Copyright ª Blackwell Munksgaard 2003

Bipolar Disorders 2003: 5: 436–442 BIPOLAR DISORDERS

Review Article

The bipolar spectrum: a clinical perspective

Katzow JJ, Hsu DJ, Ghaemi SN. The bipolar spectrum: a clinical Jacob J Katzowa, Douglas J Hsub
perspective. and S Nassir Ghaemib
Bipolar Disord 2003: 5: 436–442. ª Blackwell Munksgaard, 2003 a
George Washington University, Washington, DC,
USA, bBipolar Disorder Research Program,
The relative misdiagnosis and underdiagnosis of bipolar disorder is due
Cambridge Hospital, Cambridge, MA and Harvard
in part to the ÔsoftÕ symptoms of bipolarity that characterize patients with
Medical School, Boston, MA, USA
non-classical bipolar disorder. While no agreement has been reached on
the term for this group of patients, the most common classification used
is Ôbipolar spectrumÕ, which shifts the emphasis in diagnosis away from
Key words: antidepressants – bipolar disorder –
polarity and toward other diagnostic validators. In order to recognize
bipolar spectrum – diagnosis – mood stabilizers –
and properly treat patients with bipolar disorder, clinicians should focus
treatment
on careful evaluation of patients with mixed anxiety/depressive
symptoms or impulsivity conditions (substance abuse, borderline
Received 4 October 2002, revised and accepted
personality, bulimia, and attention deficit disorder). Furthermore, in the
for publication 17 February 2003
treatment of bipolar disorder, clinicians should also recognize that
antidepressants can have a negative effect on patients by increasing the Corresponding author: S Nassir Ghaemi, MD,
likelihood of more severe rapid cycling. While antidepressants may be Cambridge Hospital, 1493 Cambridge St.,
useful in particularly difficult cases, emphasis should be placed on mood Cambridge, MA 02139, USA. Fax: 617 665 1623.
stabilizers for treatment of the bipolar spectrum. e-mail: ghaemi@[Link]

One of the major debates in the treatment of gleaned from intensive patient contact, have not
bipolar disorder revolves around the use of anti- been examined in randomized clinical trials. We
depressants. One side believes that antidepressants hope this clinically oriented paper will help guide
are necessary and the danger is either exaggerated researchers to topics that merit such rigorous
or mitigated by the potential benefits, while the study, as well as serve as a practical interpretation
other side views antidepressants as potentially of these complex issues for the immediate needs of
dangerous. This debate is further inflamed when clinicians.
looking at non-classical forms of bipolar disorder,
grouped under the term bipolar spectrum disorder.
The evolution of psychopharmacology practice
Based on clinical experience, the efficacy of anti-
since the 1960s
depressant treatment of bipolar disorder likely lies
between the two extremist views. While antide- From the 1960s to the 1980s, the only proven
pressants are problematic in the treatment of treatment for bipolar disorder that had received
bipolar disorder, and should thus be minimized regulatory approval was lithium. Lithium, how-
while mood stabilizers are maximized, many bipo- ever, was a generic drug and thus the pharmaceu-
lar patients with bipolar spectrum disorder may tical industry put a weak effort into marketing
need antidepressants along with mood stabilizer lithium and diagnosing bipolar disorder. In con-
treatment. trast, non-generic antipsychotic agents were heav-
In this paper, we will use our qualitative clinical ily studied and marketed for the treatment of
experience (especially that of the first author who schizophrenia. It was perhaps not a coincidence
has been practicing psychopharmacology in the that, 25 years ago, researchers identified that
Washington DC area since the late 1960s) to schizophrenia was overdiagnosed and bipolar dis-
inform a discussion of the concept of the bipolar order underdiagnosed (1, 2). Schizophrenia, how-
spectrum from the perspective of the practicing ever, was still not a condition seen in outpatient
clinician. A focus on clinical trials and random- practices and diagnostic habits for depressive and
ized data, while useful, is not the purpose of this anxiety disorders were generally amorphous until
paper, and will be found in the other articles in the arrival of the serotonin reuptake inhibitors
this special issue. Many of our observations, (SRIs) (3).
436
 The bipolar spectrum: a clinical perspective

Towards the end of the 1980s, a watershed event tions in methodology still pertain, it is of interest
in the history of modern psychiatric medicine was that a reanalysis of the ECA data to include all
the arrival of fluoxetine on pharmacy shelves. Prior patients in the bipolar spectrum reported a lifetime
to fluoxetine, primary care physicians did not play prevalence rate of 6.4% (8). We think it is import-
a major role in the treatment of anxiety or ant to emphasize that the ratio of unipolar to
depressive disorders. In addition, the efficacy of bipolar depression is probably about two to one,
older antidepressants, such as tricyclics, was min- and not 5-10 to 1. Certainly, one cannot simply
imized because of their increased side effects as assume, as has been the case previously, that
compared with SRIs. With the introduction of the bipolar disorder is highly uncommon relative to
newest generation of SRIs, however, the psycho- unipolar depression.
pharmacologic treatment of anxiety and mood
disorders skyrocketed and primary care physicians
The mixed anxiety/depression picture
were soon in the vanguard of treatment (3).
Roughly around this time, the practice patterns In our experience, the most common type of
in the United States were also moving steadily patient seen by psychopharmacologists present
towards a managed care environment where pri- with various admixtures of anxiety and depression.
mary care physicians were taking on more of the A significant percentage of this group of patients
responsibilities of specialists. This intertwining of do not respond well to antidepressants, and ulti-
the newer antidepressants and historical reversion mately prove to have bipolar illness. Unless the
from specialists back to primary care physicians patient has been previously hospitalized with a
still influences the present practice of psychophar- manic diagnosis, proper diagnosis is very difficult
macology. based on the patient’s history. It is from this
The type of patients seen by psychopharmaco- anxiety/depressive group of patients that a subset
logists today typifies the effect of the above- of patients are eventually diagnosed and treated
mentioned phenomena. Many patients coming to properly as having bipolar disorder. This problem
see a psychopharmacologist will have tried a num- with diagnosis is due to the ego-dystonic nature of
ber of antidepressants, previously provided by anxiety-depressive symptoms – patient’s complain
another doctor, that have been found to be ineffec- of and desire treatment for such symptoms. But
tive. A significant number of these patients, while grandiose, euphoric, irritable, or angry emotions
eventually being diagnosed with some form of are frequently not thought of as pathological, and
bipolar disorder, have been misdiagnosed with thus a patient’s lack of insight on the manic side of
unipolar depression or other conditions (4). the spectrum can make a proper bipolar diagnosis
difficult. Moreover, patients do not have more
insight when they are euthymic, rather they are
The ratio of bipolar to unipolar depression
more insightful of past rather than current episodes
The Epidemiologic Catchment Area (ECA) study (9). Studies have shown that insight in bipolar
reported that mania and hypomania occur in 1.2% disorder is more impaired than in unipolar major
of the population over a lifetime, which is roughly depressive disorders, and equally impaired as
one-fourth the prevalence of major depression (5). compared to schizophrenia (10, 11). Thus, the
Since this study, some researchers in bipolar reliance on patient insight in self-reports on mania
disorder have raised concerns over the accuracy most likely contributes to the underdiagnosis of
of this 1:4 ratio of unipolar major depression to bipolar disorder.
bipolar disorder. A follow-up study, done by
Anthony and colleagues, on the diagnostic validity
Impulsivity disorders
of the ECA study found poor interrater agreement
(kappa values) for Axis I psychiatric diagnoses (the In addition to mixed anxiety/depressive patients,
highest kappa value was 0.35, although conven- the other group of patients from which a subset
tionally acceptable kappa values for epidemiolog- of bipolar spectrum diagnoses can be made
ical studies are greater than 0.50). The confusion consists of patients with impulsivity disorders
regarding the ratio of diagnosis between unipolar including- substance abuse, borderline personality,
and bipolar depression is highlighted in other bulimia, and attention deficit disorder (ADD).
analyses. Goodwin and Jamison’s comprehen- Space precludes a careful discussion of each of
sive review of the topic led to an estimate of a these presentations, but a few points need to be
2:1 ratio of unipolar to bipolar disorder (6), and emphasized. The impulsivity disorders have many
an epidemiologic study among the Amish reported symptoms in common with bipolar disorder. More
a ratio of 1:1 (7). Furthermore, while the limita- importantly, patients diagnosed with impulsivity
437
Katzow et al.

disorders who present with common symptoms can tional forms of bipolar illness may exist. In these
have bipolar disorder either instead of or in forms, spontaneous mania or hypomania do not
conjunction with impulsive conditions. Symptom exist, making the condition difficult to recognize in
assessment is often limited and difficult to disen- a clinical setting.
tangle, and thus careful attention to other diag- A good way of understanding the bipolar
nostic validators such as family history, course, spectrum concept is to use an analogy from general
and treatment response can help identify the medicine, such as hypertension, that can also be
bipolar subset of patients who present with these viewed along a continuum. After first ruling out
impulsive features. Antidepressant response, in other specific causes, such as kidney disease, we are
particular, can be informative. For instance, we left with essential hypertension. While it is likely
frequently observe that the level of substance abuse that in the future other specific causes will be
increases with antidepressant use in patients who discovered, the spectrum from normal to high
are later determined to have bipolar illness. Fur- blood pressure will still exist. The line between
thermore, children with ADD symptoms whose normal and abnormal is determined empiric-
parents have bipolar disorder should be carefully ally (in the case of blood pressure, currently
assessed, especially as the preadolescent presenta- 140/90 mm Hg), where research has determined
tion of manic symptoms may be significantly that the tradeoffs become better to treat the with
different than the adult criteria used in DSM-IV anti-hypertensives than to withhold treatment.
diagnoses. Persons with borderline personality This line, however, is arbitrary in that the line will
traits should also be carefully assessed for bipolar change over time as we learn more about hyper-
criteria and a bipolar diagnosis should be consid- tension or as new medications are introduced. The
ered. In another situation, patients with bulimia above analogy demonstrates how the idea of a
are often so devastated by the condition that their spectrum already exists within medicine. It may be
resulting depression often overshadows other that psychiatric disorders may be best understood
manic symptoms or bipolar history. In general, a with the concept of spectra/continua. While
characteristic of bipolar disorder is impulsive present diagnostic frameworks, such as in the
behavior, and thus other diagnoses, including but DSM-IV, are helpful for researchers to achieve
not limited to a bipolar diagnosis, should be consistency in diagnosis, from a clinical perspective
considered in patients with impulsive disorders. they are often artificial in their diagnostic categor-
ies. Instead of specific categories, the idea of a
spectrum better fits the facts seen in clinical
The bipolar spectrum
practice.
The diagnosis of bipolar disorder is further com- ÔSoftÕ symptoms of bipolarity have been studied
plicated if we are ready to diagnose patients with for over 2 decades (12–14). A review of six studies
non-classical bipolar features. From a practical carried out since 1978 suggests that broadening
perspective, patients with non-classical symptoms the bipolar diagnostic criteria to include other
tend to be diagnosed under the current large aspects of the bipolar spectrum, such as hypoma-
heterogeneous label of Ômajor depressionÕ, by nia and cyclothymia, yields a higher prevalence
which clinicians in effect mean unipolar depression. range (3–8.8%) than previously expected (15).
Many of these patients, however, are unresponsive While Baldessarini has emphasized the potential
to standard antidepressants, and ultimately prove pitfalls for research if the bipolar diagnostic
to have evidence of bipolarity, responding to spectrum is broadened (16), this paper outlines
medications used for classical bipolar illness, like several advantages to the concept for the practic-
standard mood stabilizers, novel anticonvulsants, ing clinician.
or atypical neuroleptic agents. If we are willing to accept the bipolar spectrum
There is no term on which a consensus has concept, the question arises of how broad the
developed for this group of patients with non- spectrum should be. Clinical data and experience
classical bipolar features, but Ôbipolar spectrumÕ is suggest that the continuum is quite large, ranging
probably the most common label used. Bipolarity from bipolar I disorder to cyclothymia (14). One
is a disorder that is characterized by unstable approach, developed by Akiskal and Klerman, is
mood and behavior, and any recurrent cycling to split the spectrum into many subgroups (types
psychiatric disturbance can be evaluated with II, III, IV, V, VI, or more) based on specific
regard to being a symptom or form of bipolar characteristics of each subgroup (17). Another
disorder. Thus, the hypothesis of the bipolar approach, suggested by Ghaemi and Goodwin,
spectrum is that outside of classical manic-depres- lumps all the non-type I or type II subgroups into
sive illness, or type I bipolar disorder, less conven- one generic label (bipolar spectrum disorder) (18).
438
 The bipolar spectrum: a clinical perspective

Fig. 1. The bipolar spectrum.

From the standpoint of the practicing clinician, tained data, such as family history or response to
these categorical labels may be less useful than antidepressant medications.
the simple idea of a smooth continuum, as The specific soft signs of the bipolar spectrum
shown in the figure, ranging from bipolar I have been described in detail elsewhere (12).
disorder to psychotic depression (Fig. 1). Patients Clinically, we find the following list of soft symp-
can cycle from any two points on the spectrum toms useful: hyperthymic personality, seasonality
including (very importantly) cycling just within or light sensitivity, having a high from staying up
the depressive range. The Kraepelinian concept all night, times of diminished need for sleep
of Ômanic-depressive, depressedÕ has not transla- accompanied by high energy, atypicality (increased
ted well into the concept of bipolar depression appetite or sleep), any admixture of manic and
because clinicians are forgetting that manic depressed symptoms, lower age of onset, severity
depressive illness can present with just various of depression, melancholic features, postpartum
grades of depression, i.e. as cycling within the reactions, any recurrent out-of-control, impulsive,
depressive pole of the illness. Unfortunately, the or reckless behavior, or a family history of any of
term ÔbipolarÕ implies cycling between mania and the above. While Ghaemi and Goodwin have
depression, whereas the key to the illness may be previously suggested specific diagnostic guidelines
the cycling rather than the occurrence of a manic for bipolar spectrum disorder (18), there is not yet
pole. consensus as to which specific symptom or how
many symptoms need to be present to diagnose a
bipolar spectrum condition. Common sense, how-
Shifting away from an emphasis on polarity
ever, suggests that the more such signs are present,
The bipolar spectrum concept shifts the emphasis the more likely the diagnosis of a bipolar spectrum
in diagnosis of bipolar disorder away from polarity condition.
(e.g. presence of spontaneous manic episodes) and
toward other diagnostic validators (course, family
Involving families
history, and antidepressant outcomes). As Good-
win and Jamison emphasized (6), an excessive While a specialist usually examines patients alone,
focus on polarity, as seen in the diagnostic schema involving family members in the clinical process
of DSM-III and IV, obscures the relationship can aid in proper diagnosis and treatment. The
between bipolar and recurrent forms of unipolar patient may believe that the symptoms of mania
depression leading to a lack of attention to soft are not unusual: a manic emotion such as irritab-
symptoms such as family history or antidepressant- ility can be rationalized as a legitimate reaction to
induced hypomania. DSM-IV describes hypoma- real situations. Family members, however, can
nia as a major diagnosis that requires absence of often report behavioral symptoms of mania better
Ôsignificant social or occupational dysfunctionÕ, and than the patient can. A study on the prodromal
thus hypomania differs from mania based on symptoms of mania and depression demonstrated
function rather than symptoms. This creates diffi- that families reported behavioral symptoms of
culty in proper diagnosis for clinicians because the mania more than twice as frequently as patients
term ÔsignificantÕ in the DSM-IV is vague, making (47% vs. 22%) (20). These results are in compar-
identification of hypomania unreliable (19). Patient ison to findings on unipolar depression, where
histories are often so sparse and untrustworthy families and patients reported symptoms at similar
that it is almost impossible for the clinician to rates. Thus, obtaining information on symptoms
confidently identify hypomanic episodes. The con- from family members or another third-party
cept of the bipolar spectrum shifts the clinician’s (therapist, nurse, social worker) offsets the con-
attention to more objective and accurately ob- cealing effects of patient’s impaired insight.

439
Katzow et al.

stabilizers. We define ÔaggressiveÕ mood stabilizer

Antidepressant treatment
use as routine polypharmacy with two or three
As highlighted by this special issue, the use of mood-stabilizing agents soon after insufficient
antidepressants in bipolar disorder is controversial. response with a single mood stabilizer. We
There is some evidence that antidepressants may would also hope that clinicians and patients
worsen the long-term course of bipolar illness. Our make a concerted effort, even in the face of side
clinical experience is that negative response to effects, to keep mood stabilizers in the treatment
antidepressants is an important feature of patients mix. Too frequently, clinicians will try mood
with bipolar spectrum conditions. One observed stabilizers for only brief periods, often stopping
effect to antidepressant treatment in patients with them because of side effects or apparent ineffi-
bipolar spectrum illness is an increase in cycling cacy. On the other hand, many more antidepres-
frequency and in the amplitude of highs and lows. sants will have been tried for much longer
In contrast, another common effect of antide- durations of treatment. We would certainly
pressant use in this group of patients is increased encourage the opposite pattern – brief trials of
cycling but with milder depressive swings (mitiga- antidepressants, and multiple long trials of sta-
ted depression). This is where the patient, after bilizers. A naturalistic outcome study indicates
beginning antidepressant therapy, has an increase that with aggressive use of mood stabilizers only
in cycling without the most severe part of the 19% of bipolar patients required long-term
depressive cycle. This clinical observation is sup- antidepressant treatment (22). While we do not
ported by a study which showed that while advocate a prohibition on antidepressant treat-
antidepressants increased the number of mood ment for patients with soft bipolar disorders, we
episodes per year, the percent of time ill with suggest applying the lessons learned from the
depression was marginally decreased in patients treatment of classic bipolar disorder, such as
with type II bipolar disorder (4). In these patients, emphasizing mood stabilizers over antidepres-
antidepressants are a mixed blessing, with some sants to control cycling.
benefit but no marked overall improvement. Patients with soft bipolar illnesses usually have
Tolerance, or the Ôwear-off Õ effect, is an impor- already tried many antidepressants that resulted in
tant aspect of antidepressant outcomes in patients poor outcomes. Regardless of whether or not
with bipolar spectrum conditions (21). For exam- classic bipolar disorder is present, when features
ple, antidepressant 1 demonstrates strong initial of bipolarity are present, shifting the emphasis
effectiveness, but over time loses its efficacy. The from antidepressants to mood stabilizers often
patient is then switched to antidepressant 2, which proves beneficial. In these patients, it is important
does not work quite as well as 1 and also wears off to recognize the possibility that by inducing
more quickly. The patient responds even worse cycling, antidepressants can act as mood destabi-
when switched to antidepressant 3. Technically, lizers, serving to counteract the potential benefits
these patients might be acutely responsive to the of mood stabilizers. When considering the use of
antidepressants; however, the antidepressants fail antidepressants in treating bipolar depressed pa-
to prevent future mood episodes. tients, we tend to limit their application to cases of
A related feature of antidepressant response in severe depression that are unresponsive to multiple
these patients is quicker onset of benefit with mood stabilizers or to situations where rapid
antidepressants. Although we observe and hear of control of depressive symptoms is imperative, such
such an effect from other clinicians, we are as in marked suicidality. In general, a proper mood
unaware of any empirical evidence on this topic. stabilizer trial should occur in the absence of
Unlike most patients with unipolar depression, we concurrent antidepressant use; otherwise one can-
sometimes observe rapid antidepressant response not be sure that lack of response is due to inefficacy
on the order of hours to days in patients with of the mood stabilizer as opposed to destabilizing
bipolar disorder. In our experience, this initial effects of the antidepressant. In contrast, many
good news often heralds later bad news, as these patients take antidepressants so continuously that
patients seem more likely to develop increased they never receive even one mood stabilizer
mood cycling on antidepressants, or experience monotherapy trial.
tolerance with eventual depressive relapse. We also recommend using atypical neuroleptics
in cases of anxiety or agitation, and novel anti-
convulsants as potential mood stabilizers in
Principles of treatment for the bipolar spectrum
patients who cannot tolerate or accept lithium,
The impact of the antidepressant dilemma can valproate, or carbamazepine.
often be minimized with aggressive use of mood
440
 The bipolar spectrum: a clinical perspective

attention on the less classical presentations of

The skeptic’s view
bipolarity. To recognize and therefore treat
We are very aware that this paper will generate bipolarity, clinicians should focus on patients
skepticism in many quarters. We are not unaware who present with two types of conditions- anxi-
of some important potential criticisms of ideas in ety/depressive illnesses and impulsivity disorders
this paper, which we would like to discuss here. (substance abuse, borderline personality, bulimia,
The ideas expressed here about the bipolar spec- and ADD). For proper treatment of bipolar
trum concept are not meant to be definitive. We do disorder, it is important to recognize that antide-
not provide evidence intended to prove the bipolar pressants can have a detrimental effect on a
spectrum concept from the perspective of empirical patient’s condition. This destabilization of bipolar
research. While necessary, such research is still in disorder is often manifested by a worsening
its relative infancy. Instead, we wished to provide a condition and/or increased cycling. Mood stabi-
venue for a description of the contours and lizers, which are generally underutilized, should
relevance of the bipolar spectrum concept from be emphasized in treatment. To adequately test
the point of view of clinical experience. the efficacy of a mood stabilizer, monotherapy
It may also be suggested that our perspective will should at some point be attempted. It is import-
lead to an overdiagnosis of bipolar disorder and ant, however, to recognize that while mood
that we may be unaware of important political and stabilizers should be emphasized over antidepres-
economic factors that might be driving such over- sants, effective treatment for difficult cases may
diagnosis. For instance, it might be argued that require both types of medications.
interest in bipolar disorder has risen with the
marketing of mood-stabilizing medications by
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