Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Quality of life in treated and never-treated schizophrenic patients.

OBJECTIVE: To evaluate quality of life (QOL) among treated and never-treated schizophrenic patients. METHOD: QOL ratings were obtained for (a) 112 Moroccan participants with schizophrenia who had never received neuroleptic medications, (b) matched samples of chronically-medicated schizophrenic patients in Morocco and the United States and (c) matched community controls in both countries. RESULTS: QOL ratings were generally higher for US groups, although Moroccan controls obtained higher ratings than US controls for some domains. QOL ratings were higher for controls compared to patients within each country, although US patients' scores were similar to controls on some dimensions. We found no differences between treated and untreated Moroccan patients for any QOL domain, although relationships among predictors were different. CONCLUSION: Within the context of Moroccan culture, benefits of medications alone are not evident in QOL scores. QOL appears to be a complex construct influenced by different factors within each of the groups studied.

Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist.

Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.

Correlates of suffering in amyotrophic lateral sclerosis.

OBJECTIVES: 1) To determine the prevalence of pain, suffering, poor quality of life, depression, and hopelessness in people with ALS, and the correlates of suffering and poor quality of life; 2) to analyze the relationship between pain, suffering, quality of life, and attitudes toward life-sustaining medical treatment and physician-assisted suicide; and 3) to determine concordance between patients with ALS and their caregivers in rating the patients' pain, quality of life, and suffering. METHODS: Subjects completed a single interview. We measured the subject's pain, quality of life, suffering, hopelessness, depression, social support, perception of burden to others, level of disability, desire for life-sustaining medical treatment, and interest in assisted suicide. Caregivers also rated the patient's quality of life, pain, and suffering. RESULTS: A total of 100 subjects with ALS and 91 caregivers participated. Suffering was rated as 4 or greater on a six-point scale by 20% of subjects with ALS, and 19% rated their pain as 4 or greater on a six-point scale. Eleven percent had clinical depression. Physicians frequently failed to recognize and treat pain and depression. The correlates of suffering were increasing pain, hopelessness, and level of disability. The correlates of poor quality of life were poor social support and increasing hopelessness. The correlation between subjects' and caregivers' rating of the patient's suffering was r = 0.47. There was no relationship between subjects' ratings of pain, suffering, and quality of life, and their interest in life-sustaining treatment or physician-assisted suicide. CONCLUSION: Many patients with ALS suffer, and their suffering is correlated to pain and hopelessness. Physicians caring for patients with ALS frequently fail to recognize and treat their patients' pain and depression.

Nonpeptide glycoprotein IIB/IIIA inhibitors. 19. A new design paradigm employing linearly minimized, centrally constrained, exosite inhibitors.

A new series of potent, linearly-minimized, orally active, selective GPIIb/IIIa inhibitors is identified. Thus 15 (L-750,034) achieves interaction via a constrained, non-turned conformation that maintains the proper distance between its charged termini and full sulfonamide exosite interaction. The diminutive stature and the proposed linear conformation of L-750,034 define a new paradigm for the conceptualization of RGD mimics.

Neuroleptic intolerance.

This article reviews antipsychotic medication side effects, especially those that require the physician to discontinue or the patient to be noncompliant with otherwise useful medication. They include such common problems as extrapyramidal syndromes (dystonia, akathisia, drug-induced Parkinsonism, tardive dyskinesia), sedation, weight gain, and sexual dysfunction, as well as less frequent concerns, such as seizures, neuroleptic malignant syndrome, agranulocytosis, torsade de pointes, hepatitis, and dermatological and ophthalmological syndrome. The adverse events associated with some of the new antipsychotic drugs are included. Available information about individual susceptibility to side effects is addressed by syndrome.

Movements in never-medicated schizophrenics: a preliminary study.

Descriptions of schizophrenia dating to the beginning of this century include mention of abnormal movements which are similar to tardive dyskinesia (TD), currently thought to be sequelae of neuroleptic medication. In order to examine the extent to which such movements might appear in the normal course of schizophrenia, we examined a sample of 22 never-medicated DSM-III-R schizophrenics who presented for treatment at a psychiatric center in Casablanca, Morocco. Duration of illness in this sample ranged from 1 to 10 years. Patients were assessed for choreoathetoid movements using the Abnormal Involuntary Movement Scale (AIMS). Videotaped and live examinations were rated by the investigators. Three patients (14%) met research diagnostic criteria for probable SD. Mild movements in one body part (AIMS = 2) were seen in an additional five (23%) patients. The movements were characteristic of TD, although their somatic distribution differed from previous studies. Total AIMS score increased with age and duration of illness (r = 0.64, P < 0.01). These findings suggest that choreoathetoid movements may appear spontaneously in patients with schizophrenia.

Characteristics of male and female veterans who use VA psychiatric emergency services.

Retrospective chart review was used to compare the demographic characteristics and psychiatric diagnoses of 150 consecutive female patients seen in psychiatric consultation in the emergency service at a Veterans Affairs medical center between 1987 and 1991 with those of two groups of 150 male patients matched by age or psychiatric diagnosis. Compared with the men, the women were younger and more likely to be divorced, to complain of anxiety or psychotic symptoms, and to have a diagnosis of a depressive disorder or borderline personality disorder. Men were more likely to have a diagnosis of schizophrenia or antisocial personality disorder.

The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders.

BACKGROUND: Metoclopramide hydrochloride, a neuroleptic dopamine receptor antagonist used to treat gastric ailments, is reported to cause extrapyramidal movement disorders. The goals of this study were (1) to determine the prevalence and severity of tardive dyskinesia and acute extrapyramidal movement syndromes including akathisia, acute dystonia, and drug-induced parkinsonism in metoclopramide-treated patients and (2) to compare the prevalence and severity of tardive dyskinesia in metoclopramide-treated diabetics and nondiabetics. METHODS: From a list of metoclopramide-treated patients received from the Portland (Ore) Veterans Affairs Medical Center pharmacy, 53 patients met inclusion criteria and 51 (96%) agreed to participate. Controls consisted of a convenience sample drawn from the Portland Veterans Affairs Medical Center Outpatient Clinic who were matched to subjects on age (+/- 10 years), gender, and presence or absence of diabetes. Of 61 potential controls contacted, 51 (84%) agreed to participate. Metoclopramide-treated subjects and controls were seen by a rater who was "blind" to all diagnoses and treatments. The rater performed a standardized examination used to elicit signs and symptoms of tardive dyskinesia and acute extrapyramidal movement syndromes. RESULTS: The relative risk for tardive dyskinesia was 1.67 (95% confidence interval, 0.93 to 2.97), and the relative risk for drug-induced parkinsonism was 4.0 (95% confidence interval, 1.5 to 10.5). Metoclopramide-treated patients had significantly greater severity of tardive dyskinesia, drug-induced parkinsonism, and subjective akathisia than controls. Use of metoclopramide was associated with impairment in ambulation and increased use of benzodiazepines. Metoclopramide-treated diabetics had significantly greater severity of tardive dyskinesia than metoclopramide-treated nondiabetics. CONCLUSIONS: Metoclopramide use is associated with a significantly increased prevalence and severity of several extrapyramidal movement disorders.

Tardive dyskinesia and diabetes mellitus.

Two studies examine the prevalence of tardive dyskinesia (TD) in neuroleptic-treated diabetic patients. Study 1 compared 38 diabetic patients with 38 nondiabetic patients treated for psychotic disorders with low to moderate doses of neuroleptics (mean chlorpromazine equivalents = 300 mg/day) for an average of 18 years. Study 2 compared 24 diabetic and 27 nondiabetic patients treated for an average of 2.6 years with a mean 31 mg/day of metoclopramide for gastrointestinal disease. Patients were examined for TD using standardized scales by raters blind to all treatment and illness variables. In both studies, there were no differences between the diabetic and nondiabetic groups in age, sex, type of psychiatric illness, and dose and duration of neuroleptic treatment or severity of parkinsonism. In both studies, the diabetic patients had significantly greater prevalence and severity of TD. No measures of diabetes severity were associated with TD in either study. Possible pathophysiologic mechanisms for the increased prevalence of TD in neuroleptic-treated patients with diabetes will be discussed.

A longitudinal study of correlations among tardive dyskinesia, drug-induced parkinsonism, and psychosis.

Tardive dyskinesia (TD) and drug-induced parkinsonism (DIP) have been hypothesized to reflect opposing states of dopamine (DA) function. In this longitudinal study, 57 psychotic inpatients were rated repeatedly for TD, DIP, and psychosis while receiving neuroleptic medication. Cross-sectional correlations among TD, DIP, and psychosis were weak or nonexistent. Factor and cluster analyses found that 13 patients (23%) were classified into groups characterized by the expected negative correlations. Thus, only partial support was found for the hypothesis that TD and DIP represent opposing states of DA function.

Three-year follow-up of older schizophrenics: extrapyramidal syndromes, psychiatric symptoms, and ventricular brain ratio.

Longitudinal evaluation of psychiatric patients often yields information that cross-sectional study does not. We previously examined 31 older (age greater than 55) chronic schizophrenics for prevalence of extrapyramidal side effects, severity of psychiatric symptoms, and ventricular brain ratio (VBR). We reexamined 22 of these patients after 2-4 years. Tardive dyskinesia (TD) and drug-induced parkinsonism (DIP) were common (mean prevalences were 52% and 62%, respectively) and often occurred together (38%). The overall prevalences of the disorders did not change significantly with time, although there was some individual fluctuation in diagnosis. Severity of TD was constant, but severity of DIP decreased, probably because neuroleptic doses were significantly decreased. Magnitude of DIP was positively correlated with VBR and severity of negative symptoms of schizophrenia. The correlation of DIP and negative symptoms occurred primarily because of the similarity between masked facies and blunted affect. VBR did not change over the follow-up period. Negative symptoms of schizophrenia were prevalent, moderately severe, and quite stable over time in this cohort. Positive symptoms were less severe but highly variable between examinations.

Acute extrapyramidal syndromes in neuroleptic-treated elders: a pilot study.

The incidence, morbidity, and risk factors for acute extrapyramidal syndromes (EPS) such as akathisia and drug-induced parkinsonism (DIP) in neuroleptic-treated elders have not been systematically explored. This study presents data on 17 elderly patients who were prospectively examined for up to 4 weeks for acute EPS, functional and cognitive status, and behavioral disturbances. Seventy-one percent of subjects developed DIP, and 18% developed akathisia. Predictors of DIP included pre-neuroleptic treatment parkinsonian signs and neuroleptic dose, despite use of low doses of neuroleptics. Development of acute EPS was associated with failure to improve behaviorally. New-onset urinary incontinence was the most common functional abnormality.

Computed tomographic evaluation of patients with tardive dyskinesia.

X ray computed tomography has been used since its introduction to evaluate patients with tardive dyskinesia (TD). A critical review of the 18 reports which have appeared since 1976 suggests that TD may be associated with neuroanatomical abnormalities. In particular, a meta-analysis of the reports of ventricular brain ratio found a trend for patients with TD to have larger lateral ventricles than unaffected patients. The magnitude of the difference appears to be small, however, and several well conducted studies have reported negative results. A careful analysis revealed that low statistical power, concurrent neuroleptic treatment, insensitive measures of ventricular dilatation, and variable diagnostic criteria for TD may have led to negative findings in most of the investigations. The possible significance of these results and suggestions for further research are discussed.

The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study.

In a controlled study, we compared the prevalence of tardive dyskinesia in 38 neuroleptic-treated diabetics with the prevalence of tardive dyskinesia in a group of 38 nondiabetic neuroleptic-treated controls, matched for age, sex, psychiatric diagnosis, and dose and duration of neuroleptic treatment. Members of each group were evaluated for movement disorders by a rater who used standard rating scales and was "blind" to all diagnoses and treatments. Neuroleptic-treated diabetics had a significantly higher prevalence and severity of tardive dyskinesia. There were no differences between groups on other possible risk factors for tardive dyskinesia, including parkinsonism, anticholinergic drug treatment, or cognitive function. These data suggest that diabetes mellitus should be examined further as a risk factor for tardive dyskinesia.

Biotransformation of lovastatin. I. Structure elucidation of in vitro and in vivo metabolites in the rat and mouse.

Structures of in vitro microsomal and in vivo metabolites of lovastatin, a new cholesterol-lowering drug, were elucidated with the combined application of HPLC, UV, fast atom bombardment-MS, and NMR spectroscopy. Liver microsomes from rats and mice catalyzed the biotransformation of lovastatin, primarily at the 6'-position of the molecule, to form 6'-hydroxy-lovastatin and a novel 6'-exomethylene derivative. Hydroxylation at the 6'-position occurred stereoselectively, giving 6'-beta-hydroxy-lovastatin. Stereoselective hydroxylation at the 3"-position of the methylbutyryl side chain and hydrolysis of the lactone group to the corresponding hydroxy acid were the other two pathways of microsomal metabolism. 3'-Hydroxy-iso-delta 4',5'-lovastatin was isolated, but is not believed to be a direct metabolite since 6'-beta-hydroxy-lovastatin rearranges to this compound under mildly acidic conditions. The major metabolites excreted in bile of rats treated with the hydroxy acid form of the drug were identified as the 3'-hydroxy analog and a taurine conjugate of a beta-oxidation product of lovastatin. The pentanoic acid derivative of lovastatin, formed by beta-oxidation of the heptanoic acid moiety, was a major metabolite in livers of mice dosed with the hydroxy acid form of lovastatin. The microsomal metabolites, in their hydroxy acid forms, were active inhibitors of HMG-CoA reductase. The relative enzyme inhibitory activities of hydroxy acid forms of lovastatin, 6'-beta-hydroxy-, 6'-exomethylene-, and 3"-hydroxy-lovastatin were 1, 0.6, 0.5, and 0.15, respectively.

The coexistence of physical and mental illness among two samples of Oregon's chronically mentally ill.

Physical or medical illness among chronically mentally ill patients is common. Treatment programs must make provisions for the many implications of this fact.

Neuroleptic-induced parkinsonism in older schizophrenics.

The association of neuroleptic drug-induced parkinsonism (DIP) with factors related to brain structure and function are poorly understood. Twenty-one medicated schizophrenics over age 55 years were evaluated for parkinsonism, tardive dyskinesia, psychiatric symptoms, ventricular/brain ratio (VBR), and neuropsychological function. Sixteen (76%) of the patients had DIP, whereas 10 (48%) had tardive dyskinesia. Increased severity of parkinsonism was significantly associated with larger VBR and the severity of negative symptoms. Severity of parkinsonism predicted poor visual-spatial function, whereas negative symptoms were modestly predictive of impairment in both verbal ability and cognitive flexibility. These findings suggest that brain atrophy may be a risk factor for DIP. The pattern of cognitive dysfunction associated with DIP in this sample is similar to that found in idiopathic Parkinson's disease. Dopaminergic dysfunction may underlie the pattern of pathology described in this report.