Manic Symptoms During Depressive Episodes in 1,380 Patients With Bipolar Disorder: Findings From the STEP-BD

Table 1 presents a comparison of characteristics for the three depressed bipolar subgroups. Depressed bipolar patients with either subsyndromal or fully mixed mania were significantly more likely than those with no concomitant manic features to be male, to have bipolar II disorder, to have had rapid cycling in the past year, and to have attempted suicide. They also had an earlier illness onset, including earlier first episodes of both mania and depression. Those with full mixed episodes were significantly more likely to have a history of substance abuse or dependence as compared to those with pure bipolar depression. Although the three groups did not differ in their mean number of days spent with depression in the past year, those with any concomitant mania features had more days in the past year with irritable mood or abnormal mood elevation.

First recognized by Kraepelin (8), mixed states are known to be associated with poorer response to various forms of treatment and a poorer overall illness prognosis (25) . Reported prevalence rates of mixed states among bipolar patients with syndromal mania or hypomania have varied from 50% to 70% (25), in part depending on whether an inclusive or restrictive approach was used to define the syndrome. DSM-IV-TR employs restrictive criteria for classifying mixed episodes, specifying that an individual must meet full syndromal criteria for both a major depressive episode and a manic episode. Using this approach, we found that only 14.8% of 1,380 consecutively assessed bipolar patients experiencing a major depressive episode also met criteria for mania. However, slightly more than one-half of the bipolar patients with syndromal depression had concomitant subsyndromal features of mania. By current DSM-IV-TR criteria, these individuals would be classified as having purely depressed rather than mixed phases of illness. Yet, the subsyndromally mixed subjects in the present study differed from those with pure bipolar depressive episodes on a wide range of clinically relevant variables.

Results from this large study group indicate that manic symptoms, to varying degrees, are present in a substantial number of bipolar I (30%) and bipolar II (71%) patients experiencing a depressive episode. Distractibility, racing thoughts/flight of ideas, and agitation were the most frequently identified manic symptoms. In addition, irritable mood was frequent in general, but particularly so when mixed mania features accompanied bipolar depression. Since irritability has previously been demonstrated to occur often in both unipolar and bipolar depression (26, 27), it likely does not hold pathognomonic value for differentiating the polarity of affective episodes in patients with bipolar illness. It is also noteworthy that the specific manic symptoms with the highest frequency in bipolar patients in depressed episodes (distractibility, flight of ideas/racing thoughts, and psychomotor agitation) do not include either elation or grandiosity. This suggests that the DSM-IV-TR “B” criteria for mania may, unintentionally, serve to reduce recognition of manic symptoms in bipolar depressed patients.

Most commonly, clinicians organize information gathering around their patients’ self-report of the current or most recent mood state (i.e., the presenting chief complaint) rather than assessing all of the symptoms of depression and mania in every patient at every visit. The present findings indicate that about one-half of people seeking treatment for bipolar depression have concomitant signs of mania or hypomania that fall below the DSM-IV-TR threshold for a mixed episode. Our findings indicate that patients presenting in such subsyndromal mixed states are much more similar to those who meet the full DSM-IV-TR criteria for mixed episodes and differ substantially from those with pure bipolar depressive episodes. These differences have important clinical implications. Specifically, when compared to pure bipolar depression, subsyndromal mixed states are associated with greater lifetime illness severity, particularly more extensive suicide attempts and a greater frequency of historical rapid cycling. These data demonstrate the clinical importance of assessing patients with bipolar disorder for current symptoms of both poles of the illness regardless of patients’ self-reported current mood state.

Our observation of prominent mania symptoms in about two-thirds of syndromally depressed bipolar patients is similar to the frequency of mixed depression identified by Benazzi (19) among 389 bipolar II depressed patients. That study, similar to the current one, also found a significantly earlier age at onset of bipolar disorder among subjects with mixed than nonmixed depression, consistent with mixed depression being a nosologically distinct entity from pure bipolar depression. The greater frequency of mixed depressive features among men than women in the current study is at variance with gender differences reported by Suppes and colleagues (15), who identified a greater propensity for mixed hypomania in women than men with bipolar II disorder. However, that study compared the predominance of depressed versus elevated mood during full hypomanic episodes that arose over a 7-year follow-up period, rather than in patients during a full depressive episode. While other phenomenologic studies have pointed to a higher prevalence of mixed (as opposed to euphoric) mania in women than men (28, 29), to our knowledge neither gender nor other patient characteristics have distinguished bipolar disorder patients with and without manic symptoms during a full depressive syndrome. Prior work has reported a comparable number of lifetime depressive episodes among women versus men with bipolar disorder (30), although less is known about the phenomenology of depression in men versus women with bipolar disorder. The present findings suggest that full depressive episodes are more likely to involve concomitant manic symptoms among bipolar men than bipolar women. Future efforts are needed to confirm these observed sex differences and the potential link between subsyndromal mixed symptoms and other male traits associated with affective illness, such as impulsivity and aggression (31) .

The presence of psychomotor agitation, while nonspecific to mania versus depression, has long been a focus of debate in the distinction between mixed episodes and unipolar agitated depression, as defined by the Research Diagnostic Criteria (RDC) (32) . Maj and colleagues (33) identified RDC agitated depression in about 20% of bipolar disorder subjects during a full depressive episode, noting that motor hyperactivity, pressured speech, or racing thoughts were evident in about one-quarter of the patients. A somewhat higher frequency (31.2%) of psychomotor agitation was observed in the present cohort of depressed bipolar subjects, lending further support to the concept that agitated depression in bipolar disorder patients likely falls within a continuum between pure depression and a full mixed episode. Although motor retardation and anergic features are frequently reported in bipolar depression (34), the present findings, in conjunction with other data (35), indicate that psychomotor agitation is also a frequent characteristic of bipolar depression. Using the RDC definition of agitated depression—i.e., a full depressive syndrome involving at least two symptoms from the constellation of 1) motor agitation, 2) psychic agitation or intense inner tension, and 3) racing or crowded thoughts (32) —we observed racing thoughts and psychomotor agitation in 20%–30% of subjects, respectively. These two features were correlated to a moderate but highly significant degree, suggesting that a number of patients with bipolar mixed features in the present study group met at least some of the RDC criteria (32) for agitated depression.

Notably, the higher risk for lifetime suicide attempts we observed among depressed bipolar patients with mixed than among those with pure depressed features is consistent with prior findings that suggest an especially increased risk for recurrent suicidal features in bipolar disorder patients with mixed affective presentations (13) . Moreover, while prior suicide research has emphasized the importance of depression as a driving factor contributing to suicide risk in patients with bipolar disorder, the current findings suggest the possibility that it is not only depression, but the superimposition of mania features (at even a subthreshold level) during bipolar depression that may denote a bipolar subgroup with an increased lifetime potential for suicide attempts. This hypothesis requires further investigation in prospective studies of longitudinal suicide risk in patients with bipolar disorder.

The limitations of the present study include the ascertainment of DSM-IV-TR mania symptoms and severity by means of the Affective Disorders Evaluation and the Young Mania Rating Scale; a more extensive symptom battery would have included symptoms now understood to be characteristic of manic states (i.e., impulsivity, affective lability, risky behaviors [35] ). The present study intentionally focused on individual affective symptoms rather than the DSM-IV entity of a mixed episode, limiting the inferences one can draw about mania symptoms among patients with frank mixed episodes. The study group participants were predominantly white, were diagnosed more often with bipolar II than bipolar I disorder, had a relatively high rate of prior suicide attempts, and were willing to participate in treatment-based research; generalizability to broader populations of individuals with bipolar disorder may be limited by characteristics such as these. The cross-sectional nature of the present study also did not provide an opportunity to determine the longitudinal stability of mixed features in recurrences of depression in bipolar disorder patients, although prior studies suggest a high probability for depressive mixed states to recur (36) . Data from subsequent prospective follow-up of the STEP-BD cohort may help to shed further light on this issue.

Since the ascertainment of depression occurred in a group of individuals who, for the most part, had received some form of treatment before entry into STEP, one cannot rule out the possibility that treatments received for the current episode contributed to the results. Because subjects who were taking antidepressants at the time of study entry had fewer (rather than more) threshold-level symptoms of mania as compared to those not taking antidepressants, antidepressant pharmacotherapy would not appear to have been a major factor contributing to symptom presentations at study entry. The data on naturalistic pharmacotherapy at the time of study entry suggest that practitioners may be less inclined to use either lithium or antidepressants for bipolar patients with mixed features, a possibility consonant with recommendations made in current practice guidelines that advise against the use of antidepressants in mixed episodes (37) and favoring other mood-stabilizing agents over lithium (38) when manic and depressive symptoms co-occur.

In summary, the present findings indicate that a majority of patients with bipolar disorder with a full depressive episode have clinically relevant manic symptoms. Bipolar mixed depression represents a clinically relevant entity with features that differ fundamentally from those of pure bipolar depression. Future studies are needed to compare treatment response, recovery rates, and illness course among these subtypes in order to further consolidate evidence for their nosologic validity.

Presented in part at the 161st annual meeting of the American Psychiatric Association, Washington, D.C., May 3–8, 2008. Received May 20, 2008; revisions received July 28 and Sept. 12, 2008; accepted Sept. 25, 2008 (doi: 10.1176/appi.ajp.2008.08050746). From the Department of Psychiatry, Mount Sinai School of Medicine, New York; the Affective Disorders Research Program, Silver Hill Hospital, New Canaan, Conn.; the Department of Psychiatry, Harvard Medical School, Boston; the Department of Psychiatry, Massachusetts General Hospital, Boston; the Department of Psychiatry, University of Texas Health Science Center at San Antonio; the Department of Psychiatry, University of Pennsylvania, Philadelphia; the Department of Psychiatry, University of Pittsburgh; the Departments of Psychology and Psychiatry, University of Colorado, Boulder; the Department of Psychiatry, Baylor College of Medicine, Houston; and the Department of Psychiatry, Case Western Reserve University, Cleveland. Address correspondence to Dr. Goldberg, 128 East Ave., Norwalk, CT 06851; [email protected] (e-mail).

Dr. Goldberg serves on the scientific advisory boards of Eli Lilly and GlaxoSmithKline; he is on the speakers bureaus for Abbott, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pfizer; and he receives income royalties from American Psychiatric Press. Dr. Perlis has received honoraria or consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Pfizer. Dr. Bowden receives research funding from Abbott, Bristol-Myers Squibb, Elan, GlaxoSmithKline, Janssen, Lilly Research, NIMH, Parke Davis, R.W. Johnson Pharmaceutical Institute, Smith Kline Beecham, and Stanley Medical Research Foundation; he serves on the speakers bureaus for Abbott, AstraZeneca, GlaxoSmithKline, Janssen, Lilly Research, and Pfizer; and he serves as a consultant to Abbott, GlaxoSmithKline, Janssen, Lilly Research, Sanofi Synthelabo, and UCB Pharma. Dr. Thase has provided scientific consultation to Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Seprecor, Shire, Supernus, and Wyeth; he has been a member of the speakers’ bureaus for AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, Sanofi Aventis, and Wyeth; he has equity holdings in MedAvante and receives royalty income from American Psychiatric Publishing, Guilford Publications, Herald House, and W.W. Norton & Company; he has provided expert testimony for Jones Day and Philips Lyttle, L.L.P., and Pepper Hamilton, L.L.P.; and his wife is employed by Advogent. Dr. Marangell is currently an employee of Eli Lilly and Company Research Laboratories. Dr. Calabrese receives federal funding from the Department of Defense, Health Resources Services Administration, and NIMH; he receives research funding or grants from the following private industries or nonprofit funds: Cleveland Foundation, NARSAD, Repligen, and Stanley Medical Research Institute; he receives research grants from Abbott, AstraZeneca, Cephalon, GlaxoSmithKline, Janssen, and Eli Lilly; he serves on the advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forest, France Foundation, GlaxoSmithKline, Janssen, Organon, OrthoMcNeil, Repligen, Servier, Solvay/Wyeth, and Supernus Pharmaceuticals; and he reports CME activities with AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson, Organon, and Solvay/Wyeth. Dr. Nierenberg receives research support from Bristol-Myers Squibb, Cederroth, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lichtwer, the National Alliance for Research in Schizophrenia and Depression, NIMH, PamLabs, Pfizer, the Stanley Foundation, and Wyeth; he serves as an advisor or consultant to AstraZeneca, Basilea, Brain Cells, Bristol-Myers Squibb, Dainippon Sumitomo, Eli Lilly, EpiQ, Genaissance, GlaxoSmithKline, Innapharma, Jazz Pharmaceuticals, Merck, Neuronetics, Novartis, Pfizer, PGx Health, Sepracor, Shire, Targacept, and Takeda; he receives speaking fees from Eli Lilly, GlaxoSmithKline, Organon, Wyeth, and Massachusetts General Psychiatry Academy (whose talks were supported in 2008 through independent medical education grants from AstraZeneca, Eli Lilly, and Janssen); and he holds shares in Appliance Computing. Dr. Sachs serves on the speakers bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Novartis, Pfizer, Sanofi-Aventis, and Wyeth; he serves as an advisory board member or consultant for AstraZeneca, Bristol-Myers Squibb, Cephalon, Concordant Rater Systems, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Novartis, Organon, Otsuka, Pfizer, Repligen, Sanofi-Aventis, Schering, Plough, Sepracor, and Wyeth; and his spouse holds shares in Concordant Rater Systems. Dr. Miklowitz reports no competing interests.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded with federal funds from NIMH under contract N01 MH-80001; portions of this research were funded by NIMH K-23 Career Development Award MH-01936 to Dr. Goldberg. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of NIMH.

The contents of this article were reviewed and approved by the STEP-BD Steering Committee. Additional detail on STEP-BD can be located at http://www.nimh.nih.gov/health/trials/practical/step-bd/questions-and-answers-for-the-systematic-treatment-enhancement-program-for-bipolar-disorder-step-bd-study-background.shtml.