Ulla Knorr

Cognitive impairment in the remitted state of unipolar depressive disorder: A systematic review

BACKGROUND It is unclear whether cognitive impairment is prevalent in the remitted state of unipolar disorder. AIM To evaluate whether cognitive function is impaired in the remitted state in patients with unipolar depression compared with healthy control individuals, and to investigate the association to prior course of illness, i.e. the number, duration and severity of prior depressive episodes. METHOD Systematic search on existing on-line databases and hand-search of original published papers. RESULTS A total of 11 studies fulfilled the selection criteria and were included in the review, including a total of 500 patients remitted from unipolar depression and 471 healthy control individuals. In nine of the eleven studies performance on neuropsychological tests was found to be decreased in patients compared to healthy control individuals in at least one of the tests. Methodological drawbacks were prevalent including non-stringent definition of remission and non-correction for multiple testing. Only few studies investigated the association between cognition and prior course of illness and the results were divergent. LIMITATIONS Stringent criteria were used in the assessment of eligibility of studies. The studies were first and foremost selected according to the criteria for remission used. CONCLUSION Cognitive dysfunction seems to be present in individuals suffering from unipolar disorder in the remitted state. We recommend that future studies should focus on disentangling the state and trait characteristics of cognitive dysfunction in unipolar disorder and further clarify the associations with clinical phenotype, course of illness and subsyndromal psychopathology. Furthermore, there is a need to identify the cognitive difficulties in individuals suffering from unipolar disorder in relation to psychosocial function, quality of life and risk of recurrence and to assess the effect of treatment intervention on cognitive function.

Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis.

The pathophysiology of depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis and the use of salivary cortisol measures is increasingly being incorporated into research. The aim of the present study was to investigate whether salivary cortisol differs for patients with depression and control persons. We did a systematic review with sequential meta-analysis and meta-regression according to the PRISMA Statement based on comprehensive database searches for studies of depressed patients compared to control persons in whom salivary cortisol was measured. Twenty case-control studies, including 1354 patients with depression and 1052 control persons were identified. In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/l (95% C.I.: 0.95-4.21) p=0.002 in the morning and on average 0.27 nmol/l (95% C.I.: 0.03-0.51) p=0.03 in the evening. In a fixed-effects model the mean difference was 0.58 nmol/l (95% C.I.). Study sequential cumulative meta-analyses suggested random error for the finding of this rather small difference between groups. The reference intervals for morning salivary cortisol in depressed patients (0-29 nmol/l) and control persons (1-23 nmol/l) showed substantial overlap suggesting lack of discriminative capacity. These results should be interpreted with caution as the heterogeneity for the morning analysis was large and a funnel plot, suggested presence of bias. Further, in meta-regression analyses higher intra-assay coefficients of variation in cortisol kits (p=0.07) and mean age (p=0.08) were associated with a higher mean difference of morning salivary cortisol between depressed and controls, while gender and depression severity were not. Based on the available studies there is not firm evidence for a difference of salivary cortisol in depressed patients and control persons and salivary cortisol is unable to discriminate between persons with and without depression.

The BDNF Val66Met polymorphism: Relation to familiar risk of affective disorder, BDNF levels and salivary cortisol

BACKGROUND Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. METHOD In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. RESULTS Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. CONCLUSION Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

Cognitive Deficits in the Remitted State of Unipolar Depressive Disorder

BACKGROUND Patients with unipolar depressive disorder may present with cognitive deficits in the remitted state, and the aim of the present study was to investigate whether cognitive deficits within specific cognitive domains are present. METHOD Via the Danish registers (Civil Person Register, Danish Psychiatric Register) we identified individuals between 40 and 80 years of age with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital, and a gender- and age-matched control group. Particular emphasis was placed on assuring that patients were in a remitted state. Cognitive function was assessed with a broad range of neuropsychological tests. RESULTS A total of 88 patients and 50 controls were included in the study. In multiple linear regression analyses with simultaneous adjustment for age, gender, education level, premorbid IQ, and residual depressive symptoms, a diagnosis of unipolar disorder predicted lower performance on the Trail Making Test, the Symbol Digit Modalities Test, and on the Stroop test. CONCLUSION Cognitive deficits are present in patients with unipolar disorder in the remitted state. The deficits seem to reside more within the cognitive domain of attention than within other domains, and may be characterized by impairment of processing speed and cognitive flexibility.

Differences in psychomotor activity in patients suffering from unipolar and bipolar affective disorder in the remitted or mild/moderate depressive state.

BACKGROUND Abnormalities in psychomotor activity are a central and essential feature of affective disorder. Studies measuring differences in psychomotor activity between unipolar and bipolar disorder show divergent results and none have used a combined heart rate and movement monitor for measuring activity during free-living conditions. OBJECTIVE To compare objectively measured psychomotor activity in patients with unipolar and bipolar disorder in a remitted or mild/moderate depressive state. Further, both groups were compared to a healthy control group. METHODS A cross-sectional study of outpatients suffering from unipolar (n=20) and bipolar (n=18) disorder and healthy controls (n=31), aged 18-60 years. For three consecutive days a combined acceleration (m/s(2)) and heart rate (beats per minute) monitoring was used in conjunction with a step test to estimate activity energy expenditure (J/min/kg) as measures of psychomotor activity and physical fitness. RESULTS Overall score on Hamilton-17 items ranged between 0 and 22. Patients had higher sleeping heart rate (p<0.001), lower fitness (p=0.02), lower acceleration (p=0.004), and lower activity energy expenditure (p=0.004) compared to controls. Comparing unipolar and bipolar patients and adjusting for differences in Hamilton-17 revealed lower acceleration (p=0.01) and activity energy expenditure in bipolar patients (p=0.02); the difference was most prominent in the morning. CONCLUSIONS Electronic monitoring of psychomotor activity may be a promising additional tool in the distinction between unipolar and bipolar affective disorder when patients present in a remitted or depressive state.

Daily electronic self-monitoring in bipolar disorder using smartphones - the MONARCA I trial: a randomized, placebo-controlled, single-blind, parallel group trial.

BACKGROUND The number of studies on electronic self-monitoring in affective disorder and other psychiatric disorders is increasing and indicates high patient acceptance and adherence. Nevertheless, the effect of electronic self-monitoring in patients with bipolar disorder has never been investigated in a randomized controlled trial (RCT). The objective of this trial was to investigate in a RCT whether the use of daily electronic self-monitoring using smartphones reduces depressive and manic symptoms in patients with bipolar disorder. METHOD A total of 78 patients with bipolar disorder according to ICD-10 criteria, aged 18-60 years, and with 17-item Hamilton Depression Rating Scale (HAMD-17) and Young Mania Rating Scale (YMRS) scores ≤17 were randomized to the use of a smartphone for daily self-monitoring including a clinical feedback loop (the intervention group) or to the use of a smartphone for normal communicative purposes (the control group) for 6 months. The primary outcomes were differences in depressive and manic symptoms measured using HAMD-17 and YMRS, respectively, between the intervention and control groups. RESULTS Intention-to-treat analyses using linear mixed models showed no significant effects of daily self-monitoring using smartphones on depressive as well as manic symptoms. There was a tendency towards more sustained depressive symptoms in the intervention group (B = 2.02, 95% confidence interval -0.13 to 4.17, p = 0.066). Sub-group analysis among patients without mixed symptoms and patients with presence of depressive and manic symptoms showed significantly more depressive symptoms and fewer manic symptoms during the trial period in the intervention group. CONCLUSIONS These results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder

OBJECTIVE To investigate whether the cumulative number, duration and subtypes (severity and presence of psychotic features) of previous episodes of depression in patients with unipolar depressive disorder in a remitted state are associated with decreased global cognitive function. METHODS Via the Danish registers individuals between 40 and 80 years of age were identified: (1) patients with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital in the period 1994 to 2002, and (2) gender and age matched control individuals. The participants were assessed with the Cambridge Cognitive Examination (CAMCOG), which provides a composite measure of global cognitive function. RESULTS A total of 88 patients and 50 controls accepted our invitation to participate, fulfilled the selection criteria and were included in the study. The cumulative duration of depressive episodes was associated with a decreased CAMCOG score adjusted for age, gender, education, premorbid IQ and residual depressive symptoms (B=-0.14, 95% C.I. (-0.26, -0.02), R(2)adj=0.31, P=.02). Significant associations were also found between CAMCOG score and the cumulative duration and total number of depressive episodes with psychotic features, respectively. CONCLUSION Our findings suggest that cognitive dysfunction is associated with the cumulative duration of depressive episodes, and that, in particular, depressive episodes with psychotic features in the course of illness may be a significant predictor of future impairment of cognitive function.

Discrete neurocognitive subgroups in fully or partially remitted bipolar disorder: Associations with functional abilities

BACKGROUND Neurocognitive impairment in remitted patients with bipolar disorder contributes to functional disabilities. However, the pattern and impact of these deficits are unclear. METHODS We pooled data from 193 fully or partially remitted patients with bipolar disorder and 110 healthy controls. Hierarchical cluster analysis was conducted to determine whether there are discrete neurocognitive subgroups in bipolar disorder. The pattern of the cognitive deficits and the characteristics of patients in these neurocognitive subgroups were examined with analyses of covariance and least significance difference pairwise comparison. RESULTS Three discrete neurocognitive subgroups were detected: one that was cognitively intact (46.1%), one that was selectively impaired with deficits in processing speed (32.6%), and one that was globally impaired across verbal learning, working memory, and executive skills (21.2%). The globally and selectively impaired subgroups were characterized by greater perceived stress and subjective cognitive complaints, poorer work and social adjustment, and reduced quality of life compared to patients who were cognitively intact. LIMITATIONS The study design was cross-sectional which limits inferences regarding the causality of the findings. CONCLUSION Globally and selectively impaired bipolar disorder patients displayed more functional disabilities than those who were cognitively intact. The present findings highlight a clinical need to systematically screen for cognitive dysfunction in remitted bipolar disorder and to target residual cognitive dysfunction in future treatment strategies.

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

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.

The effect of selective serotonin reuptake inhibitors in healthy subjects. A systematic review

Background: Selective serotonin reuptake inhibitors (SSRIs) show antidepressant properties in many patients with a diagnosis of depression. An understanding of the underlying mechanisms of the effect of SSRIs in healthy patients may lead to an understanding of the yet unclear pathophysiology of depression. Recent reviews of studies investigating the effect of SSRIs in healthy persons conclude that the results are inconsistent and that—in relation to a wide range of outcomes—the effect of SSRIs is limited; however, reasons for the inconsistencies are poorly studied. Aims and Methods: To investigate whether methodological artefacts can explain the diverging findings, we conducted a systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of treatment by SSRI for at least a week in healthy persons published before January 2009. Results: We identified 33 trials, investigating six SSRIs and 163 outcome tests. The effect of SSRI showed divergence presumably related to methodological issues. Specifically, it is likely that the majority of studies included a mix of healthy persons with and without a family history of affective disorders. Few presented information on factors that may influence outcomes such as age, gender, family history of psychiatric disorder, drug levels and ethnicity. No study fulfilled principles of conducting and reporting randomized controlled trials, according to the CONSORT Statement guidelines. Conclusions: It is unclear whether the effect of SSRIs in healthy persons may lead to an understanding of the pathophysiology of depression, since the present evidence is divergent and may be severely influenced by a number of methodological drawbacks.