Bipolar Disorder and Schizophrenia
`
`Bipolar Disorder and Schizophrenia:
`Distinct Illnesses or a Continuum?
`
`Hans-Jürgen Möller, M.D.
`
`Bipolar disorder continues to present complex diagnostic and therapeutic challenges. Originally
`considered 2 separate diseases (mania and depression), bipolar disorder is now recognized to be a
`single disorder characterized by different subtypes and degrees of severity. Despite the availability
`of official guidelines, such as the DSM-IV and ICD-10, diagnosis is still problematic. Traditionally,
`bipolar disorder has been considered a clinical entity distinct from schizophrenia, although that as-
`sumption is being increasingly challenged. Proponents of a bipolar continuum theory support the con-
`cept of an expanded psychiatric continuum ranging from unipolar to bipolar disorders all the way to
`schizophrenia. This notion is supported by various independent findings. Both bipolar disorder and
`schizophrenia demonstrate a high degree of genetic transmissibility. Some data reported in family and
`twin studies suggest hereditary overlap between the 2 disorders. Gene mapping for both diseases is in
`its early stages, but certain susceptibility markers appear to be located on the same chromosomes. Bi-
`polar disorder and schizophrenia also demonstrate some similarities in neurotransmitter dysfunction.
`As further indirect evidence of a possible association, many newer atypical antipsychotic agents ap-
`proved for the treatment of schizophrenia are also proving useful for bipolar disorder. Ongoing re-
`search should aid in the understanding of bipolar disorder and foster the development of more effec-
`tive treatment.
`(J Clin Psychiatry 2003;64[suppl 6]:23–27)
`
`BHippocrates in 400 BC. At that time, the illness was seen
`
`ipolar disorder, one of the earliest identified mental
`disorders, was recognized as early as the time of
`
`as encompassing 2 distinct disorders: mania and melan-
`cholia.1 The term manic-depressive insanity was coined in
`1921 by Kraepelin, who was instrumental in segregating
`the various psychotic disorders and pronouncing schizo-
`phrenia and manic-depressive disorder to be distinct syn-
`dromes.2,3 In the years since, definitions and diagnostic
`criteria for bipolar disorder have continued to evolve and
`generate scientific debate.
`
`DIAGNOSIS
`
`The concept of polarity was first reflected in the Ameri-
`can Diagnostic and Statistical Manual of Mental Disor-
`
`From the Psychiatric Department of the University of
`Munich, Munich, Germany.
`Presented at the roundtable discussion “Bipolar Disorder:
`From Clinical Research to Therapeutic Intervention,” which
`was held June 30, 2001, in Berlin, Germany, and supported by
`an unrestricted educational grant from AstraZeneca
`Pharmaceuticals, L.P.
`Corresponding author and reprints: Hans-Jürgen Möller,
`M.D., Psychiatric Department, University of Munich,
`Nussbaumstrasse 7, D-80336 Munich, Germany
`(e-mail: hans-juergen.moeller@psy.med.uni-muenchen.de).
`
`ders, Third Edition (DSM-III), published in 1980. This
`classification system, still widely used in North America,
`relies on 2 primary subtypes of bipolar disorder, as
`described in the DSM-IV. Bipolar I is defined as 1 or more
`manic or mixed episodes, usually accompanied in the
`course of the disease by major depressive episodes. Bi-
`polar II is characterized by recurrent major depressive
`symptoms and 1 or more episodes of hypomania. The
`DSM-IV also includes a classification for cyclothymic
`disorder, distinguished by chronic periods of mild hypo-
`manic and depressive mood fluctuations.4 In 1992, the
`World Health Organization modified its International
`Statistical Classification of Diseases and Related Health
`Problems (ICD)5 to more closely reflect the classifications
`of the DSM. However, some important diagnostic differ-
`ences between ICD and DSM-IV remain, and it is prob-
`ably clinically relevant to review them.
`In general, whereas the DSM-IV classifies mood disor-
`ders into 2 categories, depressive disorders and bipolar
`disorders, the tenth revision of ICD, ICD-10,5 mainly used
`in Europe, divides affective disorders into manic episodes,
`depressive episodes, bipolar disorders, unipolar depres-
`sive disorder, recurrent affective disorder, and other affec-
`tive disorder. The ICD-10 differentiates unipolar mania
`(ICD 10: F30) more clearly from bipolar disorders than
`does the DSM-IV, which treats unipolar mania as part of
`bipolar disorder due to the increased probability of more
`than 1 affective episode in patients with bipolar disorder.
`
`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2003;64 (suppl 6)
`
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`1
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`Exhibit 2140
`Slayback v. Sumitomo
`IPR2020-01053
`
`

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`Hans-Jürgen Möller
`
`However, it is still controversial whether unipolar mania
`exists as a separate entity. Interestingly, in the ICD-10,
`single mixed episodes are specified in “other single mood
`(affective) disorders” (F38.00).
`According to DSM-IV, the spectrum of bipolar disor-
`ders encompasses several classifications, from a single,
`manic episode (bipolar I; DSM IV: 296.0x, .4x, .40, .5x,
`.6x, .7x) to recurrent depression with hypomania (bipolar
`II; DSM IV: 296.89). This clear differentiation is not fully
`implemented in the ICD-10, where the diagnosis of
`bipolar II disorder (ICD 10: F31.80) can only be found in
`the appendix of the manual. Similarly, rapid cycling,
`which specifies the longitudinal course of bipolar disorder,
`is mentioned as a diagnosis in the ICD-10 appendix
`(F31.81), but can be an additional specification to any af-
`fective episode within bipolar I or II disorder in DSM-IV.
`Furthermore, cyclothymic disorder is identified as a sepa-
`rate diagnosis of bipolar disorders in the DSM-IV, in con-
`trast to the ICD-10, which lists cyclothymia as a separate
`entity within persistent affective disorders.
`As a result of more meticulous course observations and
`increasing knowledge about the causes of illness, bipolar
`disorders are being further differentiated. Differences in
`the prognosis and treatment of the entire spectrum of bi-
`polar disorders are now being observed more accurately
`for the first time, and future classification systems will
`certainly place more emphasis on these newly observed
`features.
`The clinical usefulness of the DSM-IV classification
`system is hindered by several barriers. Clearly, bipolar dis-
`order comprises core features that are easily recognizable
`and lend themselves to a classic bipolar diagnosis. How-
`ever, in the presence of some anomaly or variant, the diag-
`nosis becomes more difficult. Furthermore, in general
`clinical practice, primary care physicians are not likely to
`think of bipolar disorder in terms of bipolar I or bipolar II.
`When the classifications are used, the reliability of a
`bipolar II diagnosis is often poor, as hypomania is harder
`to recognize than full-blown mania. The characterization
`of hypomania includes some degree of subjective assess-
`ment on the part of the physician, and one clinician may
`view a patient as having bipolar II whereas the other may
`view the same patient as having bipolar I. This phenom-
`enon even complicates the comparison of scientific data
`from independent studies if disease classification is not
`performed uniformly.
`
`THE BIPOLAR SPECTRUM
`
`Over the past 10 to 15 years, it has become accepted to
`view bipolar disorder as a continuum of symptom severity,
`ranging from features of relatively mild depression and
`brief hypomania to debilitating patterns of rapid cycling or
`frequent mania with psychotic features.6 Further compli-
`cating diagnosis and disease classification, individual pa-
`
`tient symptoms can vary with regard to degree of polarity,
`symptom severity from episode to episode, duration of
`episodes, and cycling frequency.2
`
`BIPOLAR-SCHIZOPHRENIA CONTINUUM
`
`these diagnostic controversies,
`the midst of
`In
`Kraepelin’s assumption that manic-depression and schizo-
`phrenia are 2 distinct disorders is also being challenged,
`although many experts continue to uphold this theory. Pro-
`ponents of the bipolar continuum theory support the con-
`cept of an expanded psychiatric continuum ranging from
`unipolar to bipolar disorder, to schizoaffective psychosis,
`all the way to schizophrenia. Much research continues to
`focus on this issue, and there is a good deal of published
`support for both positions.7 Much of the evidence support-
`ing the continuum concept is based upon genetic, bio-
`chemical, and pharmacologic findings.
`
`FAMILY LINKAGE STUDIES
`
`Although genetic mapping for affective disorders is far
`from complete, it is apparent from family linkage studies
`that bipolar disorder has a substantial genetic component,
`with possibly the highest degree of genetic loading among
`all major psychiatric diseases. In fact, families of patients
`with bipolar disorder seem to have a disproportionate fre-
`quency of mood disorders. Compelling evidence of dis-
`ease concordance has been presented in studies of twins
`with manic-depressive symptoms.
`Bertelsen et al.,8 in a study of 69 bipolar probands from
`monozygotic twin pairs, found 46 co-twins with manic-
`depressive disorders. An additional 14 co-twins displayed
`other psychoses or marked affective personality disorders
`or had committed suicide. Similarly, in a study of 106
`monozygotic twin probands with functional psychotic dis-
`orders, the concordance of mania in a co-twin was ap-
`proximately 37%.9
`It is possible that data from twin studies underestimate
`the concordance of bipolar disorder, as difficulties in diag-
`nosis may cause one twin to be labeled as unipolar and the
`other twin as bipolar, while in fact they may be expressing
`different features of the disease at the time of diagnosis.
`Misdiagnosis and improper categorization of bipolar
`illness may influence data gathered among relatively
`younger subjects before the full clinical picture of their
`disease becomes apparent. Diagnosis should be more
`reliable after the first episode, which, in the vast majority
`of patients, usually occurs before the age of 30. Differ-
`ences between twins can also confuse the diagnosis, par-
`ticularly in situations in which one twin’s case is compli-
`cated by such factors as drug abuse, neurologic insult, or
`extreme social adversity, while the other’s is not.
`In 1982, Gershon et al.10 published findings from a
`study of 1254 adult relatives of patients diagnosed with
`
`24
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2003;64 (suppl 6)
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`various affective disorders and those of normal controls.
`Lifetime prevalences of major affective disorder (includ-
`ing schizoaffective) were 37%, 24%, 25%, and 20% in
`relatives of patients diagnosed as schizoaffective, bipolar
`I, bipolar II, or unipolar, respectively. Lifetime prevalence
`was 7% in relatives of normal controls. From this and
`other research has arisen the theory of a continuum of ge-
`netic vulnerability, wherein different degrees of “genetic
`loading” can raise or lower susceptibility to various forms
`of affective illness. In such a model, bipolar illness may
`manifest itself when vulnerability is more severe (severity
`defined as a capacity to transmit illness within a pedigree),
`whereas unipolar illness may surface in cases of less se-
`vere vulnerability.10
`Overall, the estimated lifetime risk of bipolar disorder
`in a first-degree relative of a bipolar patient ranges from
`40% to 70% in monozygotic twins to 5% to 10% in all
`other first-degree relatives. Despite this clear genetic link-
`age, the mode of transmission appears to be far more com-
`plex than simple Mendelian inheritance, possibly involv-
`ing several genes, genomic imprinting, and mitochondrial
`inheritance. It remains unclear why out of similar pedi-
`grees some patients may be affected only by mild depres-
`sion, whereas others develop a complete manic-depressive
`profile. However, it has been theorized that the large varia-
`tion in bipolar symptom profiles suggests that nongenetic
`factors, such as environmental and developmental factors,
`have a strong influence in disease expression.6
`
`COMPARISON OF
`BIPOLAR DISORDER AND SCHIZOPHRENIA
`
`In 1988, Gershon et al.11 studied 237 relatives of 48
`patients with schizophrenia or schizoaffective disorder.
`Relatives of patients with schizoaffective disorder had an
`increased incidence of bipolar disorder; an increase was
`not seen in relatives of patients with schizophrenia. Con-
`versely, Angst et al.12 found a slightly elevated morbidity
`risk for schizophrenia (1.9%) and schizoaffective disorder
`(1.5%) among first-degree relatives of patients having bi-
`polar disorder. Other familial and twin studies have re-
`ported concordance and overlap between the 2 illnesses.13
`
`Epidemiology
`Despite differences in clinical characteristics, etiology,
`and treatment strategies, schizophrenia and bipolar dis-
`order share certain epidemiologic characteristics, such as
`age at onset, lifetime risk, course of illness, worldwide
`distribution, risk for suicide, gender influence, and genetic
`susceptibility.14 Both illnesses exhibit similar etiologic
`risk factors, such as an excess of winter-spring births,
`abnormal dermatoglyphics, and a probable excess of peri-
`natal complications.15 Bipolar disorder, however, may be
`more prevalent among higher socioeconomic groups,
`whereas higher rates of schizophrenia are associated with
`
`Bipolar Disorder and Schizophrenia
`
`urban births and minor physical congenital defects. Ac-
`cording to one theory, there may be a subset of bipolar
`cases that represents a unique disease entity, while many
`cases fit into a “bipolar-schizophrenia” continuum.15
`The now-recognized diagnosis of schizoaffective disor-
`der, which by definition falls between schizophrenia and
`mood disorders, tends to add support for the continuum
`theory of these mental illnesses.16 It could be argued that if
`the Kraepelinian dichotomy between affective disorders
`and schizophrenia is legitimate, the occurrence of interme-
`diate variations, such as schizoaffective psychosis, should
`be quite rare. To the contrary, the prevalence of schizo-
`affective disorder has been reported to range from 5.7% in
`adult psychiatric patients to 8% in psychotic patients.7
`
`Neuroanatomy
`Various structural abnormalities have been found in im-
`aging studies of patients with bipolar disorder or schizo-
`phrenia, although none has yet provided any clear answers
`regarding a possible relationship between the 2 disorders.
`Two studies using magnetic resonance imaging found
`indications of bilateral amygdala enlargement with no
`change in the hippocampus in bipolar patients.17,18 In con-
`trast, the amygdala and other focal areas of the brain have
`been found to be reduced in schizophrenic patients.17,19
`One of the more consistent findings among patients
`with bipolar disorder is an enlargement of the lateral and
`third ventricle.20,21 Nasrallah et al.,22 using computerized
`tomography scans, found significantly larger ventricles in
`both manic and schizophrenic subjects compared with
`control subjects. Ventricle size was associated with cer-
`ebellar atrophy, observed more commonly in manic pa-
`tients, but not associated with cerebral atrophy, which was
`more common in schizophrenia patients.
`The prefrontal cortex, in particular, exhibits changes in
`bipolar disorder. Functional neuroimaging studies in pa-
`tients with bipolar disorder and depression have shown
`decreased metabolism compared with normal controls in
`the prefrontal cortex.23,24 A decrease in neuronal and glial
`cell density associated with glial hypertrophy in prefrontal
`area 9 was reported from necropsy findings taken from
`patients with bipolar disorder compared with those taken
`from controls. These findings resemble those in major de-
`pressive disorder but not schizophrenia.25
`
`Genetics
`Molecular genetic studies continue searching for chro-
`mosome linkage in bipolar disorder and schizophrenia.
`Certain potentially relevant gene loci have been identified
`in bipolar disorder, including 12q24, 18p11, 18q22, 4p16,
`21q21, 22q11, and Xq26, although specific genes have not
`yet been consistently implicated.6,26 At least 2 of these re-
`gions, 18p11 and 22q11, may also be linked to schizophre-
`nia, suggesting a possible genetic overlap between the 2
`disorders.26
`
`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2003;64 (suppl 6)
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`Hans-Jürgen Möller
`
`Pathophysiology
`Early investigations of the underlying pathophysiology
`of bipolar disorder centered around a theory of imbalance
`between cholinergic and catecholaminergic neuronal activ-
`ity, an idea based on the known antimanic properties of
`centrally active cholinergic agonists.6 However, it has be-
`come apparent that this complex disorder is likely medi-
`ated through multiple neurotransmitter pathways and bio-
`logical interactions.27 Several neurotransmitters, including
`norepinephrine, dopamine, glutamate, and (cid:97)-aminobutyric
`acid (GABA), have been implicated in bipolar disorder to
`some degree, at least during symptomatic episodes.
`Several neurobiological and pharmacologic findings
`provide further evidence that schizophrenia and bipolar
`disorder may not be completely unique disease states.
`Many neurotransmitter abnormalities identified in bipolar
`disorder resemble those associated with schizophrenia, fur-
`ther supporting the continuum theory. For example, one of
`the foremost neurotransmitters implicated in schizophrenia
`pathology is dopamine, and most antipsychotic medica-
`tions possess some degree of antidopaminergic effect.28
`The administration of amphetamine to individuals with
`schizophrenia has been shown to provoke excess dopa-
`mine release and precipitate schizophrenic behaviors, sug-
`gesting a labile dopamine system.29
`Similar research has not yet been conducted in patients
`with bipolar disorder, although dopamine agonists have
`been found to precipitate mania in these patients. However,
`abnormalities in dopaminergic activity have been noted in
`bipolar disorder, including decreased concentrations of the
`dopamine metabolite homovanillic acid in the cerebro-
`spinal fluid of depressed patients.6 The administration of
`L-dopa has been found to precipitate mania in a nonbipolar
`individual and even shorten the manic-depressive cycle
`length in a bipolar patient.30–32 Amphetamine and cocaine
`intoxication may lead to manic-like symptoms. Altered
`serotonergic activity has also been noted in both schizo-
`phrenia and depression, with a slightly less clear role in
`bipolar disorder.27,33,34 It is possible that neurotransmitter
`disruptions in bipolar disorder, especially of the dopamine
`and serotonin pathways, are an active phenomenon of the
`disease but may not actually play an etiologic role.
`Hyperactivity of the hypothalamic-pituitary-adrenal
`(HPA) axis has been documented in bipolar disorder, in
`which the presence of increased HPA activity has been cor-
`related with depression, mixed manic states, and occasion-
`ally classic manic episodes. Results of a study of patients
`with major depression suggest that HPA-axis hyperactivity
`constitutes a primary dysfunction leading to compensatory
`abnormalities in the serotonergic, and possibly other, neu-
`rotransmitter systems.27,35 Hyperactivation of the HPA axis
`and resulting elevations in glucocorticoid levels have even
`been suggested to play a role in hippocampal cell death and
`atrophy in animal models.27 HPA-system abnormalities
`have also been demonstrated in schizophrenia, although
`
`the degree of dysfunction appears to be less than that ob-
`served in bipolar disorder.36
`The presence of similarities in neurotransmitter irregu-
`larities between bipolar disorder and schizophrenia may
`account for the finding that some newer atypical antipsy-
`chotic agents, such as olanzapine, risperidone, and quetia-
`pine, have been found useful in the treatment of patients
`with bipolar disorder. The antimanic activity of olanzapine
`and risperidone is attributed to blockade of dopamine D2
`receptors and antagonism of other monoaminergic recep-
`tors. Both olanzapine and risperidone have higher anti-
`serotonergic (5-HT2A receptor) potency than quetiapine,
`which has pharmacologic antagonism at multiple sites
`in the central nervous system, including serotonergic,
`dopaminergic, histaminic, and (cid:95)-adrenergic receptors.
`Although all 3 atypical antipsychotics mentioned above
`were originally studied and marketed for the treatment of
`schizophrenia, olanzapine is now approved for the treat-
`ment of bipolar mania, and preliminary studies have re-
`ported efficacy for risperidone, quetiapine, ziprasidone,
`and aripiprazole in patients with bipolar disorder.37–42 It is
`interesting to note that from 1999 to 2001, more than 70%
`of prescriptions written for atypical antipsychotic drugs
`were for conditions other than schizophrenia, including bi-
`polar disorder.43
`
`SUMMARY
`
`A conceptual case can be made for a relationship be-
`tween schizophrenia and bipolar disorder. If each of these
`disorders is an etiologically heterogeneous syndrome, a
`single etiology could result in different phenotypes at the
`clinical level but with a shared etiology at the genetic, bio-
`chemical, or physiologic levels. If each syndrome is the
`result of multiple effects of a single gene (pleiotropic),
`e.g., change in phenomenology over time such that clini-
`cal features differ over time, subsets of persons with clini-
`cally diagnosable schizophrenia or bipolar disorder may in
`fact have the same illness at the etiologic level. For ex-
`ample, both iron deficiency anemia and vitamin B12 defi-
`ciency have symptoms of pallor, fatigue, and tachycardia.
`B12 deficiency can initially appear to be iron deficiency
`anemia, but, when fully developed, can include psychotic
`features and other localized neurologic findings.
`In summary, the Kraepelinian dichotomy between bi-
`polar disorder and schizophrenia may be gradually suc-
`cumbing to a theory of disease overlap and continuum.
`Regardless of which theory eventually proves to be accu-
`rate, the most pressing clinical need is to find safe and ef-
`fective treatments for these disorders. The emerging data
`regarding potential biological and chemical similarities
`between the 2 disorders will not only aid in the under-
`standing of these very complex diseases but, most impor-
`tantly, should bring us closer to the development of opti-
`mal management strategies.
`
`26
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2003;64 (suppl 6)
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`Drug names: aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine
`(Seroquel), risperidone (Risperdal), ziprasidone (Geodon).
`
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
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