Structural changes in the hippocampus as a biomarker for cognitive improvements in neuropsychiatric disorders: A systematic review.

Cognitive impairments are a core feature of several neuropsychiatric disorders. A common biomarker for pro-cognitive effects may provide a much-needed tool to select amongst candidate treatments targeting cognition. The hippocampus is a promising biomarker for target-engagement due to the illness-associated morphological hippocampal changes across unipolar disorder (UD), bipolar disorder (BD) and schizophrenia (SCZ). Following the PRISMA guidelines, we searched PubMed and Embase, for clinical trials targeting cognition across neuropsychiatric disorders, with longitudinal structural magnetic resonance imaging (MRI) measures of the hippocampus. Five randomized and three open-label trials were included. Hippocampal volume increases were associated with treatment-related cognitive improvement following treatment with erythropoietin across UD, BD and SCZ, lithium treatment in BD and aerobic exercise in SCZ. Conversely, an exercise intervention in UD showed no effect on hippocampal volume or cognition. Together, these observations point to hippocampal volume change as a putative biomarker-model for cognitive improvement. Future cognition trials are encouraged to include MRI assessments pre- and post-treatment to assess the validity of hippocampal changes as a biomarker for pro-cognitive effects.

The effect of erythropoietin on cognition in affective disorders - Associations with baseline deficits and change in subjective cognitive complaints.

This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials.

Screening for cognitive dysfunction in unipolar depression: Validation and evaluation of objective and subjective tools.

BACKGROUND: Persistent cognitive dysfunction in unipolar depression (UD) contributes to socio-occupational impairment, but there are no feasible methods to screen for and monitor cognitive dysfunction in this patient group. The present study investigated the validity of two new instruments to screen for cognitive dysfunction in UD, and their associations with socio-occupational capacity. METHOD: Participants (n=53) with UD in partial or full remission and healthy control persons (n=103) were assessed with two new screening instruments, the Danish translations of the Screen for Cognitive Impairment in Psychiatry (SCIP-D) and Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and with established neuropsychological and self-assessment measures. Depression symptoms and socio-occupational function were rated with the Hamilton Depression Rating Scale and Functional Assessment Short Test respectively. RESULTS: The SCIP-D and COBRA were valid for detection of objective and subjective cognitive impairment, respectively. The three parallel SCIP-D forms were equivalent. A combined SCIP-D-COBRA measure showed high sensitivity and good specificity for objective cognitive impairment (91% and 70%, respectively). There was no correlation between subjective and objective measures of cognition. Subjective cognitive difficulties correlated more with socio-occupational impairment (r=0.7, p<0.01) than did objective cognitive difficulties, for which there was a weak correlation with the executive skills domain only (r =-0.3, p=0.05). LIMITATIONS: A modest sample size. CONCLUSIONS: The SCIP-D and COBRA are valid measures of objective and subjective cognitive impairment, respectively, and should ideally be implemented together in the screening for cognitive dysfunction in UD.