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Affective Spectrum Disorders Bipolar Spectrum
The Manic Wing of the Bipolar Spectrum
a report by
J u l e s A n g s t 1 and P e t r a Z i m m e r m a n n 2
1. Professor of Psychiatry, Zurich University; 2. Molecular Psychology Unit, Max Planck Institute of Psychiatry, Munich
The International Statistical Classification of Diseases and Related
Epidemiology
Health Problems, 10th Revision (ICD-10) allows a very detailed
The Early Developmental Stages of Psychopathology (EDSP) study, a
diagnostic classification of affective disorders on the syndromal level
prospective community survey of 3,021 adolescents and young adults,
into the three classic groups of manic, bipolar and depressive episodes.
found lifetime prevalence rates of 1.5% for mania at baseline. Most
The method also takes into account severity (psychotic, severe,
subjects with mania fulfilled the criteria for more than one episode
moderate and mild) and recurrence. However, a shortcoming is that
(prevalence rate 1.4%). The prevalence of hypomanic episodes was
the ICD-10 labels the groups of manic and hypomanic (F30) and
2.0% at baseline, but only 0.4% manifested with a concomitant major
depressive syndromes (F32) as episodes only (rather than disorders),
depressive episode; the others showed m.5,6 Within bipolar-I disorder,
whereas bipolar manifestations are ranked as a fully-fledged disorder
Md and M have been described as being relatively rare. The only data so
(F31). The finely graded classification of ICD-10 has so far had
far available on cumulative incidence rates are again derived from the
regrettably little influence on clinical, psychopharmacological and
EDSP. After a 10-year follow-up (n=2,210; T0–T3 response rate = 73%),
biological research. The literature is instead dominated by a simplified
65 subjects with Diagnostic and Statistical Manual of Mental Disorders
classification of affective disorders into major depressive disorders
(DSM-IV)-defined manic episodes were identified, corresponding to a
(MDD) and bipolar-I and bipolar-II disorders. In particular, research into
lifetime prevalence rate of 3% (2.97%). Surprisingly, 40% of manic
pure mania (M) and mania with moderate or mild depression (Md) is
subjects who would usually be labelled as suffering from bipolar-I
very limited, and there has been virtually no investigation of pure
disorder did not meet the strict criteria for mania with major depressive
hypomania (m) without depression or of minor bipolar disorder
episodes (MD), but only for Md or M. The corresponding weighted
(md/MinBP, defined by the lifetime co-occurrence of mild or moderate
prevalence rates were 1.79% (MD), 0.58% (Md) and 0.60% (M).
depression with hypomanic episodes or by cyclothymic disorder).
For these reasons, this article can provide only limited data and
Studies of Manic Patients without Long-term Follow-up
provisional conclusions.
In the earlier literature, as summarised by Shulman and Tohen,3
retrospective studies of treated manic patients predominate. Abrams et al.7
Pure Mania
found more males among pure manic patients and an increased morbid
The literature on mania is both extensive and heterogenous, and consists
risk for unipolar depression among their relatives. Nurnberger et al.8
largely of studies assessing manic episodes within bipolar-I disorder. The
examined 241 patients attending a lithium clinic, 38 of whom were
drug trials on mania rarely distinguish between M and mania as an
suffering from M. Sixty-three manics had been treated but not hospitalised
element of bipolar-I disorder; therefore, they are dealing with
for depression (Md) and 140 manics had been hospitalised for depression
heterogeneous samples. A recent review of a study by Harish et al. in
(group MD). There was a trend (p<0.10) towards a gender difference: 66%
2005 summarised the literature comprehensively.1 Very few modern
of M sufferers, 51% of Md sufferers and 46% of MD sufferers were male.
studies focus on M, but some of them will be reviewed here. The
diagnosis of unipolar M (without mild or severe depression) is a function
of the duration of the follow-up. Just as with recurrent severe
depression, where the risk of a diagnostic conversion to bipolar disorder
remains constant over a patient’s lifetime,2 every new episode of mania
carries with it the risk of a diagnostic conversion to bipolar disorder. This
is why some authors have proposed a minimum number of manic
episodes as a prerequisite for the diagnosis of M. For example, three
episodes and a minimum follow-up of three years,3 or four episodes and
a minimum follow-up of four years,4 might be defined as criteria for
diagnosis. Such restrictions have proved to be of limited value in face of
Jules Angst is Emeritus Professor of Psychiatry at Zurich
University and an Honorary Doctor of Heidelberg
University. His work focuses on epidemiological and
clinical research. Prior to this, from 1969 to 1994, he was
a Professor of Clinical Psychiatry and Head of the
Research Department of Zurich University Psychiatric
Hospital (the Burghölzli). Professor Angst has received
many awards in recognition of his work, including the
Selo Prize of the National Alliance for Research on
Schizophrenia and Depression (NARSAD) in 1994 and the Lifetime Achievement Award of
the International Society of Psychiatric Genetics (ISPG) in 2002.
E: jangst@bli.uzh.ch
the results of a recent survival analysis of the diagnostic conversion from
M to bipolar disorder. In a prospective study of manic patients
conducted over more than 20 years, we found a relatively constant
(linear) lifelong conversion rate of 2.7% per year among 33 hospitalised
patients whose illness began with mania. This risk is more than double
Petra Zimmermann is a Genetic Epidemiologist in the Molecular Psychology Unit of the Max
Planck Institute of Psychiatry. She studied psychology at the Julius-Maximilians-Universität
Würzburg. Her doctoral thesis, conducted at the Max Planck Institute of Psychiatry, Munich,
and at the Technical University of Dresden, was entitled ‘The effect of primary anxiety disorders
on alcohol use, abuse and dependence in adolescents and young adults’.
the 1.25% rate we reported for the diagnostic conversion from
depression to bipolar disorder.2
© TOUCH BRIEFINGS 2008
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Affective Spectrum Disorders Bipolar Spectrum
M was less rapidly cycling (2.6%) than Md (12.7%) and MD (18.4%). The
disability/impairment. Overall, the outcome of M patients was more benign.
morbid risk data of unipolar depression among parents and siblings did not
Angst et al.14 followed up 406 patients (admitted to hospital between
differ between the three groups, but compared with the other two groups
1959 and 1963) every five years over a period of 21–26 years until 1985,
there was a trend (non-significant) among manics for a lower morbid risk
and collected mortality data regularly until 2003, by which time over
of bipolar-I disorder (M 0%, Md 1.8% and MD 2.9%) and bipolar-II
80% of the sample had died. Thirty of 155 patients (18.7%) who had
disorder (M 2.6%, Md 5.8% and MD 4.7%).
manic episodes showed signs of mania only. Fourteen of these patients
were M and 16 were Md cases. Compared with the 130 bipolar-I
A chart review by Pfohl et al.9 of 247 hospital admissions for mania
patients, the 30 manics (M/Md) had higher educational levels, a lower
compared manic with bipolar patients and found no significant
morbid risk of affective disorders and a significantly better course with
difference in clinical validators, including gender distribution, although a
fewer recurrences and lower suicide rates. These findings are compatible
family history of M tended to be twice as frequent among manic patients
with Nurnberger et al.8 regarding lower rates of suicide attempts and
whereas a family history of depression was less frequent (non-significant).
rapid cycling. The personality of manics was more frequently manic than
A six-month to four-year follow-up study by Starkstein et al. found 12
melancholic and they were more aggressive. The related mortality study15
manic patients and compared them with seven bipolar patients using
showed that manic patients died significantly less often from suicide, but
computed tomography (CT) scans and neuro-psychological tests. They
more frequently from cardiovascular disease (standardised mortality
reported no gender difference between the two groups. The manic
ratios [SMR] 2.9) than bipolar-I patients (SMR 2.0), with both groups
patients showed less cognitive impairment but higher frequencies of
differing significantly from the Swiss population.
10
cortical lesions (right frontal), whereas subcortical lesions (right head of
the caudate and thalamus) predominated among bipolar patients.
Studies in Non-Western Cultures
Makanjuola16,17 examined patients from psychiatric units responsible for
Long-term Follow-up Studies of Manic Patients
a catchment area containing about one million Yoruba Nigerians. The
Keller et al.11 found that 7% of 155 patients with bipolar-I disorder
author found a strong predominance of M (n=55), defined by at least
suffered from M (median follow-up 1.5 years). Their prognosis was better
two episodes, over bipolar disorders (n=13). Thirty-six other patients
(shorter illness, lower chronicity) than that of the bipolar-I patients.
manifested single-episode mania. Males predominated in the manic
Solomon et al.12 followed 27 manic and schizo-manic patients who had
group (62%). All three groups had previous histories of mania (average
no previous history of depression over a period of 15–20 years in the
of 5.9 years), earlier records were available and relatives were also
context of the Collaborative Depression Study, examining them every six
interviewed. A Tunisian study also found relatively high rates (37.5%) of
months during the first five years and annually thereafter with
M, with an over-representation of males compared with bipolar
retrospective weekly assessments of mood status. Twenty subjects
disorder.18 Aghanwa19 found excessively high rates of M, particularly
developed major depressive episodes, two developed Md and five
among females, compared with bipolar disorder in Fiji. A family history of
remained M patients, manifesting one to eight new hypomanic episodes
psychiatric disorders was rarer among the manic group, which did not
during follow-up. The seven subjects who did not develop major
otherwise differ from the bipolar group.
depressive episodes were all inpatients at study intake, and five of them
had psychotic symptoms. The authors concluded that M is a genuine but
Psychotic Mania
relatively rare diagnostic entity. Shulman and Tohen3 studied 50 elderly
Compared with bipolar disorder, rates of psychotic features among M
manic patients, six of whom (12%) were found to have M with at least
disorders were found to be at least equal,14 if not higher, especially with
three episodes. These patients were followed up for three to 10 years
regard to mood-incongruent features.4,7,13 Psychotic mania was not
(mean 5.6 years), and five were female and one male. The age of onset
found to correlate with the number of manic symptoms.20
of the manic patients was earlier than that of the 44 bipolar patients.
Hypomania
In a four-year follow-up study of 272 hospitalised manic patients, Yazici et al.4
The definition of m as a disorder and of hypomanic syndromes as a
identified 224 as bipolar-I and 48 (16.3%) as M, meeting the study’s criterion
diagnostic specifier for bipolar depression is a matter of ongoing debate.
of four manic episodes over four years. The authors stressed that the
Subjects experiencing hypomanic episodes without depression (m) are rare
occurrence of Md episodes in some of the patients cannot be excluded, which
and not usually seen in psychiatric care. However, they can be identified
would classify them as Md. Compared with the bipolar-I patients, those with
in epidemiological samples followed prospectively. In the Zurich Study,
M had more psychotic symptoms (85 versus 71%), were slightly more
which followed a cohort who were between 20 and 40 years of age, 23
often male (44 versus 37%) and less often had a family history
subjects (3.6%) were diagnosed as presenting with hypomanic episodes.21
of depression (2 versus 7%). Their age and age at onset were also lower. Of
The stability of the hypomanic syndrome across several interviews was very
special interest is the authors’ finding that during the free intervals, manics
low, therefore it did not correspond to persistent hyperthymia. Two-thirds
were more often hyperthymic (13 versus 5%) and less often cyclothymic
of the hypomanic subjects were male. An average of 30 days were spent
(0 versus 6%). Manic patients seemed to be less responsive to lithium
cumulatively in hypomania over the previous 12 months. Compared with
prophylaxis, a finding at variance with Nurnberger et al.8 Perugi et al.13 selected
controls, hypomanics had higher incomes, were more frequently married
87 inpatients with a history of mood disorders longer than 10 years and at
and divorced and had more children. They also rated higher on all of the
least three major affective episodes. Nineteen of these patients (21.8%) had
following measures: aggression, risk-taking behaviour, physical and social
M. Compared with the 68 bipolar patients, they did not differ in their family
overactivity, elevated and irritable mood, sleep disturbances, substance
history of major depression or bipolar disorder, but they were characterised by
abuse and binge eating. They also broke the law and received court
more psychotic symptoms, a hyperthymic temperament, lower hostility,
sentences more frequently. On the General Behavior Inventory (GBI) of
anxiety and suicidality scores and less work, financial and social
Depue,22 they scored highly for hypomania but not cyclothymia or
20
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The Manic Wing of the Bipolar Spectrum
dysthymia, differing in this respect from bipolar subjects. A special
controversial. Kraepelin’s unitarian concept of manic-depressive insanity
subgroup of hypomania, recurrent brief hypomania, has been described.
has tended to be replaced by a dimensional–proportional diagnostic
It is defined by brief episodes (one to three days) of hypomania recurring
spectrum extending from depression via bipolar-II, bipolar-I and Md to M.34
at least monthly.23 Recurrent brief hypomania was found to be
significantly associated with recurrent brief depression (RBD), recurrent
Conclusions
brief anxiety, dysthymia and alcohol use disorders.24 Brief hypomania (one
There is a continuum of affective (mood) disorders from depression via
to three days) is also very common in children.25
bipolar disorders to mania. Over a lifetime, a patient’s diagnosis can
change. Depression and mania carry with them a lifelong constant
Minor Bipolar Disorder
diagnostic risk of conversion of 1.25 and 2.7%, respectively, per year.
The Zurich Study also described a group of MinBP patients comprising
Therefore, no number of previous manic episodes can diminish the
three subgroups of depression and meeting the broad Zurich criteria for
subsequent risk of a diagnostic conversion. Along this continuum,
bipolarity.26 Hierarchically, they comprised bipolar dysthymia (cyclothymic
subgroups can be defined that differ clearly from each other.
disorder, n=6), bipolar RBD (n=39) and bipolar minor depression (n=14).
The DSM-IV and the ICD-10 definition of bipolar-I disorder embraces the
The majority of the 59 MinBP cases consisted of bipolar RBD (71%),27 and
three subgroups analysed in this paper (MD, Md and M). However, as
only a minority were cyclothymic. MinBP was found to be very common,
shown, MD accounts for only about 60% of subjects with mania up to 35
with a cumulative incidence rate of 9.4% up to the age of 40/41 years
years of age. The diagnosis of the remaining 40% is distributed almost
(males 7.8%, females 10.9%). Of the MinBP subjects, 64.4% were
equally between Md and M. These high proportions correspond closely to
treated over their lifetime compared with 70.8% in the bipolar-II and
the results of studies carried out in Nigeria, Tunisia and the Fijian islands.
57.4% in the MDD groups. MinBP patients were shown to be very similar
to bipolar-II disorder patients in terms of prevalence rates, gender ratio,
M is less common among women than men. Psychotic symptoms seem
family history of mania and depression, treatment rates, rates of
to be frequent and do not correlate with the number of diagnostic
depressive personality disorders and GBI measures of temperament.
symptoms of mania. Preponderantly manic subjects (M/Md) experience a
MinBP patients had a lower rate of co-morbidity (non-significant), with
better course (fewer recurrences) and outcome (lower suicide rates) than
generalised anxiety disorders (GADs), panic attacks and alcohol use
bipolar-I patients, but may have higher cardiovascular mortality. In
disorders less common than in those with bipolar-II disorder. It was also
temperament, manics are often hyperthymic and are less frequently
associated with a very low suicide attempt rate.27 Cyclothymic disorder
cyclothymic or depressive, and their family histories show fewer
(ICD F34) can be considered to be a persistent/chronic form of MinBP. In
depressive disorders. At the same time, there is a dearth of studies on m
children, ultra-rapid cycling seems to be very common.28
and MinBP, although more than 60% of cases of the latter require
treatment. The current concept of bipolar-I disorder is very much open to
Methodological Problems
question, embracing as it does heterogeneous groups. The manic wing
The definitions of mania and hypomania are currently the subject of great
of the bipolar spectrum is more prevalent than generally perceived, and
interest, and several subthreshold definitions have been proposed and used
a refined classification would do much to stimulate its recognition and
in some European projects.29–33 The nosology of M and m is also
research in the field. ■
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Harish T, Grover S, Basu D, Recurrent unipolar mania: Does it
warrant a seperate nosological status?, German J Psychiatry,
2005;8:8–15.
Angst J, Sellaro R, Stassen HH, Gamma A, Diagnostic
conversion from depression to bipolar disorders, J Affect Disord,
2005;84:149–57.
Shulman KI, Tohen M, Unipolar mania reconsidered: evidence
from an elderly cohort, Br J Psychiatry, 1994;164:547–9.
Yazici O, Kora K, Ücok A, et al., Unipolar mania: a distinct
disorder?, J Affect Disord, 2002;71:97–103.
Wittchen H-U, Nelson CB, Lachner G, Prevalence of mental
disorders and psychosocial impairments in adolescents and
young adults, Psychol Med, 1998;28:109–26.
Bronisch T, Schwender L, Höfler M, et al., Mania, hypomania
and suicidality: findings from a prospective community study,
Arch Suicide Res, 2005;9:267–78.
Abrams R, Taylor MA, Hayman MA, Krishna NR, Unipolar
mania revisited, J Affect Disord, 1979;1:59–68.
Nurnberger JI, Roose SP, Dunner DL, Fieve RR, Unipolar mania:
a distinct clinical entity?, Am J Psychiatry, 1979;136:1420–23.
Pfohl B, Vasquez N, Nasrallah H, Unipolar versus bipolar mania:
A review of 247 patients, Br J Psychiatry, 1982;141:453–8.
Starkstein SE, Fedoroff P, Berthier ML, Robinson RG, Manicdepressive and pure manic states after brain lesions, Biol
Psychiatry, 1991;29:149–58.
Keller MB, Lavori PW, Coryell W, et al., Differential outcome of
pure manic, mixed/cycling and pure depressive episodes in
patients with bipolar illness, JAMA, 1986;255:3138–42.
Solomon DA, Leon AC, Endicott J, et al., Unipolar mania over
the course of a 20-year follow-up study, Am J Psychiatry,
2003;160:2049–51.
Perugi G, Sanna Passino MC, Toni C, et al., Is unipolar mania a
EUROPEAN PSYCHIATRIC REVIEW
distinct subtype?, Compr Psychiatry, 2007;48:213–17.
14. Angst J, Gerber-Werder R, Zuberbühler H-U, Gamma A,
Is bipolar I disorder heterogeneous?, Eur Arch Psychiatry Clin
Neurosci, 2004;254:82–91.
15. Angst J, Angst F, Gerber-Werder R, Gamma A, Suicide in 406
mood-disorder patients with and without long-term medication:
a 40- to 44-year follow-up, Arch Suicide Res, 2005;9:279–300.
16. Makanjuola ROA, Manic disorder in Nigeria, Br J Psychiatry,
1982;141:459–63.
17. Makanjuola ROA, Recurrent unipolar manic disorder in the
Yoruba Nigerian: further evidence, Br J Psychiatry, 1985;147:
434–7.
18. Benzineb S, Choubani Z, Douki S, Unipolar mania?, Aspects
Affect, 2005;1:123.
19. Aghanwa HS, Recurrent unipolar mania in a psychiatric hospital
setting in the Fiji Islands, Psychopathology, 2001;34:312–17.
20. Azorin JM, Akiskal H, Châtenet-Duchêne L, et al., Is psychosis
in DSM-IV mania due to severity? The relevance of selected
demographic and co-morbid social-phobic features, Acta
Psychiatr Scand, 2007;115:29–34.
21. Gamma A, Angst J, Ajdacic-Gross V, Are hypomanics the
happier normals?, J Affect Disord, 2008; in press.
22. Depue RA, General Behavior Inventory (Manual). Assessment
manual, Minneapolis: University of Minnesota, 1987.
23. Angst J, Recurrent brief psychiatric syndromes: hypomania,
depression, anxiety and neurasthenia. In: Judd LL, Saletu B,
Filip V (eds), Basic and clinical science of mental and addictive
disorders, Basel Freiburg Paris: Karger, 1997;33–8.
24. Angst J, Recurrent brief psychiatric syndromes of depression,
hypomania, neurasthenia and anxiety from an epidemiological
point of view, Neurol Psychiatr Brain Res, 1992;1:5–12.
25. Leibenluft E, Charney DS, Towbin KE, et al., Defining clinical
26.
27.
28.
29.
30.
31.
32.
33.
34.
phenotypes of juvenile mania, Am J Psychiatry, 2003;160:
430–37.
Angst J, Gamma A, Benazzi F, et al., Toward a re-definition of
subthreshold bipolarity: epidemiology and proposed criteria for
bipolar-II, minor bipolar disorders and hypomania, J Affect
Disord, 2003;73:133–46.
Angst J, Marneros A, Gamma A, et al., The affective spectrum
and its neglected sub-diagnostic groups. In: Marneros A, Röttig
D (eds), Biogenese und Psychogenese, S Roderer Verlag, 2008;
in press.
Geller B, Cook EH, Ultradian rapid cycling in pre-pubertal and
early adolescent bipolarity is not in transmission disequilibrium
with val/met COMT alleles, Biol Psychiatry, 2000;47:605–9.
Akiskal H, Bourgeois ML, Angst J, et al., Re-evaluating the
prevalence of and diagnostic composition within the broad
clinical spectrum of bipolar disorders, J Affect Disord,
2000;59(Suppl. 1):S5–30.
Angst J, Gamma A, Sellaro R, et al., Recurrence of bipolar
disorders and major depression. A lifelong perspective,
Eur Arch Psychiatry Clin Neurosci, 2003;253:236–40.
Benazzi F, Challenging DSM-IV criteria for hypomania:
diagnosing based on number of no-priority symptoms,
Eur Psychiatry, 2007;22:99–103.
Benazzi F, Testing new diagnostic criteria for hypomania,
Ann Clin Psychiatry, 2007;19:1–6.
Merikangas K, Herrell R, Swendsen J, et al., Specificity of
bipolar spectrum conditions in the comorbidity of mood and
substance use disorders: results from the Zurich cohort study,
Arch Gen Psychiatry, 2008;65:47–52.
Angst J, The bipolar spectrum, Br J Psychiatry, 2007;190:
189–91.
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