Lars Vedel Kessing

Cognitive impairment in the euthymic phase of affective disorder

BACKGROUND A review of studies of cognition in the euthymic phase of unipolar and bipolar affective disorder reveals diverging results. METHODS The study was designed as a controlled cohort study, with the Danish psychiatric case register of admissions used to identify patients and the Danish civil register to identify controls. Patients who were hospitalized between 19 and 25 years ago with an affective diagnosis and who at interviews fulfilled criteria for a primary affective unipolar or bipolar disorder, according to ICD-10, were compared with age- and gender-matched controls. Interviews and assessment of the cognitive function were made in the euthymic phase of the disorder. In all, 118 unipolar patients, 28 bipolar patients and 58 controls were included. Analyses were adjusted for differences in the level of education and for subclinical depressive and anxiety symptoms. RESULTS Patients with recurrent episodes were significantly more impaired than patients with a single episode and more impaired than controls. Also, within patients the number of prior episodes seemed to be associated with cognitive outcome. There was no difference in the severity of the dysfunction between unipolar and bipolar patients. CONCLUSIONS Cognitive impairment in out-patients with unipolar and bipolar disorder appears to be associated with the number of affective episodes.

Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder

Objective: Several findings suggest that some patients with depressive or bipolar disorder may be at increased risk of developing dementia. The present study aimed to investigate whether the risk of developing dementia increases with the number of affective episodes in patients with depressive disorder and in patients with bipolar disorder. Methods: This was a case register study including all hospital admissions with primary affective disorder in Denmark during 1970–99. The effect of the number of prior episodes leading to admission on the rate of readmission with a diagnosis of dementia following the first discharge after 1985 was estimated. A total of 18 726 patients with depressive disorder and 4248 patients with bipolar disorder were included in the study. Results: The rate of a diagnosis of dementia on readmission was significantly related to the number of prior affective episodes leading to admission. On average, the rate of dementia tended to increase 13% with every episode leading to admission for patients with depressive disorder and 6% with every episode leading to admission for patients with bipolar disorder, when adjusted for differences in age and sex. Conclusion: On average, the risk of dementia seems to increase with the number of episodes in depressive and bipolar affective disorders.

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.

The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders – a life‐long perspective

Objective:  It is generally accepted that one of the most important predictors of recurrence in depressive and bipolar disorders is the number of previous episodes. However, very few studies have considered the individual tendency toward recurrence in analyses of the effect of the number of episodes on the risk of subsequent recurrence in affective disorder.

Increased risk of developing dementia in patients with major affective disorders compared to patients with other medical illnesses

BACKGROUND The association between affective disorder and subsequent dementia is unclear. Our aim was to investigate whether patients with unipolar or bipolar affective disorder have an increased risk of developing dementia compared to patients with other chronic illnesses. METHOD By linkage of the psychiatric and somatic nation-wide registers of all hospitalised patients in Denmark, 2007 patients with mania, 11741 patients with depression, 81380 patients with osteoarthritis and 69149 patients with diabetes were identified according to diagnosis at first-ever discharge from a psychiatric or somatic hospital between 1 January 1977 and 31 December 1993. The risk of receiving a diagnosis of dementia on subsequent re-admission was estimated with the use of survival analyses. RESULTS Patients with unipolar or bipolar affective disorder had a greater risk of receiving a diagnosis of dementia than patients with osteoarthritis or diabetes. Differences in age and gender and the effect of alcohol- or drug-abuse did not explain these associations. CONCLUSION Patients with unipolar or bipolar affective disorder seem to have an increased risk of developing dementia compared to patients with other illnesses. LIMITATION The study includes only patients who have been hospitalised at least once. CLINICAL RELEVANCE Patients with unipolar or bipolar affective disorder may be at increased risk of developing dementia.

Lithium Treatment and Risk of Dementia

CONTEXT It has been suggested that lithium may have neuroprotective abilities, but it is not clear whether lithium reduces the risk of dementia. OBJECTIVE To investigate whether continued treatment with lithium reduces the risk of dementia in a nationwide study. DESIGN An observational cohort study with linkage of registers of all patients prescribed lithium and diagnosed as having dementia in Denmark from January 1, 1995, through December 31, 2005. SETTING We identified all patients treated with lithium in Denmark within community psychiatry, private specialist, and general practices and a random sample of 30% of the general population. Subjects A total of 16,238 persons who purchased lithium at least once and 1,487,177 persons from the general population who did not purchase lithium. Main Outcome Measure Diagnosis of dementia or Alzheimer disease during inpatient or outpatient hospital care. RESULTS Persons who purchased lithium at least once had an increased rate of dementia compared with persons not exposed to lithium (relative risk, 1.47; 95% confidence interval, 1.22-1.76). For persons who continued to take lithium, the rate of dementia decreased to the same level as the rate for the general population. The rate of dementia decreased early after the consumption of lithium tablets corresponding to 1 prescription (typically 100 tablets) and stayed at a low level, although with a slight increase according to the number of subsequent prescriptions. The association between the number of prescriptions for lithium and dementia was unique and different from the association between the number of prescriptions for anticonvulsants and dementia. All findings were replicated in subanalyses with Alzheimer disease as the outcome. CONCLUSIONS Continued lithium treatment was associated with reduction of the rate of dementia to the same level as that for the general population. Methodological reasons for this finding cannot be excluded, owing to the nonrandomized nature of data.

Increased risk of developing Parkinson's disease for patients with major affective disorder: a register study

Objective:  To investigate whether patients with a diagnosis of affective disorder are at an increased risk of developing Parkinsons disease compared with medically ill control groups.

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.

Validity of diagnoses and other clinical register data in patients with affective disorder.

Studies validating the clinical diagnoses of affective disorder recorded in case registers against research diagnostic criteria do not exist. In the present study, a random sample of 100 patients was selected among 21,734 patients who were recorded in the Danish Psychiatric Central Register with a diagnosis of manic-depressive psychosis at their first admission to psychiatric ward in a period from January 1, 1971 to December 31, 1993. Case notes from alt over Denmark were reviewed for all 100 patients and diagnoses were made with the use of OPCRIT. Patients who were still alive were contacted and interviewed face to face or by telephone. In total, 95 out of the 100 patients received an ICD-10 diagnosis of affective disorder computed with OPCRIT and confirmed at the interviews. Other clinical characteristics such as the age at onset and the number of affective episodes estimated from the register corresponded well with information from the case notes and the interviews.

Cytokines in bipolar disorder: A systematic review and meta-analysis

BACKGROUND Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state. METHODS We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. RESULTS Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels. LIMITATIONS Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies. CONCLUSIONS This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.