[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
Frontiers in bioscience (Elite edition) 01/2014; 6:89-103.
[show abstract][hide abstract] ABSTRACT: Introduction: Cytomegalovirus (CMV) is a member of the herpesviridae family that has a limbic and temporal gray matter tropism. It is usually latent in humans but has been associated with schizophrenia, bipolar disorder and cognitive deficits in some populations. Hippocampal decreased volume and dysfunction play a critical role in these cognitive deficits. We hypothesized that CMV seropositivity and serointensity would be associated with hippocampal volume and cognitive functioning in patients with schizophrenia or bipolar disorder.
102 healthy controls, 118 patients with bipolar disorder and 69 patients with schizophrenia performed the California Verbal Learning Test (CVLT) and had blood samples drawn to assess CMV IgG levels. A subgroup of 52 healthy controls, 31 patients with bipolar disorder and 27 patients with schizophrenia underwent T1 MRI for hippocampal volumetry. We analyzed the association between CMV serointensity and seropositivity with hippocampal volume. We also explored the correlation between CMV serointensitiy and seropositivity and CVLT scores.
In both patients groups but not in controls, higher CMV serointensity was significantly associated with smaller right hippocampal volume. Further, in the group of patients with schizophrenia but not bipolar disorder, CMV serointensity was negatively correlated with CVLT scores.
CMV IgG titers are associated with decreased hippocampal volume and poorer episodic verbal memory in patients with schizophrenia or bipolar disorder. The mechanism of this association warrants further exploration.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2013; · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the longitudinal course and outcome of cognitive deficits and their clinical correlates in bipolar disorder.
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.
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.
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.
The Journal of Clinical Psychiatry 08/2012; 73(7):e899-905. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: The current study investigated whether a single brief cognitive assessment, processing speed, could be considered as a valid endophenotype for bipolar disorder (BD).
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).
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.
Pharmacotherapy was not controlled for.
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.
Journal of affective disorders 03/2012; 139(1):98-101. · 3.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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)).
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.
Journal of affective disorders 06/2011; 135(1-3):377-9. · 3.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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).
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.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of Clinical Psychiatry 08/2009; 70(8):1120-7. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of Clinical Psychiatry 07/2009; 70(7):1017-23. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Journal of Affective Disorders 04/2008; 110(1-2):1-15. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of Clinical Psychiatry 03/2008; 69(2):233-9. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Only a few studies have examined specifically the neuropsychological performance of schizoaffective patients.
The sample consisted of 34 euthymic DSM-IV schizoaffective patients, who were compared with 41 euthymic bipolar patients without history of psychotic symptoms and 35 healthy controls. 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. Patients were compared with several clinical, occupational, and neuropsychological variables such as executive function, attention, verbal and visual memory and the two groups were contrasted with 35 healthy controls on cognitive performance. The three groups were compared using mancova after checking the potential role of several co-variables.
Schizoaffective patients showed greater impairment than controls and bipolar patients, in several domains, including verbal memory, executive function, and attentional measures. Bipolar patients without history of psychosis performed similar to the controls except for verbal fluency.
Schizoaffective disorder carries more neurocognitive impairment than non-psychotic bipolar disorder and more occupational difficulties.
[show abstract][hide abstract] ABSTRACT: Few studies have examined the clinical, neuropsychological and pharmacological factors involved in the functional outcome of bipolar disorder despite the gap between clinical and functional recovery.
A sample of 77 euthymic bipolar patients were included in the study. Using an a priori definition of low versus good functional outcome, based on the psychosocial items of the Global Assessment of Functioning (GAF, DSM-IV), and taking also into account their occupational adaptation, the patients were divided into two groups: good or low occupational functioning. Patients with high (n = 46) and low (n = 31) functioning were compared on several clinical, neuropsychological and pharmacological variables and the two patient groups were contrasted with healthy controls (n = 35) on cognitive performance.
High- and low-functioning groups did not differ with respect to clinical variables. However, bipolar patients in general showed poorer cognitive performance than healthy controls. This was most evident in low-functioning patients and in particular on verbal memory and executive function measures.
Low-functioning patients were cognitively more impaired than highly functioning patients on verbal recall and executive functions. The variable that best predicted psychosocial functioning in bipolar patients was verbal memory.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Psychiatric Research 01/2007; 41(3-4):265-72. · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Identifying and modifying burdensome aspects might reduce the level of burden and their negative effects both on caregivers and patients' outcome. Most studies evaluate acutely ill patients, whereas the most relevant problems may be related to subthreshold symptoms and long-term outcome. The aims of the present study were to assess caregiver's subjective burden, to analyse which were the most burdensome aspects for caregivers and to study which variables could explain the caregiver's subjective burden.
Caregivers of 86 euthymic bipolar patients completed the subjective burden subscale from an adapted version of the Social Behaviour Assessment Schedule.
Caregivers showed a moderate level of subjective burden. The highest levels of distress were reported regarding the patient's behaviour; the most distressing behaviours were hyperactivity, irritability, sadness and withdrawal. Regarding the patient's role performance, the most worrying aspects were those associated with the patient's work or study and social relationships. Regarding adverse effects on others, caregivers were especially distressed by the way the illness had affected their emotional health and their life in general. Poorer social and occupational functioning, an episode in the last 2 years, history of rapid cycling and the caregiver being responsible for medication intake explained a quarter of the variance of the caregiver's subjective burden.
This was a cross-sectional study focused only on primary caregivers, there was no control group of non-bipolar patients.
This study provides relevant data concerning the burden of caregivers of stable bipolar patients, pointing at potential targets for psychosocial interventions.
Journal of Affective Disorders 09/2006; 94(1-3):157-63. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Persistent impairments in neurocognitive function have been described in bipolar disorder.
To compare the cognitive performance of patients with bipolar II disorder with that of patients with bipolar I disorder and a healthy control group.
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.
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).
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.
The British Journal of Psychiatry 09/2006; 189:254-9. · 6.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the clinical and therapeutic relevance of longitudinally predominant polarity for bipolar disorders long-term outcome.
Two hundred twenty-four patients (n=224) were enrolled for the study in the Bipolar Disorders Program of Barcelona, which provides integrated care for difficult-to-treat bipolar patients derived from all over Spain, but also provides clinical care to all bipolar patients coming from a specific catchment area (Eixample Esquerre) in Barcelona. Data collection regarding predominant polarity started on October 1994 and lasted for the following ten years. Patients were divided according to the predominance of depressive or manic/hypomanic episodes. The two groups were compared regarding clinical and sociodemographic variables.
135 patients (60.3%) were classified as Depressive Polarity, whilst 89 (39.7%) were considered as Manic Polarity. Manic Polarity was more prevalent amongst bipolar I patients than bipolar II. Depressive Polarity was strongly associated with depressive onset of bipolar disorder. Lifetime history of attempted suicide was strongly associated with Depressive Polarity, who also had a higher mean number of suicide attempts. As for therapeutic issues, acute and maintenance use of atypical antipsychotics and conventional neuroleptics were more common amongst Manic Polarity whilst antidepressants and lamotrigine use was highly prevalent amongst Depressive Polarity.
Prevention of depression is crucial for the maintenance treatment of bipolar II patients, whilst prevention of mania and depression would be equally important in the case of bipolar I patients. Predominant polarity is a valid prognostic parameter with therapeutic implications.
Journal of Affective Disorders 08/2006; 93(1-3):13-7. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Despite the increasing use of lamotrigine (LTG) in bipolar disorder, little is known about its impact on cognition in bipolar patients. Therefore, we have evaluated 33 bipolar I and II patients on cognitive measures (verbal memory, attention, executive functions) while receiving either LTG (n = 15) or another anticonvulsant (carbamazepine or valproate; n = 18). Patients receiving LTG were generally diagnosed as having bipolar II disorder, had experienced more depressive episodes but a lesser number of hospitalizations, and had better performance than the patients receiving carbamazepine or valproate on the verbal fluency task. A moderate effect size also suggests that both groups may differ on the immediate verbal memory test (California Verbal Learning Test). These preliminary results suggest a safer neurocognitive profile of LTG on bipolar patients, as compared with other anticonvulsants.
Journal of Clinical Psychopharmacology 05/2006; 26(2):178-81. · 3.51 Impact Factor