Carl Salzman

ACNP White Paper: Update on Use of Antipsychotic Drugs in Elderly Persons with Dementia

In elderly persons, antipsychotic drugs are clinically prescribed off-label for a number of disorders outside of their Food and Drug Administration (FDA)-approved indications (schizophrenia and bipolar disorder). The largest number of antipsychotic prescriptions in older adults is for behavioral disturbances associated with dementia. In April 2005, the FDA, based on a meta-analysis of 17 double-blind randomized placebo-controlled trials among elderly people with dementia, determined that atypical antipsychotics were associated with a significantly (1.6–1.7 times) greater mortality risk compared with placebo, and asked that drug manufacturers add a ‘black box’ warning to prescribing information for these drugs. Most deaths were due to either cardiac or infectious causes, the two most common immediate causes of death in dementia in general. Clinicians, patients, and caregivers are left with unclear choices of treatment for dementia patients with psychosis and/or severe agitation. Not only are psychosis and agitation common in persons with dementia but they also frequently cause considerable caregiver distress and hasten institutionalization of patients. At the same time, there is a paucity of evidence-based treatment alternatives to antipsychotics for this population. Thus, there is insufficient evidence to suggest that psychotropics other than antipsychotics represent an overall effective and safe, let alone better, treatment choice for psychosis or agitation in dementia; currently no such treatment has been approved by the FDA for these symptoms. Similarly, the data on the efficacy of specific psychosocial treatments in patients with dementia are limited and inconclusive. The goal of this White Paper is to review relevant issues and make clinical and research recommendations regarding the treatment of elderly dementia patients with psychosis and/or agitation. The role of shared decision making and caution in using pharmacotherapy for these patients is stressed.

Effect of fluoxetine on anger in symptomatic volunteers with borderline personality disorder.

Clinical data and uncontrolled observations have suggested that fluoxetine is helpful in some patients with borderline personality disorder. This article describes the results of a 13-week double-blind study of volunteer subjects with mild to moderately severe borderline personality disorder. Thirteen fluoxetine recipients and nine placebo recipients received treatment. Pretreatment and posttreatment measures were obtained for global mood and functioning, anger, and depression. The most striking finding from this study was a clinically and statistically significant decrease in anger among the fluoxetine recipients. This decrease was independent of changes in depression. These data support previous observations that fluoxetine may reduce anger in patients with borderline personality disorder. The number of subjects in this study was small, the placebo responsiveness was high, and the clinical characteristics of the patients were in the mild to moderate range of severity. The data cannot be extrapolated to more severely ill borderline patients, but further study of fluoxetine and other selective serotonin reuptake inhibitors is indicated in this population.

Moment-to-Moment Tracking of State Value in the Amygdala

As an organism interacts with the world, how good or bad things are at the moment, the value of the current state of the organism, is an important parameter that is likely to be encoded in the brain. As the environment changes and new stimuli appear, estimates of state value must be updated to support appropriate responses and learning. Indeed, many models of reinforcement learning posit representations of state value. We examined how the brain mediates this process by recording amygdala neural activity while monkeys performed a trace-conditioning task requiring fixation. The presentation of different stimuli induced state transitions; these stimuli included unconditioned stimuli (USs) (liquid rewards and aversive air puffs), newly learned reinforcement-predictive visual stimuli [conditioned stimuli (CSs)], and familiar stimuli long associated with reinforcement [fixation point (FP)]. The FP had a positive value to monkeys, because they chose to foveate it to initiate trials. Different populations of amygdala neurons tracked the positive or negative value of the current state, regardless of whether state transitions were caused by the FP, CSs, or USs. Positive value-coding neurons increased their firing during the fixation interval and fired more strongly after rewarded CSs and rewards than after punished CSs and air puffs. Negative value-coding neurons did the opposite, decreasing their firing during the fixation interval and firing more strongly after punished CSs and air puffs than after rewarded CSs and rewards. This representation of state value could underlie how the amygdala helps coordinate cognitive, emotional, and behavioral responses depending on the value of ones state.

Sleep in the Elderly: Normal Variations and Common Sleep Disorders

The most common complaints of older adults concern their difficulty initiating or maintaining sleep, which results in insufficient sleep and an increased risk of falls, difficulty with concentration and memory, and overall decreased quality of life. Difficulties sleeping are not, however, an inevitable part of aging. Rather, the sleep complaints are often comorbid with medical and psychiatric illness, associated with the medications used to treat those illnesses, or the result of circadian rhythm changes or other sleep disorders. Health care professionals specializing in geriatrics need to learn to recognize the different causes of sleep disturbances in this population and to initiate appropriate treatment. Nonpharmacological treatment techniques are discussed; pharmacological treatments are discussed in a companion article.

Long-Term use of quetiapine in elderly patients with psychotic disorders.

BACKGROUND Quetiapine is an atypical antipsychotic agent that does not appear to increase patient risk for treatment-emergent extrapyramidal symptoms (EPS) or anticholinergic symptoms. Previous studies of quetiapine use in elderly patients with schizophrenia and other psychoses examined short-term administration (< or = 12 weeks). Given the growing elderly population, the commensurate increase in elderly patients with psychoses, and the expected increase in disease treatment-years, the effect of long-term quetiapine administration in older patients is of considerable interest. OBJECTIVE This study assesses the long-term tolerability, safety, and clinical benefit of quetiapine in elderly patients with psychosis. METHODS Elderly patients (> or = 65 years of age) with psychotic disorders, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, participated in this 52-week, open-label, multicenter trial. Investigators increased (and later adjusted) daily doses of quetiapine on the basis of clinical response and tolerability, and assessed safety and efficacy. Efficacy assessments were made using the 18-item Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions (CGI), Simpson-Angus Scale, and the Abnormal Involuntary Movement Scale (AIMS). For patients who withdrew before week 52, analyses were performed using observed data and the last observation carried forward. RESULTS One hundred eighty-four patients with psychotic disorders (98 women and 86 men) with a mean age of 76.1 years entered the trial. Seventy-two percent had psychotic disorders due to general medical conditions such as Alzheimers disease, and 28% had other psychotic disorders, most commonly schizophrenia. Overall, 89 (48%) patients completed treatment through 52 weeks. Median total daily dose was 137.5 mg. Reasons, for withdrawal included lack of efficacy (19%), adverse events or intercurrent illness (15%), failure to return for follow-up (13%), protocol noncompliance (3%), and diminished need for treatment (2%). Somnolence (31%), dizziness (17%), and postural hypotension (15%) were common adverse events, but they rarely resulted in withdrawal from therapy. EPS-related adverse events occurred in 13% of patients. At end point (week 52), mean total score on the Simpson-Angus Scale had decreased from baseline by 1.8 points, whereas changes in AIMS scores were negligible. No clinically important effects were reported relative to mean changes in hematologic, thyroid function, or hepatic function variables. Quetiapine treatment appeared to have no associated cardiovascular adverse outcomes despite cardiovascular comorbidities and unrestricted use of concomitant cardiovascular medications. Significant decreases in BPRS total score (n = 170, P < 0.001) and CGI Severity of Illness item score (n = 177, P < 0.002) were seen at end point (observed data and last observation carried forward). Decreases of > or = 20% in mean BPRS total score were observed in 83 (49%) patients. CONCLUSIONS These results provide preliminary information to clinicians regarding tolerability, safety, and clinical improvement with quetiapine in elderly patients with psychotic symptoms, and support controlled studies of quetiapine in this patient population.

Depression in the Elderly. I. Relationship between Depression, Psychologic Defense Mechanisms and Physical Illness*

Diagnosis of depression in the elderly is sometimes difficult owing to the presence of ego defensive mechanisms or somatic symptoms that can disguise the affect. Depression also may precede, or be associated with a variety of medical illnesses which are common among older persons. Specific ego defenses and representative medical illnesses are discussed. The concepts of a depressive equivalent and pseudodementia, which particularly act to disguise the depression, are reviewed in detail.

A Double-Blind Study of Paroxetine, Fluoxetine, and Placebo in Outpatients with Major Depression

We report results from a multicenter, placebo-controlled, randomized, double-blind comparison of the efficacy and tolerability of paroxetine and fluoxetine in outpatients with major depression. Across five U.S. sites, 128 outpatients (mean age: 41.3 +/- 12.6; 63 men and 65 women) with moderate to moderately severe major depression without a history of mania or hypomania were recruited between 1993 and 1994. All 128 patients completed a 1-week placebo washout period, and were then randomized to 12 weeks of double-blind treatment with paroxetine up to 50 mg/day (n = 55), fluoxetine up to 80 mg/day (n = 54), or placebo (n = 19). Subjects were evaluated weekly for the first 4 weeks, then at weeks 6, 9, and 12 with the 21-item HAMD and the Covi Anxiety Scale. There were no significant differences among the three treatment groups in baseline and endpoint depression and anxiety severity, as well as in the degree of depression and anxiety improvement. There were no statistically significant differences in rates or mean numbers of adverse events between paroxetine-treated patients and fluoxetine-treated patients. In summary, our results, although limited by the lack of a significant difference from placebo in treatment outcome, suggest that the SSRIs paroxetine and fluoxetine have comparable antidepressant and antianxiety efficacies among depressed outpatients, as well as similar safety and tolerability profiles.

SSRI Treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22–39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31‐day home‐based study consisting of: 7 days drug‐free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self‐scored specific emotions in their reports and rated seven general dream characteristics using 5‐point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep‐related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge‐rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine‐treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from serotonergic suppression.

Drug and ECT treatment of depression in the elderly, 1996–2001: a literature review

A computer-based literature search of all antidepressant and electroconvulsive therapy (ECT) treatment studies published between 1995 and September 2001 was conducted. In addition, a review of published chapters, review articles, and metaanalyses was also conducted. Articles were categorized into those reporting comparative studies, those in which the therapeutic agent was not compared with another, articles about ECT, and review articles. These recent publications support the conclusions from prior reviews that antidepressants and ECT are effective and safe treatments for depressed elderly patients. Differences in efficacy and side effects appear to be slight among the various types of antidepressants. Research studies of depressed elderly increased markedly since 1995 compared with all previous years although more studies are still necessary.

Depression in a Long‐Term Care Facility: Clinical Features and Discordance Between Nursing Assessment and Patient Interviews

OBJECTIVE: Nurses commonly observe more depression than is diagnosed and treated in nursing homes. Accordingly, we aimed to describe the clinical features of untreated nursing home residents whom nurses identify as depressed and to compare nurse ratings of depressed nursing home residents with ratings from direct interviews and patient self‐reports.