Meta-analysis of longitudinal studies of cognition in bipolar disorder: comparison with healthy controls and schizophrenia.

BACKGROUND: Bipolar disorder (BP) is associated with significant cognitive impairment. Recent evidence suggests that cognitive deficits are already evident after first-episode mania. However, it is not clear whether BP is associated with further decline in cognitive functions in individuals with established illness. Aim of this meta-analytic review was to examine longitudinal neurocognitive changes in BP and to compare trajectory of cognitive deficits in BP with schizophrenia and healthy controls. METHODS: Electronic databases were searched for the studies published between January 1987 and November 2016. In total 22 reports were included in the current meta-analysis. The main analysis assessed the longitudinal change in cognition in 643 patients with BP. Further analyses were conducted in studies investigating cognitive changes in BP along with healthy controls (459 BP and 367 healthy controls) and schizophrenia (172 BP and 168 schizophrenia). RESULTS: There was no cognitive decline overtime neither in short-term (mean duration = 1.5 years) nor in long-term (mean duration = 5.5 years) follow-up studies in BP. In contrast, there was evidence for modest improvements in task performance in memory and working memory at follow-up. The trajectory of cognitive functioning in BP was not significantly different from changes in schizophrenia and healthy controls. CONCLUSIONS: Together with the findings in early BP and individuals at genetic risk for BP, current findings suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BP and do not support the notion of progressive cognitive decline in most patients with BP.

A meta-analysis of neurocognition in youth with familial high risk for bipolar disorder.

OBJECTIVE: Neuropsychological impairment, including deficits in social cognition is evident in subjects at genetic high-risk for psychosis. However, findings in youth at genetic risk to bipolar disorder (BP) have been suggested to be less supportive of premorbid deficits. We aimed to conduct a meta-analysis of cognitive deficits in youth with familiar risk for bipolar disorder (FHR-BD). METHODS: A novel meta-analysis of FHR-BD (mean age 10-25), including 18 studies (786 offsprings/siblings of patients with BD and 794 healthy controls), was conducted. RESULTS: Both general cognition (d=0.29, CI=0.15-0.44) and social cognition (d=0.23, CI=0-0.45) were impaired in FHR-BD. In comparison to controls, FHR-BD had significant deficits in several cognitive domains, including visual memory (d=0.35), verbal memory (d=0.21), processing speed (d=0.26) and sustained attention (d=0.36). There was no significant difference between FHR-BD and controls in planning and working memory. CONCLUSIONS: Cognitive deficits are evident in individuals who are at genetic high-risk for developing BD. Neurodevelopmental abnormalities are likely playing a role not only in schizophrenia but also in BD.

Abnormal white matter integrity as a structural endophenotype for bipolar disorder.

BACKGROUND: Several lines of evidence suggest that bipolar disorder (BD) is associated with white matter (WM) pathology. Investigation of unaffected first-degree relatives of BD patients may help to distinguish structural biomarkers of genetic risk without the confounding effects of burden of illness, medication or clinical state. In the present study, we applied tract-based spatial statistics to study WM changes in patients with BD, unaffected siblings and controls. METHOD: A total of 27 euthymic patients with BD type I, 20 unaffected siblings of bipolar patients and 29 healthy controls who did not have any current or past diagnosis of Axis I psychiatric disorders were enrolled in the study. RESULTS: Fractional anisotropy (FA) was significantly lower in BD patients than in the control group in the corpus callosum, fornix, bilateral superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, posterior thalamic radiation, cingulum, uncinate fasciculus, superior corona radiata, anterior corona radiata and left external capsule. In region-of-interest (ROI) analyses, we found that both unaffected siblings and bipolar patients had significantly reduced FA in the left posterior thalamic radiation, the left sagittal stratum, and the fornix compared with healthy controls. Average FA for unaffected siblings was intermediate between the healthy controls and bipolar patients within these ROIs. CONCLUSIONS: Decreased FA in the fornix, left posterior thalamic radiation and left sagittal stratum in both bipolar patients and unaffected siblings may represent a potential structural endophenotype or a trait-based marker for BD.

What does the broken brain say to the neuroscientist? Oscillations and connectivity in schizophrenia, Alzheimer's disease, and bipolar disorder.

The application of the concept and methods of brain oscillations has been an important research area in neurosciences. In the last decades, besides the application in cognitive processes, the study of changes in brain oscillations in diseases has also become an important focal point of research. In the present paper, some remarkable examples in three different diseases are taken into consideration: 1) schizophrenia (SZ), 2) Alzheimer's disease (AD), 3) bipolar disorders (BD). In the current literature, decreased oscillations in cortical recordings are observed in most of the pathologies. For example, decrease of gamma activity in SZ, decrease of delta activity in almost all diseases, as well as frequency shifts in alpha and the lower frequencies were recorded. However, there are also paradoxical cases in which an increase of oscillatory activities is observed. In BD, whereas alpha activity is greatly decreased, a huge increase of beta activity is observed. Or, in SZ, a paradoxical increase of gamma activity can be observed during cognitive loading. We also observed paradoxical changes in the analysis of connectivity. In AD, we find that alpha, delta, and theta coherences between distant parts of the cortex are greatly decreased, whereas in the gamma band, event-related coherences attain very high values. The comparison of the results and paradoxical changes in diseases may lead to important conclusions related to the web of oscillations and neurotransmitters. In turn, we could gain new insights to approach "brain function", in general.

Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. METHODS: BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non-patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. RESULTS: While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive-compulsive disorder were positively correlated. CONCLUSION: Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania.

Decrease of theta response in euthymic bipolar patients during an oddball paradigm.

Theta oscillations are related to cognitive functions and reflect functional integration of frontal and medial temporal structures into coherent neurocognitive networks. This study assessed event-related theta oscillations in medication-free, euthymic patients with bipolar disorder upon auditory oddball paradigm. Twenty-two DSM-IV euthymic bipolar I (n = 19) and II (n = 3) patients and twenty-two healthy subjects were included. Patients were euthymic for at least 6 months, and psychotropic-free for at least 2 weeks. EEG was recorded at 30 electrode sites. Auditory oddball paradigm and sensory stimuli were used. Event-related Oscillations were analyzed using adaptive filtering in two different theta frequency bands (4-6 Hz, 6-8 Hz). In healthy subjects, slow theta (4-6 Hz) responses were significantly higher than those of euthymic patients upon target, non-target and sensory stimuli (p < 0.05). Fast theta (6-8 Hz) responses of healthy subjects were significantly higher than those of euthymic patients upon target-only stimuli (p < 0.05). Reduced theta oscillations during auditory processing provide strong quantitative evidence of activation deficits in related networks in bipolar disorder. Fast theta responses are related to cognitive functions, whereas slow theta responses are related to sensory processes more than cognitive processes.

Brain's alpha activity is highly reduced in euthymic bipolar disorder patients.

Brain's alpha activity and alpha responses belong to major electrical signals that are related to sensory/cognitive signal processing. The present study aims to analyze the spontaneous alpha activity and visual evoked alpha response in drug free euthymic bipolar patients. Eighteen DSM-IV euthymic bipolar patients (bipolar I n = 15, bipolar II n = 3) and 18 healthy controls were enrolled in the study. Patients needed to be euthymic at least for 4 weeks and psychotrop free for at least 2 weeks. Spontaneous EEG (4 min eyes closed, 4 min eyes open) and evoked alpha response upon application of simple visual stimuli were analyzed. EEG was recorded at 30 positions. The digital FFT-based power spectrum analysis was performed for spontaneous eyes closed and eyes open conditions and the response power spectrum was also analyzed for simple visual stimuli. In the analysis of spontaneous EEG, the ANOVA on alpha responses revealed significant results for groups (F(1,34) = 8.703; P < 0.007). Post-hoc comparisons showed that spontaneous EEG alpha power of healthy subjects was significantly higher than the spontaneous EEG alpha power of euthymic patients. Furthermore, visual evoked alpha power of healthy subjects was significantly higher than visual evoked alpha power of euthymic patients (F(1,34) = 4.981; P < 0.04). Decreased alpha activity in spontaneous EEG is an important pathological EEG finding in euthymic bipolar patients. Together with an evident decrease in evoked alpha responses, the findings may lead to a new pathway in search of biological correlates of cognitive impairment in bipolar disorder.

The relatively good prognosis of bipolar disorders in a Turkish bipolar clinic.

BACKGROUND: Bipolar affective disorder is considered to be a disabling illness with a relapsing and remitting course resulting in enduring psychosocial consequences. In this study, we aimed to determine the demographic and clinical characteristics of patients with bipolar illness, types of treatment at inpatient and outpatient settings and their outcome. METHOD: Life charts of 61 bipolar outpatients and hospital charts of 47 manic inpatients were retrospectively evaluated regarding the demographics, course of illness and the treatment at both settings. RESULTS: 82.5% of the outpatients were euthymic and 42.5% were on lithium monotherapy at the time of investigation. Psychosocial adjustment was good. High level of education and marital status affected compliance positively. In the outpatient group, 24.2% were bipolar 2 (BP-II): they differed from bipolar 1 (BP-I) patients in having a higher number of lifetime episodes. Females outnumbered males in both settings, 11 had suffered higher numbers of previous episodes, as well as longer stays in hospital. Lithium was the most commonly used agent in acute mania (78.7%); 89.4% of the inpatients received combination treatment, mainly a mood stabilizer with a neuroleptic. Adjunctive neuroleptics decreased from 82.4 to 56.7% after 1995: This resulted in longer lengths of stay in hospital. LIMITATIONS: Data were collected naturalistically in a non-blind fashion. CONCLUSION: Lithium is still the leading mood stabilizer of choice for the acute and maintenance phases of bipolar disorder in our patient population. We submit that family support, high levels of education as well as an in-depth follow-up represented the contributory factors in the good overall outcome.