Raphael J. Braga

The MATRICS Consensus Cognitive Battery in Patients with Bipolar I Disorder

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was devised to identify a neurocognitive battery to be used in clinical trials targeting cognition in schizophrenia, a process, which resulted in the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has been selected by the United States Food and Drug Administration to be used as the primary outcome measure in registry trials for cognitive agents in schizophrenia. Given the clinical and cognitive overlap between schizophrenia and bipolar disorder (BPD), it is likely that any compound shown to have cognitive benefits in schizophrenia will subsequently be tested in BPD. Unlike the MCCB for schizophrenia, there remains no consensus regarding outcome measures if cognitive trials were to be undertaken in BPD. The utility of the MCCB in BPD has not yet been systematically investigated. We administered the MCCB to 80 bipolar I patients; 37 were strictly euthymic and 43 were symptomatic. We compared their performance with a demographically matched healthy sample (n=148) on seven MCCB domains, and the composite. BPD patients were statistically significantly impaired on five of seven MCCB domains at levels consistent with meta-analytic studies of cognition in BPD. In contrast, patients’ performance was less impaired on the Reasoning and Problem-solving and Social Cognition domains, differences that did not survive statistical correction for multiple testing. Symptomatic status only modestly influenced performance. These data suggest that the MCCB, devised for use in schizophrenia, may also represent a useful outcome measure in cognitive trials for BPD. Additional studies should address important psychometric features such as repeatability and potential practice and/or ceiling effects.

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications.

BACKGROUND Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 s.d. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. METHOD A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. RESULTS Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. CONCLUSIONS These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment.

Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study

OBJECTIVE Up to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine. Pharmacological augmentation to clozapine has been studied with unimpressive results. The authors examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia. METHOD In a randomized single-blind 8-week study, patients with clozapine-resistant schizophrenia were assigned to treatment as usual (clozapine group) or a course of bilateral ECT plus clozapine (ECT plus clozapine group). Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase). ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant. Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale, a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2. RESULTS The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19). All 19 patients from the clozapine group received ECT in the crossover phase. Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%. There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion. CONCLUSIONS The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.

Cognitive dysfunction in bipolar disorder: future place of pharmacotherapy.

Bipolar disorder is an episodic affective illness, once believed to involve complete inter-episode remission. More recent data have highlighted the presence of persistent symptoms during purported periods of Wellness, including subsyndromal affective symptoms and neurocognitive impairment. These unremitting symptoms are of extreme clinical importance, as they are directly related to a worsening of clinical course, functional impairments and psychosocial difficulties in patients with bipolar disorder. Although there is now substantial evidence demonstrating the prevalence of neurocognitive impairment during euthymia, there have been few studies, to date, targeting this disabling aspect of the illness using pharmacological strategies.While treatment approaches have previously focused on primary affective and psychotic symptoms of the disease, it is important to consider the debilitating impact that impaired cognition has on patients with bipolar disorder. A recent focus has been placed on the significant need for large-scale clinical trials designed to specifically target cognitive impairment in patients with schizophrenia, with a parallel need existing in the field of bipolar research.There is now early evidence for the presence of neurocognitive deficits in patients with bipolar disorder and a relationship between these impairments and functional disability, making this a symptom domain that requires immediate clinical attention. Convergent data indicate a compelling need for formal assessment of cognition in patients with bipolar disorder, and for researchers and clinicans alike to consider the necessity for treatment specific to cognition in this population. Although limited data exist from cognitive enhancement trials in this population, there are a number of potential pharmacotherapy targets based on evidence from neuroimaging, molecular genetic, pharmacological and animal studies related to the pathophysiology of bipolar disorder. Future directions for potential cognitive enhancement strategies in bipolar disorder may include medications that influence dopaminergic or glutamatergic neurotransmission; however, urther work is needed to adequately assess the safety and effectiveness of these agents in bipolar patients. Finally, psychosocial intervention and/or cognitive remediation should be considered as alternatives to medications, although these techniques will also require additional systematic study.

Resting-State fMRI Connectivity Impairment in Schizophrenia and Bipolar Disorder

BACKGROUND Schizophrenia and bipolar disorder share aspects of phenomenology and neurobiology and thus may represent a continuum of disease. Few studies have compared connectivity across the brain in these disorders or investigated their functional correlates. METHODS We used resting-state functional magnetic resonance imaging to evaluate global and regional connectivity in 32 healthy controls, 19 patients with bipolar disorder, and 18 schizophrenia patients. Patients also received comprehensive neuropsychological and clinical assessments. We computed correlation matrices among 266 regions of interest within the brain, with the primary dependent measure being overall global connectivity strength of each region with every other region. RESULTS Patients with schizophrenia had significantly lower global connectivity compared with healthy controls, whereas patients with bipolar disorder had global connectivity intermediate to and significantly different from those of patients with schizophrenia and healthy controls. Post hoc analyses revealed that compared with healthy controls, both patient groups had significantly lower connectivity in the paracingulate gyrus and right thalamus. Patients with schizophrenia also had significantly lower connectivity in the temporal occipital fusiform cortex, left caudate nucleus, and left thalamus compared with healthy controls. There were no significant differences among the patient groups in any of these regions. Lower global connectivity among all patients was associated with worse neuropsychological and clinical functioning, but these effects were not specific to any patient group. CONCLUSIONS These findings are consistent with the hypothesis that schizophrenia and bipolar disorder may represent a continuum of global disconnectivity in the brain but that regional functional specificity may not be evident.

The combined use of electroconvulsive therapy and antipsychotics in patients with schizophrenia.

Objectives: We sought to review the literature on the use of combined antipsychotic medications and electroconvulsive therapy (ECT) for the treatment of schizophrenia, with regard to efficacy, side effects, and ECT technique. Methods: A computerized search of the literature published from 1980 to 2004 was conducted on Medline and PsychoInfo using the words schizophrenia, antipsychotic, neuroleptic, psychotropic, and ECT. Only studies including patients with the diagnosis of schizophrenia were included. Results: We identified 42 articles including 1371 patients. The majority of the reports consist of uncontrolled studies (n = 31), mostly with typical antipsychotics (n = 23). Results from open studies suggest that the combination of ECT and antipsychotics is a very useful and safe strategy for the treatment of refractory schizophrenia. Double-blind controlled studies (n = 8) were inconclusive. Twelve articles were on the combination of clozapine and ECT. Initial concerns about the safety of the coadministration of clozapine and ECT were not substantiated, but despite the auspicious results from several case reports and 2 open trials, this combination remains understudied. Most studies preferred the bitemporal placement (n = 28), but because of insufficient data derived from direct comparisons, no conclusion on placement superiority can be reached. One study indicates that with the bilateral placement higher electrical dosages yields faster responses in this population. Conclusions: The body of the data provided by research is still insufficient to allow definitive conclusions on the combination of antipsychotics and ECT. However, the literature reviewed indicates that the combination is a safe and efficacious treatment strategy for patients with schizophrenia, especially those refractory to conventional treatments.

Anxiety comorbidity in schizophrenia.

Diagnostic and treatment hierarchical reductionisms have led to an oversight of anxiety syndromes in schizophrenia. Nevertheless, recent data have indicated that anxiety can be a significant source of morbidity in this patient group. This paper reviews current knowledge concerning anxiety comorbidity in schizophrenia, its epidemiology, course, and treatment. A computerized search of the literature published from 1966 to July 2012 was conducted on Medline. Comorbid anxiety disorders are present in 38.3% of subjects with schizophrenia spectrum disorders. The most common anxiety disorder is social phobia followed by post-traumatic stress disorder and obsessive compulsive disorder. The presence and severity of symptoms of anxiety are associated with more severe clinical features and poorer outcomes. Available literature on the treatment consists primarily of case reports and open trials. Fragments of data support the notion of treating these anxiety states and syndromes as co-occurring clinical conditions with adjunctive medications and psychosocial interventions. However, additional work remains to be done on this issue before firm conclusions can be drawn.

Placebo-Controlled Adjunctive Trial of Pramipexole in Patients With Bipolar Disorder: Targeting Cognitive Dysfunction

OBJECTIVE Patients with bipolar disorder suffer from significant cognitive impairment that contributes directly to functional disability, yet few studies have targeted these symptoms for treatment, and the optimal study design remains unclear. We evaluated the effects of the dopamine D₂/D₃ receptor agonist pramipexole on cognition in bipolar disorder. METHOD Fifty stable outpatients with DSM-IV-diagnosed bipolar I or bipolar II disorder enrolled in an 8-week, double-blind, randomized, placebo-controlled cognitive enhancement trial between July 2006 and April 2010. Patients completed neurocognitive testing at baseline and at week 8, and the primary outcome measures were change scores calculated for each of the 11 tasks. Symptoms and side effects were monitored weekly. RESULTS Forty-five patients completed the study (placebo, n = 24; pramipexole, n = 21), and groups were well matched on demographic and clinical features. Primary cognitive analyses indicated no compelling cognitive benefit of pramipexole versus placebo; however, secondary analyses highlight several important methodological issues for future trials and identify a subgroup of patients who might benefit more readily from cognitive enhancement strategies. This outcome suggests that the study design played a very important role in the results-implying a failed rather than altogether negative trial. Specifically, we found that even very subtle, subsyndromal mood symptoms at baseline had a significant influence on the degree of improvement due to active drug, with strictly euthymic patients faring best (multivariate analysis of variance, P = .03 in euthymic subgroup). In addition, the extent of baseline cognitive impairment also contributed to the likelihood of treatment response. Finally, concomitant medications may weaken, or in some cases enhance, response to cognitive treatment and should be accounted for in study design. CONCLUSIONS Although our results point toward a lack of clear effect of pramipexole on cognition in bipolar patients, our data revealed a potentially beneficial effect of pramipexole in a subgroup, providing some enthusiasm for pursuing this line of research in the future. Moreover, this study emphasizes the importance of rigorous subject selection for cognitive trials in bipolar illness. Future studies will be necessary to determine the possible clinical and functional implications of these results. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00597896.

Impulsivity in bipolar disorder: relationships with neurocognitive dysfunction and substance use history.

Impulsivity is a core feature in bipolar disorder. Although mood symptoms exacerbate impulsivity, self‐reports of impulsivity are elevated, even during euthymia. Neurocognitive processes linked to impulsivity (e.g., attention, inhibition) are also impaired in patients with bipolar disorder, and a high frequency of comorbidities associated with impulsivity, such as substance use disorders, further highlights the clinical relevance of this dimension of the illness. Our objective was to assess the relationship between impulsivity and cognition in bipolar disorder.

Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder.

BACKGROUND Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. METHODS We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. RESULTS The FA differed significantly (p<.05; corrected) among the three groups within the right temporal WM. Unaffected siblings had FA values that were intermediate to and significantly different from those of healthy volunteers and patients with BD (healthy control subjects>unaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. CONCLUSIONS Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD.