Posted by jrbecker on February 11, 2005, at 12:20:07
In reply to Bipolar II Series -irritable/psychomotr agitation, posted by jrbecker on February 11, 2005, at 12:18:52
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 197-207
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.07.006
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
Irritable-hostile depression: further validation as a bipolar depressive mixed state
Franco Benazzia, b, , , and Hagop AkiskalcaE. Hecker Outpatient Psychiatry Center, Ravenna, Italy
bDepartment of Psychiatry, National Health Service, Forli, Italy
cDepartment of Psychiatry and Director, International Mood Center, University of California at San Diego, La Jolla, CA, USAReceived 10 February 2004; accepted 13 July 2004. Available online 27 September 2004.
Abstract
Background
“Hostile depression” has unofficially long been described as a depressive subtype, but since DSM-III, the affect has been made a defining characteristic of borderline personality disorder. The related affect of irritability in DSM-IV-TR subsumes various hostile nuances and is included in the stem question for mood disorders—especially for hypomanic episodes; in children, it is nonetheless a sign of depression. Then, there is the unofficial more general concept of depression with anger attacks, until recently ostensibly a “unipolar” (UP) disorder. A veritable tower of Babel indeed. In the present analyses, our aim was to extend previous research on irritable-hostile depression to more specific parameters of bipolarity and depressive mixed state (DMX).
Methods
Consecutive 348 bipolar-II (BP-II) and 254 unipolar (UP) major depressive disorder (MDD) outpatients (off psychoactive agents, including substances of abuse), were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen. Borderline personality, a confounding variable, rare in the FB setting, was excluded. Irritability was defined according to DSM-IV-TR, which includes various features of hostility and anger. Depressive mixed state (DMX) was defined as a major depressive episode (MDE) plus three or more concurrent intradepressive hypomanic symptoms, whether it occurred in BP-II or MDD.
Results
MDE with irritability was present in 59.7% (208/348) of BP-II and in 37.4% (95/254) of MDD (p=0.0000). In BP-II, MDE with, versus MDE without, irritability had significantly younger index age, higher rates of axis I comorbidity, atypical depressive features, and DMX. Upon logistic regression, we found a significant independent association between BP-II MDE with irritability and DMX. In UP, MDE with, versus without, irritability had significantly younger age and age at onset, higher rates of atypical depression, DMX, and bipolar family history. Logistic regression revealed a significant independent association between MDE with irritability and DMX. Given that we had excluded patients with borderline personality, the high prevalence of irritable-hostile depressives in this outpatient population means that hostility cannot be considered the signature of that personality. Factor analysis revealed independent “psychomotor activation” and “irritability-mental activation” factors. Odds ratios of irritability for DMX were highest in the “UP” MDD group (=12.2); for predicting DMX, irritability had the best psychometric profile of sensitivity of 66.3% and a specificity of 86.1% for this group as well.
Limitation
We did not use specific instruments to measure irritable, hostile, and angry affects.
Conclusions
These analyses show that irritable-hostile depression is distinct from agitated depression. Whether arising from a BP-II or MDD baseline, irritable-hostile depression emerges as a valid entity with strong links to external bipolar validators, such as bipolar family history. Irritable-hostile phenomenology in depression appears to be a strong clinical marker for a DMX. Irritable-hostile depression as a variant of DMX deserves the benefit of what seems to work best in practice, i.e., anticonvulsant mood stabilizers and/or atypical antipsychotics. Formal treatment studies are very much needed.
Keywords: Hostile depression; Bipolar II disorder; Atypical depression; Depressive mixed state; Major depressive disorder
1. Introduction
Hostile depressions have long been known as an unofficial nosologic subtype of depression (Paykel and Henderson, 1977 and Overall and Zisook, 1980). Recently, it has been the subject of more formal research (reviewed in Fava and Rosenbaum, 1999). Yet it is not an official subtype since DSM-III, where hostility and anger appear as the signature of borderline personality (Snyder and Pitt, 1985 and Gardner et al., 1991). The confusion does not stop here! According to DSM-IV-TR criteria (American Psychiatric Association, 2000), a major depressive episode (MDE) must have depressed mood (or loss of interest) in adults, and mood can be irritable only in children and adolescents. In the differential diagnosis section of the MDE, it is reported that there may be MDEs “with prominent irritable mood”, which can occur in bipolar and in depressive disorders (as MDE criteria are identical). In the text description of the MDE, it is stated that “many individuals report or exhibit increased irritability (e.g., persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters).” Irritability is present in the diagnostic criteria of hypomania as a criterion A.
To resolve the foregoing issues, we set off with the hypothesis that in adults, irritable-hostile depression would be linked to a bipolar depressive mixed state (DMX). In an earlier report (Benazzi, 2003a) from the present database, this hypothesis was upheld. However, due to the sample size, in that study, it was not possible to test this hypothesis in unipolar (UP) MDE patients separately from bipolar II (BP-II). In addition, it was uncertain from the results of that study whether irritable-hostile depression was distinct from agitated depression; in an earlier study, the two constructs had appeared in the same factor of “excited depression (Akiskal and Benazzi, 2004).
The hypothesis being entertained by us was actually anticipated by Kraepelin (1921, 1913 English translation by Barclay). According to him, irritability was a hypomanic (excitement) symptom, which could be present in depression (inhibition) only when it was a depressive mixed state (i.e., when symptoms of excitement and inhibition were present in the same episode). Kraepelin and Weygandt (English translation by Marneros, 2001) described a depressive mixed state, the “excited depression, which included irritability and the other excitement symptoms psychomotor agitation and more talkativeness. These ideas are also in line with the views of the Vienna School (Berner et al., 1992).
Fava et al., 1990 and Fava et al., 1993 have extensively published on depressions with anger attacks within a “unipolar” MDD framework. Only recently do they appear to have become aware that such patients might be more prevalent among bipolar patients (Perlis et al., 2004). Interestingly, Deckersbach et al. (2004) found, in bipolar-I depression, that irritability was present in 26–68%, depending on how strict were the criteria used, and that it was associated with psychomotor agitation. This study, however, had several limitations, including being based on chart review, small sample, and strict definitions of hypomanic symptoms; as a result, they could not unravel the relevance of irritable depression to mixed states. Two recent studies, using better methods, found that irritability often had a clustering of hypomanic symptoms in bipolar-I depression (Maj et al., 2003 and Perugi et al., 2001). Irritability is also seen as a core feature of depressive mixed states (Koukopoulos and Koukopoulos, 1999, Dayer et al., 2000, Akiskal et al., 2003 and Akiskal and Benazzi, 2004).
In a recent series of studies on depressive mixed states in bipolar-II (BP-II) and major depressive disorder (MDD), we found that irritability was one of the most common hypomanic symptoms present (and appearing) during depression (Akiskal and Benazzi, 2003, Benazzi, 2002, Benazzi, 2003a, Benazzi, 2003b and Benazzi, 2003c). The definition of depressive mixed states used in these studies (i.e., three or more concurrent intra-MDE hypomanic symptoms) was validated by its strong association with BP-II and bipolar family history.
The DSM-IV-TR definition of the symptom “irritability” includes anger and anger outbursts. Fava et al., 1990 and Fava et al., 1993 described, in 30–40% of MDD, a syndrome of long-lasting irritability and anger attacks, defined as spells of anger with autonomic and behavioral outbursts. Anger attacks and anger (irritability) were reported to be more common (53–62% versus 26–36%; Perlis et al., 2004 and Posternak and Zimmerman, 2002) or not (Fava and Rosenbaum, 1999) in bipolar-I depression versus MDD. Anger was found in 33% of BP-II depressions (Posternak and Zimmerman, 2002). Anger attacks responded to antidepressants in MDD (Fava and Rosenbaum, 1999 and Tedlow et al., 1999), while antidepressants were reported to induce/increase irritability/anger in bipolar depression, especially when mixed (Koukopoulos and Koukopoulos, 1999, Akiskal and Pinto, 1999, Baldessarini, 2001, Ghaemi et al., 2003, Goldberg and Truman, 2003 and Bottlender et al., 2004).
The aim of the present analyses was to shed light on the nosologic status of hostile-irritable depressions, by comparing MDE with and without irritability in BP-II and MDD samples, and by examining the relationship between MDE and irritability with bipolar validators in an MDD sample. To the best of our knowledge, this is the first study including BP-II as a comparison sample versus UP MDD.
2. Methods
The present analyses in the Ravenna–San Diego Collaborative Study were conducted on the extensive and systematically collected database of FB. The specific design of the present analyses on hostile-irritable depression were designed by HSA. We highlight herein the essential features of our overall methodology, which are generic to our collaborative studies. For full documentation, we refer the reader to previous reports (Akiskal and Benazzi, 2003, Benazzi and Akiskal, 2003a and Benazzi, 2003d). We then enlarge upon those features in our methods most relevant to defining irritable-hostile depressions.
2.1. Study setting
An outpatient psychiatry private practice, which is more representative of mood disorders usually seen in clinical practice in Italy (apart from bipolar-I).
2.2. Interviewer
A senior clinical (20 years in practice) and mood disorder research psychiatrist.
2.3. Patient population
Consecutive 348 BP-II and 254 MDD outpatients, presenting voluntarily for major depressive episode (MDE) treatment (off psychopharmacotherapy and without substance-related problems), were included in the last 5 years. Borderline personality and clinically significant general medical illnesses and cognitive disorders, which too can confound the phenomenology of labile-irritable depressions, were also excluded.
2.4. Assessment instruments
During the index assessment visit, the following instruments were used: (1) the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (First et al., 1997; SCID-CV), as modified by Benazzi and Akiskal (2003a) to improve detection of BP-II; the question on racing thoughts was supplemented by the Koukopoulos and Koukopoulos' definition (1999) of crowded thoughts (i.e., mind continuously full of nonstop thoughts); (2) the Global Assessment of Functioning scale (GAF, in the SCID-CV) for index MDE severity; (3) the Hypomania Interview Guide (HIGH; Williams et al., 1994) to assess intra-MDE hypomanic symptoms; (4) the structured Family History Screen (Weissman et al., 2000) for assessing bipolar disorders family history in probands' first-degree relatives. Often, family members or close friends supplemented clinical information during the interview, increasing validity of BP-II diagnosis and family history (Akiskal et al., 2000).
2.5. Interview procedures
Systematic interviews about history of hypomanic episodes were always conducted soon after MDE diagnosis before the assessment of study variables, thereby avoiding a possible bias related to knowledge of bipolar signs (Ghaemi et al., 2002). The SCID-CV is partly semistructured and based on clinical evaluation, thus wording of the sentences can be changed to improve and to check the understanding by the interviewed. This is an important advantage versus fully structured interviews, because it reduces the false negative BP-II and mood disorders (Dunner and Tay, 1993, Brugha et al., 2001, Simpson et al., 2002, Benazzi, 2003e and Benazzi, 2004). The skip out instruction of the stem question on history of mood changes was not followed, in order to assess all past hypomanic symptoms, especially overactivity (increased goal-directed activity), this procedure being in line with previous reports (Dunner and Tay, 1993, Akiskal et al., 2001, Simpson et al., 2002, Angst et al., 2003, Benazzi and Akiskal, 2003a, Benazzi and Akiskal, 2003b and Benazzi, 2003f).
2.6. Diagnostic definitions
Irritability was defined according to DSM-IV-TR. In the SCID-CV for DSM-IV, irritability is defined only for mania, by the question “you were so irritable that you found yourself shouting at people, or starting fights or arguments”. There is no similar structured question for irritability in hypomania, but the features must be similar, apart from severity. DSM-IV-TR text description of irritability is “easily annoyed and provoked to anger”, “persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters”. The anger attacks described by Fava et al., 1990 and Fava et al., 1993 in MDD are included by DSM-IV-TR in the definition of irritability. In the present study, irritability was scored present if at least one of the above features was positive. Depressive mixed state was defined as an MDE plus three or more concurrent intra-MDE hypomanic symptoms (DMX3, according to Akiskal and Benazzi, 2003). Hypomanic symptoms had to appear during the MDE (i.e., a hypomanic symptom-free interval of at least 1 month before the MDE was required), to last at least 1 week and to be present at the time of the interview (to increase reliability).
2.7. Statistics
Univariate and multivariate logistic regression were used to study associations and to control for confounding. The two-sample test of proportion was used to compare proportions. Principal component factor analysis (varimax rotation, eigenvalue>1, item loading>0.40) was used to study the relationships among the intra-MDE hypomanic symptoms (those present in more than 10%, to reduce the “noise” effect of low-frequency symptoms), following previous factor analysis studies of hypomania (Hantouche et al., 2003, Benazzi and Akiskal, 2003b, Cassidy et al., 1998, Dilsaver et al., 1999 and Bauer et al., 1991). ROC analysis was used to study predictive power. STATA Statistical Software, Release 7, was used (Stata Corporation, College Station, TX, USA, 2001). P values were two-tailed, and alpha level was set at 0.05, given the exploratory nature of the study.
Comparisons were made between MDE with and without irritability, independently, in both the BP-II and MDD samples, on clinical and family history variables. As diagnostic and bipolar validators were used age at onset, number of MDE recurrences, frequency of atypical depressions and depressive mixed states, and bipolar (type I and type II) family history, following previous reports (Kraepelin, 1921, Robins and Guze, 1970, Kendler, 1990, McMahon et al., 1994, Ghaemi et al., 2002, Akiskal, 2003, Angst et al., 2003, Akiskal and Benazzi, 2003, Sato et al., 2003, Coryell, 1999, Dunner, 2003 and Goodwin and Jamison, 1990).
3. Results
3.1. Prevalence
MDE with irritability was present in 59.7% (208/348) of BP-II, and 37.4% (95/254) of MDD (z=5.4, p=0.0000).
3.2. Comparisons in the BP-II sample
Comparisons between MDE with and without irritability are presented in Table 1. MDE with irritability had significantly lower index age, more axis I comorbidity, and more atypical depressions. Among the intra-MDE hypomanic symptoms, it had significantly more depressive mixed states and more psychomotor agitation. Among the MDE symptoms, it had significantly more weight gain, increased eating, and more leaden paralysis.
Forward stepwise logistic regression of MDE with irritability (dependent variable) versus the variables found significantly different in the pairwise comparisons of Table 1, found significant independent associations with DMX (coefficient=0.4, 95% CI=0.3–0.5, p=0.000), increased eating (coefficient=0.1, 95% CI=0.0–0.2, p=0.024), and psychomotor agitation (coefficient=−0.1, 95% CI=−0.2–0.0, p=0.029). The odds ratio of irritability for DMX was 7.3.
Factor analysis (Table 2) found two factors: a motor activation factor 1 and irritability-mental activation factor 2 (risky activities present only in 21.6%).
Sensitivity, specificity, and area under the ROC curve of irritability for predicting depressive mixed state were sensitivity=80.2%, specificity=64.2%, ROC area=0.72.
3.3. Comparisons in the MDD sample
Comparisons between MDE with and without irritability are presented in Table 3. MDE with irritability had significantly lower index age, lower age at onset, more atypical depressions, and more bipolar family history. Among the intra-MDE hypomanic symptoms, it had significantly more depressive mixed states, more distractibility, racing/crowded thoughts, psychomotor agitation, and risky activities. Among the MDE symptoms, it had significantly more hypersomnia, psychomotor agitation, leaden paralysis, and difficulty concentrating.
Forward stepwise logistic regression of MDE with irritability (dependent variable) versus the variables found significantly different in the pairwise comparisons of Table 3, found significant independent associations with DMX (coefficient=0.7, 95% CI=0.6–0.9, p=0.000), psychomotor agitation (coefficient=−0.2, 95% CI=−0.4–0.1, p=0.000), racing/crowded thoughts (coefficient=−0.1, 95% CI=−0.3–0.0, p=0.005), and age (coefficient=−0.0, 95% CI=−0.0–0.0, p=0.006). The odds ratio of irritability for DMX was 13.8.
Factor analysis (Table 4) found two factors: a motor activation factor 1 and an irritability-mental activation factor 2 (risky activities present only in 14.7%).
Sensitivity, specificity, and area under the ROC curve of irritability for predicting depressive mixed state were sensitivity=66.3%, specificity=86.1%, ROC area=0.76.
3.4. MDE with irritability in BP-II and MDD
Comparisons on bipolar validators between BP-II and MDD major depressive episode with irritability are presented in Table 5. There were significant differences on all validators.
4. Discussion
In the present analyses, we have observed a great many strong associations linking irritable-hostile depressions to various parameters of bipolarity. Given that the interview was conducted by one psychiatrist (FB), unintended biases cannot be entirely excluded. However, systematic biases are unlikely, because all patients underwent rigorous diagnostic work-up with the use of reliable and validated instruments. Finally, as the designs of these analyses were enunciated by HA, FB could not have been aware of the potential use of this database in the present manner. The main limitation of our study is that we did not use a validated instrument specifically geared to measure hostility and anger attacks (Fava et al., 1991).
Frequency of MDE with irritability in this outpatient BP-II and MDD sample was high (ranging from 37% in MDD to 60% in BP-II), suggesting that irritability is a common symptom of MDE. It was however significantly more common in BP-II MDE. The finding is in line with the less conservative frequency of irritability in bipolar-I depression found by Deckersbach et al. (2004), and with the frequency of anger attacks (included in the DSM-IV-TR definition of irritability) in bipolar-I depression found by Perlis et al. (2004). Factor analysis, done independently in the BP-II and in the MDD samples, supported the subtyping MDE with and without irritability.
In the BP-II sample, MDE with irritability was strongly associated with many intra-MDE hypomanic symptoms (depressive mixed state), a finding buttressed by multivariate logistic regression. A higher rate of psychomotor agitation in MDE with irritability was found also in a bipolar-I sample by Deckersbach et al. (2004). Atypical features were also more common in MDE with irritability, a finding which may account for the association found between atypical depression and hypomanic symptoms (Benazzi, 2001).
Our results indicate that, in BP-II, MDE with irritability is highly likely to have several concurrent hypomanic symptoms (OR=7.3), in brief that irritability may be a marker of depressive mixed state. ROC analysis supported this finding, showing an area under the ROC curve of 0.72 (meaning adequate predictive power, with high sensitivity, and relatively high specificity).
In the UP sample, MDE with irritability had significant associations with bipolar validators, such as young age at onset, atypical depression, depressive mixed state, and, most importantly, bipolar family history. Also in the UP sample, MDE with irritability was significantly highly likely to have many concurrent hypomanic symptoms (OR=12.2), such as distractibility, racing/crowded thoughts, psychomotor agitation, and risky activities, again suggesting that it may serve as a marker of depressive mixed state in MDD. This association was supported by multivariate logistic regression. ROC analysis showed that the area under the ROC curve was 0.76 (meaning adequate predictive power, with relatively high sensitivity, and high specificity). Overall, these findings suggest that MDE with irritability in MDD may be related to the bipolar spectrum (as described by Akiskal and Pinto, 1999), and that it may be even a more robust marker of bipolarity in MDD.
That both BP-II and MDD with irritable cross-sectional symptoms have underlying bipolar familial diathesis is of great significance in classification and genetics. That depressions with anger attacks have more offspring with delinquency and aggressive behavior (Alpert et al., 2003) could reflect the passing on of “mood genes” of bipolar nature from one generation to another.
The analyses done independently in the two samples of BP-II and MDD showed that MDE with irritability had several important common features, such as the association with depressive mixed state. This finding represents further strong independent association, as shown by multivariate logistic regression. These results suggest that MDE with irritability may be associated with many concurrent hypomanic symptoms independently of the BP-II and MDD distinction, in brief that irritability by itself is likely to be associated with a clustering of hypomanic symptoms.
Among the atypical symptoms significantly more common in MDE with irritability (in the MDD sample) there was hypersomnia. In classic textbooks (Goodwin and Jamison, 1990 and Akiskal, 2002), in Hecker's description of “cyclothymia” (corresponding to DSM-IV-TR BP-II; 1898, English translation by Koukopoulos, 2003), and in more recent studies (Mitchell et al., 2001), hypersomnia was reported to be a typical feature distinguishing bipolar depression versus MDD. This is another finding supporting the bipolar nature of MDE with irritability in MDD.
MDE with irritability in BP-II versus MDD had significant differences on bipolar validators. A finding suggesting that MDE with irritability may lie along a continuum linking MDD and BP-II, thereby bridging the gap created by DSM-IV-TR between bipolar and depressive disorders.
Kraepelin described irritability only in hypomania (i.e., as an excitement symptom), which could be present in depression only when depression was mixed (i.e., it had concurrent inhibition and excitement symptoms), like in the depressive mixed state he termed “excited depression”. Both irritability and psychomotor excitement were core features of this depressive subtype. However, the present analyses suggest that agitated depression and irritable depression might be distinct. Our findings further suggest that 60% of BP-II MDE (a similar percentage was found by other studies in bipolar-I MDE) may have concurrent irritability, running against the DSM-IV-TR criteria for MDE, which are the same in bipolar and depressive disorders and do not include irritability in adults. The results of our studies in both BP-II and UP suggest that irritability may be a symptom distinguishing bipolar depression from MDD. Curiously, a recent study (Posternak and Zimmerman, 2002) found anger limited in mood disorders to BP-I and MDD; however, given that very few patients in their sample of 1300 outpatients had BP-II diagnosis, one can conclude that these authors seem to have a systematic bias against this diagnosis.
Despite the DSM-IV-TR description of hostility as the signature affect in borderline personality, there is no evidence that this affect is unique to this particular personality disorder. At any rate, such anger in borderline personality responds significantly to fluoxetine (Salzman et al., 1995), divalproex (Frankenburg and Zanarini, 2002), and lamotrigine (Pinto and Akiskal, 1998). Such pharmacologic response suggests that the anger in these patients has affect disorder origins. Finally, the fact that in the present study we demonstrated a high prevalence of irritability in an outpatients sample from which we had excluded borderline personality disorder indicates that hostile affect should not be viewed as a pathognomonic indication of borderline personality disorder. Our patients instead were suffering from depressive mixed states with bipolar substrate—an entity to be yet recognized by the official classification of both the American (DSM-IV-TR, 2000) and International (ICD-10) classifications.
Whereas validating MDE with irritability as a bipolar spectrum disorder needs further studies, from what we know already, it seems to have important diagnostic and therapeutic utility. Actually, thioridazine is FDA indicated for depression with hostile features (Schatzberg and Nemeroff, 2004, p. 432). More recently, in MDD, at least one controlled trial has shown that anger attacks in bipolar patients respond well to a combination of an SSRI added to a mood stabilizer (Mammen et al., 2004). Further studies are needed to determine the optimal short-term and long-term treatment of hostile depressions. Antidepressants were effective in MDE with anger attacks (included in DSM-IV-TR definition of irritability) in the short term (Fava et al., 1993). Instead, in bipolar depression, many open reports showed that antidepressants can induce hypomanic symptoms (Akiskal et al., 1977, Goodwin and Jamison, 1990, Altshuler et al., 1995, Baldessarini, 2001, Ghaemi et al., 2003 and Goldberg and Truman, 2003), and bipolar-I mixed depression was shown to have a higher risk of switching with antidepressants versus nonmixed bipolar-I depression (Bottlender et al., 2004).
5. Conclusion
These findings suggest that depression with irritability is associated with many intradepressive hypomanic symptoms (depressive mixed state) and with external bipolar validators. It is noteworthy that this was so both in BP-II and MDD, suggesting that MDD with irritability may lie along a continuum linking BP-II and nonirritable MDD. The finding of a strong association between irritable-hostile depression and numerous noneuphoric concurrent hypomanic symptoms suggests that its treatment may first (or concurrently) require mood-stabilizing agents and not antidepressant monotherapy, in order to reduce a possible worsening of irritability (and of the other often present intradepressive hypomanic symptoms). Atypical antipsychotics would also be relevant. Controlled trials are required to test the possible treatment impact of subtyping depression on the basis of irritability.
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