[Psychopharmacotherapy of the elderly]. / Psychopharmaka im Alter.

Pharmacokinetic and pharmacodynamic changes related to aging and age-associated disorders influence the choice and dosage of psychotropic drugs in the treatment of the elderly. Renal and hepatic clearance is limited and the sensitivity to pharmacological effects is increased. To avoid side effects most psychotropic drugs should be introduced in a 'start low--go slow' approach. The final dose may also be lower than in the treatment of younger adults. Drug interactions may occur as a consequence of a complex medication. Peculiarities of the treatment of older adults with antidepressants, antipsychotics, anxiolytics, mood-stabilizers and hypnotics is described.

[Antidementia drugs]. / Antidementiva.

The pharmacological treatment of dementias aims to improve cognitive deficits, activities of daily living and behavioural and psychiatric symptoms. The weighting of theses therapeutic aims varies with disease progression. Behavioural symptoms may dominate especially in the more severe stages of the disease and may further deteriorate global functional level of the patient. Today there is no causal therapy for Alzheimer's disease (AD). Based on preclinical disease models novel therapeutic approaches are under development that target the beta-amyloid and tau protein metabolism. Some of them aim to inhibit the formation, aggregation and toxicity of beta-amyloid peptides or promote their clearance from the brain. Others inhibit the formation of neurofibrillary tangles or have neuroprotective effects. Active or passive immunisation against beta-amyloid may be a very specific and effective approach. The efficacy of acetylcholine esterase inhibitors (AchEI) in the treatment of mild to moderate AD is well documented. They are first line therapeutics in the treatment of the disease and lead to a delay of symptomatic progression. Memantine is effective in the treatment of moderate to severe stages of AD. The evidence for the treatment of vascular dementia is comparatively weak. However, positive effects have been shown for all available AchEI and memantine. Non pharmacological therapy is an indispensable part of the treatment of dementia patients and should be adapted to the individual needs of the patient in the respective stage of the disease. The efficacy of antipsychotics in the treatment of behavioural and psychiatric symptoms of dementia is limited. These drugs are associated with increased morbidity and mortality in dementia patients. Therefore, their application should be based on a critical and individual evaluation of risks and benefits.

Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice.

BACKGROUND: Mitochondrial dysfunction has been identified in neurodegenerative disorders including Alzheimer's disease, where accumulation of beta-amyloid (Abeta) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction. OBJECTIVE: In order to study the in vivo effect of Abeta load during aging, we evaluated the mitochondrial function of brain cells from transgenic mice bearing either mutant amyloid precursor protein (tgAPP) or mutant amyloid precursor protein and mutant PS1 (tgAPP/PS1) as well as from nontransgenic wild-type littermates. tgAPP mice exhibit onset of Abeta plaques at an age of 6 months, but the intracellular soluble Abeta load is already increased at 3 months of age. In contrast, onset of Abeta plaques starts at an age of 3 months in tgAPP/PS1 mice. In addition, we investigated the effects of different Abeta preparations on mitochondrial function of brain cells from tau transgenic mice. RESULTS: Of note, mitochondrial damage such as reduced mitochondrial membrane potential and ATP levels can already be detected in the brains from these mice before the onset of plaques. In agreement with our findings in tgAPP mice, soluble Abeta induced mitochondrial dysfunction in brain cells from tau transgenic mice. CONCLUSION: Our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble Abeta species as a very early event during pathogenesis.

The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease.

The pineal and retinal melatonin regulates endogenous circadian rhythms, and has various physiological functions including neuromodulatory and vasoactive actions, antioxidative and neuroprotective properties. We have previously demonstrated that the melatonin 1a-receptor (MT(1)) is localized in human retinal cells and that the expression of MT(1) is increased in Alzheimer's disease (AD) patients. We now present the first immunohistochemical evidence for the cellular distribution of the second melatonin receptor, MT(2), in the human retina and in AD patients. In elderly controls, MT(2) was localized to ganglion and bipolar cells in the inner nuclear layer, and to the inner segments of the photoreceptor cells. In addition, cellular processes in inner and outer plexiform layers were strongly positive for MT(2). In AD patients the overall intensity of MT(2)-staining was distinctly decreased in all observed cellular localizations. Our results indicate that MT(2) in the humans, similar to MT(1), may indeed be involved in transmitting melatonin's effects in the retina, and AD pathology may impair MT(2) expression. Since our previous results showed an increase in MT(1) expression in AD retina, the two melatonin receptor subtypes appear to be differentially affected by the course of the neurodegenerative disorder.

Aging sensitizes toward ROS formation and lipid peroxidation in PS1M146L transgenic mice.

Mutations in the presenilins (PS) account for the majority of familial Alzheimer disease (FAD) cases. To test the hypothesis that oxidative stress can underlie the deleterious effects of presenilin mutations, we analyzed lipid peroxidation products (4-hydroxynonenal (HNE) and malondialdehyde) and antioxidant defenses in brain tissue and levels of reactive oxygen species (ROS) in splenic lymphocytes from transgenic mice bearing human PS1 with the M146L mutation (PS1M146L) compared to those from mice transgenic for wild-type human PS1 (PS1wt) and nontransgenic littermate control mice. In brain tissue, HNE levels were increased only in aged (19-22 months) PS1M146L transgenic animals compared to PS1wt mice and not in young (3-4 months) or middle-aged mice (13-15 months). Similarly, in splenic lymphocytes expressing the transgenic PS1 proteins, mitochondrial and cytosolic ROS levels were elevated to 142.1 and 120.5% relative to controls only in cells from aged PS1M146L animals. Additionally, brain tissue HNE levels were positively correlated with mitochondrial ROS levels in splenic lymphocytes, indicating that oxidative stress can be detected in different tissues of PS1 transgenic mice. Antioxidant defenses (activities of antioxidant enzymes Cu/Zn-SOD, GPx, or GR) or susceptibility to in vitro oxidative stimulation was unaltered. In summary, these results demonstrate that the PS1M146L mutation increases mitochondrial ROS formation and oxidative damage in aged mice. Hence, oxidative stress caused by the combined effects of aging and PS1 mutations may be causative for triggering neurodegenerative events in FAD patients.

Immunohistochemical Localization of Fas-associated phosphatase-1 (FAP-1) in Alzheimer disease hippocampus.

Fas-associated phosphatase-1 (FAP-1) is a regulatory peptide inhibiting apoptotic signal transduction via the death receptor Fas. Because apoptosis is a common mechanism leading to neuronal death in neurodegenerative disorders, the authors investigated the immunohistochemical distribution of FAP-1 in the hippocampus of elderly control subjects and Alzheimer disease (AD) patients. The current study provides the first evidence that FAP-1 is localized in the human hippocampus in pyramidal neurons of the hippocampal subfields CA1-4 and in granular cells. Cellular and extracellular FAP-1 intensity was increased in some control subjects and AD patients, but was not related to the stage of the illness. Rather, these data may indicate a general role for FAP-1 in neuronal death both in adult CNS and during the course of neurodegenerative disorders.

Distribution of melatonin MT1 receptor immunoreactivity in human retina.

Melatonin is synthesized in the pineal gland and retina during the night. Retinal melatonin is believed to be involved in local cellular modulation and in regulation of light-induced entrainment of circadian rhythms. The present study provides the first immunohistochemical evidence for the localization of melatonin 1a-receptor (MT1) in human retina of aged subjects. Ganglion, amacrine, and photoreceptor cells expressed MT1. In addition, MT1 immunoreactivity was localized to cell processes in the inner plexiform layer and to central vessels of the retina, as well as to retinal vessels but not to ciliary or choroidal vessels. These results support a variety of cellular and vascular effects of melatonin in the human retina. Preliminary evidence from patients with Alzheimer's disease (AD) revealed increased MT1 immunoreactivity in ganglion and amacrine cells, as well as in vessels. In AD cases photoreceptor cells were degenerated and showed low MT1 expression.

First vs multiple episode schizophrenia: two-year outcome of intermittent and maintenance medication strategies.

Results of studies on intermittent neuroleptic treatment strategies in first episode (FE) schizophrenia have not been published. Aims of the present study were to elucidate the comparative efficacy of prodrome-based neuroleptic intervention in first vs multiple episode (ME) schizophrenia. As to the methods, three randomly assigned open neuroleptic treatment strategies were compared over 2 years in 363 schizophrenic outpatients (115 FE, 248 ME; ICD-9, RDC): maintenance medication vs two intermittent medication strategies (prodrome-based intervention and crisis intervention). Concerning relapse prevention, the results demonstrate that ME patients seemed to profit most from maintenance medication compared to both intermittent treatments, whereas FE patients did equally well under maintenance medication and prodrome-based intervention treatment. Psychopathology, social adjustment, subjective well-being, and side-effects after two years did not differ significantly between the FE and ME patients irrespective of treatment strategy. Concerning treatment adherence, FE patients complied better with prodrome-based intervention than with maintenance medication. Cumulative neuroleptic dosage was lowest in FE patients under intermittent treatment. In conclusion, maintenance medication is the best strategy for relapse prevention in ME patients. In FE patients, prodrome-based intermittent intervention seems to be equivalent or even better with respect to compliance and dosage applied.

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Behavioral disturbances in dementia.

Psychological symptoms and behavioral abnormalities are common and prominent characteristics of dementia. They include symptoms such as depression, anxiety psychosis, agitation, aggression, disinhibition, and sleep disturbances. Approximately 30% to 90% of patients with dementia suffer from such behavioral disorders. There are complex interactions between cognitive deficits, psychological symptoms, and behavioral abnormalities. A large number of standardized, reliable, and well-validated instruments for assessing the behavioral and psychological symptoms of dementia have been developed in order to evaluate the efficacy of treatment. Neurodegenerative processes in various brain areas, particularly in the frontotemporal cortex and limbic regions, leading to cholinergic, serotonergic, and noradrenergic neurotransmitter dysfunctions constitute the biological matrix of behavioral symptoms, whereas psychological factors and personality traits play a modifying role. A large number of pharmacological, psychoeducational, psychotherapeutic, and social strategies have been developed to improve the quality of life of patients and their caregivers.

Validation of the Symptom Checklist SCL-27 in psychiatric patients: Psychometric testing of a multidimensional short form.

Abstract SCL-90-R, a multidimensional assessment instrument for mental health status, is among the most widely used instruments for the evaluation of therapies and quality management in mental institutions. With 90 items it is rather long and has a high redundancy as can be seen in its highly correlated scales. Thus many short versions have been constructed, among them the SCL-27, which was devised as a screening tool. It has 27 items, retains six of the nine SCL-90 dimensions and has shown a good factor structure. So far it has only been validated in non-psychiatric samples. The aim of this study is to determine validity and other psychometric qualities of the SCL-27, compared to the SCL-90-R within a group of 449 psychiatric patients. The study found a large concordance between the symptom scales of the SCL-27 and the corresponding scales of the SCL-90-R. The SCL-27 further showed good reliability and a sensitivity to change comparable to that of the 90-item version. A confirmatory factor analysis yields an acceptable factor validity which is better than that of the long version. This study concludes that the SCL-27 is suitable as a short assessment instrument for psychological health in psychiatric patients.

Mismatch and conflict: neurophysiological and behavioral evidence for conflict priming.

Conflict-related cognitive processes are critical for adapting to sudden environmental changes that confront the individual with inconsistent or ambiguous information. Thus, these processes play a crucial role to cope with daily life. Generally, conflicts tend to accumulate especially in complex and threatening situations. Therefore, the question arises how conflict-related cognitive processes are modulated by the close succession of conflicts. In the present study, we investigated the effect of interactions between different types of conflict on performance as well as on electrophysiological parameters. A task-irrelevant auditory stimulus and a task-relevant visual stimulus were presented successively. The auditory stimulus consisted of a standard or deviant tone, followed by a congruent or incongruent Stroop stimulus. After standard prestimuli, performance deteriorated for incongruent compared to congruent Stroop stimuli, which were accompanied by a widespread negativity for incongruent versus congruent stimuli in the event-related potentials (ERPs). However, after deviant prestimuli, performance was better for incongruent than for congruent Stroop stimuli and an additional early negativity in the ERP emerged with a fronto-central maximum. Our data show that deviant auditory prestimuli facilitate specifically the processing of stimulus-related conflict, providing evidence for a conflict-priming effect.

Individualized preventive psychiatry: syndrome and vulnerability diagnostics.

The development of prevention and treatment strategies of psychiatric disorders will depend on a more profound knowledge of the complex relationships between gene-environment interactions, particularly the interplay of vulnerability and resilience factors within a person's biography. In this article, the advantages and limitations of the current psychiatric classification systems will be discussed. New directions for a future multiaxial system including biological, psychological, social, life span, gender and cultural factors based on the DSM-V- and ICD-11-research agenda are going to be outlined. Psychiatry without psychopathology is impossible. However, in the future, psychopathology will be closer linked to the biological and psychological nature of the disease process and more function-based. Future diagnostic classification manuals should include dimensional and categorical aspects as well as vulnerability and resilience diagnostic elements. There is a need for a personalized integrative diagnosis and care.

Humour therapy in patients with late-life depression or Alzheimer's disease: a pilot study.

BACKGROUND: Of the disabling disorders of the elderly, depression is the most common affective disorder and Alzheimer's disease (AD) the most common neurodegenerative disorder. Pharmacological treatment strategies for these disorders are often accompanied with severe side effects. Therefore non-pharmacological treatment strategies are of great importance. The aim of the present study was to investigate the impact of humour therapy on quality of life in patients with depression or AD. METHODS: Twenty patients with late-life depression and 20 patients with AD were evaluated. Ten patients in each group underwent a humour therapy group (HT) once in two weeks for 60 min in addition to standard pharmacotherapy, which was given as usual to the other group as standard therapy (ST). All patients completed a psychometric test battery at admission and before discharge from the clinic. RESULTS: The quality of life scores improved both in HT and ST groups for depressive patients but not for patients with AD irrespective of the therapy group. Depressive patients receiving HT showed the highest quality of life after treatment. In addition, patients with depression in both therapy groups showed improvements in mood, depression score, and instrumental activities of daily living. CONCLUSIONS: Although there was no significant effect of humour therapy comparing with standard therapy on quality of life, these findings suggest that humour therapy can provide an additional therapeutic tool. Further studies with higher frequently humour groups are required in order to investigate the impact of humour therapy in gerontopsychiatric treatment.

Age-related changes in cognitive conflict processing: an event-related potential study.

Cognitive tasks involving conflicting stimuli and responses are associated with an early age-related decline in performance. Conflict and conflict-induced interference can be stimulus- or response-related. In classical stimulus-response compatibility tasks, such as the Stroop task, the event-related potential (ERP) usually reveals a greater negativity on incongruent versus congruent trials which has often been linked with conflict processing. However, it is unclear whether this negativity is related to stimulus- or response-related conflict, thus rendering the meaning of age-related changes inconclusive. In the present study, a modified Stroop task was used to focus on stimulus-related interference processes while excluding response-related interference. Since we intended to study work-relevant effects ERPs and performance were determined in young (about 30 years old) and middle-aged (about 50 years old) healthy subjects (total n=80). In the ERP, a broad negativity developed after incongruent versus congruent stimuli between 350 and 650 ms. An age-related increase of the latency and amplitude of this negativity was observed. These results indicate age-related alterations in the processing of conflicting stimuli already in middle age.

Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine.

This 5-wk, open-label, comparative study investigated the effects of quetiapine and haloperidol on behavioural, cognitive and circadian rest-activity cycle disturbances in patients with Alzheimer's disease (AD). Out of a total of 30 patients enrolled in the study, there were 22 completers, 11 in the quetiapine group (mean age 81.9+/-1.8 yr, mean baseline MMSE 19.9+/-1.3, mean dose 125 mg) and 11 in the haloperidol group (mean age 82.3+/-2.5 yr, mean baseline MMSE 18.1+/-1.3, mean dose 1.9 mg). As shown in the Neuropsychiatric Inventory, both medications reduced delusion and agitation, whereas quetiapine additionally improved depression and anxiety. Haloperidol worsened aberrant motor behaviour and caused extrapyramidal symptoms. In the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery which assessed cognitive parameters, quetiapine improved word recall; significant interaction terms revealed differences between quetiapine and haloperidol in word-list memory and constructional praxis. According to the Nurses' Observation Scale for Geriatric Patients (NOSGER) quetiapine improved instrumental activities of daily living. Actimetry documented the circadian rest-activity cycle before and after treatment. Sleep analysis revealed that patients receiving quetiapine had shorter wake bouts during the night, whereas patients receiving haloperidol had fewer though longer immobile phases. The study provides evidence that quetiapine at a moderate dose may be efficacious in treating behavioural disturbances in AD, with better tolerability than haloperidol.

Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.

Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease. To determine which mechanisms cause the origin of oxidative damage, we analyzed enzymatic antioxidant defense (Cu/Zn-superoxide dismutase Cu/Zn-SOD, glutathione peroxidase GPx and glutathione reductase GR) and lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE in two different APP transgenic mouse models at 3-4 and 12-15 months of age. No changes in any parameter were observed in brains from PDGF-APP695(SDL) mice, which have low levels of Abeta and no plaque load. In contrast, Thy1-APP751(SL) mice show high Abeta accumulation with aging and plaques from an age of 6 months. In brains of these mice, HNE levels were increased at 3 months (female transgenic mice) and at 12 months (both gender), that is, before and after plaque deposition, and the activity of Cu/Zn-SOD was reduced. Interestingly, beta-amyloidogenic cleavage of APP was increased in female Thy1-APP751(SL) mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751(SL) mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751(SL) transgenic mice, and these findings are closely linked to increased beta-amyloidogenic cleavage of APP.

Reduced hippocampal MT2 melatonin receptor expression in Alzheimer's disease.

The aim of the present study was to identify the distribution of the second melatonin receptor (MT2) in the human hippocampus of elderly controls and Alzheimer's disease (AD) patients. This is the first report of immunohistochemical MT2 localization in the human hippocampus both in control and AD cases. The specificity of the MT2 antibody was ascertained by fluorescence microscopy using the anti-MT2 antibody in HEK 293 cells expressing recombinant MT2, in immunoblot experiments on membranes from MT2 expressing cells, and, finally, by immunoprecipitation experiments of the native MT2. MT2 immunoreactivity was studied in the hippocampus of 16 elderly control and 16 AD cases. In controls, MT2 was localized in pyramidal neurons of the hippocampal subfields CA1-4 and in some granular neurons of the stratum granulosum. The overall intensity of the MT2 staining was distinctly decreased in AD cases. The results indicate that MT2 may be involved in mediating the effects of melatonin in the human hippocampus, and this mechanism may be heavily impaired in AD.

Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity.

BACKGROUND: beta-Amyloid peptide (Abeta), a neutrotoxic substance, has been implicated to a great degree in cell death during the course of AD. Resveratrol, a natural polyphenol mainly found in red wine, has been shown to be cardioprotective and chemoprotective. Since a moderate wine intake correlates with a lower risk for Alzheimer disease (AD), an additional neuroprotective effect has been postulated for resveratrol. OBJECTIVE: The present study aimed at elucidating the possible neuroprotective effects of resveratrol against Abeta-induced neurotoxicity. METHODS: The neuroprotective capacity against Abeta-related oxidative stress was studied in a cell culture model suitable for studying such potentially neuroprotective substances. RESULTS: Resveratrol maintains cell viability and exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione. CONCLUSION: Our findings suggest that red wine may be neuroprotective through the actions of resveratrol.