Posted by jrbecker on February 11, 2005, at 12:18:52
In reply to Re: Bipolar II Series -Atypical depression, posted by jrbecker on February 11, 2005, at 12:16:18
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 187-196
Bipolar Depression: Focus on Phenomenology
doi:10.1016/S0165-0327(02)00172-6
Copyright © 2002 Elsevier B.V. All rights reserved.
Research report
Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression
T. Sato , , R. Bottlender, N. Kleindienst and H. -J. MöllerPsychiatrische Klinik, Ludwig-Maximilians-Universität München, Nussbaumstrasse 7 80336, Munich, Germany
Received 10 January 2002; accepted 6 May 2002. Available online 10 February 2005.
Abstract
Background: Early authors described hypomanic symptoms as mixed features in depressive episode, but this syndrome has not been sufficiently explored in previous studies. Methods: 958 consecutive depressed patients were assessed by using a standardized method in terms of 43 psychiatric symptoms at hospitalization. Results: A principal component analysis, followed by varimax rotation, extracted six interpretable factors: typical vegetative symptoms, depressive retardation/loss of feeling, hypomanic syndrome, anxiety, psychosis, and depressive mood/hopelessness. The extracted factor structure was relatively stable among several patient groups. There was no evidence that the hypomanic factor was exaggerated by antidepressant pretreatments before hospitalization. Bipolar diagnoses were associated with higher scores on depressive retardation and hypomanic symptoms, and a lower score on anxiety. Limitations: Psychiatric syndromes and their interrelationships, found in the present study, may be strongly influenced by the rating instrument used. The sample of this study was depressed inpatients. The results should not be generalized for depressed outpatients or epidemiological depressed populations. Conclusions: Hypomanic symptoms, as characterized by the flight of ideas, racing thought, increased drive, excessive social contact, irritability, and aggression are a salient syndrome in acutely ill depressed patients, lending support to the factor validity of mixed depression. The symptoms may not be related to pretreatments with antidepressants, or comorbidity of substance abuse, suggesting that they reflect various natural phenomenological manifestations of depressive episodes. Anxiety is unlikely to play a major role in the core phenomenological features of mixed depression. Hypomanic symptoms during a depressive episode were more represented in bipolar disorders, which may serve for further clarifications of latent bipolarity in unipolar depression, and prediction of switch into maniform states under biological depression treatments.
Author Keywords: Mixed states; Mixed depression; Depression; Bipolar disorder; Anxiety; Hypomania
1. Introduction
Since early classic authors, it has long been recognized that some depressed patients demonstrate considerable hypomanic symptoms such as flight of idea and increased drive, mostly accompanied by irritable mood (Kraepelin, 1921 and Himmelhoch et al., 1976; Braden and Qualls, 1979; Abrams and Taylor, 1980, a review by Koukopoulos and Koukopoulos, 1999). The classical authors described these affective states as mixed states, which are not a transient phenomenon such as a cycling process in manic–depressive illness, but relatively long lasting affective states. However, an intensive exploration of these hypomanic symptoms during a depressive episode has rarely been made. Traditional authors occasionally referred to agitated depression, an extremely high level of anxiety, in relation to hypomanic symptoms during a depressive episode (see Koukopoulos and Koukopoulos, 1999): but the relationship between hypomanic features and anxiety has not been systematically investigated in depressed patients. Many studies with multivariate techniques have been conducted to seek for evidence supporting depressive subtypes, especially melancholic and nonmelancholic subdivisions of depressive episodes (see a review by Nelson and Charney, 1981); but most of these studies did not include a broad range of hypomanic symptoms. To our knowledge, only two of such studies included hypomanic symptoms in their analyses: these studies found a symptom cluster related to psychomotor elation ( Raskin et al., 1969) and a depressive subtype characterized by hypomanic symptoms ( Andreasen and Grove, 1982) in depressed patients. However, potential implications of these findings have occupied nearly no interest in the literature.
Recent findings indicating the differential nature between mixed and pure mania in terms of phenomenological presentations (McElroy et al., 1992; Swann et al., 1993; Dilsaver et al., 1994; Dilsaver et al., 1999; Cassidy et al., 1998; Cassidy et al., 2000 and Sato et al., 2002a), natural course ( Bauer et al., 1994; Arnold et al., 2000; Perugi et al., 2000 and Sato et al., 2002b); and specific treatment responses ( Swann et al., 1997 and Greil et al., 1998) have newly aroused our interest in hypomanic symptoms during a depressive episode. Several researchers have begun to report that hypomanic symptoms are not infrequent during a major depressive episode. Akiskal and Pinto (1999) were the first to turn researchers’ attention to the potential clinical implications of hypomanic symptoms during a major depressive episode. Other authors report that these hypomanic symptoms may be associated with bipolar diagnoses, in particular bipolar II diagnosis, and atypical depressive features in their study groups ( Benazzi, 2000 and Benazzi, 2001). Depressed patients with hypomanic features, called mixed depression, have been implied to have a similar natural course to mixed mania ( Perugi et al., 1997), and to possibly demonstrate less beneficial response to tricyclics ( Koukopoulos et al., 1995), although clinical implications of these features in depressive episodes have to date not been well investigated ( Akiskal et al., 2000). These recent authors used differently defined criteria for hypomanic symptoms admixed in depressive episode. A potential role of anxiety was stressed by several authors (see Koukopoulos and Koukopoulos, 1999), while irritable mood, combined with flight of idea and increased drive, was suggested to be the core of these hypomanic symptoms ( Perugi et al., 1997). This may be because the boundary and the relationship of hypomanic symptoms to other depressive syndromes have not been systematically studied in depressed patients.
Factor analysis is one way of clarifying a psychiatric syndrome underlying various manifestations in depressed patients. We therefore carried out a factor analysis of 43 symptoms including a broad range of depressive as well as hypomanic symptoms, systematically assessed them by using a standardized method in 958 acutely ill depressed patients.
2. Methods
2.1. Patients
All patients, who were consecutively hospitalized at the Psychiatric Hospital of the Ludwig-Maximilian University in Munich, Germany for treatments of depressive states during the period of 1995–2000, were considered as subjects in this study. Clinical diagnoses of these patients were made according to ICD-10 (WHO, 1992) by means of a consensus among three experienced psychiatrists including at least one person with a professor degree. Patients, who were diagnosed as currently having major depressive episode (ICD-10 diagnoses: depressive episode F32.0–32.3; recurrent depressive episode F33.0–33.3; and bipolar affective disorder, current depressive episode F31.3–31.5), were included. Patients older than 70 years were excluded. If a patient experienced more than one hospitalization during the whole study period, only data for the last admission were included. Finally, 958 depressed patients were included. Of these patients, 863 had no lifetime history of hypomania or mania that occurred spontaneously (i.e. without effects of depression treatments) (nonbipolar depressives, UP), while 25 had experienced spontaneous hypomania that continued for at least 4 days without requirement of hospitalization (bipolar II disorder, BPII). The remaining 70 patients had a history of mania that required treatments in psychiatric hospitals (bipolar I disorder, BPI).
The demographic and clinical variables of the patients included are shown in Table 1. Among the three diagnostic groups, there was significant difference in onset age (younger onset in patients with bipolar disorders), as shown by previous studies (Cassano et al., 1992 and Hantouche et al., 1998). The frequency of antidepressant pretreatments before admission was also significantly different among the three groups.
2.2. Clinical assessments
A broad range (198 symptoms) of psychiatric symptoms were systematically assessed at admission. The AMDP system (Association for Methodology and Documentation in Psychiatry, 1981) was used for assessing psychiatric symptoms. All included patients gave informed consent to be assessed by using this instrument. The AMDP system is a comprehensive rating instrument, developed on the basis of German traditional descriptive psychopathology on functional psychoses: it is commonly used in most psychiatric institutes in German-speaking countries. Each psychiatric symptom of the AMDP system is scored from 0 (absent) to 3 (severe) with defined anchor statements by using a semi-structured interview method. Several studies indicated moderate to high inter-rater agreements for included symptoms ( Renfordt et al., 1983 and Kuny et al., 1983). Among the psychiatric symptoms assessed, 43 symptoms, which were considered from a careful review of the literature as being related to various depressive manifestations and manic features in depressed patients, were selected.
Suicidality at admission was defined in this study as a score on the AMDP suicide item higher than 1 (mild: ‘the patient repeatedly expresses the feeling that her/his life has no meaning to live’). The depression severity was measured by using the AMDP depression scale, which is calculated by summing up 13 AMDP item scores for rumination, loss of feeling, loss of vitality, depressed mood, hopelessness, feeling of inadequacy, feeling of guilt, inhibition of drive, worse in the morning, interrupted sleep, shortened sleep, early waking, and decreased appetite. This scale was previously validated in large psychiatric samples (Baumann et al., 1983 and Pietzcker et al., 1983). The coefficient for this scale in our study group was 0.793, indicating substantial internal consistency.
2.3. Statistical analyses
Principal component analysis, followed by varimax rotation, was carried out for included symptoms. The extracted factor structure was examined in terms of model fit by using confirmatory factor analyses, with factors to be correlated. This calculation was made for all subjects, for UP patients only (n=863), and for subjects without a lifetime history of drug and alcohol abuse only (n=902). The invariance of the factor structure was explored across subjects with and without antidepressant pretreatments before admission (n=732 and 226, respectively), across younger (younger than 51 years, n=458) and older (n=500) subjects, and across male (n=394) and female (n=564) subjects. Two indices for measures of fit, the goodness-of-fit index (GFI) and the adjusted goodness-of-fit index (AGFI), were used to estimate the degree to which the models fit the data. The GFI usually ranges from zero to unity, where values >0.9 indicate a good fit (Bentler, 1990). The AGFI ranges from zero to unity, where a value >0.8 indicates an acceptable fit ( Cuttance, 1987 and Cole, 1987).
Factor scores for each subject were saved, and were then compared among the three diagnostic groups (UP, BPII, and BPI). Factor scores were firstly adjusted for sex and age, and these adjusted factor scores were used for the group comparisons. An overall difference in factor scores was examined by means of the discriminant function analysis with the three diagnostic groups being used as the dependent variable, and all adjusted factor scores being used as independent variables. As posthoc univariate comparisons, Kruskal–Wallis tests or analyses of variance (ANOVA) were used, according to whether or not statistical assumptions for ANOVA were violated. The significance level for each univariate comparison was adjusted by using Bonferroni’s method. Significant statistics, produced by univariate analyses, were followed by multiple group comparisons by using Scheffe’s simultaneous confidence intervals. All statistical statements were two-tailed. Statistical packages, SPSS (1995) and AMOS ( SPSS, 1997).
3. Results
The principal component analysis produced eight eigenvalues greater than unity. However, scree-test and parallel analysis (Lautenschlager et al., 1989) indicated that a six-factor solution was more appropriate to extract interpretable factors. We therefore chose a six-factor solution. The six factors explained 49.4% of the total variance. Rotated factor loadings greater than 0.4 and percentage variance explained by each extracted factor are shown in Table 2. All symptoms loaded on only one factor each. The first factor isolated eight typical vegetative symptoms. The second factor represented depressive retardation/loss of feeling. On the third factor, hypomanic symptoms such as flight of idea, logorrhea, aggression, excessive social contact, increased drive had high loadings. Irritability also had high loading on this factor, while symptoms representative of classic mania, such as euphoria, grandiosity, and distractivity, did not have high loading on this factor. The fourth factor isolated five symptoms related to anxiety. The fifth factor represented psychotic symptoms, while symptoms related to depressive mood and hopelessness loaded on the sixth factor. None of these six factors showed bimodal distribution. Several symptoms (reverse vegetative function, morning worsening, euphoria, grandiosity, and distractivity) had no loading higher than 0.4 on any extracted factor, as shown in Table 2.
The results of confirmatory factor analyses are shown in Table 3. For these analyses, items without a clear loading on any extracted factor (reverse vegetative function, morning worsening, euphoria, grandiosity, and distractivity) were not used. The fit-indices for the factor structure were in a range, suggestive of an acceptable or good fit for all subjects, for UP patients only, and for subjects without a lifetime history of drug or alcohol abuse only. The fit-indices for the hypothesis of invariance of the factor structure across subjects with and without antidepressant pretreatments, across female and male subjects, and across younger and older subjects also remained in a similar range, indicating that the hypothesis is statistically supported.Table 4 demonstrates results of comparisons of the computed factor scores among the three diagnostic groups. The discriminant function analysis, with the diagnostic groups being used as the dependent variables, and all computed factor scores being used as independent variables, produced a significant F value (Wilks’ =0.95, F=3.20, DF=14,1894, P=0.000), indicating that factor scores significantly differed among the three groups. Posthoc univariate analysis for each factor score was carried out with a significance level of P<0.0083 (0.05/6: Bonferroni’s correction). A significant effect of diagnosis was found in factor scores 3 (hypomanic factor) and 4 (anxiety factor). Multiple comparison procedures showed that BPI patients scored higher than UP patients on hypomanic factor; and that UP patients scored higher than bipolar patients on anxiety factor. The psychomotor retardation factor (factor 2) tended to differ among the three diagnoses, with a higher score in bipolar patients.
Scores on the hypomanic factor were also compared between patients with and without antidepressant pretreatments by using an ANOVA, with diagnosis, age and gender being used as covariates. Since the number of BPII patients without pretreatments was quite small (n=2), this diagnostic group was combined with BPI patients in this analysis. The mean scores on this factor were −0.06 (S.D.=0.92) and 0.18 (S.D.=1.2) for patients with and without antidepressant pretreatments, respectively, indicating a significant difference (F=8.11, DF=1, 953, P=0.005). Patients without pretreatments scored even higher on this factor than did patients with pretreatments, suggesting that the hypomanic factor was unlikely to be exaggerated by antidepressant pretreatments in this study group.
4. Discussion
The factor analysis in the present study isolated six independent factors. The extracted factor structure appeared relatively stable across several patient groups, as shown by the confirmatory factor analyses. The fit indices computed for patients without a lifetime history of abuse were suggestive of a good or an acceptable fit. The invariance of the factor structure across patients with and without antidepressant pretreatments was also statistically supported: these suggest that the factor structure is relatively robust against effects of having a history of abuse and antidepressant pretreatments. The extracted factors were typical vegetative symptoms, depressive retardation/loss of feeling, hypomanic symptoms, anxiety, psychosis, and depressive mood. Besides several factors, which were repeatedly identified by previous factor analyses for depressed patients (Nelson and Charney, 1981; Mullaney, 1984; Rush et al., 1986 and Enns et al., 1998), hypomanic symptoms were extracted as the third factor: this indicates that hypomanic symptoms are not negligible but rather a salient syndrome in depressed patients. Our results indicated lower scores on the hypomanic factor in patients with antidepressant pretreatments: this suggests that the successful identification of this factor in the present study is unlikely to be exaggerated by antidepressant pretreatments, but is likely to reflect various natural manifestations of depressed patients. Several early studies with multivariate techniques included hypomanic symptoms in their analyses. Consistent with our results, they found a factor related to hypomanic symptoms ( Raskin et al., 1969) and a depressive subtype characterized by hypomanic features ( Andreasen and Grove, 1982) in depressed patients, although these authors did not discuss potential implications of their findings. Our results, combined with these previous investigations, indicate that some depressed patients demonstrate hypomanic symptoms in their natural course, lending support to the factor validity of mixed depression.
Symptoms composing the hypomanic factor in the present study appear somewhat different from typical manic symptoms. Recently, four studies have conducted a factor analysis for psychiatric symptoms including a broad range of atypical features in manic patients (Cassidy et al., 1998; Dilsaver et al., 1999; Rossi et al., 2001 and Sato et al., 2002a). Besides several factors associated with atypical manic features, these studies consistently found a factor representative of the typical manic syndrome, on which euphoria, grandiosity, and psychomotor elation had high loadings. Compared to the typical manic factor in manic patients, the hypomanic factor in the present study clearly lacked high loadings of euphoria and grandiosity. Instead of euphoria and grandiosity, irritability and aggression, which are usually thought to be associated with atypical manic manifestations ( Beigel and Murphy, 1971a), had high loadings on the factor. This suggests that hypomanic features in mixed depression qualitatively differ from the typical manic syndrome in manic patients. The phenomenology of mixed depression may be characterized not by a simple admixture of depressive syndromes and the typical manic syndrome, but by a relatively specific presentation composed of irritable aggressive mood and psychomotor elation.
Some factors, identified in the present study, were associated with bipolar diagnoses. Patients with bipolar disorders were more likely to present lower anxiety, slightly higher psychomotor retardation and higher hypomanic symptoms, although the results for the retardation factor did not reach a significance level after Bonferroni’s correction (F=4.53, DF=2,955, P=0.011). The findings regarding the former two factors in the present study are consistent with well-established evidence, which has repeatedly been replicated by a large number of studies (see a review by Mitchell et al., 1992; Mitchell et al., 2001 and Beigel and Murphy, 1971b). The finding that a higher score on hypomanic symptoms was associated with bipolar diagnoses in acutely ill depressed patients has firstly been reported by an early study ( Abrams and Taylor, 1980). Their study found that bipolar endogeneous depressives scored higher on a manic scale than did unipolar endogeneous depressives, although it is unclear whether or not the manic symptoms assessed in their study have similar contents, compared to the hypomanic factor identified in our present study. Since then, only Perugi et al. (1997) and Benazzi (2000) provided similar results. The consistency between these previous studies and ours strongly indicates the affinity with bipolar disorder of depresses patients with hypomanic symptoms suggesting the clinical importance of hypomanic symptoms in differentiating between bipolar and unipolar depressives. Hypomanic symptoms may also be associated with the hypothesised latent bipolarity in unipolar depressives ( Akiskal, 1996 and Akiskal and Pinto, 1999), which requires future studies investigating family history, comorbidity, specific treatment responses and natural history in unipolar depressives with hypomanic symptoms. A recent study reports that manic patients with several depressive symptoms (i.e. patients with broadly defined mixed mania) are more likely to experience a cycling into depressive episode from a first manic episode in bipolar disorder ( Zarate et al., 2001). On the analogy of this finding, one may speculate that a switch from a depressive episode into a hypomanic or manic episode under biological depression treatments is more likely to occur in depressed patients with hypomanic symptoms. This definitely requires further study since such a switch is not infrequent at least in bipolar depressives ( Bottlender et al., 2001), and is believed to be associated with phenomena suggestive of deteriorated outcome such as rapid cycling in depressed patients ( Wehr and Goodwin, 1979 and Wehr, 1993).
Hypomanic symptoms and anxiety loaded on two separate factors in our results, where only hypomanic symptoms were associated with bipolar diagnoses. This finding requires some comment, since traditional authors occasionally referred to agitated depression (an extreme pole of anxiety) in relation to a potential mixed state in depressed patients. Our results did not provide evidence that higher anxiety is likely to be accompanied by hypomanic symptoms, indicating that agitated depression (i.e. an affective state, where extremely high anxiety is accompanied by psychomotor elation) is probably heterogeneous in terms of statistically refined phenomenological factors. Some depressive patients may present both high anxiety and hypomanic symptoms, as these two syndromes were orthogonal in our results. However, our findings appear to suggest that this complex affective state can only be called a mixed depression, as far as hypomanic symptoms are accompanying. It is likely from our results that anxiety plays only a minor role in the core phenomenological features of mixed depression.
One of possible limitations in the present study is that our subjects were composed of depressed inpatients only, which raises a question as to the generalizability of our results. In particular, atypical depressive features, which are thought to be more common in outpatient or epidemiological populations (Rabkin et al., 1996), were very infrequent in our study group. Only 26 patients (2.7%) of our subjects showed reverse vegetative function, which may have resulted in our failure in clarifying relationships between atypical features and other identified factors. Several studies with multivariate techniques succeeded in identifying a factor or a depressive subtype related to atypical depressive features in outpatient and epidemiological populations ( Rush et al., 1986; Davidson et al., 1989; Kendler et al., 1996 and Sullivan et al., 1998), though some did not obtain similar results in an outpatient population ( Paykel et al., 1983) or in a sample of out- and inpatients combined ( Robertson et al., 1996). Some recent studies reported that atypical features might be correlated to hypomanic symptoms in outpatients with major depressive episode ( Benazzi, 2001). Our results indicate that this is not the case in depressed inpatients. These different findings are definitely related to different populations studied. Our sample consists of relatively few patients with bipolar diagnoses. Further study with a large outpatient or epidemiological cohort may help further clarify the relationships between atypical depressive features and other depressive syndromes including hypomanic symptoms during depressive episodes. Psychiatric syndromes and their interrelationships, found in the present study, may be strongly influenced by the rating instrument used (the AMDP-system). Further study using other rating instruments is required to confirm our findings.
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