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Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features

2009; Wiley; Volume: 8; Issue: 3 Linguagem: Inglês

10.1002/j.2051-5545.2009.tb00245.x

2051-5545

Alan C. Swann, Joel L. Steinberg, Marijn Lijffijt, Gerard F. Moeller,

Mental Health Research Topics

Depressive and manic features can combine during the same episode of bipolar disorder. Patients who are susceptible to mixed states may differ in clinical, illness-course, and treatment response characteristics from those who are not susceptible 1–4. The definition of mixed states and its relationship to depressive and manic syndromes has been elusive. Kraepelin posited six mixed states based on combinations of depressive or manic affect, thought and behavior, resulting in mixed states that could be construed as predominately depressive or manic 5. Subsequent formulations focused on mixed mania, consisting of depressive symptoms during manic episodes 3,6. DSM-IV, for example, requires combined syndromal depression and mania for a mixed state and considers these states to be a form of mania 7. The mixed mania formulation is problematic. First, clinical reality appears less restrictive than this definition. For example, only two depressive symptoms, not a full mixed state, can alter treatment response during mania 8. Second, there is increasing evidence that depressive mixed states, where manic symptoms occur during a predominately depressive episode, are clinically important and may be at least as prevalent as mixed mania 9. As with predominately manic states, depressive episodes require only two or three manic symptoms to have significant differences in course of illness and clinical characteristics 10,11. In addition to the combination of depressive and manic symptoms, anxiety appears to be a prominent aspect of mixed states 12. Mixed states that are predominately depressive or predominately manic may share clinical characteristics that are relevant to course of illness and response to treatment 13. We have reported that, during bipolar depressive episodes, increases in severity of the course of illness, impulsivity, and complications like head trauma, substance abuse and attempted suicide emerged with modest levels of manic symptoms 11. If even mild manic symptoms were present, depressive episodes differed substantially from those without manic symptoms in the course of illness and clinical history. Characteristics of patients with mixed manias or mixed depressions suggest that mixed states are symptomatically continuous with depressive and manic states, but have characteristics related to a more severe course of illness. Susceptibility to mixed states may accordingly be a trait characteristic of a subset of patients with severe bipolar disorder 4,14–16. For example, patients with mixed episodes early in the course of illness had a higher prevalence of severe suicide attempts compared to other patients with bipolar disorder 17,18. Here, we report the manner in which combinations of depressive and manic symptoms produce a continuum of mixed states. The main hypotheses of the study were that: a) clinical correlates of mixed states would be related to severity of manic symptoms in depressed subjects and depressed symptoms in manic subjects; b) the extent to which episodes were mixed could be measured quantitatively and independently of specific depressive or manic symptoms; and c) specific depressive or manic symptoms, related to activation, would be associated with mixed states. Subjects were outpatients meeting DSM-IV criteria for bipolar I or II disorder 7. Before they participated in the study, it was thoroughly discussed with them and written informed consent was obtained. The study was reviewed and approved by the Committee for the Protection of Human Subjects, the Institutional Review Board of the University of Texas Houston Health Science Center. Subjects were recruited to cover a range of symptoms and represented euthymic (n=19, mean age 36.0±12.3 years), DSM-IV manic (n=23, age 32.2±9.7 years), DSM-IV depressive (n=28, age 38.2±9.5 years), and mixed states (defined as meeting symptomatic DSM-IV criteria for both depressive and manic states) (n=18, age 36.6±6.0 years). Age did not differ across subject groups (F(3,84) = 1.4, p=0.25). Subjects were receiving one or more treatments, including lithium (n=7), anticonvulsants (n=44; predominately valproate and/or lamotrigine), atypical antipsychotics (n=15), or antidepressants (n=31). Seventeen subjects were receiving no psychopharmacological treatments, 30 were receiving one drug class, 26 were receiving two classes, and 5 were receiving three or more classes. Number of drugs was not related to episode type (X2 (9 df) = 5.3, p=0.8). Subjects were studied when specific treatments had not changed, and doses not changed by over 20%, over the previous seven days. Participation in the study had no influence on treatment decisions. Diagnoses were rendered using the Structured Clinical Interview for DSM-IV (SCID) 19 and confirmed in diagnostic consensus meetings. Symptoms of depression, mania, anxiety, and psychosis were measured using the Change Version of the Schedule for Affective Disorders and Schizophrenia (SADS-C), which was designed to measure these symptom domains concomitantly 20. As discussed in previous work, scores were reduced by one unit so that symptoms were scored as zero if absent, rather than one 8. Personnel were trained, using standard video training materials, in the SCID and SADS-C. DSM-IV mixed states were defined as subjects meeting full symptomatic criteria for manic and major depressive episodes. Symptoms were scored as present if they had a score of at least 2 on the modified SADS-C (mild but definitely present; equivalent to 3 on the original instrument). For the purposes of identifying subjects in putative depressive or manic mixed states, we excluded SADS-C rating scale items that might, in a circular way, be related to the nominal opposite polarity. Depression item scores used included subjective depression, worry, self-reproach/guilt, negative evaluation of self, hopelessness, suicidal ideation or behavior, anhedonia, fatigue, and psychomotor retardation. Items possibly related to mania, including sleep disturbance, agitation, subjective or objective anger, or irritability, were excluded. Mania item scores included elevated mood, decreased need for sleep, increased energy, manifest anger, goal-directed activity, grandiosity, visible hyperactivity, accelerated speech, racing thoughts, and poor judgment. Anxiety and psychosis factor scores were not used in identifying subjects in mixed states but were compared in mixed vs. non-mixed subjects. Subjects were defined as euthymic if they did not meet DSM-IV criteria for current depressive or manic episodes and had not had a depressive, hypomanic, or manic episode for at least three months. "Depressed" or "manic" subjects were those who met criteria for a depressive or manic episode, regardless of associated symptoms of the other polarity; subjects whose opposite polarity symptoms were less than relevant threshold criteria are referred to as "non-mixed". A predominately depressed mixed state, DM3, was defined as meeting criteria for a depressive episode and having three or more manic symptoms, corresponding to Benazzi's MX3 9. A predominately manic state was defined, based on our data on treatment response, as a manic episode with at least three depressive symptoms, which will be referred to here as MD3 8. Because of the lack of definitive data on duration of specific SADS-C symptoms, one cannot be certain which of these subjects met DSM-IV criteria for a mixed state. Distributions were checked for normality; if they departed from normal, appropriate non-parametric methods were used. Statistical analyses used standard regression and analysis of variance procedures, or their non-parametric analogs, as described in the text. For correlations of variables whose distributions were not normal, Kendall tau was used, because it was shown to balance power and control of type 1 error more effectively than Pearson or Spearman correlation coefficients 21. Significance of differences between standard correlation coefficients was determined using the Fisher r-z transformation 22. The extent to which an episode was mixed was estimated using the product of z-transformed depression and mania scores. This is referred to as the Mixed State Index (MSI). The MSI is high if both depression and mania scores are high, but low if either is low (even if the other is high). Z-transformation was used to reduce bias from any difference in numerical values between depression and mania scores (depression scores ranged from 0 to 36, mean 15.3±9.4; mania scores ranged from 0 to 37, mean 10.8±8.6). The absolute value of the minimum z-transformed depression or mania score for all subjects was added to the z-transformed score for each subject so all scores would be non-negative numbers. DSM-IV defines a mixed state as meeting full criteria for a manic and a major depressive episode, for at least one week. Descriptions of mixed states in the literature, however, include predominant depression with subsyndromal mania 9 and predominant mania with subsyndromal depression 8. Table 1 compares psychiatric symptoms in subjects experiencing a depressive episode with three or more manic symptoms (DM3) 9 and subjects experiencing manic episodes with at least three depressive symptoms (MD3) 8. Anxiety scores correlated positively with mania scores in depressed subjects (r=0.427, n=46, p=0.003) and with depression scores in manic subjects r=0.671, n=41, p=0.001). Mixed states defined as predominately depressive or manic were essentially identical in symptom severity. Subjects with DM3 or MD3, considered separately, did not differ from corresponding non-mixed depressed or manic subjects with respect to gender (Fisher exact test = 0.52 and 0.23, respectively). However, subjects with either DM3 or MD3 had a greater proportion of women than depressed or manic subjects not in a mixed state (women: 7 non-mixed and 15 mixed; men: 26 non-mixed and 17 mixed; Fisher exact test = 0.028). This confirms earlier reports that patients in broadly defined mixed states are more likely to be women 3,23. There have been many alternative definitions of mixed states. We investigated two Kraepelinian mixed states 5 that can be considered as varieties of mixed depression 24: depression with flight of ideas (subjects having depressive episodes who also had definite flight of ideas/racing thoughts on SADS-C) and excited depression (depressive episode with hyperactivity on SADS-C). These subjects were essentially identical, in severity of depression, mania, anxiety, and psychosis to the DM3 or MD3 subjects in Table 3. Next, we investigated subjects with at least three depressive symptoms and at least three independent mania symptoms, without the requirement for meeting a full depressive or hypomanic/manic episode. These subjects (n=32) also did not differ in clinical characteristics from those described in Table 2 (data available on request). The extent to which an episode is mixed can potentially be expressed as the extent to which both depression and mania are present. As defined in Methods, we used the product of z-transformed depression and mania scores as an index of how strongly mixed an episode was (Mixed State Index or MSI). Table 2 compares MSI in subjects experiencing euthymic, depressed, manic, and depression- or mania-based mixed states. MSI was similarly elevated in predominately depressive or manic mixed states. Across all subjects, MSI correlated positively with anxiety (Kendall tau = 0.27, p=0.001) and psychosis (Kendall tau = 0.24, p=0.004). Figure 1 shows relationships between MSI scores and complications of bipolar disorder. Indices of severe illness, like early onset and suicide attempt, were associated with high MSI scores. Subjects with histories of a substance or alcohol use disorder, however, did not differ from those who had not met criteria for a substance-related disorder. Mixed State Index score and clinical characteristics In order to determine which specific depressive or manic symptoms were more likely to be associated with being in a mixed state, we conducted a discriminant function analysis using the depression and mania items in the SADS, and a broad classification of mixed states combining MD3 and DM3. After an initial analysis using all SADS depressive and manic symptoms, we repeated the analysis using only those symptoms with F>1 to remove from the model. Symptoms in the final group were worry, negative evaluation of self, suicidal ideation or behavior, anhedonia, psychomotor retardation, decreased need for sleep, increased energy, grandiosity, visible hyperactivity, accelerated speech, and racing thoughts. The resultant analysis had Wilks' lambda of 0.38 and overall F(11,57) = 8.56 (p<10−4). The model classified 90% of cases correctly (86.5% of non-mixed and 93.7% of mixed). Depressive symptoms contributing to the model were worry (F (1,57) to remove = 7.4, p=0.009) and negative evaluation of self (F = 3.74, p=0.05). Manic symptoms were increased energy (F = 5.6, p=0.02), visible hyperactivity (F = 21.9, p 0.4). This was a cross-sectional study, focusing on presence of symptoms at a given time rather than their duration or order of occurrence. The number of subjects limited ability to investigate possible contributing factors reliably. Treatment was not standardized. Combined depression and mania, regardless of which predominates, is associated with increased psychosis and anxiety during the current episode, compared with episodes of depression or mania alone. A continuum of mixed states and a metric of susceptibility to these states may describe their characteristics better than a more syndrome-driven categorical model. It will be important to determine the neurobiological mechanisms and clinical course of illness underlying susceptibility to mixed states. This study was supported in part by the Pat R. Rutherford, Jr. Chair in Psychiatry (ACS) and by NIH grants RO1 MH 69944 (ACS), RO1 DA08425 (FGM), and KO2 DA00403 (FGM). We thank Saba Abutaseh, Glen Colton, Stacey Meier, and Mary Pham for their assistance.