Neural correlates of improved executive function following erythropoietin treatment in mood disorders

Miskowiak, KW; Vinberg, M; Glerup, L; Paulson, OB; Knudsen, GM; Ehrenreich, H; Harmer, CJ; Kessing, LV; Siebner, HR; Macoveanu, J

Psychol Med, 2016 (in press)

BACKGROUND: Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magnetic resonance imaging (fMRI) study investigated the effects of EPO on neural circuitry activity during working memory (WM) performance.

METHOD: Patients with treatment-resistant major depression, who were moderately depressed, or with BD in partial remission, were randomized to eight weekly infusions of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task.

RESULTS: EPO improved WM accuracy compared with saline (p = 0.045). Whole-brain analyses revealed that EPO increased WM load-related activity in the right superior frontal gyrus (SFG) compared with saline (p = 0.01). There was also enhanced WM load-related deactivation of the left hippocampus in EPO-treated compared to saline-treated patients (p = 0.03). Across the entire sample, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28-0.30, p < 0.05). The effects of EPO were not associated with changes in mood or red blood cells (p ⩾0.08).

CONCLUSIONS: The present findings associate changes in WM-load related activity in the right SFG and left hippocampus with improved executive function in EPO-treated patients.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT00916552.

 

Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders

Miskowiak KW, Vinberg M, Macoveanu J, Ehrenreich H, Køster N, Inkster B,
Paulson OB, Kessing LV, Skimminge A, Siebner HR

Biol Psychiatry. 2015 Aug 15;78(4):270-7

Abstract

BACKGROUND:
Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients’ functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects.

METHODS:
Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender.

RESULTS:
Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change.

CONCLUSIONS:
EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition.

TRIAL REGISTRATION:
ClinicalTrials.gov NCT00916552.

Assessment of subjective and objective cognitive function in bipolar disorder: Correlations, predictors and the relation to psychosocial function

Demant KM, Vinberg M, Kessing LV, Miskowiak KW

Psychiatry Res. 2015 Sep 30;229(1-2):565-71

Abstract

Cognitive dysfunction is prevalent in bipolar disorder (BD). However, the evidence regarding the association between subjective cognitive complaints, objective cognitive performance and psychosocial function is sparse and inconsistent. Seventy seven patients with bipolar disorder who presented cognitive complaints underwent assessment of objective and subjective cognitive function and psychosocial functioning as part of their participation in two clinical trials. We investigated the association between global and domain-specific objective and subjective cognitive function and between global cognitive function and psychosocial function. We also identified clinical variables that predicted objective and subjective cognitive function and psychosocial functioning. There was a correlation between global subjective and objective measures of cognitive dysfunction but not within the individual cognitive domains. However, the correlation was weak, suggesting that cognitive complaints are not an assay of cognition per se. Self-rated psychosocial difficulties were associated with subjective (but not objective) cognitive impairment and both subjective cognitive and psychosocial difficulties were predicted by depressive symptoms. Our findings indicate that adequate assessment of cognition in the clinical treatment of BD and in drug trials targeting cognition requires implementation of not only subjective measures but also of objective neuropsychological tests.

Optimising screening for cognitive dysfunction in bipolar disorder: validation and evaluation of objective and subjective tools

Jensen JH, Støttrup MM, Nayberg E, Knorr U, Ullum U, Purdon SE, Kessing LV, Miskowiak LV    

Journal of Affective Disorders (in press)

Abstract

Introduction: Cognitive impairment is common in bipolar disorder and contributes to socio-occupational difficulties. The objective was to validate and evaluate instruments to screen for and monitor cognitive impairments, and improve the understanding of the association between cognitive measures and socio-occupational capacity.

Methods: Patients with bipolar disorder in partial or full remission (n=84) and healthy controls (n=68) were assessed with the Screen for Cognitive Impairment in Psychiatry (SCIP), Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA), and established neuropsychological tests and subjective rating scales. Socio-occupational function and affective symptoms were evaluated with the Functional Assessment Short Test, and the Hamilton Depression Rating Scale 17-items and Young Mania Rating Scale, respectively. Concurrent validity of the SCIP and COBRA were assessed by correlation with established objective and subjective cognitive measures, and decision validity was determined with Receiver-Operating-Characteristic analyses. Correlations and linear regression analyses were conducted to determine the associations between objective and subjective cognitive impairment, and socio-occupational difficulties.

Results: The SCIP and COBRA correlated strongly with established objective and subjective cognitive measures, respectively. The SCIP yielded higher sensitivity and specificity for detection of cognitive dysfunction than the COBRA or a combined SCIP-COBRA measure. Correlations between objective and subjective cognitive impairment were weak but both were associated with socio-occupational difficulties.

Limitations: Influence of ageing was not investigated.

Conclusions: The SCIP and COBRA are valid for detection of objective and subjective cognitive impairment in bipolar disorder. Screening for cognitive dysfunction should be conducted with an objective measure like the SCIP.

Assessment of subjective and objective cognitive function in bipolar disorder: Correlations, predictors and the relation to psychosocial function

Demant KM, Vinberg M, Kessing LV, Miskowiak KW

Psychiatry Res. 2015 Jun 3. pii: S0165-1781(15)00291-7.

Abstract

Cognitive dysfunction is prevalent in bipolar disorder (BD). However, the evidence regarding the association between subjective cognitive complaints, objective cognitive performance and psychosocial function is sparse and inconsistent. Seventy seven patients with bipolar disorder who presented cognitive complaints underwent assessment of objective and subjective cognitive function and psychosocial functioning as part of their participation in two clinical trials. We investigated the association between global and domain-specific objective and subjective cognitive function and between global cognitive function and psychosocial function. We also identified clinical variables that predicted objective and subjective cognitive function and psychosocial functioning. There was a correlation between global subjective and objective measures of cognitive dysfunction but not within the individual cognitive domains. However, the correlation was weak, suggesting that cognitive complaints are not an assay of cognition per se. Self-rated psychosocial difficulties were associated with subjective (but not objective) cognitive impairment and both subjective cognitive and psychosocial difficulties were predicted by depressive symptoms. Our findings indicate that adequate assessment of cognition in the clinical treatment of BD and in drug trials targeting cognition requires implementation of not only subjective measures but also of objective neuropsychological tests.

Is there an association between subjective and objective measures of cognitive function in patients with affective disorders?

Svendsen AM, Kessing LV, Munkholm K, Vinberg M, Miskowiak KW

Nord J Psychiatry. 2012 Sep;66(4):248-53.

Abstract

BACKGROUND: Patients with affective disorders experience cognitive dysfunction in addition to their affective symptoms. The relationship between subjectively experienced and objectively measured cognitive function is controversial with several studies reporting no correlation between subjective and objective deficits.

AIMS: To investigate whether there is a correlation between subjectively reported and objectively measured cognitive function in patients with affective disorders, and whether subjective complaints predict objectively measured dysfunction.

METHODS: The study included 45 participants; 15 with bipolar disorder (BD), 15 with unipolar disorder (UD) and 15 healthy individuals. Participants’ subjectively experienced cognitive function and objective cognitive function were assessed with the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) and the Screen for Cognitive Impairment in Psychiatry (SCIP), respectively. Patients were rated for affective symptoms with Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS).

RESULTS: Patients demonstrated subjective and objective cognitive dysfunction relative to controls (P-values ≤ 0.01) but there were no differences between patient groups (P > 0.1). We found no correlation between subjectively experienced and objectively measured cognitive dysfunction in BD (P = 0.7), and a non-significant trend towards a correlation in UD (P = 0.06), which disappeared when controlling for gender (P = 0.1).

CONCLUSION: Our results suggest that it is not necessarily patients who have cognitive complaints that are most impaired. If confirmed in a larger sample, our findings suggest that neuropsychological assessment is warranted to elucidate the potential role of cognitive dysfunction in patients’ everyday lives and to inform treatment strategies targeting these difficulties.

Is there a difference in subjective experience of cognitive function in patients with unipolar disorder versus bipolar disorder?

Miskowiak K, Vinberg M, Christensen EM, Kessing LV

Nord J Psychiatry. 2012 Dec;66(6):389-95.

Abstract

BACKGROUND: Cognitive dysfunction in unipolar disorder (UD) and bipolar disorder (BD) may persist into remission and affect psychosocial function. Executive and memory deficits during remission may be more pronounced in BD than UD. However, patients’ subjective experience of cognitive difficulties is poorly understood, and it is unclear whether BD and UD patients experience different cognitive difficulties.

AIMS: To investigate whether there are differences in the quality and magnitude of subjective cognitive difficulties between UD and BD, and which factors influence the subjective cognitive difficulties in these patients.

METHODS: Patients with BD (n = 54) or UD (n = 45) were referred to the outpatient mood disorder clinic at Department of Psychiatry, Copenhagen University Hospital, following hospital discharge. Affective symptoms and patients’ experience of cognitive symptoms were assessed at their initial consultation at the clinic.

RESULTS: Patients experienced mild to moderate cognitive impairment despite being in partial or full remission, but there were no differences in subjective difficulties between BD and UD. Subjective cognitive dysfunction was predicted by depression severity, anxiety and mania symptoms rather than by diagnosis, age, gender or alcohol misuse.

CONCLUSION: The absence of difference in subjective cognitive difficulties between UD and BD contrasts with evidence of greater objective dysfunction in BD. This highlights a potential discord between subjective and objective measures of cognitive function. Subjective cognitive function was predicted by affective symptoms, perhaps suggesting that this reflects mood symptoms rather than objective deficits. This points to a clinical need for objective assessment of cognitive function in these patient groups.