Manning JS, Haykal RF, Akiskal HS.
The role of bipolarity in depression in the family practice setting.
Psychiatr Clin North Am. 1999 Sep;22(3):689-703, x.
"The literature suggests that bipolar spectrum disorders are more prevalent than previously thought but still poorly recognized. In the primary care setting, this poor recognition is largely the result of an insensitive, cross-sectional approach and clinicians' lack of familiarity with the phenomenology of bipolar II. Failure to recognize the role of bipolarity in depressive illness is more often a cause of the poor outcome of this illness in this setting than under dosing with antidepressants. Hypomania is easily missed in clinical evaluations and, as currently defined by DSM-IV, may not represent the most diagnostic marker for all variants of bipolar illness: Mood lability and energetic activity, temperamental traits embodied in the construct of cyclothymia, have emerged as more specific. Given emerging data that as much as one third of depressions in both psychiatric and primary care settings belong to the soft bipolar spectrum, practitioner education on the necessity to consider course, temperament, and family history in the approach to depression may improve the identification of bipolar spectrum disorders and limit unproductive or potentially harmful antidepressants use unprotected with mood stabilizers." [Abstract]

Hinkle P.
Bipolar illness in primary care: an overview.
Lippincotts Prim Care Pract. 2000 Mar-Apr;4(2):163-73.
"Primary care providers are in the front line of detecting and diagnosing psychiatric illness. Managed care barriers to direct psychiatric treatment have made it necessary for primary care providers to increase their sophistication in the recognition of psychiatric disorders. Primary care providers often formulate provisional diagnoses and initiate treatment or specialty referral in spite of the time constraints of the primary care setting. The patient presenting in primary care with an affective disturbance must be evaluated for a major mood disorder, which includes unipolar and bipolar illness. Research has shown that more patients than previously estimated have milder forms of bipolar illness disorder, such as bipolar type II and cyclothymia. Patients with these milder forms of bipolar are less likely to present for treatment in a psychiatric setting and more likely to share symptoms of the illness in a primary care setting." [Abstract]

Perugi G, Toni C, Travierso MC, Akiskal HS.
The role of cyclothymia in atypical depression: toward a data-based reconceptualization of the borderline-bipolar II connection.
J Affect Disord 2003 Jan;73(1-2):87-98
"OBJECTIVE: Recent data, including our own, indicate significant overlap between atypical depression and bipolar II. Furthermore, the affective fluctuations of patients with these disorders are difficult to separate, on clinical grounds, from cyclothymic temperamental and borderline personality disorders. The present analyses are part of an ongoing Pisa-San Diego investigation to examine whether interpersonal sensitivity, mood reactivity and cyclothymic mood swings constitute a common diathesis underlying the atypical depression-bipolar II-borderline personality constructs. METHOD: We examined in a semi-structured format 107 consecutive patients who met criteria for major depressive episode with DSM-IV atypical features. Patients were further evaluated on the basis of the Atypical Depression Diagnostic Scale (ADDS), the Hopkins Symptoms Check-list (HSCL-90), and the Hamilton Rating Scale for Depression (HRSD), coupled with its modified form for reverse vegetative features as well as Axis I and SCID-II evaluated Axis II comorbidity, and cyclothymic dispositions ('APA Review', American Psychiatric Press, Washington DC, 1992). RESULTS: Seventy-eight percent of atypical depressives met criteria for bipolar spectrum-principally bipolar II-disorder. Forty-five patients who met the criteria for cyclothymic temperament, compared with the 62 who did not, were indistinguishable on demographic, familial and clinical features, but were significantly higher in lifetime comorbidity for panic disorder with agoraphobia, alcohol abuse, bulimia nervosa, as well as borderline and dependent personality disorders. Cyclothymic atypical depressives also scored higher on the ADDS items of maximum reactivity of mood, interpersonal sensitivity, functional impairment, avoidance of relationships, other rejection avoidance, and on the interpersonal sensitivity, phobic anxiety, paranoid ideation and psychoticism of the HSCL-90 factors. The total number of cyclothymic traits was significantly correlated with 'maximum' reactivity of mood and interpersonal sensitivity. A significant correlation was also found between interpersonal sensitivity and 'usual' and 'maximum' reactivity of mood. LIMITATION: Correlational study. CONCLUSIONS: Mood lability and interpersonal sensitivity traits appear to be related by a cyclothymic temperamental diathesis which, in turn, appears to underlie the complex pattern of anxiety, mood and impulsive disorders which atypical depressive, bipolar II and borderline patients display clinically. We submit that conceptualizing these constructs as being related will make patients in this realm more accessible to pharmacological and psychological interventions geared to their common temperamental attributes. More generally, we submit that the construct of borderline personality disorder is better covered by more conventional diagnostic entities." [Abstract]

Levitt AJ, Joffe RT, Ennis J, MacDonald C, Kutcher SP.
The prevalence of cyclothymia in borderline personality disorder.
J Clin Psychiatry. 1990 Aug;51(8):335-9.
"Sixty patients with personality disorders were evaluated by several different diagnostic instruments to determine the prevalence of cyclothymia in borderline personality disorder (BPD) and in other personality disorders (OPD). Cyclothymia occurred more frequently in BPD than in OPD, regardless of which diagnostic system was used. In contrast, the prevalence of major, minor, and intermittent depression, hypomania, and bipolar disorder was not significantly different in BPD as compared with OPD. Cyclothymic borderlines and noncyclothymic borderlines could not be distinguished on behavioral or functional measures. These results have implications for the diagnostic validity of both BPD and cyclothymia." [Abstract]

Allilaire JF, Hantouche EG, Sechter D, Bourgeois ML, Azorin JM, Lancrenon S, Chatenet-Duchene L, Akiskal HS.
[Frequency and clinical aspects of bipolar II disorder in a French multicenter study: EPIDEP]
Encephale 2001 Mar-Apr;27(2):149-58
"This paper presents the definite data from a French multi-center study (EPIDEP). The aim of EPIDEP was to show the feasibility of validating the spectrum of soft bipolar disorders by practicing clinicians. In this report we focus on data concerning the frequency of BP-II disorder and the key characteristics of BP-II by systematic comparison versus Unipolar depression. EPIDEP involved training 48 french psychiatrists in 15 sites; it is based on a common protocol following the DSM IV criteria (Semi-Structured Interview for Hypomania and Major Depression), and Akiskal (Soft Bipolarity), as well as criteria modified from the work of Angst (Hypomania Checklist), the Ahearn-Carroll Bipolarity Scale, HAM-D and Rosenthal Atypical Depression Scale; Semi-Structured Interview for Affective Temperaments (based on Akiskal-Mallya), self-rated Cyclothymia Scale (Akiskal). Comorbidity and family history (Research Diagnostic Criteria) were also obtained; EPIDEP was globally scheduled in two phases: Phase 1 devoted to recruiting major depressives, and phase 2 involved in more sophisticated assessment of soft bipolarity and administrating related measures. Results are presented on the total of 537 patients included at "visit 1" and 493 assessed for soft bipolarity at "visit 2". The BP-II global rate which was 21.7% at initial evaluation, nearly doubled (39.8%) by systematic evaluation of hypomania. Intergroup comparison versus unipolar depressives showed the following key characteristics of BP-II disorder: 1) distinct clinical presentation at index depressive episode despite uniformity in global intensity of depression (overrepresentation in BP-II of "suicidal thoughts", "guilt feelings", "depersonalisation-derealisation", "hypersomnia" "and weight gain"; and of "psychic anxiety" and "initial insomnia" in UP); 2) different course of illness with younger age of onset of first depression, higher rate of suicidal attempts, recurrency and hospitalisations; 3) more difficulties for recognition of the correct diagnosis; 4) more complex temperamental dysregulations (mixture of cyclothymic, hyperthymic and irritable traits which are highly represented in BP-II group); 5) higher rate in family history of mental disorders, especially bipolar disorders. Finally, EPIDEP data confirmed the diagnostic reliability of self-rating of hypomania and cyclothymia. With a systematic search of hypomania, almost 40% of major depressive episodes seen in psychiatric settings were classified as BP-II, of which only half were recognized by the clinicians at study inclusion. The BP-II validity as a distinct disorder from Unipolars was confirmed. Moreover, EPIDEP emphasized the reliability of self-rating in assessing soft-bipolarity (hypomania and cyclothymia). In total, EPIDEP data indicated that recognition of BP-II is feasible in diverse practice settings and proposed for clinicians some adapted clinical tools for assessing soft bipolarity." [Abstract]

Perugi G, Akiskal HS, Lattanzi L, Cecconi D, Mastrocinque C, Patronelli A, Vignoli S, Bemi E.
The high prevalence of "soft" bipolar (II) features in atypical depression.
Compr Psychiatry. 1998 Mar-Apr;39(2):63-71.
"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." [Abstract]

Depue RA, Kleiman RM, Davis P, Hutchinson M, Krauss SP.
The behavioral high-risk paradigm and bipolar affective disorder, VIII: Serum free cortisol in nonpatient cyclothymic subjects selected by the General Behavior Inventory.
Am J Psychiatry. 1985 Feb;142(2):175-81.
"The degree of biologic concordance between bipolar affective disorder and cyclothymia was assessed within a 3-hour protocol of cortisol functioning. Cyclothymic subjects, selected by the General Behavior Inventory, showed cortisol hypersecretion approaching that of subjects with major affective disorders; they also showed poor modulation of cortisol levels over time, the degree of which was related to increased current level of depression and to a chronic, intermittent depressive course. These results not only support the validity of the General Behavior Inventory but also suggest that cyclothymic subjects with a chronic depressive course may experience persistent biologic disturbance similar to that found during episodes of major depression." [Abstract]

Deltito JA.
The effect of valproate on bipolar spectrum temperamental disorders.
J Clin Psychiatry. 1993 Aug;54(8):300-4.
"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 temperaments." [Abstract]

Jacobsen FM.
Low-dose valproate: a new treatment for cyclothymia, mild rapid cycling disorders, and premenstrual syndrome.
J Clin Psychiatry. 1993 Jun;54(6):229-34
"BACKGROUND: Valproate has proved useful in the treatment of manic-depressive and schizoaffective disorders, usually in daily doses above 500 mg with corresponding blood levels in the range established for treatment of epilepsy (50-100 micrograms/mL). Since milder bipolar disorders may be more prevalent than bipolar I disorder, a prospective study was undertaken to determine whether lower doses of valproate might be useful for stabilization of mood cycling in patients having primary diagnoses of cyclothymia or rapid cycling bipolar II disorder. Additionally, open trials of low-dose valproate were conducted in a small number of women complaining of premenstrual syndrome. METHOD: Over a 3-year period, outpatients with non-menstrually-related rapid cycling who had fulfilled DSM-III-R criteria for cyclothymia or bipolar II disorder were started on open trials of valproate at daily doses of 125 or 250 mg. Doses were adjusted upward on approximately a monthly basis depending upon clinical response, and valproate blood levels were obtained. RESULTS: Twenty-six (79%) of 33 patients (15 cyclothymics, 11 bipolar II) reported sustained partial or complete stabilization of mood cycling with valproate doses ranging from 125 to 500 mg (mean = 351.0 mg) corresponding to serum valproate levels (mean = 32.5 micrograms/mL) substantially below the current recommended range. Cyclothymics required significantly lower doses and blood levels of valproate than patients with bipolar II disorder for stabilization of mood. Five patients (all bipolar II) failed to respond fully to low doses of valproate but improved with higher doses corresponding to blood levels in the 50 to 100 micrograms/mL range. Two patients had poor responses to valproate or intolerable side effects. In contrast to bipolar spectrum patients, only three (38%) of eight women with menstrually related cycling of mood reported good responses to low doses of valproate, while five reported no response to valproate. CONCLUSION: The findings suggest that (1) low-dose valproate may be useful in the treatment of cyclothymia and milder rapid cycling bipolar disorders and (2) there may be a correlation between the severity of bipolar disorder and the blood level of valproate required for stabilization such that milder forms of bipolar cycling require lower doses of valproate." [Abstract]

Klein DN, Depue RA, Slater JF.
Inventory identification of cyclothymia. IX. Validation in offspring of bipolar I patients.
Arch Gen Psychiatry. 1986 May;43(5):441-5.
"We present the ninth in a series of validation studies that support the effectiveness of the General Behavior Inventory (GBI) in identifying cyclothymia. This study assessed the potential utility of the GBI in family and offspring studies by evaluating its ability to satisfy three prerequisites for use in such research: (1) identification of cyclothymia familially related to bipolar I disorder, (2) use with young adolescents, and (3) "insensitivity" to the effects of nonaffective psychopathology and parental nonaffective disorder in the offspring of control probands. The GBI and a blind, structured diagnostic interview were administered to 37 offspring of bipolar I patients and 21 offspring of psychiatric control patients, Twenty-seven percent of the offspring of bipolar patients, but none of the control offspring, were found to have bipolar forms of affective disorder, primarily cyclothymia (24%). Concordance between the GBI and interview-derived diagnoses was 95% to 97%, with 98% specificity and 80% to 90% sensitivity, depending on cutting score location. Together with the results of previous studies, the findings suggest that the GBI holds promise for the identification of cyclothymia in several research and clinical contexts." [Abstract]

Schraufnagel CD, Brumback RA, Harper CR, Weinberg WA.
Affective illness in children and adolescents: patterns of presentation in relation to pubertal maturation and family history.
J Child Neurol 2001 Aug;16(8):553-61
"Affective illness is now recognized as a common problem in all age groups, and the various patterns have been well documented in adults. The objective of this study was to evaluate the patterns of affective illness in children and determine changes with increasing age and family history. One hundred children/adolescents with affective illness (72 boys and 28 girls; age range 2-20 years; mean age 10 years), who were consecutively referred to the Pediatric Behavioral Neurology Program, Children's Medical Center at Dallas, were evaluated for the pattern and course of affective illness symptoms, family history, and pubertal stage. Seven patterns of affective illness were identified. In the 65 prepubertal children (Tanner stage 1), disorders with hypomanic/manic symptomatology were most common (47/65, 72%): mania (2/65, 3%), hypomania (8/65, 12%), cyclothymia (11/65, 17%), juvenile rapid-cycling bipolar disorder/ultradian cycling bipolar disorder (8/65, 12%), and dysthymia with bipolar features (18/65, 28%). In contrast, the 26 fully pubertal adolescents (Tanner stages 3-5) had a predominance of patterns with only depressive symptomatology (16/26, 61%): dysthymia (4/26, 15%) and depression (12/26, 46%), along with juvenile rapid-cycling bipolar disorder/ultradian cycling bipolar disorder (6/26, 23%). Affective illness, alcoholism, and drug abuse were prominent in the family histories, regardless of the child's pattern of symptoms. Family histories of character disorder and Briquet's syndrome were also common, but thought disorder, suicide, and homicide were infrequent. This study supports the clinical observation that the presentation of affective illness changes with age: manic features predominate in younger children, whereas depressive symptomatology is more evident with pubertal maturation." [Abstract]

Akiskal HS, Hantouche EG, Allilaire JF.
Bipolar II with and without cyclothymic temperament: "dark" and "sunny" expressions of soft bipolarity.
J Affect Disord 2003 Jan;73(1-2):49-57
"BACKGROUND: In the present report deriving from the French national multi-site EPIDEP study, we focus on the characteristics of Bipolar II (BP-II), divided on the basis of cyclothymic temperament (CT). In our companion article (Hantouche et al., this issue), we found that this temperament in its self-rated version correlated significantly with hypomanic behavior of a risk-taking nature. Our aim in the present analyses is to further test the hypothesis that such patients-assigned to CT on the basis of clinical interview-represent a more "unstable" variant of BP-II. METHODS: From a total major depressive population of 537 psychiatric patients, 493 were re-examined on average a month later; after excluding 256 DSM-IV MDD and 41 with history of mania, the remaining 196 were placed in the BP-II spectrum. As mounting international evidence indicates that hypomania associated with antidepressants belongs to this spectrum, such association per se did not constitute a ground for exclusion. CT was assessed by clinicians using a semi-structured interview based on in its French version; as two files did not contain full interview data on CT, the critical clinical variable in the present analyses, this left us with an analysis sample of 194 BP-II. Socio-demographic, psychometric, clinical, familial and historical parameters were compared between BP-II subdivided by CT. Psychometric measures included self-rated CT and hypomania scales, as well as Hamilton and Rosenthal scales for depression. RESULTS: BP-II cases categorically assigned to CT (n=74) versus those without CT (n=120), were differentiated as follows: (1). younger age at onset (P=0.005) and age at seeking help (P=0.05); (2). higher scores on HAM-D (P=0.03) and Rosenthal (atypical depressive) scale (P=0.007); (3). longer delay between onset of illness and recognition of bipolarity (P=0.0002); (4). higher rate of psychiatric comorbidity (P=0.04); (5). different profiles on axis II (i.e., more histrionic, passive-aggressive and less obsessive-compulsive personality disorders). Family history for depressive and bipolar disorders did not significantly distinguish the two groups; however, chronic affective syndromes were significantly higher in BP-II with CT. Finally, cyclothymic BP-II scored significantly much higher on irritable-risk-taking than "classic" driven-euphoric items of hypomania. CONCLUSION: Depressions arising from a cyclothymic temperament-even when meeting full criteria for hypomania-are likely to be misdiagnosed as personality disorders. Their high familial load for affective disorders (including that for bipolar disorder) validate the bipolar nature of these "cyclothymic depressions." Our data support their inclusion as a more "unstable" variant of BP-II, which we have elsewhere termed "BP-II 1/2." These patients can best be characterized as the "darker" expression of the more prototypical "sunny" BP-II phenotype. Coupled with the data from our companion paper (Hantouche et al., 2003, this issue), the present findings indicate that screening for cyclothymia in major depressive patients represents a viable approach for detecting a bipolar subtype that could otherwise be mistaken for an erratic personality disorder. Overall, our findings support recent international consensus in favoring the diagnosis of cyclothymic and bipolar II disorders over erratic and borderline personality disorders when criteria for both sets of disorders are concurrently met." [Abstract]

Hantouche EG, Angst J, Akiskal HS.
Factor structure of hypomania: interrelationships with cyclothymia and the soft bipolar spectrum.
J Affect Disord 2003 Jan;73(1-2):39-47
"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 conditions." [Abstract]

Perugi G, Akiskal HS.
The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II and related conditions.
Psychiatr Clin North Am 2002 Dec;25(4):713-37
"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." [Abstract]

Kilzieh N, Akiskal HS.
Rapid-cycling bipolar disorder. An overview of research and clinical experience.
Psychiatr Clin North Am. 1999 Sep;22(3):585-607.
"Although many studies of RCBD have been reported over the last 2 decades, knowledge remains limited. Higher incidence in women is the sole clearly replicated finding in most studies. This finding might be mediated by cyclothymia, a temperament that is of higher prevalence in women and that might be considered as a normal variant of RC. Many questions remain unanswered. Review of putative risk factors, such as hypothyroidism and treatment with antidepressants, provides no conclusive answers. There is clinical evidence to implicate both factors. In principle, the thyroid connection can be approached rationally, yet there seems to be no relationship between thyroid status and response to thyroid augmentation. For this reason and given the potential risks of long-term thyroid use, this strategy should not be the first one to be tried in RC. Cumulatively, naturalistic studies over the past 30 years have strongly implicated antidepressants in switching and cycle acceleration, yet the double-blind, controlled, prospective studies that are needed to provide definitive answers are unlikely to be conducted for ethical reasons discussed in this article. Bipolar family history of RC probands appears indistinguishable from non-RC probands, indicating that most likely RCBD does not breed true. Although RC seems to be more lithium resistant with less likelihood of being symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless have resolution of the RC course. There is no marked difference in suicide rates. An association of RC with bipolar type II, D-M-I pattern and those who switch into mania or hypomania on antidepressants is a provocative possibility: Antidepressants might introduce RC by first inducing a switch during a depressive episode, creating a D-M-I pattern, a pattern that is poorly responsive to lithium, which eventually degenerates into RC. Again, this sequence might be mediated by the high prevalence of cyclothymia in bipolar II patients. Thus, data from phenomenology, family history, and long-term outcome do not support RC as a separate entity. RC appears to be a temporary complicated phase in the illness, not a stable feature. This was noted by Kraepelin: I think I am convinced that that kind of classification must of necessity wreck on the irregularity of the disease. The kind and duration of the attacks and the intervals by no means remain the same in the individual case but may frequently change, so that the case must be reckoned always to new forms. Data by Gottschalk et al testify to the chaotic mood swings of contemporary bipolar disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in which patients have phases of increase in frequency of episodes (seizures) that become refractory to treatment. Further longitudinal prospective studies are required to understand the complexity of this intriguing phenomenon and to provide better treatments. Algorithms deriving from tertiary research or university-based clinical experience may not generalize to RC or otherwise treatment-resistant bipolar patients seen in more routine practice. Illness severity in RCBD generally precludes double-blind controlled investigations. Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining patients on combined mood stabilizers--of which valproate is probably the most useful--and making judicious use of atypical neuroleptics. Benzodiazepines and alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright light, and sleep deprivation during excited phases should be avoided. Thyroid and nimodipine augmentation can be considered in those with the most malignant course. These are patients who need the maximal support that their psychiatrist can provide them. Office visits must be arranged as the last appointment of the day." [Abstract]

Savino M, Perugi G, Simonini E, Soriani A, Cassano GB, Akiskal HS.
Affective comorbidity in panic disorder: is there a bipolar connection?
J Affect Disord. 1993 Jul;28(3):155-63.
"Although theoretical explanations for comorbidity in panic disorder (PD) abound in the literature, the complex clinical challenges of these patients have been neglected, especially where panic, obsessive-compulsive and 'soft' bipolar (e.g., hypomanic, cyclothymic and hyperthymic) conditions might co-exist. The aim of the present study has been to systematically explore the spectrum of intra-episodic and longitudinal comorbidity of 140 DSM-III-R PD patients--67.1% of whom concomitantly met the criteria for Agoraphobia--and who were consecutively admitted to the ambulatory service of the Psychiatric Clinic of the University of Pisa over a 2-year period. Comorbidity with strictly defined anxiety disorders--i.e., not explained as mere symptomatic extensions of PD--was relatively uncommon, and included Simple Phobia (10.7%), Social Phobia (6.4%), Generalized Anxiety Disorder (3.6%), and Obsessive-Compulsive Disorder (4.2%). Comorbidity with Major Depression--strictly limited to the melancholic subtype--occurred in 22.9%. Comorbidity with Bipolar Disorders included 2.1% with mania, 5% with hypomania, as well as 6.4% with cyclothymia, for a total of 13.5%; an additional 34.3% of PD patients met the criteria for hyperthymic temperament. We submit that such comorbid patterns are at the root of unwieldy clinical constructs like 'atypical depression' and 'borderline personality'. The relationship of panic disorder to other anxious-phobic and depressive states has been known for some time. Our data extend this relationship to soft bipolar disorders. Studies from other centers are needed to verify that the proposed new link is not merely due to referral bias to a tertiary university setting." [Abstract]

Young LT, Cooke RG, Robb JC, Levitt AJ, Joffe RT.
Anxious and non-anxious bipolar disorder.
J Affect Disord. 1993 Sep;29(1):49-52.
"Eighty-one outpatients with bipolar disorder (BD) were grouped by SADS anxiety symptom scores (high vs. low) or diagnosis of generalized anxiety disorder, and/or panic disorder. BD patients with high anxiety scores were more likely to have suicidal behaviour (44% vs. 19%), alcohol abuse (28% vs. 6%), cyclothymia (44% vs. 21%) and an anxiety disorder (56% vs. 25%) with a trend toward lithium non-responsiveness. Diagnosis of an anxiety disorder was related only to high anxiety and lower GAS scores. Thus, anxiety may have similar clinical relevance in BD as it does in unipolar patients." [Abstract]

Hantouche EG, Angst J, Demonfaucon C, Perugi G, Lancrenon S, Akiskal HS.
Cyclothymic OCD: a distinct form?
J Affect Disord. 2003 Jun;75(1):1-10.
"BACKGROUND: Clinical research on the comorbidity of obsessive compulsive disorder (OCD) and other anxiety disorders has largely focused on depression. However in practice, resistant or severe OCD patients not infrequently suffer from a masked or hidden comorbid bipolar disorder. METHOD: The rate of bipolar comorbidity in OCD was systematically explored among 453 members of the French Association of patients suffering from OCD (AFTOC) as well as a psychiatric sample of OCD out-patients (n=175). As previous research by us has shown the epidemiologic and clinical sample to be similar, we combined them in the present analyses (n=628). To assess mood disorder comorbidity, we used structured self-rated questionnaires for major depression, hypomania and mania (DSM-IV criteria), self-rated Angst's checklist of Hypomania and that for the Cyclothymic Temperament (French version developed by Akiskal and Hantouche). RESULTS: According to DSM-IV definitions of hypomania/mania, 11% of the total combined sample was classified as bipolar (3% BP-I and 8% BP-II). When dimensionally rated, 30% obtained a cut-off score >/=10 on the Hypomania checklist and 50% were classified as cyclothymic. Comparative analyses were conducted between OCD with (n=302) versus without cyclothymia (n=272). In contrast to non-cyclothymics, the cyclothymic OCD patients were characterized by more severe OCD syndromes (higher frequencies of aggressive, impulsive, religious and sexual obsessions, compulsions of control, hoarding, repetition); more episodic course; greater rates of manic/hypomanic and major depressive episodes (with higher intensity and recurrence) associated with higher rates of suicide attempts and psychiatric admissions; and finally, a less favorable response to anti-OCD antidepressants and elevated rate of mood switching with aggressive behavior. LIMITATION: Hypomania and cyclothymia were not confirmed by diagnostic interview by a clinician. CONCLUSION: Our data extend previous research on "OCD-bipolar comorbidity" as a highly prevalent and largely under-recognized and untreated class of OCD patients. Furthermore, our data suggest that "cyclothymic OCD" could represent a distinct form of OCD. More attention should be paid to it in research and clinical practice." [Abstract]

Hantouche EG, Kochman F, Demonfaucon C, Barrot I, Millet B, Lancrenon S, Akiskal HS.
[Bipolar obsessive-compulsive disorder: confirmation of results of the "ABC-OCD" survey in 2 populations of patient members versus non-members of an association]
Encephale 2002 Jan-Feb;28(1):21-8
"Clinical data are largely focused on depressive comorbidity in OCD. However in practice, treating resistant or severe OCD sufferers revealed many cases who seem to have an authentic OCD with a hidden comorbid bipolar disorder. Most reports had evaluated the OCD comorbidity in unipolar and bipolar mood disorders (Kruger et al., 1995; Chen et Dilsaver, 1995). The only investigation in clinical population focused on the reverse issue was conducted in Pisa. Perugi et al. (1997) have showed in a consecutive series of 315 OCD outpatients, that 15.7% presented a bipolar comorbidity, mostly with BP-II disorder. Further analyses suggested that when comorbidity occurs with bipolar and unipolar depression, it has a differential impact on the clinical picture and course of OCD. The rate of bipolar comorbidity in OCD was analyzed in a recent epidemiological survey undertaken by the French Association of patients suffering from OCD (FA-OCD or AFTOC in French). In a sample of 453 OCD patients, 76% had suffered from a major depression, 11% from bipolar disorder (DSM IV mania or hypomania), 30% from hypomania (cases that obtained a score > or = 10 on the self-rated Angst Hypomania Checklist). According to the score > or = 10 on Self-rated Questionnaire for Cyclothymic Temperament, 50% were classified as cyclothymic. The self-assessment of soft-bipolar dimensions, such as hypomania and cyclothymia was previously validated in a multi-site study in major depression (Hantouche et al., 1998). Further analyses showed that comorbidity with soft bipolarity was characterized by significant interactions with high levels of impulsivity, anger attacks and suicidal behavior. In order to confirm these data, another cohort (n = 175 patients treated by psychiatrists for OCD) was formed and named "PSY-OCD". Comparative analyses between the two populations allowed showing very few demographic and clinical differences. The frequency rate of "bipolar OCD" was equivalent in both populations: BP-II disorder (DSM IV criteria) was present in 11% of FA-OCD and 16% of PSY-OCD. Furthermore using the Hypomania Checklist showed that BP-II disorder rate (score > or = 10) was higher: 32% of in both populations. Cyclothymic rate was also globally higher, but significant difference was obtained: 56% of FA-OCD versus 45% of PSY-OCD (p = 0.02). Moreover, mood switching rate under anti-OCD drugs was equivalent in both OCD populations (respectively 38% and 33%, p = ns). In case of BP comorbidity, patients had presented a greater number of concurrent major depressive episodes and suicidal attempts. When concurrent depression was considered, the rate diagnosis of soft bipolarity was 2.5 fold, and the number of suicidal attempts augmented by 7 fold (by comparison versus non-depressed OCD). Despite very early descriptions (since the beginning of the last century) of particular relationships between so-called "psychasthenia, folie de doute, folie raisonnante" and "circular and intermittent madness or cyclothymia", a few attention has been devoted to this complex pattern of comorbidity. The comparative data deriving from the collaborative survey with patients who are members of AFTOC and with a cohort of psychiatric outpatients, confirm the reality of bipolar-OCD comorbidity, which is largely under-recognized in clinical practice. More in depth analyses are now undertaken in order to investigate the characteristics of "bipolar OCD" by comparison to "non bipolar OCD"." [Abstract]

Hantouche EG, Demonfaucon C, Angst J, Perugi G, Allilaire JF, Akiskal HS.
[Cyclothymic obsessive-compulsive disorder. Clinical characteristics of a neglected and under-recognized entity]
Presse Med 2002 Apr 13;31(14):644-8
"OBJECTIVE: Clinical research is largely focused on depressive comorbidity in obsessional compulsive disorder (OCD). However some recent publications have suggested that bipolar comorbidity occurs in authentic OCD and its presence has a differential impact on the clinical picture and course of OCD. METHOD: Recent data from the collaborative survey conducted with AFTOC (French Association of patients suffering from OCD) have revealed a high rate of bipolar comorbidity in OCD: 30% for hypomania and 50% for cyclothymia. RESULTS: The present paper presents further comparative analyses between OCD with (n = 302) versus without cyclothymia (n = 272). The sub-group "Cyclothymic OCD" is characterized by a different clinical picture (higher frequency of aggressive, impulsive, religious and sexual obsessions, and compulsions of control, hoarding, repetition), episodic course, higher rate of major depressive episodes (with more intensity and recurrence) associated with higher rates of suicide attempts and psychiatric admissions, and less favorable response to anti-OCD treatments. CONCLUSION: These data suggested that cyclothymic OCD could represent a specific distinct variant form of OCD. More vigilance is needed toward this entity which is largely under-recognized in clinical practice." [Abstract]