[Stopping antidepressants: withdrawal symptoms and rebound effects : Review and practical recommendations]. / Absetzen von Antidepressiva ­ Absetzsymptome und Rebound-Effekte : Übersicht und praktische Empfehlungen.

Stopping antidepressants can cause withdrawal (discontinuation) symptoms, the return of the original illness, and rebound. The latter means that the disease will return stronger, faster, or with greater likelihood than if it had not been treated with medication. The Psychiatry Working Group of the Drug Commission of the German Medical Association (AkdÄ) presents the scientific findings and provides practical recommendations for action. Withdrawal symptoms are multiform; unspecific physical symptoms are predominant. Distinguishing them from the recurrence of depressive symptoms can be difficult. Most of them are mild and self-limiting. There is insufficient evidence on the extent and frequency of rebound depression. The rebound risk implies that when establishing the medication, the short-term benefit must be weighed against the possible long-term risk of chronic depression or the possible need for long-term medication. Patients should be informed about the risk of withdrawal both as early as the joint decision-making process about treatment initiation and regularly during the course of treatment. Withdrawal should take place gradually, except in emergency situations, whereby small steps should be taken, especially in the low-dose range.

Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

[Antipsychotics for treatment of neuropsychiatric disorders in dementia]. / Antipsychotika zur Behandlung neuropsychiatrischer Störungen bei Demenz.

Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.

A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI.

OBJECTIVES: Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. DESIGN, SETTING AND PARTICIPANTS: For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. INTERVENTION: Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. MEASUREMENTS: The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. RESULTS: After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status. CONCLUSION: In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease.

OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aß(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

[Diagnosis without therapy: early diagnosis of Alzheimer's disease in the stage of mild cognitive impairment]. / Diagnose ohne Therapie : Frühdiagnostik der Alzheimer-Krankheit im Stadium der leichten kognitiven Beeinträchtigung.

Alzheimer's disease (AD) is a histopathologically defined progressive neurodegenerative disorder. Its clinical manifestation can be subdivided into the stage of mild cognitive impairment (MCI) and the stage of dementia. According to ICD-10 the diagnosis of AD can only be made in the stage of dementia. The indication for anti-dementia drugs is restricted to the stage of dementia in AD, too. Diagnostic tools to detect AD have improved considerably in recent years. They include the MRI findings of atrophy of the medial temporal lobe, cerebrospinal fluid (CSF) biomarkers ß-amyloid and τ, the visualisation of metabolic deficits on positron emission tomography (PET) using [(18)F]-fluoro-2-deoxy-D-glucose (FDG) and the emerging possibility to demonstrate amyloid deposits in vivo using PET ligands. The application of these methods allows the diagnosis of AD to be established already in the stage of MCI. While diagnostic methods improve and enable us to make the diagnosis of AD very early, there is no such progress in the development of treatment options. Early diagnosis of AD appears to have benefits and drawbacks. It is most important to include the patient in the decision on early diagnosis and to make clear that there is a lack of therapeutic options if the diagnosis is positive.

Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing.

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer's disease: a multicenter assessment.

OBJECTIVE: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. METHODS: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. RESULTS: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). CONCLUSION: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.

Critical evaluation of self-rated quality of life in mild cognitive impairment and Alzheimer's disease--further evidence for the impact of anosognosia and global cognitive impairment.

OBJECTIVES: The present study investigates the effect of anosognosia (impaired insight for an illness) and cognitive deficits on the reliability and validity of self-rated Quality of Life (QoL) in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). DESIGN: Cross-sectional study. SETTING: Cross-sectional study with a consecutive clinical sample from a memory clinic in Leipzig (Germany). SUBJECTS: 27 patients (aged 65 years or above) with a diagnosis of either MCI (N=12) or AD (N=15), each together with a caregiver. MEASUREMENTS: The patients' QoL was measured using the Dementia Quality of Life self and proxy ratings (DEMQoL and DEMQoLproxy). The degree of anosognosia was rated by means of the Clinical Insight Rating Scale (CIR). In addition the Mini-Mental-State Examination (MMSE), and for diagnostic purposes the Bayer Activities of Daily Living Scale (B-ADL) and the Consortium to Establish a Registry of Alzheimer;s Disease (CERAD) word list were applied. RESULTS: In accordance with the results of Ready et al. (1), patients with impaired insight were found to produce less reliable QoL ratings than those with unimpaired insight. The validity (concordance between self- and proxy QoL ratings) is influenced by cognitive deficits, anosognosia and the interaction between these factors. CONCLUSIONS: Data which are based on dementia patients' QoL self-ratings need to be interpreted with caution when anosognosia is present.

[MCI-plus: mild cognitive impairment with rapid progression. Part II: Biomarkers and research methods]. / MCI-plus: leichte kognitive Beeinträchtigung mit rascher Progredienz. Teil II: Biomarker und Untersuchungsmethoden.

Long-term studies will be pivotal in order to examine the efficacy of preventive and early therapeutic interventions during the preclinical phase of dementia. Biomarkers will be of importance due to the large sample sizes and the necessary logistic efforts, high drop-out rates and slow clinical progression. The validity of functional and even structural imaging methods is currently investigated with early and promising results; it is presently unclear whether conventional csf-markers of Alzheimer's disease (beta-amyloid and tau-proteins) are sufficiently sensitive to monitor the effects of early interventions. It also remains doubtful whether modifications of these methods will ever be useful and available for practical purposes.

[MCI-plus: mild cognitive impairment with rapid progression. Part I: prevention and therapy]. / MCI-plus: leichte kognitive Beeinträchtigung mit rascher Progredienz. Teil I: Prävention und Therapie.

Mild Cognitive Impairment (MCI) is a prevalent problem in the elderly and many patients show predictors of rapid cognitive decline ("MCI-plus"). MCI-plus represents a syndrome with growing importance in an ageing society, which will increasingly affect primary medicine and most other clinical specialties. We will have to face the dilemma of fast progress in the field of neurodiagnostics with innovative therapeutic strategies lagging behind. Psychological and medical co-morbidity in MCI-plus will therefore offer important opportunities to delay and to avoid the manifestation of dementia. We will review and discuss current training and treatment options including symptomatic and causal interventions.

[Critical observations on measuring quality of life of persons suffering from dementia]. / Ist die Lebensqualität von Demenzpatienten messbar?: Ein kritischer Diskussionsbeitrag.

The assessment of quality of life (QoL) in patients suffering from dementia is increasingly called for by public health authorities, particularly for pharmacological intervention studies. From a clinical point of view, until now a critical discussion about determining the QoL of dementia patients has scarcely taken place. The extent to which a demented patient may be able to assess his or her own QoL is analysed with regard to the specific deficits associated with the dementia syndrome. Although a subjective assessment represents the gold standard of Qol measurement, the capacity to provide a reliable subjective QoL estimation is limited in dementia patients. Given the present state of knowledge, it seems reasonable to adhere to objectively measurable data. The question of QoL in dementia must be solved normatively and cannot be based on the subjective assessment of cognitively impaired persons.

[Mild cognitive impairment with predictors of rapid decline]. / Leichte kognitive Beeinträchtigung mit Vorzeichen rascher Verschlechterung.

Half the patients with mild cognitive impairment (MCI) will develop dementia over a four-year period. The scientific literature was searched and analysed for predictors of rapid decline (MCI-plus) in patients with MCI. The most important predictors of fast cognitive deterioration were found to be: old age, previous rapid decline, severity and multiplicity of cognitive deficits, somatic co-morbidity, vascular and Alzheimer-type changes in the brain, Alzheimer-type cerebrospinal fluid findings and apolipoprotein E4 polymorphism. Many patients with MCI suffer from anxiety, depression or apathy and subtle, but subjectively significant, difficulties in the activities of daily living. It is concluded that MCI-plus offers a window for medical and psychological prophylaxis and rehabilitation.

Hippocampal atrophy in Alzheimer disease: age matters.

Hippocampal atrophy is a marker of Alzheimer disease (AD). It remains unclear whether this holds true for younger patients as well. Hippocampal volume was measured on MRI scans of 103 clinically diagnosed AD patients and 73 controls (aged 51 to 85 years). Aging and AD were independently associated with smaller hippocampal volume. Both young and old AD patients have hippocampal atrophy abnormal for age. Age-dependent criteria for hippocampal atrophy, suggestive of AD, are needed.

[The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs]. / Versorgungssituation von Demenzkranken kann durch Ginkgo biloba verbessert werden. Ergebnisse einer Studie zur Versorgungsforschung hinsichtlich der Leistungsfähigkeit der Demenzkranken, der Lebensqualität der Pflegenden und der Gesamtkosten der Behandlung.

UNLABELLED: BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined. PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society's perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted. RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis. RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.

Association between global brain volume and the rate of cognitive change in elderly humans without dementia.

Patients with mild cognitive deficits experience different types of evolution. They are at increased risk of developing dementia, but they have also a chance of remaining stable in cognition or of improving. We investigated whether global brain volume, callosal size and hippocampal size are associated with the rate of cognitive change in elderly without dementia. Volumetric MR images were recorded from 39 controls and 35 patients with questionable dementia who were followed up longitudinally for a mean of 2.3 years. The outcome measure was the annual change in the test score in the Structured Interview for the Diagnosis of Alzheimer's Dementia and Multi-Infarct Dementia, which includes all items of the Mini-Mental State Examination. Global brain volume, grey matter volume and white matter volume were the only significant independent predictors of the rate of cognitive change.