A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Shape analysis of the cingulum, uncinate and arcuate fasciculi in patients with bipolar disorder.

BACKGROUND: Abnormal maturation of brain connectivity is supposed to underlie the dysfunctional emotion regulation in patients with bipolar disorder (BD). To test this hypothesis, white matter integrity is usually investigated using measures of water diffusivity provided by MRI. Here we consider a more intuitive aspect of the morphometry of the white matter tracts: the shape of the fibre bundles, which is associated with neurodevelopment. We analyzed the shape of 3 tracts involved in BD: the cingulum (CG), uncinate fasciculus (UF) and arcuate fasciculus (AF). METHODS: We analyzed diffusion MRI data in patients with BD and healthy controls. The fibre bundles were reconstructed using Q-ball-based tractography and automated segmentation. Using Isomap, a manifold learning method, the differences in the shape of the reconstructed bundles were visualized and quantified. RESULTS: We included 112 patients and 82 controls in our analysis. We found the left AF of patients to be further extended toward the temporal pole, forming a tighter hook than in controls. We found no significant difference in terms of shape for the left UF, the left CG or the 3 right fasciculi. However, in patients compared with controls, the ventrolateral branch of the left UF in the orbitofrontal region had a tendency to be larger, and the left CG of patients had a tendency to be smaller in the frontal lobe and larger in the parietal lobe. LIMITATIONS: This was a cross-sectional study. CONCLUSION: Our results suggest neurodevelopmental abnormalities in the left AF in patients with BD. The statistical tendencies observed for the left UF and left CG deserve further study.

Corpus callosum area in patients with bipolar disorder with and without psychotic features: an international multicentre study.

BACKGROUND: Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls. METHODS: We analyzed anatomic T1 MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features. RESULTS: We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features. LIMITATIONS: We found small to medium effect sizes, and there was no calibration technique among the sites. CONCLUSION: Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.

Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients.

BACKGROUND: Different factors may influence cognitive functioning in bipolar disorder such as the effect of subsyndromal symptoms, the history of psychotic symptomatology or substance abuse, negative symptomatology, chronicity, sleep disturbances, and hormonal factors. The effect of pharmacologic treatment on cognition is still uncertain because of an insufficient number of studies examining this issue. OBJECTIVE: The aims of this study were to compare neuropsychologic performance of treated bipolar patients with that of controls, including unmedicated patients and healthy subjects, as well as to evaluate possible neurocognitive differences among 3 different atypical antipsychotics. RESEARCH DESIGN AND METHODS: A total of 119 subjects were included in the study. Of 79 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition euthymic bipolar patients, 68 were treated with one atypical antipsychotic, quetiapine (n = 12), olanzapine (n = 26), or risperidone (n = 30). Sixteen patients were drug-free. The 4 groups were compared with a sample of drug-naïve patients and a healthy control group (n = 35) on several clinical and neuropsychologic variables, especially on the domains of attention, verbal memory, and executive functions. Euthymia was defined by a score of 6 or less at the Young Mania Rating Scale and a score of 8 or less at the Hamilton Depression Rating Scale for at least 6 months. RESULTS: The 5 groups did not differ in age, years of education, sex distribution, or estimated premorbid IQ. The 4 patients groups did not differ in chronicity, age of onset, total number of episodes, and number of hospitalizations. No differences were found regarding antipsychotic dosages between the groups. Bipolar patients performed poorly on most neuropsychologic measures as compared with healthy controls. After controlling for Hamilton Depression Rating Scale symptoms, no significant change in the results was observed. Because many patients with antipsychotic treatment had a history of psychotic symptoms, we performed multivariate analysis of covariance controlling for this variable. Bipolar patients taking 1 of the 3 antipsychotics presented with dose-independent significant deficits in most cognitive tasks compared with healthy controls. After several head-to-head group comparisons, the patients receiving quetiapine showed a better performance in learning task, short-term memory, and recognition task assessed with the California Verbal Learning Test and verbal fluency (P < .05). CONCLUSIONS: Our results confirm the findings of previous studies of cognitive deficits in bipolar disorder. Untreated euthymic patients showed better cognitive performance than did patients on atypical antipsychotics. Some iatrogenic-pharmacologic effect, therefore, cannot be excluded, but quetiapine seemed to be less associated with impairment in measures of verbal memory than olanzapine or risperidone. We suggest to use drugs in bipolar disorder with a lower risk of cognitive adverse effects. However, randomized controlled trials are urgently needed to give a definite answer to this critical problem.

Individual factors influencing the duration of untreated psychosis.

AIM: Duration of untreated psychosis (DUP), or the time between onset of psychosis and treatment initiation, is a prognostic factor of schizophrenia. However, few studies evaluated the relative influence of individual-related factors on this duration. The objective of this study was to evaluate the influence of socio-demographic, clinical and cannabis use on DUP. METHODS: This study was part of a large prospective study in help-seeking individuals referred to our specialized early detection / intervention clinic in the Service Hospitalo-Universitaire of Sainte-Anne Hospital in Paris (ICAAR study). We explored 33 consecutive patients who crossed the CAARMS' threshold of psychosis. The DUP and cannabis consumption history were explored during the baseline comprehensive assessment using all available sources (direct interviews of patients, parents, practitioners). Correlations between socio-demographic, clinical and cannabis use, and DUP were studied. A multiple linear regression model was used to determine the variables that could significantly predict DUP. RESULTS: When considered individually, none of the socio-demographic and disease characteristic factors was associated with DUP, with the exception of level of education. In the multivariate analysis, age at inclusion, negative symptoms and history of cannabis use significantly influenced DUP. CONCLUSION: The determinants of DUP are multi-factorial and include individual centred factors, such as age, cannabis and negative symptoms. The identification of factors resulting in delayed access to care may promote the development of effective strategies to reduce DUP in early psychosis and target effective early intervention.

Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review.

OBJECTIVE: The main objective of this review of the literature was to evaluate the safety and efficacy of Vagus Nerve Stimulation (VNS) in treatment-resistant depression (TRD) by means of systematic review and meta-analysis. METHODS: A systematic review of the literature was made using the major databases (Medline, Psychological Abstracts, Current Contents), beginning in January 2000 and ending in September 2007. Ninety-eight references were found, but only 18 add-on studies met the required quality criteria and were included in this review. Only one double-blind, randomized study was available and therefore a meta-analysis was not feasible. RESULTS: In a majority of the preliminary open studies selected for this review, VNS was associated with a significant reduction of the depressive symptoms (primary outcome: Hamilton Depression Rating Scale, HDRS) in the short and long term. Unfortunately, the only double-blind study gave rather inconclusive results. Generally, VNS is reported to be a safe and feasible procedure, despite its invasive nature. CONCLUSIONS: VNS seems to be an interesting new approach to treating TRD. However, despite the promising results reported mainly in open studies, further clinical trials are needed to confirm its efficacy in major depression. Moreover, studies on its mechanism of action and cost-effectiveness are also required to better understand and develop VNS therapy for affective disorder.

Bipolar I patients with and without a history of psychotic symptoms: do they differ in their cognitive functioning?

Recently, many reports have consistently demonstrated cognitive deficits in patients with bipolar disorder (BD), but their relationship with symptomatology, specifically psychotic symptoms, remains unclear. Our main hypothesis was that a history of hallucinations and/or delusions in the course of BD-I is associated with severe cognitive deficits. We investigated several cognitive functions (memory, attention, verbal fluency and executive functions) in 18 BD-I patients with a history of psychotic symptoms (HPS+), 17 BD-I patients without a history of psychotic symptoms (HPS-), 33 schizophrenic patients and 26 healthy control subjects. Both groups of BD-I patients were more impaired than the normal controls in attention, verbal memory, verbal fluency and executive functions. Only HPS+ BD-I patients showed more difficulties in completing the Stroop test than nonpsychotic bipolar patients. Nevertheless, after adjustment for the effects of current psychopathology, this difference disappeared. Schizophrenic subjects showed worse performance than BD-I subjects in verbal memory and verbal fluency. These results suggest that a history of psychotic symptoms in bipolar I disorder may not be associated with more cognitive deficits. Further research on euthymic bipolar patients with and without HPS is required to confirm these findings.

Childhood trauma and the limbic network: a multimodal MRI study in patients with bipolar disorder and controls.

BACKGROUND: Childhood trauma (CT) is a major risk factor for psychiatric conditions. It is hypothesized that CT effects are mediated by the limbic system. Few multimodal neuroimaging studies allow an integrated perspective of this impact. Our goal was thus to study the effects of CT on the limbic network. METHODS: We acquired multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 79 subjects (47 healthy controls and 32 patients with bipolar disorder, BD). We performed correlational analyses between Childhood Trauma Questionnaire (sub)scores (physical and emotional abuse/neglect and sexual abuse) and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, prefronto-limbic functional connectivity, uncinate fractional anisotropy). RESULTS: We found CTQ total scores to be negatively correlated with amygdala volume, prefronto-limbic functional connectivity (FC) and uncinate fractional anisotropy in our sample. Considering subscores, neglects (physical and emotional) were the only to affect neural parameters. The patients with BD drove most of the results. LIMITATIONS: Small sample size and low level of trauma in controls. CONCLUSIONS: Our multimodal approach enabled an integrated view of the long-term effects of CT on the limbic system.

Cognitive dysfunctions in medicated and unmedicated patients with recent-onset schizophrenia.

Schizophrenia is associated with impairments in many cognitive domains on which the influence of antipsychotics, whether conventional or atypical, remains unclear. We conducted a study of recent-onset schizophrenic patients (DSM IV) that included unmedicated (n=19), and medicated (n=19) patients matched for age and IQ. Both groups of patients had comparably low extra-pyramidal symptoms (EPS). Cognitive tasks included attentional tasks (alertness and divided attention tests), a working memory task (a verbal n-back test) and the Wisconsin Card Sorting Test (WCST). After adjustment for the Total PANSS score, we found no significant difference between the two groups of patients in any of the cognitive tasks. When compared to a group of healthy controls (n=20) matched for IQ level, unmedicated patients performed significantly worse in all cognitive tasks, with significantly longer reaction times for alertness, divided attention and working memory. These results confirm the presence of cognitive impairments in attentional and executive functions in recent-onset patients whether or not they are medicated. There was no evidence that either conventional or atypical antipsychotics had an influence on patients when EPS were excluded. Altogether, our results further support the idea that cognitive deficits in schizophrenia are enduring features per se and cannot be considered as secondary to psychiatric symptoms or to the adverse effects of medication. In addition our results suggest that antipsychotics do not have a major effect on these impairments.

Correlation between clinical syndromes and neuropsychological tasks in unmedicated patients with recent onset schizophrenia.

The aim of this study is to circumscribe the cognitive deficits according to schizophrenic syndromes in a population of sub-acute untreated patients. We have studied the cross-sectional correlation between cognitive deficits and schizophrenic symptoms, in a group of 24 untreated patients (including 17 neuroleptic-naive patients) with recent onset of the disease. A task of alertness, a working memory (WM) test (including two levels of difficulty) and an abbreviated version of the Wisconsin Card Sorting Test (WCST) were selected. WM deficits and poor performance on the WCST were highly correlated with disorganized symptoms, modestly with the positive syndrome and not with the negative syndrome. Thus, disorganized symptoms, more than any other, appear to be related to the impairment of executive function and WM in recent onset unmedicated patients with schizophrenia.

Neurocognitive performance as an endophenotype for bipolar disorder.

Identification of the underlying liability to develop bipolar disorders (BD) is hindered by the genetic complexity and phenotypic heterogeneity of the disease. The use of endophenotypes has been acknowledged as a promising approach that may detect the hidden manifestations of a genetic liability for an illness. One of the most commonly proposed endophenotypes in BD is neurocognitive performance. We identified and examined previously published review articles that had any data pertaining to endophenotypes in BD and combined this with an extensive review of studies of cognitive deficits in BD from 2000 onwards. Using criteria for a valid endophenotype, we identifed that the domains of executive functioning and verbal memory are the most promising candidate endophenotypes for BD. However, they do not meet the criteria for specificity as similar deficits present in schizophrenia and/or severe or psychotic major depressions. Further research is needed as the findings regarding endophenotypes show between-study heterogeneity. In the future, examination of quantitative traits may offer a more promising approach to the study of endophenotypes rather than solely focusing on diagnostic categories.

A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity.

IMPORTANCE: Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES: To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS: Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES: Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS: Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE: In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Is processing speed a valid cognitive endophenotype for bipolar disorder?

OBJECTIVES: The current study investigated whether a single brief cognitive assessment, processing speed, could be considered as a valid endophenotype for bipolar disorder (BD). METHODS: Processing speed was assessed using the Digit Symbol Test (DST) in 53 euthymic BD probands (BD-P), 50 unaffected first-degree relatives (UFDR) and 60 unrelated healthy controls (HC). RESULTS: Euthymic BD-P and the UFDR were significantly more impaired on DST performance even after controlling for demography and current mood symptoms (effect sizes 0.89 and 0.52). Clinically significant performance impairment was present in about 30% BD-P and 25% UFDR. LIMITATIONS: Pharmacotherapy was not controlled for. CONCLUSIONS: Processing speed, as measured with the DST, is a brief reliable measure that could be used in clinical assessments of at risk populations. Our findings support the hypothesis that processing speed may be a valid endophenotype, highly specific for differentiating both euthymic BD-P and UFDR, from HC.

Long-term outcome of cognitive impairment in bipolar disorder.

OBJECTIVE: To evaluate the longitudinal course and outcome of cognitive deficits and their clinical correlates in bipolar disorder. METHOD: One hundred thirteen participants (68 patients and 45 healthy controls) were assessed by the means of a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions at baseline: 68 euthymic outpatients with a DSM-IV diagnosis of bipolar disorder (53 bipolar I and 15 bipolar II) were enrolled at the Bipolar Disorder Unit of the Hospital Clinic of Barcelona. Forty-five patients completed the follow-up. The assessments started in February 1999 and finished in July 2010. The primary outcome of the study was the change in the neuropsychological performance in the patient group. RESULTS: Repeated-measures analyses showed significant effects of time in 2 cognitive domains: attention and executive functions. Attention slightly improved (P = .043) but executive function worsened (P = .001). Regression analyses showed that the duration of illness and baseline subdepressive symptoms were associated with poor performance in executive function. Subdepressive symptoms at endpoint were associated with poor functioning. The best predictor of low functioning was verbal memory dysfunction at baseline. CONCLUSIONS: The cognitive impairment remained stable across the follow-up period in many measures assessed except for a worsening of executive measures, which have been found to be associated with the duration of illness and subdepressive symptoms.

MRI exploration of pineal volume in bipolar disorder.

BACKGROUND: Circadian rhythm instability and abnormalities of melatonin secretion are considered as trait markers of bipolar disorder. Melatonin is secreted by the pineal gland. We investigated pineal volume in patients with bipolar disorder, and expected to observe smaller than normal pineal glands in cases of bipolar disorder. METHODS: The primary outcome was the total pineal volume measured for each pineal gland with T1 MRI sequence. Twenty patients with bipolar I and II disorder and twenty controls were recruited. Pineal glands with large cysts (type 3) were excluded. RESULTS: After exclusion of individuals with type 3 cysts, 32 subjects were analyzed for total pineal volume (16 patients with bipolar disorder and 16 controls). Total pineal volume did not differ significantly between patients (total pineal volume=115+/-54.3mm(3)) and controls (total pineal volume=110+/-40.5mm(3)). CONCLUSIONS: Contrary to our hypothesis, no difference in total pineal volume between patients with bipolar disorder and healthy subjects was observed. These results indicate that the putative dysfunction of the pineal gland in bipolar disorder could be not directly related to an abnormal volume of the pineal gland.

Treatment nonadherence and neurocognitive impairment in bipolar disorder.

OBJECTIVE: Little is known regarding the relationship between treatment adherence and residual cognitive dysfunction in euthymic bipolar disorder patients. This study aimed to investigate whether poor treatment adherence is associated with cognitive impairment in euthymic bipolar patients and whether other factors may be associated with both adherence and cognitive functioning. METHOD: Euthymic DSM-IV bipolar I or II disorder patients (N = 103: 61 with high levels of treatment adherence and 42 with poor treatment adherence) were assessed using a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions and compared with 35 healthy controls of similar age, sex distribution, and education. Data were collected from September 2005 to June 2007. RESULTS: Bipolar patients with poor treatment adherence had more hospitalizations than those with high adherence. After controlling for age, gender, estimated IQ score, and Young Mania Rating Scale and 17-item Hamilton Rating Scale for Depression scores, non-treatment-adherent patients performed less well than normal controls in verbal learning and some executive functions. Among treatment-adherent and poorly adherent bipolar disorder patients, performance was similar in attention tasks and short-term and long-term verbal recall, but non-treatment-adherent patients were more impaired in ability to inhibit interferences and in spatial working memory. Poorer treatment adherence also was associated with the bipolar I subtype and with greater illness severity, as indicated by number of manic episodes and hospitalizations and history of psychosis. Pharmacologic factors, such as treatment with lithium, may also influence the relationship between neurocognition and adherence. CONCLUSIONS: There is a close relationship between poor treatment adherence and cognitive impairment, but the causal inferences of these findings are uncertain. Poor treatment adherence may worsen the course of bipolar disorder and so indirectly worsen cognitive performance, or cognitive impairment may contribute to poor treatment adherence and reflect more severe illness.

Neurocognitive dysfunctions in euthymic bipolar patients with and without prior history of alcohol use.

OBJECTIVE: Despite the additional complications associated with alcohol misuse in bipolar populations, it is generally the case that studies exploring neurocognitive aspects of bipolar disorder specifically exclude patients with alcohol abuse or dependence. Given the role of cognitive dysfunctions in overall illness outcome, this study addressed the neurocognitive functioning of patients with a history of alcohol abuse or dependence as compared to bipolar patients without such a history and healthy controls. METHOD: The study sample included 100 subjects: 65 bipolar patients, 30 of whom with a history of alcohol abuse or dependence and 35 without a previous history of alcohol abuse or dependence, based on DSM-IV criteria, and a control group of 35 healthy subjects. Comprehensive neuropsychological tests were carried out during strictly defined clinical remission. Differences between groups were analyzed and a linear regression analysis was undertaken to establish predictors of psychosocial functioning as measured using the Global Assessment of Functioning. Data were collected from September 2006 to July 2007. RESULTS: Bipolar patients with a history of alcohol abuse or dependence obtained lower scores in the interference task of the Stroop test compared to the control group. Both patient groups showed a poorer performance in some verbal memory and executive function measures than healthy controls. Verbal learning impairment was significantly associated with poor psychosocial functioning. CONCLUSIONS: Cognitive dysfunctions appeared to be more strongly associated with bipolar disorder than with the "history of alcohol abuse or dependence" factor. Bipolar patients with history of alcohol misuse may have greater difficulties of inhibitory control, probably due to higher impulsivity.

Neurocognitive impairment in bipolar patients with and without history of psychosis.

OBJECTIVE: Little is known regarding the impact of psychotic symptoms on the cognitive functioning of bipolar patients. Findings from previous reports are controversial and mainly focused on current psychotic symptoms. The main aim of this study was to ascertain whether the history of psychotic symptoms was associated with greater cognitive impairment in euthymic bipolar patients. METHOD: Sixty-five euthymic bipolar disorder patients (DSM-IV criteria; 35 with a history of psychotic symptoms and 30 without such a history) were assessed through a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions. Thirty-five healthy controls were also included in the study in order to compare the neuropsychological performance among groups. Multivariate analysis of covariance was performed controlling for the effect of residual depressive symptoms as a covariate. The study was conducted from June 2005 to June 2006. RESULTS: Bipolar patients with a history of psychotic symptoms showed a higher number of manic episodes and more hospitalizations than patients without such a history (both p < .001). Regarding neuropsychological performance, patients with a history of psychotic symptoms performed more poorly than those without such a history or controls in all verbal memory measures (p < .005). Furthermore, patients with a history of psychotic symptoms were more impaired on tasks related to executive functions compared to healthy controls (p < .05). History of psychotic symptoms was found to be a predictor of verbal memory impairment. CONCLUSIONS: Our findings suggest that the history of psychotic symptoms may partly account for the cognitive dysfunctions seen in euthymic bipolar patients, especially with regard to persistent verbal memory dysfunction, as well as with some executive dysfunctions.

Clinical correlates of first-episode polarity in bipolar disorder.

OBJECTIVE: To determine the clinical and long-term implications of mood polarity at illness onset. METHODS: During a 10-year follow-up prospective study, systematic clinical and outcome data were collected from 300 bipolar I and II patients. The sample was split into 2 groups according to the polarity of the onset episode (depressive onset [DO] vs manic/hypomanic onset [MO]). Clinical features and social functioning were compared between the 2 groups of patients. RESULTS: In our sample, 67% of the patients experienced a depressive onset. Depressive onset patients were more chronic than MO patients, with a higher number of total episodes and a longer duration of illness. Depressive onset patients experienced a higher number of depressive episodes than MO patients, who in turn had more manic episodes. Depressive onset patients made more suicide attempts, had a later illness onset, were less often hospitalized, and were less likely to develop psychotic symptoms. Depressive onset was more prevalent among bipolar II patients. Bipolar I patients with DO had more axis II comorbidity and were more susceptible to have a history of psychotic symptoms than bipolar II patients with DO. CONCLUSION: The polarity at onset is a good predictor of the polarity of subsequent episodes over time. A depressive onset is twice as frequent as MO and carries more chronicity and cyclicity.

Cognitive impairment in bipolar II disorder.

BACKGROUND: Persistent impairments in neurocognitive function have been described in bipolar disorder. AIMS: To compare the cognitive performance of patients with bipolar II disorder with that of patients with bipolar I disorder and a healthy control group. METHOD: The study included 71 euthymic patients with bipolar disorder (38 bipolar I, 33 bipolar II), who were compared on clinical and neuropsychological variables (e.g. executive function, attention, verbal and visual memory) and contrasted with 35 healthy controls on cognitive performance. RESULTS: Compared with controls, both bipolar groups showed significant deficits in most cognitive tasks including working memory (DigitSpan Backwards, P=0.002) and attention (DigitSpan Forwards, P=0.005; Trail Making Test, P=0.001). Those with type II disorders had an intermediate level of performance between the bipolar I group and the control group in verbal memory (P<0.005) and executive functions (Stroop interference task, P=0.020). CONCLUSIONS: Cognitive impairment exists in both subtypes of bipolar disorder, although more so in the bipolar I group. The best predictors of poor psychosocial functioning in bipolar II disorder were subclinical depressive symptoms, early onset of illness and poor performance on a measure related to executive function.