Suicidal Risks in 12 DSM-5 Psychiatric Disorders.

OBJECTIVE: As modern studies evaluating suicidal behaviors in large samples of major psychiatric disorder patients are rare, we compared suicidal risks associated with a variety of psychiatric diagnoses. METHODS: We quantified rates of intake suicidal ideation and lifetime attempts, suicides, and violent acts (attempts + suicides) in 6050 adult patients in a European psychiatric center, diagnosed with 12 prevalent, DSM-5 psychiatric disorders. RESULTS: Ideation ranged from 53.9% of subjects with bipolar disorder (BD) with mixed features, to 8.70% in anxiety disorders. Subjects making at least one suicide attempt were most prevalent in BD with mixed or psychotic features. Suicide rates ranked: substance abuse > BD with psychotic features > psychotic disorders ≥ BD-I > major depressive disorder (MDD). Suicidal intensity (acts/100 PEY) was highest with BD, psychotic disorders, and MDD; lethality (lower attempt/suicide ratio) was greatest with substance abuse, psychotic disorders, and BD with psychotic features. Rates of suicidal acts in BD vs. MDD were similarly high among ever-hospitalized subjects but much lower in never-hospitalized MDD subjects. Women had higher overall risks of ideation and attempts, but violent acts and suicide were more likely among men, whereas SMR for suicide was greater among women, presumably reflecting very low risks among women in the regional general population. CONCLUSIONS: Suicidal risks were particularly high in BD with psychotic or mixed features as well as with substance abuse and in severe MDD with hospitalization.

Melancholic versus Nonmelancholic Major Depression Compared.

BACKGROUND: The concept of melancholia has been associated with psychiatric nosology for centuries. Nevertheless, its definition, relationship to the contemporary concept of Major Depressive Disorder, and clinical implications remain uncertain. METHODS: In a total sample of 3211 closely evaluated patient-subjects diagnosed with DSM-5 Major Depressive or Bipolar Disorder and meeting DSM-5 criteria for major depression with melancholic features or not at a European mood disorder center, we matched 1833 for depression severity (baseline HDRS21 score ≥18) and compared rates and ratings of characteristics of interest between the subgroups, using bivariate and multivariate methods. RESULTS: Observed prevalence of melancholic features was 35.2% in the 1833 subjects matched for severity, and 21.0% among all 3211 subjects. Diagnosis was highly dependent on depression-severity measured three ways. Very few clinical characteristics differed between melancholic and nonmelancholic subjects matched for illness-severity; more suicidal ideation with melancholic features was a notable exception. CONCLUSIONS: Study findings leave the distinction of melancholic features from depression-severity unclear and the potential clinical value of diagnosing melancholic features uncertain.

Characteristics of depressive and bipolar disorder patients with mixed features.

OBJECTIVE: To assess differences between subjects with vs. without mixed features in major affective disorders. METHODS: In 3099 out-patient subjects with DSM-5 major depressive disorder (MDD, n = 1921) or bipolar disorders (BD, n = 1178), we compared those with (Mx) vs. without (Non-Mx) mixed features (agitated-irritable depression or dysphoric [hypo]mania) in an index episode. RESULTS: Prevalence of Mx averaged 21.9% [CI: 20.5-23.4] overall, ranking: BD-II > BD-I > MDD, and in BD depression ≥ [hypo]mania > MDD. Mx subjects were significantly more likely than Non-Mx cases to (i) have other mixed episodes, (ii) have higher irritable and agitated ratings, (iii) have more substance abuse, (iv) switch into mixed episodes, (v) have more suicide attempts and higher suicidal ratings, (vi) change diagnosis from depression to BD, (vii) have higher hypomania scores when depressed or depression scores when [hypo]manic, (viii) be unmarried or separated with fewer children and siblings, (ix) be diagnosed more with BD than MDD, (x) be unemployed, (xi) have BD, suicide and divorce among first-degree relatives, (xii) be female, (xiii) be younger at illness-onset. Both BD and MDD Mx subjects also received antidepressants less, but antipsychotics and mood-stabilizers more, alone and in combination with antidepressants. CONCLUSIONS: Mood disorder subjects with agitated-irritable depression or dysphoric [hypo]mania differed from those without such mixed features, including having a less favorable clinical course and repeated mixed episodes. They may represent a distinct and prevalent, syndromal clinical subtype with prognostic and therapeutic significance.

Early clinical predictors and correlates of long-term morbidity in bipolar disorder.

OBJECTIVES: Identifying factors predictive of long-term morbidity should improve clinical planning limiting disability and mortality associated with bipolar disorder (BD). METHODS: We analyzed factors associated with total, depressive and mania-related long-term morbidity and their ratio D/M, as %-time ill between a first-lifetime major affective episode and last follow-up of 207 BD subjects. Bivariate comparisons were followed by multivariable linear regression modeling. RESULTS: Total % of months ill during follow-up was greater in 96 BD-II (40.2%) than 111 BD-I subjects (28.4%; P=0.001). Time in depression averaged 26.1% in BD-II and 14.3% in BD-I, whereas mania-related morbidity was similar in both, averaging 13.9%. Their ratio D/M was 3.7-fold greater in BD-II than BD-I (5.74 vs. 1.96; P<0.0001). Predictive factors independently associated with total %-time ill were: [a] BD-II diagnosis, [b] longer prodrome from antecedents to first affective episode, and [c] any psychiatric comorbidity. Associated with %-time depressed were: [a] BD-II diagnosis, [b] any antecedent psychiatric syndrome, [c] psychiatric comorbidity, and [d] agitated/psychotic depressive first affective episode. Associated with %-time in mania-like illness were: [a] fewer years ill and [b] (hypo)manic first affective episode. The long-term D/M morbidity ratio was associated with: [a] anxious temperament, [b] depressive first episode, and [c] BD-II diagnosis. CONCLUSIONS: Long-term depressive greatly exceeded mania-like morbidity in BD patients. BD-II subjects spent 42% more time ill overall, with a 3.7-times greater D/M morbidity ratio, than BD-I. More time depressed was predicted by agitated/psychotic initial depressive episodes, psychiatric comorbidity, and BD-II diagnosis. Longer prodrome and any antecedent psychiatric syndrome were respectively associated with total and depressive morbidity.

Age at menarche predicts age at onset of major affective and anxiety disorders.

BACKGROUND: Menarche age has been associated inconsistently with the occurrence, timing or severity of major depressive disorder (MDD), but rarely studied in women with bipolar (BDs) or anxiety disorders. METHODS: We investigated women patients at a Sardinian mood disorder center for associations of age at menarche with age at illness onset for major affective or anxiety disorders, year of birth, and other selected factors, using bivariate comparisons and multivariate regression modeling. RESULTS: Among women (n=1139) with DSM-IV MDD (n=557), BD-I (n=223), BD-II (n=178), or anxiety disorders (n=181), born in 1904-1998, of mean age 42.9 years, menarche age averaged 12.8 [CI: 12.7-12.9] years. Illness onset age averaged 30.9 [30.1-31.8] years, ranking: BD-I, 25.8; anxiety disorders, 28.0; BD-II, 30.3; MDD, 34.1 years. Menarche age declined secularly over birth years, and was associated with younger illness-onset, having no or fewer siblings, more psychiatrically ill first-degree relatives, living in rural environments, being suicidal, substance abuse, and being unemployed. Earlier menarche and earlier illness-onset were significantly associated for onset age groups of ≤ 20, 20-39, and > 40 years. Menarche age versus diagnosis ranked: BD-II

Suicide attempts in bipolar disorders: comprehensive review of 101 reports.

OBJECTIVE: Assess reported risk of suicide attempts by patients with bipolar disorder (BD). METHOD: Systematic searching yielded 101 reports from 22 countries (79 937 subjects). We analyzed for risk (%) and incidence rates (%/year) of attempts, comparing sex and diagnostic types, including by meta-analysis. RESULTS: Attempt risk averaged 31.1% [CI: 27.9-34.3] of subjects, or 4.24 [3.78-4.70]%/year. In BD-I (43 studies) and BD-II subjects (30 studies), risks (29.9%, 31.4%) and incidence rates (4.01, 4.11%/year) were similar and not different by meta-analysis. Among women vs. men, risks (33.7% vs. 25.5%) and incidence (4.50 vs. 3.21%/year) were greater (also supported by meta-analysis: RR = 1.35 [CI: 1.25-1.45], P < 0.0001). Neither measure was related to reporting year, % women/study, or to onset or current age. Risks were greater with longer exposure, whereas incidence rates decreased with longer time at risk, possibly through 'dilution' by longer exposure. CONCLUSION: This systematic update of international experience underscores high risks of suicide attempts among patients with BD (BD-I = BD-II; women > men). Future studies should routinely include exposure times and incidence rates by diagnostic type and sex for those who attempt suicide or not.

Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study.

OBJECTIVE: Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. METHOD: We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. RESULTS: In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. CONCLUSION: SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

Early-life stress and psychiatric disorders: epidemiology, neurobiology and innovative pharmacological targets.

The modern concept of stress is based on responses to events or factors ("stressors") experienced as aversive, threatening or excessive for maintaining physiological equilibrium of an organism. Prolonged exposure to stressors, particularly during early life, is strongly associated with later psychiatric disorders. Underlying mechanistic connections between stress responses and development of psychiatric illnesses remain uncertain and typically appear to be nonspecific. Relevant candidate mechanisms are likely to include the hypothalamic-pituitary-adrenal (HPA) axis, marked by sustained excessive release of cortisol from the adrenal cortex. In turn, this process is influenced by and alters various central neurotransmitter and other molecular signaling systems that include glutamate, dopamine, serotonin, and neurotrophic peptides. Additional manifestations of stress include altered neurogenesis and neuroplasticity, as well as oxidative neuron-damaging effects. The complex molecular systems involved in these processes present many opportunities for innovative pharmacological interventions that may have preventive or therapeutic benefits regarding mental illnesses arising from stress.

A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania.

BACKGROUND: Evidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence-based guidance on the efficacy and all-cause discontinuation of antimanic treatments. METHOD: We conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with bipolar-I mania. RESULTS: Altogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges' g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v. aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all-cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers. CONCLUSIONS: Hierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers.

Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics.

BACKGROUND: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). RESULTS: We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). DISCUSSION: Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.

Improvements in metabolic abnormalities among overweight schizophrenia and bipolar disorder patients.

PURPOSE: As weight-gain and metabolic abnormalities during treatment with psychotropic drugs are of great concern, we evaluated effects of psycho-education and medical monitoring on metabolic changes among severely mentally ill patients. MATERIALS AND METHODS: During repeated, systematic psycho-education about general health among 66 consecutive patients diagnosed with DSM-IV-TR schizophrenia (n=33) or type-I bipolar disorder (n=33), we evaluated (at intake 1, 2, 3, and 6 months) clinical psychiatric status, treatments and doses, recorded physiological parameters, and assessed attitudes about medication. RESULTS: At intake, patients with schizophrenia vs bipolar disorder were receiving 3-7 times more psychotropic medication, with 14% higher initial body-mass index (BMI: 29.1 vs 25.6 kg/m²), 12 times more obesity, and significantly higher serum lipid concentrations. During 6-months follow-up, among bipolar disorder patients, polytherapy and serum lipid concentrations declined more than among schizophrenia patients (e.g., total cholesterol+triglycerides, by 3.21 vs 1.75%/month). BMI remained stable. Declining lipid levels were associated with older age, bipolar disorder, being unemployed, higher antipsychotic doses, and lower initial BPRS scores (all P ≤ 0.001). CONCLUSIONS: Psychotropic treatments were more complex, and metabolic measures more abnormal among bipolar disorder than schizophrenia patients. Intensive psycho-education, clinical monitoring, and encouragement of weight-control for six months were associated with improvements in metabolic measures (but not to BMI), and more realistic attitudes about medication.

Antecedents of manic versus other first psychotic episodes in 263 bipolar I disorder patients.

OBJECTIVE: As initial episode type can predict later morbidity in bipolar disorder, we tested the hypothesis that clinical antecedents might predict initial episode types. METHOD: We studied 263 first-episode, adult, DSM-IV-TR type I bipolar disorder (BD-I) subjects within the McLean-Harvard-International First-Episode Project. Based on blinded assessments of antecedents from SCID examinations and clinical records, we compared first lifetime manic vs. other (mixed, depressive, or non-affective) major psychotic episodes. RESULTS: We identified 32 antecedents arising at early, intermediate or later times, starting 12.3±10.7 years prior to first lifetime major psychotic episodes. Based on multivariate modeling, antecedents associated significantly and independently with other (n=113) more than manic (n=150) first lifetime major psychotic episodes ranked by odds ratio: more early attentional disturbances, more late depression, more early perplexity, more detoxification, more early unstable mixed affects, more antidepressants, more early dysphoria, more intermediate depression, more early impulsivity, more late anhedonia, longer early-to-intermediate intervals, more intermediate substance abuse, more family history of major depression, and younger at earliest antecedents. Antecedents selectively preceding manic more than other first psychotic episodes included more late behavioral problems and more risk of familial BD-I. CONCLUSION: Clinical antecedents in adult, BD-I patients, beginning a decade before first major episodes and progressing through sequential stages were dissimilar in manic vs. other first psychotic episodes.

First-episode types in bipolar disorder: predictive associations with later illness.

OBJECTIVE: Characteristics of initial illness in bipolar disorder (BD) may predict later morbidity. METHOD: We reviewed computerized clinical records and life charts of DSM-IV-TR BD-I or BD-II patients at affiliated mood-disorder centers to ascertain relationships of initial major illnesses to later morbidity and other clinical characteristics. RESULTS: Adult BD patient-subjects (N=1081; 59.8% BD-I; 58.1% women; 43% ever hospitalized) were followed 15.7±12.8 years after onsets ranking: depression (59%)>mania (13%)>psychosis (8.0%)≥anxiety (7.6%)≥hypomania (6.7%)>mixed states (5.5%). Onset types differed in clinical characteristics and strongly predicted later morbidity. By initial episode types, total time-ill ranked: mania≥hypomania≥mixed-states≥psychosis>depression>anxiety. Depression was most prevalent long-term, overall; its ratio to mania-like illness (D/M, by per cent-time-ill) ranked by onset type: anxiety (4.75)>depression (3.27)>mixed states (1.39)>others (all<1.00). The MDI (mania or hypomania-depression-euthymia interval) course-pattern was most common (34.4%) and associated with psychotic or manic onset; the depression before mania (DMI) pattern (25.0%) most often followed anxiety (38.8%), depression (30.8%), or mixed onsets (13.3%); both were predicted by initial mania depression sequences. CONCLUSION: First-lifetime illnesses and cycles predicted later morbidity patterns among BD patients, indicating value of early morbidity for prognosis and long-term planning.

Course sequences in bipolar disorder: depressions preceding or following manias or hypomanias.

BACKGROUND: Inferior response to lithium treatment has been reported in bipolar disorder (BD) patients with mania or hypomania following episodes of major depression (DMI) versus preceding depression (MDI), with intervening euthymic periods. However, additional characteristics of BD course-patterns require further assessment. METHODS: We reviewed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences. RESULTS: Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals. Prevalent sequences included: major depression-hypomania (15.0%), mania-major depression (14.6%), major depression-mania (11.6%), and rapid-cycling (9.6%). Among subjects grouped by course-sequences (based on mania, mixed-states, or hypomania and major or minor depression), depression-before-[hypo]mania (DMI) cases were more likely to be women, diagnosed BD-II, have first-episodes of depressive or anxiety disorder, spend more time ill in depression, and benefit less with long-term mood-stabilizing treatments than with the opposite pattern (MDI). MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments. Meta-analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29% [CI: 18-40%] (p<0.0001). LIMITATIONS: Some data were retrospective and subject to recall bias, and treatment was clinical (non-randomized). CONCLUSIONS: The DMI course was strongly associated with first-episode depression or anxiety, excess depressive morbidity, and inferior treatment response, especially for depression.

Heterogeneity of schizoaffective disorder compared with schizophrenia and bipolar disorder.

OBJECTIVE: Low diagnostic reliability, the need to meet criteria of two disorders, and its status as residual diagnosis in clinical practice led us to hypothesize that schizoaffective disorder (SAD) is characterized by considerable heterogeneity, particularly in comparison with schizophrenia (SZ) and bipolar disorder (BD). As this has not been investigated the aim of this study is to test whether heterogeneity is larger in SAD than in SZ and BD. METHOD: Systematic search for studies simultaneously comparing all three diagnoses regarding demographic, clinical, psychometric (clinical rating scales and IQ tests), and biological parameters; comparison of heterogeneity as measured by standard deviation (SD). RESULTS: Standard deviation of SAD samples (N = 47) was smaller than in both differential diagnoses. SDs were 7% higher in BD than in SAD (SZ: 2% higher); in studies employing DSM-IIIR/-IV pooled SD was 4% higher in BD (8% lower in SZ). Differences between diagnoses were limited to the comparison of SAD and BD, and became smaller when only psychotic BD was considered. CONCLUSION: Heterogeneity of SZ and BD is not smaller than that of SAD. SAD seems not to be more diverse than other functional psychoses. Results are preliminary because of the novelty of the approach and to the small number of studies.

Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders.

OBJECTIVE: Whether responses to antidepressants differ in bipolar and unipolar depression remains unresolved. METHOD: We analyzed patient characteristics and outcomes of antidepressant treatment of 1036 depressed patients with bipolar-I or bipolar-II disorder, or unipolar major depression, using bivariate and multivariate methods and survival analysis, testing the hypothesis that responses would be superior in unipolar depression. RESULTS: Antidepressants were given to 84.8% (878/1036) of depressed patients: 58.9% of 93 bipolar-I, 80.1% of 117 bipolar-II, and 91.3% of 668 unipolar disorder cases. The 158 not given antidepressants had more manias/year, spent more months in mania and depression, and were far more likely to receive mood stabilizers or antipsychotics long term. Improvement of HDRS21 depression ratings ranked: bipolar-II (69.6%) > bipolar-I (62.9%) > unipolar (57.9%; P < 0.0001), independent of initial illness severity. Responder rates (≥50% improved without switching) ranked: bipolar-II (77.0%) > bipolar-I (71.6%) > unipolar (61.7%; P < 0.0001). Remission rates (final HDRS < 7) ranked: 54.0%, 50.6%, and 40.8% respectively (P = 0.02); 67.5% remitted within 12 weeks of treatment. Survival-computed median time to remission (15.0 weeks, overall) was shortest for bipolar-II patients (10.7 weeks). The 3-month risk of switching into mania-hypomania ranked: bipolar-II (15.8%) > bipolar-I (8.60%) > unipolar (0.56%). Multivariate modeling found bipolar diagnosis, shorter latency to remission, more recent trial year, and fewer weeks depressed before treatment to be associated with greater percent improvement of HDRS ratings. CONCLUSION: Selective use of antidepressants with or without mood stabilizers in non-agitated, depressed bipolar disorder patients for short periods was effective with moderate risk of potentially dangerous, manic mood elevation.

Episode cycles with increasing recurrences in first-episode bipolar-I disorder patients.

BACKGROUND: Preliminary review of a century of studies of the course of manic-depressive syndromes produced 40 reports, of which approximately one-third report evidence of shortening wellness intervals or cycle-lengths with more recurrences, and two-thirds did not. METHODS: We evaluated inter-episode intervals (cycle-length) in 128 clinically-treated, DSM-IV bipolar-I disorder patients followed prospectively and systematically over 5.7 years, with 6.5 episodes/person. RESULTS: As expected, cycle-length varied inversely with total cycle-count/person; however, multivariate linear regression found only longer initial hospitalization and fewer total cycles to be associated with cycle-length, whereas cycle-number (1, 2, 3, etc.), sex, intake-age, and first-episode polarity were not. Regression of within-subject cycle-length versus cycle-number yielded individual slope-functions with pseudo-random distribution (28% fell within ±1 month/cycle of the null [zero-slope]). Mean duration of early and late euthymic intervals (cycles 2 vs. 5) in patients with matched recurrence-counts was nearly identical. CONCLUSIONS: The course of bipolar-I disorder from onset was largely random or chaotic over nearly 6 years from onset. Only a minority of patients showed either cycle-acceleration or slowing, without changes in wellness intervals. The findings may be influenced by treatment-effects, but seem to indicate that most current bipolar-I disorder patients are unlikely to show progressive shortening of recurrence-cycles.

Predominant recurrence polarity among 928 adult international bipolar I disorder patients.

OBJECTIVE: To test the hypothesis that patients with bipolar disorder (BPD) differ demographically and clinically within subgroups based on the predominant-polarity of major recurrences. METHOD: We tested factors for association with predominantly (≥2 : 1) depressive vs. mania-like episodes with 928 DSM-IV type-I BPD subjects from five international sites. RESULTS: Factors preliminarily associated with predominant-depression included: electroconvulsive treatment, longer latency-to-BPD diagnosis, first episode depressive or mixed, more suicide attempts, more Axis-II comorbidity, ever having mixed-states, ever married, and female sex. Predominant-mania was associated with: initial manic or psychotic episodes, more drug abuse, more education, and more family psychiatric history. Of the 47.3% of subjects without polarity-predominance, risks for all factors considered were intermediate. Expanding the definition of polarity-predominance to ≥51% added little, but shifting mixed-states to 'predominant-depression' increased risk of suicidal acts from 2.4- to 4.5-fold excess over predominant-mania-hypomania, and suicidal risk was associated continuously with increasing proportions of depressive or mixed episodes. CONCLUSION: Subtyping by predominant-polarity yielded predictive associations, including the polarity of first episodes and risk of suicide attempts. Such subtyping may contribute to improve planning of clinical care and to biological studies of BPD.