Alzheimer Disease: Sultzer DL

Sultzer DL. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, and Gero/Neuropsychiatry Division, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. · Dement Geriatr Cogn Disord. · Pubmed #14566100 No free full text.

Abstract: Psychosis is common in patients with Alzheimer's disease (AD) and contributes substantially to patient morbidity and caregiver distress. Antipsychotic medications are used to treat psychosis and other psychiatric or behavioral symptoms in AD, although optimal treatment guidelines have been elusive. Choosing the most advantageous medication for an individual patient is challenging. This article provides an overview of clinical management principles and medication treatment strategies for patients with AD and psychosis. Effects of individual medications are also described. Medications in the conventional neuroleptic, atypical antipsychotic, cholinesterase inhibitor, and serotonergic classes have been shown to ameliorate psychosis and behavioral symptoms in patients with AD, although the evidence is not conclusive for many medications. Side effects vary substantially across medication classes and modestly among individual patients. Improvement in agitation, aggression, or other behaviors with antipsychotic medication treatment may not depend on distinct antipsychotic effects. In contrast, there is preliminary evidence that delusions and hallucinations may respond to treatment with medications outside the antipsychotic class. Many important clinical questions warrant further research study. In particular, studies to compare how individual symptoms respond to different medications, and to examine how to best manage overlapping symptoms or incomplete treatment response are needed.

Sultzer DL, Gray KF, Gunay I, Wheatley MV, Mahler ME. · Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, and VA Greater Los Angeles Healthcare System, California, USA. · J Am Geriatr Soc. · Pubmed #11890487 No free full text.

Abstract: OBJECTIVES: Several previous studies have examined the effects of pharmacological interventions for agitated behavior in patients with dementia. However, the choice of medication in clinical practice continues to be directed largely by local pharmacotherapy culture rather than empirical treatment guidelines. We examined the relationship between behavioral improvement and co-occurring delusions and mood symptoms in patients with dementia who were treated with haloperidol, an antipsychotic medication, or trazodone, a serotonergic antidepressant. DESIGN: Randomized, double-blind, parallel-group, 9-week treatment trial. SETTING: Inpatient geropsychiatry unit. PARTICIPANTS: Twenty-eight patients with dementia and agitated or aggressive behaviors. INTERVENTION: Haloperidol 1 to 5 mg/day or trazodone 50 to 250 mg/day. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI), Hamilton Depression Rating Scale (Ham-D), and delusional thoughts subscale and hallucinations subscale of the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). RESULTS: CMAI scores improved in each treatment group over the 9 weeks of treatment (P < .001 in each group). Within the haloperidol treatment group, CMAI improvement was not associated with baseline delusional thoughts score or with change in delusional thoughts score over the course of treatment. Within the trazodone treatment group, CMAI improvement was associated with baseline score on total Ham-D (r = -0.60, P = .02), Ham-D items measuring subjective mood symptoms (r = -0.50, P = .07), and Ham-D items measuring neurovegetative signs (r = -0.49, P = .08). CMAI improvement was also associated with improvement in Ham-D total score over the course of treatment (r = 0.62, P = .02). CONCLUSIONS: Mild depressive symptoms in patients with dementia and agitated behavior are associated with greater behavioral improvement by trazodone-treated patients. In contrast, the presence of delusions in concert with behavioral disturbance does not necessarily predict greater behavioral improvement with haloperidol treatment than in subjects without signs of psychosis.

Zheng L, Mack WJ, Dagerman KS, Hsiao JK, Lebowitz BD, Lyketsos CG, Stroup TS, Sultzer DL, Tariot PN, Vigen C, Schneider LS. · Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA. · Am J Psychiatry. · Pubmed #19369318 No free full text.

Abstract: OBJECTIVE: The second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimer's disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects. METHOD: The authors assessed 186 male and 235 female Alzheimer's disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models. RESULTS: Women showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., > or = 7% of body weight) was seen among patients with antipsychotic use < or = 12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and > 24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (-0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides. CONCLUSION: Second-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimer's disease treated with second-generation antipsychotics should be monitored closely.

Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, Rosenheck RA, Hsiao JK, Lieberman JA, Schneider LS, Anonymous00049. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Am J Psychiatry. · Pubmed #18519523 links to  free full text

Abstract: OBJECTIVE: The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior. METHOD: The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. RESULTS: In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. CONCLUSION: In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL. · Department of Neurology, University of California, Los Angeles, CA, USA. · Arch Neurol. · Pubmed #17620493 links to  free full text

Abstract: BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.

Hashimoto H, Monserratt L, Nguyen P, Feil D, Harwood D, Mandelkern MA, Sultzer DL. · Department of Neuropsychiatry, Osaka City University Medical School, 1-4-3 Asahi-machi, abeno-ku, Osaka-city, Osaka 545-8585, Japan. · J Neuropsychiatry Clin Neurosci. · Pubmed #17135378 links to  free full text

Abstract: In this study, the authors investigated the relationship between anxiety and regional cortical metabolism in Alzheimer's disease. Using the Neuropsychiatric Inventory (NPI), the authors evaluated anxiety in 41 patients with Alzheimer's disease. Regional cortical glucose metabolism was measured using [(18)F] fluorodeoxyglucose positron emission tomography in the resting state. Relationships were assessed using voxel-based (SPM2) and anatomic region-based analyses. Higher NPI anxiety score (frequency x severity) was associated with lower metabolism in bilateral entorhinal cortex, anterior parahippocampal gyrus, and left superior temporal gyrus and insula. Functional activity changes in distinct regions of the cortex contribute to the expression of anxiety in Alzheimer's disease.

Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA, Anonymous00024. · Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. · N Engl J Med. · Pubmed #17035647 links to  free full text

Abstract: BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Harwood DG, Sultzer DL, Feil D, Monserratt L, Freedman E, Mandelkern MA. · Neuropsychiatric Institute and Hospital, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, Univ. of California, Los Angeles, CA, USA. · Am J Geriatr Psychiatry. · Pubmed #16286436 No free full text.

Abstract: OBJECTIVE: The authors examined the relationship between impaired insight regarding cognitive and functional deficits and frontal cortex hypometabolism in 41 patients with Alzheimer disease (AD). METHODS: Regional cerebral glucose metabolism was determined with (18F)fluorodeoxyglucose and positron emission tomography. Level of insight was measured with the clinician-rated Neurobehavioral Rating Scale, and severity of global cognitive impairment was determined with the Mini-Mental State Exam. RESULTS: Inaccurate insight was correlated with glucose metabolic rate in the right lateral frontal cortex (Brodmann areas 6 and 45, and the lateral aspect of Brodmann areas 8 and 9) after controlling for global cognitive dysfunction. CONCLUSIONS: The findings from this study help to further elucidate the neurobiological mechanisms underlying impaired insight in AD, indicating a link between this important clinical phenomenon and dysmetabolism in a focal region of the right prefrontal cortex.

Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, Pfeiffer E, Ryan JM, Sultzer DL, Tariot PN. · Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA. · Schizophr Bull. · Pubmed #12908661 links to  free full text

Abstract: This article describes the development of the protocol for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer's disease trial, which was developed in collaboration with the National Institute of Mental Health to assess the effectiveness of atypical antipsychotics for psychosis and/or agitation occurring in outpatients with Alzheimer's disease. The article provides a detailed description of the methodology used in the trial as well as the clinical outcomes and effectiveness measures incorporated into it, discussing the most salient issues encountered in developing the design of the trial, as well as the unique features of the trial.

Sultzer DL, Brown CV, Mandelkern MA, Mahler ME, Mendez MF, Chen ST, Cummings JL. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, USA. · Am J Psychiatry. · Pubmed #12562582 links to  free full text

Abstract: OBJECTIVE: Delusional thoughts are common in patients with Alzheimer's disease and contribute prominently to morbidity. The pathophysiologic underpinnings for delusions in Alzheimer's disease are not well understood. In this study the authors examined the relationship between delusional thoughts and regional cortical metabolism in patients with Alzheimer's disease. METHOD: Twenty-five patients with probable Alzheimer's disease were included. None was taking psychotropic medication. Severity of delusions and other neuropsychiatric symptoms was assessed by using a semistructured interview and the Neurobehavioral Rating Scale just before the imaging procedure. [(18)F]Fluorodeoxyglucose positron emission tomography was used to measure resting cerebral glucose metabolic rates in the cortical lobes and in anatomically defined subregions of the frontal and temporal cortexes. RESULTS: A linear regression model, controlling for the effects of cognitive deficits, revealed a significant relationship between severity of delusional thought and the metabolic rates in three frontal regions: the right superior dorsolateral frontal cortex (Brodmann's area 8), the right inferior frontal pole (Brodmann's area 10), and the right lateral orbitofrontal region (Brodmann's area 47). Bivariate partial correlation analysis indicated that severity of delusions was associated with hypometabolism in additional prefrontal and anterior cingulate regions. Robust relationships with metabolism in regions of the temporal cortex were not apparent. CONCLUSIONS: Dysmetabolism in specific regions of the right prefrontal cortex may be associated with delusional thought in Alzheimer's disease. Delusions appear to reflect the pathophysiologic state of particular cortical regions. Activity across distributed neuronal networks and the specific content of delusional thoughts may modulate these relationships.

Sultzer DL, Chen ST, Brown CV, Mahler ME, Cummings JL, Hinkin CH, Mandelkern MA. · Departments of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #12154149 links to  free full text

Abstract: The authors measured subcortical hyperintensities (SH) on magnetic resonance images (MRI) in 18 patients with probable Alzheimer's disease and examined the relationships of SH severity with cortical metabolic function and clinical symptoms. Severity of SH was not correlated with absolute metabolic rates in cortical lobes. However, anterior SH severity was inversely correlated with frontal/ parietal metabolic ratios after covarying for cognitive impairment. SH severity in some areas was associated with the severity of global neuropsychiatric symptoms, but marked effects on individual symptoms were not apparent. The small sample size and multiple variables limit conclusions that can be drawn. These preliminary findings indicate that subcortical MRI hyperintensities may play a role in the pathophysiology and clinical expression of Alzheimer's disease.

Harwood DG, Sultzer DL. · Mental Health Services, VA Greater Los Angeles Healthcare System, California 90073, USA. · J Geriatr Psychiatry Neurol. · Pubmed #11936242 No free full text.

Abstract: This study investigated the prevalence and clinical correlates of hopelessness among 91 patients diagnosed with probable Alzheimer's disease (AD) according to National Institute of Neurological Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Hopeless ideation was measured with Item 3 on the Hamilton Depression Rating Scale (Suicide), which inquires specifically whether the patient thinks "life is not worth living." The results showed that hopelessness was present in 10% (n = 9) of the sample. Patients with these cognitions evidenced greater psychological symptoms of mood disturbance and more insight into their cognitive and functional impairments. Unrelated factors included age, education, Mini-Mental State Examination score, neurovegetative signs of depression, affective expressions of depression, agitation/disinhibition, and psychosis. Although indifference is frequent in AD, these results indicate that thoughts of hopelessness are also a common phenomenon, occurring in approximately 10% of our probable AD cohort. These thoughts appear to be related to the subjective expressions of depression and anxiety rather than the neurovegetative or affective signs and are more prominent among patients with greater deficit awareness.

Harwood DG, Sultzer DL, Wheatley MV. · Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, and Veterans Affairs Medical Center, Greater Los Angeles Healthcare System, USA. · Neuropsychiatry Neuropsychol Behav Neurol. · Pubmed #10780626 No free full text.

Abstract: OBJECTIVE: The purpose of this study was to evaluate symptoms associated with impaired insight in patients with Alzheimer disease (AD). BACKGROUND: Although unawareness of deficits is common in AD, the relation of awareness to psychiatric and behavioral disturbances has not been extensively studied. METHOD: We conducted a cross-sectional investigation of 91 patients with probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. Awareness of cognitive and functional deficits was measured with the Inaccurate Insight item from the Neurobehavioral Rating Scale. Psychiatric and behavioral symptoms were measured using factor scores and individual items from the Neurobehavioral Rating Scale. Global cognitive deficits were measured using the Mini-Mental State Examination (MMSE). RESULTS: Stepwise regression analysis showed that insight was associated with MMSE score, depression/anxiety factor score, and agitation/disinhibition factor score. Variables not associated with awareness of deficits included patient age, behavioral retardation factor score, verbal output disturbance factor score, and psychosis factor score. Post hoc analyses showed a positive relation (i.e., greater insight, more symptomatology) between deficit awareness and symptoms of depressed mood and anxiety. There was a negative relation (i.e., greater insight, less symptomatology) between insight and symptoms of hostility, agitation, inattention, and tension. In a follow-up stepwise regression analysis, increased deficit awareness was associated with a higher MMSE score, greater depressed mood, and decreased agitation. CONCLUSIONS: These findings suggest that patients with AD may experience symptoms of depressed mood in relation to increased awareness of decrements in functioning. The data also indicate that patients with poor insight demonstrate greater agitated behavior. Consistent with previous research, impaired insight was higher in the later stages of the illness.

Levy ML, Cummings JL, Fairbanks LA, Sultzer DL, Small GW. · Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine 90095-1769, USA. · Biol Psychiatry. · Pubmed #10071711 No free full text.

Abstract: BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele confers significant risk for Alzheimer's disease and is associated with a greater amyloid burden in the brain. Future treatments may target molecular mechanisms associated with this allele, and it is important to define any phenotypic characteristics that correspond to this genotype. We sought to clarify the relationship between ApoE status and noncognitive symptoms in Alzheimer's disease patients. METHODS: Possible and probable Alzheimer's disease patients from a clinical trial (n = 605) were assessed with the 10-item Neuropsychiatric Inventory cross-sectionally prior to treatment, and their ApoE genotype was determined. Among the population studied, the following numbers with specific genotypes were studied: 23-2/3, 17-2/4, 209-3/3, 288-3/4, 68-4/4. RESULTS: When correlations were controlled for the patient's level of cognitive impairment, there was no relationship between epsilon 4 dose and any of the 10 noncognitive symptoms assessed, including psychosis, mood changes, and personality alterations. CONCLUSIONS: Among patients with comparable disease severity, the epsilon 4 allele does not confer additional psychiatric morbidity.