MEDLINE search on
Soft Bipolar Spectrum – Hyperthymia

By, Ivan Goldberg, M.D.

1: Am J Psychiatry. 2005 Jan;162(1):137-45.

Does sustained-release lithium reduce impulsive gambling and affective
instability versus placebo in pathological gamblers with bipolar spectrum

Hollander E, Pallanti S, Allen A, Sood E, Baldini Rossi N.

Compulsive, Impulsive, and Anxiety Disorders Program, Department of Psychiatry,
Mount Sinai School of Medicine, New York, NY 10029, USA.

OBJECTIVE: Selective serotonin reuptake inhibitors may be effective for some
patients with pathological gambling, but those with comorbid conditions, such as
bipolar spectrum disorders, may relapse during treatment. To the authors’
knowledge, this is the first placebo-controlled treatment study in pathological
gamblers with bipolar spectrum disorders; it compares sustained-release lithium
carbonate to placebo. METHOD: Forty pathological gambling patients with bipolar
spectrum disorders entered a 10-week randomized, double-blind,
placebo-controlled treatment study of sustained-release lithium carbonate.
Outcome measures included gambling severity, mood, anxiety, and impulsivity
scales. RESULTS: Pathological gambling patients with bipolar spectrum disorders
significantly improved while taking sustained-release lithium carbonate compared
to placebo on total pathological gambling scores on the Yale-Brown Obsessive
Compulsive Scale, including both thoughts/urges and behavior, as well as on the
Clinical Global Impression severity of pathological gambling scale. Affective
instability (the Clinician-Administered Rating Scale for Mania score) was also
lower in the group treated with sustained-release lithium carbonate compared to
placebo. Ten (83%) of 12 completers were rated as responders in the
sustained-release lithium group versus five (29%) of 17 in the placebo group. Of
note, improvement in gambling severity was significantly correlated with
improvement in mania ratings. CONCLUSIONS: Sustained-released lithium may be an
effective treatment in reducing both gambling behavior and affective instability
in pathological gamblers with bipolar spectrum disorder. This study highlights
the need to identify subgroups of pathological gambling patients with bipolar
spectrum conditions because this may have important treatment implications.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 15625212 [PubMed – indexed for MEDLINE]


2: Bull Acad Natl Med. 2004;188(2):285-96; discussion 296.

[From circular insanity (in double form) to the bipolar spectrum: the chronic
tendency for depressive recurrence] [Article in French]

Akiskal HS.

Centre International de l’Humeur, Departement de Psychiatrie, Universite de
Californie a San Diego, 9500 Gilman Drive, La Jolla, CA 92093-9603V, USA.

From a cycling standpoint, “circular insanity” (Falret) and “dual-form insanity”
(Baillarger), both described in hospital patients in 1854, are at the severe end
of the spectrum of what we now call “bipolar disorders”. Falret was prescient in
suggesting that circular insanity was rare in the community, where depressive
cycles are prevalent. These disorders are now respectively referred to as the
“hard” (manic-depressive) and “soft” (bipolar spectrum) phenotypes of the
disorder. This paper focuses on the latter, more prevalent depressive
expressions of the spectrum, which share with the manic and circular forms a
lifelong tendency to recur. Their cyclicity may involve putative “clock genes”.
The genetics of psychotic mania overlaps somewhat with the genetics of
schizophrenia. As regards depressive recurrence, putative genetic factors have
been identified, including a polymorphism of the serotonin transporter, which
significantly increases the subject’s vulnerability to stress; a mediating
pathogenetic variable appears to be temperamental dysregulation (e.g.
neuroticism and cyclothymic lability), which produces hyperemotional reactivity
to such stressors. The growing recognition that many depressive recurrences
belong to a broad spectrum, affecting 5-10% of the population, represents a new
public health challenge. Although the new class of serotoninergic
antidepressants offer a practical approach to the management of depressive
episodes, further research is needed to determine the point of the spectrum at
which mood-stabilizing therapy should be started–and in what combinations–in
order to prevent recurrence and suicide.

Publication Types:
Review, Tutorial

PMID: 15506719 [PubMed – indexed for MEDLINE]


3: Harv Rev Psychiatry. 2004 May-Jun;12(3):140-5.

Comment in:
Harv Rev Psychiatry. 2004 May-Jun;12(3):146-9.

Borderline or bipolar? Distinguishing borderline personality disorder from
bipolar spectrum disorders.

Paris J.

Department of Psychiatry, McGill University, Institute of Community and Family
Psychiatry, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec,

This article addresses the question whether borderline personality disorder
(BPD) can be understood as a variant of bipolar disorder. In the past,
borderline pathology has been seen as a variant of psychosis, depression, or
posttraumatic stress disorder, but there are important differences between all
of these conditions and BPD. The proposal that BPD falls within the bipolar
spectrum depends on the assumption that affective instability develops through
the same mechanism in both diagnostic categories. There are major differences in
phenomenology, family history, longitudinal course, and treatment response
between BPD and bipolar disorder, and the findings of comorbidity studies are
equivocal. Thus, existing evidence is insufficient to support the concept that
BPD falls in the bipolar spectrum.

Publication Types:

PMID: 15371068 [PubMed – indexed for MEDLINE]


4: Harv Rev Psychiatry. 2004 May-Jun;12(3):133-9.

Comment in:
Harv Rev Psychiatry. 2004 May-Jun;12(3):146-9.

Is borderline personality disorder part of the bipolar spectrum?

Smith DJ, Muir WJ, Blackwood DH.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital,
Edinburgh, Scotland.

In recent years, advances in the areas of both bipolar and borderline
personality disorders have generated considerable interest in the clinical
interface between these two conditions. Developments in the study of the
neurobiology of borderline personality disorder suggest that many patients with
this diagnosis have etiological features in common with those diagnosed with
bipolar disorders. This claim is supported by new insights into the
phenomenology of both disorders and by evidence that mood stabilizers are
efficacious in the pharmacological management of borderline patients. This area
of research is an important one because of the considerable morbidity and public
health costs associated with borderline personality disorder. Since borderline
patients can be so challenging to care for, it may be that a reframing of the
disorder as belonging to the broad clinical spectrum of bipolar disorders holds
benefits for patients and clinicians alike.

Publication Types:

PMID: 15371067 [PubMed – indexed for MEDLINE]


5: Psychopathology. 2004 Sep-Oct;37(5):222-6. Epub 2004 Sep 7.

Bipolar spectrum disorder: a pilot study.

Ghaemi SN, Hsu DJ, Ko JY, Baldassano CF, Kontos NJ, Goodwin FK.

Bipolar Disorder Research Program, Department of Psychiatry, Cambridge Health
Alliance, Cambridge, MA 02139, USA.

OBJECTIVE: To assess depressive features of a proposed definition of bipolar
spectrum disorder (BSD). METHODS: Thirty-six patients with bipolar disorder type
I or II were compared to 37 patients with unipolar major depressive disorder
through patient interview and chart review. RESULTS: Univariate analysis
suggests that 7 of 12 (recurrent major depressive episodes, brief major
depressive episodes, atypical depressive symptoms, early age of onset, family
history of bipolar disorder, antidepressant tolerance, and
antidepressant-induced mania) features of major depressive episodes were more
likely to occur in bipolar versus unipolar patients. After adjustment in a
multivariable regression model, however, the five most powerful predictors of
bipolar disorder were brief major depressive episodes, early age of onset,
antidepressant- induced mania, postpartum depression, and atypical depressive
symptoms. CONCLUSIONS: This preliminary study supports the idea that bipolar
disorder is characterized by some depressive features less likely to be found in
unipolar depression. Further prospective study needs to be conducted comparing
BSD with unipolar depression.

PMID: 15353888 [PubMed – indexed for MEDLINE]


6: Clin Child Fam Psychol Rev. 2004 Jun;7(2):71-88.

Psychosocial interventions for children with early-onset bipolar spectrum

Lofthouse N, Fristad MA.

Department of Psychiatry, The Ohio State University, Columbus, Ohio 43210-1250,

Once considered virtually nonexistent, bipolar disorder in children has recently
received a great deal of attention from mental health professionals and the
general public. This paper provides a current review of literature pertaining to
the psychosocial treatment of children with early-onset bipolar spectrum
disorder (EOBPSD). Commencing with evidence of the emerging interest in this
topic, we then focus on terminology, the rationale for studying EOBPSD in
children, current research and clinical progress, possible explanations for the
recent increase in recognition, and essential issues that form the foundation of
effective psychosocial treatment. Next we explore areas of research with direct
implications for psychosocial treatment. These include biological and
psychosocial risk factors associated with bipolar disorder; and the psychosocial
treatment of adult-onset bipolar disorder, childhood-onset unipolar disorder,
and anger management in children. Following this, we discuss treatments being
developed and tested for children with EOBPSD. Finally, we conclude with
recommendations for future studies needed to move the field forward.

Publication Types:

PMID: 15255173 [PubMed – indexed for MEDLINE]


7: BMC Psychiatry. 2004 Jul 5;4(1):19.

The Bipolar Affective Disorder Dimension Scale (BADDS)–a dimensional scale for
rating lifetime psychopathology in bipolar spectrum disorders.

Craddock N, Jones I, Kirov G, Jones L.

Department of Psychological Medicine, University of Wales College of Medicine,
Heath Park, Cardiff CF14 4XN, UK.

BACKGROUND: Current operational diagnostic systems have substantial limitations
for lifetime diagnostic classification of bipolar spectrum disorders. Issues
include: (1) It is difficult to operationalize the integration of diverse
episodes of psychopathology, (2) Hierarchies lead to loss of information, (3)
Boundaries between diagnostic categories are often arbitrary, (4) Boundaries
between categories usually require a major element of subjective interpretation,
(5) Available diagnostic categories are relatively unhelpful in distinguishing
severity, (6) “Not Otherwise Specified (NOS)” categories are highly
heterogeneous, (7) Subclinical cases are not accommodated usefully within the
current diagnostic categories. This latter limitation is particularly pertinent
in the context of the increasing evidence for the existence of a broader bipolar
spectrum than has been acknowledged within existing classifications. METHOD: We
have developed a numerical rating system, the Bipolar Affective Disorder
Dimension Scale, BADDS, that can be used as an adjunct to conventional
best-estimate lifetime diagnostic procedures. The scale definitions were
informed by (a) the current concepts of mood syndrome recognized within DSMIV
and ICD10, (b) the literature regarding severity of episodes, and (c) our own
clinical experience. We undertook an iterative process in which we initially
agreed scale definitions, piloted their use on sets of cases and made
modifications to improve utility and reliability. RESULTS: BADDS has four
dimensions, each rated as an integer on a 0 – 100 scale, that measure four key
domains of lifetime psychopathology: Mania (M), Depression (D), Psychosis (P)
and Incongruence (I). In our experience it is easy to learn, straightforward to
use, has excellent inter-rater reliability and retains the key information
required to make diagnoses according to DSMIV and ICD10. CONCLUSIONS: Use of
BADDS as an adjunct to conventional categorical diagnosis provides a richer
description of lifetime psychopathology that (a) can accommodate sub-clinical
features, (b) discriminate between illness severity amongst individuals within a
single conventional diagnostic category, and (c) demonstrate the similarity
between the illness experience of individuals who have been classified into
different disease categories but whose illnesses both fall near the boundaries
between the two categories. BADDS may be useful for researchers and clinicians
who are interested in description and classification of lifetime psychopathology
of individuals with disorders lying on the bipolar spectrum.

PMID: 15236660 [PubMed – indexed for MEDLINE]


8: J Affect Disord. 2004 Apr;79 Suppl 1:S9-14.

The effectiveness of divalproate in all forms of mania and the broader bipolar
spectrum: many questions, few answers.

Bowden C.

Department of Psychiatry, University of Texas Health Science Center, Mail Code
7792, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

Divalproate (VPA) was the first drug, other than lithium, reported to be
efficacious for the treatment of bipolar disorder. Since then, the effectiveness
of VPA, alone, in combination, and as maintenance therapy, has been investigated
in a number of studies. As a monotherapy, clinical studies revealed that VPA was
superior to lithium with regard to being effective in a broader patient
population: patients with depressive symptoms concurrent with their mania,
patients previously poorly responsive to lithium, patients with more lifetime
episodes, and on specific symptoms of elation/grandiosity and reduced need for
sleep. In addition, while VPA had superior efficacy versus carbamazepine (CBZ),
an anti-manic agent, and equivalent efficacy to the anti-psychotic agent
olanzapine (OLZ) in manic patients with psychotic manic features, patients
showed much better tolerability to VPA than CBZ, anti-psychotics, and, in
particular, lithium. Recently, combination therapy (mood stabilizers plus
anti-psychotic agents) has shown some advantages compared with monotherapy.
Manic symptoms have been observed to improve to a greater extent when the mood
stabilizer was co-administered with an anti-psychotic rather than either agent
used alone. While only a few maintenance studies have been conducted to date,
two randomized studies have indicated consistent trends toward greater efficacy
of VPA than lithium, and significant superiority over placebo on most, although
not all, measures. In general, VPA provides a well-tolerated treatment that is
efficacious for a broad spectrum of manic states and improves outcomes during
maintenance treatment.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 15121342 [PubMed – indexed for MEDLINE]


9: Curr Psychiatry Rep. 2004 Apr;6(2):101-7.

Defining and identifying early onset bipolar spectrum disorder.

Quinn CA, Fristad MA.

Departments of Psychiatry and Psychology, The Ohio State University, Columbus,
OH 43210, USA.

Early onset bipolar spectrum disorder (EOBPSD) is difficult to diagnose because
of symptom overlap with other disorders and nearly ubiquitous comorbidity. A
thorough assessment of EOBPSD should include the following: 1) a timeline of the
child’s development, from birth to present, showing the episodic nature of
EOBPSD; 2) a structured clinical interview determining comorbidity and
differential diagnosis; 3) a family history genogram to ascertain familial
loading and environmental stressors, which informs case conceptualization; 4)
depression and mania rating scales to assess symptom severity and track
treatment outcome; 5) global rating scales to obtain cross-informant data and
inform broad-based treatments; and 6) a current mood log to document baseline
functioning and track treatment outcome. Examples of a timeline, family history
genogram, and current mood log are presented. This comprehensive approach to
assessing EOBPSD, a severe and possibly lifelong disorder, is strongly
advocated. No scale, instrument, or technique alone is adequate to diagnose

Publication Types:
Review, Tutorial

PMID: 15038912 [PubMed – indexed for MEDLINE]


10: J Child Adolesc Psychopharmacol. 2003 Winter;13(4):471-88.

Employing parent, teacher, and youth self-report checklists in identifying
pediatric bipolar spectrum disorders: an examination of diagnostic accuracy and
clinical utility.

Kahana SY, Youngstrom EA, Findling RL, Calabrese JR.

Case Western Reserve University, Cleveland, Ohio 44106, USA.

The diagnosis of bipolar spectrum disorders (BPSD) is difficult to evaluate in
child and adolescent populations. The current study examines whether commonly
used behavior checklists- the Child Behavior Checklist, Teacher Report Form, and
the Youth Self-Report form-are clinically useful in making a differential
diagnosis between BPSD and other disorders. This study is the first to
investigate the validity of integrating pairs of informants using these
instruments to differentiate individuals with BPSD from those with disruptive
behavior disorders, major depressive disorder, and any child or adolescent not
meeting criteria for BPSD. Parent report best predicted diagnostic status, yet
diagnostic efficiency statistics associated with these checklists were
relatively poor. Results indicate that the Child Behavior Checklist has limited
utility when attempting to derive clinically meaningful information about the
presentation of juvenile BPSD.

Publication Types:
Clinical Trial

PMID: 14977460 [PubMed – indexed for MEDLINE]


11: Bipolar Disord. 2003;5 Suppl 2:53-61.

Cognitive effects of atypical antipsychotics: focus on bipolar spectrum

Macqueen G, Young T.

St. Joseph’s Center for Mental Health Services, D1, Mood Disorders Program, 100
West 5th St, Hamilton, ON, L9C 2E4, Canada.

Studies examining cognitive dysfunction in bipolar disorder have documented
neuropsychologic impairment in some patients. Recollection memory, attention,
and visual information processing may be particularly impaired in patients with
bipolar illness. Cognitive impairment appears to worsen with illness
progression, and may have a significant impact on function. Pharmacotherapy to
treat bipolar disorder including lithium, anticonvulsants, antidepressants, and
atypical antipsychotics may have varying effects on cognitive functioning.
Treatment with atypical antipsychotics has been associated with improvement in
various cognitive measures in patients with schizophrenia, and the little data
available in patients with bipolar disorder suggest the potential for similar
benefits. Studies to determine if current treatments for bipolar disorder can
prevent, delay, or even improve cognitive dysfunction are needed.

Publication Types:

PMID: 14700013 [PubMed – indexed for MEDLINE]


12: Bipolar Disord. 2003 Dec;5(6):456-63.

Clinical consequences of under-recognized bipolar spectrum disorder.

Dunner DL.

Department of Psychiatry and Behavioral Sciences, Center for Anxiety and
Depression, University of Washington School of Medicine, Seattle, WA 98105, USA.

The prevalence of bipolar disorder is higher than previously believed,
especially when bipolar spectrum disorders (BSD) are taken into account, and may
approach rates as high as 5%. Difficulties in diagnosing bipolar II and BSD
arise from complexities associated with defining and diagnosing hypomania.
Additionally, bipolar disorder and BSD are often misdiagnosed because of
symptoms that overlap with other psychiatric disorders, particularly unipolar
depression. Recognition of the broader spectrum of bipolar disorders and their
adequate treatment is paramount because bipolar disorder exacts such a high
personal and societal toll, with high rates of suicide and interpersonal
problems and a substantial economic burden. Recognition can be improved with
active screening, and screening tools such as the Mood Disorders Questionnaire
can be easily included in the initial assessment of patients who present with
depressive symptoms. Depressive episodes are common in patients who experience
BSDs, and increasingly treatment approaches designed specifically for bipolar
depression are being studied.

Publication Types:
Review, Tutorial

PMID: 14636371 [PubMed – indexed for MEDLINE]


13: Bipolar Disord. 2003 Dec;5(6):436-42.

Comment in:
Bipolar Disord. 2003 Dec;5(6):443-5.

The bipolar spectrum: a clinical perspective.

Katzow JJ, Hsu DJ, Nassir Ghaemi S.

George Washington University, Washington, DC, USA.

The relative misdiagnosis and underdiagnosis of bipolar disorder is due in part
to the ‘soft’ symptoms of bipolarity that characterize patients with
non-classical bipolar disorder. While no agreement has been reached on the term
for this group of patients, the most common classification used is ‘bipolar
spectrum’, which shifts the emphasis in diagnosis away from polarity and toward
other diagnostic validators. In order to recognize and properly treat patients
with bipolar disorder, clinicians should focus on careful evaluation of patients
with mixed anxiety/depressive symptoms or impulsivity conditions (substance
abuse, borderline personality, bulimia, and attention deficit disorder).
Furthermore, in the treatment of bipolar disorder, clinicians should also
recognize that antidepressants can have a negative effect on patients by
increasing the likelihood of more severe rapid cycling. While antidepressants
may be useful in particularly difficult cases, emphasis should be placed on mood
stabilizers for treatment of the bipolar spectrum.

Publication Types:
Review, Tutorial

PMID: 14636367 [PubMed – indexed for MEDLINE]


14: Psychother Psychosom. 2003 Nov-Dec;72(6):300-6.

Major depressive disorder with anger: a bipolar spectrum disorder?

Benazzi F.

Outpatient Psychiatry Center, University of California, San Diego, Calif., USA.

BACKGROUND: Depression with anger may be more common in bipolar disorders. The
aim of the study was to assess whether major depressive disorder (MDD) with
anger could be included in the bipolar spectrum, by comparing it to MDD without
anger and to bipolar II disorder. METHODS: Consecutive outpatients (281 bipolar
II disorder and 202 MDD) presenting for major depressive episode (MDE) treatment
were interviewed with the DSM-IV structured clinical interview. Clinical
variables used to support the inclusion of MDD with anger in the bipolar
spectrum were age of onset, many MDE recurrences, atypical features of
depression, depressive mixed state (an MDE plus some concurrent hypomanic
symptoms), and bipolar family history. RESULTS: Frequency of MDE with anger was
50.5% [61.2% in bipolar II, and 35.6% in MDD (z = 5.5, p = 0.0000, 95% CI
16.8-43.3%)]. Logistic regression of MDE with anger (dependent variable) versus
bipolar variables showed that MDE with anger was significantly associated with
all bipolar variables, apart from recurrences. MDD with anger, compared with MDD
without anger, had significantly lower age of onset, more marked depressive
mixed state, a bipolar family history with more cases, but comparable atypical
features and Global Assessment of Functioning scores. MDD with anger, compared
with bipolar II disorder, had significantly higher age of onset, less atypical
features, and a bipolar family history with less cases. CONCLUSIONS: MDE with
anger was common in outpatients (more in bipolar II disorder). MDD with anger
may be midway between MDD without anger and bipolar II disorder, and might be
included into the bipolar spectrum. However, MDD with anger does not appear to
be associated with the often reported negative response to monotherapy with
antidepressants. Copyright 2003 S. Karger AG, Basel

PMID: 14526132 [PubMed – indexed for MEDLINE]


15: Psychiatry Clin Neurosci. 2003 Oct;57(5):497-503.

Unipolar depression with bipolar family history: links with the bipolar

Benazzi F.

Outpatient Psychiatry Private Center, Ravenna and Forli (a University of
California at San Diego Collaborating Center), Department of Psychiatry,
National Mental Health Service, Forli,

The aim of the present paper was to find if unipolar major depressive disorder
(MDD) with bipolar family history could be included in the bipolar spectrum, by
comparing it to unipolar MDD without bipolar family history, and to bipolar II
disorder, on typical bipolar variables. A sample of 280 consecutive bipolar II
outpatients, and a sample of 135 consecutive unipolar MDD outpatients,
presenting for major depressive episode (MDE) treatment, were interviewed with
the Structured Clinical Interview for Diagnostic and Statistical Manual of
Mental Disorders (4th edn). Hypomanic symptoms during the MDE were
systematically assessed. Clinical variables used to validate the inclusion of
unipolar MDD with bipolar family history in the bipolar spectrum were young age
of onset, many MDE recurrences, atypical features, and depressive mixed state
(DMX; an MDE plus >2 concurrent hypomanic symptoms), following many previous
studies reporting that these variables were typical features of bipolar
disorders. Means were compared by t-test and frequencies by chi2 test (stata 7).
Two-tailed P < 0.05 was chosen. Unipolar MDD with bipolar family history was
present in 20% of MDD patients. Comparisons among unipolar MDD with bipolar
family history (UP+BPFH), unipolar MDD without bipolar family history (UP-BPFH),
and bipolar II (BPII), found that UP+BPFH versus UP-BPFH had a significantly
lower age, lower age of onset, fewer recurrences, and more DMX; that UP+BPFH
versus BPII had no significant differences (apart from recurrences); and that
UP-BPFH versus BPII had significantly different age, age of onset, recurrences,
atypical features, and DMX. Findings suggest that UP+BPFH shows many bipolar
signs, and that it could therefore be included in the bipolar spectrum. Unipolar
MDD with bipolar family history had a clinically significant 20.0% frequency in
the unipolar MDD sample, supporting the clinical usefulness of this depression
subtype. The subtyping of MDD based on bipolar family history could have
treatment implications.

PMID: 12950704 [PubMed – indexed for MEDLINE]


16: Eur Arch Psychiatry Clin Neurosci. 2003 Aug;253(4):203-8.

Frequency of bipolar spectrum in 111 private practice depression outpatients.

Benazzi F.

Via Pozzetto 17, 48010 Castiglione di Cervia RA, Italy.

BACKGROUND: Mood disorders included into the bipolar spectrum are increasing,
and overactivity (increased goal-directed activity) has reached the status of
mood change for the diagnosis of hypomania in the recent studies by Angst and
Akiskal. STUDY AIM: was to find frequency of bipolar spectrum in remitted
depressed outpatients by including sub-syndromal hypomania. METHODS: 111
depression-remitted outpatients were interviewed for history of hypomania and
hypomanic symptoms with the Structured Clinical Interview for DSM-IV-Clinician
Version (a partly semistructured interview), as modified by Benazzi and Akiskal.
Bipolar I patients were not included. All past hypomanic symptoms (especially
overactivity) were systematically assessed. Wording of the questions could be
changed to increase/check understanding. Subsyndromal hypomania was defined as
an episode of overactivity (increased goal-directed activity) plus at least 2
hypomanic symptoms. RESULTS: Frequency of bipolar II (BPII) was 68/111 (61.2%,
95% confidence interval 52% to 69.8 %), frequency of major depressive disorder
(MDD) was 43/111. The most common hypomanic symptom was overactivity. In the MDD
sample, sub-syndromal hypomania was present in 39.5% (15.3% of the entire
sample), and had 4 median symptoms. Bipolar spectrum frequency was 76.5% (95%
confidence interval 67.9% to 83.5 %). Overactivity had higher sensitivity than
elevated mood for predicting BPII diagnosis. LIMITATIONS: Single interviewer.
CONCLUSIONS: By systematic probing more focused on past overactivity than mood
change, and by inclusion of sub-syndromal hypomania, bipolar spectrum frequency
was higher than the near 1 to 1 ratio versus MDD reported up to now (Angst et
al.). Given the wide confidence interval, the value in the depression population
should be around 70%. Better probing skills by clinicians, and use of
semi-structured interviews could much reduce the current high underdiagnosis of
BPII and related disorders in usual clinical practice.

PMID: 12910352 [PubMed – indexed for MEDLINE]


17: J Clin Psychiatry. 2003;64 Suppl 8:9-14.

Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders.

Evins AE.

Schizophrenia Research Program, Department of Psychiatry, Massachusetts General
Hospital, Boston, USA.

BACKGROUND: More treatment options for all phases of bipolar disorder are
needed. While lithium, valproate, and carbamazepine remain the standard of care
for treatment of bipolar disorder, many patients do not respond adequately to
these treatments. Some new antiepileptic medications such as lamotrigine,
gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide are beginning
to be used to treat bipolar disorder. DATA SOURCES: Evidence for effectiveness
of these novel antiepileptic drugs in treating acute mania and depression as
well as in preventing the recurrence of mania and depression is reviewed. A
MEDLINE search (1966-2001) was performed for clinical trials that were published
in English using the keywords lamotrigine, gabapentin, topiramate,
oxcarbazepine, tiagabine, and zonisamide, plus the terms bipolar disorder and
mania. Evidence for effectiveness of monotherapy is presented first when it is
available. Data from augmentation treatment studies and open case series in
which standard ratings of symptoms were employed are presented when these are
the only available data. DATA SYNTHESIS: Twenty-eight reports of the efficacy of
novel antiepileptic medications in bipolar disorder are reviewed. Evidence is
strongest for lamotrigine monotherapy in patients with bipolar depression, in
some patients with rapid-cycling bipolar disorder, and as prophylaxis. Evidence
for the efficacy of topiramate in acute and refractory mania is promising but
comes predominantly from open trials. Although some very small studies have
found that oxcarbazepine and zonisamide may have some effectiveness for treating
mania, these data are very preliminary. Results are mixed from the 2 small open
trials of tiagabine. Although gabapentin is widely used in bipolar disorder,
controlled data do not support the use of gabapentin as an antimanic medication
or mood stabilizer. CONCLUSION: More controlled trials are needed to assess the
effectiveness of novel antiepileptic medications in bipolar disorder.

Publication Types:

PMID: 12892536 [PubMed – indexed for MEDLINE]


18: J Affect Disord. 2003 Jun;75(1):83-91.

The clinical use of gabapentin in bipolar spectrum disorders.

Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B.

Division of Psychiatry, Department of Public Health, University of Cagliari, Via
Liguria 13, 09127 Cagliari, Italy.

BACKGROUND: with increasing awareness of lithium’s limitations, several new
anticonvulsants had been tested for their mood stabilisation during recent
years. Among the innovative third generation mood stabilizing anticonvulsants,
gabapentin (GBP) seems to have a broad spectrum of efficacy, although no certain
data are available as to its efficacy and use in clinical practice. Accordingly,
an extensive review on this subject has been carried out. METHODS: A
computer-generated search of the biomedical literature and abstract books of the
more important scientific psychiatric congresses until June 2000 was undertaken
to identify all pertinent case reports, case series and studies of GBP as
monotherapy or adjunctive therapy in mood disorders. We identified 40 open-label
studies on the use of GBP in at least 600 patients with bipolar disorder (BP),
manic, depressed, or mixed episodes and unipolar depression and four controlled
studies. RESULTS: The 40 open-label studies and two of the controlled trials
suggested that GBP may have a role as adjunctive agent in the treatment of
patients with bipolar disorders particularly when complicated by co-morbid
anxiety disorder or substance abuse. GBP is usually very well tolerated and has
no pharmacological interference with other mood stabilisers. However, in the
other two double-blind studies GBP has not been found to be efficacious in the
treatment of refractory mania or refractory bipolar depression. CONCLUSIONS:
Although failing to show clear antimanic efficacy in randomized trials,
gabapentin still remains a clinically useful agent when it comes to combination
treatment in refractory and co-morbid patients.

Publication Types:

PMID: 12781355 [PubMed – indexed for MEDLINE]


19: Curr Psychiatry Rep. 2003 May;5(1):36-40.

Kleptomania in impulse control disorders, obsessive-compulsive disorder, and
bipolar spectrum disorder: clinical and therapeutic implications.

Marazziti D, Mungai F, Giannotti D, Pfanner C, Presta S.

Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology,
University of Pisa, via Rome 67, Italy.

This paper aims to critically review currently available data on kleptomania and
to analyze the possible future evolution of clinical research and therapeutic

Publication Types:
Review, Tutorial

PMID: 12686000 [PubMed – indexed for MEDLINE]


20: Acta Psychiatr Scand. 2003 Apr;107(4):268-74.

Frequency of manic symptoms during a depressive episode and unipolar ‘depressive
mixed state’ as bipolar spectrum.

Sato T, Bottlender R, Schroter A, Moller HJ.

Psychiatrische Klinik, Ludwig-Maximilian University, Munich, Germany.

OBJECTIVE: To report the frequency of intra-episode manic symptoms in depressive
episodes, and to evaluate unipolar depressive mixed state (DMS) as bipolar
spectrum. METHOD: A total of 958 (863 unipolar, 25 bipolar II, and 70 bipolar I)
depressive in-patients were assessed in terms of manic symptoms at admission,
and several clinical variables using standardized methods. RESULTS: The
frequency of manic symptoms (flight of idea, logorrhea, aggression, excessive
social contact, increased drive, irritability, racing thoughts, and
distractibility) was significantly higher in bipolar depressives than in
unipolar depressives. Unipolar depressives with DMS – defined as having two or
more manic symptoms – had more similarities to bipolar depressives than to other
unipolar depressives in clinical variables such as onset age, family history of
bipolar disorder, and possibly suicidality. CONCLUSION: Depressive mixed state
is frequent, particular in bipolar depressives. Unipolar depressives with DMS
may be better classified into bipolar spectrum.

PMID: 12662249 [PubMed – indexed for MEDLINE]


21: J Affect Disord. 2003 Jan;73(1-2):183-97.

Arguments for the genetic basis of the bipolar spectrum.

Kelsoe JR.

Department of Psychiatry, University of California, San Diego, CA, USA.

Family members of bipolar probands have been repeatedly shown to have an
increased risk for mood disorders. However, a range of different syndromes in
the bipolar spectrum are commonly observed in these relatives. This suggests the
hypothesis that these different syndromes may be genetically related. It further
suggests that bipolar disorder may be better conceptualized from a genetic
standpoint as a quantitative trait. In such a model, the same genes may
predispose to a variety of phenotypes ranging from schizoaffective disorder to
cyclothymic temperament. Previous attempts to test such a multifactorial model
have provided some limited support. However, other studies argue that some forms
of bipolar disorder such as bipolar II may be genetically distinct. In this
review, various quantitative and categorical models of illness are considered
and the data supporting them reviewed. It is proposed that the existing data may
best fit a model in which different sets of genes predispose to overlapping
phenotypes that are in part both quantitative and distinct in nature.

Publication Types:
Review, Tutorial

PMID: 12507751 [PubMed – indexed for MEDLINE]


22: J Affect Disord. 2003 Jan;73(1-2):123-31.

The prevalence and disability of bipolar spectrum disorders in the US
population: re-analysis of the ECA database taking into account subthreshold

Judd LL, Akiskal HS.

Department of Psychiatry, University of California, San Diego (UCSD), 9500
Gilman Drive, La Jolla, CA 92093-0603, USA.

BACKGROUND: Despite emerging international consensus on the high prevalence of
the bipolar spectrum in both clinical and community samples, many skeptics
contend that narrowly defined bipolar disorder with a lifetime rate of about 1%
represents a more accurate estimate of prevalence. This may in part be due to
the fact that higher figures proposed for the bipolar spectrum (5-8%) have not
been based on national data and have not included all levels of manic symptom
severity. In the present secondary analyses of the US National Epidemiological
Catchment Area (ECA) database, we provide further clarification on this
fundamental public health issue. METHODS: All respondents in the first wave
(first interview) of the ECA household five site sample (n=18252) were
classified on the basis of DSM-III criteria into lifetime manic and hypomanic
episodes, as well as those with at least two lifetime manic/hypomanic symptoms
below the threshold for at least 1 week duration (subsyndromal manic symptoms
[SSM] group). Odds ratios were calculated on lifetime service utilization for
mental health problems, measures of adverse psychosocial outcome, and suicidal
behavior compared to subjects with no mental disorders or manic symptoms.
RESULTS: As originally reported nearly two decades ago by the primary
investigators of the ECA, the lifetime prevalence for manic episode was 0.8%,
and for hypomania, 0.5%. What is new here is the inclusion of subthreshold SSM
subjects, which accounted for 5.1%, yielding a total of 6.4% lifetime prevalence
for the bipolar spectrum. All three (manic, hypomanic and SSM) groups had
greater marital disruption. There were significant increases in lifetime health
service utilization, need for welfare and disability benefits and suicidal
behavior when the SSM, hypomanic and manic subjects were compared to the no
mental disorder group. Suicidal behavior was non-significantly highest in the
hypomanic (bipolar II) group. Otherwise, hypomanic and manic groups had
comparable level of service utilization and social disruption. LIMITATIONS:
Comorbid disorders, which might influence functioning, were not included in the
present analyses. CONCLUSION: These secondary analyses of the US National ECA
database provide convincing evidence for the high prevalence of a spectrum of
bipolarity in the community at 6.4%, and indicate that subthreshold cases are at
least five times more prevalent than DSM-based core syndromal diagnoses at about
1%. These SSM subjects, who met the criteria of “caseness” from the point of
view of harmful dysfunction, are of great theoretical and public health

PMID: 12507745 [PubMed – indexed for MEDLINE]


23: J Affect Disord. 2003 Jan;73(1-2):39-47.

Factor structure of hypomania: interrelationships with cyclothymia and the soft
bipolar spectrum.

Hantouche EG, Angst J, Akiskal HS.

Psychiatry Department, Mood Center, Pitie-Salpetriere Hospital, Paris, France.

BACKGROUND: No systematic data exists on the phenomenology and psychometric
aspects of hypomania. In this report we focus on the factor structure of
hypomania and its relationships with cyclothymic temperament in unipolar (UP)
and bipolar II (BP-II) spectrum (soft bipolar) patients. METHOD: The combined
sample of UP and BP-II spectrum patients (n=427) derives from the French
National multi-center study (EPIDEP). The study involved training 48
psychiatrists at 15 sites in France in a protocol based on DSM-IV
phenomenological criteria for major depressive disorder, hypomania, and BP-II,
as well as a broadened definition of soft bipolarity. Psychometric measures
included Angst’s Hypomania Checklist (HCA) and Akiskal’s Cyclothymic Temperament
(CT) Questionnaires. RESULTS: In the combined sample of the UP and BP-II
spectrum, the factor pattern based on the HCA was characterized by the presence
of one hypomanic component. In the soft bipolar group (n=191), two components
were identified before and after varimax rotation. The first factor (F-1)
identified hypomania with positive (driven-euphoric) features, and the second
factor (F-2) hypomania with greater irritability and risk-taking. In exploratory
analyses, both factors of hypomania tentatively distinguished most soft BP
subtypes from UP. However, F-1 was generic across the soft spectrum, whereas F-2
was rather specific for II-1/2 (i.e., BP-II arising from CT). CT, which was
found to conform to a single factor among the soft bipolar patients, was
significantly correlated only with irritable risk-taking hypomania (F-2).
LIMITATION: In a study conducted in a clinical setting, psychiatrists cannot be
kept blind of the data revealed in the various clinical evaluations and
instruments. However, the systematic collection of all data tended to minimize
biases. CONCLUSION: EPIDEP data revealed a dual structure of hypomania with
‘classic’ driven-euphoric contrasted with irritable risk-taking expressions
distributed differentially across the soft bipolar spectrum. Only the latter
correlated significantly with cyclothymic temperament, suggesting the hypothesis
that repeated brief swings into hypomania tend to destabilize soft bipolar

PMID: 12507736 [PubMed – indexed for MEDLINE]


24: J Affect Disord. 2003 Jan;73(1-2):1-5.

Validating ‘hard’ and ‘soft’ phenotypes within the bipolar spectrum: continuity
or discontinuity?

Akiskal HS.

University of California at San Diego and VA Psychiatry Service (116A), 3350 La
Jolla Village Drive, San Diego, CA 92161, USA.

The unitary Kraepelian concept of manic-depressive illness which incorporated
attenuated forms, personal dispositions to mood instability, as well as much of
the terrain of remitting depressions, may be considered by many to be too broad.
On the other hand, the presently preferred unipolar-bipolar dichotomy in
official nosology fails to account for the very common occurrence of clinical
and subclinical conditions in the interface of major depressive disorders and
bipolarity. The emerging concept of the bipolar spectrum represents a
provocative working hypothesis to account for these conditions.

PMID: 12507732 [PubMed – indexed for MEDLINE]


25: Bipolar Disord. 2002;4 Suppl 1:11-4.

A new bipolar spectrum concept: a brief review.

Angst J, Gamma A.

Zurich University Psychiatric Hospital, Zurich, Switzerland.

Research on the broad bipolar spectrum is dependent on the definition of
hypomania. We recently proposed a new, softer syndromal definition with clinical
validity. This broadens the diagnosis of bipolar II (BP-II) disorder at the
expense of major depressive disorder (MDD). There is evidence for a third group
of suspected BP-II manifesting major depression plus hypomanic symptoms. The two
bipolar-II groups together are as prevalent as MDD. A new concept of minor
bipolar disorder embracing dysthymia, minor and recurrent brief depression with
hypomanic syndromes and symptoms is discussed. Some methodological pitfalls of
research on drug-induced hypomania as an element of the bipolar spectrum are
also summarized.

Publication Types:
Review, Tutorial

PMID: 12479669 [PubMed – indexed for MEDLINE]


26: Psychiatr Clin North Am. 2002 Dec;25(4):713-37.

The soft bipolar spectrum redefined: focus on the cyclothymic,
anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II
and related conditions.

Perugi G, Akiskal HS.

Institute of Behavioral Sciences G. De Lisio, Viale Monzone 3, 54031 Carrara,

The bipolar II spectrum represents the most common phenotype of bipolarity.
Numerous studies indicate that in clinical settings this soft spectrum might be
as common–if not more common than–major depressive disorders. The proportion
of depressive patients who can be classified as bipolar II further increases if
the 4-day threshold for hypomania proposed by the DSM-IV is reconsidered. The
modal duration of hypomanic episodes is 2 days; highly recurrent brief hypomania
is as short as 1 day, and when complicated by major depression, it should be
classified as a variant of bipolar II. Another variant of the bipolar II pattern
is represented by major depressive episodes superimposed on cyclothymic or
hyperthymic temperamental characteristics. The literature is unanimous in
supporting the idea that depressed patients who experience hypomania during
antidepressant treatment belong to the bipolar II spectrum. So-called alcohol-
or substance-induced mood disorders may have much in common with bipolar II
spectrum disorders, in particular when mood swings outlast detoxification.
Finally, many patients within the bipolar II spectrum, especially when
recurrence is high and the interepisodic period is not free of affective
manifestations, may meet criteria for personality disorders. This is
particularly true for cyclothymic bipolar II patients, who are often
misclassified as borderline personality disorder because of their extreme mood
instability. Subthreshold mood lability of a cyclothymic nature seems to be the
common thread that links the soft bipolar spectrum. The authors submit this to
represent the endophenotype likely to be informative in genetic investigations.
Mood lability can be considered the core characteristics of the bipolar II
spectrum, and it has been validated prospectively as a sensitive and specific
predictor of bipolar II outcome in major depressives. In a more hypothetical
vein, cyclothymic-anxious-sensitive temperamental disposition might represent
the mediating underlying characteristic in the complex pattern of anxiety, mood,
and impulsive disorders that bipolar II spectrum patients display throughout
much of their lifetimes. The foregoing conclusions, based on clinical experience
and the research literature, challenge several conventions in the formal
classificatory system (i.e., ICD-10 and DSM-IV). The authors submit that the
enlargement of classical bipolar II disorders to include a spectrum of
conditions subsumed by a cyclothymic-anxious-sensitive disposition, with mood
reactivity and interpersonal sensitivity, and ranging from mood, anxiety,
impulse control, and eating disorders, will greatly enhance clinical practice
and research endeavors. Prospective studies with the requisite methodologic
sophistication are needed to clarify further the relationship of the putative
temperamental and developmental variables to the complex syndromic patterns
described herein. The authors believe that viewing these constructs as related
entities with a common temperamental diathesis will make patients in this realm
more accessible to pharmacologic and psychological approaches geared to their
common temperamental attributes. The authors submit that the use of the term
“spectrum” is distinct from a simple continuum of subthreshold and threshold
cases. The underlying temperamental dimensions postulated by the authors define
the disposition for soft bipolarity and its variation and dysregulation in
anxious disorders and dyscontrol in appetitive, mental, and behavioral
disorders, much beyond affective disorders in the narrow sense.

Publication Types:
Review, Tutorial

PMID: 12462857 [PubMed – indexed for MEDLINE]


27: J Clin Psychopharmacol. 2002 Aug;22(4):431-5.

Use of topiramate in treatment-resistant bipolar spectrum disorders.

Vieta E, Torrent C, Garcia-Ribas G, Gilabert A, Garcia-Pares G, Rodriguez A,
Cadevall J, Garcia-Castrillon J, Lusilla P, Arrufat F.

Clinical Institute of Psychiatry and Psychology, Hospital Clinic, Barcelona,

To evaluate the effectiveness and safety of topiramate as add-on, long-term
therapy for treatment-resistant bipolar-spectrum disorders, 34 DSM-IV
bipolar-spectrum patients, including bipolar I (n = 28), bipolar II (n = 3),
bipolar not otherwise specified (n = 2), and schizoaffective disorder bipolar
type (n = 1), considered to be resistant to treatment with lithium,
carbamazepine, and valproate, received increasing doses of topiramate as
adjunctive therapy for their manic (n = 17), depressive (n = 11), hypomanic (n =
3), or mixed (n = 3) symptoms. Outcome measures included the Young Mania Rating
Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), and the Clinical
Global Impression (CGI) for Severity. Patients were followed up for 6 months.
Twenty-five patients (74%) completed the 6-month follow-up. Nine patients (26%)
dropped out early due to lost of follow-up (n = 4), worsening of symptoms (n =
2), side effects (n = 1), hospitalization due to intercurrent illness (n = 1),
and noncompliance (n = 1). By intent-to-treat analysis, there was a significant
reduction in YMRS, HAM-D, and CGI scores (p < 0.0001 for all measures at the
endpoint) after the introduction of topiramate. Most therapeutic effects
appeared between weeks 2 and 6. Fifty-nine percent of manic patients and 55% of
depressed patients were considered to be responders to the drug, which was well
tolerated; only one patient discontinued due to side effects. The most common
side effect was paraesthesia (n = 2). Ten patients experienced moderate weight
loss during the follow-up period. The mean topiramate dose at endpoint was 202
+/- 65 mg/day. These preliminary results indicate that adjunctive topiramate may
be useful in the long-term treatment of bipolar spectrum disorders, even in the
most difficult-to-treat patients.

PMID: 12172346 [PubMed – indexed for MEDLINE]


28: Nurse Pract. 2002 Jun;27(6):15-29; quiz 30-1.

Identify bipolar spectrum disorders.

Mynatt S, Cunningham P, Manning JS.

Psychiatric Family NP Program, The University of Tennessee Health Science
Center, Memphis, TN, USA.

Patients with bipolar spectrum disorders commonly present with depressive
symptoms to primary care clinicians. This article details bipolar spectrum
disorder assessment, treatment, and treatment response. By intervening early in
the course of depressive and hypomanic episodes, you can help decrease the
morbidity and suffering associated with bipolar spectrum disorders.

PMID: 12094083 [PubMed – indexed for MEDLINE]


29: Can Fam Physician. 2002 May;48:896-904.

Erratum in:
Can Fam Physician 2002 Jul;48:1190.

Bipolar spectrum disorders. New perspectives.

Piver A, Yatham LN, Lam RW.

Nelson Mental Health Centre, Kootenay Lake Regional Hospital, Nelson, BC.

OBJECTIVE: To review new perspectives on diagnosis, clinical features,
epidemiology, and treatment of bipolar II and related disorders. QUALITY OF
EVIDENCE: Articles were identified by searching MEDLINE and ClinPSYCH from
January 1994 to August 2001 using the key words bipolar disorder, type II or 2;
hypomania; spectrum; or variants. Reference lists from articles were reviewed.
Overall, the quality of evidence was not high; we found no randomized controlled
trials that specifically addressed bipolar II or bipolar spectrum disorders
(BSDs). MAIN MESSAGE: Characterized by elevated mood cycling with depression,
BSDs appear to be much more common than previously thought, affecting up to 30%
of primary care patients presenting with anxiety or depressive symptoms.
Hypomania, the defining feature of bipolar II disorder, is often not detected.
Collateral information, semistructured interviews, and brief screening
instruments could improve diagnosis. Antidepressants should be used with
caution. The newer mood stabilizers or combinations of mood stabilizers might be
the treatments of choice in the future. CONCLUSION: Family physicians, as
primary providers of mental health care, should try to recognize and treat BSDs
more frequently. These disorders are becoming increasingly common in primary
care populations.

Publication Types:
Review, Tutorial

PMID: 12053634 [PubMed – indexed for MEDLINE]


30: Ann Clin Psychiatry. 2001 Dec;13(4):185-9.

Topiramate treatment of bipolar spectrum disorders: a retrospective chart

Ghaemi SN, Manwani SG, Katzow JJ, Ko JY, Goodwin FK.

Bipolar Disorder Research Program, Cambridge Hospital, Massachusetts 02139, USA.

The objective of this paper was to determine if topiramate is effective as
treatment for bipolar spectrum disorders in a naturalistic setting. All charts
of outpatients treated with topiramate (n = 76) were reviewed, and clinical
response was assessed retrospectively using the Clinical Global Impressions
Scale for Improvement. Mild improvement was seen in 47% (n = 36) and
moderate-to-marked improvement in 13% (n = 10). Responders received a higher
mean dose (180 mg/day) than did nonresponders (83.2 mg/day, p = 0.002).
Topiramate dose was also higher in those who lost weight (138.3 mg/day) than in
those who did not (70 mg/day, p = 0.007). Weight loss was experienced by 50% of
the sample, with a mean loss of 14.2 lbs. Side effects were reported by 82% (n =
62) of the population, including cognitive effects, sedation, parasthesias,
nausea, insomnia, headache, and dizziness. Adverse effects led 36% (n = 27) of
the total sample to discontinue treatment with topiramate. Topiramate led to
significant weight loss in about half of this bipolar population, while also
improving mood symptoms at least mildly in most patients. Topiramate response
and weight loss were both dose-related, with efficacy, in particular, associated
with higher doses (mean = 180 mg/day) than frequently used in current clinical

Publication Types:
Multicenter Study

PMID: 11958360 [PubMed – indexed for MEDLINE]


31: Can J Psychiatry. 2002 Mar;47(2):125-34.

Comment in:
Can J Psychiatry. 2003 Feb;48(1):64; author reply 64-5.

“Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed
definition for bipolar spectrum disorder.

Ghaemi SN, Ko JY, Goodwin FK.

Department of Psychiatry, Cambridge Hospital, 1493 Cambridge Street, Cambridge,
MA 02139, USA.

The diagnosis and treatment of bipolar disorder (BD) has been inconsistent and
frequently misunderstood in recent years. To identify the causes of this problem
and suggest possible solutions, we undertook a critical review of studies
concerning the nosology of BD and the effects of antidepressant agents. Both the
underdiagnosis of BD and its frequent misdiagnosis as unipolar major depressive
disorder (MDD) appear to be problems in patients with BD. Underdiagnosis results
from clinicians’ inadequate understanding of manic symptoms, from patients’
impaired insight into mania, and especially from failure to involve family
members or third parties in the diagnostic process. Some, but by no means all,
of the underdiagnosis problem may also result from lack of agreement about the
breadth of the bipolar spectrum, beyond classic type I manic-depressive illness
(what Ketter has termed “Cade’s Disease”). To alleviate confusion about the less
classic varieties of bipolar illness, we propose a heuristic definition,
“bipolar spectrum disorder.” This diagnosis would give greater weight to family
history and antidepressant-induced manic symptoms and would apply to non-type I
or II bipolar illness, in which depressive symptom, course, and treatment
response characteristics are more typical of bipolar than unipolar illness. The
role of antidepressants is also controversial. Our review of the evidence leads
us to conclude that there should be less emphasis on using antidepressants to
treat persons with this illness.

Publication Types:
Review, Tutorial

PMID: 11926074 [PubMed – indexed for MEDLINE]


32: Fortschr Neurol Psychiatr. 2002 Mar;70(3):117-25.

[The concept of hyperthymia] [Article in German]

Fritze F, Ehrt U, Brieger P.

Klinik und Poliklinik fur Psychiatrie und Psychotherapie der
Martin-Luther-Universitat Halle-Wittenberg, Germany.

The article reviews the conceptual history of “hyperthymia”. Since K. W. Stark
had used this term in the early 19(th) century, it has developed in two
different directions: (1) to delineate a psychopathological syndrome and (2) to
define a type of personality disorder (psychopathy). As Kurt Schneider’s
personality disorder (psychopathy) concept was easily understood and highly
practicable, it became influential during the 20(th) century. Earlier before,
psychiatrists such as E. Mendel, C. Wernicke and C. G. Jung had described
entities such as “chronic mania”, “hypomania” or “sanguinic degeneration”, which
were rather similar to each other. We analyze the historical development of such
concepts. Emil Kraepelin was highly influential, as he introduced
“constitutional excitation” into a broad concept of manic-depressive illness and
saw it as a very mild form. After Kraepelin such spectrum concept was first
forgotten. Only in recent years these historical considerations were confirmed
by empirical observations, although a separate hyperthymic disorder is neither
part of DSM-IV nor ICD-10. The concept of a hyperthymic temperament or a
hyperthymic personality is a trait-marker and should be differentiated from
hypomania as a state-marker. Nowadays, the importance of hyperthymia is not so
much one of a disorder requiring treatment; rather the concept has interesting
genetic, diagnostic and conceptual consequences.

Publication Types:
Historical Article

PMID: 11880944 [PubMed – indexed for MEDLINE]


33: J Affect Disord. 2001 Dec;67(1-3):221-8.

Do patients with borderline personality disorder belong to the bipolar spectrum?

Deltito J, Martin L, Riefkohl J, Austria B, Kissilenko A, Corless C Morse P.

Anxiety and Mood Disorders Program, The New York Hospital-Cornell Medical
Center, Westchester Division, USA.

BACKGROUND: This report examines clinical indicators for bipolarity in a cohort
of patients suffering from Borderline Personality Disorder (BPD). METHODS: The
study was conducted in the Cornell-Westchester Hospital, famed for its expertise
in BPD. To avoid biasing our sample, we excluded all BPD patients who were
active patients in our anxiety and mood disorders program. Through the use of
both open clinical interviews and standardized diagnostic interviews (SCID),
borderline patients were examined for evidence of bipolarity by five indicators:
history of spontaneous mania, history of spontaneous hypomania, bipolar
temperaments, pharmacologic response typical of bipolar disorder, and a positive
bipolar family history. RESULTS: Depending on the level of bipolar disorder from
the most rigorous (mania) to the most ‘soft’ (bipolar family history), between
13 and 81% of borderline patients showed signs of bipolarity. Based on what the
emerging literature supports as rigorously defined bipolar spectrum (bipolar I
and II), we submit that at least 44% of BPD belong to this spectrum; adding
hypomanic switches during antidepressant pharmacotherapy, the rate of bipolarity
in BPD reaches 69%. As expected from this formulation, most responded negatively
to antidepressants (e.g. hostility and agitation) and positively to mood
stabilizers. LIMITATIONS: Small sample size and retrospective gathering of data
on treatment response. CCONCLUSION: Patients with BPD more often than not
exhibit clinically ascertainable evidence for bipolarity and may benefit from
known treatments for Bipolar Spectrum Disorders. Large scale, systematic
treatment studies with mood stabilizers are indicated.

PMID: 11869772 [PubMed – indexed for MEDLINE]


34: J Clin Psychiatry. 2001;62 Suppl 14:5-9.

Bipolar spectrum disorder: improving its recognition and diagnosis.

Hirschfeld RM.

Department of Psychiatry and Behavioral Sciences, University of Texas Medical
Branch, Galveston 77555-0188, USA.

The lifetime prevalence of bipolar I disorder is approximately 1%. However, the
prevalence of bipolar spectrum disorder is substantially higher. Bipolar
spectrum disorder is a longitudinal diagnosis characterized by abnormal mood
swings comprising some of the following cross-sectional clinical states: mania,
hypomania, mixed states, hyperthymic temperament, major depressive episode, and
depressive mixed state. Most bipolar spectrum patients present for treatment
during a depressive episode, and therefore clinicians often miss the diagnosis
of bipolar spectrum disorder. Several studies have documented that patients
often wait as long as 10 years for the correct diagnosis of bipolar spectrum
disorder. One way to increase recognition of bipolar spectrum disorder is to
screen for it. A recently introduced screening instrument for bipolar spectrum
disorder, the Mood Disorder Questionnaire, is described.

Publication Types:
Review, Tutorial

PMID: 11469675 [PubMed – indexed for MEDLINE]


35: J Affect Disord. 2001 Jul;65(2):167-71.

Gabapentin treatment of the non-refractory bipolar spectrum: an open case

Ghaemi SN, Goodwin FK.

Psychopharmacology Program, Cambridge Hospital, Consolidated Department of
Psychiatry, Harvard Medical School, Cambridge, MA, USA.

OBJECTIVE: To determine if gabapentin is effective in monotherapy or add-on
treatment of non-refractory bipolar disorder in open prospective treatment.
METHODS: Charts of 21 outpatients meeting DSM-IV criteria for bipolar spectrum
disorder (type I, type II, NOS, and cyclothymia) and who were treated with
gabapentin were reviewed and clinical response was assessed based on prospective
application of the Hamilton Depression Rating Scale (HDRS), the Young Mania
Rating Scale (YMRS), the Clinical Global Impression scale (CGI), and the Global
Assessment of Functioning scale (GAF). Also, response was rated retrospectively
using the Clinical Global Impression scale for Bipolar Disorder (CGI-BP).
RESULTS: Eight patients received gabapentin monotherapy and 13 received
adjunctive therapy. Similar improvement in depression was noted in the
monotherapy group, without induction of mania. Gabapentin was associated with a
43.8% improvement in manic symptoms and a 27.6% improvement in depressive
symptoms in the overall sample. In the depressed subsample (n=10), there was a
57.5% improvement in depressive symptoms (P=0.10). Using the CGI-BP, gabapentin
was moderately to markedly effective in 43% of patients for overall bipolar
illness, 38% for depressive symptoms, and 25% for manic symptoms. Of those in
the study, 62% reported side effects, mainly sedation and nausea, with 14% of
the total sample discontinuing treatment due to adverse events. CONCLUSIONS:
Gabapentin, either alone or as an adjunct, appeared moderately effective in
treating depression in this small, uncontrolled, heterogeneous sample of
non-refractory bipolar spectrum illness. Coupled with the earlier clinical
literature, these data suggest the need for prospective double-blind studies of
depressive illness in the bipolar spectrum.

Publication Types:
Case Reports

PMID: 11356240 [PubMed – indexed for MEDLINE]


36: Psychiatry Res. 2001 Apr 15;101(3):249-58.

The contrasting influence of depressive and hyperthymic temperaments on
psychometrically derived manic subtypes.

Perugi G, Maremmani I, Toni C, Madaro D, Mata B, Akiskal HS.

Department of Psychiatry, University of Pisa, Via Roma 67, 56100, Pisa, Italy.

The present investigation focused on symptomatological subtypes of mania and
their relationships with affective temperaments and other clinical features of
bipolar disorder. In 153 inpatients with mania diagnosed according to DSM-III-R,
symptomatological subtypes have been investigated by means of principal
component factor analysis of 18 selected items of the Comprehensive
Psychopathological Rating Scale (CPRS). We compared other clinical features,
depressive and hyperthymic temperamental attributes, and first degree-family
history for mood disorders among the various manic subtypes on the basis of the
highest z-scores obtained on each CPRS factor (dominant CPRS factor groups).
Five factors–Depressive, Irritable-Agitated, Euphoric-Grandiose,
Accelerated-Sleepless, Paranoid-Anxious–emerged, accounting for 59.8% of the
total variance. When the factor-based groups were compared, significant
differences emerged in terms of the duration of the current episodes, rates of
chronicity and incongruent psychotic features–being highest in the ‘Depressive’
and ‘Paranoid-Anxious’ dominant groups. The patients with highest z-scores for
the ‘Euphoric-Grandiose’, ‘Paranoid-Anxious’ and ‘Accelerated-Sleepless’ factors
were those most likely to belong to the hyperthymic temperament, while the
‘Depressive’ dominant group had the highest rate of depressive temperament.
Finally, it is noteworthy that the ‘Irritable-Agitated’ group was high for both
temperaments. The foregoing multidimensional structure of mania–revealing five
factors–is generally concordant with the emerging literature. Consistently with
our original hypothesis, a hyperthymic temperament seems to underlie the most
extreme manic excitement with euphoric-accelerated-paranoid phenomenology. By
contrast, the depressive temperament seemed to mute the expression of mania into
a depressive-manic phenomenology.

PMID: 11311928 [PubMed – indexed for MEDLINE]


37: J Intellect Disabil Res. 2001 Apr;45(Pt 2):139-45.

Adjunctive gabapentin in patients with intellectual disability and bipolar
spectrum disorders.

Carta MG, Hardoy MC, Dessi I, Hardoy MJ, Carpiniello B.

Psychiatric Unit, Department of Public Health, University of Cagliari, Cagliari,

The aim of the present study was to assess the efficacy of adjunctive gabapentin
(GBP) in the treatment of patients with intellectual disability (ID) and bipolar
spectrum disorders. Ten affected subjects with demonstrable increases in
symptomatology during ‘significant’ life events which had interfered with or
induced the interruption of their rehabilitation programmes were chosen for this
study. The meaning of ‘significant’ was defined for each patient as a frequently
repeated life event which had elicited a marked increase in symptoms on at least
two occasions. Gabapentin (300-900 mg day-1) was added to the standard therapy.
The subjects’ psychopathological conditions during the significant life event
were assessed by means of standardized tools both before and after adjunctive
therapy with GBP. A positive response to therapy was observed, with subsequent
improvement of psychopathological conditions, particularly for anxiety and
depressive symptoms. The promising results obtained with GBP suggest the need
for further trials. Adjunctive GBP may become an alternative treatment approach
for patients with ID in whom traditional mood-stabilizing agents have frequent

PMID: 11298253 [PubMed – indexed for MEDLINE]


38: J Affect Disord. 2000 Sep;59 Suppl 1:S69-S79.

Current issues in the identification and management of bipolar spectrum
disorders in ‘special populations’.

Cassano GB, McElroy SL, Brady K, Nolen WA, Placidi GF.

DPNFB, Universita degli di Pisa, Via Rome 67, 561 00, Pisa, Italy.

Bipolar disorder is a common, lifelong condition that can present during
childhood, adolescence, adulthood or later in life. It may occur alone but, more
frequently, is complicated by comorbid psychiatric and medical disorders. As
such, bipolar disorder presents in many different special populations, each of
which warrants specific considerations of diagnosis, treatment and management.
This review summarizes common issues concerning recognition of bipolar disorder,
particularly in younger patients, discusses the prevalence and treatment of
anxious disorder and addictive comorbidity, and considers bipolar disorder in
the institutionalized and forensic populations. Treatment options and the
supporting evidence are discussed.

Publication Types:
Review, Tutorial

PMID: 11121828 [PubMed – indexed for MEDLINE]


39: Am J Psychiatry. 2000 Nov;157(11):1873-5.

Comment in:
Am J Psychiatry. 2001 Oct;158(10):1743-4.

Development and validation of a screening instrument for bipolar spectrum
disorder: the Mood Disorder Questionnaire.

Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE Jr, Lewis
L, McElroy SL, Post RM, Rapport DJ, Russell JM, Sachs GS, Zajecka J.

Department of Psychiatry and Behavioral Sciences, Medical Branch, the University
of Texas at Galveston 77555-01888, USA.

OBJECTIVE: Bipolar spectrum disorders, which include bipolar I, bipolar II, and
bipolar disorder not otherwise specified, frequently go unrecognized,
undiagnosed, and untreated. This report describes the validation of a new brief
self-report screening instrument for bipolar spectrum disorders called the Mood
Disorder Questionnaire. METHOD: A total of 198 patients attending five
outpatient clinics that primarily treat patients with mood disorders completed
the Mood Disorder Questionnaire. A research professional, blind to the Mood
Disorder Questionnaire results, conducted a telephone research diagnostic
interview by means of the bipolar module of the Structured Clinical Interview
for DSM-IV. RESULTS: A Mood Disorder Questionnaire screening score of 7 or more
items yielded good sensitivity (0.73) and very good specificity (0.90).
CONCLUSIONS: The Mood Disorder Questionnaire is a useful screening instrument
for bipolar spectrum disorder in a psychiatric outpatient population.

PMID: 11058490 [PubMed – indexed for MEDLINE]


40: Psychiatr Clin North Am. 1999 Sep;22(3):517-34, vii.

The evolving bipolar spectrum. Prototypes I, II, III, and IV.

Akiskal HS, Pinto O.

Department of Psychiatry, University of California at San Diego, La Jolla, USA.

This article argues for the necessity of a partial return to Kraepelin’s broad
concept of manic-depressive illness, and proposes definitions–and provides
prototypical cases–to illustrate the rich clinical phenomenology of bipolar
subtypes I through IV. Although considerable evidence supports such extensions
of bipolarity encroaching upon the territory of major depressive disorder,
further research is needed in this area. From a practice standpoint, the
compelling reason for broadening the bipolar spectrum lies in the utility of
mood stabilizers as augmentation or monotherapy in the treatment of major
depressive disorders with soft bipolar features falling short of the current
strict standards for the diagnosis of bipolar II and hypomania in DSM-IV and

Publication Types:
Case Reports
Review, Tutorial

PMID: 10550853 [PubMed – indexed for MEDLINE]


41: J Affect Disord. 1999 Aug;54(3):319-28.

The bipolar spectrum: a clinical reality in search of diagnostic criteria and an
assessment methodology.

Cassano GB, Dell’Osso L, Frank E, Miniati M, Fagiolini A, Shear K, Pini S, Maser

Department of Psychiatry, University of Pisa, Italy.

Failure to recognize subthreshold expressions of mania contributes to the
frequent under-diagnosis of bipolar disorder. There are several reasons for the
lower rate of recognition of subthreshold manic symptoms, when compared to the
analogous pure depressive ones. These include the lack of subjective suffering,
enhanced productivity, ego-syntonicity, and diurnal and seasonal rhythmicity
associated with many of the manic and hypomanic symptoms, and the psychiatrists’
tendency to subsume persistent or even alternating symptoms among personality
disorders. Furthermore, the central diagnostic importance placed on alterations
in mood distracts clinicians from paying attention to other more subtle but
clinically meaningful symptoms, such as changes in energy, neurovegetative
symptoms and distorted cognitions. Although officially accepted in both ICD-10
and DSM-IV, we believe bipolar II disorder is underdiagnosed because of
inattention to symptoms of hypomania. Moreover, by requiring the presence of
both full-blown hypomanic and major depressive episodes, current nosology fails
to include symptoms or signs which are mild and do not meet threshold criteria.
There is already agreement in the field that such symptoms are important for
depression. We now propose that attention should also be devoted to mild
symptomatic manifestations of a manic diathesis, even if such manifestations may
sometimes enhance quality of life. The term ‘spectrum’ is used to refer to the
broad range of such manifestations of a disorder from core symptoms to
temperamental traits. Spectrum manifestations may be present during, between, or
even in the absence of, an episode of full-blown disorder. We have developed a
structured clinical interview to assess the mood spectrum (SCI-MOODS) to
evaluate the whole range of depressive and manic symptoms. This instrument is
currently undergoing psychometric testing procedures. Similar to the SCID
interview, the SCI-MOODS interview provides a separate rating for each of the
major DSM-IV symptoms, but the latter also identifies and rates subthreshold and
atypical manifestations. This paper presents the concept of a subthreshold
bipolar disorder and discusses the potential epidemiological, diagnostic and
therapeutic relevance of such a spectrum conditions. We also describe the
SCI-MOODS interview used reliably to identify the occurrence of a bipolar
spectrum condition. Obviously a great deal of systematic research needs to be
conducted to ascertain the reliability and validity of subthreshold bipolarity
as summarized in this paper and embodied in our instrument.

Publication Types:
Review, Tutorial

PMID: 10467978 [PubMed – indexed for MEDLINE]


42: J Affect Disord. 1998 Oct;51(1):7-19.

TEMPS-I: delineating the most discriminant traits of the cyclothymic,
depressive, hyperthymic and irritable temperaments in a nonpatient population.

Akiskal HS, Placidi GF, Maremmani I, Signoretta S, Liguori A, Gervasi R, Mallya
G, Puzantian VR.

International Mood Center, Department of Psychiatry, University of California,
San Diego, USA.

BACKGROUND: Although most personality constructs have been standardized in
population studies, cyclothymic, depressive, irritable and hyperthymic
temperaments putatively linked to mood disorders have been classically derived
from clinical observations. METHODS: We therefore administered the
semi-structured affective temperament schedule of Memphis, Pisa, Paris and San
Diego, Interview version (TEMPS-I) — in its original University of Tennessee
operationalization — to 1010 Italian students aged between 14 and 26. The
interview, administered in a randomized format, took 20 min per subject.
RESULTS: The semi-structured interview was easy to administer and well accepted
by subjects, with no refusals. Principal component analysis with varimax
rotation confirmed the hypothesized four-dimensional factor structure of the
interview, with good to excellent internal consistency. Furthermore,
discriminant analysis and multiple regression provided suggestions for
identifying the traits that are most useful in defining a weighted cut-off for
each of the temperaments (and which, with minor exceptions, are in agreement
with those previously proposed on clinical grounds). In an additional
exploratory factorial analysis, a depressive type which loads negatively on
hyperthymia was distinguished from cyclothymia; the irritable temperament did
not appear to have significant loading on either factor. LIMITATION: All the
present analyses were internal to the scale itself, but ongoing studies are
comparing them with other systems of temperament as well as testing their
clinical cogency for affectively ill populations. CONCLUSION: While more work
needs to be done on better operationalization of the irritable temperament, our
findings overall support the existence — in a relatively young nonpatient
population — of cyclothymic, depressive and hyperthymic types according to the
classic descriptions of Kraepelin, Kretschmer and Schneider, in their TEMPS-I
operationalization. CLINICAL IMPLICATIONS: Coupled with a previous report
identifying 10% of the same 14-26-year-old nonpatient population meeting an
empirically defined statistical cut-off for these temperaments, the present data
define the putative ‘fundamental states’ that Kraepelin considered to be the
personal predisposing anlage of major affective disorders.

PMID: 9879799 [PubMed – indexed for MEDLINE]


43: J Affect Disord. 1998 Sep;50(2-3):215-24.

The high prevalence of bipolar II and associated cyclothymic and hyperthymic
temperaments in HIV-patients.

Perretta P, Akiskal HS, Nisita C, Lorenzetti C, Zaccagnini E, Della Santa M,
Cassano GB.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology,
University of Pisa, Italy.

BACKGROUND: Although recent studies have shown high rates of current and
lifetime depression in HIV-infected patients, there is little systematic data on
the occurrence of bipolarity in these patients. METHOD: We compared 46 HIV
patients with index major depressive episode (MDE) to an equal number of age-
and sex-matched seronegative MDE patients, and systematically examined rates of
DSM-III-R bipolar subtypes (enriched in accordance with Akiskal’s system of
classifying soft bipolar disorders). RESULTS: Although HIV and psychiatric
clinic patients had comparable background in terms of familial affective
loading, HIV patients had significantly higher familial rates for alcohol and
substance use. The more important finding was the significantly higher
proportion of HIV patients with lifetime bipolar II disorder (78%), and
associated cyclothymic (52%) and hyperthymic (35%) temperaments; the findings
were the same irrespective of HIV risk status (intravenous drug user vs.
homosexual and other risk groups combined). LIMITATIONS: The major methodologic
limitation of our study is that clinicians evaluating temperament were not blind
to affective diagnoses and family history. The comparison affective group was a
sample of convenience drawn from the same tertiary care university facility.
CONCLUSION: The finding of a high rate of bipolar II disorder in HIV patients
has treatment implications for seropositive patients presenting with depression.
More provocatively, we submit that premorbid impulsive risk-taking traits
associated with cyclothymic and hyperthymic temperaments may have played an
important role in needle-sharing drug use and/or unprotected sexual behavior,
leading ultimately to infection with HIV. Given their public health importance,
these clinical findings and insights merit further investigation. In particular,
systematic case-control studies, as well as other large scale studies with
prospective methodology need to be conducted.

PMID: 9858080 [PubMed – indexed for MEDLINE]


44: J Affect Disord. 1998 Sep;50(2-3):203-13.

Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical

Himmelhoch JM.

Department of Psychiatry, University of Pittsburgh School of Medicine,
Pennsylvania, USA.

Reports in the literature indicate a subtle but consistent relationship between
panic and bipolar II disorder. The possible connection between social phobia and
bipolarity is less investigated. When we studied the treatment outcome of 32
social phobic patients administered either the reversible monoamine oxidase
inhibitor (RIMA) meclobomide or the irreversible inhibitor MAOI phenelzine, we
found that eighteen had remission > 50% of their socially anxious symptoms.
Moreover, 14/18 of those improved became hypomanic, according to the Raskin
Mania Scale (RMS) and the Young Mania Scale (YMS) coupled with expert clinical
diagnosis. These findings possibly allude to a relationship of social phobia to
bipolarity. Treatment with RIMA or MAOI exposed these subjects as having an
atypical bipolar syndrome which is part of the bipolar spectrum. We then
compared this special subset of subjects to the 18 socially phobic patients who
failed to respond to RIMA’s or MAOI’s and to 26 patients with generalized
anxiety disorder (GAD). Eleven of the 14 hypomanic responders gave histories of
serious developmental deprivation (anaclisis); only 5/18 social phobics and 3/26
GADs without hypomanic responses had anaclitic histories. The author raises the
possibility that anaclisis may have interacted with the impediment of volition
of uncomplicated bipolar depression to produce social inhibition and anxiety.
Finally, the author upholds the central role of depressive inhibition in bipolar
disorder, which during antidepressant therapy often overshoots in a hypomanic
direction; even in the absence of prior spontaneous hypomania, such
disinhibition should classify this special subset of social phobic patients
within the bipolar spectrum.

PMID: 9858079 [PubMed – indexed for MEDLINE]


45: Compr Psychiatry. 1998 Mar-Apr;39(2):63-71.

The high prevalence of “soft” bipolar (II) features in atypical depression.

Perugi G, Akiskal HS, Lattanzi L, Cecconi D, Mastrocinque C, Patronelli A,
Vignoli S, Bemi E.

Institute of Psychiatry, University of Pisa, Italy.

Seventy-two percent of 86 major depressive patients with atypical features as
defined by the DSM-IV and evaluated systematically were found to meet our
criteria for bipolar II and related “soft” bipolar disorders; nearly 60% had
antecedent cyclothymic or hyperthymic temperaments. The family history for
bipolar disorder validated these clinical findings. Even if we limit the
diagnosis of bipolar II to the official DSM-IV threshold of 4 days of hypomania,
32.6% of atypical depressives in our sample would meet this conservative
threshold, a rate that is three times higher than the estimates of bipolarity
among atypical depressives in the literature. By definition, mood reactivity was
present in all patients, while interpersonal sensitivity occurred in 94%.
Lifetime comorbidity rates were as follows: social phobia 30%, body dysmorphic
disorder 42%, obsessive-compulsive disorder 20%, and panic disorder
(agoraphobia) 64%. Both cluster A (anxious personality) and cluster B (e.g.,
borderline and histrionic) personality disorders were highly prevalent. These
data suggest that the “atypicality” of depression is favored by affective
temperamental dysregulation and anxiety comorbidity, clinically manifesting in a
mood disorder subtype that is preponderantly in the realm of bipolar II. In the
present sample, only 28% were strictly unipolar and characterized by avoidant
and social phobic features, without histrionic traits.

PMID: 9515190 [PubMed – indexed for MEDLINE]


46: Arch Fam Med. 1998 Jan-Feb;7(1):63-71.

The bipolar spectrum: a review of current concepts and implications for the
management of depression in primary care.

Manning JS, Connor PD, Sahai A.

Department of Family Medicine, University of Tennessee, Memphis, and the
University of Tennessee Baptist Memorial Hospital Family Medicine Residency
Program, 38104, USA.

Family physicians inevitably encounter patients with bipolar disorders, often
when the patient is depressed. For most of these patients, the attendant
elevations in mood fall short of mania. Such milder periods of expansive mood,
hypomanias, may go unrecognized unless the physician specifically queries the
patient to uncover them. In addition, patients with bipolar disorders often
manifest other distinctive characteristics. An understanding of these hints of
bipolarity is helpful to clinicians treating depressive illness. Patients with
bipolar disorders are at risk for treatment complications caused by the
administration of antidepressants without the concurrent use of mood
stabilizers, such as lithium carbonate, valproate sodium, and carbamazepine.
Such complications include exacerbation of hypomania or mania, induction of
refractory states, and, perhaps, rapid cycling or mixed states. We review
current issues in classification of bipolar disorders and emphasize the
importance of identifying hypomania. An introduction to the concept of affective
temperaments and a brief review of treatment strategies and treatment
complications are included.

Publication Types:
Review, Tutorial

PMID: 9443702 [PubMed – indexed for MEDLINE]


47: Am J Psychiatry. 1996 Dec;153(12):1541-7.

Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial
syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar
affective disorder?

Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen

Department of Psychiatry, Albert Einstein College of Medicine, Yeshiva
University, Bronx, NY 10461, USA.

OBJECTIVE: The purpose of this study was to conduct a systematic assessment of
psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a
genetic syndrome that involves over 40 somatic anomalies, learning disabilities,
and behavioral disorders and is associated with a microdeletion on chromosome
22q11. METHOD: Subjects were referred for psychiatric diagnostic evaluation
without regard to age or previous psychiatric history. In order to establish
DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to
34 years, the Diagnostic Interview for Children and Adolescents–Revised or the
Structured Clinical Interview for DSM-III-R (SCID) was used. A review of
available medical and psychiatric records and a clinical interview performed by
two research psychiatrists to validate specific symptoms and syndromes reported
in the Diagnostic Interview for Children and Adolescents–Revised and the SCID
were used to elucidate the chronological appearance and duration of symptoms.
RESULTS: Sixty-four percent (N = 16 of 25) of this unselected series of patients
with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of
bipolar disorders with full syndromal onset in late childhood or early
adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met
DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while
16% (N = 4) met criteria for attention deficit disorder without hyperactivity.
In contrast to previous reports of a high prevalence of schizophrenia, none of
the patients was diagnosed with schizophrenia, and only four had psychotic
symptoms during a phase of their illness, all in their 20s or 30s. CONCLUSIONS:
Given that the prevalence of bipolar disorder in the general population is
estimated to be 1.5% and that the average age at onset is 24, these findings
support an unusually strong association between velo-cardio-facial syndrome and
early-onset bipolar disorder and suggest that a gene deleted at the 22q11
chromosomal locus may be involved in its pathogenesis. If confirmed, these
findings may provide a new and fruitful line of investigation into the molecular
basis of bipolar spectrum disorders.

PMID: 8942449 [PubMed – indexed for MEDLINE]


48: Encephale. 1995 Dec;21 Spec No 6:37-42.

[Epidemiology of the bipolar spectrum] [Article in French]

Angst J.

Psychiatric University Hospital Zurich, Switzerland.

The majority of epidemiologic studies indicate a prevalence rate of bipolar
disorder of between 0 to 1.6% in the population. Some studies using other
instruments have suggested lifetime prevalence rates of between 3 and 6.5%.
Higher rates are often obtained when a wider range of cases belonging to the
bipolar spectrum are included in data, for instance, cyclothymia or atypical
bipolar illness. The Zurich cohort community study reported a prevalence rate of
5.5% for bipolar disorder and, moreover, found evidence for the existence of
“brief hypomania”, a condition characterized by short episodes of 1-3 days
duration and a high recurrence. The prevalence rate found for this group was
2.2%, and is as such comparable in validity to DSM IV hypomania or mania
measured by family history of depression, history of suicide attempts and
treatment of depression. The quality of life for brief hypomanics is starkly

Publication Types:
Review, Tutorial

PMID: 8582316 [PubMed – indexed for MEDLINE]


49: Encephale. 1995 Dec;21 Spec No 6:3-11.

[The bipolar spectrum: research and clinical perspectives] [Article in French]

Akiskal HS.

Centre international de l’Humeur, Universite de Californie, San Diego, La Jolla,
CA 992093-0603, USA.

Although epidemiologic figures place the lifetime prevalence of bipolar
disorders at about 1%, current evidence indicates that the spectrum of bipolar
disorders may account for 3-6% of the general population. This summarizes two
decades of research conducted by the author and other investigators that
supports the existence of such a spectrum that at the one extreme merges with
severe psychotic disorder and at the other with temperamental dysregulation. The
enlargement of the territory of bipolar disorders is due to new data that have
validated mixed, rapid cycling, and “soft” bipolar conditions. The hallmark of
bipolar I disorders is mania; extreme psychotic pictures often emerge when mania
is mixed with depression, giving rise to “dysphoric mania”. Attenuated or soft
bipolar conditions refer to major depressive episodes interspersed with milder
hypomanic excursions; the latter may occur spontaneously or upon pharmacologic
challenge with antidepressants. Bipolar II disorder is often characterized by
cyclothymic intermorbid or premorbid temperament. Bipolar III refers to major
depressives without hypomanic episodes, yet arising from the background of a
relatively stable level of hyperthymic temperamental adjustment and/or bipolar
family history. These soft bipolar conditions are particularly liable to
depressive rapid cycling as well as to depressive mixed states. The proper
diagnostic characterization of these patients is important because new
anticonvulsant treatments (as well as practical educational approaches to
address these patients’ temperament-based rythmopathy) need to be applied in
their clinical care.

Publication Types:
Review, Tutorial

PMID: 8582314 [PubMed – indexed for MEDLINE]


50: Percept Mot Skills. 1995 Oct;81(2):419-28.

Styles of regulation in the bipolar spectrum.

Rubino IA, Dotti A, Greco E, Zanna V, Fieramonti E, Ciani N.

Tor Vergata University, Rome, Italy.

Styles of regulation were assessed with the Serial Color-Word Test in a group of
35 compensated DSM-III–R bipolar patients (Bipolar) and in 3 control groups:
Major Depression (n = 35), Schizophrenia (n = 50), and self-rated Personality
Disorder (n = 40). On several measures of nonlinear change (V), patients in the
Bipolar group had mean scores between those of the Personality Disorder and the
Schizophrenic groups, and overlapped with those of the Major Depression group.
Patients in the Bipolar group with clearcut temperaments (hyperthymic or
depressive) were significantly more dissociative and less stabilized than other
patients in the same group. A further group of nonclinical subjects with
hyperthymic temperament (n = 20) was significantly more dissociative than the
Personality Disorder group.

PMID: 8570335 [PubMed – indexed for MEDLINE]


51: Zh Nevropatol Psikhiatr Im S S Korsakova. 1994;94(5):50-4.

[The comorbidity of hyperthymia and hypochondria] [Article in Russian]

Dubnitskaia EB, Chudakov VM.

The authors examined 88 patients with hyperthymic-hypochondriac disturbances.
Their typological differentiation is presented. Clinical and prognostic
heterogeneity of euphoria and dysphoric-maniacal hypochondria is conditioned by
relationships between different comorbid elements within complicated
affective-hypochondriac syndrome.

PMID: 7900454 [PubMed – indexed for MEDLINE]


52: J Clin Psychiatry. 1993 Aug;54(8):300-4.

The effect of valproate on bipolar spectrum temperamental disorders.

Deltito JA.

Anxiety and Mood Disorders Program, New York Hospital-Cornell Medical Center,
White Plains 10605.

BACKGROUND: Cyclothymic or hyperthymic temperaments may belong to a bipolar
spectrum of disorders. Patients with such temperaments, especially if there is a
family history of bipolar disorder or an exacerbation of these conditions when
exposed to tricyclic antidepressants, should be conceptualized as possessing
variants of bipolar disorder. This conceptualization suggests that standard
psychopharmacologic regimens used in treating bipolar disorder may be useful. In
this report I examine the potential usefulness of valproate in treating
temperamental variants of bipolar disorder. METHOD: The author reports his
experience of treating patients with bipolar temperamental disorders in an
Outpatient Affective Disorder Specialty Clinic. Three representative case
reports are offered, as well as a discussion of the general issues in the
diagnosis and treatment of these patients. RESULTS: In these cases, valproate
not only treated the acute symptomatology that caused these patients to seek
treatment, but also led to an amelioration of noxious life-long temperamental
traits. These findings strengthen other research findings that suggest a link
between bipolar disorder and limbic dysfunction and add to the validation of the
concept of bipolar temperamental disorders. CONCLUSION: Valproate may be a safe
and effective treatment for patients with cyclothymic and hyperthymic

Publication Types:
Case Reports

PMID: 8253697 [PubMed – indexed for MEDLINE]


53: Encephale. 1993 Mar-Apr;19(2):103-7.

[Hyperthymic disorders] [Article in French]

Feline A.

Hyperthymia, as referring to the book by J. Delay: “les dereglements de
l’humeur” (1946), means from a clinical point of view, an exaggeration of the
level of mood, as well on the one hand, expansive and joyful, as, on the other
hand, distressing, within a withdrawn self. K. Schneider had described an
hyperthymic personality in 1923: optimist, dynamic, taking initiatives, or more
simply hypomanic. He opposed this type of personality to depressive personality
types. Delay unified these two pathologic evolutions within a physiopathological
and psychopathological unique concept. Conversely, H. Ey denied this unique
affective conceptualization of the disease. From his physiopathologic jacksonian
point of view, a certain level of destruction of consciousness explains, solely,
both affective and noetic disorganization of these so called hyperthymias. Since
the early eighties, Angst, Akiskal, Cassano, brought up to date the adjective
hyperthymic. They assessed the correlation between premorbid personality
disorder and mood disorder: a number of bipolar disorders are linked with
premorbid hyperthymic disorders. This was the K. Schneider’ position who linked
traits and states, as Kraepelin did for the manic premorbid disposition.
Choosing a dimensional approach, one question has to be asked: can hyperthymia
be found as a previous personality trait of different other diseases? An anxious
hyperthymia can be found linked to some panic attacks and other neurotic
symptoms. A delusional hyperthymia is described by Janzarik who thinks that
delusional ideas are linked to a kind of delusional mood. G. Petit, in 1933,
subsumed the existence of a paranoid hyperthymia within the more general concept
of the passional psychoses described by de Clerambault, Delmas and Borel.

Publication Types:
Review, Tutorial

PMID: 8275895 [PubMed – indexed for MEDLINE]


54: Lik Sprava. 1993 Feb-Mar;(2-3):90-2.

[The effect of pharmacological and heliogeophysical factors on the
pathomorphosis of hyperthymic states] [Article in Russian]

Sonnik GT, Miliavskii VM.

A clinico-statistical analysis of 1006 case histories of in-patients with
affective psychoses treated in the Poltava Regional Mental Hospital from 1957
through 1978 revealed that maniacal conditions underwent significant changes
during 22 years. This occurred against the background of more intensive use of
psychotropic agents and changing heliogeophysical factors.

Publication Types:
Case Reports

PMID: 8191749 [PubMed – indexed for MEDLINE]


55: J Affect Disord. 1992 Oct;26(2):127-40.

Proposed subtypes of bipolar II and related disorders: with hypomanic episodes
(or cyclothymia) and with hyperthymic temperament.

Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G.

Institute of Clinical Psychiatry, University of Pisa, Italy.

In an attempt to improve the classification of Bipolar II disorders, we have
examined a consecutive series of 687 primary major depressives: 5.1% gave a past
history of mania (Bipolar I), 13.7% met our operational criteria for hypomania
(Bipolar II), and the remaining 81.2% were provisionally categorized as
‘unipolar.’ Although Bipolar II was in some respects intermediate between
Bipolar I and Unipolar, gender, familial bipolar history, age at onset and
course characteristics generally supported its closer kinship to bipolar
illness. Seventy one of the unipolars (10.3% of the total series) further met
our operational criteria for hyperthymic temperament (U-HT), leaving behind a
purer unipolar group of 487 major depressives. With respect to the proportion
having male gender and bipolar family history, U-HT was similar to Bipolar I and
II, and all three differed significantly from pure unipolar; as for age at
onset, number of episodes and related indices of course, BI and BII were
similar, and U-HT was closer to pure unipolar. These findings suggest that major
depressive episodes arising from a hyperthymic temperament (constituting 12.4%
of the ‘unipolar’ universe by conventional definition) are ‘genotypically’
closer to Bipolar II defined by hypomania, and course-wise similar to other

PMID: 1447430 [PubMed – indexed for MEDLINE]


56: Am J Psychiatry. 1990 May;147(5):655-7.

Comment in:
Am J Psychiatry. 1991 Feb;148(2):276-7.

Lithium treatment for cocaine abusers with bipolar spectrum disorders.

Nunes EV, McGrath PJ, Wager S, Quitkin FM.

Depression Evaluation Service, New York State Psychiatric Institute, New York

An open trial of lithium carbonate showed little efficacy for 10 cocaine abusers
with bipolar spectrum disorders. It may be that the bipolar subgroup of cocaine
abusers is heterogeneous and that only a fraction are lithium responsive.

Publication Types:
Clinical Trial

PMID: 2109540 [PubMed – indexed for MEDLINE]


57: Psychopathology. 1989;22(5):268-77.

Psychopathology, temperament, and past course in primary major depressions. 1.
Review of evidence for a bipolar spectrum.

Akiskal HS, Cassano GB, Musetti L, Perugi G, Tundo A, Mignani V.

University of Tennessee, Department of Psychiatry, Memphis.

In reviewing recent findings on affective conditions in the interface of
unipolar and bipolar disorders, we find evidence favoring a partial return to
Kraepelin’s broad concept of manic-depressive illness, which included many
recurrent depressives and temperamental variants. This review addresses
methodologic, clinical, and familial considerations in the definition and
characterization of a proposed spectrum of bipolar disorders which subsumes
episodic and chronic forms. Episodic bipolar disorders are subclassified into
bipolar schizoaffective, and bipolar I and II, and bipolar III or
pseudo-unipolar forms. Chronic bipolar disorders could be either intermittent or
persistent, and are subclassified into chronic mania, protracted mixed states,
and rapid-cycling forms, as well as the classical temperaments (cyclothymic,
hyperthymic, irritable and dysthymic).

Publication Types:
Review, Tutorial

PMID: 2690170 [PubMed – indexed for MEDLINE]


58: Neuropsychopharmacology. 1988 Dec;1(4):257-64.

Delusional depression and bipolar spectrum: evidence for a possible association
from a family study of children.

Weissman MM, Warner V, John K, Prusoff BA, Merikangas KR, Wickramaratne P,
Gammon GD.

Department of Psychiatry, College of Physicians and Surgeons, Columbia
University New York, New York 10032.

Recent pedigree studies demonstrating a possible linkage of bipolar disorder to
markers on different chromosomes have included family members with major
depression and cyclothymia as affected. There is general agreement that
cyclothymia is related to bipolar disorder and that major depression is
heterogenous. It is unclear which subtype of major depression is related to
bipolar disorder. Data suggesting a relationship between delusional subtype of
major depression and bipolar spectrum are presented. The data derive from a
direct-interview study of 220 offspring (ages 6 to 23 years) of probands with
either delusional or nondelusional major depression and normal controls. The
children of delusional as contrasted with nondelusional probands had nearly a
threefold increase in cyclothymia, were more often described by health
professionals as hyperactive, and had increased school and social impairments.
These findings in children replicate earlier findings in adults on the possible
relationship between delusional depression and bipolar disorder and its
spectrum. The findings must be considered tentative, however, because of the
small sample of children in the subgroups of interest.

PMID: 3251505 [PubMed – indexed for MEDLINE]