Mixed Features in Depression: The Unmet Needs of Diagnostic and Statistical Manual of Mental Disorders Fifth Edition.

The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition introduced the specifier "with mixed features" including 3 or more nonoverlapping typical manic symptoms during a major depressive episode in bipolar disorder type I or II or unipolar major depressive disorder. Excluding overlapping excitatory symptoms, which are frequently observed in mixed depression, leaves many patients with mixed depression undiagnosed. As a consequence, alternative diagnostic criteria have been proposed, claiming for the inclusion in the rubric of mixed features the following symptoms: psychomotor agitation, mood lability, and aggressiveness. A deeper diagnostic reconsideration of mixed features in depression should be provided by the new nosologic classification systems.

Relationships between recurrence and polarity in major depressive disorders: Pooled analysis of the BRIDGE and BRIDGE-II-MIX cohorts.

BACKGROUND: current classifications of mood disorders focus on polarity rather than recurrence, separating bipolar disorder from major depressive disorder (MDD). The aim of the present study is to explore the possible relationships between number and frequency of depressive episodes and clinical variables associated to bipolarity, in a large sample of MDD patients. METHODS: the clinical characteristics of 7055 patients with MDD were analyzed and compared according to the number and frequency of depressive episodes. Two stepwise backward logistic regression model were used to identify the predictive value of clinical features based on the presence of high number (≥3 episodes) and high frequency (≥3 episodes/year) of depressive episodes. RESULTS: high-recurrence and high-frequency MDD patients showed greater family history for bipolar disorder, higher prevalence of psychotic features, more suicide attempts, higher rates of treatment resistance and mood switches with antidepressants (ADs) and higher rates of bipolarity diagnosis according to Angst criteria, compared to low-recurrence and low-frequency patients. Logistic regressions showed that a brief current depressive episode, a previous history of treatment resistance and AD-induced mood switches, a diagnosis of bipolarity and comorbid borderline personality disorder were the variables associated with both high-recurrence and high-frequency depression. LIMITATIONS: the study participating centers were not randomly selected and several variables were retrospectively assessed. CONCLUSIONS: even in the absence of hypomanic/manic episodes, high-recurrence and high-frequency MDD seem to be in continuity with the bipolar spectrum disorders in terms of clinical features and, perhaps, treatment response.

Long-Acting Injectable (LAI) Aripiprazole Formulations in the Treatment of Schizophrenia and Bipolar Disorder: a Systematic Review.

BACKGROUND: Several second-generation antipsychotics (SGAs) are available in long-acting injectable (LAI) formulations. OBJECTIVE: To systematically review the effects of the two formulations, Monohydrate and Lauroxil, of Aripiprazole LAI in patients with schizophrenia and bipolar disorder during an acute episode or during maintenance treatment. METHODS: On September 18, 2018, we adopted the following search strategy: (aripiprazole OR OPC-14597 OR Abilify) AND (long-acting OR depot OR LAI OR once monthly OR prolonged release OR monohydrate OR lauroxil) on PubMed, Cochrane, Scopus, CINAHL, PsycINFO, and Web of Science to identify randomised controlled trials. Furthermore, we searched the ClinicalTrials.gov site for possible additional studies. RESULTS: We included 28 papers dealing with randomised assignment of aripiprazole LAI formulations in schizophrenia and bipolar disorder in survival studies after stabilisation, in acute studies, and in head-to-head comparisons. Both monohydrate and lauroxil formulations reduced relapses/recurrences with respect to comparators (placebo or 50 mg once-monthly monohydrate) and improved symptomatology in acute schizophrenia. LIMITATIONS: Only a small number of studies were included in our review, with widely overlapping samples. While a high proportion of studies were wholly or partly industry-sponsored, their outcomes do not appear to have been affected. CONCLUSION: Aripiprazole LAI may to be efficacious in reducing relapse of schizophrenia and bipolar disorder in the long term in stabilised patients and in improving symptoms of schizophrenia during its acute phase, with both monohydrate and lauroxil formulations showing efficacy.

Is recurrence in major depressive disorder related to bipolarity and mixed features? Results from the BRIDGE-II-Mix study.

BACKGROUND: Current classifications separate Bipolar (BD) from Major Depressive Disorder (MDD) based on polarity rather than recurrence. We aimed to determine bipolar/mixed feature frequency in a large MDD multinational sample with (High-Rec) and without (Low-Rec) >3 recurrences, comparing the two subsamples. METHODS: We measured frequency of bipolarity/hypomanic features during current depressive episodes (MDEs) in 2347 MDD patients from the BRIDGE-II-mix database, comparing High-Rec with Low-Rec. We used Bonferroni-corrected Student's t-test for continuous, and chi-squared test, for categorical variables. Logistic regression estimated the size of the association between clinical characteristics and High-Rec MDD. RESULTS: Compared to Low-Rec (n = 1084, 46.2%), High-Rec patients (n = 1263, 53.8%) were older, with earlier depressive onset, had more family history of BD, more atypical features, suicide attempts, hospitalisations, and treatment resistance and (hypo)manic switches when treated with antidepressants, higher comorbidity with borderline personality disorder, and more hypomanic symptoms during current MDE, resulting in higher rates of mixed depression according to both DSM-5 and research-based diagnostic (RBDC) criteria. Logistic regression showed age at first symptoms < 30 years, current MDE duration ≤ 1 month, hypomania/mania among first-degree relatives, past suicide attempts, treatment-resistance, antidepressant-induced swings, and atypical, mixed, or psychotic features during MDE to associate with High-Rec. LIMITATIONS: Number of MDEs for defining recurrence was arbitrary; cross-sectionality did not allow assessment of conversion from MDD to BD. CONCLUSIONS: High-Rec MDD differed from Low-Rec group for several clinical/epidemiological variables, including bipolar/mixed features. Bipolarity specifier and RBDC were more sensitive than DSM-5 criteria in detecting bipolar and mixed features in MDD.

Hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice.

Drug-induced changes in serum prolactin (sPrl) levels constitute a relevant issue due to the potentially severe consequences on physical health of psychiatric patients such as sexual dysfunctions, osteoporosis and Prl-sensitive tumors. Several drugs have been associated to sPrl changes. Only antipsychotics have been extensively studied as sPrl-elevating agents in schizophrenia, but the extent to which bipolar disorder (BD) treatments affect sPrl levels is much less known. The objective of this systematic review is to summarize the evidence of the effects of drugs used in BD on Prl. This review followed the PRISMA statement. The MEDLINE/PubMed/Index Medicus, EMBASE, and Cochrane Library databases were systematically searched for articles in English appearing from any time to May 30, 2014. Twenty-six studies were included. These suggest that treatments for BD are less likely to be associated with Prl elevations, with valproate, quetiapine, lurasidone, mirtazapine, and bupropion reported not to change PRL levels significantly and lithium and aripiprazole to lower them in some studies. Taking into account the effects of the different classes of drugs on Prl may improve the care of BD patients requiring long-term pharmacotherapy. Based on the results of this review, lithium and valproate appear to be safer due to their low potential to elevate sPrL; among antipsychotics, quetiapine, lurasidone and aripiprazole appear to be similarly safe.

The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.

OBJECTIVE: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

The symptom structure of bipolar acute episodes: in search for the mixing link.

OBJECTIVE: The nature of mixed mood episodes is still a matter of controversy amongst experts. Currently, the approach to this syndrome is mainly categorical and very restrictive. The factor-structure of bipolar mood episodes has not been studied yet. We performed a dimensional analysis of the structure of bipolar episodes aimed at identifying a factor deconstructing mixed episodes; furthermore, we analyzed correlations of factors emerging from the factorial analysis of the Brief Psychiatric Rating Scale (BPRS) with Temperament Evaluation of Memphis-Pisa-Paris-San Diego (TEMPS-A) and predominant polarity. METHOD: 187 consecutive bipolar I inpatients hospitalized for DSM-IV-TR acute mood episodes (depressive, manic or mixed) underwent a standardized assessment, including the 24-item Brief Psychiatric Rating Scale (BPRS 4.0), the 21-item Hamilton Depression Rating Scale (HDRS-21), the Young Mania Rating Scale (YMRS) and the TEMPS-A. Principal factor analysis was performed on BPRS-24 items. RESULTS: This analysis revealed five factors corresponding to "psychosis", "euphoric mania", "mixity", "dysphoria" and "inhibited depression", capturing 71.89% of the rotated variance. The mixity factor was characterized by higher rates of suicidal ideation, more mixed episodes, higher frequencies of antidepressant (AD) use, depressive predominant polarity and anxious temperament. DISCUSSION: The factor-structure of the BPRS in inpatients with bipolar I disorder with an acute episode of any type is pentafactorial; one factor identified is the mixity factor, which is independent from other factors and characterized by anxiety and motor hyperactivity and by the absence of motor retardation. Our results should prompt reconsideration of proposals for DSM-5 diagnostic criteria for the mixed features specifier. Limitations of the study include the relative small sample, the absence of drug-naïve patients and the use of rating scales no specific for mixed states.

Effectiveness of short-term olanzapine in patients with bipolar I disorder, with or without comorbidity with substance use disorder.

OBJECTIVES: Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. METHODS: Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. RESULTS: SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02-2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). CONCLUSIONS: The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

Treatment strategies according to clinical features in a naturalistic cohort study of bipolar patients: a principal component analysis of lifetime pharmacological and biophysic treatment options.

BACKGROUND: The treatment of patients with bipolar disorder (BD) is complex and psychiatrists often have to change treatment strategies. However, available data do not provide information about the most frequent patterns of treatment strategies prescribed in clinical practice and clinical/socio-demographic factors of drugs prescription. OBJECTIVE: The aims of this study were: (1) to identify specific patterns of life-time treatment strategies in a representative sample of bipolar patients; (2) to assess consistency with guidelines recommendations; and (3) to investigate clinical/socio-demographic of patients. METHODS: Six-hundred and four BD I and II out-patients were enrolled in a naturalistic cohort study at the Barcelona Bipolar Disorders Program, in a cross-sectional analysis. A principal component analysis was applied to group psychotropic drugs into fewer underlying clusters which represent patterns of treatment strategies more frequently adopted in the life-time naturalistic treatment of BD. RESULTS: Three main factors corresponding to three main prescription patterns were identified, which explained about 60% of cases, namely, Factor 1 (21.1% of common variance), defined the "antimanic stabilisation package" including treatments with antimanic mechanism of action in predominantly manic-psychotic BD I patients; Factor 2 (20.4%), "antidepressive stabilisation package" that grouped predominantly depressed patients, and Factor 3 (16.4%) defined the "anti-bipolar II package", including antidepressant monotherapy in BD II patients with depressive predominant polarity, melancholic features and higher rates of suicide behaviours. CONCLUSIONS: This study identified three patterns of lifetime treatment strategies in three specific and different groups of naturalistically treated bipolar patients.

Prevention of relapse with maintenance electroconvulsive therapy in elderly patients with major depressive episode.

OBJECTIVES: To evaluate the effectiveness and safety of maintenance electroconvulsive therapy (mECT) in elderly patients with treatment-resistant Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive episode. METHODS: Seven elderly patients with treatment-resistant major depressive episode were treated with a complete ECT cycle. Thereafter, they received one monthly ECT session as maintenance for 1 year. Response to treatment was defined as at least a 50% drop from baseline on the Hamilton Depression Rating Scale (HamD) and remission as not meeting criteria for major depression, a HamD score of 7 or less, and Clinical Global Impressions-Severity of Illness score of 1. We compared their response with the response of 7 elderly patients with treatment-resistant major depression who were treated with a full cycle of ECT but did not receive mECT (non-mECT). We compared the 2 groups for the number of relapses or recurrences of major depressive episodes after remission was achieved; a relapse or a recurrence occurred when HamD scores were 14 or higher, or when Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision major depressive episode criteria were met, or when Clinical Global Impressions-Severity of Illness score was 3 or higher and increased by at least 2 points from response/remission. RESULTS: The mECT group (4 women and 3 men; mean age, 73 years) had significantly less mean relapses/recurrences (0 vs 1.57) and hospitalizations (0 vs 1) and received less drug treatment than the nonMECT group (similar for age and sex composition) during the 12-month follow-up period. All patients with mECT improved during treatment and did not relapse. CONCLUSIONS: Maintenance ECT protected elderly patients from recurrent depressive episodes from relapsing/recurring more than standard ECT.

Deep transcranial magnetic stimulation for treatment-resistant bipolar depression: a case report of acute and maintenance efficacy.

Deep Transcranial Magnetic Stimulation (dTMS) is currently being evaluated as a possible treatment for several neuropsychiatric disorders and has been demonstrated as a safe and effective procedure. This case presents a patient with bipolar depression that has been treated with 20 daily consecutive dTMS sessions and with one dTMS session every 2 weeks for the following 3 months. Depressive symptoms improved rapidly and response was maintained during the next 6 months; cognitive performances also improved. This report suggests that add-on dTMS may help overcoming drug-resistance in bipolar depression and protect from subsequent bipolar episodes of any polarity.

Successful and rapid response to electroconvulsive therapy of a suicidal patient with comorbid bipolar I disorder and histrionic personality disorder.

A woman with bipolar disorder I, histrionic personality disorder, and suicidal ideation with repeated suicide attempts, who had been treated for 2 years with mood stabilizers, antipsychotics, and benzodiazepines, received a total of 8 bitemporal-biparietal electroconvulsive therapy sessions. Her suicidal ideation and self-harm behavior disappeared immediately after the first session and her psychopathology soon after. This supports the existence of a relatively independent suicidal syndrome and confirms data on its immediate responsiveness to electroconvulsive therapy. Electroconvulsive therapy must not be long withheld from patients with such characteristics to reduce unnecessary sufferance and suicidality.

Affective temperaments in general population: a review and combined analysis from national studies.

BACKGROUND: The aim of this study was to investigate the characteristics of affective temperaments in general non-clinical population in different countries METHOD: We performed a detailed search of published studies (one unpublished) investigating affective temperaments in non-clinical populations by administering the Temperament Evaluation of Memphis, Paris and San Diego Auto-questionnaire (TEMPS-A) in its 110-items version. We have included a total of six studies published from different countries (Argentina, Germany, Hungary, Korea, Lebanon, and Portugal) and one unpublished with preliminary data from Spain. We analyzed the combined data from the collected studies. RESULTS: We found significant gender differences, with men scoring higher in irritable and hyperthymic, and women in anxious, depressive and cyclothymic temperaments. Age had a significant effect in women with depressive temperament. Correlations among temperament scores have shown positive associations between depressive and anxious, and cyclothymic and irritable. CONCLUSIONS: There was a similarity in gender differences and the association between different affective temperaments. Our results indicate that affective temperaments show both universal and distinctive characteristics. LIMITATION: The sample populations in different countries were not homogeneous for age and socio-economic composition. In the Korean study of Kang et al. the version of the TEMPS was not validated.

Suicide in a large population of former psychiatric inpatients.

AIMS: The aim of this study was to identify predictors of completed suicide in a wide sample of psychiatric inpatients receiving retrospective and prospective DSM-IV diagnoses. METHODS: We followed up 4441 severe psychiatric patients who were hospitalized for some time during a 35-year period in a private hospital setting. We collected sociodemographic, clinical and temperamental data. RESULTS: Ninety-six patients from the sample committed suicide. There were no sex differences in suicide completion and no differences between major psychiatric disorders, but people who had been hospitalized for anxiety disorders did not commit suicide and people with bipolar disorders were more likely to commit suicide than people with unipolar major depression. Shorter-term treatment with lithium and anticonvulsants, longer-term treatment with antidepressants, history of suicide attempts, suicidal thinking, and single status positively predicted completed suicide. Suicide tended to occur after a mean period of about 14 years of duration of disease. Patients' symptoms during the period preceding suicide were assessed through interviewing patients' physicians or family members. Symptoms occurring in >10% of cases were, in decreasing order, inner tension, racing/crowded thoughts, aggressive behavior, guilt, psychomotor agitation, persecutory ideation, anxiety, and hallucinations. Surprisingly, cyclothymic temperament was less associated with completed suicide as compared to other temperaments. CONCLUSIONS: Suicide is likely to occur in a milieu of agitation, mixed anxiety and depression, and psychosis. Longer-term mood stabilizer treatment may reduce the rate of completed suicide.

Mania and depression. Mixed, not stirred.

OBJECTIVE: Current criteria for mixed bipolar episode do not allow an adequate understanding of a vast majority of bipolar patients with mixed (hypo) manic-depressive features, keeping the qualification of "mixed episodes" for bipolar type I only. This study was aimed to test the existence of a bipolar-mixed continuum by comparing the characteristics of three groups classified according to patterns of past and current manic or mixed episodes. METHOD: 134 bipolar I inpatients were divided according to their pattern of excitatory "mixed-like" episodes in three groups: 1) lifetime history of purely manic episodes without mixed features (PMA); 2) lifetime history of both manic and mixed episodes (MIX) and 3) lifetime history exclusively of mixed, but not manic, episodes (PMIX). Differences in clinical and demographic characteristics were analyzed by using chi-square head-to-head for categorical data, one-way ANOVA for continuous variables and Tukey's post-hoc comparison. Logistic regression was used to control for data validity. RESULTS: PMIX had higher rates of depressive predominant polarity and less lifetime history of psychotic symptoms, and had received more antidepressants both lifetime and during 6 months prior to index episode. PMIX had more suicide attempts and Axis I comorbidity than PMA. DISCUSSION: PMIX is likely to have a higher risk for suicide and higher rates of comorbidities; current DSM-IV-TR criteria are not fit for correctly classifying these patients and this may affect treatment appropriateness. The concept of "mixicity" should be extended beyond bipolar I disorder to other bipolar disorder subtypes.

Personality changes after Toscana virus (TOSV) encephalitis in a 49-year-old man: A case report.

Toscana virus (TOSV) infection may often cause symptomatic meningitides and encephalitides. These usually subside in few days and their sequelae do not last for more than few weeks. We here report the case of a 49-year-old man who developed encephalitis after being bitten by phlebotomi in a region near southern Tuscany, where TOSV is endemic, and who developed postencephalitic seizures and subsequently, persistent personality alterations, characterized by sexually dissolute behavior and aggressiveness. One year after infection, the patient needs a combination of an SSRI antidepressant and a mood stabilizer/anticonvulsant to obtain less than optimal symptom improvement. This points to the need of establishing better preventive measures in Tuscany and nearby regions.

Psychotic versus non-psychotic bipolar II disorder.

INTRODUCTION: Psychotic symptoms in bipolar II disorder, allowed by definition only during a depressive episode, are present in a range between 3% and 45%. Little is known regarding the impact of psychotic symptoms on the clinical course of bipolar II patients. Findings from previous reports are controversial and focused specifically on bipolar I disorder. The aim of this study was to ascertain the clinical characteristics of individuals with bipolar II disorder with and without lifetime history of psychotic symptoms. METHODS: The sample consisted of 164 DSM-IV Bipolar II patients consecutively recruited from the Barcelona Bipolar Disorder Program. Patients were divided in Bipolar II patients with (N=32) and without (N=132) lifetime history of psychotic symptoms. Clinical and sociodemographic features were compared. RESULTS: Thirty-two out of 164 patients with bipolar II disorder had a history of psychosis during depression (19.5%). Bipolar II patients with a history of psychotic symptoms showed a higher number of hospitalizations than patients without such a history (p<0.001). They were also older but were less likely to have a family history of bipolar illness and any mental disorder than non-psychotic bipolar II patients. Melancholic and catatonic features were significantly more frequent in psychotic bipolar II patients (p<0.001). CONCLUSIONS: Our findings confirm that the presence of psychotic symptoms in bipolar II disorder is not rare. Psychotic bipolar II disorder may be a different phenotype from non-psychotic bipolar disorder.

Assessment of the capacity to express informed consent for organ donation in patients with schizophrenia.

In Italy, the "silent-consent" principle of donor's willingness regulates organ donation for postmortem transplantation, but civil incompetence excludes it. We investigated decisional capacity for organ donation for transplantation of 30 controls and 30 nonincompetent patients with schizophrenia as related to clinical symptoms, cognition, and functioning. Assessments were carried out through the Competence for Donation Assessment Scale (CDAS), Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms, Life Skills Profile (LSP), Raven's Colored Progressive Matrices (RCPM), Wisconsin Card Sorting Test, Rey RI, Rey RD, and Visual Search. Patients and controls differed on the CDAS Understanding and Choice Expression areas. Patients showed significant inverse bivariate correlations between CDAS Understanding and scores on total BPRS, LSP self-care scale, and RCPM cognitive test. Our results show that decisional capacity for participating in research does not predict decisional capacity for postmortem organ donation in patients with schizophrenic or schizoaffective psychosis; hence, before judging consent for donation, patients must be provided with enhanced information to better understand this delicate issue.

Has number of previous episodes any effect on response to group psychoeducation in bipolar patients? A 5-year follow-up post hoc analysis.

UNLABELLED: Colom F, Reinares M, Pacchiarotti I, Popovic D, Mazzarini L, Martínez-Arán A, Torrent C, Rosa A, Palomino-Otiniano R, Franco C, Bonnin CM, Vieta E. Has number of previous episodes any effect on response to group psychoeducation in bipolar patients? A 5-year follow-up post hoc analysis. OBJECTIVE: One of the main utilities of staging in bipolar disorder is enhancing the formulation of pharmacological and non-pharmacological treatment strategies. Hence, it is essential to ascertain whether the number of previous episodes influences treatment response. Hereby, we present a 5-year post hoc study on the efficacy of group psychoeducation for bipolar disorders according to the number of previous episodes. METHODS: For this subanalysis, we have compared the 5-year outcome of 120 euthymic psychoeducated versus non-psychoeducated bipolar patients according to the number of previous episodes at study entry. RESULTS: Patients with more than seven episodes at study entry did not show any significant improvement with psychoeducation according to time to recurrence. Patients with more than 14 episodes did not benefit from psychoeducation in terms of a reduction of time spent ill. Patients with 7 or 8 episodes showed a benefit in terms of fewer days spent in hypomania, depression, mixed episodes or any episodes but not mania, while patients with 9-14 episodes showed a benefit in terms of fewer days spent in hypomania and depression but not in mixed states or mania. Only patients who presented up to 6 episodes showed reduction in time spent in any episode polarity. CONCLUSION: The number of previous episodes clearly worsens response to psychoeducation, perhaps in a more subtle way than that observed with other psychological therapies. Psychoeducation should be delivered as soon as possible in the illness course, supporting the idea of early intervention.