Leo Sher, M.D.

Prof. Zoltan Rihmer and his colleagues have recently published an interesting Editorial entitled, “Hypomania and bipolar II disorder – diagnostic validity and clinical utility.” This article was published in Psychiatria Hungarica (2013; 28:345-348). Most readers of our web site, www.internetandpsychiatry.com do not have access to articles published in this Journal. The Editors of Psychiatria Hungarica have graciously given a permission to publish this Editorial to www.internetandpsychiatry.com Therefore, we are publishing the article, “Hypomania and bipolar II disorder – diagnostic validity and clinical utility.”
 
Hypomania and bipolar II disorder – diagnostic validity and clinical utility 

Zoltan Rihmer, Maurizio Pompili, Gabriele Sani, Xenia Gonda, Péter Dome

Classification of mood disorders in the ICD-10 (WHO, 1992) and DSM-IV (APA, 1994) is based primarily on the polarity and severity of episodes.  However, in spite of the fact that they are official diagnostic categories in ICD-10 and DSM-IV (WHO, 1992; APA, 1994) for more than 20 years, some clinicians (Spence 2011; Malhi et al, 2010) question the clinical significance and construct validity of hypomania and bipolar II disorder. The separation of unipolar depression from bipolar (manic-depressive) disorder as well as the subdivision of bipolar disorder further into bipolar I (mania-major/minor depression) and bipolar II (hypomania-major depression) subtypes has been accepted for many years (Coryell, 1996; Rihmer and Angst, 2005, Benazzi 2007; Goodwin and Jamison, 2007). Several studies have demonstrated that bipolar II disorder represents a quite common, clinically and biologically distinct form of major mood disorders that should be separated both from bipolar I and, of course, from unipolar major depressive disorder (Angst et al, 1980, Coryell, 1996,  Judd et al, 2003; Judd and Akiskal, 2003; , Benazzi 2003, Rihmer and Angst, 2005; Liu 2010), and that bipolar II disorders show the same, or even worse, psychiatric and social consequences as do bipolar I and unipolar patients (Benazzi, 2007, Rihmer and Angst, 2005, Judd et al, 2003; Judd and Aksikal, 2003;  Sani et al, 2011; Pompili et al, 2013).
 
Since the very beginning (Dunner et al, 1970, 1976), researchers collected a growing amount of biological and clinical data regarding the Bipolar I-Bipolar II distinction. Nowadays, what we know is that patients with bipolar II disorder, compared to patients with bipolar I, are more likely to be female (Cassano, 1999; Rihmer and Angst, 2005), have more frequent and more chronic depressions (Judd, and Aiskal, 2003),  a shorter interepisode time and a longer time spent in depression (Judd and Akiskal, 2003), a higher number of episodes (Akiskal and Benazzi, 2005), a higher risk of committing suicide attempts and complete suicide (Pompili et al, 2009; 2013; Rihmer, 2011; Sani et al, 2011) and  more comorbid anxiety and  alcohol abuse (Ferrier et al, 2001). Moreover, patients with bipolar II disorder are more likely to become rapid cyclers, thus is having at least four affective episodes per year (Koukopoulos 1980, 2003; Corryel, 1996) and to develop mixed affective states, particularly agitated depression (Koukopoulos et al, 2005; Benazzi, 2007). Reporting on a significant difference in the distribution of AB0 blood group types (Rihmer and Arató, 1981) and in serum dopamine-beta-hydroxylase level (Rihmer et al, 1984) between bipolar I and bipolar II patients more than thirty years ago we concluded that these results indicated a possible genetic difference between bipolar I and bipolar II disorders. A few years later our conclusion was corroborated when it was published that levels of dopamine-beta-hydroxilase activity were controlled by a gene linked to the AB0 blood group locus on chromosome 9 (Wilson et al, 1988). These results are also in good agreement with later family studies suggesting the possibility that bipolar I and bipolar II disorders are genetically distinct categories (Coryell, 1996).

One should know that many researchers (Koukopoulos et al., 1980, Rihmer and Akiskal, 2006 Benazzi, 2007, Sani et al, 2011) believe that the risk of developing rapid cycling, mixed states and suicidality may be increased when antidepressant monotherapy (unprotected by mood stabilizers) is used for treatment of major depressive episode in patients with an unrecognized bipolar disorder. The mis/under-diagnosis of bipolar disorder affects more bipolar II than bipolar I patients. This underdiagnosis is more common than overdiagnosis and may have tragic and sometimes fatal consequences (Dunner, 2003; Schaffer et al, 2010; Pompili et al, 2013).  

Hypomania is a strictly definied condition that markedly differs from one’s usual mood and activity level as well as from a manic episode (WHO, 1992; APA, 1994). Major depression with hypomania but not with mania was first referred to as bipolar II disorder in 1970 (Dunner et al, 1970; 1976) and as a result of several subsequent clinical studies (Goodwin and Jamison, 2007) it became an official diagnosis in the 4 th edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association 19 years ago (APA, 1994). Hypomania and mania are also described as two distinct syndromes in the WHO classification of diseases (WHO, 1992). Based on co-rated interviews, test-retest interviews and best-estimate diagnostic procedures it has been shown that hypomania and bipolar II disorder are quite reliable and stable diagnostic categories (Cohen kappa coefficients: 1.0, 0.72, and 0.99, respectively, Simpson et al, 2002). Community-based epidemiological studies show that lifetime prevalence of DSM-IIIR/DSM-IV defined bipolar II disorder in the United States and in Europe is ”only” between 0.4 and 2.0 percent (Pini et al, 2005; Merikangas et al, 2007). Re-analysing the US-National Comorbidity Survey database in the light of the clinical significance criterion it has been found that while the past-year prevalence of unipolar major depression decreased substantially (from 8.9% to 5.4%) the figures for bipolar II and bipolar I disorders remained exactly the same (0.2% and 0.2%, as well as 1.3% and 1.3%, respectively, Narrow et al, 2002).

In addition, patients may show major depression and some hypomanic symptoms that do not reach the severity and/or duration thresholds for official hypomania (bipolar II disorder) in the DSM-IV system and therefore these patients could not be diagnosed as hypomanic or bipolar II patients. However, external validators strongly suggest that these patients (major depressives with hypomania lasting less than 4 days and major depressives with some hypomanic symptoms not reaching the DSM-IV severity threshold of hypomania beside elevated/irritable mood considering overactivity as another stem criteria of hypomania) could be correctly classified as bipolar II cases or more precisely as bipolar spectrum disorder patients (Angst et al, 2003; Judd and Akiskal, 2003). Moreover, while according to DSM-IV/DSM-IV-TR and ICD-10 “antidepressant-associated” hypomania does not belong to the category of bipolar II disorder, several lines of evidence show that these patients (called also bipolar III) are much closer to bipolar II disorder than to unipolar major depression (Akiskal et al, 2003; Rihmer and Angst, 2005).

Of note is also the fact that classification of mood disorders may be related to suicide risk. In fact, apart from the fact mixed states very common in the bipolar II spectrum, cyclothymic temperament is also most prevalent in bipolar II. Rapid mood shifts are the hallmark of bipolar II which often carries a higher risk of suicide. Moreover, bipolar II suicides are the most lethal – they use the most aggressive methods often succeeding in their intent to die (Akiskal, 2007).
         
Some authors are concerned about the overdiagnosis of bipolar disorder (Zimmerman et al, 2008; Spence, 2011) However, an overdiagnosis doesn’t seem to carry the same negative consequences as underdiagnosis (Dunner, 2003; Schaffer et al, 2010). First of all, underdiagnosis of bipolar I and particularly bipolar II patients as unipolar depression can lead doctors to overprescribe antidepressant monotherapy (unprotected by mood stabilizers) with a potential worsening of the course and clinical picture of the disorder, as we mentioned before. Secondly, it’s very well known that newly recognized medical disorders catch the attention of clinicians and researchers. The distinction between bipolar I and bipolar II is similar to the categorization of diabetes mellitus into types I and II. Some decades ago after discovering insulin resistant elevated blood sugar level that develops later in life named type II diabetes, this diagnosis has increased rapidly without any concern of its overdiagnosis. Type I or type II diabetes as a condition making “life sentence for pharmacotherapy” has never been questioned. The recognition of bipolar (mostly bipolar II or subthreshold bipolar) nature of major depressive episode is particularly important for treatment response, as it has been demonstrated that antidepressant monotherapy is a common cause of “treatment-resistant” depression (Rihmer et al, 2013). In sum, clinical, epidemiological and treatment-response studies clearly show that hypomania (and bipolar II disorder) is a valid, common and reliable clinical diagnosis with important treatment implications (Dunner, 2003; Koukopoulos et al, 2005; Goodwin and Jamison, 2007; Amsterdam and Shults, 2010; Rihmer et al, 2013). 
 
Acknowledgement
Peter Dome and Xenia Gonda are recipients of the János Bolyai Research Fellowship of Hungarian Academy of Sciences.

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