Coping with the New Era: Noise and Light Pollution, Hperactivity and Steroid Hormones. Towards an Evolutionary View of Bipolar Disorders.

Human population is increasing in immense cities with millions of inhabitants, in which life is expected to run 24 hours a day for seven days a week (24/7). Noise and light pollution are the most reported consequences, with a profound impact on sleep patterns and circadian biorhythms. Disruption of sleep and biorhythms has severe consequences on many metabolic pathways. Suppression of melatonin incretion at night and the subsequent effect on DNA methylation may increase the risk of prostate and breast cancer. A negative impact of light pollution on neurosteroids may also affect mood. People who carry the genetic risk of bipolar disorder may be at greater risk of full-blown bipolar disorder because of the impact of noise and light pollution on sleep patterns and circadian biorhythms. However, living in cities may also offers opportunities and might be selective for people with hyperthymic temperament, who may find themselves advantaged by increased energy prompted by increased stimulation produced by life in big cities. This might result in the spreading of the genetic risk of bipolar disorder in the coming decades. In this perspective the burden of poor quality of life, increased disability adjusted life years and premature mortality due to the increases of mood disorders is the negative side of a phenomenon that in its globality also shows adaptive aspects. The new lifestyle also influences those who adapt and show behaviors, reactions and responses that might resemble the disorder, but are on the adaptive side.

More inclusive bipolar mixed depression definitions by requiring fewer non-overlapping mood elevation symptoms.

OBJECTIVE: Assess strengths and limitations of mixed bipolar depression definitions made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by requiring fewer than three 'non-overlapping' mood elevation symptoms (NOMES). METHOD: Among bipolar disorder (BD) out-patients assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using less inclusive (≥3 NOMES, DSM-5), more inclusive (≥2 NOMES), and most inclusive (≥1 NOMES) definitions. RESULTS: Among 153 depressed BD, compared to less inclusive DSM-5 threshold, our more and most inclusive thresholds, yielded approximately two- and five-fold higher mixed depression rates (7.2%, 15.0%, and 34.6% respectively), and important statistically significant clinical correlates for mixed compared to pure depression (e.g. more lifetime anxiety disorder comorbidity, more current irritability), which were not significant using the DSM-5 threshold. CONCLUSION: Further studies assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including assessing the extent to which enhanced statistical power vs. other factors contributes to more vs. less inclusive mixed bipolar depression thresholds having more statistically significant clinical correlates, and whether 'overlapping' mood elevation symptoms should be counted.

More inclusive bipolar mixed depression definition by permitting overlapping and non-overlapping mood elevation symptoms.

OBJECTIVE: The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability). METHODS: Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions. RESULTS: Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold. CONCLUSION: To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.

Bipolar disorder with frequent mood episodes in the national comorbidity survey replication (NCS-R).

Virtually nothing is known about the epidemiology of rapid cycling bipolar disorder (BPD) in community samples. Nationally representative data are reported here for the prevalence and correlates of a surrogate measure of DSM-IV rapid cycling BPD from the National Comorbidity survey Replication (NCS-R), a national survey of the US household population. DSM-IV disorders were assessed in the NCS-R with the WHO Composite International Diagnostic Interview (CIDI). Although the CIDI did not assess rapid cycling, it did assess the broader category of 12-month BPD with frequent mood episodes (FMEs), having at least four episodes of mania/hypomania or major depression in the 12 months before interview. Roughly one-third of NCS-R respondents with lifetime DSM-IV BPD and half with 12-month BPD met criteria for FME. FME was associated with younger age-of-onset (of BP-I, but not BP-II) and higher annual persistence (73% of the years since first onset of illness with an episode) than non-FME BPD. No substantial associations of FME vs non-FME BPD were found with socio-demographics, childhood risk factors (parental mental disorders, other childhood adversities) or comorbid DSM-IV disorders. However, FME manic episodes had greater clinical severity than non-FME episodes (assessed with a fully structured version of the Young Mania Rating Scale) and FME hypomanic episodes had greater role impairment than non-FME episodes (assessed with the Sheehan Disability Scales). Whether these indicators of severity merely reflect attenuated effects of rapid cycling or independent effects of sub-threshold rapid cycling warrants further study given the high proportion of lifetime cases who met criteria for FME.

Depressive disorders: toward a unified hypothesis.

Our scientific understanding of psychiatric syndromes, including the phenomena of depression, has been hampered because of: (i) the use of metapsychological concepts that are difficult to test; (ii) methodological and linguistic barriers that prevent communication among psychoanalysts, behaviorists, experimental psychologists, and psychiatrists; and (iii) the reluctance of psychiatrists to accept animal models as possible approximations of certain aspects of human psychopathology. We have attempted to demonstrate that the animal models simulate some of the central features of clinical depression (for example, helplessness and object loss), thereby allowing one to rigorously investigate them from developmental, behavioral, and biochemical perspectives. The object loss model, as a concrete version of a metapsychological-psychoanalytic concept, has enabled primatologists to study the disruption of an attachment bond. The behavioral model accommodates this concept to a broader generalization: loss of reinforcement or loss of control over reinforcement. We have reviewed the evidence that these processes involve the diencephalic centers of reward or reinforcement, thereby permitting integration of the psychoanalytical and behavioral formulations with the biochemical hypotheses. Also, we have presented data strongly suggesting that the breaking of an attachment bond in the primate represents significant loss of reinforcement that induces helplessness and disrupts motivated behavior. Finally, we have argued that the depressive syndrome could be caused by interactions of genetic, chemical, developmental, and interpersonal factors, all of which impinge on the diencephalic centers of reinforcement.

Towards a genetically validated new affective temperament scale: a delineation of the temperament phenotype of 5-HTTLPR using the TEMPS-A.

BACKGROUND: Although it has been described that affective temperaments are associated with the 5-HTTLPR, less attention was paid to the association between this polymorphism and subscales and items related to each affective temperament. The aim of our study was to investigate the association of affective temperament subscales and individual items with the s allele of the 5-HTTLPR. METHOD: 138 psychiatrically healthy women completed the TEMPS-A questionnaire and were genotyped for 5-HTTLPR. Scores of subjects on the temperament scales, subscales and items in the three genotype and the two phenotype groups were compared using ANOVA. We selected items with significantly different mean scores between the three genotype groups and the two phenotype groups separately and performed item analysis. RESULTS: Subjects in the different 5-HTTLPR genotype and phenotype groups have significantly different score on scales measuring depressive, cyclothymic, irritable and anxious temperaments, and several subscales composing these temperamental scales. Subjects in the three genotype groups scored significantly different on 11 items, 8 of these remained in a derived genotype scale after item analysis. Subjects in the two phenotype groups had significantly different scores on 12 items, 9 of them were retained in a derived phenotype scale after item analysis. LIMITATIONS: Our sample was relatively small and included only women. CONCLUSIONS: Our data provide support for the association of affective temperaments with the s allele. Although the cyclothymic temperament shows the strongest association, all temperaments within the depressive superfactor have a similar share in this association. The newly derived 5-HTTLPR Phenotype Scale shows strong association with 5-HTTLPR genotype and phenotype, therefore this scale should be further investigated in relation to psychiatric disorders, as well as psychological traits and temperaments.

[Predicting risk of suicide in bipolar and unipolar depression: correlation between temperament and personality]. / Prädiktion des Suizidrisikos bei bipolar und unipolar depressiven Patienten: Wechselwirkung von Temperament und Persönlichkeit.

OBJECTIVE: The aim of this study was to evaluate the roles of personality and affective temperament traits in the prediction of suicide risk in mood disorders. METHODS: The participants were 147 psychiatric inpatients with bipolar disorders I and II and major depressive disorder. Patients undertook the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego self-rating questionnaire, the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and the Beck Hopelessness Scale. RESULTS: Sixty-four subjects were diagnosed with increased suicidal risk based on the Mini International Neuropsychiatric Interview (MINI). Logistic regression analysis resulted in two models predictive of MINI-based suicidal risk: irritable temperament and the MMPI-2 scale. Multiple regression analysis further indicated that higher hyperthymic values are protective against hopelessness, while MINI-based suicidal intent is a predictor of hopelessness. CONCLUSIONS: Personality and affective temperament traits may have a role in the prediction of suicide.

Toward a definition of a cyclothymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder?

BACKGROUND: Although the cyclothymic temperament appears to be related to the familial diathesis of bipolar disorder, exhibiting high sensitivity for bipolar II (BP-II) disorder, it is presently uncertain which of its constituent traits are specific for this disorder. METHODS: In a sample of 446 major depressive patients (BP-II and unipolar), in the French National EPIDEP study, the cyclothymic temperament was assessed by using clinician- and self-rated scales. We computed the frequency of individual traits and relative risk for family history of bipolarity. RESULTS: From both clinician- and self-rated scales, four items related to mood reactivity, energy, psychomotor and mental activity were significantly highly represented in the subgroup with positive family history of bipolarity. The item "rapid shifts in mood and energy" obtained the highest relative risk (OR=3.42) for positive family history of bipolarity. CONCLUSION: These findings delineate those cyclothymic traits which are most likely to tap a familial-genetic diathesis for BP-II, thereby identifying traits which can best serve as a behavioral endophenotype for this bipolar subtype. Such an endophenotype might underlie the cyclic course of bipolar disorder first described in France 150 years ago by Falret and Baillarger.

Validating the soft bipolar spectrum in the French National EPIDEP Study: the prominence of BP-II 1/2.

BACKGROUND: Much of the current literature on bipolar disorder is focused on bipolar I (BP-I), and to a much lesser extent on bipolar II (BP-II). The French multi-center national EPIDEP study has, among its objectives, the feasibility of validating a broader spectrum of bipolarity (the so-called "soft spectrum") by practicing clinicians. In this report we test aspects of a bipolar schema proposed earlier by Akiskal and Pinto [Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22: 517-534.]. METHODS: EPIDEP was scheduled in three phases: Phase 1 to recruit DSM-IV major depressives; Phase 2 to assess hypomania and affective temperaments; and Phase 3 to obtain history on course of illness, family history, and comorbidity. Comparative analyses are presented between affective subgroups constructed on a hierarchical basis: spontaneous hypomania (BP-II), cyclothymic temperament (BP-II 1/2), antidepressant-associated hypomania (BP-III), hyperthymic temperament (BP-IV), versus "strict unipolar" (UP). RESULTS: We present data on 490 patients for whom we obtained full assessment during all three phases of the study, classified as BP-II 1/2 (N=164), II (N=61), III (N=28), IV (N=22), as well as UP (N=174) as the reference nonbipolar group. Systematic inter-group comparison among the soft spectrum showed significant differences along clinical, descriptive, course, pharmacologic response and familial affective disorder patterns, which confirm the heterogeneity of the soft bipolar spectrum, with special characteristics for each of the subgroups. In terms of external validation, familial bipolar loading characterized all soft bipolar subgroups except type IV. LIMITATION: Data collection conducted in a practice setting, clinicians cannot be entirely held "blind" to all measures. This is an exploratory attempt, with many variables examined, to help characterize the clinical terrain of soft bipolarity. CONCLUSION: This is nonetheless the first systematic clinical attempt to validate the bipolar spectrum beyond mania (BP-I). BP-II 1/2, BP-III and BP-IV appeared distinct from BP-II and strict UP -- along most of the variables examined. BP-II 1/2 -- with early onset complex temperament structure, and high mood instability, rapid switching, irritable ("dark") hypomania and suicidality -- emerged as the most prevalent and severe expression of the bipolar spectrum, and accounting for 33% of all MDE. These results, which are of great public health relevance, testify to the cyclic nature of bipolarity in its softest expressions. The soft phenotypes are also of interest for genetic investigations of bipolar disorder.

Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients.

BACKGROUND: Despite extensive research recently focused on mixed mania, it is uncertain as how best to define it clinically, psychometrically (which has major bearing on its prevalence), and the methodology needed for future research. This topic is also of historical interest, because Magnan (1890) [Magnan, V., 1890. La Folie Intermittente. G Masson, Paris.] suggested that "combined [mixed] states" linked Falret's "circular insanity" with Baillarger's "dual insanity" (both described in 1854). This work eventually led to the Kraepelinian synthesis of all manic, mixed, and depressive states into the unitary rubric of "manic-depressive insanity (1899/1921). METHOD: EPIMAN-II Thousand" (EPIMAN-II MILLE) is a French national collaborative study, which involved training 317 psychiatrists working in different sites representative of psychiatric practice in France. We recruited 1090 patients hospitalized for acute DSM-IV mania. assessed at index admission by the following measures: the Mania Rating Scale (MRS), the Beigel-Murphy Scale (MSRS), a newly derived checklist of depressive symptoms least contaminated by mania, MADRS for severity of depression, and the SAPS for psychotic features. RESULTS: The rate of mixed mania, as defined by at least 2 depressive symptoms, was 30%. Even with this broad definition, we found significantly higher female representation. This clinical sub-type of mania was characterized by high frequency of past diagnostic errors, particularly those of anxiety and personality disorders. Refined definition of co-exiting depression was obtained from an abbreviated version of the MADRS (6 items), with distinct "emotional-cognitive" symptoms, and "psychomotor inhibition" factors, both of which were separable from an "irritable" factor linked to lability and poor judgment. Mixed mania was psychometrically best identified by a MADRS score of 6 (80% sensitivity, 94% specificity) and validated by a mixed polarity of first episodes, a higher rate of recurrence, psychotic features, and suicide attempts. LIMITATION: Cross-sectional study. CONCLUSIONS: The data deriving from EPIMAN, the largest and only national study ever conducted on mania, provide definitive characterization of the clinical and psychotic structure of mixed mania, which accounts for 1 out of 3 patients who present with mania. This figure is more accurate than higher rates reported in the literature because, in describing "mixity", we eliminated depressive features that could be contaminated by mania. Despite the prominent affective features described herein, the bipolar nature of mixed mania is often missed, with the result that these patients are diagnosed as having anxiety and/or personality disorders. It is of great public health significance for psychiatrists to recognize the bipolar nature of this condition that has been known as a major phase of manic-depressive illness since at least Magnan, a disciple of Falret and Baillarger.

The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention.

BACKGROUND: Previous reports have shown a significant relationship between suicide ideation and mixed depression. The aim of this study was to explore the prevalence and clinical characteristics of mixed depression among non-violent suicide attempters. METHODS: Using a structured interview (modified Mini International Neuropsychiatric Interview) and assessing all the symptoms of 16 psychiatric diagnoses, the authors examined 100 consecutive nonviolent suicide attempters (aged 18-65) within 24 h after their attempts. Mixed depression was defined as a major depressive episode (MDE)/dysthymic disorder plus 3 or more co-occurring hypomanic symptoms, according to the definition validated by Akiskal and Benazzi [Akiskal, H.S., Benazzi, F., 2003a. Delineating depressive mixed states: Their therapeutic significance. Clin. Approaches Bipolar Disord. 2, 41-47, Akiskal, H.S., Benazzi, F., 2003b. Family history validation of the bipolar nature of depressive mixed states. J. Affect. Disord. 73, 113-122.]. RESULTS: Current mixed depression was present in 63.0% in the total sample, and in 70.8% among the 89 depressive suicide attempters. Irritability, distractibility and psychomotor agitation were present in more than 90% of the subjects with mixed depression. The rate of mixed depression was significantly higher among bipolar than non-bipolar depressive suicide attempters (90% vs. 62%). Patients with mixed depression had the following concurrent disorders: bipolar disorders 41.0%, panic disorder 30.0%, generalized anxiety disorder 89.0%, alcohol abuse/dependence 56.0%, and substance abuse 27.0%. Mixed depression versus non-mixed depression had the following significant associations (odds ratio=OR): females 2.4, bipolar II disorder 9.3, generalized anxiety disorder 41.3, irritability 101.6 and psychomotor agitation 61.1. LIMITATIONS: The study didn't include suicide attempters with very high risk of fatality. CONCLUSIONS: The important new finding of this study is the very high prevalence of mixed depression among depressed suicide attempters. The rates of mixed depression among bipolar and non-bipolar depressive suicide attempters were much higher than previously reported among nonsuicidal bipolar II and unipolar depressive outpatients, suggesting that suicide attempters come mainly from mixed depressives with predominantly bipolar II base. Irritability and psychomotor agitation were the strongest predictors of suicide attempt. From a public health standpoint, our data highlight the necessity of detecting and treating mixed (bipolar) depression in the prevention of suicidal behaviour.

Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame.

Disciplinary fragmentation and nosological and semantic controversies have obscured the impressive advances made in the area of depressive disorders during the past decade. This article is an attempt to translate data derived from psychodynamic, sociobehavioral, and neurobiologic research into a clinically meaningful framework. We review ten models of depression with special emphasis on newer models supported by empirical and experimental studies, and present a new model, which incorporates and synthesizes findings from different schools. Depressive illness is conceptualized as the feedback interaction of three sets of variables at chemical, experiential, and behavioral levels with the diencephalon serving as the field of action.

Childhood-onset dysthymic disorder. Clinical features and prospective naturalistic outcome.

OBJECTIVES: To characterize the clinical presentation, course, and outcome of childhood-onset dysthymic disorder and assess the predictive validity of this diagnosis. DESIGN: As part of a longitudinal prospective study, school-age, clinically referred youngsters (n = 55) whose first depression was dysthymic disorder and a comparison group of youngsters (n = 60) whose first affective episode was major depressive disorder (MDD) were repeatedly examined during a 3- to 12-year interval. The diagnoses were based on DSM-III criteria. RESULTS: Dysthymic disorder was associated with earlier age at onset than MDD, similarly frequent symptoms of affective dysregulation, but low rates of anhedonia and neurovegetative symptoms and greater overall risk of any subsequent affective disorder. The affective disorders that dysthymic children developed, including first-episode MDD (76%) and bipolar disorder (13%), far outnumbered nonaffective conditions. After the first episode of MDD, the clinical course of the initially dysthymic youths was similar to the course of the comparison patients with regard to rates of recurrent major depression, bipolar disorder, and certain nonaffective disorders. CONCLUSIONS: Childhood-onset dysthymic disorder is an early marker of recurrent affective illness. Although on long-term follow-up, dysthymic disorder and MDD are associated with similar rates of certain outcomes, there exist sufficient differences to warrant diagnosis of each disorder. Dysthymic children who have subsequent mood disorders are most likely first to have an episode of MDD, and that episode appears to be the "gateway" to recurrent affective illness. The interval between the onset of dysthymia and the first major depression provides a window of opportunity for intervention and possible prevention of later episodes.

The relationship of personality to affective disorders.

Although characterologic constellations such as obsessionalism, dependency, introversion, restricted social skills, and maladaptive self-attributions are popularly linked to the pathogenesis of depressive disorders, the evidence in support of this relationship remains modest. Indeed, many of these attributes may reflect state characteristics woven into the postdepressive personality. Current evidence is strongest for introversion as a possible premorbid trait in primary nonbipolar depressions. By contrast, driven, work-oriented obsessoid, extroverted, cyclothymic, and related dysthymic temperaments appear to be the precursors of bipolar disorders. Other personalities, while not necessarily pathogenic in affective disorders, nevertheless may modify the clinical expression of affective disorders and their prognosis.

The nosological status of neurotic depression: a prospective three- to four-year follow-up examination in light of the primary-secondary and unipolar-bipolar dichotomies.

One hundred patients with "mild" depressive states, variously referred to as "situational," "reactive," or "neurotic," were studied. During a three- to four-year prospective follow-up, 4% had developed bipolar I, 14% bipolar II, and 22% unipolar disorders with predominantly favorable social outcome. Most of the remainder were suffering from nonaffective disorders; in this group, intermittent depressive symptomatology followed a protacted course (paralleling the underlying disorder) with generally unfavorable outcome. Irrespective of diagnostic subtype, a "characterological" component occurring in 24% of the total sample appeared to predict unfavorable prognosis, including three suicides. The diagnostic usage of the concept of neurotic depression may no longer be clinically meaningful, since it lacks sufficient phenomenological characterization and refers to a heterogeneous group of disorders. The data suggest the merits of a biaxial approach to the nosology of depressive disorders whereby phenomenologically based affective diagnoses are qualified as to the presence or absence of character disorder.

Characterological depressions. Clinical and sleep EEG findings separating 'subaffective dysthymias' from 'character spectrum disorders'.

Early-onset characterological depressions are distinguished from late-onset chronic depressions that complicate the long-term course of unipolar and nonaffective illnesses. In turn, characterological depressions are divisible into at least two subtypes: (1) "Subaffective dysthymias" have even sex distribution, are often complicated by superimposed depressive episodes, rapid eye movement latency is shortened, and they tend to respond to tricyclics of lithium carbonate. In brief, they share many features of primary affective illness. (2) "Character spectrum disorders," by contrast, represent a heterogeneous mixture of personality disorders with inconstant depressive features, are more common in women, are often complicated by alcohol and drug abuse, and outcome tends to be unfavorable.

Differentiation of primary affective illness from situational, symptomatic, and secondary depressions.

Analysis of family history and antidepressant drug response variables of 100 "neurotic" depressives followed up prospectively over three to four years disclosed that primary depressions (unipolar and bipolar) could be distinguished from nonprimary cases by (1) the early occurrence of "pharmacological-hypomania;" (2) family history of bipolar illness; (3) family history for affective disorder in two or three consecutive generations, especially when "loaded." Although each of these variables alone occurred in only one fifth to one third of the primary group, they individually displayed better than 95% specificity for it. Thus, the confidence with which the diagnosis of primary affective illness could be made in the presence of any of these variables ranged from 88% to 100%. These findings argue for considering such nonsymptomatological variables for their potential in strengthening the phenomenologic diagnostic criteria for depressive illness.

Affective disorders in referred children and younger siblings of manic-depressives. Mode of onset and prospective course.

We studied 68 referred juvenile offspring or siblings of adult bipolar patients. Mean age at onset of affective and related disturbances was 15.9 years (range, 6 to 24 years). Although four of the ten prepubertal children had hypomanic features, full-blown manic psychosis did not appear before puberty. In the sample at large, 12 were classified as dysthymic and ten as cyclothymic. Eleven additional subjects with polysubstance abuse, who at onset did not meet criteria for affective disorder, were reclassified as having either a dysthymic or a cyclothymic disorder during follow-up. Of the remaining patients--24 depressive, eight manic, and three mixed state--71% experienced recurrences; mood-incongruent features, present in four cases at onset, recurred in only one patient during subsequent episodes. Overall, half the sample evidenced signs of bipolarity during a mean prospective follow-up period of three years.

The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies.

BACKGROUND: Most natural history studies of affective disorders have emphasized the prediction of eventual recovery. Little is known of changes over time in the immediate probability of recovery. METHODS: To identify regularities in the timing of recovery from nonbipolar major depressive disorders, we considered only episodes that began during follow-up to increase the accuracy with which onsets were timed and to limit the study sample to individuals who had a demonstrably episodic course. Five participating centers conducted baseline assessments and followed probands (N = 605) and nonclinical subjects (relatives, controls, and spouses, N = 826) up for 6 years. During that time, 359 probands had at least one prospectively observed episode, and 181 had two episodes; corresponding numbers for the nonclinical subjects were 216 and 78, respectively. Our analyses considered the distribution of episode lengths across ascertainment source (probands vs nonclinical subjects), center, and episode number (first vs second prospectively observed episode). RESULTS: Distribution was remarkably uniform. Regardless of ascertainment source, center, or episode number, recovery occurred within 3 months in 40% of episodes, within 6 months in 60%, and within 1 year in 80%; 20% had more protracted courses. CONCLUSIONS: Once triggered, the immediate likelihood of recovery changes over time in a predictable fashion. This has practical implications for the study of antidepressant efficacy and theoretical implications for factors involved in affective dysregulation.

Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients.

BACKGROUND: Given the therapeutic and prognostic importance of the unipolar-bipolar dichotomy, predicting which patients will become bipolar subsequent to index diagnosis of major depressive disorder (MDD) is of paramount clinical significance. We sought to characterize the profile of patients with MDD who would convert to the more subtle bipolar subtype (known as BPII) on the basis of clinical and personality variables obtained during MDD episodes. METHODS: A total of 559 patients, comprehensively evaluated with the Schedule of Affective Disorders and Schizophrenia and "unipolar" MDD at entry, were administered 17 self-report personality measures. Hypomanic and manic episodes were systematically recorded over a prospective observation period of up to 11 years. We compared 48 converters to BPII (8.6%) with 22 converters to bipolar I (BPI) (3.9%) and the remaining larger group of unipolar patients. RESULTS: Except for greater acuteness, severity, and psychotic symptomatology, BPI converters were essentially similar to MDD nonconverters. By contrast, BPII converters were robustly distinguished from those with MDD who remained unipolar on the basis of self-report measures along the newly derived factors of Mood Lability, Energy-Activity, and Daydreaming. This profile was associated with early age at onset of MDD and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Overall, BPII switchers had a more protracted and tempestuous course with shorter well intervals. "Habitual self" descriptions of temperamental instability during MDD episodes provided useful clinical information for predicting which depressed patients will switch to BPII, attaining a sensitivity of 91% for all three factors combined (23 items); Mood Lability alone (nine items) was the most specific predictor (86%), though of lower sensitivity (42%). CONCLUSIONS: The BPII subtype is best understood by such lability intruding into, and possibly its accentuation during, depressive episodes, thereby creating an intimate interweaving of trait and state. Clinicians must note that the foregoing temperamental profile appears more fundamental in defining the affective dysregulation of the BPII subtype than hypomanic episodes emphasized in DSM-IV.