Neuropsychiatric symptoms in the dementias

PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.     

Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients

BACKGROUND/AIMS: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. METHODS: The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. RESULTS: Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. CONCLUSION: Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well-characterized cohorts.     

Neuropsychiatric symptoms and quality of life in Alzheimer disease.

OBJECTIVE: Authors examined the impact of neuropsychiatric symptoms in Alzheimer disease (AD) patients' and caregivers' quality of life (QOL) and assessed the relationship of caregiver distress to neuropsychiatric symptoms and caregiver QOL. METHODS: Sixty-two patients with probable or possible AD and their caregivers participated. Neuropsychiatric symptoms of patients were assessed with the Neuropsychiatric Inventory (NPI). QOL of both patients and caregivers was assessed using the QOL-Alzheimer's Disease (QOL-AD) scale. Each patient and caregiver completed patient QOL ratings; caregivers also completed caregiver QOL assessments. RESULTS: Caregiver QOL-AD was negatively correlated with agitation/aggression, anxiety, disinhibition, irritability/lability, and total NPI score. Patient QOL on both patient and caregiver ratings was negatively correlated with depression. Patient-reported QOL-AD ratings at different levels of cognitive functioning were not correlated with caregiver-reported ratings. The lack of relationship between patient and caregiver assessments of patient QOL was evident in both mildly and moderately affected patients. Caregiver QOL was negatively correlated with distress related to agitation/aggression, disinhibition, irritability/lability, and total NPI distress. CONCLUSION: Neuropsychiatric symptoms of AD patients adversely affect both patient and caregiver QOL. These results suggest that identifying and treating neuropsychiatric symptoms in AD may improve both patient and caregiver QOL.     

5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease

OBJECTIVE: To investigate the association between 5-HT(2A) receptor polymorphism and neuropsychiatric (NP) symptoms in Chinese elderly with Alzheimer's disease (AD). METHODS: This case-control study evaluated Chinese subjects with AD first presented to an university affiliated psychogeriatric clinic. Eighty-seven subjects with NINCDS-ADRDA diagnosis for probable and possible AD were recruited consecutively from the psychogeriatric clinics of the Prince of Wales Hospital in Hong Kong. 5-HT(2A) receptor polymorphisms were examined by polymerase chain reaction (PCR), enzyme digestion and gel electrophoresis. NP symptoms were assessed by the Chinese version of the Neuropsychiatric Inventory (NPI). RESULTS: The genotype frequencies were significantly different in subjects with regards to the presentation of delusions, aggression, aberrant motor behavior and apathy (Pearson Chi Squares, p < 0.05). If only homozygote states were included, there were significantly fewer subjects of CC genotype with delusion (Pearson chi square, p < 0.05). CONCLUSIONS: Specific NP symptoms in AD were significantly associated with 5-HT(2A) receptor polymorphisms. Possible ethnic differences in the behavioral expression of 5-HT(2A) receptor polymorphisms are worthy of further exploration.     

The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease

BACKGROUND: Psychotic symptoms in subjects with Alzheimer disease (AD+psychosis, AD+P) are a marker for a distinct phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. We recently found that AD subjects homozygous for long alleles (l) of an insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTPR) had elevated rates of aggressive behavior. OBJECTIVE: To examine whether the 5-HTTPR ll genotype confers an increased risk of AD+P, and of the combined AD+P/aggressive phenotype. METHODS: The 5-HTTPR genotype was determined in 332 subjects diagnosed with possible or probable AD. All subjects received structured psychiatric assessments and were categorized with regard to their history of aggressive behaviors and psychotic symptoms. RESULTS: Consistent with other reports, AD+P was associated with a significant increased risk for aggressive behavior. AD+P and aggression were both significantly associated with 5-HTTPR ll genotype and with an increased l allele frequency. Subjects with the combined behavioral phenotype (AD+P and aggressive behavior) had the highest rate of ll genotype and highest l allele frequency. CONCLUSION: The 5-HTTPR l allele appears to confer risk for the combined AD+P/aggressive phenotype. Confirmation of this association in a similar behaviorally well-characterized independent sample is needed.     

Premorbid personality and behavioral and psychological symptoms in probable Alzheimer disease.

OBJECTIVES: Previous research investigating the influence of premorbid personality on behavioral and psychological symptoms in dementia (BPSD) has produced mixed findings. Addressing some limitations of previous studies, the authors aimed to investigate whether some of the common individual symptoms of BPSD (depression, anxiety, irritability, and aggression) were associated with key aspects of previous personality (neuroticism and agreeableness); and also to perform an exploratory investigation into the broader influence of personality factors on behavioral and psychological syndromes. METHODS: Two hundred eight patients with a diagnosis of probable Alzheimer disease were assessed for the presence of BPSD over the disease course using the caregiver-rated Neuropsychiatric Inventory (NPI). One or two knowledgeable informants rated patients' midlife personalities using a retrospective version of the NEO-FFI questionnaire. RESULTS: Premorbid neuroticism was correlated with anxiety and total NPI score, although not with depression. Premorbid agreeableness was negatively correlated with agitation and irritability. Principal components analysis of the 10 NPI behavioral domains identified three syndromes: "agitation/apathy," "psychosis," and "affect." In stepwise linear regression analyses, including personality domains from the Five-Factor Model and a range of potential confounders as independent variables; the only significant personality predictor of a behavioral syndrome was "agitation/apathy," predicted by lower premorbid agreeableness. CONCLUSION: Lower premorbid agreeableness is associated with agitation and irritability symptoms in Alzheimer disease and also predicts an "agitation/apathy" syndrome. The relationship between premorbid neuroticism and BPSD is less straightforward, and premorbid neuroticism does not appear to be associated with depression in Alzheimer disease or predict an "affect" syndrome.     

Neuropsychiatric symptoms in nursing home patients: factor structure invariance of the Dutch nursing home version of the neuropsychiatric inventory in different stages of dementia

BACKGROUND/AIMS: To examine the influence of dementia stage and psychoactive medication use on the factor structure of the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) in Dutch nursing home patients. METHODS: The NPI-NH was administered to a large sample of 1,437 patients with mild to severe dementia receiving nursing home care. Exploratory factor analysis was used to examine behavioural dimensions underlying neuropsychiatric symptoms indicated by the NPI-NH across dementia stages (as assessed with the Global Deterioration Scale - GDS) and in patients with or without psychoactive medication prescribed. RESULTS: In GDS stages 4/5, 6 and 7, a 4- or 5-factor solution was found, with factors referred to as agitation/aggression, depression, psychosis, psychomotor agitation and apathy. These symptom clusters were replicated in the group of drug-naive patients, but only partially in the group of patients on psychoactive medication. CONCLUSION: The factor structure of the NPI-NH in nursing home patients is consistent with the clinical taxonomy of symptoms, is relatively stable across dementia stages, and is only moderately influenced by psychoactive medication use. The division of depression and apathy into separate behavioural dimensions - also in patients with severe dementia - may have important therapeutic consequences.     

Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease

AIM: We investigated differences in the prevalence and severity of 10 neuropsychiatric and behavioral symptoms according to apolipoprotein E (APOE) genotype and dementia severity in Alzheimer disease (AD). METHODS: Neuropsychiatric and behavioral symptoms of 110 AD patients were assessed using the Neuropsychatric Inventory. Dementia severity was assessed using the Mini Mental State Examination (MMSE). RESULTS: There were 27 APOE-epsilon4-negative patients, 65 heterozygous patients and 18 homozygous patients. There was a significant association between the number of APOE epsilon4 alleles and prevalence and severity of neuropsychiatric and behavioral symptoms that was mainly attributable to delusions and agitation/aggression, which were more common and severer among homozygous APOE epsilon4 carriers. In addition, the presence of hallucinations, anxiety, apathy and aberrant motor behavior increased with deteriorating MMSE score, independently of APOE epsilon4 status. CONCLUSIONS: The present study showed that the APOE epsilon4 genotype modifies neuropsychiatric and behavioral phenotype in AD. In particular, it was shown that delusions and agitation/aggression were more common and severer among homozygous APOE epsilon4 carriers than among heterozygous or APOE-epsilon4-negative patients.     

Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease.

OBJECTIVE: To systematically review published clinical trials of the pharmacotherapy of neuropsychiatric symptoms of Alzheimer disease (AD). METHOD: We searched MEDLINE and EMBASE for published English-language medical literature. Our review focused on randomized controlled trials (RCTs) and corresponding metaanalyses. RESULTS: The pharmacotherapy of neuropsychiatric symptoms of AD has been studied with numerous RCTs. The largest number of studies has focused on antipsychotics. Data are of reasonably high quality and indicate that risperidone and olanzapine are more effective than placebo for institutionalized patients with severe agitation, aggression, and psychosis. The efficacy of antipsychotics is counterbalanced by safety concerns that include cerebrovascular adverse events and mortality. Cholinesterase inhibitors and memantine appear to have modest benefits for patients with mildly to moderately severe symptoms. Antidepressants are effective for treating depression in AD, but more data are required to determine the efficacy of trazodone and citalopram for agitation and aggression. Carbamazepine appears to be efficacious, although side effects and concerns about drug-drug interactions limit its use. The data do not support the use of valproate. Benzodiazepines should only be used for short-term, as-needed use. There are insufficient data on other pharmacologic interventions, such as beta blockers, buspirone, and estrogen preparations. CONCLUSIONS: Although there have been numerous well-designed studies of the pharmacotherapy of neuropsychiatric symptoms in AD, safer and more effective treatments are urgently needed.     

The 5-HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer disease

BACKGROUND: Aggressive behavior in Alzheimer disease (AD) has been linked to dysfunction of serotonin neurotransmission. Homozygosity for the long variant (*L) of an identified biallelic polymorphism of the serotonin transporter promoter region (5-HTTPR) is associated with increased expression of the transporter protein and increased speed of response to serotonin reuptake inhibitor treatment. OBJECTIVE: To determine whether the *L/*L genotype and the *L allele are associated with an increased risk of aggressive symptoms in patients with AD. DESIGN: Case-control study. SETTING: University hospital geriatric psychiatry inpatient program and Alzheimer disease research center. SUBJECTS: Fifty-eight patients with AD with a history of aggressive behavior and 79 never-aggressive patients with AD with comparable severity of cognitive impairment. MAIN OUTCOME MEASURES: The 5-HTTPR genotype and allele frequency. RESULTS: The *L/*L genotype was significantly associated with aggression in patients with AD (odds ratio, 2.8; 95% confidence interval, 1.2-6.5). Similar results were obtained for *L allele frequency. CONCLUSION: The 5-HTTPR*L allele and *L/*L genotype may predispose patients with AD to develop aggressive behavior.     

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.     

Genetics of the serotonergic system in suicidal behavior

Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.     

Psychosis and aggression in Alzheimer''s disease: the effect of dopamine receptor gene variation

This study investigated possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset Alzheimer's disease. An association was found between the presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism and between the presence of psychosis, but not aggression, and the DRD3 polymorphism. Specifically, carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions.     

Serotonin transporter gene polymorphism and BPSD in mild Alzheimer's disease

The purpose of the present study was to confirm an association of functional polymorphism within the serotonin transporter (5-HTT) gene with Alzheimer's disease (AD) and behavioral and psychological symptoms of dementia (BPSD) in mild AD. Apolipoprotein E (ApoE) gene polymorphism and 2 types of functional polymorphism in the 5-HTT gene, 5-HTT-linked polymorphic region (5-HTTLPR) and a 5-HTT variable number of tandem repeats sequence (5-HTTVNTR) were analyzed longitudinally in outpatients with mild AD to find out whether there was a relation between any such polymorphisms and the occurrence of BPSD. No significant differences in genotype distribution or allele frequencies were identified for 5-HTTLPR or 5-HTTVNTR between AD patients and age- and sex-matched non-demented controls regardless of ApoE epsilon4 allele. No significant differences were noted in 5-HTTLPR genotype or allele distributions between AD patients with or without BPSD. However, significant associations were observed between presence of 5-HTTVNTR allele 10 and BPSD or aggressiveness. This difference was independent of the presence of the ApoE epsilon4 allele. As a result, 5-HTT polymorphisms are unlikely to play any substantial role in susceptibility to AD. Conversely, 5-HTTVNTR influences the risk of developing BPSD or aggressiveness and genetic variations in the 5-HTT gene may be involved in the development of symptomatology for mild AD.     

Prevalence of neuropsychiatric symptoms in a large sample of Dutch nursing home patients with dementia

OBJECTIVE: To estimate the prevalence of neuropsychiatric symptoms of dementia patients in Dutch nursing homes. METHODS: Cross-sectional study in a large sample of 1322 demented patients living in 59 dementia special care units (SCUs) in The Netherlands. Symptoms were observed by licensed vocational nurses during regular care-giving in a 2-week observational period prior to assessment. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory- Nursing home version (NPI-NH; frequency X severity score >/= 4) and the Cohen-Mansfield Agitation Inventory (CMAI; symptoms occurring at least once a week). RESULTS: More than 80% of these patients suffered from at least one clinically significant symptom, as defined with the NPI-NH frequency X severity score >/= 4. Measured with the NPH-NH agitation/aggression, apathy and irritability were the most frequently observed behaviors, with prevalences of 30-35%. Using the CMAI, 85% of the patients showed at least one symptom of agitation, of which general restlessness was observed most frequently (44%). Other frequently observed symptoms with prevalence rates of 30% were cursing or verbal aggression, constant request for attention, negativism, repetitious sentences, mannerisms, pacing, and complaining. Physically aggressive symptoms such as hitting, kicking, biting occurred less often (less than 13%). CONCLUSIONS: Prevalence rates of neuropsychiatric symptoms in Dutch nursing home patients with dementia residing in SCUs are high, especially agitation and apathy. Insight into the prevalence rates of individual symptoms in patients with dementia has important practical consequences for the accurate planning of staff allotment and stresses the need for patient oriented care.     

Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease.

OBJECTIVE: To examine whether the use of psychiatric medication and the presence of abnormal behaviors affects the progression of Alzheimer disease. DESIGN: Cross-sectional with longitudinal follow-up and the likelihood of arriving at 4 end points: (1) Mini-Mental State Examination score of 9 or lower; (2) Blessed Dementia Rating Scale score of 15 or higher for activities of daily living; (3) nursing home admission; and (4) death, evaluated using a proportional hazard model with 9 variables: psychosis, insomnia, wandering, aggression, psychomotor agitation, depression, and use of antidepressants, antipsychotic agents, or sedatives/hypnotics. SETTING: Multidisciplinary dementia research clinic. PATIENTS: We examined baseline and follow-up behavioral symptoms and the use of psychiatric medication in 179 mildly to moderately impaired patients with probable Alzheimer disease participating in a longitudinal study of dementia. Patients were observed from 2.4 to 172 months (mean duration +/- SD, 49.5+/-27.4 months). RESULTS: Nine patients (5%) were taking sedatives/ hypnotics; 16 (9%), antipsychotic agents; and 22 (12%), antidepressants at study entry. Patients taking antipsychotic agents had lower Mini-Mental State Examination scores and higher Blessed Dementia Rating Scale scores for activities of daily living than patients not taking any medication. Using proportional hazard analysis with time-dependent covariates for individual psychiatric symptoms and medications, we found that the development of psychosis was associated with functional decline (time to Blessed Dementia Rating Scale score of > or =15), institutionalization, aggression, and agitation with functional decline after adjusting for age at study entry, education, Mini-Mental State Examination scores, and Blessed Dementia Rating Scale scores. Use of antipsychotic medication was associated with functional decline, and sedatives/hypnotics with death. Neither the presence of psychiatric symptoms nor use of medication was associated with rate of cognitive decline (time to Mini-Mental State Examination score of < or =9). CONCLUSIONS: These findings indicate that the use of antipsychotic agents and sedatives can affect the natural course of Alzheimer disease. Psychosis, agitation, and aggression are important predictors of outcome, even when the effects of medication to treat them is taken into account.     

Neuropsychiatric symptoms in dementia: importance and treatment considerations

Neuropsychiatric symptoms are frequent in people with dementia, result in distress for the people experiencing them and their caregivers, and are a common precipitant of institutional care. The safe and effective treatment of these symptoms is a key clinical priority, but is a long way from being achieved. Psychological interventions are recommended as the first line treatment strategy in most good practice guidelines, and there is emerging evidence of efficacy for agitation and depression. Neuroleptics remain the mainstay of pharmacological treatment, although meta-analyses indicate that they are mainly of benefit for the short-term (up to 12 weeks) treatment of aggression in people with Alzheimer's disease, and there have been increasing concerns about serious adverse effects including mortality. The evidence is limited for other pharmacological approaches for the treatment of agitation, and psychosis in people with Alzheimer's disease is limited, but post-hoc analyses do indicate that memantine may be a promising therapy and aromatherapy may be a useful alternative. Autopsy studies indicate that the adrenergic system may be an important therapeutic target. Clinical experience suggests that antidepressants are effective in people with severe depression in the context of dementia, but the evidence base regarding the broader value of antidepressants is far from clear. There are very few trials specifically focusing upon the treatment of neuropsychiatric symptoms in common non-Alzheimer dementias, which is a major limitation and urgently needs to be addressed to provide an evidence base to enable the safe and effective treatment of these individuals.     

No evidence for allelic association of serotonin 2A receptor and transporter gene polymorphisms with depression in Alzheimer disease

Patients with Alzheimer disease (AD) often exhibit psychiatric symptoms associated with cognitive impairment. The serotoninergic system may be involved in the development of depressive symptoms in AD patients, as suggested by the evidence that antidepressant drugs having the serotonin transporter as their target are effectively used to treat depressive AD patients. The aim of this study was to investigate the role of serotonin in depression, searching for association of two serotoninergic polymorphisms (T102C of serotonin receptor 5-HT2A and serotonin transporter linked polymorphic region -5-HTTLPR- of SLC6A4 gene) with depressive symptoms and considering their possible interactions with Apolipoprotein E (ApoE) and between themselves, in a sample of 208 sporadic AD patients and 116 normal controls from Italy. 5-HTTLPR and T102C are not associated with AD when separately analysed. However, we found out an interaction between the two polymorphisms in L/L and C/C genotype carriers increasing the risk for the disease (p=0.015, OR=8.048; 95% CI: 1.497-43.262). No association of the polymorphisms was detected with depression linked to AD. No interaction between 5-HTTLPR and T102C was detected in depressive AD subjects, even after stratification according to the presence of ApoE4 allele. These results suggest that the serotoninergic system may be not involved in the pathogenesis of depressive symptoms in AD patients, and it may be involved in other aspects of disease pathophysiology like cognitive symptoms and psychosis.     

The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement.

The authors assessed the validity of the nursing home version of the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH), comparing the responses of certified nurses' aides (CNAs) and licensed vocational nurses (LVNs) with research observations. Correlations were significant but moderate for all of the domains of the NPI-NH (delusions, hallucinations, agitation/aggression, depression, apathy, disinhibition, euphoria, irritability/lability, and aberrant motor disturbances) except anxiety and appetite disturbance. The LVNs' ratings showed consistently higher correlations with the researchers' behavioral observations than did the CNAs', but were moderate and generally better for residents with high levels of neuropsychiatric symptoms, thus, caution should be used with any untrained rater in the nursing home setting. The NPI-NH used by non-research staff can be useful in identifying residents with significant neuropsychiatric disturbances, but may be limited as an instrument for tracking behavioral changes.     

Neuropsychiatric disturbance after aneurysmal subarachnoid hemorrhage

Although aneurysmal subarachnoid hemorrhage (aSAH) accounts for only 3–5% of all strokes, a high degree of morbidity has been reported in this relatively young subset of patients. Neuropsychiatric disturbance has often been neglected in these reports. We aimed to investigate the pattern and pathological factors of chronic neuropsychiatric disturbance in aSAH patients. This cross-sectional observational four-center study was carried out in Hong Kong. Neuropsychiatric outcome (Neuropsychiatric Inventory Chinese Version [CNPI]) assessments were conducted cross-sectionally 1–4 years after ictus. Pathological factors considered were early brain injury as assessed by admission World Federation of Neurosurgical Societies grade, aneurysm treatment (clipping versus coiling), delayed cerebral infarction, and chronic hydrocephalus. One hundred and three aSAH patients’ spouses or caregivers completed the CNPI. Forty-two (41%) patients were reported to have one or more domain(s) of neuropsychiatric disturbance. Common neuropsychiatric disturbance domains included agitation/aggression, depression, apathy/indifference, irritability/lability, and appetite/eating disturbance. Chronic neuropsychiatric disturbance was associated with presence of chronic hydrocephalus. A subscore consisting of the five commonly affected domains seems to be a suitable tool for aSAH patients and should be further validated and replicated in future studies.