Validity of the DSM-5 Mixed Features Specifier Interview.

OBJECTIVES: To examine the reliability and validity of a semi-structured interview assessing the features of the DSM-5 mixed features specifier. Our goal was to develop an instrument that could be used for both diagnostic and severity measurement purposes. METHODS: Four hundred fifty-nine psychiatric patients in a depressive episode were interviewed by a trained diagnostic rater who administered semi-structured interviews including the DSM-5 Mixed Features Specifier Interview (DMSI). We examined the inter-rater reliability and psychometric properties of the DMSI. The patients were rated on clinician rating scales of depression, anxiety, and irritability, and measures of psychosocial functioning, suicidality, and family history of bipolar disorder. RESULTS: The DMSI had excellent joint-interview interrater reliability. More than twice as many patients met the DSM-5 mixed features specifier criteria during the week before the assessment than for the majority of the episode (9.4% vs. 3.9%). DMSI total scores were more highly correlated with a clinician-rated measure of manic symptoms than with measures of depression and anxiety. More patients with bipolar depression met the mixed features specifier than patients with MDD. Amongst patients with MDD, those with mixed features more frequently had a family history of bipolar disorder, were more frequently diagnosed with anxiety disorders, attention deficit disorder, and borderline personality disorder, more frequently had attempted suicide, and were more severely depressed, anxious, and irritable. CONCLUSION: The DMSI is a reliable and valid measure of the presence of the DSM-5 mixed features specifier in depressed patients as well as the severity of the features of the specifier.

Phenotypic clustering of bipolar disorder supports stratification by lithium responsiveness over diagnostic subtypes.

INTRODUCTION: The aim of this study was to determine whether the clinical profiles of bipolar disorder (BD) patients could be differentiated more clearly using the existing classification by diagnostic subtype or by lithium treatment responsiveness. METHODS: We included adult patients with BD-I or II (N = 477 across four sites) who were treated with lithium as their principal mood stabilizer for at least 1 year. Treatment responsiveness was defined using the dichotomized Alda score. We performed hierarchical clustering on phenotypes defined by 40 features, covering demographics, clinical course, family history, suicide behaviour, and comorbid conditions. We then measured the amount of information that inferred clusters carried about (A) BD subtype and (B) lithium responsiveness using adjusted mutual information (AMI) scores. Detailed phenotypic profiles across clusters were then evaluated with univariate comparisons. RESULTS: Two clusters were identified (n = 56 and n = 421), which captured significantly more information about lithium responsiveness (AMI range: 0.033 to 0.133) than BD subtype (AMI: 0.004 to 0.011). The smaller cluster had disproportionately more lithium responders (n = 47 [83.8%]) when compared to the larger cluster (103 [24.4%]; p = 0.006). CONCLUSIONS: Phenotypes derived from detailed clinical data may carry more information about lithium responsiveness than the current classification of diagnostic subtype. These findings support lithium responsiveness as a valid approach to stratification in clinical samples.

Depression, Mood Disorders and Bipolar Spectrum: One or Different Diseases?

The concept of mixity is the essential cognitive cornerstone for quantifying and understanding unstable mood and restlessness, which are components of all mood disorders, diseases that always present fluctuations in mood, from the depressive component to the restless one and to the hypomanic and manic one. The GT-MSRS Mixed States Rating Scale becomes an essential means for early diagnosis.

Bipolar disorders.

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

Progression of the functional deficit in a group of patients with bipolar disorder: a cluster analysis based on longitudinal data.

We aimed to examine the trajectory of psychosocial functioning in a sample of euthymic patients with bipolar disorder (BD) throughout a 5-year follow-up. Ninety-nine euthymic bipolar patients and 40 healthy controls (HC) were included. A neurocognitive assessment (17 neurocognitive measures grouped in 6 domains) was carried out at baseline. The split version of the Global Assessment of Functioning scale (GAF-F) and the Functioning Assessment Short Test (FAST) were used to examine psychosocial functioning at baseline (T1), and after a 5-year follow-up (T2). The statistical analysis was performed through repeated measures ANOVA and hierarchical cluster analysis based on the GAF-F and the FAST scores at T1 and T2. Eighty-seven patients (87.9%) were evaluated at T2. The cluster analysis identified two groups of patients. The first group included 44 patients (50.6%) who did not show a progression of the functional impairment (BD-NPI). The second cluster, which included 43 patients (49.4%), was characterized by a progression of the functional impairment (BD-PI). The BD-PI had a higher number of relapses and a higher number of hospitalizations during the follow-up period, as well as worse neurocognitive functioning than the BD-NPI. The repeated measures ANOVA confirmed that the psychosocial performance of BD-NPI is stable while there was a progression of the functional deterioration in BD-PI. The trajectory of the psychosocial functioning of patients with BD is not homogeneous. Our results suggest that in at least one subset of patients with BD, which might account for half of the patients, the disease has a progressive course.

Altered ethanolamine plasmalogen and phosphatidylethanolamine levels in blood plasma of patients with bipolar disorder.

AIM: Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP. METHODS: Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored. RESULTS: Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients. CONCLUSIONS: Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.

[Attention-deficit/hyperactivity disorder in adults in the clinical description and classification of Emil Kraepelin]. / Die Aufmerksamkeitsdefizit­/Hyperaktivitätsstörung bei Erwachsenen in der klinischen Beschreibung und der Klassifikation von Emil Kraepelin.

This study presents descriptions of symptoms specific to the adult form of attention-deficit/hyperactivity disorder (ADHD) in the 8th edition of the Textbook on Psychiatry by Emil Kraepelin (1856-1926). To identify whether ADHD is a new, fashionable phenomenon in adults or whether early psychiatrists also saw such patients and how they classified them, this textbook is an essential source. Published between 1905 and 1915, it can be perceived as the culmination and at the same time terminal point of Kraepelin's conceptual and nosological work, which in turn marked the beginning of present-day psychiatric classification. Kraepelin did not perceive ADHD as a psychiatric entity of its own, which is either due to the fact that he saw no necessity to do so or that he did not recognize this. If the latter, Kraepelin may have been misled by the manifold psychiatric comorbidities typical for ADHD, which may have masked ADHD. Kraepelin seems to have grouped patients obviously suffering from the adult form of ADHD into two groups: on the one hand into the so-called basic constitution (Grundzustand) of manic-depressive disorder, which he called manic disposition or constitutional excitement (manische Veranlagung oder konstitutionelle Erregung) and on the other hand into the so-called group of anchorless people (Haltlose), which he perceived as a special form of psychopathic personality. It seems that Kraepelin grouped milder grades of ADHD with predominantly ADHD-associated mood swings into the group of manic disposition while grouping more severe forms, which usually occur together with distinct personality disorders and addictive disorders, into that of anchorless people.

Clinical course predicts long-term outcomes in bipolar disorder.

BACKGROUND: The long-term outcomes of bipolar disorder range from lasting remission to chronic course or frequent recurrences requiring admissions. The distinction between bipolar I and II disorders has limited utility in outcome prediction. It is unclear to what extent the clinical course of bipolar disorder predicts long-term outcomes. METHODS: A representative sample of 191 individuals diagnosed with bipolar I or II disorder was recruited and followed for up to 5 years using a life-chart method. We previously described the clinical course over the first 18 months with dimensional course characteristics and latent classes. Now we test if these course characteristics predict long-term outcomes, including time ill (time with any mood symptoms) and hospital admissions over a second non-overlapping follow-up period in 111 individuals with available data from both 18 months and 5 years follow-ups. RESULTS: Dimensional course characteristics from the first 18 months prospectively predicted outcomes over the following 3.5 years. The proportion of time depressed, the severity of depressive symptoms and the proportion of time manic predicted more time ill. The proportion of time manic, the severity of manic symptoms and depression-to-mania switching predicted a greater likelihood of hospital admissions. All predictions remained significant after controlling for age, sex and bipolar I v. II disorder. CONCLUSIONS: Differential associations with long-term outcomes suggest that course characteristics may facilitate care planning with greater predictive validity than established types of bipolar disorders. A clinical course dominated by depressive symptoms predicts a greater proportion of time ill. A clinical course characterized by manic episodes predicts hospital admissions.

Upregulation of the nitrosylome in bipolar disorder type 1 (BP1) and major depression, but not BP2: Increased IgM antibodies to nitrosylated conjugates are associated with indicants of leaky gut.

OBJECTIVE: Major depression (MDD) and a lifetime history of MDD are characterized by increased nitrosylation, while bipolar disorder type 1 (BP1), but not BP2, is accompanied by highly increased levels of oxidative stress and nitric oxide (NO) production. Nevertheless, it is unknown whether nitrosylation is involved in BP and whether there are differences in nitrosylation between BP1 and BP2. METHODS: Serum IgM antibodies directed against nitroso (NO)-adducts were examined in MDD, BP1, BP2 and healthy controls, namely IgM responses to NO-cysteine, NO-tryptophan (NOW), NO-arginine and NO-albumin (SBA) in association with IgA/IgM responses to LPS of Gram-negative bacteria, IgG responses to oxidized low-density lipoprotein (ox-LDL) and serum peroxides. RESULTS: Serum IgM levels against NO adducts were significantly higher in BP1 and MDD as compared with healthy controls, whereas BP2 patients occupied an intermediate position. IgM responses to NO-albumin were significantly higher in BP1 and MDD than in BP2 patients. There were highly significant associations between the IgM responses to NO-adducts and IgG responses to ox-LDL and IgA/IgM responses to Gram-negative bacteria. CONCLUSIONS: BP1 and MDD are characterized by an upregulation of the nitrosylome (the proteome of nitrosylated proteins) and increased IgM responses to nitrosylated conjugates. Increased nitrosylation may be driven by increased bacterial translocation and is associated with lipid peroxidation processes. Innate-like (B1 and marginal zone) B cells and increased nitrosylation may play a key role in the major affective disorders through activation of immune-inflammatory and oxidative pathways, cardiovascular comorbidity and impairments in antioxidant defenses, neuro-glial interactions, synaptic plasticity, neuroprotection, neurogenesis.

Acute and Transient Psychotic Disorders: Newer Understanding.

PURPOSE OF REVIEW: We review the ongoing research in the area of acute and transient psychotic disorders (ATPDs) with regard to their nosology, epidemiology, clinical description, genetics, and neurobiology, examining evidence for distinctiveness or otherwise of ATPDs. We further highlight the lacuna in research in ATPDs. RECENT FINDINGS: Studies on ATPDs as defined in the ICD 10 have been reported from different parts of the world, more so from the developing countries. There is consistent evidence that there exist a group of ATPDs that occur more commonly among females, are often precipitated by stressful life events or exposure to physiological stresses like fever, child birth, are associated with well-adjusted premorbid personality, and show complete recovery in a short period. Although in some cases of ATPDs, there is symptomatic overlap with schizophrenic symptoms in the acute phase, they follow a completely different course and outcome, exhibit genetic distinctiveness, and do not share genetic relationship with schizophrenias or bipolar affective disorder (BPAD). Comparative studies on neurophysiology and neuroimaging in ATPDs and schizophrenias have demonstrated evidence of hyper arousal and hyper metabolism in ATPDs vs hypo arousal and hypo metabolism as noted in the P300 response and on FDG PET studies, respectively. Immune markers such as IL-6, TNF-alpha, and TGF-beta show higher levels in ATPDs as compared to healthy controls. Findings on the neurobiological mechanisms underlying ATPDs, so far, point towards significant differences from those in schizophrenia or BPAD. Although the studies are few and far between, nevertheless, these point towards the possibility of ATPDs as a distinct entity and underscore the need for pursuing alternate hypothesis such as neuro inflammatory or metabolic. Research on ATPDs is limited due to many reasons including lack of harmony between the ICD and DSM diagnostic systems and clinician biases. Available research data supports the validity of ATPDs as a distinct clinical entity. There is also evidence that ATPDs are different from schizophrenias or BPAD on genetic, neuroimaging, neurophysiological, and immunological markers and require further studies.

Mixed states in bipolar disorder: modelling, measuring and managing.

OBJECTIVE:: To consider whether consensus exists in recommendations for managing bipolar mixed states published in recent reviews and treatment guidelines, and to summarise what might be their best management. CONCLUSION:: Limitations to and changes in the definition of mixed states compromise diagnosis and management. The striking comparison between DSM-IV and DSM-5 criteria sets risks under-diagnosis and over-diagnosis. Current reviews and guidelines offer limited evidence to guide treatment; however, management should involve addressing the contribution of any antidepressant medication, and the introduction of a second-generation antipsychotic medication to stabilise the condition.

Crossed prevalence results between subtypes of eating disorder and bipolar disorder: A systematic review of the literature.

OBJECTIVE: To assess the association between sub-types of bipolar disorder (BD) (types I and II) and sub-types of eating disorders (EDs) (Anorexia Nervosa, Bulimia Nervosa, Binge-eating disorders) as well as their relative order of occurrence. METHODOLOGY: A systematic review of articles estimating prevalence rates for BD among patients with ED and vice versa. We also analysed all articles assessing their relative order of occurrence. RESULTS: Comorbid BD is common among patients with an ED. From 0.6 to 33.3% of bipolar subjects have an eating disorder. Conversely, from 0 to 35.8% of subjects with an ED can present a BD. This co-occurrence has mostly been observed among patients with anorexia of the bulimic/purging type, with bulimia or with binge-eating disorders. The association is less frequent in cases of anorexia of the restrictive type. In contrast, the BD sub-type does not seem to have an impact on the association with EDs. Whilst age at BD onset is earlier in case of a comorbid ED, age at ED onset does not seem to be impacted by the presence of an associated BD. There has been little data on the relative order of occurrence of the two disorders or on the impact of the thymic phase on the expression of EDs. CONCLUSIONS: EDs and BD are frequently comorbid, suggesting the need for crossed screening of these pathologies, in particular for EDs with purging behaviours and for patients with early BD onset.

Fractional anisotropy of the uncinate fasciculus and cingulum in bipolar disorder type I, type II, unaffected siblings and healthy controls.

BACKGROUND: Fractional anisotropy in the uncinate fasciculus and the cingulum may be biomarkers for bipolar disorder and may even be distinctly affected in different subtypes of bipolar disorder, an area in need of further research.AimsThis study aims to establish if fractional anisotropy in the uncinate fasciculus and cingulum shows differences between healthy controls, patients with bipolar disorder type I (BD-I) and type II (BD-II), and their unaffected siblings. METHOD: Fractional anisotropy measures from the uncinate fasciculus, cingulum body and parahippocampal cingulum were compared with tractography methods in 40 healthy controls, 32 patients with BD-I, 34 patients with BD-II, 17 siblings of patients with BD-I and 14 siblings of patients with BD-II. RESULTS: The main effects were found in both the right and left uncinate fasciculus, with patients with BD-I showing significantly lower fractional anisotropy than both patients with BD-II and healthy controls. Participants with BD-II did not differ from healthy controls. Siblings showed similar effects in the left uncinate fasciculus. In a subsequent complementary analysis, we investigated the association between fractional anisotropy in the uncinate fasciculus and polygenic risk for bipolar disorder and psychosis in a large cohort (n = 570) of healthy participants. However, we found no significant association. CONCLUSIONS: Fractional anisotropy in the uncinate fasciculus differs significantly between patients with BD-I and patients with BD-II and healthy controls. This supports the hypothesis of differences in the physiological sub-tract between bipolar disorder subtypes. Similar results were found in unaffected siblings, suggesting the potential for this biomarker to represent an endophenotype for BD-I. However, fractional anisotropy in the uncinate fasciculus seems unrelated to polygenic risk for bipolar disorder or psychosis.Declaration of interestNone.

Stratification of the risk of bipolar disorder recurrences in pregnancy and postpartum.

BACKGROUND: Pregnancy and childbirth are a period of high risk for women with bipolar disorder and involve difficult decisions particularly about continuing or stopping medications.AimsTo explore what clinical predictors may help to individualise the risk of perinatal recurrence in women with bipolar disorder. METHOD: Information was gathered retrospectively by semi-structured interview, questionnaires and case-note review from 887 women with bipolar disorder who have had children. Clinical predictors were selected using backwards stepwise logistic regression, conditional permutation random forests and reinforcement learning trees. RESULTS: Previous perinatal history of affective psychosis or depression was the most significant predictor of a perinatal recurrence (odds ratio (OR) = 8.5, 95% CI 5.04-14.82 and OR = 3.6, 95% CI 2.55-5.07 respectively) but even parous women with bipolar disorder without a previous perinatal mood episode were at risk following a subsequent pregnancy, with 7% developing postpartum psychosis. CONCLUSIONS: Previous perinatal history of affective psychosis or depression is the most important predictor of perinatal recurrence in women with bipolar disorder and can be used to individualise risk assessments.Declaration of interestNone.

Heterogeneity of functional outcomes in patients with bipolar disorder: a cluster-analytic approach.

OBJECTIVE: The aim was to examine the heterogeneity of psychosocial outcomes in euthymic bipolar disorder (BD) patients and analyse the potential influence of distinct variables on functioning. METHOD: Using a hierarchical cluster exploratory analysis, 143 euthymic patients with diagnosis of BD were grouped according to their functional performance based on domains scores of the Functioning Assessment Short Test (FAST). The resulting groups were compared on sociodemographic, clinical and neurocognitive variables to find factors associated with each functional cluster. RESULTS: Patients were grouped in three functional profiles: patients with good functioning in all the FAST areas, patients with an intermediate profile showing great difficulties in the occupational domain and milder difficulties in most of the rest domains, and a third group with serious difficulties in almost all functional areas. Both functionally impaired groups were characterized by higher subthreshold symptoms (depressive and manic) and higher unemployment rates. The most functionally impaired group also showed lower scores on some measures of processing speed. CONCLUSION: Two of three functional profiles showed some kind of impairment which was associated with subsyndromal symptoms and cognitive performance. These patterns should be taken into consideration to develop more individualized interventions to restore, or improve, psychosocial outcomes.

Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression.

BACKGROUND: Atypical depression may show lowered rather than raised short-term cortisol levels. Atypical major depressive episodes (A-MDE) may also be more closely linked to environmental factors and show overlap with somatic symptom disorders. Hair specimens allow measuring long-term cortisol levels. METHODS: Twenty-seven A-MDE and 44 NA-MDE patients and 40 matched controls were tested. Measures of hair cortisol concentration [HCC] covering the previous 3 months and short-term cortisol parameters (six saliva specimens to assess the cortisol awakening response [CAR] and total daily cortisol output calculated as the area under the curve [AUCg]) were taken alongside measures of environmental factors and clinical variables. RESULTS: There were no differences in HCC between the three groups (P = 0.8), and no difference in the CAR (P = 0.95). However, A-MDE showed lowered short-term cortisol output (AUCg) compared to controls (P = 0.04). A-MDE patients also reported a higher number of daily hassles, and higher levels of fatigue and impaired concentration than NA-MDE. CONCLUSIONS: Normal long-term (HCC) and reduced short-term (AUCg) cortisol levels in A-MDE could suggest a disrupted long-term cortisol rhythm, perhaps affected by environmental factors or by certain symptoms, such as mid-nocturnal insomnia. However, other underlying explanations for these findings should also be investigated in the future.

Complexity in mood disorder diagnosis: fMRI connectivity networks predicted medication-class of response in complex patients.

OBJECTIVE: This study determined the clinical utility of an fMRI classification algorithm predicting medication-class of response in patients with challenging mood diagnoses. METHODS: Ninety-nine 16-27-year-olds underwent resting state fMRI scans in three groups-BD, MDD and healthy controls. A predictive algorithm was trained and cross-validated on the known-diagnosis patients using maximally spatially independent components (ICs), constructing a similarity matrix among subjects, partitioning the matrix in kernel space and optimizing support vector machine classifiers and IC combinations. This classifier was also applied to each of 12 new individual patients with unclear mood disorder diagnoses. RESULTS: Classification within the known-diagnosis group was approximately 92.4% accurate. The five maximally contributory ICs were identified. Applied to the complicated patients, the algorithm diagnosis was consistent with optimal medication-class of response to sustained recovery in 11 of 12 cases (i.e., almost 92% accuracy). CONCLUSION: This classification algorithm performed well for the know-diagnosis but also predicted medication-class of response in difficult-to-diagnose patients. Further research can enhance this approach and extend these findings to be more clinically accessible.

Factors associated with poor functional outcome in bipolar disorder: sociodemographic, clinical, and neurocognitive variables.

OBJECTIVE: The current investigation aimed at studying the sociodemographic, clinical, and neuropsychological variables related to functional outcome in a sample of euthymic patients with bipolar disorder(BD) presenting moderate-severe levels of functional impairment. METHODS: Two-hundred and thirty-nine participants with BD disorders and with Functioning Assessment Short Test(FAST) scores equal or above 18 were administered a clinical and diagnostic interview, and the administration of mood measure scales and a comprehensive neuropsychological battery. Analyses involved preliminary Pearson bivariate correlations to identify sociodemographic and clinical variables associated with the FAST total score. Regarding neuropsychological variables, a principal component analysis (PCA) was performed to group the variables in orthogonal factors. Finally, a hierarchical multiple regression was run. RESULTS: The best fitting model for the variables associated with functioning was a linear combination of gender, age, estimated IQ, Hamilton Depression Rating Scale (HAM-D), number of previous manic episodes, Factor 1 and Factor 2 extracted from the PCA. The model, including all these previous variables, explained up to 29.4% of the observed variance. CONCLUSIONS: Male gender, older age, lower premorbid IQ, subdepressive symptoms, higher number of manic episodes, and lower performance in verbal memory, working memory, verbal fluency, and processing speed were associated with lower functioning in patients with BD.