The phenomenology of recurrent brief depression with and without hypomanic features

Journal of Affective Disorders 112 (2009) 151 – 164 www.elsevier.com/locate/jad

Research report

The phenomenology of recurrent brief depression with and without hypomanic features H. Lövdahl a,b,c,⁎, S. Andersson b , T. Hynnekleiv b , U.F. Malt a,b b

a Institute of Psychiatry, University of Oslo, Norway Department of Neuropsychiatry and Psychosomatic Medicine, Division of Clinical Neurosciences, Rikshospitalet University Hospital, Oslo, Norway c Department of Clinical Psychiatry, Sørlandet Hospital, P.O. box 605, N-4809, Arendal, Norway

Received 13 November 2007; received in revised form 21 April 2008; accepted 21 April 2008 Available online 9 June 2008

Abstract Background: The nosologic status of recurrent brief depression (RBD) is debated. We studied the phenomenology of RBD in a clinical sample of outpatients. Methods: Forty patients (mean age 33; 73% females) and 21 age- and gender-matched mentally healthy controls were examined (clinical interview, M.I.N.I. neuropsychiatric interview, MADRS, Stanley Foundation Network Entry Questionnaire). Exclusion criteria were bipolar I or II disorders, a history of psychosis, concurrent major depressive episode, organic brain or personality disorders (clusters A and B). Results: The mean age of onset of RBD was 20 years with a mean of 14 episodes/year with brief (mean 3 days) severe depressive episodes. Nineteen (47%) reported additional short episodes of brief hypomania (N 1 day duration; RBD-H) of which nine (23%) never had experienced a major depression. Twenty-one (53%) patients reported RBD only (RBD-O) with or without (n = 12) past history of major depression or dysthymia. During the last depressive episode, 76% of the RBD-O and 90% of the RBD-H patients had a melancholic depression. Seventy-one % of the RBD-O and 79% of the RBD-H reported at least two out of three atypical symptoms. Nineteen (48%) of the patients reported anger attacks and panic disorder, the latter being more prevalent in the RBD-H subgroup (68% versus 29%, p = 0.012). Limitations: Cross-sectional study of self-referrals or patients referred by primary care physicians or psychiatrists. Conclusions: The study supports the validity of RBD as a disorder separate from bipolar II, cyclothymia and recurrent major depression. A brief episode of hypomanic symptoms is a severity marker of RBD. © 2008 Elsevier B.V. All rights reserved. Keywords: Recurrent brief depression; Bipolar disorder; Chronic depression; Atypical depression; Melancholia

1. Introduction

⁎ Corresponding author. Department of Clinical Psychiatry, Sørlandet Hospital, P.O. box 605, N-4809, Arendal, Norway. E-mail address: [email protected] (H. Lövdahl). 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.04.007

Disorders characterized by periods with depressive episodes lasting hours to days have been described since 1852 and have been labelled “periodic melancholia”, “intermittent depressive disorder” or “very brief depression” (Pezawas et al., 2005). Nevertheless, the third

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version of the Diagnostic and Statistical Manual of mental disorders which relied heavily on findings from studies conducted in psychiatric in- and outpatient settings, required at least 14 days duration for a diagnosis of depression. No diagnostic category allocated a depressive episode of shorter duration. Intermittent depressive disorder, included in the Research Diagnostic Criteria was considered to identify minor versions of major depression (“minor depression”) and not included in the DSM-III (Baldwin, 2003). However, the prospective Zürich epidemiological study conducted by Jules Angst and co-workers (Angst and Dobler-Mikola, 1985) observed a subtype of mood disorders characterized by recurrent but brief (mostly days) major depressive episodes corresponding to earlier clinical reports. Although of short duration, the depressive episodes had similar severity and functional consequences that were observed in patients with major depressive disorder. Angst and co-workers observed that recurrent brief depression (RBD) might develop into major depression and vice versa in about the same percentage of cases. A significant subgroup remained stable RBD patients over time, however. RBD was associated with considerable suicidality and treatmentseeking and was co-morbid with anxiety disorders (Angst and Hochstrasser, 1994). Those observations corresponded to clinical descriptions by Paskind (1929) and Buzzard et al. (1930) (cit. (Baldwin, 2003)). Further support for the clinical importance of RBD was provided by Montgomery (Montgomery et al., 1990). In a prospective follow up study of patients with a history of repeated suicidal behaviour almost all suffered recurrent episodes of brief depression, mainly of moderate to severe intensity (Montgomery et al., 1990). Two thirds of the episodes lasted between 2 and 4 days. The recurrences were frequent, irregular, and apparently unpredictable. The episodes were distinguishable from major depression only by their short duration. Jules Angst coined the concept “recurrent brief depression” (RBD) for this type of mood disorder (Angst and Dobler-Mikola, 1985; Angst, 1990). RBD was defined as intermittent depressive episodes, in women not related to menstrual cycles, occurring at least once a month that fulfilled the diagnostic criteria for major depressive episodes apart from duration, which was stipulated to be less than 14 days. RBD was included in the 10th classification of mental and behavioural disorders (ICD-10 F38.1) published by the World Health Organization in 1992 (WHO, 1992, 1993). Less frequent episodes of brief depressions were labelled infrequent brief depression and not included in ICD-10.

A number of studies addressing the prevalence of RBD have used the Zürich research criteria adopted in the ICD-10 (WHO, 1993). In four different communitybased cross-sectional studies the lifetime prevalence was estimated at 2.6 to 10.0%, and the one-year prevalence at 5.0–8.2% (Altamura et al., 1995; Carta et al., 2003; Maier et al., 1994a,b; Pezawas et al., 2001). The World Health Organization project on “Psychological problems in general health care”, which was based on primary care samples, reported a one-year prevalence of 3.7–9.9% (Maier et al., 1994a; Weiller et al., 1994). However none of these studies differentiate between RBD with and without a history of other mood disorders (e.g. major depression). The prevalence of RBD in psychiatric settings is not known, but is claimed by clinicians to be lower than the above figures. This may be because greater attention is paid to co-morbid disorders. Another explanation may be the misdiagnosis of RBD as dysthymia, premenstrual dysphoric syndrome, or a personality disorder. However, the low prevalence may also simply reflect lack of referral of RBD patients to psychiatric services due to the short duration of the depressive episodes. The nosological status of RBD has remained controversial, however. In the DSM-IV field trial 91% of the subjects met the criteria for current or lifetime major depression or dysthymia compared to 2–3% of RBD only (Keller et al., 1995a). Despite these findings, the authors concluded that additional categories for milder forms of depression were not needed, but provisional criteria were provided. However, in contrast to the ICD10, the DSM-IV provisional criteria limit RBD to subjects who have never experienced a major depressive or hypomanic episode. This requires the clinician or researcher to decide whether a previous depressive episode fulfilled the symptomatic criteria for a major depressive episode or was merely a sub-threshold episode. The issue is further complicated by the observation that a significant subgroup of patients may have very brief hypomanic episodes (Angst et al., 2003b), suggesting that RBD perhaps may belong to the bipolar spectrum. Such observations also stress the importance of differentiating RBD from cyclothymia. 1.1. Objectives and hypotheses Considering the prevalence rates and severity of RBD reported, and the conflicting views on the nosological status of the disorder, it is surprising that so few studies have addressed the phenomenology of RBD in clinical samples (Baldwin, 2003). The present paper is part of a comprehensive study of the phenomenology

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and neurobiology of RBD. The objective of this paper is to provide phenomenological data on RBD defined according to the ICD-10 research criteria. We included a healthy comparison group in the study in order to control for baseline phenomena occurring in the general population. On the basis of epidemiological findings (e.g. Angst and Gamma, 2002; Angst et al., 2003b) we hypothesized two subgroups in our clinical sample, one group with symptoms suggesting RBD only (RBD-O) with or without a history of major depressive episode, and one group of RBD patients with a history of episodes of hypomanic symptoms inbetween the brief depressive episodes (RBD-H). With reference to studies of phenomenological differences between non-bipolar and bipolar mood disorders (MacKinnon et al., 2002; Perlis et al., 2005, 2006); we hypothesized that there would be significant differences in the profile of depressive symptomatology between RBD-H and RBD-O, with the first showing more anxiety disorders and more atypical and melancholic symptomatology. 2. Methods 2.1. Inclusion and exclusion criteria Given the current state of knowledge, we found it premature to restrict clinical studies of RBD to those that fulfill the DSM-IV provisional criteria only. Thus the ICD-10 RBD research criteria were used for including patients. Patients with a current diagnosis of major depressive episode, dysthymia or a history of severe mental disorder with psychosis (e.g. schizophrenia, or schizoaffective disorders) were excluded. Brief severe episodes of major depression or hypomania are very frequent in bipolar I and II disorders (Bauer et al., 2007). Thus patients with a bipolar I or II disorder were excluded as well. Since subtle organic brain disorders occur more often among older persons, we limited our sample to subjects between 18 and 45 years. Recent research casts doubt on the current diagnostic criteria for hypomania (Wicki and Angst, 1991; Angst et al., 2003a; Benazzi, 2001, 2007). There is no consistent empirical evidence in either clinical or neurobiological terms to support the view that patients with recurrent brief episodes (e.g. 1–3 days) of hypomania are significantly different from those with hypomanic episodes of 4 days, the cut-off point for hypomania in the DSM-IV and ICD-10. Retrospectively, it is also hard to determine the exact duration of a brief hypomanic episode, e.g. 3 or 4 days. We therefore did not use a duration of less than 4 days as an exclusion criterion.

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However, it turned out to be extremely difficult to decide the clinical validity of symptoms suggesting hypomanic features with a duration of less than 1 day (e.g. personality or temperament, mood swings in unstable personality disorders and ultra-short reactive mood swings from other causes). Thus we required a duration of at least three hypomanic symptoms for at least 1 day in order to consider the episode to be hypomanic. Brief episodes of severe depression are fairly common in personality disorders, and the separation from RBD is debated. Only a few studies have addressed the neurobiological similarities and differences between RBD and personality disorders (i.e. unstable personality disorder (De la Fuente et al., 1992, 2002, 2004)). Therefore the presence of DSM-IV axis II cluster A or B disorders was an exclusion criterion in our study. Exclusion was based on responses to the personality disorder questionnaire (PDQ) version 4 (Hyler et al., 1992). A PDQ-4 total score of ≥ 25 is considered to reflect the presence of a personality disorder (Davison et al., 2001) and low PDQ-4 scores have been found to be a valid predictor of the absence of severe personality disorders (Guthrie and Mobley, 1994). If PDQ scores indicated a cluster A and/or B personality disorder, the patient was excluded from the study. It is often hard to differentiate cluster C personality disorders from axis I anxiety disorders. Cluster C personality disorders are also less well validated as being separate from chronic anxiety disorders than cluster A and B disorders. Furthermore, a high co-occurrence of features suggesting anxiety and cluster C disorders has been reported in epidemiological studies of RBD (Angst and Hochstrasser, 1994). In the light of the limited knowledge of the phenomenology of RBD we therefore did not exclude cluster C personality disorders. Other exclusion criteria were brief depressive episodes with a fixed relation to menstrual cycle (as specified in the ICD-10 research criteria). Daily mood rating dynamics have shown that in contrast to RBD, brief depressive episodes in women with premenstrual dysphoric disorder are more regular and less staccato (Pincus et al., 2008). We also excluded patients with brain injury since they may suffer from frequent ups and downs, that sometimes mimic RBD (e.g. Muller et al., 2006). 2.2. Recruitment procedures and sample We informed personnel working in the psychiatric health services and the public about RBD and about the study. We also presented our research in newspapers, and in periodicals. Thirty-five patients diagnosed with

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RBD were referred to the project by either a psychiatrist or a general practitioner. All these patients were given a full examination. Two of the referred patients did not qualify for the diagnosis of RBD. One was diagnosed with unstable personality disorder (borderline) only, while the other had depressive episodes with a fixed relation to the menstrual cycle. Two patients were excluded because their depressive episodes lasted less than 1 day. Ten were excluded due to concurrent co-morbid psychiatric disorders listed among the exclusion criteria: concurrent major depressive disorder (n = 1); bipolar I disorder (n = 2); delusional disorder (paranoid psychosis) (n = 1); paranoid personality disorder (n = 2); unstable personality disorder (n = 1); schizoid personality disorder (n = 2) and hypoxic brain damage (n = 1). Of the remaining 21 referred patients, eight failed to comply with the full protocol and were excluded, providing a full data set of 13 referred patients. A total of 89 individuals were self-referred. In a preclinical screening procedure (telephone, mail) 52 were excluded, leaving 37 who underwent a full clinical examination. Seven of the 37 self-referred individuals were excluded: bipolar I disorder (n = 1); drug induced psychosis (n = 1); major depressive disorder with an episode length of three weeks (n = 1); unstable (borderline) (n = 1); paranoid (n = 2) and schizotypal (n = 1) personality disorders. Of the remaining 30 self-referred individuals, three had to be excluded due to failure to comply with the full protocol, providing a full data set of 27 patients. 2.3. Healthy controls Twenty-one mentally healthy controls matched with the RBD-O patients for age, gender, handedness, and length of education were recruited through randomized selection from the general population register of Oslo (population: approximately half a million). Prior to a clinical examination they had been screened for mental problems and epilepsy through a self-report questionnaire with the following questions: 1. Do you take any medication of the following kinds more than once a week: anxiolytics, sedatives, antidepressants, neuroleptics, anticonvulsants? 2. Have you ever been on sickleave due to mental problems? 3. Have you ever been treated for mental problems? 4. Have you ever been hospitalized for mental problems? 5. Have you ever deliberately hurt yourself? 6. Have you ever tried to end your life? 7. Do you yourself, or others, think that you have epilepsy or mental problems? Subjects who responded negatively to all the above screening questions underwent a full examination simi-

lar to that of the included RBD patients. None of the controls revealed symptoms or signs suggesting mental disorders. However, one of the controls most likely abused alcohol despite no clues for (other) mental disorder. 2.4. Psychiatric assessment The clinical examinations were carried out by the first author, who is a qualified psychiatrist. Demographic, amnesic, and supplementary information was obtained by means of an abbreviated version of the Stanley Foundation Network Entry Questionnaire (aNEQ) formerly known as the Patient Questionnaire, and the Clinician Questionnaire (Suppes et al., 2001). Axis I diagnoses were determined by means of the M.I.N.I. neuropsychiatric diagnostic interview, DSM-IV criteria version 5.0 (Sheehan et al., 1998). This was applied as a semistructured interview. When probing for hypomanic symptoms all questions were posted disregarding response to the initial probing (skip–no skip) questions. The duration of hypomanic symptoms was elicited by direct questioning (Angst et al., 2003b), supplemented by the Hypomania Checklist (Angst et al., 2005). The reliability and validity of the diagnostic process were checked by randomly selecting 10 patients (25%) for a second independent interview by the senior psychiatrist (UFM) who was blinded to the original diagnosis. In one case, the second interview elicited information suggesting the occurrence of a very short hypomanic episode in the past that had not been revealed in the first interview. Depressive symptoms at the time of interview were assessed by the Montgomery–Asberg Rating Scale (MADRS) (Montgomery and Asberg, 1979; Uher et al., 2008; Zimmerman et al., 2004). Twenty four (60%) of the subjects were euthymic at the time of examination (scores of 0–11). Twelve (30%) were in an intermediate state with a score between 12 and 19, while four (10%) had a score higher than 19 suggesting clinically significant depressive symptoms. Due to the additional focus on neurobiology of RBD, all included patients were tapered off medication before the assessments. 2.5. Statistics SPSS statistical package version 14 was used. Categorical variables were analysed by means of the chisquare test for independence. When an expected cellvalue was b 5, the two-tailed Fisher's exact test was used. Continuous variables were analysed by means of the Mann–Whitney U test.

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Fig. 1. Self-rated mood level during 3 months obtained from a 23 year old male with recurrent brief depressive episodes without intermingled brief episodes with hypomanic symptoms of at least one day duration. A score b4 represents depressed mood while 4–6 represents variation in normal mood.

Fig. 2. Self-rated mood level during 3 months obtained from a 22 year old female with recurrent brief depressive episodes with additional brief episodes of hypomanic symptoms of at least one day duration. A score b4 represents depressed mood while >6 denotes hypomanic symptoms.

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2.6. Ethical aspects The protocol was reviewed by the regional committee for medical research ethics and by a committee under the auspices of the Data Inspectorate in accordance with the Personal Health Data Filing System Act. All participants gave informed written consent prior to examination. The study was carried out in accordance with the Helsinki and Madrid Declarations. 3. Results Of the 40 patients included in the study, 29 (73%) were females. The mean age was 33.4 years (SD = 7.4) for women, and 34.1 years (SD = 7.5) for men. The mean length of education was 14.5 years (SD=2.3) for women, and 13.6 years (SD = 2.5) for men. Based on the psychiatric history, the 40 RBD patients were sub-classified into two main groups: 21 patients who denied hypomanic symptoms in the M.I. N.I. neuropsychiatric interview (RBD-O), and 19 patients who reported at least three hypomanic symptoms (DSM-IV criteria) for at least 1 day (RBD-H). In the RBD-O group five patients answered positive to one or two supplemental questions on hypomania without reaching the threshold of at least

three positive symptoms. The other 16 subjects in the RBD-O group responded negative on all hypomania items. For illustrative purposes, two untreated RBD patients: one female with and one male without short hypomanic episodes filled in a life-chart consisting of a 1–9 point self-report scale, on a daily basis over a three-month period. A mood entry b 4 was considered to be depression, and N 6 to be hypomania (Figs. 1 and 2). The sociodemographic and clinical characteristics of the subjects are listed in Table 1. No statistically significant differences were found between the two subgroups, although there was a tendency for shorter intervals free of symptoms among the RBD-H patients. Of the 21 RBD-O patients, twelve had never experienced any major depressive episodes while nine had experienced such an episode. Of the 19 RBD-H patients, nine had no history of major depressive episodes; seven of these had had short hypomanic episodes 1–3 days, and two had had previous hypomanic symptoms of at least 4 days duration. Another ten RBD-H patients had a past history of major depressive episodes; seven with short hypomanic episodes 1–3 days. Three subjects reported a duration of hypomanic symptoms of at least 3 days, but possibly longer. Due to the uncertainty about the length, we decided to keep those subjects in the

Table 1 Sociodemographic and clinical characteristics of patients with recurrent brief depression (RBD) with (RBD-H) or without (RBD-O) additional episodes of brief hypomanic episodes (see text) All RBD patients

RBD-O (RBD only)

RBD-H a (RBD + hypomania)

Healthy controls

RBD-O vs. RBD-H

n = 40

n = 21

n = 19

n = 21

p

Sociodemographic data Men/women Mean age at inclusion in years Mean length of education in years Number living alone

11/29 33.60 (7.34) 14.20 (2.37) 19 (48%)

6/15 33.10 (7.05) 14.33 (2.52) 11 (52%)

5/14 34.16 (7.80) 14.05 (2.25) 8 (42%)

6/15 34.05 (6.97) 15.05 (2.31) 6 (29%)

0.873 b 0.597 c 0.642 c 0.516 b

Clinical characteristics Family history of depression Mean age at symptom onset Mean number of years with RBD symptoms Mean length of depressive episodes in days Mean length of symptom-free intervals in days Mean number of depressive symptoms Mean number of melancholic symptoms Mean number of atypical depressive symptoms Seasonality Prodromal symptoms Precipitated by life-events Precipitated by medication

23 (58%) 20.05 (6.39) 13.55 (7.13) 3.20 (2.17) 15.90 (7.78) 7.05 (1.01) 3.45 (1.04) 2.03 (0.86) 6 (15%) 15 (38%) 6 (15%) 0

11 (52%) 20.05 (7.48) 13.00 (7.20) 2.90 (1.67) 18.19 (6.51) 7.00 (1.23) 3.33 (1.07) 2.00 (0.89) 5 (24%) 9 (43%) 2 (10%) 0

12 (63%) 20.05 (5.13) 14.16 (7.21) 3.53 (2.63) 13.37 (8.43) 7.11 (0.74) 3.58 (1.02) 2.05 (0.85) 1 (5%) 6 (32%) 4 (21%) 0

7 (33%) – – – – 0 0 0 – – – –

a b c

0.721

Episodes of hypomanic symptoms without regard to duration. Pearson chi-square. Mann–Whitney U.

0.407 c 0.606 c 0.428 c 0.057 c 0.874 c 0.300 c 0.851 c 0.101 b 0.462 b 0.308 b –

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RBD-H group and not exclude them as being bipolar II disorders. Table 2 shows the depressive symptomatology during the most recent episode of RBD. More than 90% of the RBD patients had experienced diminished interest or pleasure; subjective retardation; diminished ability to concentrate, fatigue or loss of energy, lack of emotional reactivity and leaden paralysis during a brief depressive episode. The prevalence of different types of depressive, melancholic, and atypical symptoms did not differ significantly between the two RBD groups. During the last depressive episode 16 (76%) of the RBD-O patients fulfilled the criteria for the melancho-

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lia specifier (DSM-IV) compared with 17 (90%) of the RBD-H patients (M.I.N.I.) (p = 0.412). There was no statistically significant difference between the RBD-O (71%) and RBD-H (79%) patients with regard to the presence of at least two of the three atypical symptoms hypersomnia, increased appetite and leaden paralysis. Nor was there any significant difference between the two groups regarding the presence of combined hypersomnia and increased appetite (33% versus 32%). Eleven (52%) of the RBD-O patients and 13 (68%) of the RBD-H patients fulfilled the criteria for both the melancholia specifier as well as two out of three atypical symptoms. Nineteen (48%) of the RBD patients had

Table 2 Clinical features during last depressive episode in patients with recurrent brief depression (RBD) with (RBD-H) or without (RBD-O) additional episodes of brief hypomanic episodes (see text) All RBD patients

RBD-O (pure RBD)

Depressive symptoms (last brief depressive episode) Depressed mood Diminished interest or pleasure Loss of appetite Insomnia Subjective retardation Fatigue or loss of energy Feelings of worthlessness or excessive guilt Diminished ability to concentrate Recurrent suicidal ideation etc Lack of emotional reactivity Depressed mood different from grief Depression worse in the morning Early morning awakening

40 (100%) 40 (100%) 17 (43%) 11 (28%) 40 (100%) 38 (95%) 24 (60%) 39 (98%) 24 (60%) 37 (93%) 37 (93%) 11 (28%) 9 (23%)

21 (100%) 21 (100%) 9 (43%) 6 (29%) 21 (100%) 20 (95%) 11 (52%) 20 (95%) 13 (62%) 20 (95%) 20 (95%) 5 24%) 5 (24%)

19 19 8 5 19 18 13 19 11 17 17 6 4

Atypical features (last episode) Increased appetite Hypersomnia Leaden paralysis

17 (43%) 26 (65%) 38 (95%)

8 (38%) 14 (67%) 20 (95%)

9 (47%) 12 (63%) 18 (95%)

Episodic hypomanic symptoms outside depressive episodes (M.I.N.I.) 1 Elevated mood 17 (43%) 2 Hyperirritability 13 (33%) 3 Grandiosity 5 (13%) 4 Decreased need for sleep 16 (40%) 5 Increased talkativeness 12 (30%) 6 Racing thoughts 21 (53%) 7 Distractability or difficulty in concentration 11 (28%) 8 Psychomotor agitation or restlessness 10 (25%) 9 Pleasurable activities or overspending 9 (23%) Hypomania/mania criteria except duration 19 (48%)

0 1 ** (5%) 0 1 (5%) 0 3 (14%) 1 (5%) 1 (5%) 1 (5%) 0

Other symptoms: Hyperirritability when depressed Previous anger attacks

13 (62%) 8 (38%)

* ** a

29 (73%) 19 (48%)

RBD-H (RBD + hypomania)

17 * 12 * 5 15 12 18 10 9 8 19

(100%) (100%) (42%) (26%) (100%) (95%) (68%) (100%) (58%) (90%) (90%) (32%) (21%)

(90%) (63%) (26%) (79%) (63%) (95%) (53%) (47%) (42%) (100%)

16 (84%) 11 (58%)

Two patients experienced hyperirritability but not elevated mood during hypomania. One patient had hyperirritability but did not have the minimum requirement of three supplementary symptoms. Fisher's exact test/all the other tests in the table are Pearson chi-square.

RBD-O vs. RBD-H p 1.000 1.000 0.962 0.873 1.000 1.000 a 0.301 1.000 a 0.796 0.596 a 0.596 a 0.583 1.000 a

0.554 0.816 1.000 a

0.000 0.000 0.000 0.000 0.000 0.000 0.001 0.003 a 0.007 a 0.000

0.115 0.210

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Table 3 Psychiatric and somatic co-morbidity among patients with recurrent brief depression (RBD) with (RBD-H) or without (RBD-O) additional episodes of brief hypomanic episodes (see text) Co-morbid disorder

All RBD patients

RBD-O (pure RBD)

RBD-H (RBD + hypomania)

Healthy controls

RBD-O vs. RBD-H

Psychiatric disorders Panic disorder with or without agoraphobia a GAD a Specific phobias a Social phobia a OCD a PTSD a Alcohol abuse a Substance abuse a

19 (48%) 13 (33%) 7 (18%) 12 (30%) 9 (23%) 5 (13%) 4 (10%) 1(3%)

6 (29%) 4 (19%) 2 (10%) 7 (33%) 4 (19%) 2 (10%) 1 (5%) 1 (5%)

13 (68%) 9 (47%) 5 (26%) 5 (26%) 5 (26%) 3 (16%) 3 (16%) 0

0 0 0 0 0 0 1 (5%) 0

0.012 0.056 0.163 0.629 0.583 0.550 0.246 0.335

Somatic disorders Tension headache Migraine b Epilepsy b Previous minor head concussion b

22 16 1 21

11 (5%) 9 (43%) 0 10 (48%)

11 (5%) 7 (37%) 1 (5%) 11 (58%)

0 3 (14%)

0.928 0.698 0.287 0.516

a b

(55%) (40%) (3%) (53%)

p

MINI version 5.0. aNEQ.

experienced anger attacks while none of the controls had had such attacks (p b 0.001). We also divided the total group of RBD patients into one group with a probable episode of major depression (MDE) in the past (n = 19), and one group with no history of MDE (n = 21). When the depressive symptoms during most recent episode of RBD were compared, the only significant differences between the groups were that the patients with a previous history of MDE had significantly fewer instances of early awakening (1; 5%) than patients with no previous MDE (7; 33%) (p = 0.046), and a significantly higher prevalence of hypersomnia (17; 90%) versus (9; 43%) (p = 0.002). Patients with a previous history of MDE also had a significantly higher point-prevalence of headache (selfreported migraine) (11; 58%) versus (5; 24%) (p = 0.028). There were no significant differences between the groups with and without a previous history of MDE on any of the suicidality items in the M.I.N.I. neuropsychiatric interview. Psychiatric and somatic co-morbidity is shown in Table 3. The prevalence of panic disorder with or without agoraphobia was significantly higher in the RBD-H (13; 68%) than in the RBD-O patients (6; 29%) (p = 0.012). No other statistically significant differences were found. No patient suffered from an eating disorder or agoraphobia only. On a total group level, RBD patients had suffered minor head concussion in the past more often than the healthy controls (p = 0.004). The prevalence of tension headache and migraine was high among RBD patients

as a whole (55% and 40% respectively), but there was no statistically significant difference between the two subgroups. The lifetime prevalence of mental disorders and anger attacks among first-degree relatives was elicited by the aNEQ. Health controls reported fewer mood and anxiety disorders (24%) among their first-degree relatives than patients with RBD (58%) (p = 0.012). Similarly, the prevalence of anger attacks was more frequent among first-degree relatives of RBD patients (55%) than among healthy controls (10%) (p = 0.001). 4. Discussion In this clinical study of the phenomenology of ICD10-defined RBD, we confirm the existence of RBD without a history of other mood disorders. Nineteen (47%) reported additional short episodes of brief hypomania of which nine (23%) never had experienced a major depression. The remaining 53% of patients reported RBD with or without (n = 12; 30%) past history of major depression or dysthymia. The findings correspond to findings in epidemiological studies (Angst and Dobler-Mikola, 1985; Angst, 1992, 1996; Angst et al., 2007b, 2003b). This indicates that in a life-long perspective pure unipolar RBD still occurs, but it is possible that — if longitudinal observations are taken into account — two-thirds of patients with current RBD may be reclassified as having other subtypes of mood disorders. This finding corresponds with that of Pezawas and co-workers as well (Pezawas et al., 2003).

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Our study also confirms the clinical severity of RBD (Table 2). With a lifetime prevalence of RBD without a history of major depressive episodes at least as high as that found for dysthymia (Keller et al., 1995b; Pezawas et al., 2003), our finding is another argument for the validity of including RBD in psychiatric classification systems. We also confirmed the presence of a small subgroup of patients with seasonal changes as earlier reported by Kasper and co-workers (Kasper et al., 1992). Montgomery noticed in his study of RBD that the conversion rate to bipolar illness was low at 3% and suggested that pure RBD is a unipolar depressive illness (Montgomery and Montgomery, 1992). However, proper identification of brief hypomanic episodes is the clue to a correct classification. Montgomery and co-workers did not assess the presence of brief hypomanic episodes. Thus the low conversion rate to bipolar I or II disorder observed by Montgomery is not an argument for RBD being a unipolar disorder if RBD in fact is a subtype of bipolar disorder characterised by not only brief depressive episodes, but also brief hypomanic episodes. Nevertheless, the discussion about how to classify RBD remains unsettled. Should the two RBD subgroups found, with or without brief episodes of hypomania, be considered to reflect the same or different underlying etiology? 4.1. RBD with brief hypomanic episodes We interpret the presence of hypomania of 1–3 days duration to be a marker for bipolar spectrum disorder. This interpretation is supported by the rather high prevalence of anxiety disorders in the RBD-H group that is similar to some reports on patients with bipolar II disorders (Akiskal et al., 2006b; Gao et al., 2008; Perlis et al., 2004; Simon et al., 2003). However, some studies report lower prevalence of co-morbid anxiety disorders in bipolar II disorder compared to our sample of RBD-H (Albert et al., 2008; Simon et al., 2004). Also the high family load of depression in RBD-H (Table 1) and high prevalence of melancholic and atypical clinical features support this interpretation. High percentages of atypical depressive symptoms (leaden paralysis, overeating and hypersomnia) have been found in Bipolar Disorder type II, and are considered an indicator of a bipolar spectrum disorder (Akiskal and Benazzi, 2005; Benazzi, 2000, 2006b; Thase, 2007). Angst et al. found that the presence of at least two out of three atypical symptoms showed the highest sensitivity for bipolarity, while the presence of only two atypical symptoms (overeating and hypersomnia), showed the

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highest specificity for bipolarity (Angst et al., 2006). Thirty (75%) RBD patients in our sample were positive according to the 2/3 definition of atypical specifier, and 13 (33%) according to the 2/2 definition. But not all researchers think that atypical symptoms separate bipolar from non-bipolar mood disorders. The diagnostic criteria for cyclothymic disorder requires at least 2 years of instability of mood characterised by numerous periods with hypomanic and depressive symptoms. The person should not have been without the symptoms for more than 2 months at a time. I.e. by definition cyclothymia requires more days per year should be associated with change in mood than not. In RBD, by contrast, “only” 10% of a year is associated with depressed mood given 12 episodes a year. With 20 episodes a year, the RBD patients still remain free of mood change 80% of the time. Furthermore, in cyclothymia depressive symptoms should not meet criteria for a major depressive episode (APA, 2000, page 398) or moderate or severe episodes in ICD-10 (WHO, 1993, page 87) (Hantouche et al., 2003). All our RBD patients had severe depressive symptoms when depressed (Table 2). Thus none of the patients in the present sample qualified for the diagnosis of cyclothymic disorder. Bipolar II 1/2 is a concept coined by Akiskal and coworkers (e.g. Akiskal et al., 2006a). Those patients are characterized by early age at onset, high recurrence of hypomania, high level of “dark” hypomania and irritable temperament which coupled with cyclothymia [by definition] and depressive temperament makes them the most complex and unstable subgroup in Akiskal's study. Those patients also have more agitated or “mixity” depression than other bipolar disorder, and rapid mood switching during treatment, and are highly suicidal. Such patients may be difficult to separate from patients with co-morbid borderline personality disorder. We did not identify any of those subjects, perhaps because we excluded patients with cluster A and B personality disorders from our study. 4.2. RBD without brief hypomanic episodes Our hypothesis that RBD with and without history of hypomanic symptoms would represent different subtypes based on the prevalence of melancholic and atypical symptoms was not confirmed. On the contrary, we found that both RBD subtypes had a high prevalence of such symptoms. In fact, patients with depressive symptoms only (RBD-O) did not differ from those with a history of brief hypomania on any of the clinical characteristics (Tables 1 and 2). However, there was a consistent trend across data that RBD-O patients had numerical lower

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frequency of psychiatric co-morbidity and longer symptom-free intervals (p = 0.057) compared to RBD-H. The significant co-morbidity of anxiety and RBD-O, and the high prevalence of irritability and atypical features (e.g. hypersomnia) may suggest that RBD-O is a variation of a brief recurrent bipolar disorder (Angst et al., 2006, 2007a; Benazzi, 2006b). The frequency of family history of depression and migraine observed in the RBD-O may support such an interpretation. Migraine seems to be overrepresented among patients with bipolar spectrum disorders (e.g. McIntyre et al., 2006; Hamelsky and Lipton, 2006; Oedegaard and Fasmer, 2005). Furthermore, onset of first depressive episode (b21 years) has been suggested to be superior to high recurrence (N 4 depressive episodes) in identifying an MDD subgroup close to BP-II, which might be subsumed under the broad bipolar spectrum (Klein et al., 1999; Benazzi and Akiskal, 2008). The low mean age at onset in RBD-O may thus suggest an association to the bipolar spectrum as well. If this is the case, subtypes of RBD may just reflect a continuum on a unipolar–bipolar dimension where the presence of brief hypomanic episodes may be a severity marker. A recent study by Akiskal and Benazzi of major depression and bipolar II disorders may support this interpretation (Akiskal and Benazzi, 2006b). In that study, even in clinically depressed patients without past hypomanic episodes (so-called “unipolar” MDD), some hypomanic features could nevertheless be identified corresponding to our observation among several of the RBD-O subjects. They observed a dose–response relationship between bipolar family history and hypomanic scores in the sample at large, suggesting a continuity between BP-II and MDD. The scores were normally rather than bimodally distributed during MDE. Moreover, the absence of a ‘zone of rarity’ in the distribution of hypomanic scores in the combined total, MDD and BP-II MDE samples, indicated that MDD and BP-II existed on a dimensional spectrum (Akiskal and Benazzi, 2006a; Benazzi, 2007). From a nosologic perspective, the data were contrary to what one would expect from a categorical unipolar–bipolar distinction. Extrapolated to our findings, even few hypomanic symptoms below the threshold for symptom number required for a diagnosis of hypomania combined with a history of bipolarity in the family, may represent strong indicators of bipolarity. Taken all together, we think a dimensional interpretation of our findings fits our data best (Angst, 2007). “Combined depression” has been found to be associated with the highest suicide attempt-rate of all depressive disorders (Montgomery et al., 1990; Judd et al., 1998). RBD during the course of recurrent major de-

pressive episodes has therefore been designated as an important marker of severity for depression (Pezawas et al., 2005). But compared to those without a history of MDE, we did not find a significant higher risk of suicide in our group of RBD patients with a past history of major depressive episode (module C in MINI neuropsychiatric interview). This may be due to the small sample, however. The high prevalence of anger attacks in the two subgroups also support an association between RBD and bipolar spectrum disorders, since such features have been described as indicators of bipolarity by several authors (Angst et al., 2003b; Mammen et al., 1999; Akiskal, 2005; Perlis et al., 2004; Benazzi, 2006b; Bowden, 2005). About half of our RBD patients had experienced anger attacks. However, anger attacks have also been reported to occur frequently in patients with major depressive episodes and co-morbid anxiety. We observed a higher prevalence of previous minor head concussion in the RBD groups than in the healthy controls. Anxiety and depression symptoms are quite frequent and play a role in the development of persistent post-concussion syndrome, but ICD-10 defined recurrent brief depression has not been reported after trauma (Malt, 2008; Vanderploeg et al., 2007). To which extent single episodes of minor head concussion can cause long-term mood disorders is debated, but current evidence does not support such an association (Kim et al., 2007). In pediatric samples head injury has not been found to predict bipolar disorder (Pavuluri et al., 2006). In conclusion, we do not think the somewhat increased prevalence of head concussion in our sample explains the presence of RBD. In conclusion, the higher prevalence of minor head concussion observed may be a consequence of impaired attention associated with RBD or represent a recall bias among ill compared to healthy subjects when asked about trauma history. Our RBD patients mostly described their episodes as unexpected and unrelated to life-events. In most cases the transition from normal state to that of deep depression took less than a couple of hours. Loss of energy resulting in apathy and immobilisation appeared to be the leading and dominant subjective symptom. The immobilisation may explain why these patients rarely contact health-care professionals when depressed, but it also underlines the need for neurobiological studies of such rapid behavioural transitions. 4.3. Limitations The sample is based on referral by physicians and self-referrals. This sampling procedure may explain the

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higher number of women than would be expected from epidemiological studies (e.g. Pezawas et al., 2003). A similar preponderance of women has been reported in samples of bipolar disorders based on a combination of physician and self-referrals (Benazzi, 2006a; Michalak et al., 2007). A bias towards sampling more severely affected patients with RBD may also explain why the differential diagnosis of RBD versus cyclothymia was not an issue in this study. A limitation of cross-sectional studies is the partly retrospective collection of clinical data. Retrospective data collection increases the risk of misclassification. In order to control for this source of error, we conducted an inter-rater reliability check which indicated that our data had acceptable reliability and quality. This procedure does not exclude some difficult classification issues, however. We noticed that several patients with current RBD symptomatology had a history suggesting possible major depression several years previously and a duration of hypomanic symptoms of at least four days. Such patients were diagnosed as bipolar II patients and excluded. However, in three patients included in our study it was hard at the time of our study examination to decide if the duration of their depressive episodes several years ago had lasted for as much as 2 weeks. Also the threshold issue creates diagnostic problems. In five patients classified as RBD-O, there were suggestions for the presence of one or two hypomanic symptoms during non-depressed episodes in the past. We cannot rule out that patient-independent sources may have provided information suggesting that those or other patients in the past in fact may have had symptoms sufficient for a diagnosis of hypomania. It may also be difficult to differentiate between RBD with brief hypomania and ultra-rapid cycling bipolar II. RBD with hypomania is supposed to be a stable condition lasting for years (Angst et al., 1990), while ultrarapid cycling bipolar II is a transient form of bipolar II (Akiskal et al., 2000). In conclusion, the exact classification of our subjects does have potential sources of errors inherited in any phenomenological crosssectional approach to psychiatric classification. Those limitations must be kept in mind when interpreting our results. However, we do not think the potential errors are large enough to invalidate our main findings. Another important limitation is the small size of our sample. This is due to the neurobiological focus of the study, but makes the sample underpowered to detect statistically significant differences between several of the clinical features of the two subgroups. This means that only the largest differences between the two groups could be expected to show statistical significance. How-

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ever, the comprehensive and detailed assessment of the patients increases the sensitivity to differences, and may to some degree reduce the limitation inherent in the small sample. Nevertheless, despite these methodological limitations, the clinical characteristics of RBD found in the present study (see Table 1) correspond to the characteristics reported by Jules Angst and others. Furthermore, the distribution of RBD patients with and without discrete episodes of hypomanic symptoms of at least one day's duration corresponds to the distribution observed in epidemiological samples (Angst et al., 2003b). Also the profile of co-morbid psychiatric disorders corresponds roughly to the findings reported in the Zürich epidemiological study. However, we cannot rule out that the relative high prevalence of anxiety disorders compared to some sample of bipolar patients (Albert et al., 2008; Simon et al., 2004; Smith et al., 2007), may reflect a selection bias, i.e. those who have more co-morbid anxiety are more severely affected and more frequently referred or may have a lower threshold for self-referral. Also the rather high rates of atypical symptoms may reflect a sampling bias towards women (Mitchell et al., 2008; Smith et al., 2007). However, all data viewed together, we think our sample may provide important information about the phenomenology and neurobiology of RBD. 5. Conclusion and clinical implications Our study confirms epidemiological studies indicating that RBD is a valid diagnostic category that can be separated from bipolar II disorder, cyclothymia and recurrent major depression. Our findings further suggest that a history of hypomanic symptoms in addition to recurrent brief depressive episodes is a marker of severity. Our study does not provide any evidence of the best treatment for RBD, however. But our own (Malt and Fladvad, 2001) and others (Ravindran and Ravindran, 2007) clinical experiences, and the many clinical features observed in this study suggesting a link between RBD and the bipolar spectrum, may suggest that mood stabilizers should be the first line treatment of ICD-10-defined RBD. However, randomized controlled treatment trials of RBD are needed to validate this hypothesis. Role of the funding source The project was partly financed by a grant from the Research Council of Norway, and by financial support from the following sources: Rikshospitalet, Sørlandet hospital, the South-Eastern Norway Regional Health Authority, Medinnova AS, and Josef og Haldis Andresens legat. None of the funding sources had any further role in study design; in the collection, analysis and interpretation of data; in

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the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest Dr Løvdahl and Dr. Malt have received speaker's fee for lecturing about RBD in meetings organized by pharmaceutical companies including GlaxoSmithKline, the manufacturer of lamotrigine, and professional organizations.

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