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.

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.

Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients.

BACKGROUND: Recognition by the DSM-IV of rapid cyclicity as a course specifier has raised the question of the stability and long-term outcome of rapid-cycling (RC) patients. Data on this topic is sparse and often inconsistent. To our knowledge, these are the first personally followed patients over the long term, dealing directly with the issue of the duration of the RC course. METHODS: We examined the evolution of the course of 109 RC patients (68 women and 41 men) followed for a minimum of 2 years and up to 36 years, beginning with the index episode when the RC course was diagnosed by the authors (A.K., G.P.M., P.G., L.P., D.R.). Patients were included in the study if they met criteria for RC as defined by>or=4 affective episodes per year (Dunner and Fieve, 1974). The follow-up period varied from 2-5 years for 25 patients, 6-10 years for 24 patients, 11-15 years for 24 patients, 16-20 years for 19 patients, 21-25 years for 13 patients, 30-36 years for four patients. RESULTS: In 13 patients (12%), RC emerged spontaneously and in 96 patients (88%), it was associated with antidepressant and other treatments. In 19 women (28% of all women) RC course started in perimenopausal age (45-54 years). The mean duration of RC during the follow-up period was 7.86 years (range 1-32) and its total duration (including RC course prior to the follow-up period) was 11 years (range 1-40). The total duration of the affective disorder, from the first episode to the end of the follow-up, was 21.78 years (range 1-70). At the end of the follow-up, 36 patients (33%) had complete remission for at least the past year, 44 (40%) stayed rapid cycling with severe episodes (six of this group committed suicide), while 15 (14%) were rapid cycling but with attenuated episodes. The other 14 patients (13%) became long cyclers, eight with severe episodes and six with milder ones. The main distinguishing features between those who remitted from and those who persisted in the RC course were: (1). the initial cycle pattern: patients with Depression-Hypomania(mania)-Free interval cycles (53 patients) had a worse outcome: 26.4% remitted and 52.8% persisted in the RC course through to the end of the follow up period. The Mania/Hypomania-Depression-Free interval cycles (22 patients) had a significantly better outcome, with 50% remitted and 27.2% persisting RC; and (2). the occurrence of the switch process from depression to hypomania/mania and the occurrence of agitated depressions made the prognosis worse. Continuous treatment was more effective against mania/hypomania than against depression, yet in all persisting RC cases the mania/hypomania remitted only partially. LIMITATIONS: These data derive from clinics known for their expertise in mood disorders, and they may have attracted and retained patients with a more severe course. Treatment was uncontrolled and consisted more of lithium than divalproex, lamotrigene and olanzapine, recently shown to be beneficial in subgroups of patients with rapid-cycling. CONCLUSIONS: Our findings suggest that rapid cyclicity, spontaneous or induced, once established, becomes for many years a stable rhythm in a substantial proportion of patients, linked to endogenous and environmental factors. The suggestion is made to consider as rapid-cyclers, at least for research purposes, those patients who have had a rapid cycling course for at least 2 years, borrowing the duration criterion currently employed for other chronic disorders such as Dysthymia and Cyclothymia. That our patients had poorer prognosis than some other cohorts in the literature is probably due to the shorter duration of "rapid-cycling" at entry in the latter cohorts. A true understanding of the nature of rapid-cycling will require a rigorous definition of not only duration, but also pole-switching and course patterns at entry into study.

[Anxious-excited depression: a mixed affective syndrome]. / La dépression anxieuse-excitée: un syndrome affectif mixte.

A mixed affective syndrome is described which meets the criteria for major depression but not those of the DSM III-R for a mixed state. The clinical picture is characterized by lack of motor retardation and fluent verbalization; the facial expression is animated and sometimes dramatic. Patients suffer considerably and are often tearful. They complain of inner tension and restlessness, racing thoughts and despair. Emotional lability and momentary irritability are observed. Insomnia occurs initially or with frequent early waking. Suicidal ideation occurs and makes the syndrome of concern in view of its impulsive nature. Antidepressants increase restlessness, insomnia, aggressiveness and the impulsiveness of suicidal ideation. Low-dose neuroleptics, lithium and anticonvulsivants are highly effective. A few sessions of ECT offer rapid improvement.

Poor prophylactic lithium response due to antidepressants.

50 manic-depressive patients with rapid cycles received lithium for more than 1 year, during depression they received antidepressant drugs. Response was poor in 36, partial in 6, and good in 8. 21 of the poor responders were persuaded to endure depression without antidepressants; anxiolytics were allowed, 15 stabilized after the end of the untreated depression or after a few milder, shorter episodes; 4 improved partially; 2 were unchanged. 15 other rapid cycle patients started on lithium and stopped antidepressants at the same time. Response was good in 13, partial in 1, and poor in 1. Patients with a course of depression-hypomania (or mania)-free interval also responded poorly to prophylactic lithium when the depression was treated with antidepressants. They responded well when antidepressants were withdrawn. Antidepressants often cause or accentuate a switch from depression to hypomania or mania, and temporary refractoriness to lithium of the hypomania or mania. In this way lithium fails to prevent depression.

Spontaneous length of depression and response to ECT.

Electro-convulsive treatment (ECT) was therapeutically ineffective in 27 (20%) of 136 depressed patients. Failure to respond occurred in long-lasting depressions and in patients with a history of long-lasting depressions. In these cases the depression lasted at least 6 months. The hypothesis is proposed that ECT is effective only when given within 6 months of thespontaneous end of the depression. Clinical and nosological implications are discussed.