online © ML CommREVIEW ARTICLE

http://dx.doi.org/10.4306/pi.2013.10.3.218

Print ISSN 1738-3684 / On-line ISSN 1976-3026
OPEN ACCESS

Bipolar Spectrum: A Review of the Concept anda Vision for the Future
S. Nassir Ghaemi
Department of Psychiatry, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA

This paper reviews the bipolar spectrum concept historically and empirically. It describes how the concept derives from Kraepelin, but
was lost with DSM-III, which divided the broad manic-depressive illness concept, based on recurrent mood episodes of either polarity,
to the bipolar versus unipolar dichotomy, based on allowing non-recurrent mood episodes of only one polarity. This approach followed
the views of Karl Leonhard and other critics of Kraepelin. Thus post DSM-III American psychiatry is not neo-Kraepelinian, as manyclaim, but neo-Leonhardian. The bipolar spectrum approach, as advocated by Akiskal and Koukopoulos first, harkens back to the original
broad Kraepelinian view of manic-depressive illness. The evidence for and against this approach is discussed, and common misconceptions,
Psychiatry Investig 2013;10:218-224
including mistaken claims that borderline personality is similar, are revealed and critiqued.
Key WordsaaBipolar spectrum, Leonhard, Kraepelin, DSM-5, Mixed, Koukopoulos, Akiskal.

BIPOLAR DISORDER≠MANICDEPRESSIVE ILLNESSThe concept of a bipolar spectrum presupposes that theconcept of bipolar illness is valid. The best introduction to theconcept of a bipolar spectrum may be to go a step back before
the bipolar concept itself, back to the earlier concept of manicdepressive insanity (MDI), usually associated with psychotic
features. Introduced by Kraepelin,1 and slightly rephrased as
manic-depressive illness (to include the majority of subjects
without psychotic features), the MDI concept was divided
officially in 1980 in the DSM-III to bipolar disorder and major depressive disorder (MDD).2 This division in turn is a variation on the original division made in the 1950s by Karl Leonhard of MDI into bipolar and unipolar recurrent psychoses,3
which, if broadened to include non-psychotic mood presentations, was rephrased in the 1960s and 1970s by American researchers (headed at the Washington University of St. Louis)
as bipolar illness and unipolar depressive illness.4 This AmerReceived: June 4, 2013 Revised: June 13, 2013
Accepted: July 13, 2013 Available online: September 16, 2013
 Correspondence: S. Nassir Ghaemi
Department of Psychiatry, Tufts Medical Center, 800 Washington St., Boston,
MA 02111, USA
Tel: +1-617-636-5735, Fax: +1-617-636-7795
E-mail: nghaemi@tuftsmedicalcenter.org
cc This is an Open Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

218 Copyright © 2013 Korean Neuropsychiatric Association

ican revision of Leonhard’s idea was the basis for the Research Diagnostic Criteria (RDC) of the 1970s,5 which became
transformed into DSM-III.6 In that last transition, from the
RDC to DSM-III, the American Psychiatric Association became involved, and decisions were no longer based on research considerations primarily, but on the political preferencesof the profession.7 Since most American psychiatrists were psychoanalytic, they tended to use the DSM-II diagnosis of “neurotic depression” frequently. Yet that term was excluded fromthe Washington University unipolar depression concept; unipolar depression consisted of severe recurrent depressive episodes. Neurotic depression was not severe (it was mild to moderate), not recurrent (it was chronic), not depressive (anxious symptoms were predominant), and not episodic (it wasconstant).8 Yet to pass DSM-III, the RDC criteria were altered
to include all those features - being non-recurrent, chronic, andanxious - as also part of the unipolar depressive syndrome;7
this hybrid condition was renamed “major depressive disorder”. The word “disorder” was tagged onto every DSM-III diagnosis to avoid making any etiological judgments;9 thus theterm “illness”, which implied a medical disease, was dropped,
producing bipolar “disorder” and MDD.
One can see, after all these distortions, that the bipolar disorder concept is very different from manic-depressive illness.
Also, one sees that MDD was broadened to include many types of depressive symptom presentations that were not seen
as part of the disease of recurrent depression. In the classic

SN Ghaemi

studies on unipolar depression that led to DSM-III, the diagnosis was made only if there were three or more depressive episodes:10 recurrence was seen as essential to the disease of unipolar depression, which was seen as an “endogenous”3 (i.e., biologically-based) disease (even limited by Leonhard only to those with concurrent psychotic features).
In sum, the broad MDI concept as a medical disease was replaced by a rump concept of bipolar “disorder”, and a large concept of depressive symptom-complexes (MDD).
The very narrow bipolar disorder concept differed from theold MDI concept considerably. Not only is it much narrower,
but its core feature is different. For bipolar disorder, the condition is defined by polarity: presence or absence of a manic
episode.3 For MDI, the condition is defined by episodicity: recurrent mood episodes define the illness, irrespective of polarity.1 Ten depressive episodes mean MDI. Ten manic episodes
mean MDI. The fact that the episodes are depressive or manicis irrelevant. The number “ten” is relevant: recurrence defines
the illness.2
MDI means recurrent manic OR depressive episodes. Bipolar disorder means recurrent manic AND depressive episodes.
These are quite different concepts.
Put otherwise, MDI is basically bipolar disorder plus muchof what we call MDD. MDI is much broader than bipolar disorder.
Often it is said that DSM-III was neo-Kraepelinian.11 It was
not: for mood illnesses, it was neo-Leonhardian.12 By accepting the bipolar concept, DSM-III turned away from Kraepelin
and toward Leonhard. This process has now been taken for
granted with DSM-IV and now DSM-5. Psychiatry has moved away from the Kraepelinian MDI concept to such an extent that many assume that the bipolar/MDD dichotomy isobviously true.
The bipolar spectrum concept is a way of trying to go backto the Kraepelinian MDI concept, or at least to reopen the scientific discussion such that we can revisit whether it was correct to make the decision in 1980 to divide MDI into a small
bipolar and large MDD concept.

VALIDATORS OF DIAGNOSISDSM-III divided MDI into bipolar disorder and MDD based on the accepted validators of psychiatric diagnosis, whichwere introduced in 1970 by the Washington University researchers13 as five-fold: symptoms, family history, course, treatment response, and biological markers. It was claimed thatbipolar disorder and MDD differed in all forms:
1. Symptoms: in both conditions, depression are present,
but in only one condition is mania present.3
2. Family history: early genetic studies indicated that if ma-

nia is present in a patient, it is also present in family members;
but if only depression is present in a patient, mania is not present in family members.10,14
3. Course: recurrent depression was seen to have fewer andlonger episodes than recurrent mania plus depression, where
episodes were shorter and more frequent. Age of onset was later in recurrent depression (around age 30) and earlier in recurrent mania plus depression (around age 20).10,14
4. Treatment response: recurrent depression responded totricyclic antidepressants; recurrent mania plus depression responded to lithium.7
5. Biological markers: recurrent depression was seen as involving abnormalities in norepinephrine and possibly serotonin function; recurrent mania was seen as involving abnormalities with dopamine function.15
Two classic studies, both published in the late 1960s in Europe were seen as central to confirming Leonhard’s work. One
large study was headed by Carlo Perris10 and a different one by
Jules Angst.14 As Dr Angst frequently says, when he presented his results to his mentors, he was told that he couldn’t becorrect, since his results contradicted Kraepelin. Angst’s work
was based on his Zurich cohort, a prospective study since thelate 1950s. About ten year prospective data were used by him
to support the Leonhardian nosology.

AFTER DSM-III
For about two decades, the neo-Leonhardian consensus of
DSM-III held. The only objections came from a few experienced clinical researchers: in the US, Hagop Akiskal,16 and inEurope, Athanasios Koukopoulos.17 Akiskal began studies in
the 1970s in the first specialized mood clinic in the US, andhe identified many patients who seemed to fall in between the
bipolar and unipolar categories of the Washington University
school.16 Yet Akiskal was part of the DSM-III process and accepted it. He thus proposed maintaining the bipolar/unipolar
distinction, but broadening the bipolar category to include a“bipolar spectrum.”16 In this spectrum, he included atypicaldepressive presentations and mood temperaments. In Rome,
Koukopoulos found that he could not confirm some of the claims made in favor of the unipolar/bipolar dichotomy. In particular, he cast doubt on the treatment response criterion: many
unipolar patients did not respond to antidepressants; they
seemed to have other features of bipolarity, such as a highly recurrent course and early age of onset.17 Even the symptom distinction was debatable: Koukopoulos found that many depressed patients had manic symptoms, and many manic patients had depressive symptoms. In other words, mixed states
were much more frequent than pure mania or pure depression,18 and thus the attempt to distinguish the two was difficult,www.psychiatryinvestigation.org 219

Bipolar Spectrum: A Review

and perhaps unnecessary. Both Akiskal and Koukopoulos returned to Kraepelin’s work and found confirmation of theirfindings in the observations of Kraepelin.
An important third critic was Frederick Goodwin, directorof the NIMH in the US in the late 1980s and early 1990s, when
he published his classic textbook, Manic-Depressive Illness.2
Goodwin, with his coauthor Kay Jamison, reviewed the scientific literature as of 1990, and found evidence contradicting the 1960s and 70s literature that had led to the DSM-III
neo-Leonhardian dichotomy. The genetic literature could beinterpreted as supporting Kraepelin or Leonhard: mania didseem to run in families, but there was as much depression (ormore) in families of manic probands as in families of depressive probands.19 In other words, depression did not run in families separate from mania. Further, Goodwin noted that lithium
was effective in depression alone, not just bipolar disorder.20
As biological research grew in the 1990s and 2000s, it also became clear that neurotransmitter theories about catecholamines had been very simplistic in the 1970s.21 Second messengers and long-term neuroplastic changes in the brain wereseen in mood illnesses,22 and there were often similarities between unipolar and bipolar disorder definitions in those biological mechanisms.23
In the 1990s and 2000s, the new class of atypical neuroleptics was developed which showed clear efficacy in acute mania, but also, in many cases, efficacy for depressive episodes,
not limited to bipolar disorder but even in MDD with someagents.24 Some anticonvulsants, like lamotrigine, were much
more effective in preventing depression rather than mania,25
and the presumed strong efficacy of antidepressants in MDD
was thrown into doubt with the discovery of a large number ofnegative unpublished studies.26 In sum, the simplistic treatment response distinction between antidepressants for MDD
and mood stabilizers/neuroleptics for bipolar disorder was
greatly weakened.

BIPOLAR SPECTRUM CONCEPTS
About two decades after DSM-III, at the turn of the newmillennium, many experts in bipolar illness began to movetowards the bipolar spectrum concepts previously advanced
by Akiskal and Koukopoulos. Different types of spectrum concepts were developed. Akiskal’s approach emphasized subtyping:27 type II had been officially accepted in DSM-IV in 1994,
allowing for mild manic episodes called hypomania, if theyoccurred with recurrent depression. Akiskal proposed adding
type III, antidepressant induced hypomania, and other subtypes including depression with a family history of bipolar disorder, and mood temperaments, in particular hyperthymia,
meaning constant hypomania as part of one’s personality (not220 Psychiatry Investig 2013;10:218-224

episodic episodes as in type II bipolar illness).
Koukopoulos emphasized mixed states:28 he defined “mixed
depression” as depression occurring with excitation, meaning
manic symptoms (like flight of ideas or talkativeness), but alsoagitation, irritability and rage, marked anxiety, and suicidal impulsivity. Koukopoulos saw this highly agitated and tense depressive state as the opposite of melancholia, which is markedly psychomotor retarded and not irritable or rageful. He thought that mixed depression gets much worse with antidepressants and responds to neuroleptics, while melancholia responds
best to ECT and sometimes to antidepressants, but is best prevented with mood stabilizers like lithium. Other researchers,
like Franco Benazzi in particular, studied mixed depression
in detail and reported high rates in bipolar illness, but also notable rates in MDD.29-33 Working with Akiskal, Benazzi replicated his Italian findings in other settings.34
Angst, whose work had been so central to the move awayfrom Kraepelin’s MDI, continued his Zurich study and foundmany intermediate forms of mood conditions between the original bipolar and unipolar ideal types.35,36 He also described
the presence of mixed states as very common in all depressive
conditions. Defined as 3 or more manic symptoms occurring
for any duration (not limited to four days or longer as in DSMIV), Angst and his colleagues have reported that about onehalf of all depressive episodes, even in MDD, involve mixed
states with the presence of manic symptoms.37 Thus, Angst has
become supportive of the bipolar spectrum concept.36,38
I have proposed an approach to the spectrum concept that
focuses on how to distinguish it from unipolar depression.39
Taking into account all of the above work, instead of subtyping
further, I suggested having a general definition for those patients who fall in the middle of the mood spectrum between
the classic unipolar and type I bipolar extremes. This “bipolar
spectrum disorder” would represent recurrent severe depression (as in Leonhard’s unipolar depression), but with a family
history of bipolar disorder or antidepressant-induced mania
or a number of other features of bipolarity to depressive symptoms, course, or treatment response (mixed or melancholicfeatures, early age of onset, many episodes, poor antidepressant response or tolerance). The presence of hyperthymic or
cyclothymic mood temperaments was also suggested to bepart of this bipolar spectrum concept.39 Defined this way,about one-third of MDD could be seen as meeting the bipolar spectrum definition.40,41

THE PRIMACY OF MANIA
A very original approach to the bipolar spectrum notion,
advanced by Koukopoulos,42 is the primacy of mania hypothesis, the notion that depression cannot happen without ma-

SN Ghaemi

nia: mania is the fire, depression is the ash. This notion harkens
back even beyond the bipolar spectrum concept to Kraepelin’s
original, much broader notion of manic-depressive illness.
Koukopoulos has suggested that mania and depression always
go together; the Leonhardian/DSM-III project of trying to separate them is thus misguided. We should not try to separate
what is inseparable.
Koukopoulos defines mania broadly, as any form of excitation; this can represent DSM-III type mania criteria, but also
psychomotor agitation, marked anxiety, and mood temperaments like hyperthymia or cyclothymia. Koukopoulos’ hypothesis is that in almost all depressive presentations, there willbe the co-occurrence or prior occurrence of mania, thus defined. Thus, often, depressive episodes follow manic episodes;
or they occur after years of hyperthymic or cyclothymic temperament, or they represent mixed depression as defined above. Pure depression, without any of the above manic-likefeatures, is relatively uncommon, according to this view. Since
mania is the preceding or driving force to depression, on thisnotion, then the treatment of most depressive conditions
would be anti-manic treatments, i.e., mood stabilizers or neuroleptics. Antidepressants are only mild symptomatic agents,
improving symptoms superficially if at all. The best treatments
for depression, in this perspective, would be, ironically, drugs
we don’t call antidepressants: the mood stabilizers or neuroleptics. Koukopoulos’ approach only seems odd when we accept the post 1980 DSM-III mood dichotomy as self-evident.
If we think about Kraepelin’s prior unitary broad MDI concept instead, Koukopoulos’ theory would be easier to understand, and would be quite consistent with Kraepelin’s nosology.

PERSONALITY “DISORDERS”
Another category of illness that becomes discussed in relation to bipolar spectrum concepts is personality “disorders”, inparticular borderline personality. By using the term “disorder”,
which I put in quotes to emphasize that it is a vague concept
with unclear meaning, proponents of DSM categories haveequalized all diagnoses.9 This is a major conceptual error, an
ontological mistake, which means a mistake in understanding
the basic nature of different things. Red skies differ from red
apples; they are very different things; they are similar only superficially by being red in color. Similarly, manic-depressive
illness is a disease of the body and brain, with many well-known biological abnormalities that are well-replicated; it has
been defined more or less as it is at least for a century or more;
its definition is squarely in the medical model, requiring no
beliefs beyond the acceptance of standard medical concepts
like signs, symptoms, syndromes, course, genetics, and biology. Borderline personality, in contrast, is, in my view, our cul-ture’s interpretation of what used to be called “hysteria”. It is a
Freudian interpretation of dissociative symptoms that happen
in persons who experience trauma, usually sexual, early inlife, in such a way that their personality development is derailed.43 It requires the ideological commitment to a host of psychoanalytic speculations, such as transference, countertransference, projection, denial, and so on.43 Its biology is poorly understood, and it is much less than genetic than manic-depressive illness.44,45 The concept, as now used, was invented about 40 years ago.
These two clinical constructs are entirely different in their
histories and key characteristics. All they share in common ismood lability and impulsivity. Many other psychiatric pictures
include impulsivity (gambling addiction, substance abuse) ormood lability (frontal lobe syndrome, agitation of multiplecauses). These superficial symptoms are like the redness ofskies versus apples. They are not core features of these conditions, which differ so markedly in other ways.
What is core to manic-depressive illness? Not mood lability.
My view would be that psychomotor activation is central tomanic-depressive illness,46 not mood per se. There is rapid thinking and feeling and movement, which sometimes can be
related to impulsivity but often is not. In borderline personality, our modern version of hysteria, the key symptom feature
is dissociation, which is related to the flashbacks and nightmares of that condition43 (which do not happen in MDI).47
Another way of trying to better distinguish these conditions
is to look at non-symptom features that increase the priorprobability of the condition, even before looking at specific manic or dissociative symptoms. This approach greatly increases true positive diagnoses, and decreases false positives.48 In
bipolar illness, those diagnostic accuracy-enhancing features
include a family history of bipolar illness and a severe episodic
course with duration of episodes being weeks to months.48 In
borderline personality, those diagnostic accuracy-enhancing
features include childhood sexual abuse and repeated non-suicidal self-injury.43 These features are multiple times more frequent in borderline personality than in bipolar illness.49,50
The aspects of the bipolar spectrum that most raise the issue of differential diagnosis with borderline personality haveto do with mood temperaments, like hyperthymia and cyclothymia.51 Since those conditions are chronic, not episodic, thecourse distinction of severe episodic recurrence is not helpful
in distinguishing those mood temperaments from borderline
personality. However, all the other distinguishing features
still apply: a bipolar family history in favor of mood temperaments, and childhood sexual abuse and repeated non-suicidal self-injury in favor of borderline personality.
It is well to give up the term “disorder” and remind ourselvesthat superficial similarities are few, and major differences arewww.psychiatryinvestigation.org 221

Bipolar Spectrum: A Review

many, when examining these conditions. Kraepelin distinguished between “disease-processes” (krankheitsprozessen), like
MDI, and “clinical pictures”,52,53 like the whole range of anxious, mood, and dissociative symptom presentations that are
seen in hysteria. The bipolar spectrum is a disease-process;borderline personality is a clinical picture, but not a disease.
They differ in kind, although they have superficial symptom
similarities. Neither is part of the other, or should be confused with the other.
Red skies are not red apples.

ANTIDEPRESSANT OUTCOMES
A key practical relevance to bipolar spectrum concepts isthat it helps identify those patients who do not do well withantidepressants, and who should not receive them, and those
who do well with mood stabilizers and/or neuroleptics. The
various bipolar spectrum concepts above predict that such patients will have more non-response to full therapeutic trialsof antidepressants.39 They get labeled “treatment-resistant depression”, which is misleading since their depression is not resistant to treatment at all, if they receive the correct treatments(mood stabilizers and/or neuroleptics). Besides not responding, bipolar spectrum patients are more likely to experienceantidepressant-induced mania, and long-term rapid-cycling
caused by antidepressants, with a worsening course of illness
over time.39,54 Sometimes, antidepressant-induced worsening
involves mixed episodes,28 which some experts believe may bepart of the reason why some patients commit suicide in association with antidepressant use.55 In my own clinical experience, I would agree with this assessment, especially when antidepressants are given to patients with mixed depression, as
defined by Koukopoulos.28 Not paying attention to the bipolar
spectrum can be fatal for patients who receive antidepressants.
Further, if these patients are misconceived as having personality “disorders”, long-term psychotherapies as the primaryintervention will also be fruitless.
Since so much of the psychiatric establishment has opposed spectrum concepts consistently for the past three decades,
there is very little research on exactly which treatments aremost effective among the neuroleptics and mood stabilizers, atwhich doses, and for how long. Some limited research on cyclothymia with valproate suggested effectiveness with low levels, in the 30s range,56 but that evidence has not been replicated or extended to other mood stabilizers.

THE BIPOLAR SPECTRUM IN
A POST-DSM-IV WORLDThe International Society for Bipolar Disorders (ISBD) con-

222 Psychiatry Investig 2013;10:218-224

vened a task force of experts which, using the available scientific evidence, recommended that a bipolar spectrum disorderdefinition be included in future psychiatric nosologies. DSM5 did not even seriously consider this idea.57
There has been a great deal of controversy in the last few
years leading up to the publication of DSM-5 in 2013. Unfortunately, in relation to mood illnesses, it is clear that the fundamental error of 1980 in defining major depressive disorder
extremely broadly will not be fixed. This MDD definition has
become immortal in psychiatry, untouchable by data. As described above, Angst, who had helped formulate the concept
in the 1970s based on his Zurich study up to that date, has provided 30 more years of follow-up in the same Zurich study,
which argues for the bipolar spectrum concept and against thecurrent MDD concept. Yet even though his work was part ofthe basis for the MDD concept in 1980, DSM-5 nosologists refused to accept his work 30 years later to revise the MDD concept.58
This illogicality is driven by something other than science,and this has become clear by the fact that three decades of biological research has failed to identify genes, or pathophysiology, or pharmacological treatment using DSM-III and IV categories. Recently, the National Institute of Mental Health (NIMH) leadership has admitted clearly what psychiatric leaders
had not admitted in the past: DSM categories are mostly unscientific and should not be the basis for scientific research.59
The bipolar spectrum concept has been excluded from DSM
categories because of a wish to maintain narrow psychiatricdiagnostic definitions to avoid overdiagnosis. We have shownthat this approach is doomed to fail, because, for low prevalence illnesses like bipolar illness, diagnostic specificities of over
95% would be needed to achieve lower than 50% false positive
overdiagnosis rates.48 The solution instead is to increase priorprobabilities by assessing risk factors that are strongly associated with a diagnosis, like family history of bipolar disorder andepisodic course and early age of onset.39,48
For the past two generations, world psychiatry has been
confined by DSM categories, with the belief that those categories were reliable (which they often are) and would be increasingly valid. They clearly have failed the validity criterion,
and it is likely, one hopes, that future psychiatry will put aside
the pretensions of DSM definitions, and turn to honest studyof psychiatric syndromes without the refusal to accept concepts based on non-scientific grounds, as is commonly thecase with DSM revisions. The NIMH Research Domains Criteria (RDoC) approach opens the way towards a scientific psychiatric nosology.60 Basing clinical criteria on clinical research
only would be another way to progress, complementary to
the RDoC approach. The ISBD diagnostic task force recommendations can form the basis of proposed new 21st century

SN Ghaemi

Research Diagnostic Criteria (RDC-21), including a definitionof bipolar spectrum disorder. These new RDC-21 are being
developed presently.
One can hope that future research will be conducted withthese bipolar spectrum definitions, further validating or invalidating them, and provide better data for future clinicians to beable to use these concepts, if validated, for better clinical outcomes.
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