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Prevalence
The first observation in this regard is that the association of both groups of mood
disorders with RBD is very common: it occurred in 44% of BP-II and 39% of MDD.
In terms of weighted prevalence rates, the association was even higher, with 64% and
44% respectively. Thus, about half of all subjects with MDEs also manifested RBD.
Given the higher recurrence risk of BP versus MDD (Marneros et al., 1991; Angst
and Preisig, 1995, Lavori et al., 1996), it is comprehensible that RBD, as a rapid-
cycling depressive condition, was more often associated with BP-II than with MDD.


Comorbidity
We hypothesized that combined cases of mood disorders (defined by an associa-
tion with RBD) were clinically more severe than pure cases. Our epidemiological
data clearly confirm that the combined forms of BP-II and MDD differ from the
pure groups on many measures: earlier age of onset, higher rates of family history
of depression and anxiety, suicidality, treatment, atypicality, comorbidity with
anxiety disorders, certain personality disorders and traits (especially impulsivity),
and seasonality (in fall/winter as well as spring).
Taken together, these characteristics of combined BP-II and MDD convincingly
demonstrate the clinical relevance of the concept of combined mood disorders and
of a diagnosis of RBD.
Our failure to find that combined mood disorders had a higher association with
substance abuse/dependence than the pure forms is intriguing. It does not support
the hypothesis that RBD is a feature of personality disorders. Our findings are in
agreement with those of Staner et al. (1992) that RBD was not an unspecific
expression of axis II disorders. Our data also showed no association between
RBD and sociopathy and conduct problems in adolescence. All this is compatible
with Pezawas et al. (2002b), who also failed to find an association between
personality disorders (assessed by Structured Clinical Interview) (SKID II)
(Wittchen et al., 1998) and RBD in a study of clinical cases.
All these findings are in line with the hypothesis that RBD is not associated with
personality disorders but is linked with affective abnormalities of the personality,
such as depressive personality disorders and high impulsivity/irritability scores.


Risk of suicide attempts
The concept of brief depression originated in observations of its frequency among
suicide attempters in an emergency clinic and in a psychiatric practice (Gregory,
1908, 1915; Paskind, 1929, 1930).
124 J. Angst et al.


The findings of our analysis of suicide attempts are puzzling. They confirm an
association of RBD with a history of suicide attempts, but its effect as a risk factor
alone is smaller than that of MDE or dysthymia. The true clinical significance of RBD
is given by its association with MDE. We found the highest suicide attempt rates
among combined BP-II subjects (38.5%), compared to 25.6% in combined MDD and
to 22.6% in pure MDD; this finding is also linked to the greater psychiatric co-
morbidity of combined cases. On the other hand, our earlier finding that suicide
attempt rates in combined MDD were several-fold higher (30%) than in the pure
forms (7.7%) (Angst et al., 1990, Merikangas et al., 1990) was not confirmed by the
new data (where the figures were 25.6% versus 22.6% respectively). This may be in
part a consequence of the diagnostic shift of many cases from MDD to BP-II disorder.
Searching for further correlates of the association of RBD with suicide
attempts, we also analyzed personality traits measured by the FPI. Although,
compared to controls, aggressiveness was higher in all diagnostic subgroups of
mood disorders, the latter did not differ from each other. The findings on
impulsivity/irritability were important. Here all diagnostic groups differed
from controls but, in addition, all groups with RBD scored systematically higher
than the pure-mood-disorder groups. Thus we were unable to replicate the
findings of Pezawas et al. (2002b), who found differences between combined
depression and RBD in clinical cases.
We could not examine a postulated impulsivity/aggression factor underlying
suicidal behavior, which was extracted by factor analysis from the
Brown“Goodwin aggression inventory, Buss“Durkee hostility inventory, and
Barratt impulsivity scale (Mann et al., 1999) This factor was found in psychiatric
inpatients suffering from a cluster of disorders, e.g., alcohol or drug dependence,
borderline personality disorder, cigarette smoking and aggressive, impulsive beha-
viors. These disorders and behaviors were significantly associated with suicide
attempts. Furthermore, aggressiveness/impulsivity was recently shown to be
linked to a malfunctioning serotonergic system (Mann et al., 2001; Pezawas
et al., 2002b). Since our analysis was based only on multiple variables, this
relationship may have been missed on account of power problems. However,
biserial correlations and logistic regressions failed to confirm those findings in
our study. On the other hand we were able to show that the risk for suicide
attempts was linked to gender and to a diagnosis of MDE plus RBD.


What is the nature of RBD?
We do not think that RBD is only a residual syndrome of MDEs, fluctuating in
short recurrences, as first described in Sardinia (Carta et al., 1994) or the residuals
of dysthymia (Angst and Wicki, 1990). RBD can undoubtedly also precede MDD.
125 Recurrent brief depression


We found a transition from RBD to MDD in 14% of cases and the reverse
transition in 25% of cases (Angst, 1990). These findings have been recently
supported by another epidemiological study in adolescents and young adults
(Pezawas et al., 2003). RBD is therefore best considered as one of many course
patterns of the natural history of depression. Moreover, it is clearly not the case that
patients suffering from recurrent major depression experience only major episodes.
It is well established that half of such patients manifest multiple brief episodes of
depression and in addition depressive symptoms under the threshold of RBD or
minor depression, including symptom-free intervals in between. This has recently
also been reported by Judd et al. (1998) on the basis of a prospective long-term study
of depression and bipolar disorders (Judd et al., 2002, 2003). We would like to see
RBD established as a firm subgroup of the dimension of depression, ranging from
symptoms to severe episodes. This seems to be the most plausible concept.
A further-reaching interpretation would be that RBD is the manifest clinical
expression of a persisting instability of mood regulation, which may also be
expressed as a lowered threshold for exhibiting mood symptoms on stressful life
events. RBD patients might be more prone to exhibit depressive symptoms in the
presence of stressful environmental factors. This hypothesis is supported by the
Early Developmental Stages of Psychopathology study (Pezawas et al., 2003),
which found a strong relationship between posttraumatic stress disorder and
RBD. The irregular pattern of occurrences of depressive symptoms which are
linked to stressful events also supports this hypothesis (Pezawas et al., 2002a).
This interpretation would be compatible with the idea of a premorbid personality
or chronic low-threshold mood disorder, which is characterized by RBD and
frequent ups and downs. The latter has been shown to be a risk and/or vulnerability
factor for mood disorders (especially for BP-II). These frequent ups and downs as a
personality feature seem to be independent of the positive family history for BP and
depression (Angst et al., 2003b). This etiological model postulates two independent
types of risk factors: (1) family occurrence of mood disorders; and (2) unstable
mood regulation. We could speculate that suicidal behavior and such mood lability
share the same underlying biological factor. Mood stabilizers may influence the
biological mood lability. This hypothesis is supported by a single case analysis
(Pazzaglia et al., 1993) and a case report (Corominas et al., 1998).


Treatment of RBD and CD
There is a growing body of evidence that RBD can be successfully treated by
maintenance medication, although there is not one treatment study that has
recruited RBD subjects by diagnostic criteria for a controlled trial. Recent method-
ological advances (Post et al., 1998; Pezawas et al., 2002a), together with published
126 J. Angst et al.


reports (including open studies) on the successful treatment of almost 70 RBD cases,
mainly by serotonergic drugs (Gertz, 1992; Joffe, 1996; Amore, et al., 1998;
Corominas et al., 1998; Pazzaglia et al., 1998; Stamenkovic et al., 1998, 2001;
Mantgomery, Pezawas et al., 2002a; Verkes et al., 1998) are promising. This is
incompatible with the therapeutic pessimism of previous studies (Montgomery
et al., 1994; Montgomery, 1997; Kocmur et al., 1998), which discouraged research
in this field. Earlier negative controlled studies did not deal with truly representative
clinical cases of RBD but recruited chronic suicide attempters with personality
disorders (e.g., borderline personality disorder) and psychiatric comorbidity. Such
subjects, whose increased impulsivity makes them poor compliers, are very difficult
to treat and have also been shown to be non-responders to other treatments (Verkes
et al., 1998). Negative reports on RBD treatment may therefore be largely attribu-
table to the selection of patients (Montgomery et al., 1989).
Moreover, the successful treatment of RBD in open single-case studies provides
enough evidence on which to base controlled clinical trials without the serious
methodological flaws of earlier studies. A first-choice antidepressant treatment
trial with substances lacking severe side-effects seems to be justified. As a second-
line treatment, mood stabilizers should be considered. The design of such trials
should clearly distinguish between pure RBD and combined cases of RBD, because
the latter, as mentioned above, are likely to have a long previous history with a
chronic course, multiple admissions to psychiatric institutions, suicidality, and
treatment resistance (Pezawas et al., 2002b). Conventionally, such patients are not
taken into drug trials since they fulfill common exclusion criteria. Therefore no
evidence is at present available regarding the optimal treatment regime for this
highly prevalent and clinically important group.


Conclusion
The example of RBD demonstrates that severity measures of mood disorders
should not be restricted to the number of symptoms and the duration of episodes
and consequences but should also include recurrence (course). The concepts of
RBD and of combined mood disorders and their integration into psychiatric
practice are clinically relevant because they enable psychiatrists to identify a highly
prevalent, severely impaired, and often suicidal subgroup of patients. It also opens
the way for new therapeutic research.


Acknowledgment
This work was supported by grant 3200“050881.97/1 from the Swiss National
Science Foundation.
127 Recurrent brief depression



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