Prediction of longitudinal functional outcomes in schizophrenia: the impact of baseline motivational deficits.

Emerging evidence suggests that motivational deficits are a central component of negative symptoms in schizophrenia, and linked to functional impairment characterizing this illness. This study extends previous cross-sectional findings by examining the concurrent contributions of baseline motivational deficits, other negative symptoms, and other symptom domains on longitudinal functional outcomes in schizophrenia. Results of this longitudinal examination of 18 patients from our previous pilot study reveal that amotivation accounts for 74% and 72% of the variance in functional outcomes at baseline and 6-month follow-up, respectively. These findings further suggest a fundamental role for motivational deficits in predicting functional outcomes in schizophrenia.

Motivational deficits as the central link to functioning in schizophrenia: a pilot study.

Negative symptoms have consistently been found to contribute to functional impairment in schizophrenia. In this pilot study, we sought to delineate the core negative symptoms that contribute to this functional impairment. Adult outpatients with schizophrenia were evaluated for the severity of positive, negative, cognitive, and depressive symptoms. The Quality of Life Scale was used to assess current functioning. Results from 21 participants revealed that a motivation was the sole predictor of functioning, accounting for 74% of the variance in current functioning. This suggests that motivational deficits are the central link between negative symptoms and functional impairment in schizophrenia.

Differential memory impairment in dementia with Lewy bodies and Alzheimer's disease.

This study was conducted in order to elucidate the functioning of the Central Executive System of Working Memory (WM) and to clarify the status of other cognitive functions in Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Fourteen DLB, 22 AD, and 23 control subjects were assessed with the dual task paradigm and other cognitive tests. When compared with controls, DLB subjects performed more poorly in concurrent conditions on semantic WM tasks, and AD subjects performed more poorly on the spatial WM task. The DLB subjects had an inferior verbal span and AD subjects, an inferior recall on the CVLT. These data suggest relative impairments of verbal and semantic WM in DLB and relative impairments of spatial WM and verbal episodic memory in AD.

Applying Bradford Hill's criteria for causation to neuropsychiatry: challenges and opportunities.

Establishing an argument of causation is an important research activity with major clinical and scientific implications. Sir Austin Bradford Hill proposed criteria to establish such an argument. These criteria include the strength of the association, consistency, specificity, temporal sequence, biological gradient, biologic rationale, coherence, experimental evidence, and analogous evidence. These criteria are reviewed with the goal of facilitating an increase in rigor for establishing arguments of causation in neuropsychiatry. The challenges and opportunities related to these criteria in neuropsychiatry are reviewed, as are two important arguments for causation: one for poststroke depression and one for brain injury as a cause of psychiatric disorders.

Dementia with Lewy bodies in Down's syndrome.

The association between Down's syndrome (DS) and Alzheimer's disease is well established. This paper presents a review of the literature, suggesting a possible association between DS and the more recently recognised dementia with Lewy bodies (DLB). Patients with DLB frequently present with changes in affect and behaviour, and in particular with psychotic symptoms. The literature suggests a possible role for atypical neuroleptics in the management of psychosis in DLB.

Relationship of psychosis to aggression, apathy and function in dementia.

BACKGROUND: Psychosis has been associated with aggression in dementia, but the nature of this relationship has been unclear. There has been very little research into the relations between apathy and functional status to psychosis in dementia. The purpose of this study is to investigate the relationship between psychosis and aggression, apathy, and functional status in outpatients with dementia. METHODS: The presence of psychosis was assessed by clinical interview and two scales: the Neuropsychiatric Inventory and the Columbia University Scale for Psychopathology in Alzheimer's Disease. The maximum likelihood estimation technique was used to determine the best estimate of the presence of psychosis. Aggression, apathy, and functional status (activities of daily living: ADLs) were measured using structured instruments. RESULTS: Sixty-one subjects were included. The CUSPAD and NPI provided low false positive and negative rates. ANCOVA analyses showed that psychosis was significantly associated with aggression, even when controlling for apathy, depression, and ADLs. Psychosis was related to apathy only when depression was controlled for. Hallucinations were related to impaired basic ADLs, even when depression and apathy were controlled for. CONCLUSIONS: Relationships were found between psychotic symptoms in dementia and aggression as well as apathy and impaired functional status. These relationships suggest pathophysiologic mechanisms and have possible treatment implications.

A review of the cognitive and behavioral symptoms in dementia with Lewy bodies.

Dementia with Lewy bodies is a relatively common cause of dementia. Much has been learned about this disorder, yet much remains to be elucidated, especially in regard to early clinical diagnosis. To clarify the future research agenda in this area, the authors critically appraise the literature on cognitive and behavioral changes in DLB and provide a brief overview of the history of DLB, the main pathological changes, and the findings related to extrapyramidal symptoms and treatment issues. Twenty-one studies on cognition and 47 on behavioral changes in DLB are reviewed. Impairments of working memory and visuospatial functions, visual hallucinations, and depression (or symptoms of depression such as apathy and anxiety) have been identified as early indicators of DLB. However, longitudinal and cross-sectional data are lacking, particularly for different aspects of working memory, visual perception, and non-psychotic behavioral symptoms.

The role of the cerebellum in cognition and behavior: a selective review.

The cerebellum has traditionally been seen primarily to coordinate voluntary movement, but evidence is accumulating that it may play a role in cognition and behavior as well. This is a selective review of studies assessing potential cognitive deficits and personality changes associated with cerebellar disease. Preliminary studies of the role of the cerebellum in schizophrenia, dementia, and other psychiatric disorders are also discussed. Efforts to understand the neurological substrates of behavior should consider the role of the cerebellum.

Can traumatic brain injury cause psychiatric disorders?

Traumatic brain injury (TBI) may cause psychiatric illness. This article reviews the evidence on the basis of an established set of causation criteria. The evidence is convincing for a strong association between TBI and mood and anxiety disorders. Substance abuse and schizophrenia are not strongly associated with TBI, and there is little research into the rates of personality disorders after TBI. Evidence for a biologic gradient is lacking, but such a gradient may not be relevant to TBI. Evidence for the correct temporal sequence is present. Preliminary evidence suggests a biologic rationale for TBI causing psychiatric illness. Further and methodologically improved research is supported and required.

The role of depression severity in the cognitive functioning of elderly subjects with central nervous system disease.

OBJECTIVE: To examine the hypothesis that there is a causal relation between depression and cognitive dysfunction in patients with central nervous system (CNS) disease. DESIGN: Retrospective analysis of a clinical database. SETTING: Tertiary geriatric day hospital. PATIENTS: Sixty-five patients with depression and CNS disease, and 201 patients with depression but without CNS disease. OUTCOME MEASURES: Scores on the Hamilton Depression Rating Scale (Ham-D) and the Mattis Dementia Rating Scale (MDRS). RESULTS: A logistic regression analysis using MDRS status as the dependent variable, and a number of clinical variables as the predictor variables, showed that, in patients with CNS disease, only the Ham-D score predicted MDRS status (R = -0.19, p = 0.02). Ham-D score even more strongly predicted scores on a frontal system subtest of the MDRS (R = -0.262, p = 0.005). Ham-D score did not predict MDRS status in patients without CNS disease. Mean Mini Mental State Examination scores for the group with CNS disease were 25.1 at admission and 26.1 at discharge (p < 0.001). CONCLUSIONS: These findings suggest that depression contributes to frontal cognitive dysfunction in patients with CNS disease.

Depression in holocaust survivors: profile and treatment outcome in a geriatric day hospital program.

The profile of depressive symptoms and the outcome of treatment in Holocaust Survivors (HS) versus non-Holocaust Survivors (NS), attending a Psychiatric Day Hospital Program for depression, were evaluated retrospectively using a clinical database. Approximately 24% of the study population were Holocaust Survivors (HS). The HS group was more likely to receive a diagnosis of major depressive disorder or episode as one of their diagnoses. The HS group, in particular those survivors who had been in ghettos or in concentration camps, were more likely to be given a diagnosis of post-traumatic stress disorder. Both groups showed improvement from baseline in their ratings of depression on the Hamilton Depression Rating Scale (HDRS) and Geriatric Depression Scale at the time of discharge (p<0.001). However, there were no significant differences between the groups in terms of their ratings of depression either at admission, at discharge or in their degree of improvement. Likewise, there was no significant difference between the groups in the profile of their depression, as per the sub-scales of the HDRS, with the exception that the HS group displayed more 'insight' than the NS group (p=0.002). The NS group scored higher on the Mattis Dementia Rating Scale compared to the HS group (119.1 versus 125.4, p<0.001), even when level of education was covaried; however, language may be an important confound. In conclusion, there was no significant difference in the profile or outcome of depression between groups. However, the HS group was more likely to receive a diagnosis of post-traumatic stress disorder, displayed more 'insight', and appear to differ in their cognitive profile.

The prediction and prevention of Alzheimer's disease--towards a research agenda.

This paper sets a research agenda for the prediction and prevention of future onset of Alzheimer's disease (AD). From a MEDLINE review of the literature, the authors found age to be a predictor of AD. The literature also indicates that memory and attentional impairments predict AD, although the relative risk is relatively low. Late-onset depression may also predict AD, but these data are limited by a lack of cohort studies. Studying cognitively impaired subjects with late-onset depression may identify a high-risk group, facilitating prevention trials. Characteristics of an "ideal" preventive agent are suggested. There is a biologic rationale, and preliminary evidence, that non-steroidal anti-inflammatory drugs (including ASA), estrogen and vitamin E may play a preventive role in AD. Other compounds (such as acetylcholinesterase inhibitors) are also promising, but costs, side effects, and lack of other health benefits may preclude their use in all but very high-risk groups.

Late-life depression as a possible predictor of dementia: cross-sectional and short-term follow-up results.

The authors explored cognitive functioning of a group of elderly subjects with depression. The group as a whole, and, in particular, the late-onset group (LOD), demonstrated cognitive impairment on the Mattis Dementia Rating Scale (MDRS). Subgroup differences were significant at P=0.004. This between-group difference was not seen when age and level of education were controlled. In the LOD group, 47.5% (vs. 31.5% of the early-onset group [P=0.025]), scored below the cutoff for dementia. Age-at-onset status in a logistic regression model predicted MDRS category, and treatment of the depression had little effect on cognition. Results support the hypothesis that late-life depression, particularly LOD, is associated with cognitive impairment that may represent early AD.

Impulsivity: core aspect of borderline personality disorder.

This prospective follow-up study addresses whether impulsivity versus other aspects of borderline personality disorder (BPD) are (1) stable over a 7-year follow-up period; (2) able to predict the persistence versus remittance of BPD over 7 years of follow-up, and (3) more predictive of the level of borderline psychopathology on follow-up than other aspects of the disorder. When the cohort was assembled, 88 of 130 subjects scored seven or higher on the Diagnostic Interview for Borderlines (DIB), indicating a definite diagnosis of BPD. The cohort was reassessed at 2 and 7 years after the index admission. At the 7-year follow up, 81(62.3%) of the original cohort were re-examined, two (1.6%) were deceased, six (4.6%) suicided, 36 (27.7%) refused to participate and five (3.8%) could not be located. The results indicated that the initial impulse action subscale score was highly correlated with the 7-year follow-up score (r = 0.53). Using a stepwise multiple regression technique, the impulse action subscale score from the DIB best predicted borderline psychopathology at the 7-year follow up, with an r2 of 0.24, F = 24.84, p < 0.001. This prospective study of subjects with BPD indicates that impulsivity is stable over time and highly predictive of borderline psychopathology over 7 years follow up. These results suggest the treatment of impulsivity may impact the course of BPD.

Memory assessment in studies of cognition-enhancing drugs for Alzheimer's disease.

There is an increasing number of cognition-enhancing drugs for Alzheimer's Disease (AD) and, consequently, drug trials represent a growing field of interest in research. As memory dysfunction is generally the first and most severe cognitive impairment in AD, the choice of memory testing to be used in these studies is of great importance. It should reflect an understanding of memory systems being assessed with neuropsychological tests and the fact that some tests can be more appropriate than others to show benefit with certain classes of cognition-enhancing drugs. Severe deterioration of episodic and semantic memory occurs very early in the AD process while working memory shows a gradual deterioration over time. Some aspects of working and implicit memory can be spared in the mild to moderate stages of AD. Tests of working, episodic, semantic and implicit memory are used as outcomes in trials with acetylcholinesterase inhibitors, drugs with other neurotransmitter strategies, metabolic enhancers and drugs which may impact upon a variety of CNS processes. The clinical scales and observational measures are largely used in trials of cognition-enhancing drugs for AD (46.66% of all the studies reviewed). The Digit Span test, the Rey Auditory Verbal Learning Test, the Buschke Selective Reminding Test and the verbal fluency tasks are the most sensitive memory tests, whereas the most sensitive scales are the Sandoz Clinical Assessment-Geriatric, the Gottfried-Bräne-Steel scale and the Blessed Dementia Scale. Finally, we suggest that future investigations should use sensitive memory tests, together with behavioural and psychiatric scales, rather than general observational evaluations.

Diagnosis of dementia and treatment of Alzheimer's disease. Pharmacologic management of disease progression and cognitive impairment.

OBJECTIVE: To highlight the importance of family physicians in the management of Alzheimer's disease (AD) and related dementias. To provide an update on the diagnostic workup of people with suspected dementia and on the pharmacologic management of cognitive impairment and disease progression in AD. QUALITY OF EVIDENCE: MEDLINE and Psychological Abstracts were searched using the terms "cognitive enhancers" or a specific drug name and "dementia (exp)." Evidence is generally limited but promising. Methodologic flaws in existing research likely to affect clinicians are briefly reviewed. MAIN MESSAGE: Increasing evidence suggests that early intervention can delay the progression of AD and improve the symptoms and function of those affected. Available treatments have modest but important effects on the outcome of patients with AD; some patients respond dramatically. Most currently available treatments are relatively safe in carefully selected cases. CONCLUSIONS: The diagnostic workup of most cases of dementia can at least be initiated in family physicians' offices. Beginning the workup is important because, for treating AD, the earlier you start, the better. Donepezil, vitamin E, and, in the near future, propentofylline are the main pharmacologic choices for improving cognition and slowing disease progression.

The pharmacologic treatment of Alzheimer's disease: a guide for the general psychiatrist.

OBJECTIVE: To review the drug treatment of Alzheimer's disease (AD) and to provide guidelines for the physician on how to integrate these treatments into the overall management of this disorder. METHOD: A qualitative review of randomized, double-blind, placebo-controlled trials of medications used to treat cognitive deficits, disease progression, agitation, psychosis, or depression in AD. A computerized search of Medline was used to identify relevant literature published during the period 1968-1998. Key words used in the search were 'randomized controlled trials,' with 'dementia' and with 'Alzheimer's disease'. RESULTS: Agents that are currently available in Canada to treat the cognitive deficits of AD include donepezil, ginkgo biloba, selegiline, and ergoloid mesylates. Donepezil and ginkgo biloba are associated with a statistically significant but clinically modest improvement in cognitive function in a substantial minority of patients with mild to moderate AD. Selegiline may have a mild beneficial effect on cognitive function in some patients with AD, but the data are inconclusive. Ergoloid mesylates have questionable efficacy in AD and can only be recommended as a last line of treatment. The results of a single trial suggest that vitamin E or selegiline (both have antioxidant properties) may slow the progression of AD. Antipsychotic medications can result in clinically significant improvement in agitation and psychosis. Carbamazepine also appears to be an effective treatment for agitation in AD, and there is preliminary evidence that the selective serotonin reuptake inhibitor citalopram reduces irritability in this disorder. There is no evidence that other nonneuroleptic medications are more efficacious than placebo in treating agitation in AD. Limited data indicate that depression in dementia responds to antidepressant medication. CONCLUSION: These data indicate that selected medications can be used to treat cognitive deficits, disease progression, agitation, psychosis, and depression in AD. However, there is considerable heterogeneity in patients' responses to these medications. Pharmacotherapy needs to be considered as a component of a package of care that also includes psychosocial and environmental interventions and support of the caregiver.

Prospective follow-up study of borderline personality disorder: prognosis, prediction of outcome, and Axis II comorbidity.

OBJECTIVE: To examine the rate of persistence of borderline personality disorder (BPD), the existence of concomitant personality disorders on follow-up, and the predictors of outcome in patients who met criteria for BPD compared with patients with borderline features who failed to meet all of the criteria. METHOD: This prospective cohort study reassessed subjects for BPD diagnosis and cooccurring personality pathology at 7 years follow-up. Initial measures of borderline and comorbid personality psychopathology were used to predict levels of borderline or other personality disorder psychopathology at follow-up. RESULTS: Of the 57 subjects who initially met the criteria for BPD, 30 (52.6%) were found to have remitted BPD, and 27 (47.4%) were characterized as having persistent BPD. The remitted group met significantly fewer comorbid personality disorder diagnoses than the persistent group (mean = 0.8, mean = 3.5 respectively; P < 0.05). Results also indicated that the initial level of borderline psychopathology was predictive of borderline psychopathology at follow-up, which explained 17% of the variance. CONCLUSIONS: This prospective follow-up study found that almost 50% of former inpatients with BPD continue to test positive for BPD at 7 years follow-up, and these persistent BPD patients also had significantly more comorbid personality psychopathology. Borderline psychopathology at follow-up was primarily predicted by the level of borderline psychopathology recorded at the initial assessment.

Cognition-enhancing drugs in dementia: a guide to the near future.

OBJECTIVES: To facilitate access to the available literature and to assist clinicians with the decision to recommend the use of medications for the enhancement of cognition in dementia. METHOD: A qualitative review of published research. Methodological issues confronting research in this area are described. An organizational scheme for the medication types, based on pathophysiologic processes relevant to Alzheimer's disease (AD), is reviewed. The paper makes extensive use of tablets to present the minimal data necessary for the reader to appraise critically all of the original publications found. The paper further presents in summary form the opinions of previous reviews on each of the medications. RESULTS: We identified 45 medications in the published research in which humans with dementia were assessed as having a change in cognition. Immediate use of tacrine is supported by the evidence, but the degree of benefit is modest, and side effects are problematic. CONCLUSION: A number of medications warrant further investigation. Tacrine can be offered to patients with careful education regarding the limited efficacy and potential side effects. Newer, perhaps safer, anticholinesterase inhibitors are now becoming available. Referral to a research study examining other medications is suggested, as are some "common sense" strategies.