Is there a continuity between bipolar and depressive disorders?

BACKGROUND: Recent studies questioned the current categorical split of mood disorders into bipolar disorders (BP) and depressive disorders (MDD). METHODS: Medline database search of papers from the last 10 years on the categorical-dimensional classification of mood disorders. Various combinations of the following key words were used: mood disorders, bipolar, unipolar, major depressive disorder, spectrum, category/categorical, classification, continuity. Only English language clinical papers were included, review papers were excluded, similar papers selected by quality. The number of papers found was 1,141. The number of papers selected was 109. RESULTS: The continuity/spectrum between BP (mainly BP-II) and MDD was supported by the following findings:(1) high frequency of mixed states (mixed mania, mixed hypomania, mixed depression, i.e. co-occurring depression and noneuphoric manic/hypomanic symptoms) because opposite polarity symptoms in the same episode do not support a hypomania/mania-depression splitting; (2) MDD was the most common mood disorder in BP probands' relatives; (3) no bimodal distribution of distinguishing symptoms between BP and MDD; (4) bipolar signs not uncommon in MDD; (5) many MDD shifting to BP; (6) many lifetime manic/hypomanic symptoms in MDD; (7) correlation between lifetime manic/hypomanic symptoms and MDD symptoms; (8) hypomania factors in MDD; (9) MDD often recurrent; (10) similar cognitive style.The categorical distinction between BP (mainly BP-I) and MDD was supported by the following findings: (1) BP more common in BP probands' relatives; (2) lower age at BP onset; (3) females as common as males in BP-I, more common than males in MDD; (4) BP-I depression more atypical and retarded, MDD depression more sleepless and agitated; (5) BP more recurrent. CONCLUSIONS: Focusing on mood spectrum's extremes (BP-I vs. MDD), a categorical distinction seems supported. Focusing on midway disorders (BP-II and MDD plus bipolar signs), a continuity/spectrum seems supported. Results seem to support both a categorical and a dimensional view of mood disorders.     

Clinical variables related to antidepressant-induced mania in bipolar disorder

BACKGROUND: The development of mania or hypomania during antidepressant treatment is a serious complication of the clinical management of bipolar disorder (BP). The primary aim of this study was to evaluate the clinical variables related to antidepressant-induced mania or hypomania (AIM) in patients with BP. METHODS: DSM-IV BP-I or BP-II patients who had had at least one depressive episode treated with antidepressants were considered. Patients were subdivided into two groups according to the presence (n = 30) or absence (n = 106) of manic or hypomanic episodes occurring during antidepressant treatment. Possible predictive clinical variables of AIM were considered: gender, diagnostic subtype, age at onset, duration of illness, duration of untreated illness, type of antidepressant administered, number of previous spontaneous hypomanic or manic episodes, number of previous depressive episodes, presence of lifetime suicide attempts, presence of mood stabilizer treatments, presence of psychotic symptoms during spontaneous episodes, family history for psychiatric disorders in first degree relatives. Data were compared between the two groups, with (AIM+) and without (AIM-) antidepressant-induced mania, using Student's t tests and chi-square tests. RESULTS: The lack of mood stabilizer treatments during antidepressant therapy (chi-square = 37.602, df = 1, p < 0.001) and the exposure to tricyclic antidepressants (chi-square = 4.901, df = 1, p < 0.05) resulted significantly associated to the development of AIM. LIMITATIONS: This study was not done under controlled conditions and the relatively small sample studied warrants further replications. CONCLUSIONS: These results point out the risk of mania induction associated to the use of tricyclic antidepressants in BP patients, mainly in absence of adequate mood stabilizers.     

How best to identify a bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset criterion over recurrence and polarity?

BACKGROUND: History of high depressive recurrence (without history of mania/hypomania) has been proposed as a mood subtype close to bipolar disorders. Herein we test whether this is the best approach to this question. METHODS: We systematically evaluated consecutive 224 Major Depressive (MDD) and 336 Bipolar II Disorders (BP-II) outpatients in a private practice, by the SCID for DSM-IV (modified for better probing hypomania by Akiskal and Benazzi [Akiskal, H.S., Benazzi, F., 2005. Optimizing the detection of bipolar II disorder in outpatient private practice: toward a systematization of clinical diagnostic wisdom. J. Clin. Psychiatry 66, 914-921]). We conducted univariate and multivariate analyses on such putative bipolar validators as early age at onset of first major depressive episode (before 21 years), high recurrence, family history for bipolar disorders, and depressive mixed states (mixed depression, i.e. depression plus concurrent hypomanic symptoms), in order to identify an MDD subgroup close to BP-II. RESULTS: All bipolar validators were independent predictors of BP-II. Early onset was the only variable which identified an MDD subgroup significantly associated with all bipolar validators. This MDD subgroup was similar to BP-II on age at onset and bipolar family history, and had a high frequency of mixed depression. A dose-response relationship was found between number of bipolar validators present in MDD, and bipolar family history loading among MDD relatives. LIMITATIONS: Study limited to outpatients. CONCLUSIONS: From among the bipolar validators, early age at onset of first major depression (<21 years) was superior to high recurrence (>4 depressive episodes) in identifying an MDD subgroup close to BP-II, which might be subsumed under the broad bipolar spectrum. Implications of unipolar-bipolar boundaries and genetic investigations are discussed.     

The distinct temperament profiles of bipolar I, bipolar II and unipolar patients

BACKGROUND: Despite a plethora of studies, controversies abound on whether the long-term traits of unipolar and bipolar patients could be differentiated by temperament and whether these traits, in turn, could be distinguished from subthreshold affective symptomatology. METHODS: 98 bipolar I (BP-I), 64 bipolar II (BP-II), and 251 unipolar major depressive disorder (UP-MDD) patients all when recovered from discrete affective episodes) and 617 relatives, spouses or acquaintances without lifetime RDC diagnoses (the comparison group, CG) were administered a battery of 17 self-rated personality scales chosen for theoretical relevance to mood disorders. Subsamples of each of the four groups also received the General Behavior Inventory (GBI). RESULTS: Of the 436 personality items, 103 that significantly distinguished the three patient groups were subjected to principal components analysis, yielding four factors which reflect the temperamental dimensions of "Mood Lability", "Energy-Assertiveness," "Sensitivity-Brooding," and "Social Anxiety." Most BP-I described themselves as near normal in emotional stability and extroversion; BP-II emerged as labile in mood, energetic and assertive, yet sensitive and brooding; MDD were socially timid, sensitive and brooding. Gender and age did not have marked influence on these overall profiles. Within the MDD group, those with baseline dysthymia were the most pathological (i.e., high in neuroticism, insecurity and introversion). Selected GBI items measuring hypomania and biphasic mood changes were endorsed significantly more often by BP-II. Finally, it is relevant to highlight a methodologic finding about the precision these derived temperament factors brought to the UP-BP differentiation. Unlike BP-I who were low on neuroticism, both BP-II and UP scored high on this measure: yet, in the case of BP-II high neuroticism was largely due to mood lability, in UP it reflected subdepressive traits. LIMITATION: We used self-rated personality measures, a possible limitation generic to the paper-and-pencil personality literature. It is therefore likely that BP-I may have over-rated their "sanguinity"; or should one consider such self-report as a reliable reflection of one's temperament? One can raise similar unanswerable questions about "depressiveness" and "mood lability." CONCLUSION: As contrasted to CG and published norms, the postmorbid self-described "usual" personality is 1) sanguine among many, but not all, BP-I; 2) labile or cyclothymic among BP-II; and 3) subanxious and subdepressive among UP. It is further noteworthy that with the exception of BP-II, the temperament scores of BP-I and MDD were within one SD from published norms. Rather than being pathological, these attributes are best conceived as subclinical temperamental variants of the normal, thereby supporting the notion of continuity between interepisodic and episodic phases of affective disorders. These findings overall are in line with Kraepelin's views and contrary to the DSM-IV formulation of axis-II constructs as being pathological and sharply demarcated from affective episodes.     

The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions

The depressive expressions of bipolar disorders have long been neglected. Current data, from both clinical and epidemiologic studies, indicate that such expressions far exceed the manic forms in both cross-section and during follow-up course. Thus, mania occurs in 1% of the population at large; bipolar depression afflicts at least 5 times more people. Much of the new literature on this subject has emphasized its high prevalence, morbidity, and mortality. There has been relatively less attention paid to the phenomenology of bipolar depression as it presents clinically. This special issue (volume 84/2-3, 2005) is devoted to a systematic data-based in-depth examination of the different clinical expressions of bipolar depression including, among others, retarded depression, agitated and/or activated depression, mood-labile depression, irritable-hostile depression, atypical depression, anxious depression, depressive mixed state, and resistant depression. Both bipolar I (BP-I), and the more prevalent yet relatively understudied bipolar II (BP-II), are covered. We trust that this extensive coverage of the "darker" side of bipolarity will set the stage for a much needed renaissance in its complex phenotypic expressions-and its delimitation from unipolar depression (UP). The phenomenology of BP-I depression ranges from depressive stupor to agitated psychosis, whereas UP depression expresses itself in psychic anxiety, and insomnia, as well as retardation. BP-II compared with UP is more likely to have atypical features, mood lability, hostility, activation, biographical instability, multiple anxiety comorbidities, suicidal tendencies, and to be rated as less "objectively" depressed. These findings are complex and do not fully agree with the conventional characterization of BP as retarded and UP as anxious and agitated. The inconsistency between the conventional and the phenomenology described herein is largely due to depressive mixed states, which tend to destabilize BP-II, and may account for the "contradictory" relationships of affect, sleep, drive, and psychomotor activity in mood disorders.     

Distinguishing bipolar and unipolar disorders: an isomer model

BACKGROUND: As division between unipolar and bipolar disorders can be problematic, we sought to develop a self-report questionnaire of mood 'highs' that would both distinguish true Bipolar Disorder from any elevated mood states in unipolar depression and sharpen the distinction between Bipolar I and II conditions. METHOD: A 46-item questionnaire was developed and completed by 157 out-patients presenting with a major depressive episode, and clinically diagnosed as having either Bipolar I (BP-I), Bipolar II (BP-II) or Unipolar (UP) depression, although DSM-IV duration criteria for BP-I and BP-II were not imposed. RESULTS: Factor analyses identified four key constructs to mood 'highs', while additional analyses refined the questionnaire to 27 items. The refined measure was highly accurate in distinguishing composite Bipolar (BP-I and BP-II) from UP subjects (AUC = 0.93, sensitivity = 81%; specificity = 98%, positive predictive value = 0.95). Questionnaire scores were similar for BP-I and BP-II subjects, raising the possibility that the core mood state differs little in severity across the two expressions, and that their distinction allows an alternative model that weights the presence or absence of psychotic features. CONCLUSIONS: Our study advances understanding of boundary distinctions between bipolar and unipolar mood disorders, and between BP-I and BP-II conditions, and allows consideration of a model distinguishing BP-I from BP-II by the presence of psychotic features only. The described model is the mirror image of a hierarchical structural model for conceptualizing psychotic and melancholic depression, allowing an 'isomer model' for linking the mood swing states.     

Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes

BackgroundThere is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.MethodsBipolar (type I or II) patients with an MDE at intake (N = 142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.ResultsSubsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.LimitationsThe findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.ConclusionsThe presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.     

Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works

Bipolar disorder, characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems, is a recurrent and often becomes chronic psychiatric illness. However, bipolar subtypes are not often recognized in psychiatric settings, especially bipolar II subtype, until Akiskal and Angst made clear definition to bipolar I (BP-I) and bipolar II (BP-II) disorder in 1999. More and more studies, not only on family inheritance, diagnosis, but also on disease process have been reported that BP-I and BP-II are two different disorders with distinct pathological mechanisms. In general, patients with BP-II express less symptoms and have shorter hypomania stages than BP-I. According to a longitudinal research, patients with BP-II have poor recovery than do BP-I patients. Memantine used to be recognized as a noncompetitive N-methyl-d-aspartate receptor antagonist. However, it was found to have neuroprotective and neurogenesis effect in several neurodegenerative diseases in the past years. We found that memantine could inhibit brain inflammatory response through its action on neuroglial cells and provide neurotrophic effect. The above evidences of benefit on auto-immune system with memantine would support that memantine as add-on therapy to valproate might be more effective than valproate alone on improvement of the neuron degeneration in bipolar disorders. Review articles indicate that not only the mood stabilizers provide with good neuroprotection, but the memantine also have conspicuous anti-autoimmune and neurogenesis effect. Therefore, we propose that drugs with neuroprotective effect and neurotrophic effect may treat neurodegenerative diseases including BP-II. The combination treatment of mood stabilizers memantine may not only augment and improve the remedy for bipolar disorders, but also repair the damaged neurons and neurogenesis through activation of astroglial cell and release of neurotrophic factors.     

The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders: evidence that they lie on a dimensional spectrum

BACKGROUND: Presently it is a hotly debated issue whether unipolar and bipolar disorders are categorically distinct or lie on a spectrum. We used the ongoing Ravenna-San Diego Collaboration database to examine this question with respect to major depressive disorder (MDD) and bipolar II (BP-II). METHODS: The study population in FB's Italian private practice setting comprised consecutive 650 outpatients presenting with major depressive episode (MDE) and ascertained by a modified version of the Structured Clinical Interview for DSM-IV. Differential assignment of patients into MDD versus BP-II was made on the basis of discrete hypomanic episodes outside the timeframe of an MDE. In addition, hypomanic signs and symptoms during MDE (intra-MDE hypomania) were systematically assessed and graded by the Hypomania Interview Guide (HIG). The frequency distributions of the HIG total scores in each of the MDD, BP-II and the combined entire sample were plotted using the kernel density estimate. Finally, bipolar family history (BFH) was investigated by structured interview (the Family History Screen). RESULTS: There were 261 MDD and 389 BP-II. As in the previous smaller samples, categorically defined BP-II compared with MDD had significantly earlier age at onset, higher rates of familial bipolarity (mostly BP-II), history of MDE recurrences (>or=5), and atypical features. However, examining hypomania scores dimensionally, whether we examined the MDD, BP-II, or the combined sample, kernel density estimate distribution of these scores had a normal-like shape (i.e., no bimodality). Also, in the combined sample of MDE, we found a dose-response relationship between BFH loading and intra-MDE hypomania measured by HIG scores. LIMITATIONS: Although the interviewer (FB) could not be blind to the diagnostic status of his private patients, the systematic rigorous interview process in a very large clinical population minimized any unintended biases. CONCLUSIONS: Unlike previous studies that have examined the number of DSM-IV hypomanic signs and symptoms both outside and during MDE, the present analyses relied on the more precise hypomania scores as measured by the HIG. The finding of a dose-response relationship between BFH and HIG scores in the sample at large strongly suggests a continuity between BP-II and MDD. Our data indicate that even in those clinically depressed patients without past hypomanic episodes (so-called "unipolar" MDD), such scores are normally rather than bimodally distributed during MDE. Moreover, the absence of a 'zone of rarity' in the distribution of hypomanic scores in the combined total, MDD and BP-II MDE samples, indicates that MDD and BP-II exist on a dimensional spectrum. From a nosologic perspective, our data are contrary to what one would expect from a categorical unipolar-bipolar distinction. In practical terms, intra-MDE hypomania and BFH, especially in recurrent MDD, represent strong indicators of bipolarity.     

The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients

BACKGROUND: Bipolar disorders (BP) are frequently diagnosed and treated as pure depression initially; accurate diagnosis often being delayed by 8 to 10 years. In prospective studies, the presence of hypomanic symptoms in adolescence is strongly predictive of later bipolar disorders. As such, an instrument for self-assessment of hypomanic symptoms might increase the detection of suspected and of manifest, but under-treated, cases of bipolar disorders. METHODS: The multi-lingual hypomania checklist (HCL-32) has been developed and is being tested internationally. This preliminary paper reports the performance of the scale in distinguishing individuals with BP (N=266) from those with major depressive disorder (MDD; N=160). The samples were adult psychiatry patients recruited in Italy (N=186) and Sweden (N=240). RESULTS: The samples reported similar clinical profiles and the structure for the HCL-32 demonstrated two main factors identified as "active/elated" hypomania and "risk-taking/irritable" hypomania. The HCL-32 distinguished between BP and MDD with a sensitivity of 80% and a specificity of 51%. LIMITATIONS: Although the HCL-32 is a sensitive instrument for hypomanic symptoms, it does not distinguish between BP-I and BP-II disorders. CONCLUSIONS: Future studies should test if different combinations of items, possibly recording the consequences of hypomania, can distinguish between these BP subtypes.     

Validating the bipolar spectrum in the French National EPIDEP Study: overview of the phenomenology and relative prevalence of its clinical prototypes

BACKGROUND: Few studies have been undertaken to ascertain the feasibility of using the bipolar (BP) spectrum in clinical practice. The only systematic national study is the French EPIDEP Study of consecutive inpatients and outpatients presenting with major depressive episodes (MDE). The protocol was developed in 1994 and implemented in 1995; publication of its first data began in 1998. This report provides the complete data set of the EPIDEP. METHODS: Forty-eight psychiatrists, practicing in 15 sites in four regions of France (Paris, Besan?on, Bordeaux and Marseille), were all trained on a common protocol based on DSM-IV criteria for MDE (n=537) subdivided into BP-I (history of mania), BP-II (history of hypomania), as well as extended definitions of the "softer spectrum" beyond BP-I and BP-II. Measures tapping into this spectrum included the Hypomania Checklist (HCA), the cyclothymic (CT), depressive (DT) and hyperthymic (HT) temperament scales. These measures and course permitted post-hoc assignment of MDE in the bipolar spectrum, based in part on the Akiskal, H.S., Pinto, O., 1999. [The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22, 517-534] proposal: depression with history of spontaneous hypomanic episodes (DSM-IV, BP-II), cyclothymic depressions (BP-II(1/2)), antidepressant-associated hypomania (BP-III) and hyperthymic depressions (BP-IV). was thereby limited to an exclusion diagnosis for the remainder of MDE. LIMITATION: In the clinical setting, psychiatrists cannot be entirely blind to the observations in the various clinical evaluations and instruments. However, the systematic multisite collection of such data tended to minimize any such biases. RESULTS: After excluding patients lost to follow-up, among 493 presenting with MDE with complete data files, the BP-II rate was estimated at index at 20%; 1 month later, systematic probing for hypomania doubled the rate of BP-II to 39%. The comparison between BP-II and UP showed differential phenomenology, such as hypersomnia, increased psychomotor activation, guilt feelings and suicidal thoughts in BP-II. Related data demonstrated the importance of CT in further qualifying of MDE to define a distinct, more severe ("darker") BP-II(1/2) variant of BP-II. Moreover, BP-III, arising from DT and associated with antidepressants, emerged as a valid soft bipolar variant on the basis of the phenomenology of hypomania and bipolar family history. Finally, we found preliminary evidence for the inclusion of BP-IV into the bipolar spectrum, its total hypomania score falling intermediate between BP-II and strict UP. Using this broader diagnostic framework, the bipolar spectrum (the combined "hard" BP-I phenotype, BP-II and the soft spectrum) accounted for 65% of MDE. CONCLUSION: The EPIDEP study achieved its objectives by demonstrating the feasibility of identifying the bipolar spectrum at a national level, and refining its phenomenology through rigorous clinical characterization and validation of bipolar spectrum subtypes, including MDE with brief hypomanias, cyclothymia and hyperthymia. The spectrum accounted for two out of three MDE, making "strict UP" less prevalent than BP as redefined herein. Our findings were anticipated by Falret, who in 1854 had predicted that many melancholic patients in the community would 1 day be classified in his circular group. We also confirmed Baillarger's observation in the same year that episodes (in this study, hypomanic episodes) could last as short as 2 days. Our findings deriving from a systematic French national database a century and a half later invite major shifts in clinical and public health services, as well as in the future conduct of psychopharmacologic trials. In this respect, the systematic training of clinicians in four regions of France represents a national resource for affective disorders and can serve as a model to effect change in diagnostic practice in other countries.     

Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states

BACKGROUND: Panic disorder (PD) occurs at high rates in bipolar disorder and more commonly than in unipolar depression. Reports of PD onset during hypomania and depressive mania (i.e., mixed states) raise questions about whether the affective disturbances of bipolar disorder play a specific role in the exacerbation or onset of PD. Anxiety sensitivity (AS), a risk factor for PD appears greater in bipolar disorder compared to unipolar depression, although the association of specific mood states with AS remains unknown. METHODS: We examined the association of current mood state (i.e., mixed state, mania or hypomania, bipolar depression, unipolar depression, and euthymia) with Anxiety Sensitivity Index (ASI) scores in 202 individuals with bipolar disorder (n=110) or major depressive disorder (n=92). RESULTS: Current mood state was significantly associated with ASI score (Chi-square=21.2, df=4, p=0.0003). In multiple regression analyses, including covariates for comorbid anxiety disorders, current mania or hypomania was a significant predictor of ASI scores (p<0.04). Current mixed state tended toward a similar association (p<0.10). LIMITATIONS: Conclusions are limited by the study's cross-sectional nature and relatively small sample size. CONCLUSIONS: These findings of elevated AS during manic states, independent of comorbid anxiety disorders, provide preliminary support for the hypothesis that manic states contribute to risk for the development or exacerbation of PD, and that AS may contribute to the high prevalence and severity of PD comorbid with bipolar disorder.     

The duration of hypomania in bipolar-II disorder in private practice: methodology and validation

BACKGROUND: DSM-IV 4-day minimum hypomania duration is not evidence-based. Epidemiologic data suggest that briefer hypomanias are prevalent in the community. We sought to find out the relative prevalence of short (2-3 days) versus long (>/=4 days) hypomanias in private practice. METHODS: 206 bipolar-II (BP-II) depressed outpatients (group B) and a group of 140 remitted BP-II (group R) were assessed with the DSM-IV Structured Clinical Interview, as modified by the authors. BP-II with short vs. longer hypomania were compared on such bipolar validators as early age at onset, depressive recurrence, atypical feature specifier, depressive mixed state and bipolar family history. In addition, to ascertain the bipolar status of depressed patients with brief hypomanias, we included a comparison group of 178 major depressive disorder (MDD) patients assessed when depressed. RESULTS: 27-30% of hypomanias (depending on whether assessment occurred when patients were depressed or in remission) had 2-3-day duration; 72% lasted less than 4 weeks. Except for the atypical feature specifier, BP-II with short vs. BP-II with longer hypomania were not significantly different on bipolar validators. Moreover, BP-II with short, like its longer hypomanic counterpart, was significantly different from the comparison MDD group on all bipolar indicators. LIMITATIONS: Single interviewer and retrospective evaluation of duration of hypomania. CONCLUSIONS: As BP-II patients almost never present clinically in a hypomanic episode, the retrospective assessment of the duration of these episodes is clinically unavoidable. Most hypomanias last from 2 days to a few weeks. BP-II with shorter vs. longer hypomanias had significantly higher rates of females, comorbidity and atypical features, but were otherwise indistinguishable on crucial bipolar validators. Furthermore, such validators, including bipolar family history, robustly distinguished BP-II with short hypomanias from the MDD group. The conservative 4-day threshold would misclassify one out of three BP-II as MDD. Such misclassification has relevant implications for treatment and outcome, as well as clinical research methodology for depressive and bipolar disorders.     

Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders

OBJECTIVE: The research literature on psychosocial disability and work in mood disorders has either focused on relatively short-term course, or did not consider direct comparisons of these domains across all three of the affective subtypes of bipolar I (BP-I), bipolar II (BP-II), and unipolar major depressive disorders (UP-MDD). METHODS: Mean composite measures of psychosocial impairment and months at specific levels of overall and work impairment were compared for 158 BP-I, 133 BP-II, and 358 UP-MDD patients based on semi-structured interviews conducted during 15 years of follow-up in the NIMH Collaborative Depression Study (CDS). These are contrasted with a single month of psychosocial impairment ratings for a sample of 1787 subjects with no current psychiatric disorder. RESULTS: Patients with mood disorders experienced some degree of disability during the majority of long-term follow-up (54 to 59% of months), including 19 to 23% of months with moderate and 7 to 9% of months with severe overall impairment. Severe disability occurred a substantial percentage of time only in the specific area of work role function. BP-I patients were completely unable to carry out work role functions during 30% of assessed months, which was significantly more than for UP-MDD and BP-II patients (21% and 20%, respectively). CONCLUSIONS: These findings have public health, economic, and clinical importance, and underscore the need to reduce the chronicity and impairment associated with these three prevalent affective disorder subtypes. Interventional research is just beginning to address these challenges.     

Bipolar II with and without cyclothymic temperament: "dark" and "sunny" expressions of soft bipolarity

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.     

Cyclothymic OCD: a distinct form?

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.     

A prospective study of the transition rates of subthreshold (hypo)mania and depression in the general population

BACKGROUND: Previous work suggests that subthreshold depression and subthreshold (hypo)mania are common, although little is known about the prognosis in terms of transition to clinical disorder. This paper presents data on the temporal relationship between subthreshold and clinical expression of mood phenotypes. METHOD: In a random general population sample of 7076 individuals, symptoms of depression and (hypo)mania were measured with the Composite International Diagnostic Interview (CIDI) at baseline, after 1 year, and 2 years later. RESULTS: At baseline, the lifetime prevalences of depressive and (hypo)manic symptoms were 17.2% and 1.2% respectively. Predictive values of mood symptoms for a DSM-III-R mood disorder ranged from 14.3% to 50%. (Hypo)manic mood symptoms had much higher predictive values than unipolar manifestations, not only for bipolar disorder but also for major depression. CONCLUSIONS: The subthreshold expressions of depression and (hypo)mania are prevalent and continuous with more severe clinical states. The cross-prediction of mood symptoms may support a continuum from depressive to (hypo)manic symptoms. The high predictive value of (hypo)manic symptoms for mood disorders suggests that the experience of (hypo)manic symptoms is a stronger indicator of vulnerability for mood dysregulation than the experience of depressive symptoms.     

Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II)

BACKGROUND: According to DSM-IV and ICD-10, hypomania which occurs solely during antidepressant treatment does not belong to the category of bipolar II (BP-II). METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 144 (29.2%) fulfilled the criteria for bipolar II with spontaneous hypomania (BP-II Sp), and 52 (10.5%) had hypomania associated solely with antidepressants (BP-H AA). RESULTS: BP-II Sp group had earlier age at onset, more hypomanic episodes, and higher ratings on cyclothymic and hyperthymic temperaments, and abused alcohol more often. The two groups were indistinguishable on the hypomania checklist score (12.2+/-4.0 vs. 11.4+/-4.4, respectively, P=0.25) and on rates of familial bipolarity (14.1% vs. 11.8%, respectively, P=0.68). But BP-H AA had significantly more family history of suicide, had higher ratings on depressive temperament, with greater chronicity of depression, were more likely to be admitted to the hospital for suicidal depressions, and were more likely to have psychotic features; finally, clinicians were more likely to treat them with ECT, lithium and mood stabilizing anticonvulsants. LIMITATION: Naturalistic study, where treatment was uncontrolled. CONCLUSION: BP-H AA emerges as a disorder with depressive temperamental instability, manifesting hypomania later in life (and, by definition, during pharmacotherapy only). By the standards of clinicians who have taken care of these patients for long periods of time, BP-H AA appears as no less bipolar than those with prototypical BP-II. We submit that familial bipolarity ('genotypic' bipolarity) strongly favors their inclusion within the realm of bipolar II spectrum, as a prognostically less favorable depression-prone phenotype of this disorder, and which is susceptible to destabilization under antidepressant treatment. These considerations argue for revisions of DSM-IV and ICD-10 conventions. BP-HAA may represent a genetically less penetrant expression of BP-II; phenotypically; it might provisionally be categorized as bipolar III.