Ayşegül Özerdem

The International Society for Bipolar Disorders–Battery for Assessment of Neurocognition (ISBD-BANC)

OBJECTIVES Although cognitive impairment is recognized as an important clinical feature of bipolar disorder, there is no standard cognitive battery that has been developed for use in bipolar disorder research. The aims of this paper were to identify the cognitive measures from the literature that show the greatest magnitude of impairment in bipolar disorder, to use this information to determine whether the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed for use in schizophrenia, might be suitable for bipolar disorder research, and to propose a preliminary battery of cognitive tests for use in bipolar disorder research. METHODS The project was conducted under the auspices of the International Society for Bipolar Disorders and involved a committee that comprised researchers with international expertise in the cognitive aspects of bipolar disorder. In order to identify cognitive tasks that show the largest magnitude of impairment in bipolar disorder, we reviewed the literature on studies assessing cognitive functioning (including social cognition) in bipolar disorder. We further provided a brief review of the cognitive overlap between schizophrenia and bipolar disorder and evaluated the degree to which tasks included in the MCCB (or other identified tasks) might be suitable for use in bipolar disorder. RESULTS Based on evidence that cognitive deficits in bipolar disorder are similar in pattern but less severe than in schizophrenia, it was judged that most subtests comprising the MCCB appear appropriate for use in bipolar disorder. In addition to MCCB tests, other specific measures of more complex verbal learning (e.g., the California Verbal Learning Test) or executive function (Stroop Test, Trail Making Test-part B, Wisconsin Card Sorting Test) also show substantial impairment in bipolar disorder. CONCLUSIONS Our analysis reveals that the MCCB represents a good starting point for assessing cognitive deficits in research studies of bipolar disorder, but that other tasks including more complex verbal learning measures and tests of executive function should also be considered in assessing cognitive compromise in bipolar disorder. Several promising cognitive tasks that require further study in bipolar disorder are also presented.

Reduced long distance gamma (28-48 Hz) coherence in euthymic patients with bipolar disorder

BACKGROUND EEG coherence represents the brains functional connectivity. Synchronous neural gamma oscillations are critical for cortico-cortical communication and large-scale integration of distributed sets of neurons. We investigated long distance gamma (28-48 Hz) coherence in bipolar disorder. METHODS Sensory evoked coherence (EC) and event related coherence (ERC) values for the gamma frequency band during simple light stimulation and visual odd-ball paradigm was assessed in 20 drug-free euthymic bipolar patients in comparison to healthy controls. Groups were compared for the coherence values of the left (F(3)-T(3), F(3)-TP(7), F(3)-P(3), F(3)-O(1)) and right (F(4)-T(4), F(4)-TP(8), F(4)-P(4), F(4)-O(2)) intra-hemispheric electrode pairs by means of a repeated measure analysis of variance (ANOVA) and t-tests. RESULTS Patients showed significantly lower gamma coherence values in response to target stimuli than the healthy controls between left and right fronto-temporal, as well as between frontal and temporo-parietal electrode pairs. Coherence values for the non-target stimuli were significantly lower in the patients than the healthy controls between frontal and temporo-parietal regions on both right and left sides. EP coherence values did not differ significantly between the groups. LIMITATIONS A relatively small sample size is the major limitation of the study. CONCLUSIONS Bipolar patients present disturbance in functional long-range connectivity between the frontal and temporal as well as temporo-parietal brain structures during a cognitive paradigm requiring attention and immediate recall. The location of the connectivity disturbance corresponds to the underlying neurobiology of executive function, memory and attention impairments in bipolar disorder and raises the question of whether gamma coherence reduction may be a candidate biomarker for bipolar disorder.

Disturbance in long distance gamma coherence in bipolar disorder

The aim of this study was to investigate long distance event-related gamma (28-48 Hz) coherence in mania before and after valproate monotherapy. Gamma coherence in response to visual oddball paradigm in ten medication-free, manic patients was studied before and after six weeks of valproate monotherapy in comparison to ten controls. Inter-hemispheric F(3)-F(4), C(3)-C(4), T(3)-T(4), T(5)-T(6), P(3)-P(4), O(1)-O(2) and intra-hemispheric F(3)-P(3), F(4)-P(4), F(3)-T(5), F(4)-T(6), F(3)-O(1), F(4)-O(2), C(3)-O(1), C(2)-O(4) electrode pairs were included in the analysis. Repeated measures ANOVA revealed a significant difference between groups with regard to pre-treatment coherence values (p: 0.018). The coherence to the target stimuli at the right fronto-temporal location was significantly reduced by 35.41% in the patients compared to controls (p: 0.003). Patients showed significantly lower pre-treatment coherence values in response to non-target stimuli compared to controls at the right fronto-temporal (28.51%, p: 0.004), right fronto-occipital (23.71%, p: 0.024), and right centro-occipital (25.69%, p: 0.029) locations. After six weeks of valproate monotherapy, manic symptoms improved significantly. Post-treatment change in target and non-target coherence values was statistically non-significant. EEG coherence is a measure of functional connectivity in the brain. Event-related gamma oscillations are essential for brain electrical activity. The results show that acute mania presents right sided long distance connectivity disturbance, thus pointing to the potential importance of measuring oscillatory responses in the search for consistent neurobiological markers in such a complicated condition as bipolar disorder.

Brain oscillatory responses in patients with bipolar disorder manic episode before and after valproate treatment.

BACKGROUND GABA/Glutamatergic dysfunction and neural circuits which regulate cognitive processing are involved in the underlying pathology of bipolar disorder. Event related oscillatory neuroelectrical activity reflects integrative brain functioning, different frequency bands representing different cognitive functions. METHODS Event Related Potentials to visual odd-ball paradigm in ten manic/hypomanic medication free, DSM-IV bipolar patients were measured before and after six weeks of valproate monotherapy in comparison to ten sex and age matched healthy controls. Different frequency band responses were obtained by digital filtration of ERPs. Young mania rating scale (YMRS) was used to assess clinical response. Repeated measures ANOVA, Wilcoxon and Mann Whitney U tests were used for statistical analysis. RESULTS Patients showed significantly higher baseline occipital beta (18-30 Hz) (p: 0.014) response than healthy controls. They were devoid of the occipito-frontal alpha (8-13 Hz) dominance presented by the control group. Occipital beta response reduced significantly (p: 0.009) and became similar to controls after treatment. Post-treatment alpha responses were significantly lower than baseline in anterior temporal (p: 0.038) and occipital (p: 0.027) locations. Healthy controls displayed a significantly increased frontal alpha response at the second assessment but the patients did not. Mean YMRS score reduced significantly compared to baseline at the end of six weeks (p: 0.004). CONCLUSIONS Alpha response is the universal operator in the brain. Increased occipital beta response in mania may be compensatory to the dysfunctional alpha operation. Its reduction after valproate may be through modulation of glutamatergic and GABAergic mechanisms and indicate medications corrective effect on the underlying pathogenesis.

Assessment of quality of life with the WHOQOL-BREF in a group of Turkish psychiatric patients compared with diabetic and healthy subjects

Abstract  Decreased quality of life is often an important cause or consequence of psychiatric illness, and needs to be included in a comprehensive treatment plan. The authors aimed to identify how psychiatric patients characterize the quality of their lives compared to others who are suffering from a chronic physical illness (diabetes) and healthy individuals. A total of 100 psychiatric patients were recruited from Dokuz Eylül University Psychiatry Department outpatient clinic. Of these, 34 had 4th edition Diagnostic and Statistical Manual diagnosis of alcohol dependence, 38 had schizophrenia, and 28 had bipolar disorder. A total of 35 patients with diabetes and 49 healthy individuals were also included in the study. The World Health Organization’s Quality of Life Questionnaire was used to measure the quality of life. Patients with alcohol dependence, bipolar disorder, and schizophrenia scored lower than healthy subjects on the physical aspects of quality of life. Patients with schizophrenia had lower scores in the psychological domain compared to patients with bipolar disorder, patients with diabetes, and healthy subjects. In the social relationship domain, patients with schizophrenia and alcohol dependence scored lower compared to healthy subjects. Patients with schizophrenia were worse with respect to social relationships than bipolar patients and diabetics. World Health Organization’s Quality of Life Questionnaire is useful for evaluating the needs and targets for interventions in psychiatric patients.

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.

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium

OBJECTIVE Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. METHOD BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 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 medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. RESULTS Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. LIMITATIONS Small sample size in different episodes and drug-free patients was the limitation of thestudy. CONCLUSION Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia.

Executive dysfunction and cognitive subgroups in a large sample of euthymic patients with bipolar disorder

Bipolar disorder (BP), at the group level, is associated with significant but modest cognitive deficits, including executive dysfunction. Among executive functions, response inhibition deficits have been suggested to be particularly relevant to BP. However, BP is associated with significant heterogeneity in neurocognitive performance and level of functioning. Very few studies have investigated neurocognitive subgroups in BP with data-driven methods rather than arbitrarily defined criteria. Other than having relatively small sample sizes, previous studies have not taken into consideration the neurocognitive variability in healthy subjects. Five-hundred-fifty-six euthymic patients with BP and 416 healthy controls were assessed using a battery of cognitive tests and clinical measures. Neurocognitive subgroups were investigated using latent class analysis, based on executive functions. Four neurocognitive subgroups, including a good performance cluster, two moderately low-performance groups, which differ in response inhibition and reasoning abilities, and a severe impairment cluster were found. In comparison to healthy controls, BP patients were overrepresented in severe impairment cluster (27% vs 5.3%) and underrepresented in good performance cluster. BP patients with lower educational attainment and older age were significantly more likely to be members of cognitively impaired subgroups. Antipsychotic use was less common in good performance cluster. These results suggest that there is a considerable overlap of cognitive functions between BP and healthy controls. Neurocognitive differences between BP and healthy controls are driven by a subgroup of patients who have severe and global, rather than selective, cognitive deficits.

International Consensus Group on Depression Prevention in Bipolar Disorder

The conference was chaired by Mark A. Frye, MD, Department of Psychiatry, The Mayo Clinic, Rochester, Minnesota, United States. The faculty were Kyooseob Ha, MD, PhD, Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, and the Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Shigenobu Kanba, MD, PhD, Department of Neuropsychiatry, University of Kyushu, Fukuoka-shi, Fukuoka, Japan; Tadafumi Kato, MD, PhD, Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Hirosawa, Wako, Saitama, Japan; Susan L. McElroy, MD, Department of Psychiatry and Behavioral Sciences, University of Cincinnati, and the Lindner Center of HOPE, Cincinnati, Ohio, United States; Aysegul Ozerdem, MD, PhD, Department of Psychiatry and the Department of Neuroscience, Dokuz Eylul University, Narlidere, Izmir, Turkey; Gustavo Vazquez, MD, PhD, Department of Neuroscience, University of Palermo, Buenos Aires, Argentina; and Eduard Vieta, MD, PhD, Bipolar Disorder Program and the Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.

Brain oscillations in bipolar disorder in search of new biomarkers

This report presents six cardinal results obtained with methods of oscillatory brain dynamics in euthymic and manic bipolar patients in comparison to healthy controls. Measurements include changes in oscillatory response activities in the theta, alpha, beta, and gamma frequency ranges. The analysis shows that spontaneous and response activities in the alpha range are highly reduced in euthymic and manic patients, respectively; conversely, beta responses are increased in euthymic and manic patients. Lithium use seems to be associated with further and significant increase in the beta frequency range in euthymic patients. Theta responses to auditory target stimulus during odd-ball paradigm appeared in two different frequency bands (4-6 and 6-8 Hz) in healthy participants. However, only fast theta responses were highly reduced under cognitive load in drug-free euthymic patients. The analysis of connectivity was performed by assessment of long-distance coherence function in the gamma frequency range. Both manic and euthymic patients presented significantly decreased fronto-temporal coherence function during visual odd-ball task, indicating a selective reduction in connectivity during cognitive processing. The present report also discusses that these six oscillatory parameters may serve as an ensemble of biomarkers for diagnostic purposes and tracking treatment response in bipolar disorder.