Antipsychotic treatment effects on cardiovascular, cancer, infection, and intentional self-harm as cause of death in patients with Alzheimer's dementia.

BACKGROUND: Alzheimer's disease (AD), the most common disease causing dementia, is linked to increased mortality. However, the effect of antipsychotic use on specific causes of mortality has not yet been investigated thoroughly. METHODS: Utilizing the Danish nationwide registers, we defined a cohort of patients diagnosed with AD. Utilizing separate Cox regressions for specific causes of mortality, we investigated the effects of cumulative antipsychotic dosage after diagnosis and current antipsychotic exposure in the time period 2000-2011. RESULTS: In total, 45,894 patients were followed for 3,803,996 person-years. A total of 6129 cardiovascular related deaths, 2088 cancer related deaths, 1620 infection related deaths, and 28 intentional self-harm related deaths are presented. Current antipsychotic exposure increased mortality rate with HR between 1.92 and 2.31 for cardiovascular, cancer, and infection related death. Cumulative antipsychotic dosages were most commonly associated with increased rates of mortality for cardiovascular and infection as cause of death, whereas the associations were less clear with cancer and intentional self-harm as cause of death. CONCLUSIONS: We showed that cumulative antipsychotic drug dosages increased mortality rates for cardiovascular and infection as cause of death. These findings highlight the need for further investigations of long-term effects of treatment and of possible sub-groups who could benefit from treatment.

Cumulative dosages of antipsychotic drugs are associated with increased mortality rate in patients with Alzheimer's dementia.

OBJECTIVE: We wished to investigate the effects of cumulative dosages of antipsychotic drug in Alzheimer's dementia, when controlling for known risk factors, including current antipsychotic exposure, on all-cause mortality. METHOD: We utilized a nationwide, population-based, retrospective cohort study design with mortality as outcome in individual patients diagnosed with Alzheimer's dementia. RESULTS: We included a total of 45 894 patients and followed them for 3 803 996 person-years in total, presenting 27 894 deaths in the study population. Cumulative antipsychotic exposure increased mortality: more than 0 Daily Defined Dosage (DDDs) but less than 90: HR 2.20, 95% CI (2.14-2.27), P < 0.001; more than or equal to 90 DDDs but less than 365: HR 1.81, 95% CI (1.74-1.89), P < 0.001; more than or equal to 365 DDDs but less than 730: HR 1.38, 95% CI (1.428-1.49), P < 0.001; and more than or equal to 730 DDDs: HR 1.06, 95% CI (0.95-1.18), P = 0.322, when controlling for proxy markers of severity, somatic and mental comorbid disorders. CONCLUSION: In this nationwide cohort study of 45 894 patients diagnosed with Alzheimer's dementia, we found that cumulative dosages of antipsychotic drugs were associated with increased mortality rates.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

The effect of age of onset of PD on risk of dementia.

BACKGROUND: Dementia occurs in the majority of patients with Parkinson's disease (PD). Late onset of PD has been reported to be associated with a higher risk for dementia. However, age at onset (AAO) and age at baseline assessment are often correlated. The aim of this study was to explore whether AAO of PD symptoms is a risk factor for dementia independent of the general effect of age. METHODS: Two community-based studies of PD in New York (n=281) and Rogaland county, Norway (n=227) and two population-based groups of healthy elderly from New York (n=180) and Odense, Denmark (n=2414) were followed prospectively for 3-4 years and assessed for dementia according to DSM-IIIR. All PD and control cases underwent neurological examination and were followed with neurological and neuropsychological assessments. We used Cox proportional hazards regression based on three different time scales to explore the effect of AAO of PD on risk of dementia, adjusting for age at baseline and other demographic and clinical variables. FINDINGS: In both PD groups and in the pooled analyses, there was a significant effect of age at baseline assessment on the time to develop dementia, but there was no effect of AAO independent of age itself. Consistent with these results, there was no increased relative effect of age on the time to develop dementia in PD cases compared with controls. INTERPRETATION: This study shows that it is the general effect of age, rather than AAO that is associated with incident dementia in subjects with PD.

Risk of dementia in Parkinson's disease: a community-based, prospective study.

OBJECTIVE: To calculate the incidence of and determine possible risk factors for dementia in PD. BACKGROUND: Dementia has important clinical consequences for patients with PD and their caregivers, but the incidence is unknown. METHODS: A population-based cohort of nondemented patients with PD (n = 171) from the county of Rogaland, Norway, was assessed at baseline and 4.2 years later with a comprehensive evaluation of motor, cognitive, and neuropsychiatric symptoms. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R) criteria, based on interview of the patient and a caregiver, cognitive rating scales, and neuropsychologic tests. A representative sample of 3,062 nondemented elderly subjects without PD served as control group. RESULTS: Forty-three patients with PD were demented at follow-up evaluation, equivalent to an incidence rate of 95.3 per 1,000 person-years (95% CI, 68.2 to 122.0). The risk for the development of dementia in patients with PD relative to the control subjects after adjusting for age, sex, and education was 5.9 (95% CI, 3.9 to 9.1). Predictive factors at baseline for dementia in PD in addition to age were Hoehn & Yahr score >2 (OR, 3.4; 95% CI, 1.3 to 8.6) and Mini-Mental State Examination score < 29 (OR, 3.3; 95% CI, 1.3 to 8.2). CONCLUSIONS: Patients with PD have an almost sixfold increased risk for becoming demented compared with subjects without PD.

CAMCOG as a screening instrument for dementia: the Odense study. Cambridge Cognitive Examination.

OBJECTIVE: The Cambridge Cognitive Examination (CAMCOG) score is correlated with age and sociodemographic variables. The aim of the study was to determine an individualized CAMCOG cut-off score for dementia, taking such correlates into account. METHOD: From the general population 150 people aged 65-84 years were examined with CAMDEX which includes CAMCOG, and a neuropsychological test battery. Data from 130 non-demented people were entered in setwise multiple regression analyses to identify variables predicting the CAMCOG score. RESULTS: The variables age, social class, matrimonial status, general knowledge and intellectual level explained 66% of the variance of the CAMCOG scores. A cut-off defined as a difference between actual and predicted CAMCOG score < or = -4.41 resulted in a sensitivity of 88.2% and a specificity of 89.2% for very mild to moderate dementia. CONCLUSION: It is possible to determine an individualized CAMCOG cut-off score for dementia in its early stages.

[Prevalence and incidence of dementia in Denmark. The Odense study]. / Praevalens og incidens af demens i Danmark. Odense-undersøgelsen.

Prevalence and incidence of dementia were determined for 65-84 year-old persons living in the municipality of Odense and randomly drawn from the Danish Civil Registration System (DCRS). All participants were examined with CAMCOG, the cognitive section of CAMDEX (The Cambridge Examination for Mental Disorders of the Elderly) and the follow-up period was two years. Individualized CAMCOG cut-off scores were determined by multiple linear regression. Possibly demented persons were further examined with the remaining part of CAMDEX and neuropsychological tests. Alzheimer's disease (AD) was diagnosed according to the NINCDS-ADRDA criteria for probable AD, and vascular dementia (VD) and dementias of other types according to the DSM-III-R criteria for dementia. The severity of dementia was determined according to the Clinical Dementia Rating scale. Of the 5,237 persons drawn from the DCRS, 3,346 participated in the prevalence study and 2,452 in the incidence study. The prevalence was 7.1% (66.7% AD, 18.3% VD, and 15.0% dementias of other types). Ninety-six (2.8%) were diagnosed as very mildly demented. The incidence rate was 29.5 new cases per 1,000 person-years and 20.9 for AD. Inclusion of cases with very mild dementia resulted in higher prevalence and incidence rates than generally reported.

Characteristics of elderly who develop Alzheimer's disease during the next two years-a neuropsychological study using CAMCOG. The Odense Study.

OBJECTIVE: The aim of the study was to determine which cognitive functions first deteriorate in Alzheimer's disease (AD) and to identify persons who would become demented 2 years following an initial examination. PARTICIPANTS: A total of 2452 initially non-demented persons, aged 65-84 years and randomly drawn from the population, who were examined 2 years apart. MEASURES: CAMCOG, the cognitive section of CAMDEX (The Cambridge Mental Disorders of the Elderly Examination). Fourteen composite measures were constructed of the 60 CAMCOG items. RESULTS: During the 2-year period, 102 developed AD; this group had significantly lower scores on all of the 14 composite measures at baseline examination than the subjects who remained non-demented. The incident demented were significantly older than the non-demented, had less formal schooling, were more often unskilled and had lower verbal intellectual level. Logistic regression analyses showed that especially higher age, together with reduced recent and remote memory, low category verbal fluency and attentional deficiency, characterized incident demented 2 years before the diagnosis was made. CONCLUSIONS: Cognitive changes, which develop years before the AD diagnosis, can be identified by means of CAMCOG, but this instrument does not allow identification of persons who later develop AD with sufficient precision.

The cost of dementia in Denmark: the Odense Study.

In a population-based study of dementia, the cost of care for 245 demented elderly and 490 controls matched by age and gender was estimated. Dementia of Alzheimer's type was diagnosed according to the NINCDS-ADRDA criteria, and vascular dementia and other types of dementia were diagnosed according to the DSM-IIIR criteria. Severity of dementia was determined by the Clinical Dementia Rating scale. The annual cost of medical care, domestic care, home help, nursing home and special equipment for nondemented patients was DKK 22,000 per person while the cost for very mildly, mildly, moderately and severely demented patients was DKK 49,000, DKK 93,000, DKK 138,000 and DKK 206,000, respectively. Except for very mild dementia the cost did not differ between elderly who suffer from Alzheimer's disease and those with other types of dementia. The net cost of dementia is the difference in cost between those with dementia and the matched controls and amounts on average to DKK 77,000 per person per year. However, priority setting cannot be based on the cost of dementia per se, but only on the cost of a specific dementia intervention compared to its health benefit.

Incidence of very mild to severe dementia and Alzheimer's disease in Denmark: the Odense Study.

OBJECTIVE: Calculation of incidence of dementia and AD, including cases in the earliest phases of the diseases. BACKGROUND: Establishment of incidence estimates is important for the future planning of the health care system, and incidence studies can offer insights into risk factors. METHODS: A total of 5,237 persons age 65 to 84 years were randomly drawn among people living in the municipality of Odense, Denmark. Of this sample 3,086 persons were eligible for the incidence study. All participants were examined with CAMCOG, the cognitive section of The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX), and the follow-up period was 2 years. Using multiple linear regression, the CAMCOG cutoff score was individualized to detect even minor cognitive decline with optimal precision. Possibly demented persons were further examined with the remaining part of the CAMDEX and neuropsychological tests. AD was diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, and vascular dementia and dementia of other types were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for dementia. Finally, the severity of dementia was determined according to the Clinical Dementia Rating scale. RESULTS: The incidence rate for very mild to severe dementia was 29.5 per 1,000 person-years and 20.9 for AD, and the rates were similar for men and women. CONCLUSION: Application of an individualized cutoff for the screening instrument resulted in detection of a substantial number of cases with very mild dementia, which subsequently resulted in higher incidence rates than those reported in most other studies.

Age-associated memory impairment--pathological memory decline or normal aging?

The aim of the study was to determine whether the memory capacity of individuals with age-associated memory impairment (AAMI) over a period of approximately 3 1/2 years declines more, if at all, than the memory capacity of persons without AAMI. Four computerized and three non-computerized memory tests, a naming test, and a test of visuo-motor speed were administered twice. Two estimates of intellectual capacity were made, one at the first examination and the other 3 1/2 years later. One person in the AAMI group (n = 44) developed vascular dementia. The group of AAMI subjects did less well on two of the seven memory tests after 3 1/2 years than they did initially; the control group (n = 18) had lower scores on one memory test at follow-up than they had previously. The data suggest that the memory capacity of subjects with AAMI is not pathologically impaired. The general intellectual level significantly influences whether an individual with memory complaints will be classified AAMI or not. People with high intelligence are less likely than people with lower intellectual capacity to fulfill the AAMI criteria. This suggests that AAMI lacks in construct validity.

Prevalence of very mild to severe dementia in Denmark.

OBJECTIVES: The prevalence of dementia has been estimated in several countries and a meta-analysis has shown moderate and severe dementia in people aged 65 years and older to be between 4% and 6%. The Odense study is aiming to estimate the prevalence and incidence of dementia and to identify risk factors. MATERIAL AND METHODS: A total of 3346 persons, equivalent to 64.5% of a random sample of 5237 persons aged 65-84 years living in the municipality of Odense, Denmark, underwent a two phase diagnostic procedure including a screening with CAMCOG, the cognitive section of The Cambridge Examination for Mental Disorders of the Elderly, seven neuropsychological tests, medical examination, and CT scan. The severity of dementia was assessed by the CDR (Clinical Dementia Rating). RESULTS: The prevalence rate was 7.1%, including the very mildly demented, defined as persons rated questionably demented according to the CDR scale. The prevalence rate of very mild dementia was 2.8%. The proportion of cases with very mild dementia decreased with increasing age while the prevalence rate increased. CONCLUSION: Inclusion of very mild cases of dementia resulted in a higher prevalence rate than generally reported, and the prevalence rate increased exponentially with age which was mainly due to Alzheimer's disease.

[Educational requirements of younger psychiatrists]. / Yngre psykiateres uddannelsesønsker.

In order to define the requirements junior medical staff in postgraduate psychiatric training would wish to make for future postgraduate training in adult psychiatry, a questionnaire with 66 questions was sent in June 1990 to postgraduate trainees at all departments of child psychiatry and adult psychiatry in the country. Response was anonymous. The article deals with the responses from 264 persons either intending to undergo specialist training in adult psychiatry or having already completed it. Sixty-four percent stated a need for better individual clinical guidance. The majority stated that eight hours every week should be earmarked for formal tuition and research (two hrs clinical tuition, two hrs theory, two hrs supervision in psychotherapy, and two hrs for research). On average, the trainees had used 4200 DKK of their own income and four free days on courses over the previous year. Twenty-four months was proposed as adequate for an introductory appointment. The majority held that appointments should be made on the basis of the traditional curriculum vitae (82%) and a personal interview (86%), while about 20% believed that written or oral references should also be a requirement. Sixty-nine percent believed that selection of applicants for teaching appointments should be made locally with central supervision. Twenty-six percent felt they had been passed over in appointment situations, and 68% claimed it was due to nepotism. Recommendations for modifications of the future postgraduate training according to the responses are proposed, and it is concluded that earmarked resources are necessary, if the intention in the educational reform now in progress is to be realized.

Benzodiazepine-induced sedation and cortisol suppression. A placebo-controlled comparison of oxazepam and nitrazepam in healthy male volunteers.

The sedative and cortisol suppressing properties of oxazepam (45 and 60 mg) and nitrazepam (10 and 15 mg) were examined in eight healthy male subjects. The most clear differences between oxazepam and nitrazepam were those seen with respect to the time course and until maximal effect (Tmax) of the different measurements. Nitrazepam showed maximal sedation after 1 h, maximal benzodiazepine level (RRA), and reaction time prolongation after 2 h, and maximal cortisol suppression after 3 h. Oxazepam showed maximal sedation after 2 h, maximal benzodiazepine levels, reaction time prolongation and cortisol suppression after 3 h. After administration of oxazepam (both doses) a transient return to baseline levels of cortisol was demonstrated. Whereas the degree of sedation correlated significantly within drug groups with the concurrent benzodiazepine levels, the Tmax of sedation was recorded 1 h earlier than the peak blood concentration (RRA) for both nitrazepam and oxazepam. The time course for cortisol suppression for the two compounds differed clearly from the other measurements and was not related to the peak blood concentration.

The accuracy of early diagnosis and predictors of death in Alzheimer's disease and vascular dementia--a follow-up study.

A total of 87 patients with mild or moderate degree of dementia of the Alzheimer type (AD) or vascular dementia (VD) was identified (DSM-III criteria), and their cognitive capacity was evaluated by means of rating scales and psychometric tests. Three years later 30 patients (34%) were dead. Significantly more VD than AD patients died. Eight of the survivors declined to participate in a follow-up study, and 1 patient was excluded by mistake. Of the survivors, 17 had indisputably suffered cognitive decline during the follow-up period (4 VD and 13 AD, 35%). In the case of 11 patients (2 VD and 9 AD) cognitive decline remained doubtful, and 20 patients (9 VD and 11 AD, 42%) underwent no intellectual deterioration during the follow-up period. The results underline the problems of early diagnosis of dementia according to DSM-III criteria. For both sexes a high ischemia score and a low body mass index predicted death. A low score on a verbal fluency test predicted death for men but not for women, and a high difference between systolic and diastolic blood pressure increased the risk of death for men but not for women.

Right atrial temperature and electrical activity during cardioplegic cardiac arrest.

In 18 patients undergoing coronary artery bypass surgery the relation between right atrial temperature and right atrial electrical reactivation during cardioplegic cardiac arrest was studied. The administration of cardioplegic solution induced immediate ventricular and atrial arrest in all patients. No recurrence of ventricular activity was observed while right atrial activity subsequently recurred in 11 patients. Activity at the surface ECG was recorded only in one patient with right atrial reactivation. No right atrial electrical activity was found below 19 degrees C. The average atrial temperature was 21.5 degrees C while the average apex temperature was 15 degrees C. The study has confirmed previous observations that during cardioplegic cardiac arrest the right atrium is not as well protected as the ventricular tissue against rewarming. Monitoring of the right atrial electrical activity or right atrial temperature is essential to ensure atrial arrest during the entire period of cardioplegic cardiac arrest.

Cortisol and treatment of depression: predictive value of spontaneous and suppressed cortisol levels and course of spontaneous plasma cortisol.

In 72 consecutive depressed hospitalized patients afternoon plasma cortisol was measured in three ways before treatment with antidepressants: 1) Spontaneous (n = 72), 2) 2h after oxazepam suppression (45 mg, n = 28; 60 mg, n = 37) and 3) 16 h after dexamethasone suppression (2 mg, n = 71). In addition, spontaneous cortisol was measured after 3 weeks' treatment (n = 55) and 5 weeks' treatment (n = 36). Both spontaneous and suppressed cortisol levels seemed to have a predictive value in the endogenously depressed patients: complete responders had significantly lower pretreatment cortisol levels compared to poor responders. However, other covarying factors such as distress and age may as well account for the differences in treatment effect. During treatment a significant decrease of spontaneous cortisol was found from about 400 nM in poor responders and 325 nM in complete responders to about 300 nM in all groups. There was a positive correlation between pre- and post-treatment cortisol levels and between pretreatment levels and per cent fall in spontaneous cortisol levels.

Afternoon plasma cortisol in relation to depression. A replication study.

In 37 consecutive depressed inpatients afternoon plasma cortisol (1500-1520 h) was measured in 3 ways: 1) spontaneously; 2) 2 h after oral administration of 60 mg oxazepam; and 3) 16 h after oral administration of 2 mg dexamethasone. Both oxazepam and dexamethasone caused a significant suppression of cortisol secretion. Spontaneous and suppressed cortisol levels correlated significantly to stress/distress items on the Hamilton Rating Scale for Depression (sum of items 8, 9, 10 and 12), whereas no correlations to age, or type of depression were found. In an earlier similar study of 35 patients both spontaneous and suppressed cortisol levels correlated significantly with age, type and severity of depression as well as with the stress/distress items. Those patients were older, more depressed (HRSD-17) and had higher stress/distress scores compared with the present sample of 37 patients. The consistent finding of a correlation with the stress/distress items suggest that this factor is important in relation to the hypersecretion of cortisol during depression and this may explain the limited diagnostic power of spontaneous and suppressed cortisol levels.

Procedures in evaluating dementia--a study of conjoint application of two rating scales (SCAG and BCRS) and psychometric tests.

Fifty-seven patients with dementia (mean age 74 years) were treated for 16 weeks with 2 different doses of a test drug or placebo. On day 0 no significant differences (Kruskal-Wallis H test) were found between the 3 treatment groups on psychometric test scores or the total scores on 3 rating scales (Modified Crichton Geriatric Behaviour Rating Scale, Sandoz Clinical Assessment - Geriatric (SCAG) scale and Brief Cognitive Rating Scale (BCRS). The score differences (the total scores on day 112 minus the total scores on day 0) on SCAG, BCRS and psychometric tests were subjected to a series of one-way analyses of variance. As no significant difference was found between the groups, they were combined into a single group. In this group the relationship between total scores on SCAG and BCRS and psychometric test scores was analysed. Setwise multiple regression analyses (with the psychometric test scores as the independent variables) showed that at most 34% and 45% (respectively) of the variance in the SCAG ratings was accounted for by the results from a small subgroup of tests (dealing with visuo-motor speed and verbal memory) on day 0 and day 112. The results of a somewhat bigger subgroup of tests (dealing with visuo-motor speed, verbal memory and general intelligence) explained 58% of the variance in the BCRS ratings both on day 0 and after 16 weeks. Canonical correlation analysis using scores on the 2 rating scales and the psychometric test results was applied complementarily to make the inferences as valid as possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Supraventricular tachyarrhythmias after coronary bypass surgery--a double blind randomized trial of prophylactic low dose propranolol.

In the present study 75 patients were double blind randomized either to receive 10 mg propranolol orally 4 times a day (35 patients) or a placebo (40 patients). Episodes of clinically important supraventricular tachyarrhythmias were recorded in the first 4 postoperative days. They appeared in 5 of 35 patients receiving propranolol and in 5 of 40 patients receiving placebo (no statistically significant difference). In conclusion this study indicates the need for further evaluation to clarify if low-dose propranolol or any other drug is effective in reducing the frequency of SVT in the early postoperative period after coronary artery bypass surgery.