Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

[Antidepressant drugs-State of the art]. / Antidepressiva ­ State of the Art.

BACKGROUND: Due to their frequency, complications, and sequelae, depressive disorders are of great significance to patients, their environment, and society. They are considered the most frequent form of mental disturbances in old age. The use of antidepressant drugs (AD) represents a cornerstone of the treatment, which is always multidimensional. OBJECTIVE: The classification, mechanism of action, efficacy and tolerability of AD are described. Furthermore, the practical treatment procedure as well as special aspects, such as treatment resistance and special features in old age are presented. MATERIAL AND METHODS: Narrative review incorporating the most recent literature and the new edition of the national healthcare guidelines on unipolar depression. RESULTS: In the past 20 years, a large number of so-called 2nd generation ADs have been approved worldwide with comparable efficacy but more favorable side effect profiles than conventional (tricyclic) substances. Almost all ADs act by enhancing monoaminergic, mostly serotonergic, neurotransmission. Other common features include a latency in the onset of action, moderate response rates, and potential efficacy on all core symptoms of depression. Side effects can include cardiovascular, metabolic, or sexual dysfunction, but these may significantly differ between drug classes. This enables individualized treatment taking age, individual risk factors, comorbidities and comedications into account. CONCLUSION: With the correct interpretation of indications, knowledge of the risks, and consideration of the defined precautionary measures outlined here, treatment with AD is a safe and effective tool in the treatment of moderate and severe depression.

Characteristics of antipsychotic drug-induced hypothermia in psychogeriatric inpatients.

OBJECTIVE: Hypothermia is a potentially lethal adverse reaction to typical and atypical antipsychotic drugs (APD). Among predisposing factors are advanced age and comorbid somatic diseases. The aim of this study was to assess the incidence of hypothermia and quantify risk factors. METHOD: Charts of N = 3002 psychogeriatric inpatients were screened for incidence of hypothermia (body core temperature <35.0°C). The frequency of hypothermia was compared between patients treated with versus without APD and, within the sample of APD-treated patients, for (1) specific APD, (2) sex, (3) main diagnosis, and (4) age. RESULTS: N = 54 cases (2.6%) of hypothermia occurred in APD-treated patients and 12 cases (1.3%) in non-APD-treated patients (p = 0.024). In APD-treated patients, only male sex (p = 0.038) and pipamperone were associated with a higher incidence of hypothermia (p = 0.0017). Whereas the main diagnosis delirium showed a trend to significance, age did not correlate with hypothermia. CONCLUSION: Medication with pipamperone was associated with an increased risk of hypothermia. The advanced age of our sample might as well explain the high incidence of hypothermia within our sample and the failure to detect high age as a risk factor due to a ceiling effect.

Effect fingerprints of antipsychotic drugs on neural networks in vitro.

We compared the acute effect of typical (haloperidol) and atypical (aripiprazole, clozapine, olanzapine) antipsychotic drugs (APDs) on spontaneous electrophysiological activity of in vitro neuronal networks cultured on microelectrode arrays (MEAs). Network burst analysis revealed a "regularizing" effect of all APDs at therapeutic concentrations, i.e., an increase of network-wide temporal synchronization. At supratherapeutic concentrations, all APDs but olanzapine mediated a decrease of burst and spike rates, burst duration, number of spikes in bursts, and network synchrony. The rank order of potency of APDs was: haloperidol > aripiprazole > clozapine > olanzapine (no suppression). Disruption of network function was not due to enhanced cell death as assessed by trypan blue staining. APDs promoted distinct concentration-dependent alterations yielding acute effect fingerprints of the tested compounds. These effects were rather characteristic for individual compounds than distinctive for typical vs. atypical APDs. Thus, this dichotomy may be of value in distinguishing clinical features but has no apparent basis on the network or local circuitry level.

A systematic evaluation of impulsive-aggressive behavior in psychogeriatric inpatients using the staff observation aggression scale-revision (SOAS-R).

BACKGROUND: Impulsive-aggressive behavior is a significant challenge in geriatric psychiatry and requires professional evaluation and management. METHODS: SOAS-R scales (Staff Observation Aggression Scale-Revision) completed by medical staff on three secure psychiatric wards were analyzed during a period of 12 months. Patients were subdivided into the following two diagnostic subgroups: dementia and other diagnoses. RESULTS: A total of 146 aggressive incidents involving 66 patients were reported (8.8% of patients treated during this period, n = 752). Fifty-seven percent of the incidents involved patients with dementia. In 20% of the incidents, no precipitating event could be identified; this was more common in patients without dementia (p = 0.005). The medical condition of the patient was considered the trigger in 55% of the cases. Aggression was directed at nurses in 82% of the cases. Visible injury was reported in 12 cases, 3 of which required medical treatment. Male gender, the presence of previous aggressive incidents, and the evening shift (in the case of dementia patients) were identified as risk factors. CONCLUSIONS: Aggression in dementia is often reactive and seems to be more predictable than if occurring with other diagnoses. Prevention measures such as de-escalations techniques, warning notes in the patient's file with previous aggressive behavior and stepping up for evening shifts are of crucial importance. As nurses were primarily affected, employer support programs, and mental health interventions are proposed to avoid long-term consequences.

[Psychiatric pharmacotherapy of older individuals with severe mental illness]. / Psychopharmakotherapie bei älteren Menschen mit schweren psychischen Erkrankungen.

BACKGROUND: Chronic schizophrenia, depression, and bipolar disorders, among other chronic psychiatric disorders with onset at youth or early adulthood are often referred to as severe mental illness (SMI). Aging with SMI is associated with various psychosocial, physiological, and medical problems with potential impact on psychiatric pharmacotherapy. OBJECTIVES: Determination and discussion of problems and special features of the psychopharmacological treatment of older persons with SMI and presentation of treatment recommendations for the distinct diagnoses. MATERIALS AND METHODS: International literature and guidelines were searched. In addition, the basic literature and expert opinions are discussed. RESULTS: General problems that influence the psychiatric pharmacotherapy of older persons with SMI include nonadherence, nonresponse, polypharmacy, and distinct pharmacokinetic changes with aging and somatic comorbidity. Psychotropic drugs may exhibit cardiovascular, metabolic, and neuropsychiatric risks, among others. The literature regarding effectiveness of psychotropic drugs, drug groups, or combination of drugs in older patients with SMI is scarce to nonexistent. CONCLUSIONS: Drug treatment of older persons with SMI should be part of an overall treatment plan that also has to include social and psychotherapeutic components that address the specific problems of this population. Most importantly, psychiatric pharmacotherapy should consider these risks and the treatment should be tailored to a patient's individual risk profile. Due to a general lack of evidence in this special population, treatment strategies of standard guidelines should be adjusted with special consideration to physiological changes of age.

Repressive Coping Does Not Contribute to Anosognosia in First-Diagnosis Patients With Alzheimer Disease.

Anosognosia is common in patients with Alzheimer disease (AD) even in early stages. Although neural correlates and the impact of cognitive dysfunctions have been described, possible psychodynamic processes such as a repressive coping style as described in other illnesses, have not been examined. Our study aimed to examine possible psychological influence factors on illness perception embracing a repressive coping style and cognitive functions in AD patients in the diagnostic process. Fifty-four subjects with mild AD diagnosed in our memory clinic were enrolled. Anosognosia was evaluated using a patient-caregiver discrepancy rating. All patients underwent comprehensive neuropsychological testing. In addition, characteristics of a repressive coping style were assessed. In total, 79.6% of our patients showed a lack of awareness at least to some degree. 33.3% of the patients were classified as repressors. Repressors and nonrepressors did not differ in cognition, or the unawareness score. Multivariate regression analysis showed that repressive coping style did not significantly contribute to anosognosia, but that verbal memory and naming ability had a strong influence. Although our data indicate that a high proportion of patients with mild AD show characteristics of repressive coping, this possible defense mechanism had no influence on the awareness of illness-related deficits measured by caregiver patient discrepancy.

Multielectrode array analysis of cerebrospinal fluid in Alzheimer's disease versus mild cognitive impairment: a potential diagnostic and treatment biomarker.

Pathological cerebrospinal fluid (CSF) alterations like changes in amyloid-ß1-42 and tau protein concentration are typical in Alzheimer's disease (AD). However, it remains unclear, if the composition of known or unknown pathological factors in native CSF has a functional significance in AD. In this pilot study, we used multielectrode array (MEA) neurochips to determine whether CSF of individuals with AD (AD-CSF) may have distinct neurofunctional properties that may distinguish it from that of individuals with mild cognitive impairment (MCI) - a differential diagnosis of high clinical importance. MEAs are neuronal cultures coupled to a multisite electrical recording system with the ability to reflect pharmacological or toxicological alterations on the functional level of whole neuronal networks. Collective rhythmical electrical activity was substantially enhanced after exposure to CSF of cognitively healthy subjects (controls) and of MCI individuals (MCI-CSF) alike. However, this activity increment was significantly reduced when MEAs were exposed to AD-CSF compared to MCI-CSF. Moreover, following AD-CSF exposure, networks showed significantly enhanced burst durations and less synchronous bursting, respectively. Thus, AD-CSF and MCI-CSF could be distinguished by characteristic changes of the network firing pattern on MEAs. When data of MCI individuals and AD patients were pooled, the network suppression correlated significantly with the degree of cognitive decline. The findings of this pilot study may set the stage for a unique and straightforward diagnostic bioassay of AD with particular value in the differential diagnosis to MCI and as a much needed biomarker for clinical trials.

Epidemiology, symptoms, and treatment characteristics of hyponatremic psychiatric inpatients.

Hyponatremia is a common phenomenon in psychiatry occurring as an adverse effect to drugs or following polydipsia. We performed a retrospective in-depth analysis of hyponatremia cases in a large unselected population of psychiatric inpatients. During a 3-year period, all cases of hyponatremia were identified among patients admitted to a large psychiatric state and university hospital by the institution's electronic laboratory database. Demographic, treatment-related, and laboratory data were obtained by consecutive chart review, respectively. Hyponatremia occurred in 347 (4.9%) of 7113 cases, of which the majority (78%) displayed only a mild manifestation. Symptoms were recorded in 28.8% of cases, already occurred in mild forms, and comprised gait impairment (45%, including falls), confusion (30%), sedation (26%), and dyspepsia (41%). Age, female sex, nonpsychiatric drug polypharmacy-particularly with thiazides and/or angiotensin-converting enzyme inhibitors-and diagnosis of a mood disorder were associated with more severe hyponatremia, respectively. The proportion of hyponatremic patients treated with venlafaxine, trazodone, carbamazepine, oxcarbazepine, and first-generation antipsychotics, respectively, was significantly higher in the hyponatremia sample than in the normonatremic population. This was, surprisingly, not the case with selective serotonin reuptake inhibitors or any other antidepressant drug class. We found prescription with second-generation antipsychotics to be significantly associated with less severe hyponatremia.Hyponatremia may be mainly attributed to the syndrome of inappropriate antidiuretic hormone secretion, as indicated by decreased serum osmolarity in our sample. Besides old age and female sex, treatment with certain drugs-rather than whole drug classes-carries a substantially increased risk.

Amyloid beta 1-42 in cerebrospinal fluid is associated with cognitive plasticity.

Cerebrospinal fluid (CSF) total tau-protein (t-tau) and amyloid-beta 1-42 (Abeta(1-42)) have been increasingly included in the diagnostic process of Alzheimer's disease (AD). We aimed to analyze whether these CSF biomarkers correlate with cognitive plasticity as measured by a dynamic recognition test strategy. We assessed 29 elderly individuals (15 with incipient and 14 without AD) from an outpatient memory clinic at a university hospital by a Testing-the-Limits (TtL) based recognition paradigm consisting of a pre-test (baseline) and two post-test conditions with an interposed encoding instruction. We identified a negative association between Abeta(1-42) and the two post-test failure rates, but not with that of the pre-test. Also, none of the standard tests correlates with Abeta 42-1 level. T-tau does not correlate with recognition performance. Our results suggest that Abeta(1-42) could be useful as a state marker for cognitive plasticity.

Transient reduction of spontaneous neuronal network activity by sublethal amyloid beta (1-42) peptide concentrations.

Soluble amyloid beta(1-42) (A beta(1-42)) peptide has recently been assigned a key role in early Alzheimer's disease (AD) pathophysiology accounting for synaptic dysfunction before amyloid plaque formation and neurodegeneration can occur. Following sublethal A beta(1-42) administration, we observed an acute but transient reduction of the spike and burst rate of spontaneously active cortical networks cultured on microelectrode arrays. This simple experimental system appears suitable for future long-term pharmacological and genetic studies of A beta(1-42) signaling, thus providing a valuable new tool in AD research.

Longitudinal progression of posterior cortical atrophy over 11 years: Relationship between lesion topology and clinical deficits.

Posterior cortical atrophy (PCA) is a rare form of dementia primarily characterized by slowly progressing deterioration of visual processing corresponding to atrophy in the posterior parietal and occipital cortices with less prominent memory loss than are usually seen in other forms of dementia such as Alzheimer's Disease (AD). In the present case report, we describe longitudinal data over a period of 11 years regarding clinical and neuropsychological impairments and their relation to the location and extent of cortical changes related to higher order visual processing in a patient with posterior cortical atrophy. In our patient, visual processing deficits concerning space, motion and object perception emerged at the age of 50 and continued to worsen. By the age of 58, while the perception of contrast, color and figure-ground separation appeared undisturbed the patient exhibited pronounced dorsal- and ventral-related visual deficits, which continued to worsen with age. The patient's MRI scans over the course of the disease revealed increasing circumscribed and bilateral atrophy of the parietal and occipital cortices, with a right-sided predominance. The specific localization of cortical atrophy, the slow progression characterized by visual processing deficits and relatively preserved memory were the main criteria for the diagnosis of posterior cortical atrophy. The case report also highlights the importance of an early extensive neurological and neuropsychological evaluation of visual deficits that occur without the presence of ophthalmological disease.

Association of Cerebrospinal Fluid S100B Protein with Core Biomarkers and Cognitive Deficits in Prodromal and Mild Alzheimer's Disease.

BACKGROUND: Increased expression of the astroglial Ca2+-binding protein S100B has been observed in various neurodegenerative diseases and also seems to play a role in the unfolding of pathophysiological events at early stages of Alzheimer's disease (AD). OBJECTIVE: To examine the association of cerebrospinal fluid (CSF) levels of S100B with 1) established CSF core biomarkers total tau (tau), hyperphosphorylated tau (p-tau), and amyloid ß1-42 (Aß1-42) as well as neuron-specific enolase (NSE) CSF levels and 2) cognition in early AD and mild cognitive impairment (MCI) due to AD (MCI-AD). METHODS: Retrospective study assessing 49 pooled charts of Memory Clinic and inpatients diagnosed with AD (N = 26) and MCI-AD (N = 23) according to the National Institute of Aging and Alzheimer's Disease Association (NIA-AA) criteria. Neuropsychological testing was performed with the Consortium to Establish a Registry for AD (CERAD)-Plus battery. RESULTS: CSF levels of S100B correlated with NSE, but not the other CSF parameters. Stepwise multiple linear regression, adjusted for age, sex, and educational level, revealed that only increased CSF S100B was independently associated with lower CERAD-Plus total and Mini-Mental Status Examination scores together with poorer performance in wordlist learning (delayed recall and overall performance). We found no independent associations with other CSF biomarkers or cognitive domains. CONCLUSION: Our data suggest that CSF S100B may have a diagnostic value particularly at early stages of AD reflecting the significance of neuroinflammatory/astroglial processes. Thus, CSF S100B may complement the established array of available AD biomarkers to improve early stage diagnosis.

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons.

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

An ultrasensitive assay for diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia. Aging is among the most significant risk factors. Today, AD can be diagnosed with certainty only post mortem, detecting insoluble beta-amyloid peptide (Abeta) aggregates in the patient's brain tissue. We have developed an ultrasensitive assay for early and non-invasive diagnosis of AD. This highly specific and sensitive assay uses fluorescence correlation spectroscopy (FCS) and is sensitive enough to detect even single aggregates in body fluids of AD patients. We investigate the correlation of aggregated Abeta concentrations in body fluids with clinical symptoms of AD.

A cross-continental analysis of weight gain, psychiatric diagnoses and medication use during inpatient psychiatric treatment. The international study on physical illness in mentally ill.

Weight gain among psychiatric inpatients is a widespread phenomenon. This change in body mass index (BMI) can be caused by several factors. Based on recent research, we assume the following factors are related to weight gain during psychiatric inpatient treatment: psychiatric medication, psychiatric diagnosis, sex, age, weight on admission and geographic region of treatment. 876 of originally recruited 2328 patients met the criteria for our analysis. Patients were recruited and examined in mental health care centres in Nigeria (N = 265), Japan (N = 145) and Western-Europe (Denmark, Germany and Switzerland; N = 466). There was a significant effect of psychiatric medication, psychiatric diagnoses and geographic region, but not age and sex, on BMI changes. Geographic region had a significant effect on BMI change, with Nigerian patients gaining significantly more weight than Japanese and Western European patients. Moreover, geographic region influenced the type of psychiatric medication prescribed and the psychiatric diagnoses. The diagnoses and psychiatric medication prescribed had a significant effect on BMI change. In conclusion, we consider weight gain as a multifactorial phenomenon that is influenced by several factors. One can discuss a number of explanations for our findings, such as different clinical practices in the geographical regions (prescribing or admission strategies and access-to-care aspects), as well as socio-economic and cultural differences.

Single particle detection of Abeta aggregates associated with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Today, AD can be diagnosed with certainty only post-mortem, by histopathologic staining of Abeta plaques and neurofibrillary tangles in brain tissue sections. We have developed an ultra-sensitive assay potentially suitable for early and non-invasive diagnosis of AD. This highly specific and sensitive assay uses fluorescence correlation spectroscopy (FCS) and is sensitive enough to detect even single aggregates in body fluids of AD patients. First results show a clear distinction between AD diseased people and non-demented controls by analysing cerebrospinal fluids (CSF) by confocal scanning of surface captured Abeta aggregates and subsequent two-dimensional fluorescence intensity distribution analysis.

Multimodal gain control at the hippocampal Schaffer collateral-CA1 synapse.

Information processing at central nervous system synapses is shaped by long-lasting modifications, such as long-term potentiation and short-lived and putatively synapse-specific modifications by various forms of short-term plasticity, such as facilitation, potentiation, and depression. Using an extracellular paired-pulse facilitation (PPF) protocol at the Schaffer collateral-CA1 (SC) connection in acute hippocampal slices in mice, we extend previous reports of optimal signal gain at intermediate interpulse intervals obtained at single SC synapses to the network level. Moreover, maximum signal gain changed when the input intensity was altered. We found further that facilitation decreased with increasing stimulus amplitude and duration in an exact exponential fashion when varied at a fixed interpulse interval. Variation of these intensity parameters accounted for significant changes in PPF adding a spatial dimension to time-based synaptic filter characteristics. Thus, this synapse functions as an amplitude window discriminator with a low-level aperture in combination with a band-pass frequency filter. By providing mathematical functions for the characteristic presynaptic parameters frequency, stimulus amplitude, and pulse duration at the network level our results lay ground for future studies on pharmacologically, genetically, or otherwise altered animal models.