Editorial on: The Underappreciated Importance of Mania

In this issue of Acta Psychiatrica Scandinavica, Drs. Manchia, Miola, Tondo, and Baldessarini [1] provide an important study of individuals with unipolar mania (UPM), defined by these authors as mania or hypomania without depressive episodes. In their study, Manchia and colleagues identified 63 consecutive individuals with UPM and compared them over the long term (up to 9.18 years) to 1210 patients with regular bipolar disorder (mania or hypomania with depressive episodes; BD) recruited from expert mood disorder centers across Italy. Compared with regular BD, the authors found that UPM was uncommon (4.5% of all BD cases over 18.2 years of risk), more common in men, predominantly BD type I (only 0.314% had unipolar hypomania), associated with more psychosis but less suicidality, and associated with greater use of antipsychotics, lithium, and mood-stabilizing anticonvulsants but much less use (27% less) of antidepressants. Over a mean follow-up of 9.18 years, the rate of UPM decreased, suggesting that some of these patients will eventually develop a first depressive episode.

Many of these findings have been noted in earlier, mostly cross-sectional studies using various definitions of UPM. For example, in a 2023 meta-analysis of 21 studies, UPM was similarly uncommon and associated with male gender and psychotic features, but with fewer suicide attempts [2, 3]. Other findings have included higher rates of hyperthymia, good sleep quality, and morning chronotype in UPM than in regular BD [2-4].

We were particularly interested in three issues arising from this important article.

First is regarding the prevalence of UPM. Many studies have suggested that UPM is a relatively uncommon form of BD. Thus, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) found that, using three definitions of UPM, 5.0%–7.2% of individuals from the U.S. with BD type I never had depression [5]. However, evidence exists that UPM may be more common in low-income versus high-income countries. Thus, a study from Ethiopia found 41.7% of participants had UPM [6], while a study from Tunisia found a rate of 56.6% [7]. Although these differences in prevalence rates could be due to methodological issues, including use of different definitions of UPM, one wonders if there are cultural differences regarding the etiology and recognition of BD, particularly manic symptoms. If such cultural issues exist, it would be important to understand them.

Second is the finding that morning chronotype may be more common in UPM while evening chronotype appears to be more common in regular BD. Our group indeed found that evening chronotype was more common among individuals participating in a BD biobank, and that it was associated with more depressive episodes than participants with non-evening chronotypes [8]. Circadian rhythm dysfunction has been implicated in the pathophysiology of BD [9]. Perhaps a greater understanding of chronotype in the broad BD spectrum would lead to important clues into the pathophysiology of this disorder.

The third issue is that of the clinical importance of hypo/manic symptoms, and how these symptoms may provide some diagnostic and treatment specificity yet have often been neglected by the field of psychiatry. For example, both DSM [10] and ICD¹¹ still require that symptoms persist for 4 days for a diagnosis of hypomania, despite evidence showing that valid durations of hypomania can also be 1, 2, or 3 days. Similarly, both DSM and ICD specify that a manic episode has to last at least 7 days, unless symptoms trigger a hospitalization or other treatment intervention [10, 11]. What if the symptoms trigger a motor vehicle accident, violent behavior, or contact with the judicial system? We argue that such DSM requirements are biased against the diagnosis of hypo/manic symptoms, which might provide greater diagnostic and treatment specificity than anxious, depressive, and even psychotic symptoms.

In short, growing literature indicates a subset of individuals who have a manic or hypomanic episode will go on to have no depressive episodes. We agree with Dr. Manchia and colleagues that it is reasonable to identify UPM as a subtype of BD. However, it is important to realize that one subtype of BD can transition into another subtype, and that there is little information on how to treat an individual with long-standing UPM who has a first onset depressive episode. Thus, treatment of these individuals requires in-depth knowledge of the phenomenology and pharmacology of this disorder.

S.L.M. drafted the initial manuscript. M.A.F. and B.S. provided feedback and edits. All three authors worked on and approved the final manuscript.

Dr. Susan L. McElroy has been a consultant to or a member of the scientific advisory boards of Axsome, Idorsia, Kallyope, Levo, Novo Nordisk, and Soleno. She has been a principal or co-investigator on studies sponsored by Axsome and the Marriott Foundation. She is also an inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patent's assignee, the University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Dr. Mark Frye has been a consultant to or member of the scientific advisory boards of Carnot Laboratories and American Physician Institute. He has been a principal or co-investigator on studies sponsored by Assurex Health, Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and Mayo Foundation. He also has financial interest/stock ownership/royalties with Chymia LLC. Dr. Balwinder Singh has received research grant support from Mayo Clinic, the National Network of Depression Centers (NNDC), Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2) and NIH. He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the National Center for Advancing Translational Science (NCATS). Dr. Singh has received honoraria (to Mayo Clinic) from Elsevier for editing a Clinical Overview on Treatment-Resistant Depression.