Prevalence, chronicity, burden and borders of bipolar disorder
Andrea Fagiolinia,n, Rocco Forgioneb, Mauro Maccaric, Alessandro Cuomoa,
Benedetto Moranad, Mario Catena Dell’Ossob, Francesca Pellegrinia, Alessandro Rossie
aUniversity of Siena, Department of Molecular Medicine and Clinical (DAI) Department of Mental Health, Viale Bracci 1, Siena 53100, Italy
cCommunity Health Trust Service AUSL 7, Siena, Italy
dCasa di Cura Morana, Contrada Dara 744/D, 91025 Marsala (TP), Italy
eDISCAB - Section of Psychiatry and Neurosciences, University of L’Aquila, Italy
a r t i c l e i n f o
Received 9 October 2012
Received in revised form
6 February 2013
Accepted 6 February 2013
Available online 7 March 2013
a b s t r a c t
Bipolar disorder (BD) has traditionally been thought of as an episodic condition, characterized by
periods of hypomania/mania and depression. However, evidence is accumulating to suggest that this
condition is associated with significant chronicity. For a large proportion of patients with BD, residual,
sub-syndromal symptoms persist between major syndromal episodes, and studies have shown that
many patients with bipolar disorder are symptomatic for approximately 50% of the time over follow-up
periods of greater than 10 years. Moreover, while the prevalence of BD has been estimated to be around
1–2%, there is growing evidence that this may be a substantial underestimation. There are a number of
reasons for this potential underestimation, including difficulties in diagnosis. Adding to the burden of
BD is the issue of comorbidity, with an increased prevalence of many chronic conditions in those with a
primary diagnosis of BD. Conversely, for many patients with chronic conditions, both medical and
psychiatric, BD frequently exists as a comorbid secondary diagnosis. This issue of comorbidity
complicates estimates of use of pharmaceutical agents for BD, such as mood stabilizers, which are
known to be used off-label in conditions such as borderline personality or substance use disorder. We
speculate that such off-label prescribing may not be truly off-label but may be instead fully justified by
an overlooked secondary diagnosis of BD. Finally, we discuss the association of bipolar disorder with a
significant economic burden, to the individual and to society, both due to the direct costs of medical
expenditure and indirect costs such as loss of productivity and increased mortality.
& 2013 Elsevier B.V. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
What is the true prevalence of bipolar disorder?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Delayed diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Comorbidities in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Off-label prescription of bipolar disorder medications may indicate a higher than estimated prevalence of BD . . . . . . . . . . . . . . . . . . . . . . . 163
Premorbid personality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Prodromal, residual and sub-syndromal symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
The natural course of bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Implications for treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
The cost of bipolar disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
10.1.Comorbidity increases costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
10.2.Occupational burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Long term outcomes and excess mortality in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Role of funding source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/jad
Journal of Affective Disorders
0165-0327/$-see front matter & 2013 Elsevier B.V. All rights reserved.
nCorrespondence to: Department of Mental Health and Molecular Medicine,
Division of Psychiatry, School of Medicine, University of Siena, Viale Bracci 1, Siena
53100, Italy. Tel.: þ39 0577 233294; fax: þ39 0577 233451.
E-mail address: email@example.com (A. Fagiolini).
Journal of Affective Disorders 148 (2013) 161–169
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Bipolar disorder is a clinically severe, episodic, lifelong mood
disorder (Fagiolini et al., 2009; Judd et al., 2002; Perlis et al., 2006;
Solomon et al., 1995). The traditional defining feature of bipolar
disorder is the occurrence of episodes of mania or hypomania
alternating, or occurring currently with, depressive episodes
(Oswald et al., 2007). Episodes in bipolar disorder are usually
separated by periods of recovery, with return to normal function,
but recurrence rates are high (Oswald et al., 2007; Prien and
Kocsis, 1995). However, the course of bipolar disease is not
entirely clear and recent research is suggesting that patients with
bipolar disorder experience symptoms over much longer periods
than previously thought (Judd et al., 2002). Moreover, there exists
substantial evidence that, for many people, residual symptoms
are present between episodes (Benazzi, 2001; Kaya et al., 2007;
Keitner et al., 1996).
The prevalence of bipolar I disorder in the general population has
been estimated to be between 1% and 2% (Oswald et al., 2007; Pini
et al., 2005), although the 2000 National Depressive and Manic-
Depressive Association survey provided an estimate of the preva-
lence of bipolar I and II in the US of 3.4% (Berk et al., 2006). It is likely
that the true prevalence of bipolar disorder is higher than reported,
as there is increasing evidence that bipolar disorder, particular
bipolar II disorder, is under diagnosed (Angst, 2006; Angst et al.,
2011; Angst and Cassano, 2005; Benazzi, 1997; Berk et al., 2006;
Ghaemi et al., 2000, 1999). This narrative review aims to provide
insight on the prevalence, course, clinical characteristics, costs and
treatment of bipolar disease.
2. What is the true prevalence of bipolar disorder?
Depression is a relatively easy condition to diagnose, whereas
bipolar disease is often more difficult to diagnose (Angst, 2006;
Angst et al., 2011; Angst and Cassano, 2005; Benazzi, 1997; Berk
et al., 2006; Ghaemi et al., 2000, 1999). Any lack of information on
hypomanic symptoms will result in depression being diagnosed,
and patients with bipolar disorders often present with depressive
features that are mistaken for unipolar depression (Angst, 2006;
Angst et al., 2011; Angst and Cassano, 2005; Benazzi, 1997; Berk
et al., 2006; Ghaemi et al., 2000, 1999).
For example, in a study conducted in a private psychiatric setting,
of the 203 consecutive patients presenting with a DSM-IV major
depressive episode, 103 (50.73%) patients were found to have
unipolar depression, with 92 (45.32%) diagnosed with bipolar II
disorder and 8 (3.94%) with bipolar I disorder. Moreover, research
has shown that between 30% and 40% of those with bipolar disorder
have previously received an incorrect diagnosis of unipolar depres-
sion (Berk et al., 2006; Ghaemi et al., 2000, 1999; Hirschfeld et al.,
2003; Manning et al., 1997). In the BRIDGE study, of 5693 patients
presenting with a major depressive episode, 16% met DSM-IV
criteria for bipolar I disorder, with 47% meeting bipolarity specifier
criteria (Angst et al., 2011).
With the publication of the DSM-5 in May 2013, the proportion of
patients with unrecognized bipolar disorders may be reduced (Amer-
ican Psychiatric Association). Currently, patients presenting with a
major depressive episode and some hypomanic or manic symptoms,
but not enough to meet the DMS-IV criteria for a mixed episode, may
be diagnosed as having unipolar depression. However, there is
evidence to suggest a significant portion of patients who have
subthreshold hypomanic symptoms at the time of presentation with
a major depressive episode subsequently undergo diagnostic conver-
sion to bipolar disorder (Fiedorowicz et al., 2011). In a recent study, of
550 participants with major depressive disorder, a diagnostic change
to bipolar disorder was noted in 108 (19.6%) of participants. Further-
more, in this study a number of subthreshold hypomanic symptoms
predicted progression to bipolar disorder (Fiedorowicz et al., 2011). In
the DSM-IV, for a mixed episode, patients must meet criteria for both
a manic episode and a major depressive episode (except for duration)
nearly every day during at least a 1-week period. In contrast, in the
most recent revision to the DSM-5, the threshold for mixed episodes
has been reduced substantially (American Psychiatric Association).
There is now a ‘‘with mixed features’’ specifier, with the current
revision stating that this mixed features specifier ‘‘applies in episodes
where subthreshold symptoms from the opposing pole are present during
a full mood episode. While these concurrent ‘‘mixed’’ symptoms are
relatively simultaneous, they may also occur closely juxtaposed in time as
a waxing and waning of individual symptoms of the opposite pole (i.e.,
depressive symptoms during hypo/manic episodes and vice versa)’’
(American Psychiatric Association).
In addition to being incorrectly diagnosed with depressive illness,
patients with bipolar disorder may also be incorrectly diagnosed
with other psychiatric illnesses, most commonly anxiety disorder,
schizophrenia and borderline or antisocial personality disorders
3. Delayed diagnosis
Patients with bipolar disorder may experience up to 10 years’
of symptoms before their hypomania is identified (Angst, 2006;
Berk et al., 2006; Hirschfeld et al., 2003). There are a number of
reasons for delayed diagnosis, including difficulties recognizing
initial hypomanic symptoms, particularly in early adolescence
when up to two thirds of cases of bipolar disorder first appear
(Angst, 2006). Additionally, patients tend to seek help for depres-
sion, with hypomania infrequently perceived by the individual
involved as being pathological and thus not reported, and obser-
vation periods are often too short to identify bipolar disorder, as it
is diagnosed on the lifetime occurrence of mania or hypomania
There are a number of deleterious consequences of delayed
diagnosis. These include prolonged patient suffering due to uncon-
trolled symptoms and a worse prognosis (Angst and Cassano, 2005).
Earlier detection and treatment of bipolar disorder is expected to
reduce the risk of serious events such as suicide, which is particu-
larly important given that the lifetime risk of at least one suicide
attempt has been reported in 25–50% of patients with bipolar
disorder (Jamison, 2000). There is evidence to suggest that when
receiving the appropriate treatment for bipolar disorder, such as
maintenance lithium treatment, this risk of suicide is reduced
(Baldessarini and Jamison, 1999). Moreover, if diagnosed with
unipolar depression rather than bipolar disorder, patients are likely
to be started on treatment with antidepressants, which has been
reported to lead to manic switch, a mixed state or rapid cycling in
bipolar disorder patients when not given in combination with
appropriate mood stabilizing therapy (Bowden, 2005).
A. Fagiolini et al. / Journal of Affective Disorders 148 (2013) 161–169
4. Comorbidities in bipolar disorder
Bipolar disorder is very frequently associated with significant
comorbidity, with one study showing that bipolar disorder may
be twice as likely to occur with another axis I psychiatric disorder
as to occur alone (McElroy et al., 2001). General medical condi-
tions also occur more frequently in patients with bipolar disorder
(Kilbourne et al., 2004). Common comorbid diseases include pain
disorders, cardiovascular disease, obesity, substance abuse, eating
disorders, anxiety disorders, impulse control disorders, person-
ality disorders and migraine (McIntyre et al., 2004; Oswald et al.,
2007). Patients with bipolar disorder are also significantly more
likely to have hyperglycemia, diabetes, angina, dyslipidaemia,
hypertension, and metabolic syndrome than the general popula-
tion (Centorrino et al., 2009).
The issue of substance abuse is of particular importance among
patients with bipolar disorder, with rates of substance abuse
significantly higher in this patient population than in the general
population (Brady and Lydiard, 1992; Sonne et al., 1994). More
specifically, rates of alcohol use have been reported in 21.4–54.5% of
patients with bipolar disorder (Pini et al., 2005), and cannabis use is
also highly prevalent, with such comorbid substance abuse asso-
ciated with worse treatment response and clinical outcomes
(De Hert et al., 2011). Notably, there is some evidence that in many
patients with bipolar disorder, substance abuse precedes the devel-
opment of bipolar disorder (Strakowski et al., 1998). It has been
reported that in patients with substance abuse disorders and
comorbid bipolar disorder, approximately 60% developed substance
abuse prior to the onset of bipolar disorder (Strakowski and DelBello,
2000). A 425-patient study showed that, among patients with
substance abuse disorder, 3% had comorbid mania (Compton et al.,
2000), and other studies have reported that rates of bipolar disorder
are elevated five to eight times in patients with substance abuse
disorders (Kessler et al., 1997; Regier et al., 1990). Persons with mood
disorders and anxiety are twice as likely to suffer from substance
abuse disorders and conversely, persons diagnosed with substance
abuse disorders are roughly twice as likely to suffer from mood and
anxiety disorders compared with the general population (Conway
et al., 2006). One survey revealed that, 40% of those with substance
use disorders had a comorbid mood disorder compared with a
prevalence of approximately 20% among all respondents (Conway
et al., 2006). This issue is a particularly difficult one to unravel, as
while substance abuse can lead to mental illness, mental illness can
also lead to substance abuse, and substance abuse disorders and
mental illness have common risk factors.
Moreover, bipolar disorder often exists as a secondary diagnosis,
or undiagnosed, in patients with other primary diagnoses, including
migraine, borderline personality disorder, post-traumatic stress
disorder and obsessive compulsive disorder (Antonaci et al., 2011;
Compton et al., 2000; Conway et al., 2006; Gross et al., 2002;
Marcinko and Vuksan-Cusa, 2009; Ruscio et al., 2010). In one study
of individuals with lifetime DSM-IV/CIDI obsessive compulsive
disorder, 90% of respondents met criteria for another lifetime
DSM-IV/CIDI disorder (Ruscio et al., 2010). The most common
comorbid conditions were anxiety disorders (75.8%), followed by
mood disorders (63.3%). This study found that the proportion of
comorbid cases where obsessive compulsive disorder began before
the mood disorder (45.6%) was very similar to the proportion where
the mood disorder began first (40.2%) (Ruscio et al., 2010).
Another comorbid condition frequently found with bipolar dis-
order is borderline personality disorder, a condition which is difficult
to treat and associated with substantial comorbidity with other axis
I disorders (Marcinko and Vuksan-Cusa, 2009). Importantly, there
exists overlap of symptoms between borderline personality disorder
and bipolar II disorder, in both the depressive and hypomanic mixed
states, making these two conditions difficult to differentiate; bipolar
disorder may be mistaken for symptoms of borderline personality
disorder, thus masking the bipolar disorder (Gross et al., 2002). The
high prevalence of residual symptoms in bipolar disorders and the
unstable and partly remitting course of borderline personality
disorder make it even more difficult to distinguish the two disorders
(Judd et al., 2003; Marcinko and Vuksan-Cusa, 2009; Paykel et al.,
2006). Furthermore, studies have reported that as many as 20% of
patients with borderline personality disorder meet criteria for
bipolar I disorder (Comtois et al., 1999; Gross et al., 2002).
Other conditions that have been shown to be associated with a
higher incidence of bipolar disorder than in those without such
conditions include migraine, particularly migraine with aura, and
psoriasis (Antonaci et al., 2011; Han et al., 2011).
5. Off-label prescription of bipolar disorder medications may
indicate a higher than estimated prevalence of BD
Off-label prescribing of psychiatric medications (i.e., prescrib-
ing medications outside their approved indication) is widespread
in clinical practice (Radley et al., 2006). For instance, antipsycho-
tic agents and other mood stabilizing agents have been reported
to be used off-label in post-traumatic stress disorder, obsessive
compulsive disorder, personality disorders and substance abuse
disorder (Rowe, 2007). In one cross-sectional survey of hospital
inpatients aged 18–65 years, interviews with consultant psychia-
trists regarding off-label usage of mood stabilizers were carried
out (Haw and Stubbs, 2005). A total of 249 inpatients were
identified, of whom 75 (30.1%) were receiving mood stabilizers.
Four patients were receiving mood stabilizers for licensed indica-
tions, with the remaining 71 patients receiving medication for
unlicensed indications, with the most common indication being
prophylaxis of mood swings (48/71, 67.6% patients). Furthermore,
in borderline personality disorder, pharmacological treatment is
used for symptoms of affective dysregulation (Bellino et al., 2008).
With the introduction of the atypical antipsychotic agents, the use
of off-label agents for borderline personality disorder has
increased further (Perrella et al., 2007).
Often ‘‘off-label treatment’’ with bipolar disorder medications
may become ‘‘in label’’ when a clinician does not limit the diagnosis
to the primary disease. For instance, patients with borderline
personality disorders or substance use disorders often meet the
criteria for bipolar disease on top of their main diagnosis. Indeed,
there is a substantial body of evidence highlighting the frequent
comorbidity of bipolar disorder, often as a secondary diagnosis, in
patients with disorders such as borderline personality disorder, post-
traumatic stress disorder, obsessive compulsive disorder and sub-
stance abuse disorders, amongst others (Freeman et al., 2002; Fyer
et al., 1988; McElroy, 2004; Sagman and Tohen, 2009; Zanarini et al.,
1998). Considerable evidence also exists regarding the prevalence of
off-label prescribing of mood stabilizers and antipsychotics among
patients with these conditions (Lieb et al., 2010). It is therefore
conceivable that a potentially substantial proportion of these patients
receiving so-called ‘off label drugs’ for affective symptoms, may in
fact have undiagnosed comorbid bipolar disorder as a secondary
6. Premorbid personality
Kraepelin (1921) was among the first authors to highlight
the importance of enduring personality characteristics, as the under-
lying ground from which affective states often stem (Kraepelin,
1921). Kraepelin observed that affective temperaments occurred in
the premorbid histories of most of manic-depressive probands who
returned to their basic temperament rather than to ‘normality’ on
remission. Hence, manic, irritable, depressive and cyclothymic
A. Fagiolini et al. / Journal of Affective Disorders 148 (2013) 161–169
personalities were the temperamental bases of the full-blown forms
of the illness. Of interest, such temperaments, without progression
to full-blown illness, were over-represented in the biologic relatives
of manic-depressive probands (Kraepelin, 1921). Another study,
conducted by Frey, studied premorbid personalities in 65 subjects
with major depressive disorder and 45 individuals with bipolar
disorder (Frey, 1977). This study observed that patients with major
depressive disorder scored higher than bipolar disorders in the scale
representing Tellenbach’s ‘‘melancholic type’’, corresponding to
being orderly, strenous, and conscientious. Conversely, patients with
bipolar disorders showed more extroversion than patients with
major depressive disorder (Frey, 1977). Hecht studied the relation-
ship between premorbid personality and subtypes of affective
disorder in 52 patients with unipolar depression or bipolar II
disorder, 32 patients with bipolar I disorder and 39 control subjects
(Hecht et al., 1997). Expert rating of ‘‘typus melancholicus’’ features
were found to be more pronounced in unipolar depression/bipolar II
disorder than in bipolar I disorder and controls. ‘‘Typus manicus’’
features were also distinguished between both clinical groups,
whereas anxious–insecure features were not significantly different
between the groups of patients. The authors concluded that pre-
morbid features of ‘‘typus manicus’’ and ‘‘typus melancholicus’’
predicted a predominant manic and a predominant depressive
course of an affective disorder, respectively (Hecht et al., 1997).
Quilty and colleagues examined the personality predictors of
bipolar disorder symptoms, in a psychiatric sample (N¼370; 45%
women; mean age 39.50 years), conceptualized as one-dimensional
(bipolarity) or two-dimensional (mania and depression) (Quilty
et al., 2009). In the monodimensional model, bipolar symptoms
were predicted by Neuroticism and (negative) Agreeableness. In the
bi-dimensional model, depression was associated with Neuroticism
and (negative) Extraversion, whereas mania was associated with
Neuroticism, Extraversion and (negative) Agreeableness (Quilty
et al., 2009).
A study conducted by von Zerssen and colleagues observed a
statistically significant association of the ‘affective types’ of
premorbid personality (‘melancholic type’ and ‘manic type’) with
affective disorders and the ‘neurotoid types’ (‘anxious insecure
type’ and ‘nervous tense type’) with non-affective disorders (von
Zerssen et al., 1994). A marked preponderance of the ‘manic type’
of personality was found in bipolar I patients, particularly
pronounced in those with a predominantly manic course of the
disorder; whereas the ‘melancholic type’ of personality prevailed
in bipolar II and unipolar depressive patients.
Koszewska and Rybakowski assessed the personality traits in
108 patients with bipolar disorders with (n¼32) or without
(n¼28) mixed state and with and without rapid cycling, using
the Neuroticism, Extraversion, and Openness Personality-five-
factor inventory (NEO-FFI) (Koszewska and Rybakowski, 2008).
Ratings were correlated with clinical data of the course of bipolar
disorders and neuroticism was found to be significantly higher in
patients with mixed state compared with patients without mixed
state history. No difference in personality measures were revealed
between patients with or without rapid cycling. These results
suggest that high neuroticism in bipolar patients may be asso-
ciated with a predisposition to mixed state but not to rapid
cycling .(Koszewska and Rybakowski, 2008)
Srivastava and Ketter reviewed the evidence suggesting that
personality and temperament contributed to enhanced creativity in
individuals with bipolar disorder, a theory that has been supported
by studies showing that certain personality/temperamental traits
are not only common in patients with bipolar disorder and creative
individuals but also correlate with measures of creativity (Srivastava
and Ketter, 2010). The authors suggest based on studies using three
personality/temperament measures (the NEO inventory, the Myers-
Briggs Type Indicator [MBTI] and the Temperament Evaluation of
the Memphis, Pisa, Paris, and San Diego Autoquestionnaire [TEMPS-
A]), that changeable (increased TEMPS-A–cyclothymia) and at times
negative (increased NEO-neuroticism) personalities and open-
minded (increased NEO-openness) and intuitive (increased MBTI-
intuition) cognition may contribute importantly to enhanced crea-
tivity in patients with bipolar disorder (Srivastava and Ketter, 2010).
L¨ onnqvist and colleagues explored the premorbid personality traits
Neuroticism, Extraversion, and Disinhibition in individuals later
diagnosed with psychotic disorders and also showed an association
between premorbid Extraversion and bipolar disorder (L¨ onnqvist
et al., 2009).
7. Prodromal, residual and sub-syndromal symptoms
Bipolar disorder is considered an episodic disease, marked by
relatively short episodes of manic, hypomanic or depressive epi-
sodes, but evidence suggests that bipolar disorder is in fact asso-
ciated with greater chronicity than is implied by this episodic
description (Judd et al., 2002; Prien and Kocsis, 1995; Solomon
et al., 2010). A high proportion of patients with bipolar disorder have
prodromal or residual symptoms during intervals between episodes
(Fagiolini et al., 2005b; Kaya et al., 2007; Keitner et al., 1996; Prien
and Kocsis, 1995; Wells et al., 1992), and it has been estimated that
between 20% and 35% of patients do not fully recover from any
given episode (American Psychiatric Association, 1993; Prien and
Keitner and colleagues evaluated the prodromal and residual
symptoms of mania and depression in 74 patients with bipolar I
disorder and observed that 78% of the patients reported prodro-
mal depressive symptoms and 87% reported prodromal manic
symptoms (Keitner et al., 1996). More than half of the patients
disclosed residual symptoms of depression (54%) and mania
(68%). Cognitive symptoms were the most common symptoms
reported by patients, followed by mood symptoms (Keitner et al.,
A study conducted by Sierra and colleagues reviewed the
literature to describe the manic and depressive prodromal symp-
toms associated with relapse (Sierra et al., 2007). They demon-
strated that the most common depressive prodromes are mood
changes, psychomotor symptoms and increased anxiety; the most
frequent manic prodromes are sleep disturbances, psychotic
symptoms and mood changes. They also noted that certain
interventions have proven effective to prevent prodromal symp-
toms evolving into a full diagnosis and suggest that learning
detection, coping strategies and idiosyncratic prodromes are
elements that should be incorporated into daily clinical practice
with bipolar patients. Likewise, residual symptoms are as impor-
tant, due to their significant impact on patient quality of life and
the risk of recurrence and chronicity (Sierra et al., 2007). One
study that clearly demonstrates this chronicity is a study in 146
patients with bipolar I disorder conducted over a mean follow-up
period of 12.8 years (Judd et al., 2002). In this study, patients were
found to be symptomatically ill for 47.3% of the weeks assessed
during the follow-up period. Depressive symptoms were more
frequent than either manic/hypomanic symptoms or cycling/
mixed symptoms. Importantly, sub-syndromal depressive and
hypomanic symptoms were three times more frequent than
syndromal-level major depressive and manic symptoms, high-
lighting the importance of such sub-syndromal symptoms (Judd
et al., 2002). These are symptoms that have been largely ignored
previously, leading to substantial underestimation of the true
burden of this disease. In a similar study conducted in patients
with bipolar II disorder, results were analogous and again high-
lighted the chronicity of bipolar disorder (Judd et al., 2003). More
specifically, in this 86-patient study with a mean of 13.4 years’
A. Fagiolini et al. / Journal of Affective Disorders 148 (2013) 161–169
follow-up, patients were found to be symptomatic for 53.9% of the
follow-up weeks, with depressive symptoms dominating over
hypomanic symptoms and cycling/mixed symptoms (Judd et al.,
2003). Further evidence comes from the Bipolar Disorder Center
for Pennsylvanians study (n¼515), in which 29% of those who
were symptomatic at study entry did not achieve recovery (at
least 8 weeks with CGI of 1 or 2) within the 24-month study
period. Of those who did meet these recovery criteria, 40% had a
new episode during the study (Fagiolini et al., 2009). Moreover, in
the STEP-BD study, only 58% of patients achieved recovery within
24 months (Perlis et al., 2006), of whom 49% experienced
recurrences. Finally, a large study including a total of 219 patients
with bipolar I disorder who had 1208 mood episodes of the study
period (median of 4 episodes per subject), investigated the time
to recovery after a mood episode (Solomon et al., 2010). In this
study, the median duration of bipolar I mood episodes was 13
weeks. Over the first five mood episodes for each individual, only
41–59% had recovered at 3 months, and at 6 months, approxi-
mately 30% of patients had not recovered (Fig. 1). Moreover, more
than 10% of patients had still not recovered at 2 years, and
between 5% and 10% of patients had not recovered by 5 years.
8. The natural course of bipolar disorder
Valuable data on the natural length of psychiatric disorders were
published before the availability of effective treatments. For instance,
the Iowa 500 study examined 200 inpatients with schizophrenia, 100
with bipolar disorder and 225 with major depressive disorder
consecutively admitted to the Iowa Psychopathic Hospital between
1934 and 1944 (Clancy et al., 1974). Prior to the introduction of
effective treatments, manic episodes lasted between 7 and 13
months. However, for patients who were followed after 1945, at
which point there was clear evidence of effective treatment (e.g.,
electroconvulsive therapy), episodes became much shorter and were
usually terminated 1.8–2.7 months from their onset (Clancy et al.,
1974; Winokur and Tsuang, 1996). As reviewed by Angst and Sellaro
(Angst and Sellaro, 2000), in 1881 Mendel reported on the length of
manic episodes in 43 patients with bipolar disorder, for whom a
median duration of 5–6 months was observed. Similarly, in 1924
Panse examined the follow up of 205 hospitalized patients with
bipolar disorder and found a mean length of 7 months for manic and
depressive episodes and in 1929 Wertham investigated 1000 male
and 1000 female patients at their first admissions for mania and
reported a mean duration of symptoms of 4–6 months (Angst and
Sellaro, 2000). Other studies suggest that the length of episodes were
shorter; Angst and Sellaro estimated from published histograms that
the median duration of episodes in patients with bipolar disorders
were 4–6 months (Angst and Sellaro, 2000), whereas a publication by
Rennie in 1942 found that there was an increase in length for
repeated manic episodes, with the first episode lasting 3.5 months,
the second 5.2 months, the third 5.8 months, and the fourth and fifth
even longer (Angst and Sellaro, 2000). Finally, in 1954 Kinkelin
described the course of bipolar disorder in 347 patients and reported
a mean length of depressive episodes ranging from 3.5 to 8.4 months,
and of manic episodes from 4 to 11.6 months (Angst and Sellaro,
2000). Apart from the availability or lack of effective treatments, the
differences in the average duration of episodes from one study to
another are likely accounted for by the differences in illness severity,
depending on the setting where patients were admitted/recruited.
Nonetheless, it is unquestionable that the availability of new treat-
ments has shortened the mean duration of episodes.
9. Implications for treatment
The increasingly apparent chronicity of bipolar disorders, both
bipolar I and bipolar II, have important implications for treat-
ment. The initial treatment given for bipolar disorder is consid-
ered acute treatment, given to achieve remission of the acute
symptoms of the current, presenting episode (Prien and Kocsis,
1995). The primary treatment for the acute phase of bipolar
disorder, for both depressive and manic episodes, is mood
stabilizers, commonly lithium or valproate semisodium, as well
as atypical antipsychotics (Fountoulakis et al., 2005; Sachs et al.,
2000). Most patients will at some stage require combination
therapy, for instance, a classic mood stabilizer and an antipsy-
chotic during manic episodes. If antidepressants are required,
these are only recommended when used in combination with
antimanic agents, to reduce the risk of switching (Fountoulakis
et al., 2005). In our clinical practice, we never consider the use an
antidepressant (not even in patients without a full blown bipolar
disorder diagnosis) before all symptoms of agitation, activation,
impulsivity, dysphoria, tension are cleared, i.e. before any manic
spectrum symptom or sign has disappeared (Fagiolini et al.,
2002). Conversely, we will consider the use of an antidepressant
in combination with a mood stabilizer or an antipsychotic, in
patients whose current symptoms are mainly represented by low
energy, psychomotor retardation, hypersomnia, lack of interest
and lack of motivation. Remission from the acute phase of bipolar
disorder is defined in various ways, often considered as a return
to the individual’s well state, but in research is usually defined as
Fig. 1. Time to recovery from the first 5 prospectively observed mood episodes. The survival curves depict the duration of the first five prospectively observed mood
episodes and are based on cumulative recovery probabilities (Kaplan–Meier estimates). The five curves are similar, indicating that time to recovery in the sample as a
whole was consistent across multiple mood episodes. Reproduced with permission from Archives of General Psychiatry. 2010;67(4):339–347. http://dx.doi.org/10.1001/
A. Fagiolini et al. / Journal of Affective Disorders 148 (2013) 161–169
when an individual no longer meets diagnostic syndrome
criteria—which often means that minor, sub-syndromal symp-
toms may still exist (Prien and Kocsis, 1995). As has been
discussed in the preceding section of this review, for many
patients, true remission may not be achieved for many weeks,
months, or even years, suggesting that so-called ‘acute treatment’
may need to be continued, and adjusted, over a long period. After
a patient has been deemed to have recovered, maintenance
treatment is usually given. This should comprise an antimanic
agent, with some patients also requiring maintenance antidepres-
sant therapy (Fountoulakis et al., 2005). Lamotrigine may be a
valuable option to prevent depressive episodes (Fountoulakis
et al., 2005; Sachs et al., 2000). However, even when a clinical
response or even remission is seen, this may not always mean
that the acute episode has actually and completely resolved,
rather the treatment may be masking an ongoing biological
process that may ‘re-emerge’ upon treatment discontinuation
(Prien and Kupfer, 1986). This period following apparent symp-
tom resolution can be considered a period where continuation
therapy should be considered, that is continuation of the treat-
ment given for the acute phase, with such therapy recommended
to continue for at least 4 months, or longer if there are sympto-
matic breakthroughs (Prien and Kocsis, 1995; Prien and Kupfer,
10. The cost of bipolar disorder
Despite advances in treatment, bipolar disorder remains asso-
ciated with high psychosocial and functional disability, with less
than 20% of the total economic costs of bipolar disorder associated
with direct treatment costs (Goldberg and Ernst, 2002). The indirect
costs of bipolar disorder, such as loss of productivity and increased
mortality, are considerable (Centorrino et al., 2009), with a large
portion of the economic burden of bipolar disorder attributed to
uncontrolled symptoms, due to inappropriate treatment, lack of
treatment and delayed treatment. Notably, the WHO burden of
disease study ranked bipolar disorder 6th worldwide in cause
of medical disability (Murray et al., 1994).
In a 1991 US study, direct costs of bipolar disorder were estimated
at $US7 billion, comprising expenses for treatment-related inpatient
and outpatient care, as well as non-treatment-related costs, such as
use of the criminal justice system, with indirect costs of $US38 billion.
These indirect costs included lost productivity of wage earners of
$US17 billion and lost productivity costs for individuals lost to suicide
of $US8 billion (Wyatt and Henter, 1995).
The growing burden of bipolar disorder was demonstrated in a
2009 study, which showed marked increases in both the direct
and indirect costs of bipolar disorder compared with the pre-
viously discussed 1991 study. These increases were even greater
than that expected from inflation alone. In this 2009 study, the
total direct costs of bipolar I and II disorders were estimated at
$US30.7 billion, with total indirect costs of $US120.3 billion,
giving a total cost of $US151.0 billion (Dilsaver, 2011). This study
found that direct costs escalated out of proportion (2.2393-fold)
to indirect costs (1.6148-fold) (Dilsaver, 2011). Importantly, the
authors note that these figures need to be considered significant
underestimations of the true cost of bipolar disorders, as the
prevalence figures used do not include the full array of bipolar
disorders, such as subthreshold cases. The evidence presented in
the current review regarding the degree to which the prevalence
of bipolar disorders is underestimated supports the authors’ view
that the above figures are likely to be significant underestima-
tions of the true cost of bipolar disorders.
An Australian study also found bipolar disorder and associated
suicide to be associated with substantial direct and indirect costs,
estimating real financial costs to be $AUS1.59 billion in 2003, over
$AUS16,000 on average for each of nearly 100,000 Australians
with the illness, with direct health system costs estimated at
$AUS298million (SANE Australia, 2003).
Many studies investigating the costs of bipolar disorders in
various settings have found that hospitalization makes up a
significant portion of the direct medical costs. In the UK, the total
annual NHS cost associated with managing bipolar disorder was
estimated at £342 million at 2009/2010 prices, with hospitaliza-
tion accounting for £207 million of this cost (Young et al., 2011).
Additionally, in a Spanish study (n¼784), direct costs associated
with healthcare resource utilization during manic episodes were
high, and the majority of this cost was associated with hospita-
lization (Tafalla et al., 2010). Furthermore, a 2004 systematic
review revealed inpatient costs to be the largest cost contributor
in bipolar disorders (Dean et al., 2004).
10.1. Comorbidity increases costs
Compared with many other chronic illnesses, including depres-
sion and coronary artery disease, bipolar disorder is associated with
significantly higher healthcare utilization costs, even after adjust-
ment for age and comorbidity, with costs comparable to those of
diabetes (Dean et al., 2004; Williams et al., 2011). Comorbidities in
bipolar disorder, both psychiatric and medical, further add to the
cost of disease—patients with bipolar disorder use resources for
both mental and non-mental healthcare at higher rates and at
higher costs than patients without the disorder (Bryant-Comstock
et al., 2002). One large (n¼67,862) cohort study found that of total
treatment costs in bipolar patients, 33% were bipolar related, with
the remaining 67% related to comorbidities (Guo et al., 2008).
Furthermore, one retrospective analysis of claims data for 28,531
patients with bipolar disorder that demonstrated a significantly
higher prevalence of metabolic comorbidities than in the general
population, also found that annual medical service treatment costs
for metabolic conditions were twice that of the control cohort
(Centorrino et al., 2009).
10.2. Occupational burden
In a systematic literature review examining the burden of
bipolar disorder, data indicated that the chronicity of bipolar
disorder was associated with a debilitating effect on patients
(Fajutrao et al., 2009). More specifically, data from Germany
revealed that 70% of patients with bipolar disorder were under-
employed, and that 72% received disability payments. In Italy,
figures were similar, with 63–67% of patients unemployed. UK
data highlighted the costs associated with this high level of
unemployment among patients with bipolar disorder, with an
annual cost of £1510 million unemployment at 1999/2000 prices
(Fajutrao et al., 2009).
Moreover, among bipolar patients who are employed, the
occupational burden is substantial, with significant impact on
worker absenteeism and diminished productivity (Goldberg and
Ernst, 2002). Research has highlighted the significantly higher costs
associated with employees with bipolar disorder compared with
those for mental health categories, including alcohol-related and
substance-related mental disorders, as well as comorbid physical/
medical conditions (Rajagopalan et al., 2006). In a study involving
761 employees (0.3%) with bipolar disorder and 229,145 eligible
employees without bipolar disorder, employees with bipolar disorder
were found to cost $US6836 more per year than employees without
bipolar disorder, and were more costly in every health benefit cost
category (Gardner et al., 2006). Furthermore, employees with bipolar
disorder missed an average of 18.9 workdays annually, while
A. Fagiolini et al. / Journal of Affective Disorders 148 (2013) 161–169
employees without bipolar disorder missed only 7.4 days annually
(po0.05) (Gardner et al., 2006).
In a review designed to elucidate the features of bipolar disorder
that are associated with treatment difficulties and high treatment
costs, results indicated that, despite recent advances in treatment,
particularly outpatient therapy, hospitalization still accounts for a
substantial portion of direct costs. Moreover, while a variety of
outpatient services are becoming increasingly important for bipolar
disorder, costs of such care are growing. Indirect costs due to
morbidity and premature mortality comprise a large portion of the
cost of illness, and lost workdays and inability to work due to the
disease cause high morbidity costs. Intangible costs such as family
burden and impaired health-related quality of life are common, but
it is difficult to quantify the costs of these (Kleinman et al., 2003).
11. Long term outcomes and excess mortality in bipolar
Bipolar disorder is a chronic, potentially lethal disease that is
associated with poor psychiatric outcome and a high rate of suicide
(Baldessarini and Tondo, 2003; Kilbourne et al., 2004). Increased
mortality is a major adverse effect in patients with bipolar disorder
and many studies have found mortality and suicide mortality rates of
approximately 2 and 10 times that of the general population,
respectively (Astrup et al., 1959; Bratfos and Haug, 1968; Høyer
et al., 2000; Petterson and Arnetz, 1997; Sharma and Markar, 1994;
Tsuang et al., 1980; Vestergaard and Aagaard, 1991). Medical risk
factors and medical disease are common in bipolar disorder and lead
to even greater morbidity and mortality. Many medical problems
have been cited in the few reports focused on this population, the
most common of which are cardiovascular disease, obesity, diabetes,
and thyroid disease (Fagiolini et al., 2005a; Kilbourne et al., 2004;
Kupfer, 2005). The accumulation of key medical risk factors related to
excessive alcohol, tobacco and drug use lead to the early onset of
medical diseases with poor long-term outcomes. In a prospective
follow-up of patients followed for at least 22 years, Angst and
colleagues demonstrated an increased risk of death from cardiovas-
cular and cerebrovascular disorders and from accidents and intox-
ication in patients with bipolar disorders compared with patients
with non-bipolar depression (Angst et al., 2002). Kilbourne and
colleagues studied the prevalence of medical comorbidities in 3709
patients with bipolar I disorder (mean age ¼52713 years) and
found that such individuals carry a substantial burden of medical
comorbidity, especially diabetes and cardiovascular problems, that
can significantly increase their risk of death (Kilbourne et al., 2004).
Such comorbidities were also more prevalent and occurred at an
earlier age (i.e., 4-8 years earlier) than in the general patient
population, suggesting the need for earlier detection and treatment
in patients with bipolar disorder. In assessing medical comorbidity in
outpatients at Duke University (mean age¼37.1 years), Krishnan and
colleagues categorized the medical diagnoses of 1326 patients
treated for bipolar disorder from 2001 to 2002 (Krishnan, 2005).
The most common comorbid systemic illnesses were endocrine and
metabolic diseases (12.7%), nervous system and sense organ diseases
(11.1%) and circulatory system diseases (10.5%). Cassidy and collea-
gues found the prevalence of diabetes among individuals with
bipolar disorder was three times higher than in the general popula-
tion (Cassidy et al., 1999). Furthermore, those bipolar patients with
comorbid diabetes had a greater number of lifetime psychiatric
hospitalizations than did the non-diabetic subjects.
Finally, O¨sby and colleagues identified from an inpatient register
all patients with a hospital diagnosis of bipolar (n¼15,386) or
unipolar (n¼39,182) disorder in Sweden from 1973 to 1995 and
linked these cases with the national cause-of-death register to
determine the date and cause of death (O¨sby et al., 2001). Overall
and cause-specific standardized mortality ratios (SMRs) and
numbers of excess deaths were calculated by 5-year age classes
and 5-year calendar periods. For patients with bipolar disorder, the
SMRs for suicide were 15.0 for males and 22.4 for females. For all
natural causes of death, SMRs were 1.9 for males and 2.1 for females.
Most excess deaths were from natural causes. The SMR for suicide
was especially high for younger patients during the first years after
the first diagnosis (O¨sby et al., 2001).
Bipolar disorder is frequently under-diagnosed, largely as it is
difficult to diagnose, and the true prevalence is therefore likely to be
much higher than has been estimated in many studies conducted to
date. In addition to the diagnostic issues, the true burden of bipolar
disorder is further underestimated due to a lack of understanding of
the chronicity of the disease and the high prevalence of residual
symptoms. Moreover, the high frequency of off-label prescribing of
mood stabilizers in particular for disorders in which bipolar disorder
is frequently comorbid, suggests that bipolar disorder is often
‘hidden’ in individuals with other primary diagnoses, leading to an
even greater underestimation of the true prevalence of this illness, an
illness that is costly, both to society and to individuals. Research to
help elucidate the true course of bipolar disorder is necessary to help
with treatment going forward.
Role of funding source
Conflict of interest
Andrea Fagiolini is a consultant and/or a speaker and/or has received grants from
Angelini, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Eli Lilly,
Janssen, Lundbeck, Novartis, Otsuka, Sigma Tau. Rocco Forgione is a consultant for
Angelini, Lundbeck and Bristol Meyers Squibb. Mauro Maccari, Benedetto Morana,
Mario Catena Dell’Osso and Alessandro Rossi declare no conflict of interest. Francesca
Pellegrini has received grants from Eli Lilly and Pfizer.
The authors thank Denis Bilotta and Simone Boniface from inScience Com-
munications, Springer Healthcare who provided editorial assistance for the
preparation of this manuscript. This assistance was sponsored by Lundbeck.
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