. 2
( 68 .)


Lenggstraße 31 Hauptstr. 5
8008 Zurich 79104 Freiburg
Switzerland Germany
ix List of contributors

Alexia E. Koukopoulos MD Giulio Perugi MD
Centro Lucio Bini Instituto di Clinica Psychiatrica
Center for the Treatment and Research of Universita degli Studi di Pisa
Affective Disorders via Roma, 67
Via Crescenzio 42 I-56100 Pisa
00193 Rome Italy
Lukas Pezawas MD
Athanasios Koukopoulos MD Dr hc Psychiatrische Universitatsklinik
Centro Lucio Bini Lenggstraße 31
Center for the Treatment and Research of 8008 Zurich
Affective Disorders Switzerland
Via Crescenzio 42
00193 Rome Frank Pillmann MD
Italy Department of Psychiatry and
Andreas Marneros MD Martin-Luther University Halle-Wittenberg
Department of Psychiatry and 06097 Halle
Psychotherapy Germany
Martin-Luther University Halle-Wittenberg
06097 Halle M. Reinares
Germany Bipolar Disorders Program
Department of Psychiatry
Kathleen R. Merikangas PhD Hospital Clinic
Section of Developmental Genetic University of Barcelona
Epidemiology Villarroel 170
National Institute of Mental Health Barcelona 08036
Building 35, Room 1A-201 Spain
35 Convent Drive
MSC 3720 Wulf Rossler MA MD
Bethesda MD 20892-3720 Psychiatrische Universitatsklinik
USA Lenggstraße 31
8008 Zurich
Gian Paolo Minnai MD Switzerland
Ospedale S. Martino
Via Rockfeller Stephan Rottig MD
09170 Oristano Department of Psychiatry and
Italy Psychotherapy
Martin-Luther University Halle-Wittenberg
06097 Halle
x List of contributors

Gary Sachs MD Eduard Vieta MD PhD
Bipolar Clinic and Research Program Bipolar Disorders Program
Massachusetts General Hospital Department of Psychiatry
Harvard Medical School Hospital Clinic
WACC 812 University of Barcelona
15 Parkman St Villarroel 170
Boston MA 02114 Barcelona 08036
USA Spain

Gabriele Sani MD Jorg Walden MD
Centro Lucio Bini Abt. Psychiatrie und Psychotherapie
Center for the Treatment and Research of University of Freiburg
Affective Disorders Hauptstraße 5
Via Crescenzio 42 79104 Freiburg
00193 Rome Germany
Andrea Wenzel MD
Leslie M. Schuh Department of Psychiatry and
Lilly Research Laboratories Psychotherapy
Lilly Corporate Center Martin-Luther University Halle-Wittenberg
Indianapolis IN 46285 06097 Halle
USA Germany

Kenneth I. Shulman MD SM FRCPsych Kelly Yu MPH
FRCP(C) Johns Hopkins University
Department of Psychiatry Bloomberg School of Public Health
Sunnybrook & Women™s 615 North Wolfe Street
University of Toronto Baltimore MD 21205
2075 Bayview Avenue USA
Ontario M4N 3M5

Mauricio Tohen MD Dr PH
Lilly Research Laboratories
Lilly Corporate Center
Indianapolis IN 46285

Bipolar disorders have a long history. Mania and melancholia are the oldest terms
and descriptions within psychiatry, having been created in Homeric times by the
Greeks, and conceptualized by Hippocrates and his school 2500 years ago. Aretaeus
of Cappadocia put melancholia and mania together, because he recognized both
psychopathological states as parts of the same disease, thereby giving birth to the
bipolar disorders. His formulation stressed that, while mania has various phenom-
enological manifestations, nevertheless all of these forms belong to the same
disease. Some of these special forms of bipolar disorder that are of major clinical
and research relevance are the topic of this book.
Even though the three groups of bipolar disorders “ mixed states, rapid-cycling,
and atypical bipolar disorder “ were well known by the nineteenth century, interest
accelerated after the psychopharmacological revolution in the middle of the
twentieth century. Thus the importance of defining rapid cycling was made clear
by the observation that the response to lithium treatment was poorer in patients
experiencing four or more episodes per year. The ˜˜rediscovery™™ of mixed states,
which were conceptualized by Emil Kraepelin and Wilhelm Weygandt at the end
of the nineteenth century, was also associated with problems concerning treatment
with antidepressants and mood stabilizers. It has been half a century since the start
of the pharmacological revolution. Its consequences across all fields of psychiatry
have been enormous: biological research and genetics, treatment and prophylaxis,
clinical and prognostic research, and psychopathological and diagnostic
approaches. Furthermore, the way our culture views mental illness has been
profoundly influenced by this revolution, and the lives of our patients are much
better for it.
This book synthesizes valuable knowledge from the past, integrates it with new
insights from the modern era, and looks to the future of mixed states, rapid-
cycling, and atypical bipolar disorders. The editors would like to thank all con-
tributors and supporters, especially Lilly Germany, for supporting this edition.


Bipolar disorders beyond major depression
and euphoric mania
Andreas Marneros1 and Frederick K. Goodwin2
Martin-Luther University Halle-Wittenberg, Halle, Germany
George Washington University Medical Center, Washington, DC, USA

Introduction: knowledge from the past, goals for the future
The last five decades have brought essential changes and developments in
psychiatry. One of the most important reasons for these developments is cer-
tainly the psychopharmacological revolution. The discovery of antipsychotics,
antidepressants, mood stabilizers, and other psychotropic substances has had an
enormous impact, not only on many fields of research, treatment, social life, and
social politics, but also on ideological aspects and attitudes. Concerning psy-
chiatric research, the psychopharmacological revolution has been an important
and sustained stimulus not only for the development of neuroscience, genetics,
and pharmacology, but also for psychiatric methodology, the development
of new diagnostic concepts, and new research on treatment, prognosis, and
rehabilitation. One indirect but fundamental development was the rediscovery
and rebirth of old diagnostic, nosological, and phenomenological concepts.
For example, new pharmacological experiences led to the rediscovery of the
relevance of the unipolar“bipolar dichotomy. The concepts examined by Falret
(1854), Baillarger (1854), Kleist (1929, 1953), Neele (1949), Leonhard (1957),
and others were confirmed in the new psychopharmacological era, including
the nosological refinements made by Jules Angst (1966), Carlo Perris (1966),
Winokur and Clayton (1967), and others. But soon the enthusiasm for the new
psychopharmacology gave way to an increasing awareness of some limitations.
Within broadly defined diagnostic groups like schizophrenia, depression, and
bipolar disorder, many patients proved to be non-responders or partial respond-
ers. The identification of such non-responder groups and their careful investiga-
tion showed some special or atypical features, like coexistence of manic and
depressive symptoms or schizophrenic and mood symptoms (depressive and manic),
as well as rapid changes of mood states or rapid onset of episodes. As a result, the
Cambridge University Press, 2005.
2 A. Marneros and F. K. Goodwin

old concepts of mixed states, schizoaffective disorders, rapid cycling, cyclothymia,
atypical depression, and others underwent a rebirth (Goodwin and Jamison, 1990;
Marneros, 1999, 2001; Marneros and Angst, 2000; Angst and Marneros, 2001). But
some of the rediscovered psychopathological states “ although very well described “
are still terra incognita and a source of confusion for many psychiatrists. Thus, more
educational efforts are needed. This book summarizes our current knowledge on
these atypical forms, and makes suggestions for much needed additional research.

Mixed states
The ancient times
The early descriptions and roots of mixed states are very closely connected with the
history and development of concepts regarding bipolar disorders. These concepts have
their roots in the work and theories of the Greek physicians of the classical period,
especially of the school of Hippocrates and, later, of the school of Aretaeus of
Cappadocia (Marneros and Angst, 2000; Angst and Marneros, 2001; Marneros, 2001).
Hippocrates based his work partially on the views of Pythagoras and his scholar
Alcmeon and partially on the views of Empedocles. Like Alcmeon, Hippocrates
(Fig. 1.1) thought that the origin of mental diseases lay in the disturbed interaction
of body fluids with the brain. Affective pathological states, as well as psychotic
states, are the results of illnesses or disturbances of brain functions. He wrote in
About the Sacred Disease:

Ei)de/nai de/ xrh/ tou/† a)nqrw/pou† o(/ti e)c ou)deno/† h(mi=n ai( h(donai/ gi/nontai kai/
eu)frosu/nai kai/ ge/lwte† kai/ paidiai/ h(= e)nteu=qen, kai/ lu=pai kai/ a)ni/ai kai/
dusfrosu/nai kai/ klauqmoi/. kai/ tou/t% frone/omen ma/lista kai/ ble/pomen kai/
a)kou/omen kai/ diagignw/skomen ta/ te ai)sxra/ kai/ kala/ kai/ kaka/ kai/ a)gaqa/ kai/
h(de/a kai/ a)hde/a, ta/ me/n no/m% diakri/nontej, ta/ de/ t%= sumfe/ronti ai)sqano/menoi,
t%= de/ kai/ ta/† h(dona/† kai/ ta/† a)hdi/a† toi=si kairoi=si diagignw/skonte† ou)
tau=ta a)re/skei h(mi=n. t%= de/ au)t%= tou/t% kai/ maino/meqa kai/ parafrone/omen, kai//
dei/mata kai/ fo/boi pari/stantai h(mi=n, ta/ me/n nu/ktwr, ta/ de/ kai/ meq° h(me/rhn, kai/
a)grupni/ai kai/ pla/noi a)/kairoi, kai/ fronti/dej ou)x i(kneu/menai, kai/ a)gnwsi/ai
tw=n kaqestw/twn kai/ a)hqi/ai. kai/ tau=ta pa/ sxwmen a)po/ tou= e)gkefa/lou pa/nta,
o(/tan ou(=to† mh/ u(giai/nh . . .
People ought to know that the brain is the sole origin of pleasure and joy, laughter and
jests, sadness and worry, as well as dysphoria and crying. Through the brain we can
think, see, hear and differentiate between feeling ashamed, good, bad, happy . . .
Through the brain we become insane, enraged, we develop anxiety and fear, which can
come in the night or during the day, we suffer from sleeplessness, we make mistakes
and have unfounded worries, we lose the ability to recognize reality, we become
apathetic and we cannot participate in social life. We suffer all those things mentioned
3 Beyond major depression and euphoric mania

Fig. 1.1 Hippocrates (460“370 BC).

above through the brain when it is ill (Hippocrates, 1897: translation of original
Greek and German quotations by Andreas Marneros).

Hippocrates also formulated the first classification of mental disorders, namely
into melancholia, mania, and paranoia. He also described, together with the so-
called Hippocratic physicians, organic and toxic deliria, postpartum psychoses,
phobias, personality disorders, and temperaments. They also coined the term
˜˜hysteria.™™ The ancient classifications and descriptions of mental disorders
provided by Hippocrates and the Hippocratic school present a basis for broader
definitions and concepts than the modern ones do. Some authors claimed that
the concepts of mania and melancholia as described by Hippocrates (and also by
Aretaeus and other Greek physicians) were different from the modern concepts.
But this is not correct. The clinical concepts of melancholia and mania were
broader than modern concepts “ but not different. They included (according to
modern criteria): melancholia or mania, mixed states, schizoaffective disorders,
4 A. Marneros and F. K. Goodwin

Fig. 1.2 Aretaeus of Cappadocia (AD 81“138).

some types of schizophrenia, and some types of acute organic psychoses and
atypical psychoses (Marneros, 1999; Marneros and Angst, 2000; Angst and
Marneros, 2001). The similarities but also the differences between the ancient
concepts and the modern ones, as well as the involvement of mixed states
in these descriptions, can be illustrated by directly quoting the texts written at
that time:
Hippocrates assumed long-lasting anxiety, fear (phobos) and moodiness (dys-
thymia) as basic characteristics of melancholia. He wrote: ˜˜Hn fo/boj kai/ dusqumi/h
polu/n xro/non diatele/ei, melagxoliko/n to/ toiou=ton.™™ If anxiety (phobos) and moodi-
ness (dysthymia) are present for a longer period, that is melancholia.
Aretaeus of Cappadocia, one of the most famous Greek physicians, lived in
Alexandria in the first century AD (Fig. 1.2). His dates of birth and death are not
exactly known (some authors say he lived from around AD 40 to 90, others from
AD 50 to 130), but he was a prominent representative of the Eclectics (Marneros
5 Beyond major depression and euphoric mania

and Angst, 2000) who described a polymorphism of symptoms in melancholia as

Tekmh/ria me/n ou)n ou)k a)/shma! h)/ ga/r h(/suxoi, h)/ stugnoi/, kathfe/e†, nwqroi/ e)/asi! e)/ti


. 2
( 68 .)