|Year : 2023 | Volume
| Issue : 1 | Page : 8-13
Personal recollections about the development of Bipolar II disorder
David L Dunner M.D
Center for Anxiety and Depression, Mercer Island; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
|Date of Submission||28-Nov-2022|
|Date of Decision||22-Dec-2022|
|Date of Acceptance||23-Dec-2022|
|Date of Web Publication||28-Mar-2023|
David L Dunner
Suite 400, 7525 SE 24th Street, Mercer Island, Washington 98040
Source of Support: None, Conflict of Interest: None
Background: This paper reviews the development of Bipolar II disorder, defining the development of diagnosis and the current state of the art in treatment. Methods: Through his training and working in psychiatry, the author recounted the early days when Bipolar II disorder was conceptualized and developed as a separate clinical entity at the Department of Psychiatry at Washington University, US National Institute of Mental Health, and New York State Psychiatric Institute/Columbia University. The author also participated in the process leading to the inclusion of Bipolar II in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) in 1994. In this review, the author presents his recollections how bipolar II disorder came about and entered the diagnostic criteria that we now use in psychiatry. Results: The diagnostic criteria of Bipolar II disorder in DSM-IV and DSM-5 were reviewed. Then, the author stressed the importance of differentiating Bipolar II disorder clinically, how to make the diagnosis of Bipolar II disorder, differentiating mania from hypomania, differentiating hypomania from unipolar depression (i.e., major depressive disorder), and provided useful clinical tips related to ascertaining this diagnosis. Then, he reviewed and raised some issues in treating Bipolar II disorder. The neuroscience-based nomenclatures were given for all drugs used in treating Bipolar II disorder in this review. Conclusion: Bipolar II disorder has come a long way to be accepted as a valid clinical entity. The author believes that more clinical knowledge can further improve the diagnosis and treatment for patients with Bipolar II disorder.
Keywords: Diagnostic and Statistical Manual for Mental Disorders Fourth Edition, mania, hypomania, Neuroscience-based Nomenclature
|How to cite this article:|
Dunner DL. Personal recollections about the development of Bipolar II disorder. Taiwan J Psychiatry 2023;37:8-13
| Introduction|| |
Department of Psychiatry at Washington University, St. Louis, 1966–1969
I received training in psychiatry at Washington University in St. Louis, Missouri. Just before completing my psychiatry residency, George Winokur and Paula Clayton along with a chief resident Ted Reich published a book detailing a family study of bipolar disorder . This study involved patients who had been hospitalized for a manic episode at Renard Hospital, the psychiatric hospital at Washington University in St. Louis. The authors of that book followed up these patients, interviewed their relatives, and performed various tests on the patients and relatives. One of the conclusions from that study was that bipolar disorder has a heavy genetic contribution and this might involve a gene on the X chromosome.
National Institute of Mental Health, Bethesda, Maryland, 1969–1971
When I finished my psychiatric residency, I needed to complete my military obligation and was assigned to a research unit at the National Institute of Mental Health in Bethesda, Maryland. That unit was involved in biological studies of patients with bipolar and unipolar depression. The unit was headed by William Bunney and Frederick Gooodwin. Elliott Gershon also began service on the unit at the same time I did.
I got to NIMH in July 1969, and it occurred to me that I could access the records of patients who had been hospitalized on this unit at NIMH and assess differences in biological factors related to depression by comparing unipolar patients to patients who had histories of being hospitalized for mania, i.e., patients similar to those who had been studied by Winokur, Clayton and Reich. I proceeded to review the medical and research records of 199 patients who had been admitted to the NIMH depression clinical research unit over the previous 10 years. Of these, 163 patients had a diagnosis of a primary affective disorder. These patients had extensive clinical and family histories documented in their records. In reviewing these patients' records, I separated out those who had a history of only depression (unipolar, n = 73), from those who had a history of having been hospitalized at least one time for mania (n = 68). My thinking about this latter group was that these subjects potentially could have been probands for the family study at Washington University. It turns out that there was additionally a group of 22 patients who had been hospitalized at the NIMH for research studies, had serious depression, had histories of symptoms of mania but had never been hospitalized for mania. I classified patients as bipolar I if they had ever been hospitalized for mania and unipolar if they had been hospitalized for depression but had no history of mania or hypomania and bipolar II if they had symptoms of mania (hypomania) and had been hospitalized for depression. What was striking in reviewing the data for these patients was that bipolar II patients had family histories of mania or hypomania similar to the bipolar I patients. More importantly, after discharge from the clinical research unit at NIMH, 10 patients committed suicide: 4 of 68 bipolar I patients, 2 of 73 unipolar patients, and 4 of 22 bipolar II patients. These data were initially presented at the annual meeting of the American Psychiatric Association in May 1970 and comprise the first study describing what is now termed bipolar II disorder . For reasons that are not clear it took several years to have the manuscript of these data finally accepted and published . The concept of bipolar versus unipolar depression was new to psychiatry in the 1960s and 1970s, and I believe the delay in publication was likely due to our subdividing a diagnosis which had not yet been widely accepted.
During my remaining time at NIMH, I and my colleagues (Bunney, Goodwin and Gershon) published several papers looking at biological and pharmacological differences comparing bipolar I with bipolar II and unipolar patients. These data are summarized in a review article and basically showed that at times bipolar II patients were more similar to unipolar patients, in some data sets, bipolar II patients were more similar to bipolar I patients than unipolar patients, and in some data sets, bipolar II patients were distinct .
New York State Psychiatric Institute/Columbia University, New York, 1971–1979
My interest in bipolar II disorder continued after I moved to Columbia University/New York State Psychiatric Institute to work with Ronald Fieve. The Lithium Clinic at NYSPI had studied over 400 patients and in reviewing data from these patients, we reported that lithium treatment in bipolar II patients showed a maintenance effect against depression which was greater than placebo treatment . This is not an early effect but was statistically significant after a year of treatment. We also studied a group of patients who failed lithium treatment. By reviewing the clinical records of these patients, we determined that patients who failed lithium maintenance treatment had a history of frequent episodes of depression. This group was largely comprised of patients who had bipolar II disorder and we termed such patients “rapid cyclers” (characterized by four or more mood episodes in the year prior to lithium treatment) . We also reported a higher rate of suicide attempts among bipolar II patients when compared to patients with bipolar I and unipolar depression .
Department of Psychiatry, University of Washington, Seattle, Washington, 1979–2005
I moved to Seattle in 1979 as a professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington. While there, I developed a clinical trial center and our group studied several medications before and after the approval of the US Food and Drug Administration. I encouraged the pharmaceutical companies to study their antidepressants in depressed bipolar patients, but this endeavor was mostly not successful. My clinical focus centered on patients with treatment-resistant depression (difficult-to-treat depression), both unipolar and bipolar depression.
Center for Anxiety and Depression, Mercer Island, Washington, 2005-present
I retired from the University of Washington in 2005 and moved my clinical work to Mercer Island, a suburb of Seattle. I continue to have focus on patients with treatment-resistant depression and am involved with treatments including transcranial magnetic stimulation, esketamine nasal spray, and we are a site for a multi-site research study of vagus nerve stimulation.
| The Diagnosis of Bipolar II Disorder|| |
Bipolar II disorder was first accepted in Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition
Bipolar II disorder was accepted into the diagnostic nomenclature as a separate diagnostic disorder in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM- IV) in 1994  and further modified slightly in DSM-5  [Table 1]. DSM-5 clearly states that bipolar II disorder is no longer thought to be a “milder” condition than bipolar I disorder largely because of (a) the greater amount of time patients with this condition spend in depression, and (b) serious impairment in work and social functioning due to instability of mood . It is clear that there are continuing issues regarding the diagnosis of bipolar II disorder. These issues include the diagnostic criteria for hypomania, differentiating bipolar II disorder from unipolar depression on the one hand, and differentiating the hypomanic experiences of these patients from the mania that bipolar I patients experience. I will discuss these issues and provide clinical tips for the clinician regarding the diagnosis of bipolar II disorder.
The importance of differentiating bipolar II disorder
Why is it important to make this diagnosis? I am offering three reasons:
- I think that patients should have the correct diagnosis as this will lead to a more precise treatment. Incorrect diagnosis can result in treatment, not appropriate for the patient. For example, if the patient has a bipolar II depression and is treated with an antidepressant, particularly a tricyclic antidepressant or certain of the newer antidepressants, the course of illness may be complicated by cycling into mania or hypomania.
- The goals of treatment are not always the same for bipolar I, bipolar II, and unipolar patients. The goals of treatment for bipolar conditions are to treat the acute episode but importantly to prevent switches into mania and to prevent cycling. The goals for treating unipolar patients are to treat the acute episode and to try to prevent a subsequent episode in the case of recurrent depression.
- The suicide rate that we found higher among bipolar II patients comparing them to unipolar and bipolar I patients has been replicated in some but not all studies. If bipolar II patients are indeed more suicide-prone than other mood disorder patients, their recognition and proper treatment may reduce their tendency to suicide.
How to make the diagnosis of bipolar II disorder
Clinical information is critical for the diagnoses. No blood tests, X-ray examinations, neuroimaging scans, or genetic markers exist that define subgroups of major depression and bipolar disorder. I prefer to interview patients when accompanied by a relative. The reason for this is that often a relative or significant other can give me a clear history of bipolar disorder when the patient cannot. Often patients underreport hypomanic episodes and this can be corrected by having a relative present during the initial interview. Some patients I evaluated do not wish to be diagnosed with bipolar and will deny the symptoms of hypomania or mania, even though it is apparent that they have had them.
Not all patients who experience hypomania or mania have a primary bipolar disorder. There is a syndrome in the literature termed “antidepressant treatment discontinuation mania or hypomania” . I encountered one such patient in Seattle. He had forgotten his antidepressants while attending a medical meeting and became quite manic. In reviewing his history with the patient and his wife, it was clear that he indeed had unipolar major depression.
Some patients who have chronic treatment-resistant unipolar depression may have infrequent hypomanic or manic episodes when treated with a certain antidepressant. We identified 16 such patients . They had negative family histories of bipolar disorder and only became hypomanic when treated with a specific antidepressant. A study of vagus nerve stimulation showed that one of 185 patients with chronic unipolar major depression became manic during treatment (personal communication of R. Rudolph of Cyberonics). This patient had no previous history of mania and had failed at least four antidepressant treatments.
Hypomania may occur in the course of substance use or due to central nervous system viral infections. Furthermore, tertiary syphilis may be associated with manic symptoms. There may be hypomanic or manic symptoms associated with certain medical disorders, such as systemic lupus erythematosus and Cushing's disease.
Differentiating mania from hypomania
The difference between mania and hypomania, i.e., bipolar I and bipolar II, can be problematic. The symptoms of mania and hypomania are the same. DSM-5  requires mania to have psychosocial impairment, whereas hypomania is the only clinical condition that DSM-5  does not require psychosocial problems. The examples of manic versus hypomanic behaviors include excessive spending, hypersexuality with perhaps unprotected sexual activity, nondelusional grandiosity, increase in substance use or alcohol use, and nonfelony police or legal difficulties. In all of these examples, the question for the clinician is whether the degree of behavior warrants a diagnosis of mania versus hypomania. I describe this to the patient as “crossing the line,” meaning have they done something that gets them into trouble because of manic or hypomanic symptoms. This distinction is frequently a judgment call on the part of the clinician.
Differentiating hypomania from unipolar depression
On the other hand, the question of bipolar II versus unipolar disorder arises with a patient who has irritable intervals in the context of chronic depression, but these are not associated with elated mood. It is my preference not to diagnose such patients as bipolar, although some clinicians and researchers disagree.
There is robust literature of patients with brief hypomanic episodes lasting < 4 days or 3 days. When I initially described hypomania, I used a three-day or longer criteria.
This duration was based on a research study that I participated in when I was a resident at Washington University. I was asked to interview women medical students and I found in these interviews a number of them described premenstrual hypomanic symptoms lasting 1 or perhaps 2 days. When I developed the duration criteria for hypomania, I selected three days or longer and this duration was based on none of the women medical students I interviewed having had hypomanic symptoms that long. For the present criteria, DSM-5  has certainly answered this by having a brief duration of hypomania subgroup, i.e., short-duration hypomanic episodes as an “other specified bipolar and related disorder” [Table 2].
Ultrarapid cycling means cycling within a day and this is quite unusual to find in true bipolar disorder but may be seen in patients with a borderline personality disorder or patients who have extensive substance abuse histories  or patients with pseudobulbar affect or neurological conditions. I have seen a number of patients with multiple sclerosis who presented with ultra-rapid cycling and I initially misdiagnosed them as having bipolar disorder.
Certainly having two or more major depressive episodes in a year raises suspicion about a diagnosis of bipolar disorder. I have seen few patients who might be termed unipolar rapid cycling .
There are patients who have depression only but who have a family history of bipolar disorder. Some clinicians may classify such patients as a subtype of bipolar disorder; I prefer that patients have distinct hypomanic episodes. There is another group of patients who have recurrent depressive episodes and between these episodes seem to be hypomanic but without episodes of hypomania. Some clinicians would diagnose these patients as bipolar, but again I would prefer patients have distinct hypomanic episodes to diagnose them as bipolar.
| Treatment for Bipolar II Disorder|| |
Treatment selection needs to be specific
Treatments for unipolar depression (i.e., major depressive disorder) may not be effective for bipolar depression. Augmentation of antidepressant nonresponse by adding second-generation (atypical) antipsychotic medications is often effective for unipolar depression, but it is unclear if bipolar depressives would also respond.
Among various indications for other psychiatric conditions, quetiapine (norepinephrine reuptake inhibitor and presynaptic receptor antagonist in neuroscience-based nomenclature (www.NbN3.org) ,, in moderated doses (300–600 mg/day) was approved in 2016 [Table 3] for both bipolar I and bipolar II disorders . This is the first time the US FDA specifically mentioned bipolar II disorder for a treatment indication. Aripiprazole (DA and 5-HT partial agonist), and brexpiprazole (DA and 5-HT partial agonist) have not been studied as “augmentors” for bipolar depression. There are only a few studies of esketamine (glutamine agonist) nasal spray or ketamine (glutamine agonist) in bipolar depression . Maintenance treatment with an antidepressant, which is a recommendation for patients with unipolar recurrent depression or chronic depression, may cause cycling in bipolar patients.
|Table 3: The years of the US food and drug administration - approved indications* of drugs to treat bipolar disorder as of December 2022|
Click here to view
There are relatively few studies demonstrating treatment efficacy for patients with bipolar disorder. Lithium (an enzyme modulator in NbN , has antimanic and antidepressant effects as well as mood stabilizing effects, i.e., preventing future episodes and is a good first-line drug for a bipolar patient. Valproic acid has antidepressant and antimanic effects and is often given for maintenance treatment for bipolar depression, although the US FDA has not given valproic acid (glutamate drug in NbN , any indication for maintenance therapy for bipolar disorder. Carbamazepine (glutamate channel blocker in NbN) similarly has antimanic effects and may have antidepressant effects and is often used as a maintenance therapy. Lamotrigine (glutamate channel blocker in NbN) is an anticonvulsant that has antidepressant and nonsignificant antimanic or hypomanic effects. Lamotrigine should not be used for bipolar I disorder as monotherapy but is often used successfully as monotherapy for bipolar II disorder.
Several antipsychotic medications have mood stabilizing effects in combination with lithium or valproic acid but not as monotherapy [Table 3].
Treatments for acute bipolar depression include lithium, lamotrigine, and some neuromodulating treatments such as ECT, transcranial magnetic stimulation , and vagus nerve stimulation, some antidepressants such as tranylcypromine (5-HT, NE and DA multimodal drug in NbN , and bupropion (NE and DA reuptake inhibitor as well as NE and DA releaser).
Some antipsychotic medications such as quetiapine, lurasidone (DA and 5-HT antagonist in NbN ,, olanzapine (DA and 5-HT antagonist), olanzapine-fluoxetine (5-HT reuptake inhibitor) combination, cariprazine (DA and 5-HT partial agonist and antagonist), and lumateperone  (5-HT and DA multimodal drug and glutamate antagonist). Most of these have been studied in bipolar I depression and lumateperone is FDA approved for both bipolar I and bipolar II depression.
Helpful tips for the clinician
I interview patients if possible in the presence of a significant other to get a confirming history. I often will have the patient read either Moodswing or Bipolar II by Fieve to get an idea if they are meeting the criteria for a bipolar disorder. I tend not to use the Mood Disorder Questionnaire  because I find the MDQ tends to become positive if patients have abused drugs in the past. It should be noted that some depressed bipolar II patients do not look as depressed as they feel. We confirmed this on an inpatient research unit at the NY State Psychiatric Institute where unipolar patients were rated as more depressed by nurses than their self-rating and the same for bipolar I depressed patients but bipolar II patients rated themselves as much more depressed than the nurses ratings. This may result in under diagnosing bipolar II patients and perhaps is a factor in their higher suicide rate. Patients with psychotic depression may be bipolar and patients who have postpartum onset of their illness may be bipolar.
Early age of onset of recurrent depression may reflect a bipolar disorder. Antidepressant-induced hypomania may reflect a bipolar condition, except as noted above . Patients who have regularly recurrent depressive episodes or seasonal mood disorder are the examples of possible bipolar disorder, although again I prefer the presence of discrete hypomanic episodes to confirm a bipolar disorder.
Areas for future research
Bipolar disorders and bipolar II disorder in particular are understudied conditions. Funding for research studies can come from foundations, government, industry, or other sources. Unfortunately, funding for research is limited and highly competitive. Areas of need, from my perspective, include a demonstration that transcranial magnetic stimulation is effective for bipolar depression resulting in the US FDA clearance so that insurance will reimburse patients for this treatment, studies of newer antidepressants, such as esketamine, to demonstrate efficacy, again leading to the US FDA approval, and studies in bipolar treatment-resistant depression in general.
| Conclusion|| |
The diagnosis of bipolar II disorder has come a long way to be accepted as a clinical entity in psychiatry, first listed in DSM-IV  in 1994 and slightly modified in DSM-5  in 2013. However, evidence -based guiding treatment for bipolar II disorder is remarkably lacking and the treatment of bipolar disorder as a whole proceeds without it ,. The clinical reality is that bipolar II disorder is not considered a “mild” condition of bipolar I disorder. Therefore, I am calling for more clinical studies regarding the treatment of bipolar II disorder.
| Acknowledgements|| |
David L. Dunner was a member of the Mood Disorders Work Group of the 1994 Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) of the American Psychiatric Association . The opinions expressed in this review are the author's personal opinions. They do not necessarily reflect those of any societies or organizations. Psychiatrists are advised to consult with information in package inserts of medications carefully before prescribing them for patients with bipolar II disorder.
| Financial Support and Sponsorship|| |
| Conflicts of Interest|| |
The author receives payment from LivaNova for treating a former research subject and also is a site Principal Investigator for the RECOVER study involving vagus nerve stimulation. He is a registered site for the administration of esketamine nasal spray. He owns a NeuroStar TMS device.
He is a consultant for Janssen, McKesson/Change Healthcare and Neuronetics. He consults with various firms regarding IME evaluations, legal testimony, and forensic consultations.
David L. Dunner is an international advisory board member of the Taiwanese Journal of Psychiatry. He is not involved in peer reviewing of this manuscript or decision making whether this manuscript was accepted for publication in the Taiwanese Journal of Psychiatry.
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[Table 1], [Table 2], [Table 3]