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Distinctions between bipolar I and bipolar II depression.


Matthew is a 28-year-old man who has experienced numerous depressive episodes on and off for about 10 years. He is an unmarried freelance information-technology specialist. During depressive periods he often misses work, sometimes staying in bed most of the day. In recent months, he has experienced sad or depressed moods on most days. He reports a loss of appetite, weight loss, loss of interest in work and personal pursuits, and social isolation. Matthew has been undergoing cognitive-behavioral therapy and previously received fluoxetine, but switched to venlafaxine because of lack of efficacy. Matthew was referred by his primary care physician for depression unresponsive to an antidepressant. His psychiatrist asked whether he ever had a period of time that was characterized by more energy and that he may have considered unusual. Matthew reported that shortly after changing medications to venlafaxine, for approximately 3 or 4 days "I was finding myself a lot more outgoing and talkative than usual."

Diagnosis of Bipolar II Disorder

Patients with bipolar I and bipolar II depression have in common a current or previous major depressive episode. The necessary feature differentiating bipolar I from bipolar II disorders is a lifetime episode of mania versus hypomania. Bipolar II disorder is frequently undiagnosed in patients with depressive episodes because of the difficulty in differentiating the disorder from unipolar major depressive disorder (MDD) and the frequent lack of history or incomplete history of hypomania. According to data from the National Comorbidity Survey Replication, 12-month prevalence is estimated to be 0.6% for bipolar I disorder, 0.8% for bipolar II disorder, and 1.4% for subthreshold bipolar disorder. (1) In a reevaluation of data from the US National Epidemiologic Catchment Area study, the lifetime prevalence of bipolar spectrum disorders in the general population was found to be 6.4%.2 This percentage included 0.8% for manic episode, 0.5% for hypomania, and 5.1% for subsyndromal but dysfunctional manic symptoms. Compared to patients without mental disorders, patients with any of these symptoms had significantly greater health care utilization, use of public assistance, and suicidal behavior. (2)

Many patients diagnosed with MDD are later found to have bipolar disorder. Among patients treated for unipolar depression in a primary care clinic, 21% screened positive for bipolar disorder. (3) Up to 45% of psychiatric outpatients diagnosed with depression have been found to have bipolar II disorder, (4) similar to the rate found in the French EPIDEP study (40%) (5) and a large study in Russia (35.9%). (4-6)

Evidence-based psychiatry depends on the empirical validation of symptom-based criteria, as reflected in the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5). Reliability of the DSM-5 criteria was assessed in the DSM Field Trials, which evaluated independent interviews by 2 different clinicians trained in the respective diagnoses; methods included a predetermined statistical approach. (7) Notably, the kappa statistic for inter-rater agreement was good for bipolar II disorder ([kappa]=0.40), which was greater than that for MDD ([kappa]=0.28) but lower than that for bipolar I disorder ([kappa]=0.56).

The diagnosis of bipolar II disorder can be challenging for several reasons. Mood elevation is the least likely presentation of patients seeking treatment, and reliance on patients' self-report can be inadequate for identifying hypomania. Busy clinicians are often limited to a nonstructured interview, and screening may supplant a formal assessment. Common diagnostic confounders include unipolar depression, substance use disorder, borderline personality disorder, attention-deficit hyperactivity disorder, and anxiety disorders. Diagnosis of bipolar II disorder has important implications in terms of therapeutic interventions and prognosis. Suicidality risk is high in those with bipolar II disorder, and rates of suicide attempts are comparable to those in patients with bipolar I disorder (31.4% and 29.9%, respectively). (8) Compared with bipolar I disorder, patients with bipolar II disorder may experience more rapid cycling, depression recurrence, and psychiatric comorbidity. (9-11) An analysis of 493 patients showed that, compared with unipolar depression, bipolar II depression was associated with hypersomnia (vs insomnia), psychomotor activation (vs psychomotor retardation), guilt feelings, and suicidal thought. (12)

The duration of hypomania as a diagnostic criterion for bipolar II disorder has recently attracted much attention. Many patients have episodes of hypomania shorter than 4 days, the required duration using the DSM-5 diagnostic criteria. Currently, a diagnosis of bipolar II disorder requires that the patient have the requisite number of hypomanic symptoms present most of the day, nearly every day, for 4 days, and the symptoms must constitute a change from usual behavior. (13) An expert panel recommended reducing the required duration of 4 days for hypomania on the basis of extensive evidence. (14) Research has shown that the usual course for hypomania episodes is 1 to 3 days and that those patients with hypomania of shorter duration do not differ substantially from those who have symptoms for 4 days. (15)

The DSM-5 includes a section called "Conditions for Further Study," which provides proposed criteria for conditions that are thought to be distinct from the clinical diagnoses of the DSM-5 but warrant further research and discussion. (13) Research criteria sets are established by expert consensus based on evidence from literature review and clinical trials. The syndrome of "depressive episodes with short-duration hypomania" is included in this section as a syndrome in which the frequency of episodes of hypomania is too short to qualify for a diagnosis of bipolar II disorder using the current criteria. This proposed condition is similar to that of bipolar II disorder and requires at least 1 major depressive episode but also requires "at least 2 lifetime episodes of hypomanic periods that involve the required criterion symptoms ... but are of insufficient duration (at least 2 days but less than 4 consecutive days) to meet criteria for a hypomanic episode." (13)

Research supports the allowance for a shorter period of hypomania. In a study of 206 patients with bipolar II disorder and depression, a group of 140 patients with bipolar II disorder in remission, and 178 patients with MDD, participants were evaluated using the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Structured Clinical Interview, and short and long periods of hypomania were compared using bipolar validators. (16) Up to 30% of hypomania episodes lasted 2 to 3 days, and most (72%) lasted less than 4 weeks. Patients with bipolar II disorder with short hypomania versus longer hypomania were largely indistinguishable on bipolar validation characteristics such as early age at onset, depressive recurrence, mixed state, and family history. Indicators such as family history distinguished bipolar II disorder with brief hypomania from MDD. The authors estimated that the current 4-day threshold for symptom duration of hypomania would misclassify 1 of 3 patients with bipolar II disorder as having MDD.

An accurate and timely diagnosis of bipolar II disorder can be assisted by specific clinical strategies. For example, screening instruments can facilitate recognition of bipolar II disorder in patients with depression. The Mood Disorder Questionnaire (MDQ) is a widely used and well-studied self-report screening tool. (17) The MDQ takes about 5 minutes to complete. Of the 15 questions, the first 13 are designed to identify manic or hypomanic symptoms, and the last 2 questions evaluate symptom clusters and functional impairment. Another validated self-report screening instrument is the Hypomania Symptom Checklist (HCL-32). (18) HCL-32 has 2 introductory questions and another 32 questions that address specific symptoms of mania and hypomania. Studies have shown that systematic probing for a history of hypomanic symptoms improves the detection rate for bipolar II disorder. (19) In the multicenter study from France (EPIDEP), 250 patients diagnosed with major depressive episode were reevaluated for "soft" bipolar disorders. (5) A total of 48 psychiatrists were trained to use a common protocol for the diagnosis of hypomania, which was developed from several clinical instruments and used to validate the diagnosis in patients with MDD. The prevalence of bipolar II disorder was 22% at the first evaluation, and this nearly doubled to 40% with systematic evaluation (Figure 1). (5) This study demonstrated both the difficulty of diagnosing bipolar II disorder in patients with a major depressive episode and the importance of the clinical interview.

Treatment-Resistant Depression: Is it Bipolar Disorder?

Treatment-resistant depression (generally defined as insufficient response to 2 or more adequate trials of antidepressants) is prevalent in primary care and psychiatric outpatient settings. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which evaluated sequential medication regimens for patients with MDD, remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively, indicating that multiple treatments have declining success rates. (20) Recently, it has been proposed that some patients with difficult-to-treat depression may actually have bipolar disorder. One study evaluated clinical characteristics and outcomes of 61 patients with resistant depression and an inadequate response to at least 2 antidepressants. (21) At the initial evaluation, 65% had MDD and 35% had bipolar disorder. At a reevaluation within 1 year, 43% had bipolar II disorder, 3% had bipolar I disorder, and 13% had bipolar disorder not otherwise specified. The results suggest that a considerable proportion of patients with unipolar treatment-resistant depression actually have a bipolar diathesis. Another study evaluated 602 patients from community practice settings with unipolar depression and nonresponse to at least 1 antidepressant trial. (22) Among these patients, 18.6% screened positive for bipolar disorder using the MDQ, regardless of the number of previous medication trials. These data suggest that clinicians should screen for bipolar disorder in patients with depression who have had an unsatisfactory response to an antidepressant.

Use of Antidepressants for Bipolar II Disorder

Guidelines often lack recommendations specific to the treatment of patients with bipolar II disorder. Depressive symptoms are more common than symptoms of hypomania in patients with bipolar II disorder, and these patients spend more time depressed than those with bipolar I disorder (reported as 50.3% vs 31.9% of follow-up weeks during about 13 years of monitoring). (23,24) Because depression is the predominant mood, the priority is to treat acute bipolar symptoms, prevent a relapse of depressive mood, and avoid inducing a switch into hypomania or mania. (25) The potential role of antidepressants in the management of patients with hypomania and mild mania has remained a controversial issue. There are few placebo-controlled, double-blind studies of antidepressant monotherapy in patients with bipolar II depression. Although there appear to be lower switch rates in depressed patients with bipolar II than bipolar I disorder who receive adjunctive antidepressants, less is known about antidepressant monotherapy in these patients. (26)

A 14-week, open-label study examined fluoxetine monotherapy in 148 patients with depression and bipolar II disorder. (27) There were 88 responders (59.5%) and 86 remitters (58.1%), and the mean time to remission was 64.4 days. Six patients had hypomania and 29 had subsyndromal hypomania, although there were no discontinuations in these patients. An additional open-label study of fluoxetine monotherapy in patients with bipolar II depression and rapid cycling course (n=42) versus those without rapid cycling course (n=124) found a greater decrease in depression scores for the patients with rapid cycling (P=.04). (28) Hypomania occurred in 5.4% of patients with rapid cycling, compared with 3.6% of those with nonrapid cycling. A randomized, double-blind study evaluated the efficacy of continuation antidepressant versus mood stabilizer monotherapy for the prevention of depressive relapse in 129 patients with bipolar II disorder and depression. (29) Venlafaxine was found to be similar to lithium with regard to relapse rate and time to relapse. Neither mania rating scores nor the frequency or duration of syndromal or subsyndromal hypomania showed any differences between the treatment groups. Repeated antidepressant use in bipolar II depression is associated with a stepwise loss in effectiveness, with a recent study reporting a 25% decrease in the likelihood of response with each increase in the number of previous antidepressant medications. (30)

In a large randomized trial of antidepressants in patients with bipolar II disorder and depression, acute treatment was evaluated among 142 patients in a multicenter 16-week trial. (31) Patients enrolled in the study were randomized to receive lithium, sertraline, or a combination of both. Rapid cycling patients (42% overall) were evenly distributed among the treatment groups. The overall study dropout rate was 56%, and the rate was highest for the combination regimen (71%). The overall treatment response rate was 63%, and most patients who responded did so within 6 weeks (Figure 2). (31) Mood switch rates (14% overall) were comparable among the 3 groups after accounting for dropouts. No patient had mania or hospitalization for a switch. Response rates were comparable for all treatment groups among patients with a rapid cycling course. In contrast, those with a nonrapid cycling course had better response rates with either monotherapy than with combination therapy. In conclusion, lithium, sertraline, or a combination of both resulted in favorable response rates within 6 weeks in patients with bipolar II depression. Although switch rates were similar with monotherapy or combination therapy, there were more discontinuations in the combination therapy group.

Very few long-term data are available on antidepressant use in bipolar II disorder. One study to assess antidepressants in patients with bipolar disorder evaluated efficacy and safety in patients with bipolar I disorder (n=21) or bipolar II disorder (n=49) who were treated for acute major depressive episodes with antidepressants plus mood stabilizers until they achieved euthymia. (32) Patients were then randomized in an open-label phase to continue or discontinue antidepressants for up to 3 years. During a mean of 1.6 years of follow-up, patients with bipolar I depression had greater improvement than those with bipolar II depression. In addition, continuing antidepressants (vs discontinuing) resulted in a lower frequency of depressive recurrences in patients with bipolar II disorder (0.76 vs 0.97) and bipolar I disorder (0.59 vs 0.94); these differences were both statistically significant.

When treating with antidepressants in patients with bipolar II disorder, clinicians are always concerned about the risk of switches to hypomania or mania. The risk of antidepressant-associated manic and hypomanic episodes in patients with bipolar I disorder, bipolar II disorder, or MDD was assessed in a large meta-analysis of acute (short-term) trials and maintenance studies. (33) In studies comparing patients with bipolar I and bipolar II disorders, mood elevations occurred in an average of 14.2% and 7.1%, respectively, during acute trials. In maintenance studies, the rates were higher, at 23.4% and 13.9% for bipolar I and bipolar II disorder, respectively. The relative risk (RR) of antidepressant-associated mood elevation was almost twice as high in bipolar I disorder than in bipolar II disorder (RR, 1.78; 95% confidence interval, 1.24-2.58; P=.002). In studies comparing patients with bipolar II disorder and MDD, mood elevation rates were 8.1% and 1.5%, respectively, in acute trials; and 16.5% and 6.0%, respectively, in maintenance trials. For patients with MDD and those with bipolar II disorder, most mood elevations were switches into hypomania, whereas patients with bipolar I disorder experienced hypomania and mania with comparable frequencies.

Overall, there is a lack of strong evidence to support a value for antidepressants in patients with bipolar disorder. Although some studies suggest that antidepressants may be helpful in some patients with bipolar II disorder, there is also evidence of potentially harmful mood elevation.


Significant psychosocial impairment is a characteristic of both bipolar I and bipolar II disorders. Bipolar disorder is difficult to diagnose, and bipolar II disorder can be especially challenging because most patients will present with a depressive episode and not mention previous hypomanic episodes. Patients with shorter durations of hypomania (1-3 days) may have clinical characteristics and outcomes similar to patients with bipolar II disorder despite not meeting the accepted criterion of a 4-day duration. Treatment with antidepressants may be just as ineffective for bipolar II as for bipolar I disorder, and there is a moderate risk of mood switching. For this reason, as well as to enhance prognostic information, it is crucial that clinicians distinguish bipolar II depression from unipolar depression.


Matthew articulated some degree of mood elevation that was consistent with hypomania. Additional interviewing is appropriate to explore the level of dysfunction associated with Matthew's mood elevation. Patients seldom seek care when they are hypomanic, and patients presenting with depression will not always volunteer sufficient information about periods of mood elevation. During further questioning, Matthew reported a period of decreased need for sleep, pressured speech, flight of ideas, and involvement in activities with painful consequences. His symptoms occurred for "about 3 or 4 days" and shortly after starting venlafaxine. Although 1 or 2 symptoms such as irritation or edginess following antidepressant use are not sufficient for diagnosis of a hypomanic episode, Matthew's potential hypomania was more elaborate and may be associated with antidepressant use.


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Claudia Baldassano, MD

Associate Professor of Psychiatry

Department of Psychiatry

University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania

Caption: FIGURE 2 Average weekly (A) depressive and (B) manic symptom scores among 142 patients treated for bipolar II disorder and depression. (31)
Increased recognition of hypomania in patients with
major depressive episodes following implementation
of systematic evaluation. (5)

                             Diagnosis at       Diagnosis at
                                Visit 1            Visit 2
                            (strict DSM-IV   (broader systematic
                              criteria)            criteria)

Unipolar Disorder                 72%                 45%
Bipolar I Disorder                 6%                  6%
Bipolar II Disorder               22%                 40%
Pseudounipolar Depression                              9%

Abbrevation: DSM-IV, Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition.

Reprinted from Journal of Affective Disorders, Vol 50(2-3),
Hantouche EG, et al. Systematic clinical methodology for validating
bipoiar-II disorder: data in mid-stream from a French national
multi-site study (EPIDEP), 163-73. Copyright [c]1998, with
permission from Elsevier.

Note: Table made from pie chart.
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Author:Baldassano, Claudia
Publication:Current Psychiatry
Geographic Code:1USA
Date:Aug 1, 2017
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