New Rx for psychoses in Alzheimer's, Parkinson's.
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Aged↗
Biomedical subjects
S D Targum
Publications and source records attributed to S D Targum.
Efficacy of quetiapine in Parkinson's patients with psychosis.
Eleven patients with Parkinson's disease (PD) and acute psychosis received flexible doses of quetiapine between 25 and 300 mg/day based on clinical response and tolerance. Ten patients were receiving dopaminergic agents at baseline. Serial efficacy ratings (Brief Psychiatric Rating Scale, Clinical Global Impressions Scale), neuromuscular symptom assessments (Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Unified Parkinson's Disease Rating Scale [UPDRS]), and adverse events monitoring were performed for up to 52 weeks. The patients had moderate hallucinations and/or delusions at baseline before the initiation of quetiapine. Nine of the 11 patients completed at least 12 weeks of treatment. Quetiapine was well tolerated in all but one patient, who became dizzy within the first week and withdrew from the study. Ten patients presented with moderate visual hallucinations. Quetiapine was markedly effective in controlling visual hallucinations in six of these patients. Symptoms of paranoia or delusions were less responsive to quetiapine. Four patients withdrew because of adverse events or comorbid medical problems, two withdrew because of a lack of efficacy, and five completed 52 weeks of treatment. The introduction of quetiapine did not exacerbate parkinsonian symptoms. Motor dysfunction, as measured by the UPDRS, revealed a slow, gradual worsening consistent with the progression of PD. Atypical antipsychotic medications such as quetiapine have a reduced likelihood of causing adverse drug-induced parkinsonism and therefore a possible role in treating psychotic symptoms in patients with PD.
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A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer's disease.
OBJECTIVE: To evaluate the safety and efficacy of controlled-release physostigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity. METHODS: A prospective, 24-week, randomized, multicenter, double-blind, parallel group study of patients was conducted. The study enrolled 475 patients at 24 sites. Patients met criteria for probable AD and were randomized to one of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage was escalated by a forced upward titration during the first 6 to 9 weeks of the trial, then maintained at a constant dose to 24 weeks. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change-Plus with caregiver input (CIBIC+). Secondary outcome measures included the Clinical Global Impression of Change (CGIC), the Geriatric Evaluation by Relatives Rating Instrument, and an Instrumental Activities of Daily Living Scale. RESULTS: In an intent-to-treat population, the last observation carried forward analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between physostigmine and placebo-treated patients for both dosages, and a 0.26 to 0.31-point difference on the CIBIC+ (p = 0.048). There were no significant differences on the secondary outcome measures except for a difference on the CGIC when analyzed by use of the Cochran-Mantel-Haenszel statistic (p = 0.014). There were significant increases in gastrointestinal side effects including nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain for patients on either dose of physostigmine, resulting in a high dropout rate. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities. CONCLUSION: CR physostigmine enhanced cognitive and global function. It is relatively safe for the treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible titration schedule might lead to a more favorable adverse event profile in the clinical arena.
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Psychoses in the elderly: a spectrum of disorders.
The incidence of psychoses increases with age with a number of factors leading to the increase in vulnerability and expression. They include comorbid physical illnesses, social isolation, sensory deficits, cognitive changes, polypharmacy, and substance abuse. Agitation and aggressiveness are also associated with psychosis in the elderly and frequently are the precipitating reasons for psychiatric consultation. A review of psychoses in the elderly must, therefore, consider psychotic symptoms within the context of the underlying etiologies of the psychotic symptoms. Elderly patients who present with psychotic symptoms require social, behavioral, and environmental interventions that are necessary for their safety and orientation. Given the likelihood of comorbid medical disorders and concomitant medications, the mere presence of delusions or hallucinations is not always an indication for additional medications. However, some patients may need pharmacologic intervention in order to manage the behavioral disturbance that often results from the psychotic symptoms. The atypical antipsychotics with their low propensity to produce extrapyramidal and cognitive side effects have greatly advanced the pharmacotherapy for elderly patients with psychoses.
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A double-blind, placebo-controlled trial of nefazodone in the treatment of patients hospitalized for major depression.
BACKGROUND: There are few published placebo-controlled clinical trials demonstrating the efficacy of the newer antidepressants in markedly or severely depressed hospitalized patients. This study demonstrates the efficacy of nefazodone compared with placebo in the treatment of patients hospitalized for major depression. METHOD: Nefazodone and placebo treatment were compared in a 6-week trial of 120 patients hospitalized for DSM-III-R diagnosed major depression (without psychosis) at 2 study centers. Efficacy was evaluated using standard psychiatric rating scales, and patients were monitored for safety. RESULTS: Nefazodone treatment resulted in a significant reduction (p < .01) of the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score compared with placebo from the end of the first treatment week through the end of the study (-12.2 nefazodone vs. -7.7 placebo). At the end of the trial, significantly more nefazodone-treated patients (50%) than placebo-treated patients (29%) had responded, as indicated by their Clinical Global Impressions-Improvement score (p = .021) or by a > or = 50% reduction in their HAM-D-17 scores (p = .017). Significantly more patients treated with nefazodone (36%) than placebo-treated patients (14%) had a HAM-D-17 score < or = 10 at the end of treatment (p = .004). Significant treatment differences (p < .01) in favor of nefazodone were also seen in the Montgomery-Asberg Depression Rating Scale; the HAM-D retardation, anxiety, and sleep disturbance factors; and HAM-D item 1 (depressed mood). Patients with dysthymia in addition to major depression also showed significant improvement (p < .05) when treated with nefazodone, with significant differences in response rates seen as early as week 2 and through the end of the trial. The mean nefazodone dose was 491 mg/day at the end of week 2 and 503 mg/day at the end of treatment. Nefazodone was well tolerated, and the number of patients discontinuing owing to adverse events was small, with no significant safety issues noted in either treatment group. Fewer nefazodone-treated than placebo-treated patients discontinued owing to lack of efficacy. CONCLUSION: Nefazodone was superior to placebo in the treatment of marked to severe major depression in patients requiring hospitalization. The clinical benefit of nefazodone was evident as early as the first week of treatment as judged by several measures of efficacy, with significant differences from placebo sustained throughout the trial.
Adult↗
A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia.
Sertindole is a novel antipsychotic agent with high selectivity for the mesolimbic dopaminergic pathway and nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine NE alpha 1 receptors. This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n = 205). Sertindole doses began at 4 mg/day and were increased to 8, 12, or 20 mg/day, depending on randomization. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Extrapyramidal symptoms (EPS) were assessed by movement rating scales, EPS-related adverse events, and use of anti-EPS medications. A dose-related improvement was observed for PANSS, BPRS, and CGI, with statistically significant mean differences (P < 0.05) between placebo and 20-mg/day sertindole (decreases from baseline of -5.8 versus -16.9 for PANSS, -4.8 versus -10.4 for BPRS, respectively). The differences in CGI final improvement score between placebo and 20-mg/day sertindole were 3.8 versus 2.9, respectively. EPS-related events were comparable in the placebo and sertindole groups. In conclusion, sertindole 20 mg/day was effective, well tolerated, and not associated with significant motor system abnormalities.
Adult↗
Variability of TRH test responses in depressed and normal elderly subjects.
Thyrotropin releasing hormone (TRH) tests were conducted in 33 elderly patients with Major Depressive Disorder and 99 normal elderly volunteers. A wide range of thyrotropin-stimulating hormone (TSH) responses to TRH injection was revealed. A gender effect was found such that men had significantly diminished TSH responses to TRH relative to women (p = 0.008). However, there were no significant differences noted between depressed patients and normal elderly subjects of either gender. It appears that the wide range of TSH responses to TRH found in normal elderly men and women blurs any measurable differentiation between depressed patients and normal subjects and thereby limits the usefulness of the TRH test in the study of depressive disorder in elderly patients.
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Cortisol response during different anxiogenic challenges in panic disorder patients.
The present study assessed the relation of cortisol response to anxiogenic reactivity during intravenous lactate infusion and oral fenfluramine in 12 panic disorder (PD) patients who responded positively to both challenges and in eight non-reactive control subjects. There was no significant cortisol response difference between the PD patients and the controls during lactate infusion, but there was s significant difference at 120 min during the fenfluramine challenge. These findings are consistent with the possibility that these challenges stimulate different neurobiologic mechanisms and that fenfluramine-precipitated anxiety is more akin to anticipatory or generalized anxiety than to true panic anxiety.
Administration, Oral↗
Panic attack frequency and vulnerability to anxiogenic challenge studies.
Intravenous lactate infusion and 60 mg oral fenfluramine challenges were administered to 26 patients with panic disorder (PD) and 12 age- and sex-matched control subjects. PD patients had significantly greater anxiety responses to either challenge than controls. When a panic attack frequency index scale of 1-4 was used, PD patients with more recent and more frequent spontaneous panic attacks scored higher on either challenge. There was a significant correlation between increasing panic attack frequency and greater anxiogenic responses to lactate and fenfluramine. Nine of 12 patients (75%) with high attack frequency (defined as having one or more panic attacks per week) reacted positively to both challenges in contrast to 0 of 14 PD patients with low frequency (less than or equal to 1 attack/month). The findings suggest that the current heightened anticipatory state of the patient (influenced by recent spontaneous panic attacks) rather than putative underlying trait factors predominates in the evocation of experimentally induced anxiety reactions. Future studies must consider the frequency of recent spontaneous panic attacks in the evaluation of anxiogenic reactivity to provocative stimuli.
Administration, Oral↗
Differential responses to anxiogenic challenge studies in patients with major depressive disorder and panic disorder.
Anxiogenic challenge studies (intravenous lactate infusion and oral fenfluramine challenge) were conducted in 17 patients with panic disorder (PD), 12 patients with major depressive disorder and a history of panic attacks (MDD-PD), 27 patients with major depression and no history of panic (MDD), and 12 normal controls. PD and MDD-PD patients revealed significantly greater anxiogenic responses to lactate infusion and fenfluramine administration than either MDD patients or controls. PD patients revealed the most robust anxiogenic responses to both challenges as well as associated significant prolactin and cortisol responses to fenfluramine. The findings suggest that the predisposition to panic attacks as seen in PD and MDD-PD patients may represent a distinct neurobiological diathesis which may coexist with a major depressive diathesis in some patients. The delineation of subgroups within the more heterogenous groups of patients with MDD and/or PD will lead to greater precision in the development of clinical treatment strategies. Thus, MDD-PD patients (better called panic-depressives) may have a more severe illness than patients with MDD alone which must be accounted for in the course of pharmacotherapy and psychotherapy.
Administration, Oral↗
Measurement of cortisol and lymphocyte subpopulations in depressed and conduct-disordered adolescents.
Lymphocyte subpopulations were analyzed in 11 adolescents with major depressive disorder, 11 with conduct disorder, and eight normal age-matched subjects. No significant differences were noted on any T or B cell measure between the groups. Further, no significant correlations were found between any cortisol measure (baseline cortisol, post-dexamethasone cortisol, urinary free cortisol) and any lymphocyte measure in either depressed or conduct-disordered adolescents. The negative findings in this small sample contrast with those reported in adult patients and suggest that an aging effect may be associated with the immunological changes reported in older depressed patients.
Adolescent↗
Prevalence of seasonal affective disorder at four latitudes.
The Seasonal Pattern Assessment Questionnaire (SPAQ) was mailed to a sample population balanced for sex and randomly selected from local telephone directories in four areas: Nashua, NH, New York, NY, Montgomery County, MD, and Sarasota, FL. On the basis of responses to this questionnaire, prevalence rates of winter seasonal affective disorder (winter SAD), summer seasonal affective disorder (summer SAD), and subsyndromal winter SAD were estimated for the four areas. Rates of winter SAD and subsyndromal SAD were found to be significantly higher at the more northern latitudes, while no correlation was found between latitude and summer SAD. The positive correlation between latitude and prevalence of winter SAD applied predominantly to the age groups over 35.
Adult↗
Mechanisms of anxiogenic vulnerability in panic disorder.
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Anxiety Disorders↗
Lymphocyte subpopulations in depressed elderly women.
Dexamethasone Suppression Tests (DST) and measurement of lymphocyte subpopulations were conducted in 21 medically healthy elderly women with major depressive disorder and 77 healthy elderly women volunteers. Depressed women revealed significantly reduced absolute lymphocytes (p less than 0.01), T cells (p less than 0.01), and T helper cells (p less than 0.02) compared to normal elderly women. Of the depressed women, 50% had positive DSTs (postdexamethasone cortisols greater than 5 micrograms/dl) compared to 5.4% of the normal women (p less than 0.0001). Within the depressed group, patients with positive DSTs had significantly reduced absolute lymphocytes (p less than 0.05) and T helper cells (p less than 0.025) compared with depressed women who had normal DSTs. Further, a significant negative correlation was found between postdexamethasone cortisols (at both 4:00 and 11:00 PM) and absolute lymphocyte count and T helper cells. These data suggest that the hypercortisolemia seen in some patients with major depressive disorder is sufficient to alter leukocyte distribution in the peripheral circulation, particularly that of the T helper cell subset. The association between cortisol and lymphopenia appears to be more pronounced in an elderly population than in younger depressed patients.
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Fenfluramine provocation of anxiety in patients with panic disorder.
Fenfluramine, and indirect serotonergic agonist, was administered to nine women with panic disorder, nine women with major depressive disorder, and nine women controls. Panic disorder patients revealed significantly greater anxiogenic responses to fenfluramine administration at all 5 hourly measurement points than either depressed patients or control subjects. Prolactin and cortisol responses to fenfluramine were also significantly greater in panic disorder patients than in either depressed patients or control subjects. Placebo administration did not elicit robust or significantly different anxiety or hormonal responses in panic disorder patients or control subjects. These data offer evidence that serotonergic hyperresponsivity must be considered as an important factor in the mechanism of events provoking overt panic attacks.
Adult↗
TRH tests in a healthy elderly population. Demonstration of gender differences.
Thyrotropin releasing hormone (TRH) tests were conducted in 99 healthy elderly men and women between the ages of 65 and 89. The TRH test identified elderly patients with subclinical thyroid dysfunction not recognized by basal TSH values alone. Men revealed significantly diminished TSH responses to TRH injection relative to women. Mean delta max TSH was 9.0 +/- 8.3 microIU/mL in men vs 15.7 +/- 14.8 microIU/mL in women (P less than .01) reflecting the need to consider gender effect in the interpretation of TRH test responses.
Age Factors↗
CSF somatostatin in Alzheimer's disease, depressed patients, and control subjects.
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Aged↗
Cognitive functioning in biological subtypes of depression.
This study describes a method for investigating clinical correlates of biological subtypes of depression, using cognitive functioning as the principal behavioral variable. Dexamethasone Suppression Test (DST) escapers were compared to DST suppressors and healthy controls on a battery of learning and memory procedures designed to investigate cognitive functioning in detail. DST suppressors, but not escapers, were cognitively impaired on our tasks. The performance of controls and DST escapers was related to depth of semantic processing, whereas performance of DST suppressors varied inversely with degree of felt hopelessness. Examination of cognitive functioning in future studies may provide useful insights into the clinical significance of biological markers of depression.
Adult↗