast, bipolar II converters were robustly distinguished from those with major depressive disorder who remained unipolar on the basis of self-report measures of mood lability, energy/ activity, and daydreaming. This profile was associated with early age at onset of major depressive disorder and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Bipolar II switchers had a more protracted and tempestuous course with shorter well intervals. Overall, descriptions of temperamental instability during major depressive disorder episodes provided useful clinical information for predicting which depressed patients will switch to bipolar II.

Recently, a 5-year prospective study showed that 2.8% and 8.9% of unipolar major depressive patients switched to bipolar I and II disorder, respectively. Together with severity, predictors for diagnostic switch included psychiatric comorbidity such as obsessive-compulsive disorder, social phobias, and symptoms of cluster B personality disorders.48

A great number of individuals with the so-called soft or subsyndromal states belong to the bipolar spectrum by virtue of their positive family histories, their pharmacological response, and their tendency to progress to full clinical disorder.49 Based on a sample of patients with bipolar II disorder and major depressive disorder, Benazzi and Akiskal24 aimed to identify validated bipolar markers. Lower age at onset (before 21 years), higher major depressive episode recurrence, mixed depression, and bipolar family history were significantly more common in bipolar II disorder. Early onset was the most discriminative feature of this major depressive disorder subgroup at possible higher risk of shifting to bipolar disorder. The authors suggested that early age at onset of depression represents a marker of a genetically based recurrent or polyphasic mood disorder.

New proposals

Based on the fact that some clinical characteristics are more common in both bipolar depression andmajor depressive disorder, respectively, or are observed in unipolar depressed patients who “convert” to bipolar disorder over time, Mitchell et al50 have suggested a probabilistic approach. Instead of proposing a categorical diagnostic distinction between bipolar and unipolar depressive disorder, they recommend a likelihood approach as follows (see Table II).

This approach uses a set of sociodemographic and clinical variables to establish which patients with depression are more or less likely to have an underlying bipolar disorder, and it is based on differences between subjects with bipolar disorder and major depressive disorder other than the presence or absence of manic symptoms.41 Therefore, the assessment of the presence of (hypo)manic symptoms would be complemented by other aspects related to the clinical history to make an accurate diagnosis. Although this approach should be carried out with new data and be further explored, the use of probabilistic models has been reinforced when the criteria of actual classifications systems have been discussed.51

As previously mentioned, Solomon et al48 suggested a preliminary screen for bipolar disorder in patients with a depressive episode bymeans of assessing the presence of delusions during the current episode of major depression, the number of prior episodes of major depression, and a family history of major depression or mania.

The influence of subsyndromal depression on psychosocial functioning and on futuremood recurrences points to the need to introduce treatments with the aim of achieving full remission. Based on the fact that the risk of subsequent recurrence and impairment increases with each new episode and that there is a poorer response to treatment when it is implemented later in the course of the illness, recent proposals have been made regarding the application of clinical staging to bipolar disorder.52,53 The staging model suggests a progression from prodromal tomore severe and refractory presentations.54 However, early intervention in bipolar disorders depends on the ability to identify individuals at high risk of developing the illness. Failure to identify minor elated states leads to misdiagnosis of bipolar spectrum patients as unipolar. It is essential to strive to make appropriate distinctions among various forms of depression and differentiate them diagnostically, prognostically, and therapeutically from ordinary unipolar major depressive disorder.14

Table II
Table II. Likelihood of diagnosis of bipolar I depression and of
unipolar depression.

A better knowledge of the characteristics that permit discrimination between unipolar and bipolar disorder, together with a good anamnesis complemented with information from family members and a higher use of screening tools, could facilitate an increase in the detection of bipolar disorder in patients with depression. The Mood Disorder Questionnaire (MDQ) may help to increase recognition of bipolar disorder.55

A recent study56 showed that the MDQ yielded a positive screen rate of bipolar patients with a diagnosis of unipolar disorder and a current depressive episode. The Hypomania Checklist (HCL-32)57 can also help to identify the hypomanic component of depressive episodes and increase the detec- tion rate of both bipolar disorder and minor bipolar disorders. Rating tools should be introduced systematically in primary care, paying special attention to young people.

A contentious issue is whether (hypo)mania that occurs during treatment of “unipolar” depression is, following DSM-IV, an antidepressant-induced mood disorder or, as suggested by some experts, the precipitation of an underlying bipolar disorder. A high increase in the number of patients who would be considered bipolar if the duration criteria of hypo(manic) symptoms were more flexible has also been reported.58 Therefore, major depressive disorder seems to be overdiagnosed at the expense of bipolar disorder. Using a broader concept and a more comprehensive screening of bipolarity, Zimmermann et al31 have suggested that major depressive disorder is a heterogeneous concept including a large group with subthreshold bipolar disorder. In contrast to the dichotomicalmodels, the development of a validated bipolar spectrum concept has been introduced to assist in more differentiated research and provide a treatment model for affective disorders, which may help reduce the underrecognition of bipolarity.59 Thismodel unifies categorical classification with a dimensional view, as some proposals for future diagnostic classification systems have suggested.60


Despite depression being the most frequent presentation of bipolar disorder associated with high morbidity and mortality, it has been a neglected field of research. Fortunately, in recent years, a number of studies have shed some light on this topic. There are areas of overlap between both forms of depression, although some differences have also been found. The distinction between bipolar and unipolar depression would assist in making an accurate and early diagnosis, in improving treatment, and in reaching a better understanding of each condition which, in turn, would contribute to improving illness outcome. The new editions of the forthcoming diagnostic classifications will face the challenge of improving the discriminant validity of bipolar and unipolar depressions. New treatments will also need to be tested in the two indications, hopefully providing a final answer to the unsolved question of the efficacy and safety of antidepressants in bipolar depression. Meanwhile, the best way to discriminate between unipolar and bipolar depression is the course and outcome of the condition. To what extent both disorders are merely different course patterns of one condition is still a matter of debate. _

The authors of this study would like to thank the CIBERSAM, and appreciate the support of the Generalitat de Catalunya for the Bipolar Disorders Group (2009 SGR 1022).

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Keywords: bipolar disorder; major depression; unipolar depressive disorder; switch; outcome; spectrum