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Background/Aims: To examine the mortality of very mildly to severely demented persons compared to nondemented persons. Methods: Participants in a randomly drawn population-based cohort study on dementia were followed for 14 years from 1992 to 2006. Participants were examined at baseline (3,065 nondemented and 234 prevalent demented), after 2 years (2,286 nondemented and 145 incident demented) and again after 5 years (1,669 nondemented and 124 new cases of dementia). Causes of death were ascertained in 884 nondemented and 286 demented participants. Survival for demented compared to nondemented persons was analyzed with the Cox proportional hazards model with time-dependent covariates adjusted for gender and age. Results: The hazard ratio of death (95% confidence interval) increased from 1.82 (1.55–2.14) for the very mildly demented to 9.52 (6.60–13.74) for the severely demented subjects. The demented participants died significantly more often of neurological causes other than dementia and of pneumonia than the nondemented participants. No other significant differences in causes of death were found. Conclusion: Dementia increased the risk of death. Even in the very early stages of dementia the risk of death was increased.

The kinetics of citalopram were studied in a group of volunteers after oral (8 subjects) and intravenous (4 subjects) single doses and repeated oral administration (7 subjects). Inter- and intraindividual variation was limited and linearity of kinetics indicated. Systemic and apparent oral clearance estimates (mean 0.42 l plasma/min.) were similar, indicating roughly complete systemic availability. The presence of unchanged drug in urine, corresponding to 1/7 of the dose, suggests elimination by renal as well as hepatic processes. The data from the intravenous test revealed two compartment kinetics; the total volume of distribution was estimated to about 1150 l and that of the central compartment to 175 l. Upon repeated administration steady-state conditions were generally achieved after one week in agreement with the 33 hrs half-life of elimination. Citalopram peak concentrations were reached within 2-4 hours after the daily dose and maximally two-fold variation was recorded in the 24 hrs dose interval. The levels of a main pharmacodynamically active metabolite were roughly half as high as the drug levels.

Background Subthreshold Depression (SD) is an impairing condition that might convert into Major Depressive Disorder (MDD). Still, the characteristics of childhood SD are largely unknown. Purpose We aim to examine how SD in children differs from MDD regarding symptom profile, comorbidity, functional impairment and associated life stressors. We will examine the frequency of childhood SD and MDD and compare previous mental health between groups. Basic procedures This is a two-phase nested case–control study within the Danish National Birth Cohort (DNBC) (N = 4500). Mothers completed the online Development and Well-Being Assessment (DAWBA) regarding their child aged 8–10 years. Main findings A total of 3421 children participated (response rate 76%); 35 children were diagnosed with MDD and 55 with SD. Anhedonia, irritability and worthlessness/guilt were more frequent in MDD than SD, and anhedonia was rare in non-depressed children (1.2%). Comorbid anxiety and conduct disorders were equally common in the groups. Children with MDD had higher functional impairment caused by the depressive condition than children with SD, but overall functional impairment was the same. Life stressors, including maternal depressive symptoms, were equally frequent for children with MDD and SD. Emotional problems and functional impairment at age 7 years predicted later SD and MDD. SD was twice as common as MDD in the DNBC (point prevalence 1.0% vs. 0.5%). Principal conclusions Children with SD and MDD display striking similarities. They differ mainly by the number of depressive symptoms and depression-related functional impairment. Both SD and MDD at age 8–10 years were preceded by emotional symptoms and functional impairment at age seven years. This indicates a continuity of childhood depressive conditions but also a window of opportunity for prevention of MDD.

Several epidemiologic studies have examined depression as a risk factor for Alzheimer disease with conflicting results. Most studies relied on self-reported depression, but the agreement between self-reported depression and clinical diagnosis has been reported to be weak, thereby diluting the association.A population-based cohort in Odense, Denmark, of 3346 persons age 65-84 years was examined at baseline (1992-1994) and after 2 years (1994-1996) and 5 years (1997-1999). History of depression was collected at baseline as self-report. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Persons with a history of depression had an increased risk of Alzheimer disease both at baseline (OR = 1.7; CI = 1.0-2.7) and at follow up (at 2 years, 1.9 [1.0-3.3] and at 5 years, 1.6 [0.9-2.7]).Depression was associated with an increased risk of Alzheimer disease. The odds ratios were lower than generally reported from follow-up studies and are similar to cross-sectional studies.

Background:Contrary to early case-control studies that suggested smoking protects against Alzheimer disease (AD), recent prospective studies have shown that elderly who smoke may be at increased risk for dementia.Objective:To examine prospectively the effect of smoking on cognition in nondemented elderly.Method:In a multicenter cohort, the European Community Concerted Action Epidemiology of Dementia (EURODEM), including the Odense, Personnes Agées Quid (Paquid), Rotterdam, and Medical Research Council: Ageing in Liverpool Project—Health Aspects (MRC ALPHA) Studies, 17,610 persons aged 65 and over were screened and examined for dementia. After an average 2.3 years of follow-up, 11,003 nondemented participants were retested. Excluding incident dementia cases and those without baseline information on smoking gave an analytical sample of 9,209 persons. Average yearly decline in Mini-Mental State Examination (MMSE) score was compared among groups, adjusting for age, sex, baseline MMSE, education, type of residence, and history of myocardial infarction or stroke.Results:MMSE score of persons who never smoked on average declined 0.03 point/year. The adjusted decline of former smokers was 0.03 point greater and of current smokers 0.13 point greater than never smokers (p< 0.001). Higher rates of decline by smoking were found in men and women, persons with and without family history of dementia, and in three of four participating studies. Higher cigarette pack–year exposure was correlated with a significantly higher rate of decline.Conclusion:Smoking may accelerate cognitive decline in nondemented elderly.

Objective: To identify psychopathological predictors for suicide in a population of major depressed Diagnostic Statistical Manual-III (DSM-III) in-patients. Method: A total of 210 previous participants in multicentre antidepressant drug trials, carried out in a randomized double-blind design, were followed prospectively through a maximum of 10 years. Patients with a drug or alcohol abuse were excluded. The association between suicide and the pretreatment psychopathological profile was analysed using survival statistics. Results: The suicide rate for non-melancholic depressed patients was significantly higher than for melancholic depressed patients. Comorbid personality disorder was independently associated with an increased suicide rate [relative hazard 3.41(CI: 1.15–10.10)]. Conclusion: The study indicates that the non-melancholic aspect of depression, and especially comorbid personality disorder, is associated with an increased suicidal vulnerability.

Objective:nThe aim of this study was to determine whether age itself is a significant factor in predicting adverse drug reactions in depressed inpatients treated with clomipramine. Method:nThe study involved 150 hospitalized, depressed patients treated with 150 mg clomipramine per day. Changes in orthostatic blood pressure during treatment as well as the patients' complaint about side-effects was examined with regard to age. The sample was divided into younger (

Background The rate of recognition of depressive disorder in general practice is reported to be low. Current classification systems, i.e. ICD-10 and DSM-III-R, and DSM-IV with operational diagnostic criteria, have led to greater agreement concerning the diagnosis of depressive disorder. The aim of this study was to assess the applicability and validity of the ICD-10 criteria for depression in general practice in Denmark. Methods After a 1-day training course in the ICD-10 criteria for depression, ten general practitioners, during an 8-week period assessed all patients aged 18 or older for depressive symptoms in accordance with the ICD-10 criteria. Results Among a total of 3505 consultations, 116 patients (3.3%) met the criteria for a depressive episode. Of these, 80 (68.8%) accepted to be reinterviewed by a psychiatrist, who confirmed the diagnosis of depressive disorder in 57 of the 80 patients (71.3%). Limitations The number of 'false negative' cases are unknown in the study. Conclusion The ICD-10 criteria for depression seem to be appropriate and valid in general practice.

Background: Depression is the most prevalent psychiatric disorder in the elderly and several studies indicate that 10–15% of persons over 65 years suffer from significant depressive symptoms. Despite the high prevalence, most cases of depression in the elderly remain unrecognized and untreated, maybe because of a different pattern of symptoms across age groups. The objective of the study was to compare symptomatology and diagnostic profile between younger and elderly DSM-III and DSM-III-R major depressed inpatients and to advise an appropriate depression scale for the elderly. Methods: The study covers 461 depressed inpatients evaluated with the Hamilton Depression Scale and the Newcastle 1965 Scale. To find differences between younger and elderly patients, the symptomatology was analyzed stepwise by principal component analyses, latent structure analyses and single item analyses. Results: No clinically significant differences in symptomatology between younger and elderly depressed patients were found. The DSM-IV concept of Major Depression and the ICD-10 criteria for depression was not influenced by patients’ age. Limitations: All patients were hospitalized and mainly endogenously depressed and generalization of the results to other populations should be made with caution. Only pretreatment data was analyzed. Conclusions: The DSM-IV concept of Major Depression and the ICD-10 criteria for depression can be used without modification for age.

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 neuro-psychological 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 −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.

The hypothesis that a low educational level increases the risk for Alzheimer's disease remains controversial. The authors studied the association of years of schooling with the risk for incident dementia and Alzheimer's disease by using pooled data from four European population-based follow-up studies. Dementia cases were identified in a two-stage procedure that included a detailed diagnostic assessment of screen-positive subjects. Dementia and Alzheimer's disease were diagnosed by using international research criteria. Educational level was categorized by years of schooling as low ( or =12). Relative risks (95% confidence intervals) were estimated by using Poisson regression, adjusting for age, sex, study center, smoking status, and self-reported myocardial infarction and stroke. There were 493 (328) incident cases of dementia (Alzheimer's disease) and 28,061 (27,839) person-years of follow-up. Compared with women with a high level of education, those with low and middle levels of education had 4.3 (95% confidence interval: 1.5, 11.9) and 2.6 (95% confidence interval: 1.0, 7.1) times increased risks, respectively, for Alzheimer's disease. The risk estimates for men were close to 1.0. Finding an association of education with Alzheimer's disease for women only raises the possibility that unmeasured confounding explains the previously reported increased risk for Alzheimer's disease for persons with low levels of education.

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. Copyright © 1999 John Wiley & Sons, Ltd.

In contrast to out-patients, hospitalized depressed patients have been reported to respond better to tricyclic antidepressants (TCAs) than to selective serotonin reuptake inhibitors (SSRIs) and moclobemide. This may be due to differences in the type of patients included in the trials. The hypothesis that hospitalized depressed patients have a different symptom profile to out-patients was tested by comparing 352 patients from three in-patient studies with 581 patients from three out-patient studies conducted in Denmark during the period 1980-1992. All patients had major depression and were evaluated using the Hamilton Depression Scale. The full version of the Newcastle Diagnostic Rating Scale (1965) was applied to 443 of the patients. In-patients were characterized by higher scores on the items 'depressed mood', 'suicidal impulses', 'work and interest (reduced)', 'retardation', 'distinct quality of depression', 'weight loss', 'feeling of guilt' and 'nihilistic delusions', and by lower scores on the items 'somatic complaints', 'hypochondriasis', 'psychological stressors' and 'anxiety'. In total, 76% of the in-patients and 40% of the out-patients had melancholic/endogenous depression. These findings may explain why TCAs are superior to SSRIs and moclobemide in hospitalized patients, since other data indicate that TCAs seem to be the most effective treatment for the melancholic/endogenous subtype.

The Major Depression Rating Scale (MDS) has been derived from the Hamilton Depression Scale and the Melancholia Scale. The MDS contains the nine DSM-IV items for major depression which all have anchoring scores from 0 to 4; hence, the theoretical score range is up to 36. The Major Depression Rating Scale has in this study been psychometrically analysed in randomized moclobemide trials. The results showed that the MDS had higher internal validity than the Hamilton Depression Scale. Thus, the homogeneity of the items was higher; factor analysis identified only one general depression factor (after 4 weeks of treatment explaining more than 50% of the variance). The inter-rater reliability of the two scales was of the same high level. The ability to measure changes (external validity) was tested in randomized clinical trials with moclobemide versus tricyclics (clomipramine and notriptyline) performed in Denmark in the psychiatric setting as well as in the general practice. The results showed that in the psychiatric setting tricyclics were superior to moclobemide with effect sizes ranging between 0.43 and 0.53. The highest effect size was obtained with the Melancholia Scale and the Major Depression Rating Scale, while the Hamilton Depression Scale was below 0.50. In the general practice setting no difference was found between moclobemide and clomipramine. In conclusion, the Major Depression Rating Scale has been found to have a more homogeneous factor structure than the Hamilton Depression Scale, but still with the same level of reliability and external validity. However, further studies are needed to standardize the scale, especially in the general practice setting.

In a recent placebo-controlled multicenter study, 38 patients, ranging in age between 62 and 88 years (median, 71) were treated with nortriptyline (NT) for up to 7 weeks. NT was administered in a divided dose of 75 mg daily and serum NT (se NT), and its 10-hydroxy-metabolites (se OH-NT) were determined at various intervals. Several clinical measures of efficacy, including the 17-item Hamilton Rating Scale for Depression, were evaluated weekly as well as side effects (anticholinergic) and electrocardiogram (ECG) changes. Eighty-one percent of patients had NT levels in the previously defined therapeutic range of 50 to 170 ng/ml, with steady state reached between 1 and 3 weeks. There was little individual variation in drug kinetics and metabolism over the study period. In general se OH-NT levels were not greater than those of se NT. Pharmacodynamic analyses showed that patients with moderate to severe anticholinergic side effects [CSE(+)] had significantly higher NT levels than those with mild or no symptoms [CSE(-)]. Furthermore, repeated-measures ANOVA modeled over time showed a highly significant decrease in clinical measures in both CSE groups of patients and also a highly significant group-time interaction. Higher se OH-NT levels were associated with less anticholinergic side effects. No ECG changes were observed.

In a double-blind, randomized, controlled, multicenter clinical trial in general practice, lasting 7 weeks, a fixed dose of moclobemide (400 mg daily) was compared with a fixed dose of clomipramine (150 mg daily). A total of 147 patients with DSM-III-R major depression were included in the study. After a 1-week drug-free washout period, patients were stratified, according to total scores on the Hamilton Rating Scale for Depression (HAM-D), into two groups-HAM-D total scores, 11 to 15 points, and HAM-D total scores, 16 points or more. A comparison of the therapeutic effect of the two treatments was based on HAM-D total scores and the classification of patients into therapeutic response categories defined on the basis of total rating score, complete response, HAM-D ≤7 points ; partial response, HAM-D, 8 to 15 points ; or no response, HAM-D ≥16 points. The Newcastle Diagnostic Rating Scale (1965) was used to classify the patients into two groups, endogenous and nonendogenous. Adverse events were registered by use of the UKU side effect scale. Clinical global assessments of severity, efficacy, and tolerance were completed during the active treatment period. Compliance to treatment was based on levels of the drugs in plasma and the number of returned capsules. One hundred forty-two patients were evaluated for clinical effects. The results of the efficacy analyses showed therapeutic equivalence between moclobemide and clomipramine. There were no differences in the outcome of the two treatment groups or the two diagnostic groups (endogenous and nonendogenous). Treatment with clomipramine resulted in a higher dropout rate (40% ), mostly as the result of adverse events and a statistically higher frequency of side effects (p < 0.05) ; clomipramine was also significantly less tolerated than moclobemide (p < 0.0001). Important differences were found in the clinical characteristics between the included patients and a similar patient sample from an inpatient study ; these clinical characteristics explained some of the differences in the conclusions of the trials with moclobemide and other new antidepressants. (J Clin Psychopharmacol 1995 ;15[Suppl 2] :24S-30S)

Moclobemide and nortriptyline were compared with placebo in a double-blind randomized multinational (Canada, Denmark and UK) trial comprising 109 patients of > 60 years of age with major depression (DSM-III-R). Patients were randomized to 7 weeks of treatment with doses of 400 mg/day moclobemide, 75 mg/day nortriptyline or placebo. It was necessary to adjust nortriptyline dosage in < 20% of patients to maintain serum levels within the postulated therapeutic window of 50-170 ng/ml. At end of treatment, the remission rates were 23% for moclobemide, 33% for nortriptyline and 11% for placebo. Anticholinergic and orthostatic events occurred more often with patients on nortriptyline than either moclobemide or placebo.

A total of 219 inpatients with a DSM-III diagnosis of major depression, 150 women and 69 men, were followed prospectively for 3-10 years and mortality was recorded. The patients were previous participants in psychopharmacological multicenter trials, which were carried out for the purpose of comparing the antidepressant effect of newer 5-HT reuptake inhibitors with that of the tricyclic antidepressant drug, clomipramine. The study comprised patients with a total Hamilton Rating Scale for Depression score of > or = 18 and/or a Hamilton subscale score of > or = 9. Diagnostic classification according to the Newcastle I Scale in endogenous and nonendogenous depression was performed. The observed mortality was significantly greater than that expected. The increased mortality was essentially due to suicides and mainly found among women. Patients scored as nonendogenously depressed had a significantly higher suicide rate than endogenously depressed patients. The excess number of suicides in the nonendogenous group largely occurred within the first year of observation. No association was found between response to the antidepressant treatment in the trial and the suicide risk in the first 3 years of observation. Language: en

The incidence of self-poisoning and suicide accomplished with tricyclic antidepressants (TCA) is unacceptably high. TCA are undeniably highly toxic, and overdosage occurs frequently. This review presents data that more than suggest that the compounds are prescribed for patients for whom TCA treatment is not indicated. Therefore, the physicians must learn to face up to the benefit-risk elements with these drugs. As TCA for many years to come probably remain the drug of choice in treatment of many depressed patients, the only way out of this dilemma is to focus on prevention. In any event, more cautious prescribing of TCA outside hospital is desirable.

Traditional neuroleptics are classified as high-, middle-, and low-dose preparations. This ranking is based not only on the dose but also on the side-effect profile. In this classification system neuroleptics are also categorized in accordance with their receptor affinities. The new established and potential antipsychotics can similarily be categorized on the basis of their receptor affinities: 1) Selective dopamine receptor antagonists; 2) Partial D2 receptor agonists; 3) Non-dopaminergic antipsychotics; and 4) “Broad-spectrum” antipsychotics. The first and the last group appear to be the most promising, compared with traditional neuroleptics, as they are characterized by a low frequency of extrapyramidal side effects and equal antipsychotic effects. It is suggested that negative symptoms in schizophrenia may be relatively unresponsive to traditional neuroleptics. It remains to be shown whether the new antipsychotics have any superiority in this respect.□ Extrapyramidal side effects, New antipsychotics, ...

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.

Udgivelsesdato: Jun Development of dementia, including Alzheimer's disease (AD), is associated with lipid dysregulation and inflammation. As the host defense lectin surfactant protein D (SP-D) has multiple effects in lipid homeostasis and inflammation, the correlation between SP-D concentrations and development of dementia was investigated. A total of 418 non-demented persons were included in the study and cognitively re-examined after 3 years, while survival was followed for 11 years. Serum SP-D concentrations were measured at baseline. Logistic regression analysis controlling for age, gender, smoking status, and CRP showed that Odds Ratio for developing dementia was 2.62 (1.12-6.15) with an SP-D concentration in the highest quartile compared to the other quartiles. The risk of AD was 2.55 (0.95-6.90). Cox regression controlling for the same variables showed that hazard ratio of death was 1.43 (1.06-1.92) in the highest quartile. SP-D concentration thus correlates to development of dementia as well as to augmented mortality.

Udgivelsesdato: 2007-Jan 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.

Background Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown. Objective To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD. Methods Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years. Results We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5). Conclusions More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.

Aims: Several studies have shown that health care costs are higher for demented than for non-demented persons and that health care costs are higher for more severe demented persons than less severe demented persons. However, most studies report on cross-sectional study designs, and thus fail to examine the influence of disease progression on changes in health care costs to individual persons. The objective of this study was, using longitudinal data, to examine changes in total health care costs with disease progression in demented persons. Methods: We assumed that disease progression could be characterised by transitions between different states of dementia which reflected the degree to which the disease progressed over time. Then, changes in health care costs were regressed on a set of explanatory variables including disease progression. A total of 465 demented and non-demented persons were interviewed twice. The time between interviews was about three years. Before each interview, the participant was examined for dementia and classified by type of dementia (Alzheimer's disease, vascular or other types of dementia) and degree of dementia (very mild, mild, moderate, severe). Results: The results of this longitudinal study confirmed that health care costs increased over time for non-demented as well as for demented persons and that health care costs increased with disease progression. In particular, the health care costs increased when the disease had progressed into the severe state of the dementia. Also, decline in functional abilities was an important factor for explaining changes in health care costs.

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.

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.

The dexamethasone suppression test (DST) was conducted in 95 elderly DSM-III-R depressed patients randomized for treatment with moclobemide (MOC; 400 mg daily), nortriptyline (NT; 75 mg daily), or placebo (PBO) in a 7-week double-blind multicenter study. Patients were assessed weekly using various clinical scales, including the 17-item Hamilton Depression Rating Scale. The DST was administered at baseline and at the end of treatment. At baseline, no relationship was found between DST status and the various clinical scales used. At the end of treatment, suppressors (DST-) had significantly improved clinical ratings compared to nonsuppressors (DST+), and were mostly found among those treated with NT (71%) as compared to MOC (41%) or PBO (33%) (p.03). On the other hand, baseline DST measures influenced treatment outcome; DST+ patients had a greater number of treatment responders to NT (48%) than MOC (19%) or PBO (20%) (p.07). For DST- patients, the situation was reversed: NT, 7%; MOC, 31%. Postdexamethasone cortisol levels were lower in MOC responders (p.07). An interaction was found between DST and drug-specific response. The DST may be a useful adjunct for predicting and evaluating the outcome of antidepressant therapy.

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.

Bromazepam was compared with placebo and with chlorprothixene in a randomized, double-blind group-comparative multicenter trial in general practice. Two hundred and forty-five patients with generalized anxiety disorder (DSM-III 1980) were treated for 2 weeks with two daily doses of bromazepam, 3 mg or chlorprothixene, 15 mg or placebo. Median reductions in Hamilton Anxiety rating were 12 (bromazepam), 10.3 (chlorprothixene) and 7.3 (placebo). The study revealed significant superiority of bromazepam over placebo (median differences 3.3, 95% confidence limits: 0.3 and 6.1) but not over chlorprothixene (median difference 1.4, 95% confidence limits −0.8 and +3.5). Significantly higher rates of tiredness, sedation and hypersomnia were found on bromazepam and chlorprothixene compared to placebo. Tolerance was rated as “at least good” in 85.6% on bromazepam, in 86% on chlorprothixene and in 87.8% on placebo. Neither previous psychopharmacological treatment nor presence of psychosocial stress were of perceptible influence. Bromazepam and chlorprothixene are both superior to placebo in generalized anxiety states treated in general practice, but spontaneous improvements/placebo effects are substantial.

Dementia is a chronic illness associated with a progressive loss of cognitive and intellectual abilities, such as memory, judgment and abstract thinking. The objective of this study was to assess the health utilities of patients with dementia in Europe and identify the key factors influencing their Health-Related Quality of Life (HRQol). This study used cross-sectional data from the Odense study; a Danish cohort of patients aged 65–84 living in Odense, Denmark. A total of 244 patients with mild to severe dementia were interviewed together with a caregiver about their health status and activities of daily living (ADL). Alzheimer's disease was diagnosed according to the NINCDS-ADRDA criteria for probable dementia. Vascular dementia and other types of dementia were diagnosed according to the DSM-IIIR criteria. Severity of dementia was defined by score intervals on the Mini Mental State Examination score: mild (MMSE 20–30), moderate (MMSE 10–19), and severe (MMSE 0–9). Based on the ADL information, the patients' dependency level was defined as either dependent or independent. Questions from the Odense Study were mapped into each of the five dimensions of the EQ-5D in order to assess patients' HRQol. Danish EQ-5D social tariffs were used to value patients' HRQol. A regression analysis of EQ-5D values was conducted with backward selection on gender, age, severity, ADL level and setting in order to determine the main factor influencing HRQoL. The EQ-5D weight in patients independent upon others in ADL was 0.641 (95% CI: [0.612–0.669]), and in those dependent upon others was 0.343 (95% CI: [0.251–0.436]). Dependency upon others to perform ADL was the main factor affecting HRQoL.

EDITOR,--The papers on suicide and antidepressants in the issue of 28 January develop our understanding of this problem further. John A Henry and colleagues point out the differences in the rate of death by overdose for different antidepressants1 but fail to relate this to efficacy and the fact that only 4-5% of all suicides are due to an overdose of antidepressant.2 Susan S Jick and colleagues show that …

Objective: To study the difference in risk for dementing diseases between men and women. Background: Previous studies suggest women have a higher risk for dementia than men. However, these studies include small sample sizes, particularly in the older age groups, when the incidence of dementia is highest. Methods: Pooled analysis of four population-based prospective cohort studies was performed. The sample included persons 65 years and older, 528 incident cases of dementia, and 28,768 person-years of follow-up. Incident cases were identified in a two-stage procedure in which the total cohort was screened for cognitive impairment, and screen positives underwent detailed diagnostic assessment. Dementia and main subtypes of AD and vascular dementia were diagnosed according to internationally accepted guidelines. Sex- and age-specific incidence rates, and relative and cumulative risks for total dementia, AD, and vascular dementia were calculated using log linear analysis and Poisson regression. Results: There were significant gender differences in the incidence of AD after age 85 years. At 90 years of age, the rate was 81.7 (95% CI, 63.8 to 104.7) in women and 24.0 (95% CI, 10.3 to 55.6) in men. There were no gender differences in rates or risk for vascular dementia. The cumulative risk for 65-year-old women to develop AD at the age of 95 years was 0.22 compared with 0.09 for men. The cumulative risk for developing vascular dementia at the age of 95 years was similar for men and women (0.04). Conclusion: Compared with men, women have an increased risk for AD. There are no gender differences in risk for vascular dementia.

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. This analysis yielded r= 0.76 on day 0 and r= 0.80 on day 112, with the BCRS score having greater influence than the SCAG score. These results questioned the validity of the SCAG as an assessment instrument in psychopharmacological treatment of cognitive decline. BCRS seems to be more valid.

– Eight patients undergoing antidepressant therapy with nortriptyline for 1–4 years were investigated. The period of the investigation was 7 weeks and included a 2-week placebo period, blind for the patients. Total saliva secretion measurement, the nortriptyline plasma level, and signs and symptoms of depression and side effects were obtained once a week during the study. The results of the investigation were: (1) long-term treatment with nortriptyline is followed by hyposecretion or xerostomia, (2) the reduction of the secretion is reversible, (3) re-establishment of treatment with dosage leading to the same serum level of nortriptyline is immediately followed by a drop in saliva secretion, and (4) the changes in salivary secretion are useful as an indicator of side effects. The practical importance of the investigation is discussed.

Below the toxic plasma level of nortriptyline (NT) an upper therapeutic limit has been postulated in patients with endogenous depression. If so the clinical significance is obvious and a double-blind, randomized study was performed in order to solve this problem. Two groups of patients were controlled at different plasma levels (less than 150 ng/ml and less than 180 ng/ml). The degree of depression was rated weekly. Only about one third (n equals 24) of the patients originally included, were carried through the full protocol, the most prominent reason for drop out beeing spontaneous remission during an initial placebo period. After 4 weeks of NT treatment the majority in the high level group was still depressed, but the difference barely significant (P equals 5.5%). However, a randomized reduction of the plasma level among the patients at the high level resulted in a significant correlation to remission. Evaluation of the total material after 6 weeks of NT treatment demonstrated a strong correlation of high plasma level to poor antidepressive effect of NT. No correlation could be obtained between side-effects, which were few, and plasma level. The non-proteinbound fraction in plasma was found to 7% (SD 1.83) by simultaneous determinations of NT in plasma and CSF in 13 patients. The variation in the proteinbinding was not likely to invalidate the over all results based on total NT determination. A therapeutic plasma range of 50-150 ng/ml is recommended.

In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.

Neuropeptides are peptides that are involved in communication between neurones. These mechanisms are mainly unclarified but it is assumed that neuropeptides are involved in normal ageing processes and development of dementia. The therapeutic effect of vasopressin-and ACTH-peptides on Alzheimer's Disease and senile dementia is examined in placebo controlled, clinical investigations. On the basis of data collected, it can be concluded that the therapeutic effects of vasopressin-peptides could be described as a nonspecific stimulation, secondary changes in mood, alertness or other memory modulating processes. However, no direct effect on memory processes was found. The results of investigations of the ACTH-peptide, Org 2766 show an effect on mood and social behaviour while here again no specific effect on cognitive function has been revealed. Own results concerning the effect of Org 2766 on patients with mild to moderate dementia of primary degenerative type are briefly described. One hundred and twenty-six ...

The relationship between therapeutic effect and plasma concentration of nortriptyline was investigated in 30 female inpatients with moderate-to-severe endogenous depression. After a placebo period of 4-7 days, all patients received 50 mg. nortriptyline thrice daily by mouth for 4 weeks. Severity of depression was assessed on a rating scale once weekly during placebo and active treatment, and plasma concentrations of nortriptyline were measured by a gas-chromatographic method twice weekly, during placebo and active therapy. Plasma concentration of nortriptyline differed widely between patients; but in most individuals the plasma concentration reached a plateau value within a week, and this value remained constant during the treatment period. The lack of therapeutic effect on excessive plasma concentrations of nortriptyline, found in an earlier study, was confirmed. The best therapeutic effect was obtained with a plasma level below 175 ng. per ml.

SYSNOPSISThe study was undertaken in order to clarify the clinical pharmacological basis for a correct design of controlled trials of the prophylactic effect of tricyclic antidepressants. Twenty-two patients, successfully treated with nortriptyline (NT) in hospital for endogenous depression, continued the treatment for up to five months in the outpatient clinic. Plasma levels of NT were checked, and ratings were performed regularly. Depressive relapses, all related to low plasma levels of NT, were seen in three patients. The gas Chromatographic method, described in detail, has proved suitable for clinical routine and the results demonstrate the value of monitoring plasma levels in achieving therapeutic control.

Kragh-Sorensen, Per, Rolf Bang Olsen, Solveig Lund, Henk Van Riezen and Kjeld Steffensen: Neuropeptides: ACTH-peptides in dementia. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1986, 10 (3–5): 179–492. 1. 1. Studies on the treatment of demented patients with ACTH neuropeptides are reviewed. The discussion is restricted to ACTH4–10 and an orally active peptide, the modified ACTH4–9 fragment; H-Met(O2)-Glu-His-Phe- d Lys-Phe-O (Org 2766). 2. 2. The first part of the review concentrates on data from animal pharmacology and basic and human studies which have relevance for the clinical effects shown in demented patients. 3. 3. The second part concerns clinical studies in man. Own results from a placebo-controlled dose finding study on the treatment of 156 PDSD patients with Org 2766 are presented. Org 2766 was in this study found to have a significant therapeutic effect in patients with PDSD measured mainly on the basis of SCAG total, although the effect was found to be rather small (average 4 points improvement on SCAG total). Post hoc analyses demonstrated that effects were clinically relevant for only 25 per cent of the patients. Analyses of SCAG factor scores indicated an effect on cognitive function and somatic function. The study failed to show clear dose-response relationship. However, before a final conclusion on the efficacy of Org 2766 can be reached the results must be confirmed by others. 4. 3. Analysis of SCAG factor scores indicated an effect on cognitive function and somatic dysfunction. 5. 4. No clear dose-response relationship was found. 6. 5. The therapeutic effects of Org 2766 are well within the range of the results obtained with HydergineR: 7. 6. Org 2766 is a very safe drug. 8. 7. Before a final conclusion can be drawn on the efficacy of Org 2766 results must be confirmed by others.

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 Conclusions: Patients with PD have an almost sixfold increased risk for becoming demented compared with subjects without PD.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.