Recurrent brief depression—past and future

Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75 – 83 www.elsevier.com/locate/pnpbp

Review article

Recurrent brief depression—past and future Lukas Pezawasa,b,*, Jules Angst c, Alex Gammac, Vladeta Ajdacicc, Dominique Eichc, Wulf Ro¨sslerc b

a Department of General Psychiatry, University of Vienna, Vienna, Austria Clinical Brain Disorders Branch, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD 20892-1379, USA c Zurich University Psychiatric Hospital, Zurich, Switzerland

Accepted 2 October 2002

Abstract Recurrent brief depressive disorder (RBD) is a well-defined and significantly prevalent affective disorder with an increased risk of suicidal behavior and significant clinical impairment in the community and general practice. RBD is characterized by depressive episodes occurring at least once a month and lasting for only a few days. The lifetime co-occurrence of both RBD and major depressive disorder (MDD), called combined depression (CD), increases substantially the risk for suicide attempts, even more than is known for ‘‘pure’’ MDD. Diagnostic criteria for RBD can be found in the ICD-10 and DSM-IV and are helpful in both, research and clinical routine. Furthermore, several methodological issues are covered in this paper, which make clinical diagnostic and drug response evaluation of RBD very different from MDD. However, clinical procedures rather bear a resemblance to those used in the treatment of migraine or epilepsy. Formal differences in the course of RBD and MDD create different needs concerning the design of drug treatment studies. Absence of special methodological requirements and highly selected patient samples has probably been responsible for false negative results in double-blind, placebo-controlled treatment studies. Although several authors reported successful treatment of RBD with different compounds in about 60 patients, it is still not possible to deduce a treatment algorithm for RBD to date. Obviously, future treatment studies without the limitations of previous studies are clearly required for RBD. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Depression; Mood disorder; Recurrent brief depression; Subthreshold; Therapy

1. Introduction

Although the concept of recurrent brief depression (RBD) was first published in 1984 (Angst and DoblerMikola, 1985), recurrent short-lived depressive episodes have been mentioned in psychiatric literature since the 19th century (Angst, 1994a).

Recurrent brief depressive episodes, persisting for a few days and occurring spontaneously or triggered by mild psychosocial stressors and that remitting completely, are common psychiatric symptoms. They are associated with psychosocial impairment and an increased risk of suicidal behavior (Pezawas et al., 2001).

2. History

Abbreviations: BPD, borderline personality disorder; CD, combined depression; EDSP, Early Developmental Stages of Psychopathology Study; MDD, major depressive disorder; PPGHC, Psychological Problems in General Health Care; PMDD, premenstrual dysphoric disorder; RBD, recurrent brief depressive disorder. * Corresponding author. Clinical Brain Disorders Branch (CBDB), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), 10 Center Drive 4S235, Bethesda, MD 20892-1379, USA. Tel./fax: +1-301-594-8393. E-mail address: [email protected] (L. Pezawas).

One hundred and fifty years ago, Pohl (1852) reported in an excellent monograph on melancholia episodes of ‘periodic melancholia’ lasting hours to days (Table 1). When Kraepelin (1899) published his pioneer work on ‘‘manic-depressive illness,’’ he included psychopathological symptoms such as hypomanic or mild depressive moods even of short duration in his concept. Almost two decades later, Gregory (1915) published a report on ‘‘transient attacks of manic-depressive insanity.’’ He mentioned in detail the phenomenon of recurrent brief depres-

0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 2 ) 0 0 3 1 8 - 4

76

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

Table 1 Historical development of RBD Author

Date

Finding

Pohl

1852

Head

1901

Gregory

1915

Paskind

1929

Read, Patrick

1929

Busse

1955

Spitzer et al.

1975

Clayton et al.

1980

Angst and Dobler-Mikola

1985

Montgomery et al.

1989

Kasper et al. World Health Organization

1992 1992

Described cases of multiple depressive episodes that lasted from hours to days; introduced the term ‘periodic melancholia.’ Described cases of multiple depressive episodes that lasted from hours to days; association with ideas of suicide and impulse for self-destruction. Described cases of multiple depressive episodes that occurred independently from the menstruation cycle; association with suicide attempts and unexpected suicides. Observed episodes of RBD in elderly patients. Increased suicidal behavior in brief depressions. Found that 14% of patients with manic depression also suffered from RBD. Attempted to operationalize an ‘‘intermittent depressive disorder.’’ Introduced the term ‘‘very brief depressions.’’ Introduced the first operationalized diagnostic category of brief depressions based on the Zurich study, which he called RBD. Studied psychiatric patients with repeated suicide attempts and borderline comorbidity; he introduced the term ‘‘intermittent 3-day depressions.’’ Described a seasonal form of RBD. Inclusion of RBD as diagnostic category in the ICD-10.

sion: ‘‘short attacks of a manic-depressive psychosis, ranging in duration from a few hours to several days, are very frequent’’ and ‘‘. . .many sudden and unexpected suicides, . . ., are due to fleeting attacks of a manicdepressive psychosis. I am led to this belief from the examination of hundreds of cases of attempted suicides.’’ Furthermore, he stated: ‘‘. . .during such attacks, patients may commit overt acts, such as assault, crimes of sexual character, attempted suicide, and even homicide.’’ These transient depressive attacks have been called ‘‘atypical’’ by him already in 1908 due to their short duration. He also observed severe intoxications related to dipsomanic alcohol abuse, which has been explained in his work by a rapid change of moods in such patients. Another decade later, Paskind (1929) underlined the clinical importance of brief depressions. He was the first psychiatrist who recognized that the majority of such patients are found more frequently in general health care settings than in psychiatric institutions. Read and Patrick confirmed the finding that recurrent brief depressions are significantly related to suicidal behavior (Paskind, 1929). Another two decades later, Busse et al. (1955) reported: ‘‘The depressive periods that we considered stat-

istically had occurred at least once a month, and their duration had varied from a portion of an hour to a few days. The subjects reported that these episodes of depression had not occurred in their younger years.’’ And he also noted: ‘‘. . .these episodes can be termed ‘reactive’ depressions.’’ In the 1970s, Spitzer et al. (1975) developed psychiatric Research Diagnostic Criteria, including a category called ‘‘intermittent depressive disorder,’’ characterizing patients being bothered for at least 2 years by depressed mood (like in minor depression) lasting from hours to about week and being in normal mood between hours and weeks. However, this definition was used rarely after its introduction. More recently, Clayton et al. (1980) called such depressions ‘‘very brief depressions,’’ which has not been picked up by the scientific community as well. The same was true for a study performed by Montgomery and colleagues in London, which should explore treatment options in repeated suicide attempters with comorbid borderline personality disorder (BPD). In these studies, Montgomery et al. found several patients, which suffered from severe recurrent brief depressive episodes being associated with suicidal behavior, which he called ‘‘intermittent 3-day depressions’’ (Montgomery et al., 1989). In his later work, he exchanged this descriptive term for the diagnostic category of RBD (Montgomery and Montgomery, 1992). More details on the early history of RBD can be found in Angst (1994a). In 1978, a longitudinal, epidemiological cohort study of young adults assessing a continuum of psychopathology from normal to disordered states was launched in Zurich, Switzerland (Fig. 1). The analysis of the first follow-up interview showed the frequent occurrence of depressive mood swings lasting less than 8 days (Angst and Dobler-Mikola, 1984). Further research on this subject generated the first operationalized definition of RBD (Angst and Dobler-Mikola, 1985), which has been revised

Fig. 1. Design of the Zurich study.

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83 Table 2 RBD as defined in ICD-10 (World Health Organization, 1992a) F38.10—RBD A. The disorder meets the symptomatic criteria for mild, moderate or severe depressive episode (F32.xx). B. The depressive episodes have occurred about once a month over the past year. C. The individual episodes last less than 2 weeks (typically 2 – 3 days). D. The episodes do not occur solely in relation to the menstrual cycle.

later (Angst, 1988). This definition of RBD (Table 2) has been integrated in the ICD-10 system (WHO, 1992b).

3. Epidemiology Table 3 summarizes prevalence rates for RBD in different epidemiological samples. So far RBD has been independently investigated in two longitudinal and two crosssectional community samples. The Zurich study (Angst and Dobler-Mikola, 1984) provides for the longest observation period of a community sample in the context of RBD starting its investigation at the age of 19 until the last interview performed at the age of 41, which is currently analyzed (Fig. 1). As far as they are related to the Zurich study, the data provided in the text or tables represent data including the last interview in 1999. This study revealed lifetime prevalence rates of pure RBD without mood disorder comorbidity of 12.5% (10.8% males, 14.2% females), which is similar to pure major depressive disorder (MDD) without mood disorder comorbidity with a prevalence rate of 14.7% (13.1% males, 16.3% females). In contrast, gender distribution of RBD is distinct from MDD showing a balanced sex ratio in RBD (1:1.3) and a female excess in MDD (1:16.3). Duration patterns in RBD and MDD also differ significantly with a median duration of brief depressive episodes of 3 days in RBD and about 10

77

weeks in MDD (Angst, 1994b). However, the cumulative number of depressive days per year has been shown to be less significantly different in RBD (43 days) and MDD (75 days) within the Zurich Study. In accordance with the Zurich study, a community sample in Mainz exhibited similar prevalence rates (Maier, 1993, personal communication). A slightly lower prevalence rate has been reported by a study in Sardinia (Table 3) (Altamura et al., 1995). These preliminary findings are supported in a larger community sample (Table 5) drawn from urban, rural and mining areas (Carta, 2000). Recently, epidemiological findings of on RBD have been re-investigated in a large community sample of adolescents and young adults in the framework of the Early Developmental Stages of Psychopathology (EDSP) Study conducted in Munich, presenting prospective lower bound estimations of findings on prevalence, incidence, clinical correlates, severity markers, comorbidity and course stability of RBD and other mood disorders (Pezawas et al., 2002c). The same holds true for findings of a community enquiry in London supporting rather high prevalence rates in the community (Snaith, 2000) (Table 4). Support for community studies is also provided by a comprehensive World Health Organization (WHO) project on ‘‘Psychological Problems in General Health Care’’ (PPGHC) and further associated studies in primary care settings (Sartorius et al., 1993). Notably two centers, Mainz (Maier et al., 1994a,b) and Paris, (Weiller et al., 1994a) confirmed patterns of clinical significance in this cross-sectional study. Furthermore, prevalence rates of RBD are available for 15 different primary care centers (N = 5438) in Brazil, Chile, Germany, France, Greece, India, Italy, Japan, the Netherlands, Nigeria, China, Turkey, the UK and the USA (Weiller et al., 1994b). In a sample including five centers, a substantial number (3.7%) of investigated primary care seekers, were identified as suffering from RBD without mood disorder comorbidity. Another sample including 10 centers (N = 3527) and using

Table 3 Prevalence and treatment prevalence of RBD in the community Sample size

Interview/method

Prevalence 1 year

Rates (%) lifetime

Community Sardinia (Altamura et al., 1995) Zurich study (Angst and Dobler-Mikola, 1984) Mainz (Maier, 1993) EDSP-study, Munich (Pezawas et al., 2002c)

n = 493, age 18 – 65 n = 367 – 591, age 20 – 41 n = 317, age 18 – 65 n = 3021, age 14 – 24

CIDI-S, cross-sectional SPIKE, longitudinal CIDI + cross-sectional CIDI-M, longitudinal

– 5.0 – 8.2 5.8 –

6.9 21.3 10.0 2.6a

General practice PPGHC-study, Paris (Weiller et al., 1994a) PPGHC-study, Mainz (Maier et al., 1994b) PPGHC-study, five centers (Weiller et al., 1994b) PPGHC-study, 10 centers (Weiller et al., 1994b)

n = 405, age 18 – 65 n = 300, age 18 – 65 n = 1911, age 18 – 65 n = 3527, age 18 – 65

CIDI + cross-sectional CIDI + cross-sectional CIDI + cross-sectional CIDI + cross-sectional

9.9 7.6 3.7 5.7

– – – –

Family studies Mainz (Maier et al., 1992)

n = 420, age 18 – 65

CIDI + cross-sectional

7.4

14.6

a

Lower bound estimations.

78

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

Table 4 Lifetime prevalence of RBD in a community survey in Sardinia including three subsamples from urban, rural and mining areas (N = 1038) (Carta, 2000)

Table 6 Symptoms occurring in at least one-third of RBD subjects in the Zurich study

Age (years)

Males (%)

Females (%)

Both (%)

< 25 25 – 44 45 – 64 >64 Total

12.8 8.0 2.1 2.3 5.9

8.1 6.8 7.1 5.5 6.8

10.4 7.3 4.8 4.3 6.4

Decreased sexual desire Loss of appetite Increased appetite or weight gain Insomnia Hypersomnia Psychomotor retardation Diminished ability to concentrate Feelings of inappropriate guilt Hopelessness Being afraid of the future Recurrent thoughts of death

RBD (%)

MDD (%)

59 41 35 47 53 47 59 41 41 53 41

64 40 27 49 53 27 64 29 49 58 31

a slightly different definition of RBD found a 5.7% prevalence of RBD. So far epidemiological studies have provided similar findings on RBD demonstrating its significant prevalence in community and primary care and its clinical significance.

ized as a course specifier of MDD as it is the case, for e.g., seasonal affective disorder (SAD).

4. Diagnosis

5. Depression symptom profile and clinical features

In 1994, RBD was integrated as a new diagnostic category into ICD-10 (WHO, 1992a) and DSM-IV (APA, 1994) due to convincing epidemiological data (Table 2). While RBD represents a distinct clinical diagnosis in ICD-10, DSM-IV still classifies RBD as being a subcategory of depressive disorders ‘‘not otherwise specified (NOS).’’The DSM-IV manual offers operational diagnostic criteria for scientific use in the appendix but does not qualify for clinical use due to numerous exclusion criteria. The psychopathological cluster of symptoms found in RBD is absolutely the same as in MDD. Therefore, RBD cannot be thought to be a milder form of depression. As a matter of fact, RBD can be distinguished from MDD only by the duration criterion (episode duration < 14 days) and the frequency criterion (approx. 1 episode/month). In addition, the ICD-10 requires independence of the menstrual cycle and an observation period of 1 year. This also implies that RBD is not operational-

Reports of on the depression symptom profile of RBD and MDD are provided by the Zurich and EDSP studies (Pezawas et al., 2002b) showing similar patterns of depression (Table 5). Regarding symptoms reported in at least two-thirds of subjects (Table 6) in the Zurich study, it is intriguing that most symptoms have been reported to be less frequent in MDD in comparison to RBD. On the other hand, symptoms reported in at least one-third of subjects have been similar frequent in RBD and MDD (Table 7). These data confirm the relevance of the diagnostic concept of RBD demonstrating that RBD presents the full-blown picture of depression. Similar findings have also been reported in the EDSP study showing only slightly less frequently reported depression symptoms in RBD than MDD except for sleeping problems, which seem more frequent in RBD. Fig. 2 displays the reported family history of depression and the history of suicide attempts of subjects investigated in

Table 5 Symptoms occurring in at least two-thirds of RBD subjects in the Zurich study

Depressed mood Loss of energy Indecisiveness Loss of self-confidence Feelings of worthlessness Irritability Social withdrawal Psychomotor inhibition Loss of interest Loss of pleasure

RBD (%)

MDD (%)

100 88 82 82 76 82 76 76 71 71

98 93 62 69 49 67 67 60 84 89

Table 7 Follow-up of MDD and RBD over 2 – 20 years Most severe subtype at follow-up MDD + dysthymia + RBD MDD + dysthymia (MDD + dysthymia) or (RBD + dysthymia) MDD + RBD MDD only Dysthymia + RBD RBD only Minor depression only No depressive disorder a

Initial depression diagnosisa MDD (n = 131) (%)

RBD (n = 132) (%)

1 6 –

0.9 3.7 0.9

3 33 – 9 2 46

7.3 19.3 1.8 20.2 0.9 45.0

Groups not mutually exclusive.

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

79

Fig. 2. Family history of depression (dashed line) and history of suicide attempts (black line) in the Zurich study. BP, bipolar disorder; MDD, major depressive disorder; RBD, recurrent brief depressive disorder; DYST, dysthymia; MinD, minor depressive disorder; No Dep Dx, no depressive diagnosis; 150% of cases were identified as suffering from comorbid RBD.

the Zurich study. These data show that about 50% of RBD and MDD subjects reported a family history of depression, which argues for a place of RBD within the mood disorder spectrum. Suicide attempts were reported to be less frequent in RBD (10.2%) without mood disorder comorbidity than in MDD (20.2%) in the Zurich study, similarly to the results of the EDSP study (Pezawas et al., 2002c). However, general practice studies revealed even higher suicide attempt rates: 16.1% in Mainz (Maier et al., 1994a), 23.3% in Paris (Weiller et al., 1994a) and 14.0% in five WHO centers (Weiller et al., 1994b). The relevance of suicidal behavior in RBD has also been supported by clinical studies (Montgomery et al., 1989; Pezawas et al., 2002b). Furthermore, the concept of RBD and its clinical significance has been supported by studies on patterns and consequences of a lifetime co-occurrence of both, RBD and MDD, called combined depression (CD), which has been introduced into psychiatric literature by Montgomery (Montgomery et al., 1989), and further developed by Angst (1990). Epidemiological (Angst and Hochstrasser, 1994; Maier et al., 1994a) and clinical (Montgomery et al., 1989; Pezawas et al., 2000b) studies demonstrated a dramatic increase of in suicide attempt rates and measures of impairment in case of CD in comparison to either single RBD or MDD. These findings are also supported by recent data from the Zurich study (Fig. 2) displaying the highest rate of a family history of depression and also the highest suicide attempt rates in this combined group.

6. Differential diagnosis The differential diagnosis between RBD and MDD from a diagnostic viewpoint is easy to make and is basing

on the totally different time pattern (1– 3 days vs. weeks or months). However, as mentioned above, there is are great similarities between the depression profiles, family histories, suicidal behavior and treatment rates of both disorders, which argues that RBD can be seen within the spectrum of depressive mood disorders like MDD, dysthymia and minor depression. From a clinical point of view, it might be necessary to differentiate other psychiatric disorders mainly characterized by short-lived symptoms (Angst, 1997; Pezawas et al., 2001). The list comprises: (1) panic disorder characterized by recurrent unexpected panic attacks. However, the attacks only last for minutes up to a few hours. (2) Premenstrual dysphoric disorder (PMDD) appearing exclusively in relation to the menstrual cycle. The PMDD starts in the last week of the luteal phase in most menstrual cycles during the past year. The symptoms begin to remit within a few days of the onset of menses (the follicular phase) and are always absent in the week following menses; (3) BPD, which—in the case of affective instability—can be associated with depressive mood fluctuations that often persist for hours but can last for days, as well. But the following characteristic symptoms (according to DSM-IV at least five symptoms) must be present in order to be able to diagnose BPD: frantic efforts to avoid real or imagined abandonment, a pattern of unstable and intense interpersonal relationships, identity disturbance, impulsivity in areas that are potentially self-damaging, recurrent suicidal behavior, affective instability due to a marked reactivity of mood, chronic feelings of emptiness, inappropriate intense anger or difficulty controlling anger, transient stress-related paranoid ideation or severe dissociative symptoms. A low BPD comorbidity has been found in our own clinical data (Pezawas et al., 2002b). Another clinical study reported similarly low dimensional symptoms of personality

80

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

7. Course

Fig. 3. Longitudinal overlap within a 20-year observation period between three mood disorders in the Zurich study (N = 591).

disorders in RBD and PMDD (Berlin et al., 2001). (4) Rapid cycling (RC) (>4 episodes/year), ultra-RC (episodes in a weekly rhythm) or ultra-ultra-RC ( = ultradian episodes) bipolar disorders must show at least hypomanic (or manic) episodes according to DSM-IV (Kramlinger and Post, 1996). In the first case, at least one depressive episode must be present, lasting for at least 14 days and, in the last case, the episodes may not last longer than a day. Generally, RC or ultra-RC are prognostic bad course specifiers of bipolar disorder, which are developed by 15 – 20% (specifically RC) of bipolar patients (Post and Weiss, 1998) and differentiating them from RBD rarely causes problems. (5) Other affective disorders such as MDD, minor depression (according to DSM-IV), bipolar disorder or dysthymia can be easily distinguished from RBD by the criterion of duration of the depressive episode. Furthermore, it is necessary to distinguish RBD from (6) drug-induced depression as found in cocaine withdrawal, for example. Recurrent brief depressive episodes have also been described in the presence of somatic diseases, e.g., postictal dysphoria or the so-called interictal dysphoric disorder in epilepsy (Blumer, 2000). Recurrent brief depressive episodes have been reported to be associated with migraine plus aura (Merikangas et al., 1993). The similar courses of migraine and RBD actually led to the hypothesis that both disorders should be classified in the category of short-lived recurrent self-limited syndromes associated with a disturbance of monoaminergic neurotransmission (Glover et al., 1993). Wermuth et al. (1998) reported that about 70% of depressive episodes occurring in patients suffering from idiopathic Parkinson’s disease also meet the operationalized criteria for RBD. Finally, we want to mention that a relationship to the Prader-Willi syndrome was described by another author (Watanabe et al., 1997). From a scientific point of view, it is currently not possible to answer the question if these RBD syndromes are part of the clinical aspects of these organic diseases, if they are a real psychiatric comorbidity or only a coincidence.

The longitudinal course of mood disorders is characterized by a substantial diagnostic overlap within these diagnostic groups (Fig. 3). Therefore, longitudinal epidemiological studies like the Zurich study or EDSP study deliver data for the solution of some critical issues concerning the concept of RBD, evaluating the degree of evidence that is given to rule out that RBD is only a prodromal or residual state of MDD or any other psychiatric disorder. Both studies indicate that RBD is not a prodromal syndrome of MDD. In this respect, the Zurich study provides the best data set, because psychiatric cases have been followed over a two-decade lasting observation period. This study indicated that RBD cases became MDD cases more often than vice versa (Table 8). About 10% of all cases initially diagnosed as MDD developed RBD during followup and 20% vice versa. This phenomenon was called ‘‘kindling-hypothesis’’ by Angst (1994b) and is in accordance with other data concerning the longitudinal development of mood disorders and other ‘‘serotonergic spectrum disorders’’ (Post and Weiss, 1998). Concerning the hypothesis that RBD might be a residual state of MDD, both studies found that only a limited proportion of subjects developed RBD after being diagnosed as MDD, which provides evidence that RBD is not merely a residual state of MDD. Here, Table 8 shows that only 9% of MDD cases developed RBD or a combination of both in the follow-up. The diagnostic stability over time is similar for RBD and MDD. Table 8 shows that no depressive disorder could be diagnosed for half the cases of RBD and MDD at follow-up. Furthermore, about 30% of MDD cases have been diagnosed with only MDD over time, which has been slightly higher than for RBD (about 20%). This table on waxing and

Table 8 Overview of double-blind, placebo-controlled, one-tailed (single case analyses) and two-tailed studies assessing treatment of patients with RBD Reference

n

Treatment

Response

a

Kocmur et al., 1998 16 Paroxetine Kasper et al., 2000 148 Paroxetine Montgomery et al., 1994b 107 Fluoxetine Kasper et al., 2000 37 Flupenthixole Montgomery et al.; Kasper et al., 2000 58 Mianserin Pazzaglia et al., 1998c 2 Carbamazepined + c Pazzaglia et al., 1998 3 Nimodipine + Pazzaglia et al., 1998c 1 Verapamil + 91 Paroxetine Verkes et al., 1998b Wermuth et al., 1998e 37 Citalopram n = number of patients included in the study; + = response to treatment; = nonresponse to treatment. a Intermittent Depressive Disorder. b Reduction of suicide attempts. c Single case analysis. d Carbamazepine was prescribed as add-on treatment to nimodipine. e Parkinson patients with RBD.

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

waning of mood disorders also shows that RBD is often associated with MDD and less frequently with dysthymia.

8. Treatment About two-thirds of all RBD patients seek professional help in the course of their life (Angst, 1994b). One quarter consults the general practitioner, one quarter sees a psychologist and the remaining half consults a psychiatrist or neurologist. In the Zurich study, almost all of these patients stated to have received treatment with psychotherapy (Angst, 1994b). However, RBD patients hardly ever receive pharmacological medication. The PPGHC study revealed that the prescription rate of psychotropic substances for patients with RBD in general practice was 19%. This rate was the lowest and was three times lower than the rate for patients with agoraphobia (Linden et al., 1999). However, patients with RBD that received previous treatment frequently have a history of inadequate therapeutic response to different pharmacological treatment strategies usually offered by their general practitioner (Kasper et al., 2000). The fact that about 10% of all ‘‘pure’’ RBD patients and about 30% of all patients with a lifetime co-occurrence of RBD and MDD (CD), as found in the Zurich study, attempted suicide during the two decades lasting observation period underlines the need for sufficient treatment. Almost two decades after the conceptualizing of RBD, clinical trials concerning psychotherapy as well as biological treatment strategies (e.g., light therapy) are still lacking, although patients suffering from RBD frequently undergo psychotherapy (Angst, 1994b). There is only one case study about a patient suffering from a seasonal type of RBD describing the induction of ultradian RC after light therapy (Meesters and van Houwelingen, 1998). However, there are a few placebo-controlled studies and several case reports, a single-case analysis, and one open trial (Table 9) assessing drug treatment of patients with RBD. All in all, those studies that chose a classical doubleblind placebo-controlled two-tailed design were not able to demonstrate a successful treatment for RBD. Main reason for this probably was that depression rating scales have been administered in a fixed interval of, e.g., 2– 4 weeks (Montgomery et al., 1994). Because of the short duration and irregularity of occurrence of brief depressive episodes there is only a low chance to observe depressive symptoms at a fixed follow up interview. Therefore, we assume that the authors failed to detect changes in recurrent brief depressive episodes during the treatment period. Recent findings indicate that studies should be conducted using designs with an appropriate statistical sensitivity (e.g., single case analyses) and other statistical evaluation procedures as well as longer observation periods than used in MDD because of rapidly undulating symptoms specific for RBD (Pezawas et al., 2002a; Post et al., 1998). Maybe this is how false negative study results came about, and pessimism that was brought

81

Table 9 Open trials and single case analyses, and case reports reported in the context of RBD Reference

n

Treatment

Response

Amore et al., 1998a Corominas et al., 1998a Corominas et al., 1998a Gertz, 1992a Gertz, 1992a Gertz, 1992a Gertz, 1992a Gertz, 1992a Pezawas et al., 2002ab Stamenkovic et al., 2001c Stamenkovic et al., 1998a

30 1 1 1 1 1 1 2 1 17 2

Fluoxetine Clomipramine Lithium Amitryptiline Carbamazepine Clomipramine Maprotiline Tranylcypromine Reboxetine Fluoxetine Mirtazapine

+ + +

+ + + +

n = number of patients included in the study; + = response to treatment; = nonresponse to treatment. a Case report. b Single case analysis. c Open trial.

up in these controlled studies concerning possible successful therapy plans for RBD might be inappropriate. Anyhow, this presumption is supported by successful results found in double-blind placebo-controlled one-tailed single case analyses with nimodipine, verapamil and carbamazepine (Pazzaglia et al., 1993, 1998). On the other hand, controlled studies were carried out with highly selected RBD patient samples, e.g., patients with repeated suicide attempts or comorbid BPD or somatic diseases (Kasper et al., 2000; Kocmur et al., 1998; Montgomery et al., 1994; Verkes et al., 1998; Wermuth et al., 1998). This might have led to a bias directed towards therapy resistance. Due to the abovementioned reasons, our own positive experience concerning treatment with mirtazapine (Stamenkovic et al., 1998), reboxetine (Pezawas et al., 2002a), fluoxetine (Stamenkovic et al., 2001) as well as other positive results from case reports with lithium (Corominas et al., 1998), carbamazepine (Gertz, 1992) and tranylcypromine (Joffe, 1996) called the negative findings resulting in other studies due to the above mentioned reasons in question (Pezawas et al., 2001). In any case, it is not possible to date to derive a specific treatment strategy for RBD from the existing data. Because the study results remain unclear and contradictory, there is a great need for future controlled clinical trials without the methodical limitations of previous studies. Taking into consideration that successful treatment of RBD was reported for about 60 patients to date, a first-choice antidepressant treatment attempt with substances lacking severe side effects seems to be justified.

9. Future In contrast to other common psychiatric disorders like MDD or schizophrenia, RBD research has its origin in epidemiological studies (Angst and Dobler-Mikola, 1985). Due to the lack of significant clinical research on RBD at this

82

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83

time, there have been several constraints towards the clinical validity of this disorder. Nevertheless, epidemiological research is the most developed field in RBD research today. In several large independent epidemiological studies, initial findings have been confirmed in different population samples. Further studies will complete the epidemiological blueprint of this disorder. Such a study, including a RBD interview section, is currently the second National Comorbidity Survey in the USA. Final results of the community survey in Sardinia will also contribute to more epidemiological data on this disorder. Finally, results of the EDSP-study will accomplish our knowledge of prevalence, comorbidity and clinical patterns of RBD in adolescents and young adults, as well as further provide details on precursors, family history and life events of this disordered group of subjects. The pessimism concerning the treatment of this disorder might probably not be justified as it stems from false negative study results. Recently, progress has been made in the prospective assessment of mood symptoms in RC depressive mood disorders such as RBD. It has been worked out that designs and statistical methods used in clinical studies in the past have been insufficient. Therefore, future treatment studies in RBD should additionally take advantage of longitudinal depression self-rating scales like depression diaries or visual analogue mood scales. Furthermore, cross-over designs seem to more appropriate to detect treatment effects in RBD. However, several questions still remain open concerning optimal clinical study designs (e.g., How to rule out adverse events due to carry-over effects in a cross-over design?), instruments for assessing RBD symptoms (What kind of longitudinal depression self-rating instruments are best for detecting treatment effects?) and appropriate statistical methods (What kind of sequential statistical tests should be considered to be a standard in RBD drug trials?). Future efforts in the field of RBD should also include these methodological aspects. Today only a few clinical studies are available in the field of RBD research. Since pure RBD is common in primary care and in the community but less common in psychiatric practice, psychiatric research institutions interested in this kind of research have to address such patients from community or general practice samples, e.g., by advertisements, etc. A clinical validation of epidemiological findings is currently under progress in Vienna. Future efforts should also encompass strategies to increase low recognition rates. In general practice, pure RBD is usually diagnosed as ‘‘depression.’’ In contrast, in psychiatric settings, where more severe (and comorbid) kinds of mood disorders are common like CD (lifetime co-occurrence of MDD and RBD), merely MDD is diagnosed, because some critical diagnostic questions have not been asked. This might also contribute to the low number of clinical studies. The optimal treatment regime for RBD remains an open question. Basing on information of treatment studies, a prescription with modern antidepressants seems to be appro-

priate. As a second line treatment, mood stabilizers can be considered. However, longer response rates (weeks to a few months) than in MDD are characteristic for this disorder since symptoms are occurring less frequently in comparison to major depressive episodes.

10. Conclusions Summarizing progress in RBD research, the authors conclude that RBD without mood disorder comorbidity is an epidemiologically well-characterized disorder that is common in primary care and in the community but less common in psychiatric practice. Therefore, merely clinical studies are lacking in the field of RBD research today and further studies are clearly needed. Pessimism concerning the drug treatment of this disorder originating from the first studies seems to be inappropriate today. Progress in methods, which should be used for the assessment and evaluation of this disorder, may contribute to the development of better treatment strategies for this disorder.

References Altamura, A.C., Carta, M.G., Carpiniello, B., Piras, A., Maccio, M.V., Marcia, L., 1995. Lifetime prevalence of brief recurrent depression (results from a community survey). Eur. Neuropsychopharmacol. 5, 99 – 102. American Psychiatric Association. Task Force on DSM-IV, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, Washington, DC. Amore, M., Ricci, M., Ferrari, G., 1998. Recurrent brief depression: clinical and therapeutic aspects. Eur. Neuropsychopharmacol. 8 (Suppl. 2), S174. Angst, J., 1988. Recurrent brief depression. A new concept of mild depression. Psychopharmacology 96, 123. Angst, J., 1990. Recurrent brief depression. A new concept of depression. Pharmacopsychiatry 23, 63 – 66. Angst, J., 1994a. The history and concept of recurrent brief depression. Eur. Arch. Psychiatry Clin. Neurosci. 244, 171 – 173. Angst, J., 1994b. Recurrent brief depression. In: Hippius, H., Stefanis, C.N. (Eds.), Research in Mood Disorders: an Update. Hogrefe and Huber Publishers, Seattle, pp. 17 – 30. Angst, J., 1997. Recurrent brief psychiatric syndromes: hypomania, depression, anxiety and neurasthenia. In: Judd, L.L., Saletu, B.F. (Eds.), Basic and Clinical Science of Mental and Addictive Disorders. Karger, Basel, pp. 33 – 38. Angst, J., Dobler-Mikola, A., 1984. The Zurich study: II. The continuum from normal to pathological depressive mood swings. Eur. Arch. Psychiatry. Neurol. Sci. 234, 21 – 29. Angst, J., Dobler-Mikola, A., 1985. The Zurich study—a prospective epidemiological study of depressive, neurotic and psychosomatic syndromes: IV. Recurrent and nonrecurrent brief depression. Eur. Arch. Psychiatry Neurol. Sci. 234, 408 – 416. Angst, J., Hochstrasser, B., 1994. Recurrent brief depression: the Zurich study. J. Clin. Psychiatry 55, 3 – 9 (Supplement). Berlin, R.E., Raju, J.D., Schmidt, P.J., Adams, L.F., Rubinow, D.R., 2001. Effects of the menstrual cycle on measures of personality in women with premenstrual syndrome: a preliminary study. J. Clin. Psychiatry 62, 337 – 342. Blumer, D., 2000. Dysphoric disorders and paroxysmal affects: recognition

L. Pezawas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 75–83 and treatment of epilepsy-related psychiatric disorders. Harv. Rev. Psychiatry 8, 8 – 17. Busse, E.W., Barnes, R.H., Silverman, A.J., Thaler, M., Frost, L.L., 1955. Studies of the processes of aging: X. The strengths and weaknesses of psychic functioning in the aged. Am. J. Psychiatry 111, 896 – 901. Carta, M.G., 2000. Personal communication. Clayton, P.J., Martin, S., Davis, M.A., Wochnik, E., 1980. Mood disorders in women professionals. J. Affect. Disord. 2, 37 – 46. Corominas, A., Bonet, P., Nieto, E., 1998. Recurrent brief depression successfully treated with lithium. Biol. Psychiatry 44, 927 – 929. Gertz, H.J., 1992. Kurzdauernde depressive Verstimmungen. Nervenarzt 63, 50 – 51. Glover, V., Jarman, J., Sandler, M., 1993. Migraine and depression: biological aspects. J. Psychiatr. Res. 27, 223 – 231. Gregory, M.S., 1915. Transient attacks of manic-depressive insanity. Med. Rec. 88, 1040 – 1044. Joffe, R.T., 1996. Tranylcypromine in recurrent brief depression: two case reports. Int. Clin. Psychopharmacol. 11, 287 – 288. Kasper, S., Stamenkovic, M., Pezawas, L., 2000. Recurrent brief depression: diagnosis, epidemiology and potential pharmacological options. In: Palmer, K.J. (Ed.), Managing Depressive Disorders. Adis International, Aukland, pp. 29 – 36. Kocmur, M., Dernovsek, M., Tavcar, R., 1998. Effect of paroxetine on intermittent brief depression episodes and suicide attempts among patients with personality disorders. A double blind, placebo-controlled study. Psychiatr. Danub. 10, 283 – 286. ¨ rzte, Kraepelin, E., 1899. Psychiatrie. Ein Lehrbuch fu¨r Studierende und A Bart, Leipzip. Kramlinger, K.G., Post, R.M., 1996. Ultra-rapid and ultradian cycling in bipolar affective illness. Br. J. Psychiatry 168, 314 – 323. Linden, M., Lecrubier, Y., Bellantuono, C., Benkert, O., Kisely, S., Simon, G., 1999. The prescribing of psychotropic drugs by primary care physicians: an international collaborative study. J. Clin. Psychopharmacol. 19, 132 – 140. Maier, W., 1993. Personal communication. Maier, W., Lichtermann, D., Oehrlein, A., Fickinger, M., 1992. Depression in the community a comparison of treated and nontreated cases in two nonreferred samples. Psychopharmacology 106, 79 – 81. Maier, W., Herr, R., Gansicke, M., Lichtermann, D., Houshangpour, K., Benkert, O., 1994a. Recurrent brief depression in general practice. Clinical features, comorbidity with other disorders, and need for treatment. Eur. Arch. Psychiatry Clin. Neurosci. 244, 196 – 204. Maier, W., Herr, R., Lichtermann, D., Gansicke, M., Benkert, O., Faust, G., 1994b. Brief depression among patients in general practice. Prevalence and variation by recurrence and severity. Eur. Arch. Psychiatry Clin. Neurosci. 244, 190 – 195. Meesters, Y., van Houwelingen, C.A., 1998. Rapid mood swings after unmonitored light exposure. Am. J. Psychiatry 155, 306. Merikangas, K.R., Merikangas, J.R., Angst, J., 1993. Headache syndromes and psychiatric disorders: association and familial transmission. J. Psychiatr. Res. 27, 197 – 210. Montgomery, S.A., Montgomery, D., 1992. Features of recurrent brief depression. Encephale 18, 521 – 523. Montgomery, S.A., Montgomery, D., Baldwin, D., Green, M., 1989. Intermittent 3-day depressions and suicidal behaviour. Neuropsychobiology 22, 128 – 134. Montgomery, D.B., Roberts, A., Green, M., Bullock, T., Baldwin, D., Montgomery, S.A., 1994. Lack of efficacy of fluoxetine in recurrent brief depression and suicidal attempts. Eur. Arch. Psychiatry Clin. Neurosci. 244, 211 – 215. Paskind, H.A., 1929. Brief attacks of manic-depressive depression. Arch. Neurol. Psychiatry 22, 123 – 134. Pazzaglia, P.J., Post, R.M., Ketter, T.A., George, M.S., Marangell, L.B., 1993. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatr. Res. 49, 257 – 272. Pazzaglia, P.J., Post, R.M., Ketter, T.A., Callahan, A.M., Marangell, L.B., Frye, M.A., George, M.S., Kimbrell, T.A., Leverich, G.S., Cora-Loca-

83

telli, G., Luckenbaugh, D., 1998. Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. J. Clin. Psychopharmacol. 18, 404 – 413. Pezawas, L., Stamenkovic, M., Kasper, S., 2001. Rezidivierende kurze depressive Episoden. Epidemiologie, Klinik, Diagnostik und Therapie. Nervenarzt 72, 169 – 180. Pezawas, L., Stamenkovic, M., Aschauer, H., Kasper, S., 2002a. Successful treatment of recurrent brief depression (RBD) with reboxetine: a single case analysis. Pharmacopsychiatry 35, 75 – 76. Pezawas, L., Stamenkovic, M., Jagsch, R., Ackerl, S., Putz, C., Stelzer, B., Aschauer, H., Kasper, S., 2002b. A longitudinal view on suicidal behavior in depression. J. Clin. Psychiatry 63, 866 – 873. Pezawas, L., Wittchen, H.-U., Pfister, H., Angst, J., Lieb, R., Kasper, S., 2002c. Recurrent brief depressive disorder reinvestigated: a community sample of adolescents and young adults. Psychol. Med. (in press). Pohl, E., 1852. Die Melancholie nach dem neuesten Standpunkte der Physiologie und auf Grundlage klinischer Beobachtungen. Verlag JG Calve’sche Buchhandlung, Prag (Chapter 4). Post, R.M., Weiss, S.R., 1998. Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders: the role of serotonergic mechanisms in illness progression. Biol. Psychiatry 44, 193 – 206. Post, R.M., L’Herrou, T., Luckenbaugh, D.A., Frye, M.A., Leverich, G.S., Mikalauskas, K., 1998. Statistical approaches to trial durations in episodic affective illness. Psychiatr. Res. 78, 71 – 87. Sartorius, N., Ustun, T.B., Costa e Silva, J.A., Goldberg, D., Lecrubier, Y., Ormel, J., Von Korff, M., Wittchen, H.U., 1993. An international study of psychological problems in primary care. Preliminary report from the World Health Organization Collaborative Project on ‘Psychological Problems in General Health Care’. Arch. Gen. Psychiatry 50, 819 – 824. Snaith, R.P., 2000. An enquiry into recurrent brief depressive episodes in the general population. Eur. Psychiatry 15, 261 – 263. Spitzer, R.L., Endicott, J., Robins, E., 1975. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. New York State Psychiatric Institute, Biometrics Research Unit, New York. Stamenkovic, M., Pezawas, L., de Zwaan, M., Aschauer, H.N., Kasper, S., 1998. Mirtazapine in recurrent brief depression. Int. Clin. Psychopharmacol. 13, 39 – 40. Stamenkovic, M., Blasbichier, T., Riederer, F., Pezawas, L., Brandstatter, N., Aschauer, H.N., Kasper, S., 2001. Fluoxetine treatment in patients with recurrent brief depression. Int. Clin. Psychopharmacol. 16, 221 – 226. Verkes, R.J., Van der Mast, R.C., Hengeveld, M.W., Tuyl, J.P., Zwinderman, A.H., Van Kempen, G.M., 1998. Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but not major depression. Am. J. Psychiatry 155, 543 – 547. Watanabe, H., Ohmori, O., Abe, K., 1997. Recurrent brief depression in Prader-Willi syndrome: a case report. Psychiatr. Genet. 7, 41 – 44. Weiller, E., Boyer, P., Lepine, J.P., Lecrubier, Y., 1994a. Prevalence of recurrent brief depression in primary care. Eur. Arch. Psychiatry Clin. Neurosci. 244, 174 – 181. Weiller, E., Lecrubier, Y., Maier, W., Ustun, T.B., 1994b. The relevance of recurrent brief depression in primary care. A report from the WHO project on psychological problems in general health care conducted in 14 countries. Eur. Arch. Psychiatry Clin. Neurosci. 244, 182 – 189. Wermuth, L., Soerensen, P., Timm, S., Christensen, B., Utzon, N., Boas, J., Dupont, E., Hansen, E., Magnussen, I., Mikkelsen, B., Worm-Petersen, J., Lauritzen, L., Bayer, L., Bech, P., 1998. Depression in idiopathic Parkinson’s disease treated with citalopram. Nord. J. Psychiatry 52, 163 – 169. World Health Organization, 1992a. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization, Geneva. World Health Organization, 1992b. International Statistical Classification of Diseases and Related Health Problems: ICD-10. World Health Organization, Geneva.