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.

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.

DSM-5 criteria for depression with mixed features: a farewell to mixed depression.

OBJECTIVE: To review the DSM-5 proposed criteria for mixed depression in light of robust and consistent historical and scientific evidence. METHOD: An extensive historical search, a systematic review of the papers used by DSM-5 as reference papers, and a PubMed search were performed. RESULTS: As Hippocrates, depressive mixed states have been described as conditions of intense psychic suffering, consisting of depressed mood, inner tension, restlessness, and aimless psychomotor agitation. In DSM-5, new criteria are proposed for a mixed features specifier, as part of depression either in major depressive disorder (MDD) or bipolar disorder. Those criteria require, as diagnostically specific, manic/hypomanic symptoms that are the least common kinds of symptoms that actually arise in depressive mixed states. The DSM-5 proposal is based, almost entirely, on a speculative wish to avoid 'overlapping' manic and depressive symptoms. Mixed states are, in fact, nothing but overlapping manic and depressive symptoms. CONCLUSION: In this article, we review the psychopathology and research on mixed depressive states, and try to demonstrate that the DSM-5 proposal has weak scientific basis and does not identify a large number of mixed depressive states. This may be harmful because of the different treatment required by these conditions.

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.

Gender differences in immediate memory in bipolar disorder.

BACKGROUND: Gender is known to modulate the clinical course and severity of bipolar disorder (BD). Although cognitive abnormalities are an established feature of BD, there is limited information regarding whether gender also influences the pattern and severity of cognitive impairment. METHOD: We evaluated the performance of 86 remitted patients with BD, type 1, (BD-I) (36 male and 50 female) and 46 healthy participants (21 male and 25 female) on tasks of general intellectual ability, memory encoding, recognition and retrieval, response inhibition and executive function (abstraction and perseveration). The impact of illness severity in patients was assessed using the global assessment of functioning (GAF). RESULTS: We found a gender effect and an interaction between diagnosis and gender on immediate memory, implicating encoding and retrieval processes, both showing male BD-I patients being disadvantaged compared with female patients and healthy controls. Immediate memory correlated with GAF scores and this association was statistically significant for male BD-I patients. CONCLUSIONS: Our findings suggest that gender differences in BD-I are associated with memory function, particularly processes relating to encoding and retrieval, and may contribute to poor functional outcome particularly in men.

Melancholia agitata and mixed depression.

OBJECTIVE: The diagnostic entity of major depressive episode includes both simple and agitated or mixed depression. Mixed depression is characterized by a full depressive episode with several symptoms of excitatory nature. Mixed depressions worsen if treated with antidepressants. METHOD: We have reviewed the clinical charts of the 2141 patients treated at the Centro Lucio Bini of Rome from January 1999 to June 2006. These patients were diagnosed according to DSM-IV criteria. Research diagnostic criteria were applied for agitated depression with motor agitation and Author's diagnostic criteria for agitated depression without motor agitation. RESULTS: One thousand and twenty-six patients had a depressive episode as index episode. Three hundred and forty six (33%) were mixed depressive states. One hundred and thirty eight (44%) of them were spontaneous; in 173 cases, the onset of the mixed depression was associated with antidepressants. CONCLUSION: Psychic and motor agitation are considered equally important for the definition of agitated depression. Treating agitated depression with antidepressants worsens the clinical picture. The use of Electroconvulsive Therapy (ECT), neuroleptics and anticonvulsants are recommended. The term Melancholia Agitata is proposed for agitated (mixed) depression.

Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression).

PURPOSE: As psychotic agitated depression is now a well-described form of mixed state during the course of bipolar I disorder, we sought to investigate the diagnostic validity of a new definition for agitated (mixed) depression in bipolar II (BP-II) and major depressive disorder (MDD). MATERIALS AND METHODS: Three hundred and thirty six consecutive outpatients presenting with major depressive episodes (MDE) but without history of mania were evaluated with the Structured Clinical Interview for DSM-IV when presenting for the treatment of MDE. On the basis of history of hypomania they were assigned to BP-II (n = 206) vs. MDD (n = 130). All patients were also examined for hypomania during the current MDE. Mixed depression was operationally defined by the coexistence of a MDE and at least two of the following excitatory signs and symptoms as described by Koukopoulos and Koukopoulos (Koukopoulos A, Koukopoulos A. Agitated depression as a mixed state and the problem of melancholia. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:547-64): inner psychic tension (irritability), psychomotor agitation, and racing/crowded thoughts. The validity of mixed depression was investigated by documenting its association with BP-II disorder and with external variables distinguishing it from unipolar MDD (i.e., younger age at onset, greater recurrence, and family history of bipolar disorders). We analyzed the data with multivariate regression (STATA 7). RESULTS: MDE plus psychic tension (irritability) and agitation accounted for 15.4%, and MDE plus agitation and crowded thoughts for 15.1%. The highest rate of mixed depression (38.6%) was achieved with a definition combining MDE with psychic tension (irritability) and crowded thoughts: 23.0% of these belonged to MDD and 76.9% to BP-II. Moreover, any of these permutations of signs and symptoms defining mixed depression was significantly and strongly associated with external validators for bipolarity. The mixed irritable-agitated syndrome depression with racing-crowded thoughts was further characterized by distractibility (74-82%) and increased talkativeness (25-42%); of expansive behaviors from the criteria B list for hypomania, only risk taking occurred with some frequency (15-17%). CONCLUSIONS: These findings support the inclusion of outpatient-agitated depressions within the bipolar spectrum. Agitated depression is validated herein as a dysphorically excited form of melancholia, which should tip clinicians to think of such a patient belonging to or arising from a bipolar substrate. Our data support the Kraepelinian position on this matter, but regrettably this is contrary to current ICD-10 and DSM-IV conventions. Cross-sectional symptomatologic hints to bipolarity in this mixed/agitated depressive syndrome are virtually absent in that such patients do not appear to display the typical euphoric/expansive characteristics of hypomania-even though history of such behavior may be elicited by skillful interviewing for BP-II. We submit that the application of this diagnostic entity in outpatient practice would be of considerable clinical value, given the frequency with which these patients are encountered in such practice and the extent to which their misdiagnosis as unipolar MDD could lead to antidepressant monotherapy, thereby aggravating it in the absence of more appropriate treatment with mood stabilizers and/or atypical antipsychotics.

Delirium during clozapine treatment: incidence and associated risk factors.

BACKGROUND: Incidence and risk factors for delirium during clozapine treatment require further clarification. METHODS: We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors. RESULTS: Subjects (n = 139) were 72 women and 67 men, aged 40.8 +/- 12.1 years, hospitalized for 24.9 +/- 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 +/- 203 mg (3.45 +/- 2.45 mg/kg) for 18.9 +/- 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated. CONCLUSIONS: Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.

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.

Agitated depression as a mixed state and the problem of melancholia.

The extensive use of antidepressant drugs in the treatment of all forms of depression makes the question of the real nature of agitated depression a crucial issue because many patients have adverse outcomes, including increased agitation, increased insomnia, increased risk of suicide, and sometimes the onset of psychotic symptoms. Agitated depression is no longer considered a mixed state in the DSM system. After a review of the literature on melancholia agitata as a mixed state and on the introduction of the concept of mixed states, this article has examined the psychopathology of agitated depression. The main symptoms are depressive mood with marked anxiety, restlessness, and often delusions. In other cases, psychic agitation and racing or crowded thoughts prevail alongside anxiety and depressed mood. The mixed nature of these symptoms has been discussed and new diagnostic criteria proposed, including those syndromes without marked restlessness but with evident psychic agitation and racing or crowded thoughts. It is suggested that all the varieties of agitated depression be called mixed depression, with the following diagnostic criteria: A. Major depressive episode B. At least two of the following symptoms: 1. Motor agitation 2. Psychic agitation or intense inner tension 3. Racing or crowded thoughts.

[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.

[Mixed depressive syndrome]. / Un syndrome dépressif mixte.

For a period of six months (april to october 1990) 361 manic-depressive in-patients or out-patients were examined and treated. 178 patients (119 females and 69 males) were suffering from depression at examination time. Among them, 34 women and 11 men had mixed mood disorders with a symptomatology near that of typical depression (major depression, according to the DSM III-R criteria) but not of mixed bipolar disorder. The main symptoms were: dysphoric mood with irritability; internal tension, psychic and sometimes physical agitation; emotional lability; head crowded with thoughouts or thoughts that vanish too quickly; sleep disorders with initial insomnia or with frequent night awakenings; suicidal thoughts or attempted suicide with impulsiveness. These patients sustained severe suffering. They were in no way slow-minded but rather talkative and expressive. Antidepressant drugs increased agitation and insomnia, and in some cases, suicidal impulses. BZDs had limited efficacy but neuroleptics given in small doses, anticonvulsants and lithium gave very effective results. A limited number of electroshocks provided rapid improvement. In many respects, depression with delirium seems a more severe form of the above-described combined depressive syndrome and responds to the same treatments. We think that this mood disorder includes excitement as an important component, although this was not clearly evident. However, it is not easy to conceive this syndrome as a mixture of depressive and manic symptoms; it should rather be regarded as another specific mood condition, either permanent or transient, situated between the two other conditions.

[Diagnostic and therapeutic considerations on agitated depression understood as a mixed affective state]. / Considerazioni diagnostiche e terapeutiche sulla depressione agitata intesa come stato misto affettivo.

Since they were first described, mixed affective states have created problems of differential diagnosis. In clinical practice various cases previously diagnosed as other conditions but identifiable as mixed states within a bipolar disorder have been encountered. In particular there are cases of agitated depression that can pose a serious clinical problem since the agitation may be exacerbated by the use of antidepressant drugs. In contrast it has been found useful to treat the maniacal component of these states, an approach that has obtained remissions and overall improvements in the clinical picture.