Journal of Affective Disorders 183 (2015) 119–133

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review

Cyclothymia reloaded: A reappraisal of the most misconceived

affective disorder
Giulio Perugi a,b,n, Elie Hantouche c, Giulia Vannucchi a, Olavo Pinto d
a
Deparment of Clinical and Experimental Medicine, University of Pisa, Italy
b
Institute of Behavioural Science "G. De Lisio", Pisa, Italy
c
Centre des Troubles Anxieux et de l’Humeur – Anxiety & Mood Center, 117, Rue de Rennes, Paris 75006, France
d
International Mood Clinic, Rio de Janeiro, Brazil

art ic l e i nf o a b s t r a c t

Article history: Data emerging from both academic centers and from public and private outpatient facilities indicate that
Received 26 March 2015 from 20% to 50% of all subjects that seek help for mood, anxiety, impulsive and addictive disorders turn
Received in revised form out, after careful screening, to be affected by cyclothymia. The proportion of patients who can be
4 May 2015
classified as cyclothymic rises significantly if the diagnostic rules proposed by the DSM-5 are
Accepted 4 May 2015
Available online 13 May 2015
reconsidered and a broader approach is adopted. Unlike the DSM-5 definition based on the recurrence
of low-grade hypomanic and depressive symptoms, cyclothymia is best identified as an exaggeration of
Keywords: cyclothymic temperament (basic mood and emotional instability) with early onset and extreme mood
Cyclothymia reactivity linked with interpersonal and separation sensitivity, frequent mixed features during depres-
Cyclothymic disorder
sive states, the dark side of hypomanic symptoms, multiple comorbidities, and a high risk of impulsive
Cyclothymic temperament
and suicidal behavior. Epidemiological and clinical research have shown the high prevalence of
Bipolar spectrum
cyclothymia and the validity of the concept that it should be seen as a distinct form of bipolarity, not
simply as a softer form. Misdiagnosis and consequent mistreatment are associated with a high risk of
transforming cyclothymia into severe complex borderline-like bipolarity, especially with chronic and
repetitive exposure to antidepressants and sedatives. The early detection and treatment of cyclothymia
can guarantee a significant change in the long-term prognosis, when appropriate mood-stabilizing
pharmacotherapy and specific psychological approaches and psychoeducation are adopted. The authors
present and discuss clinical research in the field and their own expertise in the understanding and
medical management of cyclothymia and its complex comorbidities.
& 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
2. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3. Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
4. Diagnostic aspects: the bipolar spectrum-borderline personality controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
5. “Comorbidity” and its complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
6. Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
7. Epidemiological and demographic characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
7.1. Longitudinal course and outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
8. Treatment strategies and practical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

n
Correspondence to: Dipartimento Medicina Clinica e Sperimentale, Sezione di Psichiatria, Università di Pisa, Via Roma 67, 56100 Pisa, Italy.
E-mail addresses: giulio.perugi@med.unipi.it, giulio.perugi@gmail.com (G. Perugi).

http://dx.doi.org/10.1016/j.jad.2015.05.004
0165-0327/& 2015 Elsevier B.V. All rights reserved.
120 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133

Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

1. Introduction
In this review we have reorganized the current descriptions of
cyclothymia with the purpose of clarifying the clinical pictures
Cyclothymia is by no means a new disorder; even so, and
that arise from it, its relationships with other mental disorders and
despite its deep roots in the psychiatric tradition, it has been its long-term course. Lastly, we refocus the objectives of an
widely neglected over the last 50 years, even among experts in effective pharmacological and psychoeducational treatment and
mood disorders. Major Depressive, Dysthymic, Bipolar I and II a specific clinical management of cyclothymic patients.
disorders have been the object of most epidemiological, psycho-
logical, biological and clinical studies. As a result, research on
treatment has been almost exclusively focused on acute manic and 2. History
depressive states and the long-term prevention of major mood
episodes. The relationship between severe melancholic and manic states,
In recent years the lack of uniformity in the way cyclothymia is and attenuated or subclinical forms of mood disorders has been
conceived of, and the tendency to describe this disorder only in recognized since antiquity. The term ‘cyclothymia’ was first used to
terms of mood symptoms have led to misinterpretations and con- refer to a mood disorder by Ewald Hecker, 1877 (Baethge et al.,
fusion. Cyclothymia has been conceptualized according to different 2003a), a pupil of Ludwig Kahlbaum. The accurate clinical descrip-
perspectives as a subtype of bipolar disorder (BD) (Akiskal et al., tions and profound knowledge of psychopathology of Hecker and
1977) and as an affective temperament (Akiskal et al., 1979), or even Kahlbaum make them the forerunners of modern descriptions of
as a personality style (Brieger and Marneros, 1997; Parker, 2011). cyclothymia and BD II (Koukopoulos, 2003). They initially viewed
In the current international classifications of mental disorders manic-depressive psychosis (Vesania Typica Circularis), with its
(DSM-5 and ICD-10), cyclothymic disorder is considered a subtype tendency toward a deteriorative course, and cyclothymia, which is
of BD, similarly to BD I and BD II disorders, marked out by a chronic never associated with psychosis or dementia, as separate entities
presentation of low-grade, alternating depressive and hypomanic (Baethge et al., 2003a,b). On the basis of the frequent coexistence
symptoms. According to DSM-5, if an individual with cyclothymic of attenuated and severe forms in the same patient and in the
disorder experiences a major depressive or a manic episode, the same family, Kraepelin (1921) criticized this view, and considered
diagnosis is dropped and the patient is reclassified as BD I or BD II. cyclothymia as an attenuated form of manic-depressive illness. In
This categorical approach favors the view that considers cyclothy- addition to traditional forms of mania and melancholia, Kraepelin
mia as being no more than a residual minor category, instead of included within manic-depressive illness attenuated depressive
recognizing its clinical importance and independent profile. conditions that alternate with episodes of manic excitement of
From a temperamental standpoint, cyclothymia has been con- lower intensity (hypomania). He also described: long-lasting
sidered as an affective disposition associated with moodiness and stable depressive, manic (hyperthymic), cyclothymic or irritable
impulsivity – thus functioning as a possible step between non-cli- temperamental traits, which he referred to as constitutional “basic
nical levels of mood fluctuation and full-blown BD (Akiskal et al., states” (Kraepelin, 1921).
1979). According to this approach, cyclothymic temperament sho- Almost contemporarily, the French psychiatrists Gaston Deny
uld be viewed as a risk factor for psychopathology and it may and Pierre Khan (1909) made a fundamental contribution to the
significantly increase the risk of developing BD I or II, along with description and conceptualization of cyclothymia. Mediating
many other mood, anxiety, personality, eating and impulse control between the positions of Khalbaum and Hecker on one hand and
disorders, including drug and alcohol abuse, and behavioral addic- Kraepelin on the other, Deny and Khan emphasized the constitu-
tions (Perugi and Akiskal, 2002). tional nature of cyclothymia. They considered these attenuated
The idea of cyclothymic temperament as a diathesis runs parallel forms of manic-depressive illness as exaggerations of a “special
with the conceptualization of cyclothymia as an intermediate stage in constitution” that “preexist their appearance and persist after their
the development of other mental disorders. A cyclothymic disposi- disappearance”. By adopting this perspective, Kahn (1909) pro-
tion can be considered, otherwise, as a character trait, a personality vided a careful description of the complex psychopathology and
descriptor without any direct relation to psychopathology (Brieger clinical presentation of Cyclothymia, With the support of 30 case
and Marneros, 1997). Any of these definitions of cyclothymia can be vignettes, he described depressive and hyperthymic phases, fre-
demonstrated to be empirically correct, but this range of definitions quent mixed features, mood instability and reactivity, behavioral
applied to a single term may prove to be misleading. Each of these and relational problems, comorbidity and overlap with “neurotic”
definitions of cyclothymia weaves complex relationships with other disorders such as neurasthenia, psychasthenia and hysteria (nowa-
psychiatric disorders, especially mood and personality disorders (PD), days: panic disorder/agoraphobia, OCD, social anxiety and somato-
but also anxiety, substance use, eating, impulse control disorders and form disorders), as well as alcohol and substance abuse.
so on. Those relationships can be so tangled that a failure to rec- As many as seven decades passed before Akiskal (1981) first
ognize the underlying mood disorder is almost the rule. developed a temperamental perspective for cyclothymia, incorpor-
This phenomenon of under-recognition is further favored by ating the Kraepelinian concept of “basic states” as the constitu-
current international diagnostic criteria, which are exclusively focused tional expression of manic-depressive illness. The operational
on the cyclothymic aspects of “mood” (e.g. alternation between dep- criteria proposed by Akiskal et al. (1998) reflect the classic
ressive episodes and hypomanic symptoms in an attenuated form), descriptions and the bipolar nature of cyclothymic temperament
while completely neglecting psychological aspects, behavioral symp- in a way that is supported by a series of studies that have
toms and important clinical features, such as excessive mood reactiv- highlighted the strong propensity of these subjects to switch
ity, impulsivity and anxiety. toward hypomania and/or mania when treated with
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
antidepressants and their tendency to have a positive family
history for BD (Angst and Marneros, 2001; Koukopoulos, 2003).
Thanks to the fundamental contributions of Akiskal, the diag-
nosis of “cyclothymic disorder” was included in DSM-III (1980) in
the chapter on Mood Disorders, and ICD-10 later consolidated this
trend. Cyclothymia received a broad empirical validation as a
bipolar spectrum disorder, and for this reason it remained classi-
fied as a mood disorder in DSM-IV and, similarly, in DSM-5,
alongside BD I, II and other specified or unspecified BD and related
disorders. No specific features, were, however, provided, apart
from the lower intensity of mood symptoms and their protracted
duration.
3. Psychopathology
The clinical presentation of cyclothymia is particularly rich in
psychopathological manifestations. In this sense a diagnostic
definition essentially based on the presence of mood symptoms
could be very simplistic and misleading. Indeed, mood symptoms
are by definition attenuated and may not even be reported, or may
be considered as no more than peripheral in many patients. In
reality, cyclothymia can best be defined by mood and emotional
instability, and over-reactivity to positive or negative stimulations,
whether in terms of intensity or duration.
Invariably, intense and rapid mood fluctuations of opposite
polarity are associated with rapid changes in energies and motiva-
tion, with major psychological, interpersonal and behavioral con-
sequences that usually prove to be the most prominent clinical
expression of the disorder. In most cases, such clinical features are
in continuity with the ‘habitual self’ of the individual, and because
the mood disorder or its related behavioral problems usually begin
during childhood or adolescence, they are often viewed as ‘char-
acter’ or ‘personality’ problems. Depressive symptoms are fre-
quently attributed to concomitant stressful life events, whereas
elation and related sub-excitatory symptoms go unrecognized or
are considered as a personal index of well-being and/or the con-
sequence of positive situations or new opportunities.
Cyclothymic subjects have continuous and irregular mood ‘highs’
and ‘lows’ for extended periods of time; mood switches are often
abrupt, while interposed periods of mood stability are infrequent
(Akiskal et al., 2006a; Birmaher et al., 2014; Hantouche and Akiskal,
2006; Van Meter, 2013); in some cases major mood episodes of both
polarities may appear (Akiskal et al., 1977; Perugi et al., 2012; van
Valkenburg et al., 2006). Patients with frequent and abrupt switches
of mood associated with short but definite depressive and hypo-
manic episodes have been considered as ultra-rapid or ultradian
cyclers (Mackinnon and Pies, 2006; Papolos et al., 1998). The
intensity, rapidity and unpredictability of mood swings are a major
cause of distress, and produce a considerable degree of instability in
terms of self-esteem, vocation and interpersonal relationships.
In cyclothymic patients, because of their constitutional mood
instability and reactivity, depressive and hypomanic phases are extr-
emely variable in terms of duration, severity and symptomatology
(Akiskal et al., 2003a; Depue et al., 1981; Perugi and Akiskal, 2002).
As expected, depressive symptoms are clinically identified more
often than hypomanic symptoms, regardless of severity (Cassano
et al., 1999). Severe psychomotor disorder, melancholic and psycho-
tic features are very uncommon (van Valkenburg et al., 2006),
although they are occasionally reported during major mood epi-
sodes (Perugi et al., 2012). Most commonly, cyclothymic depression
is of mild to moderate severity and is marked by despair, anguish,
fatigue and atypical features (Perugi et al., 1998). Feelings of low self-
worth and guilt, insecurity and dependence, emotionality, agitation
and extremely high sensitivity have been reported (Alnaes and
Torgensen, 1989), along with high levels of irritability and anxiety
121
(Perugi et al., 2003), as well as a tendency to emphasize social and
interpersonal difficulties (Hantouche et al., 2003a). Typically, during
depressive or mixed periods, cyclothymic patients report frequent
suicidal thoughts and, quite often, self-injuring or suicidal gestures
(Pompili et al., 2012; Rihmer et al., 2013).
The hypomanic phases may not be easy to identify. In many
cases hypomanic episodes last for hours or – but less frequently –
for more than 1 or 2 days or weeks (Angst et al., 2005). The
literature consistently describes irritability as a key characteristic
of cyclothymic disorder during both hypomanic and depressive
periods. In contrast to ‘sunny’ hypomanic episodes that are
described as a pleasant, elated, sometimes hyperactive and highly
productive state, cyclothymic hypomania can be ‘dark’, displaying
irritability, impulsivity and risk-taking behavior (Akiskal et al.,
2003a; Hantouche et al., 2003a). This can be particularly impor-
tant in young people, in whom moderate or severe irritability,
associated with aggression and outward hostility, has been
reported in over 90% of the cases examined, during periods in
which mood is elevated(Jensen et al., 2007; Masi et al., 2007). The
presence of irritability during hypomania could be a factor in the
frequent misdiagnosis of cyclothymia as depression (Utsumi et al.,
2006) or personality disorder (Perugi et al., 2011, 2013a, 2013b;
Stone, 2013b).
Although they went unrecognized in the international diagnostic
manuals until DSM-5, depressive mixed states – in which both
depressive and hypomanic symptoms are present – occur regularly
and are probably the most common presentation in clinical practice
(Azorin et al., 2011; Perugi et al., 2014). As a result, predominan-
tly depressive periods may also be marked by extreme irritability,
impulsivity and explosive temper (Akiskal et al., 1977). Crowded and
racing thoughts, pressure to keep on talking and a tendency to be
distracted have often been reported in unipolar, bipolar II (Benazzi,
2005, 2006a, 2006b) and cyclothymic depression (Perugi et al., 1998).
In some cases, the mood swings may have a circadian component
with biphasic characteristics, such as lethargy alternating with
excitement, reduced verbal productivity alternating with excessive
loquacity, and low self-esteem alternating with excessive self-
confidence (Akiskal et al., 1977). People with cyclothymic disorder
tend to be impulsive and unpredictable during hypomanic or mixed
states, with irritable mood directed at others, whereas during
depressive periods they may be very sensitive, but also tend to
experience self-directed irritability consistent with guilt, ruminations,
and low self-esteem (Akiskal et al., 1985b, 1977).
Increased mood and emotional reactivity is the major char-
acteristic of cyclothymia and stands as the ‘core’ feature of the
overall clinical presentation. Cyclothymic patients report a parti-
cular kind of increased sensitivity to environmental stimuli as a
stable trait continuing since adolescence. They react to positive
events by quickly becoming joyful, enthusiastic, dynamic and by
taking the initiative (sometimes with excessive euphoria and
impulsiveness); on the other hand, in responding to ‘negative’
events (real, or experienced as such) they become distressed,
while experiencing feelings of deep prostration, extreme fatigue,
sadness, anguish, desperation and, sometimes, suicidal thoughts.
Even minor disappointments can precipitate distress, at times
complicated by uncontrolled crushing reactions, with the imple-
mentation of self-harming gestures.
Exaggerated positive and negative mood, together with emo-
tional reactions, can be triggered by any sort of external stimuli,
whether psychological (for example, falling in love vs. sentimental
disappointments), environmental (e.g., meteorological changes or
changes of time zone), physical (e.g. immobility vs. hyperactivity) or
chemical (e.g. medications, alcohol or drugs). Mood reactivity and
instability are invariably associated with a series of psychological
and behavioral consequences that may stand as the major com-
plaints or symptoms for many of these subjects (Table 1).
122 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133

Table 1
Psychological and behavioral aspects of cyclothymia.

Psychological faults Behavioral consequences

Sensitivity to rejection, judgment and criticism Hostility toward significant others (lovers, family members, friends, coworkers), unstable and intense
interpersonal relationships
Sensitivity to separation and affective dependency Efforts to avoid real or imagined abandonments, dramatic reaction to real or dreaded abandonment,
pathological attachment
Pathological jealousy Interpersonal ‘cannibalism’
Excessive need to please others Submissiveness, pathological altruism, dependent behaviour
Compulsive need for compliments and emotional rewards Attention seeking, seductive or provocative behavior, physical appearance to draw attention, pseudo-
hypersexuality
The belief that one is not loved enough or is misunderstood Tendency to test and exceed limits in interpersonal relationships
Novelty-seeking mixed with harm-avoidance Conflicting behavior, need for psychological explanations and treatments
Compulsive and impulsive behaviors Substance use and behavioral addictions (e.g. gambling, compulsive buying, compulsive sexuality)
Shaky self-esteem, ranging from low self-confidence to Romantic, geographical and work instability
overconfidence

Interpersonal sensitivity and increased mood reactivity are
strictly associated; they should be considered two different asp-
ects, cognitive and affective, of the same psycho(patho)logical
dimension (Perugi et al., 2011, 2003). High sensitivity to judgment,
criticism and rejection by others is also related to weak self-
esteem. Some cyclothymic subjects are promptly offended and are
likely to be easily wounded, with feelings of hostility and anger
towards those who are considered the originators of these reac-
tions – those that they consider responsible for their suffering. In
some cases they may have explosions of rage following minor
disputes, which have the effect of triggering ‘avalanche’ reactions
with destructive consequences on interpersonal life. When emo-
tional reactions are very intense, sensitivity may favor the onset of
a more or less transient tendency to interpretation and over-
valued ideas.
Separation anxiety turns out to be related to cyclothymic mood
instability and, sometimes, reactivity (Perugi et al., 2012; Pini et al.,
2005). A significant correlation between separation anxiety, inter-
personal sensitivity and cyclothymic mood instability has been
demonstrated in several studies in adults with mood and anxiety
disorders (Perugi et al., 2003; Toni et al., 2008). In particular, the
link between childhood and/or adult separation anxiety and mood
instability of cyclothymic type has been confirmed by various
research groups in different populations (Pini et al., 2005; Toni
et al., 2008).
Fear of being disapproved, rejected or turned away, and anxiety
upon separation, with their negative emotional consequences, can
determine submissive behavior and persistent involvement in abu-
sive relationships. On the other hand, the tendency to please others
with excessive dedication may result in forms of conduct definable as
‘pathological altruism’. The oscillation between complacency and
excessive feelings of anger-hostility may have a negative impact on
romantic relationships, family life or employment, which become
more and more difficult and unstable (Hantouche and Perugi, 2012).
Another source of subjective and interpersonal distress is the difficult
coexistence of opposite and conflicting attitudes with temperamental
traits such as a high level of novelty seeking and harm avoidance
(Signoretta et al., 2005).
Individuals with such mood and emotional over-reactivity,
when they switch towards exhilaration, often seek for sentimental
and interpersonal relationships; conversely, when they are dys-
phoric they tend to isolate themselves from others. Indeed, the
youth of many of these patients may turn out to be a continuous
succession of tempestuous short but intense romantic relation-
ships with partners who are often unsuitable (Perugi and Akiskal,
2002). What appears to afflict these patients most is their periodic
swinging between behavioral inhibition and activation, which
prompts them towards interpersonal relations – placing them
in situations to which they respond with an avalanche of hard to
manage emotional reactions, so creating a path full of existential
dramas and tragedies (Hantouche and Perugi, 2012).
The intense mood and emotional reactivity of cyclothymic indivi-
duals might also favor sensation seeking and self-stimulating beha-
vior, which becomes amplified during hypomanic phases (Perugi and
Akiskal, 2002). In many cases we may become witnesses to the
emergence of true impulse control disorders such as pathological
gambling and compulsive sexuality in men, and compulsive buying
and binge eating in women (Chaim et al., 2014; McElroy et al., 1996,
2005; Perugi and Akiskal, 2002; Powers et al., 2013). Viewed from the
same perspective, cyclothymia also seems to offer a fertile ground for
drug abuse and addiction (Maremmani et al., 2006). On one hand
sensation-seeking behavior, on the other a high reactivity to sub-
stances, both facilitate the use of any sort of drug, alcohol, stimulant,
and cocaine, but also hypnotics and sedatives (Maremmani et al.,
2006; Mirin et al., 1991). In some subjects, for environmental reasons,
mood instability and impulsivity, when combined with substance
abuse, can favor the emergence of antisocial conducts with legal
consequences (Calabrese and Delucchi, 1990; Calabrese et al., 1993;
Masi et al., 2008).
4. Diagnostic aspects: the bipolar spectrum-borderline
personality controversy
“Attenuated” forms of bipolarity are not fully recognized either
in DSM-5 or in ICD-10, where BD is identified by giving descrip-
tions of classic manic-depressive illness (BD type I), or of forms in
which depression is associated with “hypomanic” episodes (BD
type II). In both these diagnostic systems, hypomania is conserva-
tively described as a period of euphoric or irritable mood lasting at
least 4 days and marked out by the same symptomatological
profile, but at a lower intensity and with less impairment when
compared with mania. In DSM-5 cyclothymic disorder is defined
by the occurrence of “periods with hypomanic symptoms that do
not meet criteria for a hypomanic episode and periods with
depressive symptoms that do not meet criteria for a depressive
episode”; thus no specific type or cut-off number of symptoms is
required. DSM-5 does allow for a diagnosis of cyclothymic dis-
order, even with a history of hypomania, mania, or depression –
but only if the cyclothymic disorder came first, and if it lasted for a
sufficient period of time to support that diagnosis. A good analogy
would be with the concept of “double depression”, where a
dysthymic disorder predates the onset of a full major depressive
episode (Angst, 2013; Van Meter et al., 2011; Youngstrom, 2009).
In clinical practice, most cyclothymic patients are or were referred
to clinical attention for major affective episodes. On this point
DSM-5 supports the view that cyclothymia often predates and
may lead to full-blown affective episodes or suicidal behavior
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
(Kochman et al., 2005). Lastly, in DSM-5, as in previous editions,
the key issue of the continuity with temperament and personality
dispositions is omitted.
Similarly, ICD-10 included cyclothymia in mood disorders, provid-
ing a rather broad definition of the disorder as “a persistent inst-
ability of mood involving numerous periods of depression and mild
elation, none of which is sufficiently severe or prolonged to justify a
diagnosis of bipolar affective disorder or recurrent depressive dis-
order”. ICD-10 overtly recognized that the disorder is frequently
found in the relatives of patients with bipolar affective disorder and
that some patients with cyclothymia eventually develop BD.
Both in the ICD-10 and DSM-5 many of the core symptoms,
psychological consequences and behavioral abnormalities of cycl-
othymia are left unmentioned. Excessive emphasis is given to vari-
ations in mood (hypomanic symptoms vs. depression), which at
most help to define the disorder, whereas most of the essential
motivational, volitional, emotional and cognitive aspects of the
clinical picture are not even mentioned in the diagnostic criteria or
among the associated features of cyclothymic disorder.
Mood reactivity and affective instability, extreme emotionality
and impulsivity, which should be considered as the true core features
of cyclothymia, as well as most of their psychological, behavioral and
interpersonal consequences, are described from a different perspec-
tive in the DSM-5 criteria for dramatic or anxious clusters of per-
sonality disorders and in the ICD-10 definition of emotionally unst-
able and histrionic personality disorders. This approach imposes a
major limitation on how best to understand the relationship between
constitutional traits and major episodes in mood-disordered patients,
but also the close link between cyclothymia and other anxious and
impulse control disorders, with major implications for their treat-
ment and clinical management.
The ICD-10 and DSM-5 definitions of emotionally unstable, bor-
derline and histrionic personality disorders share broad symptomatic
areas with cyclothymia. Expressed in phenomenological terms, the
moodiness, impulsivity, and interpersonal problems of cyclothymic
patients are similar to those described in DSM-5 cluster B personality
disorder (Henry et al., 2001; Mackinnon and Pies, 2006; Perugi et al.,
2011). In many cases, the distinction from histrionic or borderline
personality disorders (BPD) mainly depends on the perspective and
moment of observation, rather than on real clinical differences (Levitt
et al., 1990; Perugi et al., 2013a).
The issue of mood instability in BPD and bipolar spectrum
patients has been explored in several studies (Henry et al., 2001;
Koenigsberg et al., 2002; Reich et al., 2012) by using the Affective
Lability Scale (ALS), a self-rating instrument that examines shifts into
several affective domains – anger, depression, elation, and anxiety.
These studies found that both BPD and BD patients reported high
scores on affective lability measures. When compared with DSM-IV
bipolar II patients, BPD subjects displayed significantly more affective
lability between anger and euthymia, anger and anxiety, and oscilla-
tions between depression and anxiety. Bipolar spectrum patients
displayed significantly more affective lability between depression
and/or elation and euthymia. The authors concluded that these two
disorders share mood instability, but have different patterns of aff-
ective oscillation. This perspective is essentially based on the misc-
onception that unstable, depressive, irritable, anxious and labile
mood, with superimposed paroxysms of rage, as they are described
in setting out the criteria for BPD, must be relegated to the
personality realm and that only a classical episodic depressive–
euphoric–euthymic affective disorder should be allowed to qualify
as a ‘true’ BD. Actually, there is no clear evidence of a distinction
between the mood reactivity and instability described by BPD
patients and the subjective mood experienced in an anxious, irritable
or dysphoric, hypomania or mixed states (Dilsaver et al., 2005; Perugi
et al., 1999b; Sato et al., 2003; Young et al., 1993). Unless or until
such evidence is provided, current BPD criteria might describe a
123
subpopulation of particularly severe, impulsive irritable cyclothymic
subjects from a different perspective.
In comparison with patients suffering from emotionally unstable
personality disorders, cyclothymic patients are considered more
syntonic and outgoing – therefore capable of pursuing socially acce-
ptable objectives (Parker, 2011). Clinical experience suggests, how-
ever, that these two poles, rather than belonging to two distinct
categories, can be distinguished by the severity of impulsivity and
mood symptoms, and the presence or absence of an adequate
‘goodness of fit’. This concept refers to the possibility that some
environmental factors, as well as the expectations and requests of a
given environment, go to shape an individual’s personality and tem-
peramental characteristics as well as his/her lifestyle. By adopting
this perspective it should become easier to understand how cyclothy-
mia and its variants provide, on one hand, the background for anti-
social and psychopathic behavior, but also, on the other, those
extraordinary qualities, such as creativity and aptitude for leadership,
which distinguish some cyclothymic individuals. The latter capabil-
ities are determined by variables that are independent of the mood
disorder, such as skill, talent, intelligence, but also opportunity, luck
and external influences.
The literature on the relationship between mood disorders and
BPD has reached different and sometimes conflicting conclusions.
Evidence indicates that a significant percentage of patients with BPD
fall into the BD spectrum (Smith et al., 2004) and that the two
disorders are closely linked by their phenomenology and treatment
response (Belli et al., 2012). By contrast, several reviews have
concluded that the empirical evidence does not support a link
between BPD and the BD spectrum (Dolan-Sewell et al., 2001;
Paris, 2004). A recent clinical overview (Ghaemi et al., 2014) pointed
out that the two disorders are distinguishable clinically and diag-
nostically, and hypothesized that BD can be seen as a genetically
based biological disease, whereas BPD should be considered a
psychosocially caused disorder. However, as in the case of other
major mental disorders, hereditary, biological and environmental
factors may influence the pathogenesis and the clinical expression of
bipolar spectrum disorders in various ways, so contributing to the
extreme heterogeneity of clinical presentations.
In a recent review dedicated to the neurophysiological basis of
emotional instability in BPD, Michel Stone, a forerunner of the
modern conceptualization of BPD (Stone, 2013a), recognized that a
considerable proportion of BPD patients had strong family his-
tories of manic-depressive disorders (Stone et al., 1981; Torgersen,
1984), and some of them not only had many clinical attributes
reminiscent of BD, but, if first diagnosed with BPD when in their
late teens, then went on to develop clear-cut BD as they entered
their 20 s and 30 s (Akiskal, 1981; Stone, 1981). It has recently been
hypothesized that some abnormalities of brain function may be
responsible for the clinical features of both BD and BPD –
especially in borderline patients where BD had occurred in some
of their close relatives (Stone, 1981). Most of the debate seems to
emerge from the conflicting positions of those who give priority to
constitutional factors and those who attribute the characterologi-
cal disorder to development-related events.
Some of the diagnostic criteria for the BPD have a strong
emotional connotation: unjustified rage, emotional instability,
suicidal tendencies and unstable relationships. In various surveys
on borderline patients, a high prevalence of cyclothymia and/or
attenuated bipolar spectrum disorders has been documented,
while, symmetrically, in cyclothymic patients the prevalence of
borderline personality traits is very high (Levitt et al., 1990; Stone,
1990). In a German study in which “sub-affective personality
disorders” were rigorously assessed, patients with BPD and those
with cyclothymic-irritable temperament displayed a considerable
overlap in their clinical presentations (Sass et al., 1993). In two
multicenter, multinational cross-sectional clinical studies on two
124 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
very large clinical samples of patients with MDE, lifetime comorbidity
with BPD was significantly associated with the various different
diagnostic definitions and with all the external validators of bipolarity
(Perugi et al., 2013b). The association was particularly striking for
mania and hypomania in first-degree family members and the
presence of mixed features during the current depressive episode
(Perugi et al., 2013a). In addition, consistently with previous observa-
tions (Levy et al., 1998; Stone, 2006), BPD proved to be a predictive
factor for antidepressants-induced hypomania (Perugi et al., 2013a,
2013b). Furthermore, several follow-up studies have suggested a close
correlation of BPD with mood disorders, considering the number of
young borderline patients who, over the years, developed bipolar I or,
more frequently, bipolar II disorder (Gunderson et al., 2006).
Gunderson and Phillips (1991) pointed out that, in BPD, depres-
sive disorder shows a qualitatively different profile compared with its
features in major depression, being more developmentally and
interpersonally based. Moreover, mood swings in BD can be expected
to be more spontaneous and less responsive to environmental
triggers than in BPD. It has been hypothesized that a specific dep-
ressive subtype is often connected with BPD. Recent studies
(Gremaud-Heitz et al., 2014; Posternak and Zimmerman, 2002)
found that 27% of their BPD patients had a comorbid atypical
depression (AD) that seems to be correlated with the severity of
psychopathology and the presence of anxiety and interpersonal
problems. As for hypomania and mania, this perspective is essentially
based on the assumption that reactive, unstable, depressive, irritable,
anxious and labile depression, with superimposed paroxysms of rage,
as described in the BPD criteria, must be relegated to the personality
realm and that only classical non-reactive episodic depressive
changes are ‘true’ mood disorders. The fact remains, however, that
atypical depression has been frequently associated with BD II dis-
order (Benazzi, 2003; Perugi et al., 1998).
The essential elements of the affective deregulation experienced
by borderline patients are their extreme emotional reactivity and
affective lability, which, together with interpersonal sensitivity and
separation anxiety, may be the substrate for some of the elements
that are shared by cyclothymia, atypical depression and BPD (Perugi
et al., 2011). Suicidal behavior and other self-harming acts may reflect
the frequent presence of mixed features, with desperation and fee-
lings of hopelessness associated with impulsivity and irritability.
However, some of the authors involved in this research area mini-
mize the mood component of BPD, and prefer to consider these pat-
ients’ extreme emotional and behavioral lack of control as a result of
physical and psychological abuse (Fossati et al., 1999; Gunderson
et al., 2006), despite strong evidence that most of the borderline pati-
ents did not report a personal history of abuse {Bierer et al., 2003,
p. 279; Kuo et al., 2011).
Several studies have shown that BPD adults more frequently
report early physical and sexual abuse and mention having witnessed
domestic violence than non-borderline ones (Bandelow et al., 2005;
Battle et al., 2004; Goodman and Yehuda, 2002; Herman et al., 1989),
but a meta-analysis of 21 studies yielded a small pooled effect size
for BPD/Child abuse association (r¼0.28), so failing to support the
hypothesis that abuse is a major psychological risk factor or a causal
antecedent of BPD (Fossati et al., 1999). On the other hand, studies
have so far provided consistent evidence that a history of trauma is
not an inevitable prerequisite for the development of BPD or a
specific predictor of it; a trauma may, in fact, predispose to a wide
range of different psychiatric syndromes (Bierer et al., 2003; Kuo
et al., 2011). An estimated 20–45% of BPD probands have no history
of sexual abuse (Goodman and Yehuda, 2002), while 80% of
individuals with a history of sexual abuse have no personality
pathology (Paris, 1998). Interestingly, longitudinal studies show that
substantial numbers of severely abused children remain functionally
resilient, with little impairment across the social, occupational and
interpersonal domains (McGloin and Widom, 2001) but, regrettably,
such prospective investigations have not carried out any specific
assessments on BPD (McGloin and Widom, 2001; Silverman et al.,
1996). Moreover, the evidence in favor of the heritability of BPD casts
doubt on the view that trauma is the sole etiology and, as an
alternative, suggests the possibility of an innate hypersensitivity to
stressors. For example, the estimated morbid risk in first-degree
relatives of BPD patients amounts to 11.5%, supporting interaction
between genetic transmission and environmental factors (Nigg and
Goldsmith, 1994). A Norwegian report (Torgersen et al., 2000), by
examining a sample of 92 monozygotic and 129 dizygotic twin pairs,
yielded a concordance for BPD of 35% and 7%, respectively: these data
support the existence of a genetic component which plays its specific
role in transmission, as well as the importance of environmental
elements in triggering symptomatic manifestations and uncovering
the disease. A possible interpretation is that an underlying tempera-
mental instability (with a strong genetic component) could be the
root substrate for the development of borderline manifestations.
Several replicated findings are now available that are pertinent to
the hypothesis that BPD could in some cases have a cyclothymic
background (Akiskal et al., 1985a; Levitt et al., 1990; Perugi et al.,
2003, 2011, 2013b; Stone, 2014): cyclothymia occurred more fre-
quently in BPD than in other personality disorders, regardless of
which diagnostic system was used (Levitt et al., 1990). From a
neurobiological point of view too, bipolar spectrum disorder and
borderline personality share some similarities: a number of studies
have reported structural as well as functional abnormalities in the
amygdala of borderline subjects, as also in regulatory areas such as
vPFC, OFC, ACC (Domes et al., 2009). Taken together, these abnorm-
alities in parts of the neural network subserving emotional informa-
tion processing (i.e., amygdala hyper-reactivity in concert with
regulatory deficits of the OFC and the PFC) suggest that in these
patients emotional arousal interferes with cognitive processing
(Domes et al., 2009; Ruocco et al., 2013) and constitutes a hallmark
feature of BPD. Interestingly, many of the circuits implicated in BPD
appear to be involved in BD as well: patients with BD showed
overactivation within the parahippocampus/amygdala and thalamus,
and reduced involvement within the ventrolateral prefrontal cortex
(vlPFC), consistently with the notion of reduced emotional regulation
(Delvecchio et al., 2013). Notably, in a recent functional magnetic
resonance examination (Whalley et al., 2011) of healthy subjects
compared with individuals at high genetic risk of developing BD, the
latter revealed increased activation in the left amygdala. Moreover, a
significant association was found between cyclothymia and deactiva-
tion in ventral prefrontal regions. The Authors suggested that the
differences in activation in the left amygdala in subjects at familial
risk of developing BD may arise from a heritable endophenotype of
the disease, while deactivation in ventral prefrontal regions may act
as a biological basis of the subclinical features of the illness, such as
cyclothymia (Whalley et al., 2011). The fact that borderline and
cyclothymic patients share a strong difficulty in modulating their
behavior during negative emotional states is an unequivocal common
clinical feature that has a plausibly shared neural basis.
5. “Comorbidity” and its complications
A growing number of observations show that mood instability,
which is typical of cyclothymia, is the common factor underlying a
wide range of comorbidity and complications associated with
bipolarity, including anxiety (Perugi et al., 1999b), impulsivity
(McElroy et al., 1996), suicidality (Rihmer and Pestality, 1999)
and drug abuse (Maremmani et al., 2006). The comorbid disorders
are often the reason why these subjects require psychiatric
intervention. Patients with cyclothymia, indeed, are often referred
to psychiatrists for anxiety, binge eating, substance abuse or other
behavioral problems rather than for the mood variations that are
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
usually egosyntonic and considered part of the “normal” character
of the subject (Perugi and Akiskal, 2002; Perugi et al., 1999b).
Mood swings are common in patients with Anxiety Disorders,
often with fluctuations during the course of the day, sometimes
assuming the features of attenuated mixed states or ultra-rapid
cycling, without any constant or repetitive pattern (Bowen et al.,
2004). Panic Disorder with and without agoraphobia seems to be
one of the most common forms of comorbidity in cyclothymia
(Perugi and Akiskal, 2002; Perugi et al., 1999b). The relationship
between PD and cyclothymia is not merely a matter of chance;
cyclothymic PD has, in fact, been demonstrated to be a peculiar
subtype of familial bipolarity, distinguished by its early onset,
multiple anxiety disorder comorbidities, rapid circadian switching
and cyclothymic-type mood instability (Akiskal et al., 2006b;
Mackinnon and Pies, 2006; MacKinnon et al., 2003; Masi et al.,
2007; Nwulia et al., 2008). Interestingly, panic attacks may start or
become exacerbated during hypomania or mark the transition
from the hypomanic to the depressive phase (Perugi et al., 2001a).
Several studies on bipolar patients with rapid mood switches,
who are similar in many ways to patients affected by cyclothymia,
showed an association of rapid mood switches with a high familial
load for mood and anxiety disorders, early onset, marked suicidal
risk and comorbidity with panic disorder (Mackinnon and Pies,
2006; MacKinnon et al., 2003). These findings are consistent with
reports in children and adolescents with BD, where an association
has been observed between high familial loading, comorbidity
with multiple anxiety disorders and rapid circadian switches (Masi
et al., 2007). Rapid switches and comorbidity with panic disorder
seem to define a particular familial subtype of BD distinguished by
early onset and cyclothymic instability (MacKinnon et al., 2002;
Masi et al., 2007; Papolos et al., 1998).
Some cyclothymic subjects present social anxiety. When social
anxiety is associated with cyclothymia, it creates particularly
favorable conditions for alcohol misuse. The observation that
hypomanic switches triggered by treatment with antidepressants
are extremely frequent in patients with generalized social phobia
(Himmelhoch, 1998) or avoidant personality disorder (Perugi et al.,
1999a) prompted the hypothesis that generalized social anxiety
may, along with inhibited depression, be the opposite of hypoma-
nia, at least in some patients (Perugi et al., 2001b). Moreover, the
greater susceptibility to alcohol use found in patients with social
anxiety might be closely linked with the presence of a bipolar
diathesis (Himmelhoch, 1998; Perugi et al., 2002), with marked
reactivity to ethanol, rather than to the social-phobic symptoma-
tology per se. This hypothesis is compatible with the observation
that alcohol use did not reduce social anxiety in performance
situations and was not associated with better performance in
socially phobic patients without a comorbid BD (Himle et al.,
1999). The socializing and disinhibiting effect that many cyclothy-
mic patients with an experience of social anxiety report after
alcohol use might therefore be mediated by increased confidence,
as part of the hypomania that is facilitated by alcohol intake.
In clinical samples, OCD patients show rates of comorbidity
with cyclothymia and bipolar spectrum disorders ranging from
15.5% to 50% (D’Ambrosio et al., 2010; Hantouche et al., 2003b;
Perugi et al., 1997). Hypomania has also been associated with high
rates of comorbid OCD in community studies (Angst, 1998). When
compared with patients without cyclothymia, cyclothymic-OCD
showed a greater severity of OCD symptoms, earlier age at onset,
heavier working and learning impairment, higher frequency of
illness without free intervals, higher sensibility to precipitating
factors, a higher number of other neuropsychiatric comorbidities,
psychiatric hospitalizations and suicide attempts (Hantouche et al.,
2003b). They also showed: a higher number and severity both of
depressive and hypomanic symptoms, earlier age at the first
initiation of psychopharmacological therapy, a lower response to
125
conventional anti-OCD treatments, higher rates of hypomanic ant-
idepressant-induced switches and “paradoxical” worsening under
drug therapy. Some authors (Hantouche et al., 2003b; Perugi et al.,
1999b) have hypothesized that cyclothymic OCD might be a
distinct clinical form of OCD.
The relationship between cyclothymia and attention deficit/
hyperactivity disorder (ADHD) is controversial. Impulsivity is a
dimension that is shared by bipolarity and ADHD (Perugi et al.,
2013c; Sebastian et al., 2014), but in clinical practice the differ-
ential diagnosis between the mood instability that is typical of
ADHD and that of a comorbid mood disorder, especially if “soft”, as
in the case of cyclothymia, or if complicated by substance abuse, is
a really hard one to formulate (Asherson, 2005; Perugi et al.,
2013c). In any case, specific studies are almost entirely lacking. In
the only available study, which is focused on a sample of 586
adults with ADHD, cyclothymic temperament frequency has been
estimated at 71% (Landaas et al., 2012). Compared with their non-
cyclothymic counterparts, cyclothymic ADHD patients, besides
being more numerous, showed interference with educational
and occupational functioning both in childhood and adulthood.
Cyclothymic temperament was also associated with psychiatric
comorbidity, in particular with BD, and a preponderance of mood
symptoms in the clinical picture.
McElroy et al. (1996) have highlighted the correlation between
bipolar spectrum disorders and some impulsive behaviors, such as
those related to the control of aggression and sexual instincts,
paraphilia and pathological gambling. The impulse control dis-
orders have many affinities with cyclothymia, in terms of symp-
toms, comorbidity and response to mood stabilizers. Both are
marked out, in an egosyntonic way, by harmful or dangerous, but
rewarding, behavior, impulsiveness, poor insight and emotional
instability. Impulse control disorders and cyclothymia show a large
overlap area, on the comorbidity spectrum, with other mental
disorders, including anxiety disorders (Benatti et al., 2014; Del
Carlo et al., 2013; Perugi and Akiskal, 2002), alcohol and substance
abuse (Maremmani et al., 2006; Pani et al., 2010; Unseld et al.,
2012) and eating disorders (Alciati et al., 2007; Ellickson-Larew
et al., 2013; Lunde et al., 2009; Perugi et al., 2006). In cyclothymic
subjects, mood instability and impulsiveness are interrelated and
are key features of hypomanic or mixed periods characterized by
behavioral disinhibition, poor insight and marked instability bet-
ween tension, dysphoria and satisfaction.
Eating disorders, especially those that include impulsive beha-
viors towards food, such as bulimia, binging-purging anorexia,
binge-eating disorder, and obesity can be considered as a parti-
cular subtype of impulse control disorders (McElroy et al., 2005).
The frequent association between eating and mood disorders is
well documented, especially with unipolar depression, while the
literature on comorbidity with BD is less extensive (Alciati et al.,
2007; Blinder et al., 2006; Godart et al., 2005; Lunde et al., 2009;
Perugi et al., 2003). Several familial studies have, however,
suggested a correlation with bipolar II and cyclothymic forms
(McElroy et al., 2005). The association seems to be more common
in bulimic patients who present serious and chronic forms.
Hypomania also predicts diagnoses of binge-eating disorder in
obese patients (Alciati et al., 2007; Amianto et al., 2011), and the
severity of obesity has proved to be significantly related to bipolar
diathesis in major depressive patients (Vannucchi et al., 2014).
Besides epidemiological and clinical studies that have system-
atically explored the comorbidity between cyclothymic disorder and
alcohol and drug abuse, some information is available on affective
temperaments. Cyclothymic temperament has been shown to be a
factor that predisposes to substance and alcohol abuse in the general
population (Maremmani et al., 2006; Unseld et al., 2012). In clinical
populations of alcohol dependents (Pombo et al., 2013; Schaller et al.,
2010; Vyssoki et al., 2011), heroin-addicted subjects (Maremmani
126 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
et al., 2009), cocaine users (Maremmani et al., 2008) and substance
use disorders (Unseld et al., 2012), cyclothymic temperament and,
more generally, a bipolar spectrum diathesis showed prevalence
rates higher than in general population. The presence of cyclothymic
temperament has also been associated with the risk of unmasking a
full-blown bipolar syndrome (Maremmani et al., 2008); it predicted:
early age at onset, polydrug abuse, greatest level of psychosocial
burden and dysfunction, and worse outcome both of substance use
and mood disorders.
It has been hypothesized that cyclothymia and substance use
disorder may be considered as a psychopathological dimension
that is closely connected with a common diathesis (Maremmani
et al., 2006; Unseld et al., 2012). In particular, cyclothymic mood
reactivity may amplify the emotional and behavioral reinforce-
ment produced by substances, and thereby enhance the likelihood
of their use. Moreover, repeated exposure to a psychoactive sub-
stance and the acquisition of the euphoric experience as the new
level of satisfaction result in a further worsening of mood inst-
ability (Maremmani et al., 2006). In this kind of population cycl-
othymia seems to play a crucial role throughout, by favoring impu-
lsivity, sensation- and novelty-seeking (Bacciardi et al., 2013;
Maremmani et al., 2009).
In a more speculative way, it is possible to hypothesize that, in
cyclothymia, sensation-seeking and self-stimulating behavior might
involve any type of potentially addictive substance or activity, such
as food, alcohol, drugs, physical exercise, work, travelling, Internet
and sex. In many cases persistent addictive behavior is the main
source of distress and interference, overshadowing the underlying
mood instability.
6. Suicide
The frequent presence of mixed features and impulsivity during
depressive phases (Goldstein et al., 2005) makes cyclothymic
patients more likely to act on suicidal impulses (Algorta et al.,
2011). Multiple research studies on major depression and suicide
have found that cyclothymic temperament is linked to signifi-
cantly higher numbers of past suicide attempts (Akiskal et al.,
2006a; Mechri et al., 2011). Rapid mood cycling further increases
the risk of suicide (Azorin et al., 2010). This association has been
confirmed for different types of suicidal behavior (violent and
nonviolent attempts, suicidal ideation) and in different samples
(mood disorder patients, suicide attempters) (Pompili et al., 2009;
Rihmer et al., 2009). In addition, patients with affective tempera-
ment of cyclothymic–depressive types differ from those with
hyperthymic traits by more frequently showing the short allele
of the serotonin transporter gene (Gonda et al., 2006), which is
itself associated with suicidal behavior (more specifically, violent
suicide) (Gonda et al., 2011). A recent study in patients with mood
disorders confirmed not only a current but also a life-long
relationship between cyclothymic–depressive–anxious tempera-
ment and suicidality (Pompili et al., 2012).
This perspective strengthens the view that cyclothymic mood
reactivity and instability may play a very crucial role. Suicidality is
frequently a reactive behavior triggered by real, perceived or delu-
sional problems in a variety of areas (most often, interpersonal
relationships, money, health). Temperamental mood reactivity, with
its rapid shifts from inhibition to disinhibition, might represent the
constitutional basis that provides the energy and drive that are
necessarily associated with a suicidal act. The prominent role of
cyclothymic instability in the development of suicidal behavior has
been further supported by studies showing that a history of rapid
mood swings and panic attacks was associated with an incre-
ased likelihood of prior suicidal ideation or attempts (MacKinnon
et al., 2005), while (cyclothymic) variability in suicidal ideation was a
significantly better predictor of previous suicide attempts than
duration or intensity of ideation (Witte et al., 2005).
Cyclothymia may also provide the basis for suicidality observed in
patients with anxiety disorders. Research has accumulated over the
past years indicating that anxiety disorders bring with them a unique
risk of suicide (Bolton et al., 2008; Sareen et al., 2005; Weissman
et al., 1989). Growing evidence indicates that the coexistence of
cyclothymia and/or cyclothymic temperament identifies a subgroup
of patients suffering from anxiety disorders with an atypical pattern
of anger and aggression, high novelty-seeking, risk-prone, impulsive
and suicidal behaviors (Kashdan and Hofmann, 2008; Kashdan et al.,
2009; Perugi et al., 2011).
7. Epidemiological and demographic characteristics
Although specific and reliable epidemiologic studies on cycl-
othymia are almost entirely lacking, in the last few years the
prevalence of affective temperaments and cyclothymic disorder
has been extensively explored over a wide span of psychiatric
disorders such as: major depression (Hantouche et al., 1998;
Manning et al., 1997), OCD (D’Ambrosio et al., 2010; Hantouche
et al., 2003b), Panic Disorder/agoraphobia (Del Carlo et al., 2013;
MacKinnon et al., 2003; Manning et al., 1997), eating disorders
(Amianto et al., 2011; Blinder et al., 2006; Lunde et al., 2009;
McElroy et al., 2005), drug and alcohol abuse (Pani et al., 2010;
Unseld et al., 2012).
A meta-analysis of the studies carried out in children and
adolescents found that cyclothymia was more frequent in the
community than bipolar I (Van Meter et al., 2011). Investigations
on clinical populations have shown that depression occurring in a
cyclothymic background is the most common manifestation of
bipolarity, as found in around 50% of depressed patients seen in
psychiatric outpatient settings (Hantouche et al., 1998). This figure
was also confirmed in general medical practice (Manning et al.,
1997), assuming that the cases observed in that kind of setting are
less severe.
Among mood disorders, cyclothymia is the one that has received
the least attention in community studies, and its prevalence rates in
the general population have only recently become available. This is
surprising, given the frequency with which the disorder is found in
clinical practice. Recent studies conducted in Switzerland reported
lifetime prevalence rates ranging between 5 and 8% for brief episodes
of hypomania associated with short-lasting depression (Angst et al.,
2003), with a preponderance of women over men at a ratio of about
2:1. In other epidemiological studies, rates of cyclothymia ranged
from 0.4% to 2.5% (Angst et al., 2005; Faravelli et al., 1990; Lewinsohn
et al., 2000). Rates of undifferentiated sub-syndromal BD have been
reported to be as high as 6–13% of the general population (Angst
et al., 2003; Chang et al., 2003; Kessler et al., 2009). Some of the rates
quoted show discrepancies; this problem arises because the studies
use different diagnostic criteria, some of them assessing cyclothymic
temperament rather than mood disorders, so muddying the distinc-
tion between the two (Howland and Thase, 1993).
Cyclothymic disorder proved to be more prevalent among women
than men both in community (Angst et al., 2003) and clinical (Akiskal
et al., 1977; Dunner et al., 1982) samples. It should, however, be noted
that clinical studies reporting a preponderance of cyclothymic dis-
order among women may confound actual incidence and selective
treatment seeking.
7.1. Longitudinal course and outcome
As for the severity of manic and depressive symptoms, in patients
with BD the frequency of episodes turned out to be distributed over a
spectrum ranging from sporadic episodes to highly unstable forms,
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
with ultra-rapid cycling and circadian instability. Extreme mood
cyclicity and instability have been associated with early onset in
childhood or adolescence, high rates of comorbidity with anxiety,
attention deficit, impulse control, and also with alcohol and sub-
stance use disorders (Pani et al., 2010; Perugi and Akiskal, 2002;
Powers et al., 2013) and the presence of cyclothymic temperament
(Akiskal et al., 1977; Koukopoulos et al., 2006; Perugi and Akiskal,
2002). In these subjects, short-lasting hypomanic and depressive
phases may have alternated since childhood, in a highly unstable
way. However, in a considerable proportion of cases cyclothymia may
present an episodic course, alternating years of mood instability with
periods of remission end adequate functioning. In these cases, cycl-
othymic temperamental traits may have been present since adoles-
cence, but clinically notable manifestations of cyclothymic disorder
may be triggered by stressful life events and/or changes in adults of
variable age.
Recent longitudinal studies have investigated trajectories over
time in youths who are at high risk of contracting a bipolar
spectrum disorder (Axelson et al., 2015) or already have one
(Findling et al., 2013). In a two-year follow-up study, the severity
of manic symptoms decreased in 85% of clinically referred youths;
despite this, a substantial minority of cases showed chronic, uns-
table manic symptomatology (Findling et al., 2013). In the off-
spring of parents with BD, sub-threshold manic or hypomanic epi-
sodes have been shown to be a risk factor for the development of
full-blown manic, mixed, or hypomanic episodes (Axelson et al.,
2015).
Although depressive phases may dominate the clinical presenta-
tion in a psychiatric setting, and cyclothymic patients usually only
report depressive symptoms, the onset of hypomania is very com-
mon (Koukopoulos et al., 2006). Periods of disinhibited and impul-
sive behavior often precede the depressive, inhibited phase. The
switch from hypomania to depression may be favored by stressful life
events, separation, actual or perceived rejection or traumatic experi-
ences, physical illnesses, or substance use. Depression frequently
shows atypical features such as mood reactivity, interpersonal sen-
sitivity, hypersomnia, hyperphagia and marked fatigue (‘leaden
paralysis’), which are responsible for a significant functional impair-
ment (Benazzi, 1999; Davidson et al., 1982; Perugi et al., 1998, 2003).
Depressive mixed states with irritability, extremely severe mood
reactivity and instability are probably the most common presenta-
tion, with the interposition of periods of relative stability. In a recent
report, depressive or mixed depressive recurrences have been shown
to be favored by the presence of cyclothymic temperament (Nilsson
et al., 2012), suggesting a possible relationship between cyclothymia
and highly recurrent major depressive disorders.
Cyclothymia can be observed in some patients with full-blown
manic-depressive disorder (bipolar I), but more commonly it is
associated with the bipolar type II pattern. In a French study on
major depression, 88% of subjects with cyclothymic characteristics
belonged to the bipolar II subtype (Hantouche et al., 1998). Akiskal
and Pinto (1999) have defined major depression occurring against
a cyclothymic background as Bipolar II-1/2 disorder, in order to
distinguish it from bipolar II disorder, which is marked by major
depressive episodes alternating with protracted hypomania and
free intervals (DSM-IV bipolar II disorder).
The NIMH study (Akiskal et al., 1995) on originally unipolar
patients who, during a long-term prospective follow-up, switched
to bipolar II, has provided some important information. The variables
that characterized at treatment entry the patients who experienced
subsequent hypomanic switches were: early age at onset, recurrent
depression, high rates of divorce or separation, high rates of sch-
olastic and/or job maladjustment, isolated “antisocial acts” and drug
abuse. In addition, the index depressive episode showed distinctive
features such as: phobic anxiety, interpersonal sensitivity, separat-
ion anxiety, obsessive-compulsive symptoms, somatization (subpanic
127
symptoms), worsening in the evening, self-pity, subjective or overt
anger, jealousy, suspiciousness, and ideas of reference. This pattern
points to a broad array of cyclothymic and ‘atypical’ depressive sym-
ptoms including comorbid anxious and impulsive features. Lastly,
some temperamental attributes comprising “mood lability”, “energy
activity”, and “daydreaming”, already described by Kretschmer as
“cycloid temperament”, have been proved to be specific in identifying
unipolar depressives who switched to hypomania.
Cyclothymia seems to be the temperamental foundation (“basic
state”) of many bipolar II depressions. Regrettably, the descriptions
offered by ICD-10 and DSM-IV are primarily focused on sympto-
matology, and fail to recognize the possible role of temperamental
dispositions.
Some information on the long-term course of cyclothymia can
be derived from a series of follow-up studies on patients with BPD
treated as inpatients, published at the end of the 1980s by Michael
Stone (for a review see Stone (1990)). Many of these patients, most
of whom were in their twenties at the time of the first observation,
showed clinical presentations compatible with the diagnosis of
bipolar II disorder or cyclothymia, as admitted by Stone (2006)
himself. Approximately 2/3 of these patients presented, after 10 or
25 years, a “mild symptomatology with good overall performance,
and few significant interpersonal relationships”. Considering the
other end of the clinical spectrum, from 3% to 9% of the same
cohort had committed suicide. Age at initial assessment was lower
and the risk of suicide was greater. Favorable prognostic factors
comprised high intelligence, artistic talent and, in the case of
patients who had comorbid alcohol abuse, ability to follow
rehabilitative treatments. Conversely, negative prognostic factors,
implying a high risk of suicide, comprised physical or sexual abuse
by family members, and the combination of antisocial traits with
marked impulsiveness.
More recently, a study focused on the longitudinal impact of BPD
on the course and outcome of BD in youths showed that pre-existing
BPD is significantly associated with a more chronic and severe course
and outcome of BD. Among the BPD factors, affective dysregulation
(comprising cyclothymic dimensions such as affective instability, fear
of abandonment and anger) was the one most robustly associated
with BD chronicity and severity (Yen et al., 2015).
In several studies, the suicidal rates of cyclothymic patients are
comparable with those of patients with BD or schizophrenia
(Rihmer and Pestality, 1999), which indicates the seriousness of
the disorder. Most cases, however, presented a better long-term
prognosis than that of major psychosis. In fact, many subjects
begin to improve after passing the threshold of 40 years. This
observation is another element in common with data on BPD
(Shea et al., 2009).
8. Treatment strategies and practical management
Cyclothymia is frequently misdiagnosed and inappropriately
treated (Baldessarini et al., 2011; Parker et al., 2012; Van Meter et
al., 2012). Lack of consensus on the definition of bipolar spectrum
and difficulty in the diagnosis of hypomania should be considered
the major obstacles to formulating the correct diagnosis. Complex
clinical picture, lack of clear-cut episodes, extremely rich comor-
bidity, early onset and the overlap with personality disorders may
also be responsible for the diagnostic delay (lasting over 10 years
in 50% of cyclothymic patients) (Hantouche et al., 2003a). Com-
plicated patient–doctor relationships and a weak response to
conventional approaches may produce further diagnostic difficul-
ties. Even when properly identified, there is no evidence-based
treatment and no consensus on the strategy to be used in treating
cyclothymia.
128 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133

Treatment of cyclothymia is surprisingly under-studied, espe-
cially when compared with mania and unipolar depression. Mood
stabilizers such as lithium, valproate, carbamazepine and lamo-
trigine have been studied almost exclusively in Bipolar I and, to a
lesser extent, in Bipolar II patients. Similarly, there are only a few
controlled studies that have focused on the use of antidepressants
in bipolar depression in general, and cyclothymia in particular. The
lack of adequate research in this area is even more astonishing
when we consider the severity and recurrence of depressive and
hypomanic episodes in cyclothymia and the related risk of suicide
and substance abuse, together with the pejorative impact on
functioning (Akiskal et al., 2003b, 2006a; Azorin et al., 2010;
McElroy et al., 1996).
Cyclothymia requires a more sophisticated form of caring than
classical bipolar cases. Formulating a diagnosis of cyclothymia req-
uires a specific management of pharmachotherapy to be combined
with psychoeducation adapted to individual needs, in order to
facilitate acceptance of the disorder and to focus on the goals
of the treatment. General principles to be adopted in the practical
management of patients with cyclothymia are summarized
in Table 2.
The principal target of the therapeutic intervention should be the
basic mood dysregulation that underlies most of the psychological
dysfunctions and behavioral problems of these patients. Both the
pharmacological and psychoeducational interventions should pri-
marily focus on mood instability and emotional reactivity, and spe-
cific targets such as excitement, depression, impulsivity, hostility,
interpersonal sensitivity, risk-taking behavior, comorbidity should be
defined in every patient and considered in additions to the psycho-
logical and behavioral problems that arise from basic mood dysre-
gulation. In defining outcome measures, the ‘primacy’ of hypomania
should be established, to avoid the frequent error of considering
depression everything that is not ‘typical’ hypomania.
In order to increase treatment adherence, psychoeducation
should be provided from the beginning. As for other mood and
anxiety disorders, most patients have difficulty in realizing that
their major problem is affective instability, aggravated by exag-
gerated mood and emotional reactivity. They tend to respond by
blaming others for their suffering and easily develop anger and
hostility. They instinctively feel that they are never ‘completely
understood’, are ‘not appreciated enough’ and, in some cases, are
emotionally ‘abused’. In some instances, these beliefs are rein-
forced by previous psychological treatment focused on the past
‘traumatic’ origin of their emotional problems. From the beginning
a psychoeducational approach based on the cognitive reappraisal
of their cyclothymic disorder is necessary, in order to optimize the
therapeutic alliance.
As far as the psychoeducational approach is concerned, most
cyclothymics do not match up to the model of the disorder that is
proposed for psychoeducational groups in treating bipolar-I pat-
ients. The classical description of BD centering on manic and dep-
ressive episodes followed by periods of remission, with different
algorithms for the treatment of different episodes, does not apply to
cyclothymia, where depression and excitement are strongly related
and interepisodic mood instability is the rule. A specific model has
been elaborated in Paris by the CTAH team (Hantouche et al., 2007).

Table 2
Basic concepts for practical management of cyclothymia.

Conception of the basic illness

Episodes are probably the ‘wings’ emerging from temperaments that function as the ‘roots’
Mood episodes, psychological dysfunctions and behavioral problems result from a ‘clash’ between basic temperament (emotional and mood instability and reactivity) and
environment (importance of ‘patient’s life systems’)
Focus treatment on specific clinical targets
Primacy of hypomania (disinhibition, excitement, irritability, inner agitation, and impulsivity are fundamental hypomanic dimensions)
Avoid systematic errors: “everything that is not typical euphoric hyperactive hypomania is depression or personality disorder”.

Depression (frequent atypical and mixed features)

Psychiatric comorbidity (neurodevelopmental, anxiety, obsessive compulsive, eating, impulse control, alcool and substance use disorders)
Specific dimensions:
impulsivity,
hostility,
hyper-reactivity,
interpersonal sensitivity,
risk-taking behavior,
excitement,
inner tension

Include psychoeducation from the outset

Use mood stabilizers or anti-manic drugs before antidepressants
Be vigilant (“go slow and stay low”) when using:
antidepressants (hypomanic switches, cycle acceleration, prolonged excitement, protracted mixed states)
antipsychotics (amotivation, depression, acathysia, extrapyramidal symptoms, binge eating, increased appetitive behaviour and substance abuse, and so on)

Table 3
Treatment staregy for cyclothymia

Acute Continuation Maintenance

0–8 weeks 1–6 months Indefinite

Symptomatic recovery if MDE or Functional recovery Stability

Hypomania
Mood-stabilizers (MS) þ adjunctive Mood-stabilizers (MS) Tapering adjunctive drugs Long-term MS (which should “stay low”); anticipate
drugs if needed: Go slow hypomania and depression
Psychoeducation Cognitive reorganization, emotional coaching, changes in behavioral Optimizing adaptation: Goodness of fit
systems, monitoring, and so on
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
The format has a weekly basis, with six sessions of 2 h each focused
on: clinical characteristics of cyclothymia, monitoring of mood
swings, assessment of warning signs, coping with early relapses,
how to plan ‘positive’ routines, psychological vulnerabilities, cogni-
tive processes linked with mood instability and reactivity, inter-
personal conflicts (Hantouche and Trybou, 2011). Recent research
has shown the benefits of the sequential combination of cognitive
behavioral therapy and well-being therapy, compared with clinical
management. Therapeutic gains with combined psychotherapy
have been maintained at 2-year follow-ups (Fava et al., 2011).
Looking now at the pharmacological approach, because of
patients’ great sensitivity to drug action and its side effects, it is
very important to respect the rule of “go slow and stay low”,
independently of the drugs being utilized (Table 3). Mood stabi-
lizers or anti-manic drugs should be used before antidepressants
and, when the latter are utilized, particular attention should be
devoted to the possibility of hypomanic switches or cycle accel-
eration (Serretti et al., 2003; Tondo et al., 2010; Wehr et al., 1988).
Cyclothymic patients would benefit from small doses of mood
stabilizers such as valproate (if mixity and anxiety are dominant),
lamotrigine (when anxious-depressive polarity is dominant) or
lithium (if affective intensity is present) (Baldessarini et al., 2011;
Bowen et al., 2004; Calabrese, 2008; McElroy et al., 1992; Montes
et al., 2005; Swartz and Thase, 2011).
Considering the high risk of (hypo)manic switches, rapid cycle
induction or the formation of chronic mixed states, the use of
antidepressants in the treatment of cyclothymic depression should
be managed very carefully. But in real-world practice, almost all cyc-
lothymic patients receive antidepressants, and the correct diagnosis
is established in recurrent – resistant – difficult-to-treat depressions
(Baldessarini et al., 2011; Van Meter et al., 2012). This common reality
renders the treatment more complex than it should be: the gradual
removal of antidepressants (a very important phase because many
patients’ condition can be worsened by the sudden removal of
antidepressants) and unnecessary drugs (antipsychotics, sedatives,
anxiolytics, hypnotics, etc.) and the introduction of specific mood-
stabilizers. In this configuration, delays in achieving optimal stabili-
zation usually take longer than in cyclothymics, who are free from
antidepressants. Because of potential complications linked with the
use of antidepressants, whether they are continued (switching, cycle
acceleration, etc.) or stopped (withdrawal reactions, rapid relapses)
(Altshuler et al., 2003), the best advice is to avoid antidepressants
from the beginning. Antidepressants should be reserved for non-
responding depressives and for patients with severe anxiety dis-
orders. One possible option is quetiapine, which has been reported to
be effective in the treatment of acute bipolar depression. In our
practice, the frequency of bad tolerance of quetiapine or other
antipsychotics is high (more than half of the patients in question
will drop these drugs during the first 2 weeks). Thus, achieving an
excellent benefit/risk ratio profile should be always considered a
priority. Antipsychotics should be reserved to patients with prevalent
excitatory symptoms, impulsivity and mixed features.
Another important issue is the high frequency of comorbidity
in cyclothymia with anxiety, impulse control or eating disorders,
and attention deficit in youth. Most of the controlled trials on BD
exclude patients with comorbid drug abuse, anxiety and impulse
control disorders and vice versa; as a result, the empirical basis for
treating patients with complex comorbidity is derived almost
exclusively from open clinical experience. This is a deplorable
situation, because the most common patients treated in everyday
clinical practice are cyclothymic-bipolar II with complex comor-
bidity. The ‘pure’ mood disorder is a theoretical construct that is
never encountered in the real world.
Each comorbid condition requires a selection of treatments that
are mostly based on open clinical experience (Perugi et al., 2006,
2011). For example, a high level of anxiety, panic attacks, inner
129
tension (usually observed in mixed depressive states) and ultra-rapid
cycling appear to be predictors of response to valproate rather than
to lithium. Gabapentin, which has been shown to be effective in
panic disorder (Pande et al., 2000) and social phobia (Pande et al.,
1999) seems to be helpful when anxiety disorders or alcohol abuse
are comorbid. Less information is available for the treatment of social
phobia that is comorbid with cyclothymia; the same problem applies
in cases of comorbidity with PTSD. Comorbid obsessive-compulsive
disorder is probably the most challenging of all to treat. A complex
combination of different mood stabilizers with serotonergic drugs
and antipsychotics is often applied (Hantouche et al., 2003b; Perugi
et al., 1999b). The concomitant use of mood stabilizers reduces but
does not eliminate the risk of developing hypomanic or mixed
switches. Antidepressant-induced (hypo)manic symptoms have been
reported to occur in the course of treating virtually all anxiety dis-
orders, including obsessive-compulsive, panic disorder/agoraphobia
and social phobia (Himmelhoch, 1998; Sholomskas, 1990; Steiner,
1991). Lastly, comorbid ADHD may require a combination of mood
stabilizers with stimulants (Asherson, 2005; Ceraudo et al., 2012),
although the risk of developing addictive behaviors may be increased
by the presence of a cyclothymic background especially if there is
concomitant alcohol or drug abuse (Bacciardi et al., 2013;
Maremmani et al., 2006, 2009; Pombo et al., 2013).
It is very important to assess the psychological part of cycl-
othymia periodically, after every 3 to 6 month period of drug
therapy and psychoeducation. In fact, a significant proportion of
apparent psychological dysfunctions is linked with circularity of
mood, mixity, psychic excitation, affective intensity and extreme
mood reactivity. In half of these cases, a selective drug therapy
with focused psychoeducation is sufficient to obtain a rapid
clinical response with significant changes in behavior and cogni-
tions. A further considerable proportion of cases requires a longer
time, usually a few months of treatment, to achieve sustained
improvement and an appreciable alleviation of mood instability.
9. Conclusion
In clinical settings, percentages ranging from 20% to 50% of all
subjects that seek help for mood, anxiety, impulsive and addictive
disorders after a careful screening turn out to be affected by
bipolar spectrum disorders, and, among these, a high percentage is
affected by cyclothymia (McElroy et al., 2005; Perugi and Akiskal,
2002). These data emerge both from academic centers specialized
in mood disorders and from public and private outpatient facil-
ities. The proportion of patients who can be classified as cyclothy-
mic rises significantly if the diagnostic rules proposed by the
DSM-5 are reconsidered and a broader approach is adopted.
Because of their extreme mood and emotional reactivity and its
related psychological and behavioral consequences, many
cyclothymic patients can be diagnosed as affected by personality
disorders, especially those with frequent relapses, severe impul-
sivity and extreme mood instability. Lastly, cyclothymia, as a
clinical syndrome with early onset and protracted course, can be
considered as the common denominator of a complex comorbidity
with anxiety, impulse control and addictive disorders, which these
patients manifest from the beginning of their adult life. Alcohol
and substance misuse can be interpreted as related to self-
stimulation and sensation seeking; such misuse is likely to further
worsen impulsiveness and mood instability.
The treatment and clinical management of cyclothymia con-
stitute a huge challenge. Antidepressant use may be problematic
for a large number of patients suffering from cyclothymic depres-
sion. Mood stabilizers are the first choice, with the addition of
antidepressants only in the most resistant cases. Atypical anti-
psychotics should be considered in non-responders or in cases
130 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
where severe impulsivity or mixed features are present. A specific
psychological approach and psychoeducation, focused not only on
the prevention of the mood episodes but also on complex
comorbidity and basic temperamental dysregulation, should be
associated with pharmacotherapy from the outset. It should be
pointed out that the correct evaluation of the role and effective-
ness of this type of pharmacological and non-pharmacological int-
ervention requires better-designed prospective observations.
Beside these limitations, the early detection and treatment of
cyclothymia can guarantee a significant change in the long-term
prognosis, when appropriate mood-stabilizing pharmacotherapy,
specific psychological approaches and psychoeducation are app-
lied. Prospective observations in our practice are in favour of a
persistent significant improvement.
Role of funding source
Nothing declared.
Conflict of interest
No conflict declared.
Acknowledgment
No.
References
Akiskal, H.S., 1981. Subaffective disorders: dysthymic, cyclothymic and bipolar II
disorders in the "borderline" realm. Psychiatr. Clin. N. Am. 4, 25–46.
Akiskal, H.S., Akiskal, K.K., Lancrenon, S., Hantouche, E., 2006a. Validating the soft
bipolar spectrum in the French National EPIDEP Study: the prominence of BP-II
1/2. J. Affect. Disord. 96, 207–213.
Akiskal, H.S., Akiskal, K.K., Perugi, G., Toni, C., Ruffolo, G., Tusini, G., 2006b. Bipolar II
and anxious reactive "comorbidity": toward better phenotypic characterization
suitable for genotyping. J. Affect. Disord. 96, 239–247.
Akiskal, H.S., Chen, S.E., Davis, G.C., Puzantian, V.R., Kashgarian, M., Bolinger, J.M.,
1985a. Borderline: an adjective in search of a noun. J. Clin. Psychiatry 46, 41–48.
Akiskal, H.S., Djenderedjian, A.M., Rosenthal, R.H., Khani, M.K., 1977. Cyclothymic
disorder: validating criteria for inclusion in the bipolar affective group. Am. J.
Psychiatry 134, 1227–1233.
Akiskal, H.S., Downs, J., Jordan, P., Watson, S., Daugherty, D., Pruitt, D.B., 1985b.
Affective disorders in referred children and younger siblings of manic-
depressives. Mode of onset and prospective course. Arch. Gen. Psychiatry 42,
996–1003.
Akiskal, H.S., Hantouche, E.G., Allilaire, J.F., 2003a. Bipolar II with and without
cyclothymic temperament: "dark" and "sunny" expressions of soft bipolarity. J.
Affect. Disord. 73, 49–57.
Akiskal, H.S., Hantouche, E.G., Allilaire, J.F., Sechter, D., Bourgeois, M.L., Azorin, J.M.,
Chatenet-Duchene, L., Lancrenon, S., 2003b. Validating antidepressant-
associated hypomania (bipolar III): a systematic comparison with spontaneous
hypomania (bipolar II). J. Affect. Disord. 73, 65–74.
Akiskal, H.S., Khani, M.K., Scott-Strauss, A., 1979. Cyclothymic temperamental
disorders. Psychiatr. Clin. N. Am. 2, 527–554.
Akiskal, H.S., Maser, J.D., Zeller, P.J., Endicott, J., Coryell, W., Keller, M., Warshaw, M.,
Clayton, P., Goodwin, F., 1995. Switching from 'unipolar' to bipolar II. An 11-year
prospective study of clinical and temperamental predictors in 559 patients.
Arch. Gen. Psychiatry 52, 114–123.
Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum. Prototypes I, II, III, and
IV. Psychiatr. Clin. N. Am. 22, 517–534.
Akiskal, H.S., Placidi, G.F., Maremmani, I., Signoretta, S., Liguori, A., Gervasi, R.,
Mallya, G., Puzantian, V.R., 1998. TEMPS-I: delineating the most discriminant
traits of the cyclothymic, depressive, hyperthymic and irritable temperaments
in a nonpatient population. J. Affect. Disord. 51, 7–19.
Alciati, A., D'Ambrosio, A., Foschi, D., Corsi, F., Mellado, C., Angst, J., 2007. Bipolar
spectrum disorders in severely obese patients seeking surgical treatment. J.
Affect. Disord. 101, 131–138.
Algorta, G.P., Youngstrom, E.A., Frazier, T.W., Freeman, A.J., Youngstrom, J.K.,
Findling, R.L., 2011. Suicidality in pediatric bipolar disorder: predictor or
outcome of family processes and mixed mood presentation? Bipolar Disord.
13, 76–86.
Alnaes, R., Torgensen, S., 1989. Personality and personality disorders among
patients with major depression in combination with dysthymic or cyclothymic
disorders. Acta Psychiatr. Scand. 79, 363–369.
Altshuler, L., Suppes, T., Black, D., Nolen, W.A., Keck Jr., P.E., Frye, M.A., McElroy, S.,
Kupka, R., Grunze, H., Walden, J., Leverich, G., Denicoff, K., Luckenbaugh, D.,
Post, R., 2003. Impact of antidepressant discontinuation after acute bipolar
depression remission on rates of depressive relapse at 1-year follow-up. Am. J.
Psychiatry 160, 1252–1262.
Amianto, F., Lavagnino, L., Leombruni, P., Gastaldi, F., Daga, G.A., Fassino, S., 2011.
Hypomania across the binge eating spectrum. A study on hypomanic symptoms
in full criteria and sub-threshold binge eating subjects. J. Affect. Disord. 133,
580–583.
Angst, J., 1998. The emerging epidemiology of hypomania and bipolar II disorder. J.
Affect. Disord. 50, 143–151.
Angst, J., 2013. Bipolar disorders in DSM-5: strengths, problems and perspectives.
Int. J. Bipolar Disord. 1, 12.
Angst, J., Gamma, A., Benazzi, F., Ajdacic, V., Eich, D., Rossler, W., 2003. Toward a re-
definition of subthreshold bipolarity: epidemiology and proposed criteria for
bipolar-II, minor bipolar disorders and hypomania. J. Affect. Disord. 73,
133–146.
Angst, J., Gamma, A., Neuenschwander, M., Ajdacic-Gross, V., Eich, D., Rossler, W.,
Merikangas, K.R., 2005. Prevalence of mental disorders in the Zurich Cohort
Study: a twenty year prospective study. Epidemiol. Psichiatr. Soc. 14, 68–76.
Angst, J., Marneros, A., 2001. Bipolarity from ancient to modern times: conception,
birth and rebirth. J. Affect. Disord. 67, 3–19.
Asherson, P., 2005. Clinical assessment and treatment of attention deficit hyper-
activity disorder in adults. Expert Rev. Neurother. 5, 525–539.
Axelson, D., Goldstein, B., Goldstein, T., Monk, K., Yu, H., Hickey, M.B., Sakolsky, D.,
Diler, R., Hafeman, D., Merranko, J., Iyengar, S., Brent, D., Kupfer, D., Birmaher, B.,
2015. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar
disorder: a longitudinal study appiajp201414010035. Am. J. Psychiatry (Epub
ahead of print).
Azorin, J.M., Kaladjian, A., Adida, M., Fakra, E., Hantouche, E., Lancrenon, S., 2011.
Correlates of first-episode polarity in a French cohort of 1089 bipolar I disorder
patients: role of temperaments and triggering events. J. Affect. Disord. 129,
39–46.
Azorin, J.M., Kaladjian, A., Besnier, N., Adida, M., Hantouche, E., Lancrenon, S.,
Akiskal, H., 2010. Suicidal behaviour in a French Cohort of major depressive
patients: characteristics of attempters and nonattempters. J. Affect. Disord. 123,
87–94.
Bacciardi, S., Maremmani, A.G.I., Rovai, L., Rugani, F., Pani, P.P., Pacini, M., Dell’Osso, L.,
Akiskal, H.S., Maremmani, I., 2013. Drug (heroin) addiction, bipolar spectrum and
impulse control disorders. Heroin Addict. Relat. Clin. Probl. 15, 29–36.
Baethge, C., Salvatore, P., Baldessarini, R.J., 2003a. Cyclothymia, a circular mood
disorder. Hist. Psychiatry 14, 377–399.
Baethge, C., Salvatore, P., Baldessarini, R.J., 2003b. "On cyclic insanity" by Karl
Ludwig Kahlbaum, MD: a translation and commentary. Harv. Rev. Psychiatry 11,
78–90.
Baldessarini, R.J., Vazquez, G., Tondo, L., 2011. Treatment of cyclothymic disorder:
commentary. Psychother. Psychosom. 80, 131–135.
Bandelow, B., Krause, J., Wedekind, D., Broocks, A., Hajak, G., Ruther, E., 2005. Early
traumatic life events, parental attitudes, family history, and birth risk factors in
patients with borderline personality disorder and healthy controls. Psychiatry
Res. 134, 169–179.
Battle, C.L., Shea, M.T., Johnson, D.M., Yen, S., Zlotnick, C., Zanarini, M.C., Sanislow, C.A.,
Skodol, A.E., Gunderson, J.G., Grilo, C.M., McGlashan, T.H., Morey, L.C., 2004.
Childhood maltreatment associated with adult personality disorders: findings
from the collaborative longitudinal personality disorders study. J. Personal. Disord.
18, 193–211.
Belli, H., Ural, C., Akbudak, M., 2012. Borderline personality disorder: bipolarity,
mood stabilizers and atypical antipsychotics in treatment. J. Clin Med. Res. 4,
301–308.
Benatti, B., Dell'Osso, B., Arici, C., Hollander, E., Altamura, A.C., 2014. Characterizing
impulsivity profile in patients with obsessive-compulsive disorder. Int. J.
Psychiatry Clin. Pract. 18, 156–160.
Benazzi, F., 1999. Prevalence of bipolar II disorder in atypical depression. Eur. Arch.
Psychiatry Clin. Neurosci. 249, 62–65.
Benazzi, F., 2003. Is there a link between atypical and early-onset "unipolar"
depression and bipolar II disorder? Compr. Psychiatry 44, 102–109.
Benazzi, F., 2005. Unipolar depression with racing thoughts: a bipolar spectrum
disorder? Psychiatry Clin. Neurosci. 59, 570–575.
Benazzi, F., 2006a. A continuity between bipolar II depression and major depressive
disorder? Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1043–1050.
Benazzi, F., 2006b. Symptoms of depression as possible markers of bipolar II
disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 471–477.
Bierer, L.M., Yehuda, R., Schmeidler, J., Mitropoulou, V., New, A.S., Silverman, J.M.,
Siever, L.J., 2003. Abuse and neglect in childhood: relationship to personality
disorder diagnoses. CNS Spectr. 8, 737–754.
Birmaher, B., Gill, M.K., Axelson, D.A., Goldstein, B.I., Goldstein, T.R., Yu, H., Liao, F.,
Iyengar, S., Diler, R.S., Strober, M., Hower, H., Yen, S., Hunt, J., Merranko, J.A.,
Ryan, N.D., Keller, M.B., 2014. Longitudinal trajectories and associated baseline
predictors in youths with bipolar spectrum disorders. Am. J. Psychiatry 171,
990–999.
Blinder, B.J., Cumella, E.J., Sanathara, V.A., 2006. Psychiatric comorbidities of female
inpatients with eating disorders. Psychosom. Med. 68, 454–462.
Bolton, J.M., Cox, B.J., Afifi, T.O., Enns, M.W., Bienvenu, O.J., Sareen, J., 2008. Anxiety
disorders and risk for suicide attempts: findings from the Baltimore Epidemio-
logic Catchment area follow-up study. Depress. Anxiety 25, 477–481.
Bowen, R., Clark, M., Baetz, M., 2004. Mood swings in patients with anxiety
disorders compared with normal controls. J. Affect. Disord. 78, 185–192.
Brieger, P., Marneros, A., 1997. Dysthymia and cyclothymia: historical origins and
contemporary development. J. Affect. Disord. 45, 117–126.
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
Calabrese, J.R, 2008. Overview of patient care issues and treatment in bipolar
spectrum and bipolar II disorder. J. Clin. Psychiatry 69, e18.
Calabrese, J.R., Delucchi, G.A., 1990. Spectrum of efficacy of valproate in 55 patients
with rapid-cycling bipolar disorder. Am. J. Psychiatry 147, 431–434.
Calabrese, J.R., Woyshville, M.J., Kimmel, S.E., Rapport, D.J., 1993. Predictors of
valproate response in bipolar rapid cycling. J. Clin. Psychopharmacol. 13,
280–283.
Cassano, G.B., Dell'Osso, L., Frank, E., Miniati, M., Fagiolini, A., Shear, K., Pini, S.,
Maser, J., 1999. The bipolar spectrum: a clinical reality in search of diagnostic
criteria and an assessment methodology. J. Affect. Disord. 54, 319–328.
Ceraudo, G., Vannucchi, G., Perugi, G., Dell'osso, L., 2012. Adult ADHD: clinical
aspects and therapeutic implications. Riv. Psichiatr. 47, 451–464.
Chaim, C.H., Nazar, B.P., Hollander, E., Lessa, J.L., 2014. Pathological gambling treated
with lithium: the role of assessing temperament. Addict. Behav. 39, 1911–1913.
Chang, K.D., Blasey, C.M., Ketter, T.A., Steiner, H., 2003. Temperament characteristics
of child and adolescent bipolar offspring. J. Affect. Disord. 77, 11–19.
D'Ambrosio, V., Albert, U., Bogetto, F., Maina, G., 2010. Obsessive-compulsive
disorder and cyclothymic temperament: an exploration of clinical features. J.
Affect. Disord. 127, 295–299.
Davidson, J.R., Miller, R.D., Turnbull, C.D., Sullivan, J.L., 1982. Atypical depression.
Arch. Gen. Psychiatry 39, 527–534.
Del Carlo, A., Benvenuti, M., Toni, C., Dell'osso, L., Perugi, G., 2013. Impulsivity in
patients with panic disorder-agoraphobia: the role of cyclothymia. Compr.
Psychiatry 54, 1090–1097.
Delvecchio, G., Sugranyes, G., Frangou, S., 2013. Evidence of diagnostic specificity in
the neural correlates of facial affect processing in bipolar disorder and
schizophrenia: a meta-analysis of functional imaging studies. Psychol. Med.
43, 553–569.
Depue, R.A., Slater, J.F., Wolfstetter-Kausch, H., Klein, D., Goplerud, E., Farr, D., 1981.
A behavioral paradigm for identifying persons at risk for bipolar depressive
disorder: a conceptual framework and five validation studies. J. Abnorm.
Psychol. 90, 381–437.
Dilsaver, S.C., Benazzi, F., Akiskal, H.S., 2005. Mixed states: the most common
outpatient presentation of bipolar depressed adolescents? Psychopathology 38,
268–272.
Dolan-Sewell, R.T., Krueger, R.F., Shea, MT, 2001. Co-occurrence with Syndrome
Disorders. The Guilford Press, New Tork, NY.
Domes, G., Schulze, L., Herpertz, S.C., 2009. Emotion recognition in borderline
personality disorder—a review of the literature. J. Person. Disord. 23, 6–19.
Dunner, D.L., Russek, F.D., Russek, B., Fieve, R.R., 1982. Classification of bipolar
affective disorder subtypes. Compr. Psychiatry 23, 186–189.
Ellickson-Larew, S., Naragon-Gainey, K., Watson, D., 2013. Pathological eating
behaviors, BMI, and facet-level traits: the roles of conscientiousness, neuroti-
cism, and impulsivity. Eat. Behav. 14, 428–431.
Faravelli, C., Guerrini Degl'Innocenti, B., Aiazzi, L., Incerpi, G., Pallanti, S, 1990.
Epidemiology of mood disorders: a community survey in Florence. J. Affect.
Disord. 20, 135–141.
Fava, G.A., Rafanelli, C., Tomba, E., Guidi, J., Grandi, S., 2011. The sequential
combination of cognitive behavioral treatment and well-being therapy in
cyclothymic disorder. Psychother. Psychosom. 80, 136–143.
Findling, R.L., Jo, B., Frazier, T.W., Youngstrom, E.A., Demeter, C.A., Fristad, M.A.,
Birmaher, B., Kowatch, R.A., Arnold, E., Axelson, D.A., Ryan, N., Hauser, J.C.,
Brace, D.J., Marsh, L.E., Gill, M.K., Depew, J., Rowles, B.M., Horwitz, S.M., 2013.
The 24-month course of manic symptoms in children. Bipolar Disord. 15,
669–679.
Fossati, A., Madeddu, F., Maffei, C., 1999. Borderline personality disorder and
childhood sexual abuse: a meta-analytic study. J. Personal. Disord. 13, 268–280.
Ghaemi, S.N., Dalley, S., Catania, C., Barroilhet, S., 2014. Bipolar or borderline: a
clinical overview. Acta Psychiatr. Scand. 130, 99–108.
Godart, N.T., Perdereau, F., Jeammet, P., Flament, M.F., 2005. Comorbidity between
eating disorders and mood disorders: review. Encephale 31, 575–587.
Goldstein, T.R., Birmaher, B., Axelson, D., Ryan, N.D., Strober, M.A., Gill, M.K., Valeri,
S., Chiappetta, L., Leonard, H., Hunt, J., Bridge, J.A., Brent, D.A., Keller, M., 2005.
History of suicide attempts in pediatric bipolar disorder: factors associated with
increased risk. Bipolar Disord. 7, 525–535.
Gonda, X., Fountoulakis, K.N., Harro, J., Pompili, M., Akiskal, H.S., Bagdy, G., Rihmer,
Z., 2011. The possible contributory role of the S allele of 5-HTTLPR in the
emergence of suicidality. J. Psychopharmacol. 25, 857–866.
Gonda, X., Rihmer, Z., Zsombok, T., Bagdy, G., Akiskal, K.K., Akiskal, H.S., 2006. The
5HTTLPR polymorphism of the serotonin transporter gene is associated with
affective temperaments as measured by TEMPS-A. J. Affect. Disord. 91, 125–131.
Goodman, M., Yehuda, R., 2002. The relationship between psychological trauma
and borderline personality disorder. Psychiatr. Ann. 32, 337–345.
Gremaud-Heitz, D., Riemenschneider, A., Walter, M., Sollberger, D., Kuchenhoff, J.,
Dammann, G., 2014. Comorbid atypical depression in borderline personality
disorder is common and correlated with anxiety-related psychopathology.
Compr. Psychiatry 55, 650–656.
Gunderson, J.G., Phillips, K.A., 1991. A current view of the interface between
borderline personality disorder and depression. Am. J. Psychiatry 148, 967–975.
Gunderson, J.G., Weinberg, I., Daversa, M.T., Kueppenbender, K.D., Zanarini, M.C.,
Shea, M.T., Skodol, A.E., Sanislow, C.A., Yen, S., Morey, L.C., Grilo, C.M.,
McGlashan, T.H., Stout, R.L., Dyck, I., 2006. Descriptive and longitudinal
observations on the relationship of borderline personality disorder and bipolar
disorder. Am. J. Psychiatry 163, 1173–1178.
Hantouche, E., Perugi, G., 2012. Should cyclothymia be considered as a specific and
distinct bipolar disorder? Neuropsychiatry 2, 407–414.
131
Hantouche, E.G., Akiskal, H.S., 2006. Toward a definition of a cyclothymic behavioral
endophenotype: which traits tap the familial diathesis for bipolar II disorder? J.
Affect. Disord. 96, 233–237.
Hantouche, E.G., Akiskal, H.S., Lancrenon, S., Allilaire, J.F., Sechter, D., Azorin, J.M.,
Bourgeois, M., Fraud, J.P., Chatenet-Duchene, L., 1998. Systematic clinical
methodology for validating bipolar-II disorder: data in mid-stream from a
French national multi-site study (EPIDEP). J. Affect. Disord., 163–173.
Hantouche, E.G., Angst, J., Akiskal, H.S., 2003a. Factor structure of hypomania:
interrelationships with cyclothymia and the soft bipolar spectrum. J. Affect.
Disord. 73, 39–47.
Hantouche, E.G., Angst, J., Demonfaucon, C., Perugi, G., Lancrenon, S., Akiskal, H.S.,
2003b. Cyclothymic OCD: a distinct form? J. Affect. Disord. 75, 1–10.
Hantouche, E.G., Majdalani, C., Trybou, V., 2007. Psychoeducation in Group-Therapy
for Cyclothymic Patients; A Novel Approach. IRBD, Rome.
Hantouche, E.G., Trybou, T., 2011. Vivre heureux avec des hauts et des bas. Odile
Jacob, Paris.
Henry, C., Mitropoulou, V., New, A.S., Koenigsberg, H.W., Silverman, J., Siever, L.J.,
2001. Affective instability and impulsivity in borderline personality and bipolar
II disorders: similarities and differences. J. Psychiatr. Res. 35, 307–312.
Herman, J.L., Perry, J.C., van der Kolk, B.A., 1989. Childhood trauma in borderline
personality disorder. Am. J. Psychiatry 146, 490–495.
Himle, J.A., Abelson, J.L., Haghightgou, H., Hill, E.M., Nesse, R.M., Curtis, G.C., 1999.
Effect of alcohol on social phobic anxiety. Am. J. Psychiatry 156, 1237–1243.
Himmelhoch, J.M., 1998. Social anxiety, hypomania and the bipolar spectrum: data,
theory and clinical issues. J. Affect. Disord. 50, 203–213.
Howland, R.H., Thase, M.E., 1993. A comprehensive review of cyclothymic disorder.
J. Nerv. Ment. Dis. 181, 485–493.
Jensen, P.S., Buitelaar, J., Pandina, G.J., Binder, C., Haas, M., 2007. Management of
psychiatric disorders in children and adolescents with atypical antipsychotics:
a systematic review of published clinical trials. Eur. Child Adolesc. Psychiatry
16, 104–120.
Kahn, P., 1909. La Cyclothymie: De La Costitution Cyclothymique et de ses
Manifestations (Depression et Excitation Intermittentes). G. Steinheil, Editeur,
Paris.
Kashdan, T.B., Hofmann, S.G., 2008. The high-novelty-seeking, impulsive subtype of
generalized social anxiety disorder. Depress. Anxiety 25, 535–541.
Kashdan, T.B., McKnight, P.E., Richey, J.A., Hofmann, S.G., 2009. When social anxiety
disorder co-exists with risk-prone, approach behavior: investigating a
neglected, meaningful subset of people in the National Comorbidity Survey-
Replication. Behav. Res. Ther. 47, 559–568.
Kessler, R.C., Avenevoli, S., Green, J., Gruber, M.J., Guyer, M., He, Y., Jin, R., Kaufman, J.,
Sampson, N.A., Zaslavsky, A.M., 2009. National comorbidity survey replication
adolescent supplement (NCS-A): III. Concordance of DSM-IV/CIDI diagnoses with
clinical reassessments. J. Am. Acad. Child Adolesc. Psychiatry 48, 386–399.
Kochman, F.J., Hantouche, E.G., Ferrari, P., Lancrenon, S., Bayart, D., Akiskal, H.S.,
2005. Cyclothymic temperament as a prospective predictor of bipolarity and
suicidality in children and adolescents with major depressive disorder. J. Affect.
Disord. 85, 181–189.
Koenigsberg, H.W., Harvey, P.D., Mitropoulou, V., Schmeidler, J., New, A.S., Good-
man, M., Silverman, J.M., Serby, M., Schopick, F., Siever, L.J, 2002. Characterizing
affective instability in borderline personality disorder. Am. J. Psychiatry 159,
784–788.
Koukopoulos, A., 2003. Ewald Hecker's description of cyclothymia as a cyclical
mood disorder: its relevance to the modern concept of bipolar II. J. Affect.
Disord. 73, 199–205.
Koukopoulos, A., Sani, G., Koukopoulos, A.E., Albert, M.J., Girardi, P., Tatarelli, R.,
2006. Endogenous and exogenous cyclicity and temperament in bipolar
disorder: review, new data and hypotheses. J. Affect. Disord. 96, 165–175.
Kraepelin, E., 1921. Manic-Depressive Insanity and Paranoia. E & S Livingstone,
Edinburgh.
Kuo, J.R., Goldin, P.R., Werner, K., Heimberg, R.G., Gross, J.J., 2011. Childhood trauma
and current psychological functioning in adults with social anxiety disorder. J.
Affect. Disord. 25, 467–473.
Landaas, E.T., Halmoy, A., Oedegaard, K.J., Fasmer, O.B., Haavik, J., 2012. The impact
of cyclothymic temperament in adult ADHD. J. Affect. Disord. 142, 241–247.
Levitt, A.J., Joffe, R.T., Ennis, J., MacDonald, C., Kutcher, S.P., 1990. The prevalence of
cyclothymia in borderline personality disorder. J. Clin. Psychiatry 51, 335–339.
Levy, D., Kimhi, R., Barak, Y., Aviv, A., Elizur, A., 1998. Antidepressant-associated
mania: a study of anxiety disorders patients. Psychopharmacology (Berl) 136,
243–246.
Lewinsohn, P.M., Klein, D.N., Seeley, J.R., 2000. Bipolar disorder during adolescence
and young adulthood in a community sample. Bipolar Disord. 2, 281–293.
Lunde, A.V., Fasmer, O.B., Akiskal, K.K., Akiskal, H.S., Oedegaard, K.J., 2009. The
relationship of bulimia and anorexia nervosa with bipolar disorder and its
temperamental foundations. J. Affect. Disord. 115, 309–314.
Mackinnon, D.F., Pies, R., 2006. Affective instability as rapid cycling: theoretical and
clinical implications for borderline personality and bipolar spectrum disorders.
Bipolar Disord. 8, 1–14.
MacKinnon, D.F., Potash, J.B., McMahon, F.J., Simpson, S.G., Depaulo Jr., J.R., Zandi, P.P.,
2005. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar
Disord. 7, 441–448.
MacKinnon, D.F., Zandi, P.P., Cooper, J., Potash, J.B., Simpson, S.G., Gershon, E.,
Nurnberger, J., Reich, T., DePaulo, J.R, 2002. Comorbid bipolar disorder and
panic disorder in families with a high prevalence of bipolar disorder. Am. J.
Psychiatry 159, 30–35.
132 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
MacKinnon, D.F., Zandi, P.P., Gershon, E.S., Nurnberger Jr., J.I., DePaulo Jr., J.R., 2003.
Association of rapid mood switching with panic disorder and familial panic risk
in familial bipolar disorder. Am. J. Psychiatry 160, 1696–1698.
Manning, J.S., Haykal, R.F., Connor, P.D., Akiskal, H.S., 1997. On the nature of
depressive and anxious states in a family practice setting: the high prevalence
of bipolar II and related disorders in a cohort followed longitudinally. Compr.
Psychiatry 38, 102–108.
Maremmani, I., Pacini, M., Perugi, G., Deltito, J., Akiskal, H., 2008. Cocaine abuse and
the bipolar spectrum in 1090 heroin addicts: clinical observations and a
proposed pathophysiologic model. J. Affect. Disord. 106, 55–61.
Maremmani, I., Pacini, M., Popovic, D., Romano, A., Maremmani, A.G., Perugi, G.,
Deltito, J., Akiskal, K., Akiskal, H., 2009. Affective temperaments in heroin
addiction. J. Affect. Disord. 117, 186–192.
Maremmani, I., Perugi, G., Pacini, M., Akiskal, H.S., 2006. Toward a unitary
perspective on the bipolar spectrum and substance abuse: opiate addiction as
a paradigm. J. Affect. Disord. 93, 1–12.
Masi, G., Milone, A., Manfredi, A., Pari, C., Paziente, A., Millepiedi, S., 2008.
Comorbidity of conduct disorder and bipolar disorder in clinically referred
children and adolescents. J. Child Adolesc. Psychopharmacol. 18, 271–279.
Masi, G., Perugi, G., Millepiedi, S., Mucci, M., Pari, C., Pfanner, C., Berloffa, S., Toni, C.,
2007. Clinical implications of DSM-IV subtyping of bipolar disorders in referred
children and adolescents. J. Am. Acad. Child Adolesc. Psychiatry 46, 1299–1306.
McElroy, S.L., Keck Jr., P.E., Pope Jr., H.G., Hudson, J.I., 1992. Valproate in the
treatment of bipolar disorder: literature review and clinical guidelines. J. Clin.
Psychopharmacol. 12, 42S–52S.
McElroy, S.L., Kotwal, R., Keck Jr., P.E., Akiskal, H.S., 2005. Comorbidity of bipolar and
eating disorders: distinct or related disorders with shared dysregulations? J.
Affect. Disord. 86, 107–127.
McElroy, S.L., Pope Jr., H.G., Keck Jr., P.E., Hudson, J.I., Phillips, K.A., Strakowski, S.M.,
1996. Are impulse-control disorders related to bipolar disorder? Compr.
Psychiatry 37, 229–240.
McGloin, J.M., Widom, C.S., 2001. Resilience among abused and neglected children
grown up. Dev. Psychopathol. 13, 1021–1038.
Mechri, A., Kerkeni, N., Touati, I., Bacha, M., Gassab, L., 2011. Association between
cyclothymic temperament and clinical predictors of bipolarity in recurrent
depressive patients. J. Affect. Disord. 132, 285–288.
Mirin, S.M., Weiss, R.D., Griffin, M.L., Michael, J.L., 1991. Psychopathology in drug
abusers and their families. Compr. Psychiatry 32, 36–51.
Montes, J.M., Saiz-Ruiz, J., Lahera, G., Asiel, A., 2005. Lamotrigine for the treatment
of bipolar spectrum disorder: a chart review. J. Affect. Disord. 86, 69–73.
Nigg, J.T., Goldsmith, H.H., 1994. Genetics of personality disorders: perspectives
from personality and psychopathology research. Psychol. Bull. 115, 346–380.
Nilsson, K.K., Straarup, K.N., Jorgensen, C.R., Licht, R.W., 2012. Affective tempera-
ments' relation to functional impairment and affective recurrences in bipolar
disorder patients. J. Affect. Disord. 138, 332–336.
Nwulia, E.A., Zandi, P.P., McInnis, M.G., DePaulo Jr., J.R., MacKinnon, D.F., 2008. Rapid
switching of mood in families with familial bipolar disorder. Bipolar Disord. 10,
597–606.
Pande, A.C., Davidson, J.R., Jefferson, J.W., Janney, C.A., Katzelnick, D.J., Weisler, R.H.,
Greist, J.H., Sutherland, S.M., 1999. Treatment of social phobia with gabapentin:
a placebo-controlled study. J. Clin. Psychopharmacol. 19, 341–348.
Pande, A.C., Pollack, M.H., Crockatt, J., Greiner, M., Chouinard, G., Lydiard, R.B.,
Taylor, C.B., Dager, S.R., Shiovitz, T., 2000. Placebo-controlled study of gaba-
pentin treatment of panic disorder. J. Clin. Psychopharmacol. 20, 467–471.
Pani, P.P., Maremmani, I., Trogu, E., Gessa, G.L., Ruiz, P., Akiskal, H.S., 2010.
Delineating the psychic structure of substance abuse and addictions: should
anxiety, mood and impulse-control dysregulation be included? J. Affect. Disord.
122, 185–197.
Papolos, D.F., Veit, S., Faedda, G.L., Saito, T., Lachman, H.M., 1998. Ultra-ultra rapid
cycling bipolar disorder is associated with the low activity catecholamine-O-
methyltransferase allele. Mol. Psychiatry 3, 346–349.
Paris, J., 1998. Does childhood trauma cause personality disorders in adults? Can. J.
Psychiatry 43, 148–153.
Paris, J., 2004. Borderline or bipolar? Distinguishing borderline personality disorder
from bipolar spectrum disorders. Harv. Rev. Psychiatry 12, 140–145.
Parker, G., 2011. Clinical differentiation of bipolar II disorder from personality-
based "emotional dysregulation" conditions. J. Affect. Disord. 133, 16–21.
Parker, G., McCraw, S., Fletcher, K., 2012. Cyclothymia. Depress. Anxiety 29,
487–494.
Perugi, G., Akiskal, H.S., 2002. The soft bipolar spectrum redefined: focus on the
cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connec-
tion in bipolar II and related conditions. Psychiatr. Clin. N. Am. 25, 713–737.
Perugi, G., Akiskal, H.S., Lattanzi, L., Cecconi, D., Mastrocinque, C., Patronelli, A.,
Vignoli, S., Bemi, E., 1998. The high prevalence of "soft" bipolar (II) features in
atypical depression. Compr. Psychiatry 39, 63–71.
Perugi, G., Akiskal, H.S., Pfanner, C., Presta, S., Gemignani, A., Milanfranchi, A., Lensi, P.,
Ravagli, S., Cassano, G.B., 1997. The clinical impact of bipolar and unipolar affective
comorbidity on obsessive-compulsive disorder. J. Affect. Disord. 46, 15–23.
Perugi, G., Akiskal, H.S., Toni, C., Simonini, E., Gemignani, A., 2001a. The temporal
relationship between anxiety disorders and (hypo)mania: a retrospective
examination of 63 panic, social phobic and obsessive-compulsive patients with
comorbid bipolar disorder. J. Affect. Disord. 67, 199–206.
Perugi, G., Angst, J., Azorin, J.M., Bowden, C., Vieta, E., Young, A.H., 2013a. The
bipolar-borderline personality disorders connection in major depressive
patients. Acta Psychiatr. Scand. 128 (5), 376–383.
Perugi, G., Angst, J., Azorin, J.M., Bowden, C., Vieta, E., Young, A.H., 2013b. Is
comorbid borderline personality disorder in patients with major depressive
episode and bipolarity a developmental subtype? Findings from the interna-
tional BRIDGE study. J. Affect. Disord. 144, 72–78.
Perugi, G., Ceraudo, G., Vannucchi, G., Rizzato, S., Toni, C., Dell'Osso, L., 2013c.
Attention deficit/hyperactivity disorder symptoms in Italian bipolar adult
patients: a preliminary report. J. Affect. Disord. 149, 430–434.
Perugi, G., Fornaro, M., Akiskal, H.S., 2011. Are atypical depression, borderline
personality disorder and bipolar II disorder overlapping manifestations of a
common cyclothymic diathesis? World Psychiatry 10, 45–51.
Perugi, G., Frare, F., Madaro, D., Maremmani, I., Akiskal, H.S., 2002. Alcohol abuse in
social phobic patients: is there a bipolar connection? J. Affect. Disord. 69,
33–39.
Perugi, G., Frare, F., Toni, C., Mata, B., Akiskal, H.S., 2001b. Bipolar II and unipolar
comorbidity in 153 outpatients with social phobia. Compr. Psychiatry 42,
375–381.
Perugi, G., Nassini, S., Socci, C., Lenzi, M., Toni, C., Simonini, E., Akiskal, H.S., 1999a.
Avoidant personality in social phobia and panic-agoraphobic disorder: a
comparison. J. Affect. Disord. 54, 277–282.
Perugi, G., Quaranta, G., Dell'Osso, L., 2014. The significance of mixed States in
depression and mania. Curr. Psychiatry Rep. 16, 486.
Perugi, G., Toni, C., Akiskal, H.S., 1999b. Anxious-bipolar comorbidity. Diagnostic
and treatment challenges. Psychiatr. Clin. N. Am. 22, 565–583.
Perugi, G., Toni, C., Maremmani, I., Tusini, G., Ramacciotti, S., Madia, A., Fornaro, M.,
Akiskal, H.S., 2012. The influence of affective temperaments and psychopatho-
logical traits on the definition of bipolar disorder subtypes: a study on bipolar I
Italian national sample. J. Affect. Disord 136, e41–49.
Perugi, G., Toni, C., Passino, M.C., Akiskal, K.K., Kaprinis, S., Akiskal, H.S., 2006.
Bulimia nervosa in atypical depression: the mediating role of cyclothymic
temperament. J. Affect. Disord. 92, 91–97.
Perugi, G., Toni, C., Travierso, M.C., Akiskal, H.S., 2003. The role of cyclothymia in
atypical depression: toward a data-based reconceptualization of the
borderline-bipolar II connection. J. Affect. Disord. 73, 87–98.
Pini, S., Abelli, M., Mauri, M., Muti, M., Iazzetta, P., Banti, S., Cassano, G.B., 2005.
Clinical correlates and significance of separation anxiety in patients with
bipolar disorder. Bipolar Disord. 7, 370–376.
Pombo, S., Figueira, M.L., da Costa, N.F., Ismail, F., Yang, G., Akiskal, K., Akiskal, H.,
2013. The burden of cyclothymia on alcohol dependence. J. Affect. Disord. 151,
1090–1096.
Pompili, M., Innamorati, M., Rihmer, Z., Gonda, X., Serafini, G., Akiskal, H., Amore, M.,
Niolu, C., Sher, L., Tatarelli, R., Perugi, G., Girardi, P., 2012. Cyclothymic-depressive-
anxious temperament pattern is related to suicide risk in 346 patients with major
mood disorders. J. Affect. Disord. 136, 405–411.
Pompili, M., Rihmer, Z., Innamorati, M., Lester, D., Girardi, P., Tatarelli, R., 2009.
Assessment and treatment of suicide risk in bipolar disorders. Expert Rev.
Neurother. 9, 109–136.
Posternak, M.A., Zimmerman, M., 2002. The prevalence of atypical features across
mood, anxiety, and personality disorders. Compr. Psychiatry 43, 253–262.
Powers, R.L., Russo, M., Mahon, K., Brand, J., Braga, R.J., Malhotra, A.K., Burdick, K.E.,
2013. Impulsivity in bipolar disorder: relationships with neurocognitive dys-
function and substance use history. Bipolar Disord. 15, 876–884.
Reich, D.B., Zanarini, M.C., Fitzmaurice, G., 2012. Affective lability in bipolar disorder
and borderline personality disorder. Compr. Psychiatry 53 (3), 230–237.
Rihmer, A., Rozsa, S., Rihmer, Z., Gonda, X., Akiskal, K.K., Akiskal, H.S., 2009.
Affective temperaments, as measured by TEMPS-A, among nonviolent suicide
attempters. J. Affect. Disord. 116, 18–22.
Rihmer, Z., Gonda, X., Torzsa, P., Kalabay, L., Akiskal, H.S., Eory, A., 2013. Affective
temperament, history of suicide attempt and family history of suicide in
general practice patients. J. Affect. Disord. 149, 350–354.
Rihmer, Z., Pestality, P., 1999. Bipolar II disorder and suicidal behavior. Psychiatr.
Clin. N. Am. 22, 667–673.
Ruocco, A.C., Amirthavasagam, S., Choi-Kain, L.W., McMain, S.F., 2013. Neural
correlates of negative emotionality in borderline personality disorder: an
activation-likelihood-estimation meta-analysis. Biol. Psychiatry 73, 153–160.
Sareen, J., Cox, B.J., Afifi, T.O., de Graaf, R., Asmundson, G.J., ten Have, M., Stein, M.B.,
2005. Anxiety disorders and risk for suicidal ideation and suicide attempts: a
population-based longitudinal study of adults. Arch. Gen. Psychiatry 62,
1249–1257.
Sass, H., Herpertz, S., Steinmeyer, E.M., 1993. Subaffective personality disorders. Int.
Clin. Psychopharmacol. 8 (Suppl. 1), S39–S46.
Sato, T., Bottlender, R., Schroter, A., Moller, H.J., 2003. Frequency of manic
symptoms during a depressive episode and unipolar 'depressive mixed state'
as bipolar spectrum. Acta Psychiatr. Scand. 107, 268–274.
Schaller, G., Kretschmer, S., Gouya, G., Haider, D.G., Mittermayer, F., Riedl, M.,
Wagner, O., Pacini, G., Wolzt, M., Ludvik, B., 2010. Alcohol acutely increases
vascular reactivity together with insulin sensitivity in type 2 diabetic men. Exp.
Clin. Endocrinol. Diabetes 118, 57–60.
Sebastian, A., Jung, P., Krause-Utz, A., Lieb, K., Schmahl, C., Tuscher, O., 2014. Frontal
dysfunctions of impulse control – a systematic review in borderline personality
disorder and attention-deficit/hyperactivity disorder. Front. Hum. Neurosci. 8,
698.
Serretti, A., Artioli, P., Zanardi, R., Rossini, D., 2003. Clinical features of antidepres-
sant associated manic and hypomanic switches in bipolar disorder. Prog.
Neuropsychopharmacol. Biol. Psychiatry 27, 751–757.
Shea, T.M., Edelen, M.O., Pinto, A., Yen, S., Gunderson, J.G., Skodol, A.E., Markowitz, J.,
Sanislow, C.A., Grilo, C.M., Ansell, E., Daversa, M.T., Zanarini, M.C., McGlashan, T.H.,
 G. Perugi et al. / Journal of Affective Disorders 183 (2015) 119–133
Morey, E.A., 2009. Improvement in borderline personality disorder in relationship
to age. Acta Psychiatr. Scand. 119, 143–148.
Sholomskas, A.J., 1990. Mania in a panic disorder patient treated with fluoxetine.
Am. J. Psychiatry 147, 1090–1091.
Signoretta, S., Maremmani, I., Liguori, A., Perugi, G., Akiskal, H.S., 2005. Affective
temperament traits measured by TEMPS-I and emotional-behavioral problems
in clinically-well children, adolescents, and young adults. J. Affect. Disord. 85,
169–180.
Silverman, A.B., Reinherz, H.Z., Giaconia, R.M., 1996. The long-term sequelae of
child and adolescent abuse: a longitudinal community study. Child Abuse
Neglect 20, 709–723.
Smith, D.J., Muir, W.J., Blackwood, D.H., 2004. Is borderline personality disorder
part of the bipolar spectrum? Harv. Rev. Psychiatry 12, 133–139.
Steiner, W., 1991. Fluoxetine-induced mania in a patient with obsessive-compulsive
disorder. Am. J. Psychiatry 148, 1403–1404.
Stone, M.H., 1981. Borderline syndromes: a consideration of subtypes and an
overview, directions for research. Psychiatr. Clin. N. Am. 4, 3–24.
Stone, M.H., 1990. The Fate of Borderline Patients: Successful Outcome and
Psychiatric Practice. Guilford Publications, New York.
Stone, M.H., 2006. Relationship of borderline personality disorder and bipolar
disorder. Am. J. Psychiatry 163, 1126–1128.
Stone, M.H., 2013a. The brain in overdrive: a new look at borderline and related
disorders. Curr. Psychiatry Rep. 15, 399.
Stone, M.H., 2013b. A new look at borderline personality disorder and related
disorders: hyper-reactivity in the limbic system and lower centers. Psychodyn.
Psychiatry 41, 437–466.
Stone, M.H., 2014. The spectrum of borderline personality disorder: a neurophy-
siological view. Curr. Top. Behav. Neurosci. 21, 23–46.
Stone, M.H., Kahn, E., Flye, B., 1981. Psychiatrically ill relatives of borderline
patients: a family study. Psychiatr. Q. 53, 71–84.
Swartz, H.A., Thase, M.E., 2011. Pharmacotherapy for the treatment of acute bipolar
II depression: current evidence. J. Clin. Psychiatry 72, 356–366.
Tondo, L., Vazquez, G., Baldessarini, R.J., 2010. Mania associated with antidepressant
treatment: comprehensive meta-analytic review. Acta Psychiatr. Scand. 121,
404–414.
Toni, C., Perugi, G., Frare, F., Tusini, G., Fountoulakis, K., Akiskal, K., Akiskal, H., 2008.
The clinical-familial correlates and naturalistic outcome of panic-disorder-
agoraphobia with and without lifetime bipolar II comorbidity. Ann. Gen.
Psychiatry 7, 1–9.
Torgersen, S., 1984. Genetic and nosological aspects of schizotypal and borderline
personality disorders. A twin study. Arch. Gen.Psychiatry 41, 546–554.
Torgersen, S., Lygren, S., √òien, P.A., Skre, I., Onstad, S., Edvardsen, J., Tambs, K.,
Kringlen, E., 2000. A twin study of personality disorders. Compr. Psychiatry 41,
416–425.
133
Unseld, M., Dworschak, G., Tran, U.S., Plener, P.L., Erfurth, A., Walter, H., Lesch, O.M.,
Kapusta, N.D., 2012. The concept of temperament in psychoactive substance use
among college students. J. Affect. Disord. 141, 324–330.
Utsumi, T., Sasaki, T., Shimada, I., Mabuchi, M., Motonaga, T., Ohtani, T., Tochigi, M.,
Kato, N., Nanko, S., 2006. Clinical features of soft bipolarity in major depressive
inpatients. Psychiatry Clin. Neurosci. 60, 611–615.
Van Meter, A., Youngstrom, E.A., Demeter, C., Findling, R.L., 2013. Examining the
validity of cyclothymic disorder in a youth sample: replication and extension. J.
Abnorm. Child Psychol. 41, 367–378.
Van Meter, A., Youngstrom, E.A., Youngstrom, J.K., Feeny, N.C., Findling, R.L., 2011.
Examining the validity of cyclothymic disorder in a youth sample. J. Affect.
Disord. 132, 55–63.
Van Meter, A., Youngstrom, E.A., Findling, R.L., 2012. Cyclothymic disorder: a critical
review. Clin. Psychol. Rev. 32, 229–243.
van Valkenburg, C., Kluznik, J.C., Speed, N., Akiskal, H.S., 2006. Cyclothymia and
labile personality: is all folie circulaire? J. Affect. Disord. 96, 177–181.
Vannucchi, G., Toni, C., Maremmani, I., Perugi, G., 2014. Does obesity predict
bipolarity in major depressive patients? J. Affect. Disord. 155, 118–122.
Vyssoki, B., Bluml, V., Gleiss, A., Friedrich, F., Kogoj, D., Walter, H., Zeiler, J., Hofer, P.,
Lesch, O.M., Erfurth, A., 2011. The impact of temperament in the course of
alcohol dependence. J. Affect. Disord. 135, 177–183.
Wehr, T.A., Sack, D.A., Rosenthal, N.E., Cowdry, R.W., 1988. Rapid cycling affective
disorder: contributing factors and treatment responses in 51 patients. Am. J.
Psychiatry 145, 179–184.
Weissman, M.M., Klerman, G.L., Markowitz, J.S., Ouellette, R., 1989. Suicidal ideation
and suicide attempts in panic disorder and attacks. N. Engl. J. Med. 321,
1209–1214.
Whalley, H.C., Sussmann, J.E., Chakirova, G., Mukerjee, P., Peel, A., McKirdy, J., Hall, J.,
Johnstone, E.C., Lawrie, S.M., McIntosh, A.M., 2011. The neural basis of familial risk
and temperamental variation in individuals at high risk of bipolar disorder. Biol.
Psychiatry 70, 343–349.
Witte, T.K., Fitzpatrick, K.K., Joiner Jr., T.E., Schmidt, N.B., 2005. Variability in suicidal
ideation: a better predictor of suicide attempts than intensity or duration of
ideation? J. Affect. Disord. 88, 131–136.
Yen, S., Frazier, E., Hower, H., Weinstock, L.M., Topor, D.R., Hunt, J., Goldstein, T.R.,
Goldstein, B.I., Gill, M.K., Ryan, N.D., Strober, M., Birmaher, B., Keller, M.B., 2015.
Borderline personality disorder in transition age youth with bipolar disorder.
Acta Psychiatr. Scand. (Epub ahead of print).
Young, L.T., Cooke, R.G., Robb, J.C., Levitt, A.J., Joffe, R.T., 1993. Anxious and non-
anxious bipolar disorder. J. Affect. Disord. 29, 49–52.
Youngstrom, E.A., 2009. Definitional issues in bipolar disorder across the life cycle.
Clin. Psychol.—Sci. Pract. 16, 140–160.