Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients.

BACKGROUND: Neuroleptic-induced tardive dyskinesia (TD) is a major iatrogenic disorder that is more prevalent among older patients. The objective of this study was to determine the incidence of and risk factors for TD in neuroleptic-treated patients over age 45 years. METHODS: We studied 266 middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry. Most patients were treated throughout the study with either a high-potency or a low-potency neuroleptic and maintained on relatively low doses. The patients were followed up at 1- to 3-month intervals with "blind" assessment of psychopathologic condition, clinically as well as instrumentally (ie, using electromechanical sensors with computerized data reduction, including spectral analysis) evaluated movement disorder, and global cognitive function. RESULTS: Cumulative incidence of TD was 26%, 52%, and 60% after 1, 2, and 3 years, respectively. The principal risk factors for TD were duration of prior neuroleptic use at baseline, cumulative amount of high-potency neuroleptics, history of alcohol abuse/dependence, borderline or minimal dyskinesia, and tremor on instrumental assessment. CONCLUSION: Use of higher amounts of neuroleptics, particularly high-potency ones, should be avoided in older patients, patients with alcohol abuse/dependence, or patients with a subtle movement disorder at baseline; these patients are at a higher risk of developing TD.

Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia.

BACKGROUND: We sought to determine whether neuropsychological impairment in schizophrenia is related to current age, age at onset, or duration of illness, and whether the pattern of such impairment can be distinguished from that caused by progressive dementias of Alzheimer's type. We administered a comprehensive neuropsychological test battery to a normal control group (n = 38), a group of ambulatory patients with Alzheimer's disease (n = 42), and three ambulatory schizophrenic groups: early onset-young (n = 85), early onset-old (n = 35), and late onset (n = 22). Tests were grouped and analyzed according to eight major ability areas, and published procedures were used to remove the expected effects of normal aging. RESULTS: The three schizophrenic groups were found to be neuropsychologically similar to one another and different from normal controls and patients with Alzheimer's disease. There were no significant differences among the schizophrenic groups in level or pattern of neuropsychological functioning. Patients with Alzheimer's disease demonstrated less efficient learning and particularly more rapid forgetting than did the other groups. CONCLUSIONS: These findings suggest that neuropsychological impairment in schizophrenia is unrelated to current age, age at onset, or duration of illness. The study further suggests that the encephalopathy associated with schizophrenia is essentially nonprogressive and produces a pattern of deficits that is different from that seen in progressive cortical dementias.

Effects of transdermal clonidine treatment on withdrawal symptoms associated with smoking cessation. A randomized, controlled trial.

In a double-blind, randomized, placebo-controlled trial, we studied 40 cigarette smokers to determine the effects of one week of transdermal clonidine hydrochloride (Catapres-TTS No. 2) treatment on the withdrawal symptoms associated with smoking cessation. Subjects were instructed to maintain their usual cigarette intake during days 1 through 3 and cease smoking for days 4 through 6. All of the withdrawal symptoms measured (craving, irritability, anxiety, restlessness, difficulty concentrating, and hunger) significantly increased during the three days of smoking cessation in the placebo group. There was a 4.3-fold increase in craving, a 3.8-fold increase in irritability, a 3.7-fold increase in anxiety, and a 3.3-fold increase in restlessness in the placebo group compared with the transdermal clonidine group during the three days of smoking cessation. Impairment of concentration and hunger were not significantly diminished by transdermal clonidine treatment during smoking cessation. In addition, a trend was present in the transdermal clonidine group to spontaneously decrease the number of cigarettes smoked per day during the smoking period. Side effects were generally mild. We conclude that transdermal clonidine treatment ameliorates some of the short-term withdrawal symptoms, especially craving, associated with smoking cessation.

Clinical and neuropsychological characteristics of patients with late-onset schizophrenia.

OBJECTIVE: The goal was to compare clinical and neuropsychological characteristics of patients with late-onset schizophrenia, a poorly studied and controversial entity, with those of patients with early-onset schizophrenia and normal subjects. METHOD: The authors evaluated 25 patients who met DSM-III-R criteria as well as their own research criteria for late-onset schizophrenia (i.e., schizophrenia with onset after age 45) and compared them with 39 patients with early-onset schizophrenia and 35 normal subjects in this nonepidemiologic study. RESULTS: Patients with late-onset schizophrenia were similar to patients with early-onset schizophrenia and different from normal subjects on most clinical and neuropsychological variables assessed, such as psychopathology, family history, childhood social adjustment, and overall pattern of neuropsychological impairment. Compared with the early-onset group, the group with late-onset schizophrenia had a higher percentage of patients who were ever married, a better work history, and a greater frequency of paranoid subtype. CONCLUSIONS: These results support the diagnostic validity of schizophrenia with onset after the age of 45 years.

Cross-sectional study of older outpatients with schizophrenia and healthy comparison subjects: no differences in age-related cognitive decline.

OBJECTIVE: Little is known about the progression of cognitive deficits in older, community-dwelling patients with schizophrenia, especially in comparison to healthy subjects. METHOD: The authors examined the relationship of age to performance on the Mattis Dementia Rating Scale in 116 outpatients with schizophrenia and 122 normal comparison subjects. Subjects ranged in age from 40 to 85 years. RESULTS: Dementia Rating Scale scores were lower in the schizophrenia group but correlated negatively with age in both groups, with no significant differences seen between the schizophrenia and normal comparison groups in slopes that depicted age-related variation. CONCLUSIONS: This cross-sectional study suggests a relatively stable long-term course of cognitive impairment in individuals with schizophrenia, with no evidence of faster cognitive decline in outpatients with schizophrenia than in normal comparison subjects.

Depressive symptoms in schizophrenia.

OBJECTIVE: The authors assessed the presence and severity of depressive symptoms, as well as their associations with other clinical measures, in a group of mid- to late-life patients with schizophrenia who were not in a major depressive episode or diagnosed with schizoaffective disorder. METHOD: Sixty outpatients with schizophrenia between the ages of 45 and 79 years and 60 normal comparison subjects without major neuropsychiatric disorders, proportionally matched for age and gender, were studied. Depressive symptoms were rated primarily with the Hamilton Depression Rating Scale. Standardized instruments were also used to measure global psychopathology, positive and negative symptoms, abnormalities of movement, and global cognitive status. RESULTS: Depressive symptoms were more frequent and more severe in schizophrenic patients than in normal comparison subjects; 20% of the women with schizophrenia had a Hamilton depression scale score of 17 or more. Severity of depressive symptoms correlated with that of positive symptoms but not with age, gender, negative symptoms, extrapyramidal symptoms, or neuroleptic dose. CONCLUSIONS: Depressive symptoms are common in older patients with schizophrenia. They may be an independent, core component of the disorder or, alternatively, may be a by-product of severe psychotic symptoms.

Neuroleptic treatment of HIV-associated psychosis. HNRC group.

The aim of this rater-blinded randomized study was to evaluate the efficacy and side effects of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-positive individuals. Participants were 13 men who had no history of psychosis prior to infection with HIV, and whose psychosis was not attributable to delirium or to non-HIV-related organic factors. Participants were evaluated at baseline after at least one month without neuroleptic treatment and then weekly for six weeks of the experimental treatment using several rating scales. The mean daily dose in chlorpromazine equivalents was 124 mg. Both neuroleptics produced modest but significant reduction in overall level of psychosis and in positive symptoms, but not in negative symptoms. All the haloperidol-treated patients developed extrapyramidal side effects and required treatment with anticholinergic medication, whereas three of the five thioridazine-treated patients had noticeable side effects. We make recommendations for the treatment of HIV-associated psychosis with neuroleptics.

Gender-related clinical differences in older patients with schizophrenia.

BACKGROUND: Gender differences in the clinical presentation of young patients with schizophrenia have been well-documented, yet few studies have investigated gender-related clinical differences in older patients. Furthermore, the symptoms of late-onset schizophrenia have been described, but the interaction between gender and age at onset has not been examined. METHOD: In an older (46-85 years of age) outpatient sample, we assessed clinical characteristics of women and men with early-onset schizophrenia (N = 90) and late-onset schizophrenia (N = 34). Subjects did not differ with respect to age, education, ethnicity, severity of depression, daily neuroleptic dosage, subtype of schizophrenia, total score on the Mini-Mental State Examination, or severity of overall psychopathology. Diagnosis was made using the Structured Clinical Interview for the DSM-III-R or DSM-IV. RESULTS: A significantly greater proportion of women had late-onset schizophrenia (41% vs. 20%), and women overall had more severe positive psychotic symptoms. Although there was no overall gender difference in severity of negative psychotic symptoms, women with late onset had significantly less severe negative symptoms than men with early onset, men with late onset, and women with early onset. Furthermore, age at onset of schizophrenia was inversely correlated with severity of negative symptoms for women, but not for men. These results indicate that women overall may develop more severe positive symptoms than men, and that when women develop schizophrenia after age 45, they may suffer less severe negative symptoms than men or than women with earlier onset. Our results suggest that some of the clinical differences between late-onset and early-onset schizophrenia may relate to gender effects, and that there may be inherent differences in the clinical presentation of schizophrenia that are related to gender and gender by age at onset interactions. CONCLUSION: These differences may reflect the influence of sex hormones and menopause on the clinical presentation of schizophrenia or the possible existence of an "estrogen-related" form of schizophrenia in women with late-onset schizophrenia.

Schizoaffective disorder: a form of schizophrenia or affective disorder?

BACKGROUND: The diagnostic status of schizoaffective disorder continues to be controversial. Researchers have proposed that schizoaffective disorder represents a variant of schizophrenia or affective disorder, a combination of the 2, or an intermediate condition along a continuum between schizophrenia and affective disorder. METHOD: We compared outpatients aged 45 to 77 years with DSM-III-R diagnosis of schizoaffective disorder (N = 29), schizophrenia (N = 154), or nonpsychotic mood disorder (N = 27) on standardized rating scales of psychopathology and a comprehensive neuropsychological test battery. A discriminant function analysis was used to classify the schizoaffective patients based on their neuropsychological profiles as being similar either to schizophrenia patients or to those with nonpsychotic mood disorder. RESULTS: The schizoaffective and schizophrenia patients had more severe dyskinesia, had a weaker family history of mood disorder, had been hospitalized for psychiatric reasons more frequently, were more likely to be prescribed neuroleptic and anticholinergic medication, and had somewhat less severe depressive symptoms than the mood disorder patients. The schizophrenia patients had more severe positive symptoms than the schizoaffective and mood disorder patients. The neuropsychological performances of the 2 psychosis groups were more impaired than those of the nonpsychotic mood disorder patients. Finally, on the basis of a discriminant function analysis, the schizoaffective patients were more likely to be classified as having schizophrenia than a mood disorder. CONCLUSION: These findings suggest that schizoaffective disorder may represent a variant of schizophrenia in clinical symptom profiles and cognitive impairment.

Cognition and the corpus callosum: verbal fluency, visuospatial ability, and language lateralization related to midsagittal surface areas of callosal subregions.

Normal volunteers (28 women), 20-45 years old, completed tests of visuospatial ability, verbal fluency, and language lateralization, and the midsagittal surface areas of the splenium, isthmus, midregion, and genu of the corpus callosum were measured from inversion recovery magnetic resonance images. Multivariate statistics were used to analyze patterns of correlations. Verbal fluency correlated positively with the area of the splenium and with the area of a posterior callosal factor defined largely by the splenium. The posterior callosum, particularly the splenium, also correlated negatively with language lateralization. There were no other consistent brain-behavior relationships. These results are relevant to understanding factors involved in the development of cognitive characteristics that show sex differences and to understanding the neural basis of language lateralization and verbal abilities.

Risk factors for orofacial and limbtruncal tardive dyskinesia in older patients: a prospective longitudinal study.

Although there is a consensus that orofacial and limbtruncal subtypes of tardive dyskinesia (TD) exist and may represent distinct pathophysiologic entities, few studies have examined the incidence of and risk factors associated with the development of these TD subtypes. Two hundred and sixty-six middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry were evaluated at 1- to 3-month intervals. Using "mild" dyskinesia in any part of the body for diagnosis of TD, the cumulative incidence of orofacial TD was 38.5 and 65.7% after 1 and 2 years, respectively, whereas that of limbtruncal TD was 18.6 and 32.6% after 1 and 2 years. Preclinical dyskinesia was predictive of both orofacial and limbtruncal TD. History of alcohol abuse or dependence was a significant predictor of orofacial TD only whereas tremor was a significant predictor of limbtruncal TD only. Findings support suggestions that orofacial and limbtruncal TD may represent specific subsyndromes with different risk factors.

Validity of specific subscales of the positive and negative symptom scales in older schizophrenia outpatients.

We investigated the construct validity of subscales of the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) along with other measures of psychopathology in 109 schizophrenia outpatients aged 45-84 years. Scores on subscales of the SAPS, SANS and Brief Psychiatric Rating Scale (BPRS) and on the Hamilton Depression Scale (HAM-D) were subjected to a principal components analysis and orthogonal rotation followed by an extension analysis. In both analyses, three of four SAPS subscales had their highest loading on the positive symptom factor and four of five SANS subscales had their highest factor loading on the negative symptom factor. The SAPS bizarre behavior subscale, however, had a much higher loading on the depressive symptom factor than on the positive symptom factor, and the SANS avolition-apathy subscale had moderate loadings on both the negative symptom factor and the depressive symptom factor. The use of SAPS and SANS subscales to represent two constructs was largely (but not entirely) validated among middle-aged and elderly schizophrenia outpatients. The SAPS bizarre behavior subscale and, to a lesser extent, the SANS avolition-apathy subscale appear to represent in this older population a separate construct which may be related to depressive symptoms.

Human growth hormone releasing factor infusion effects on plasma growth hormone in affective disorder patients and normal controls.

In a preliminary, prospective pilot study, five patients with major depressive disorder and eleven age and sex matched normal controls received intravenous human growth hormone releasing factor (hGRF) (1 microgram/kg in 5 cc of normal saline infused over five minutes) and placebo. Thirty minutes after insertion of the catheter, blood was sampled every 15 minutes for thirty minutes prior to and for 2 hours subsequent to intravenous infusion of hGRF or placebo. hGRF but not placebo caused significant elevations of plasma growth hormone levels in all subjects. Of interest, the depressed patients had a significantly attenuated rise in plasma growth hormone concentrations when compared with the normal controls. These results must be considered preliminary awaiting replication with a larger subject population.

Marked suppression of gonadotropins and testosterone by an antagonist analog of gonadotropin-releasing hormone in men.

To study the dose response characteristics of a gonadotropin-releasing hormone (GnRH) antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5,dGlu6 (AA), d-Ala10] GnRH; Nal-Glu), 1.5 or 5.0 mg of Nal-Glu were administered to two groups of five normal men by daily subcutaneous injection for 21 days. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were determined on multiple occasions before, during, and after the antagonist treatment. Five milligrams Nal-Glu markedly suppressed mean serum immunoreactive LH to a mean of 1.5 +/- 0.4 IU/L (+/- SEM), immunoreactive FSH to the limit of assay detection (1 IU/L), and lowered basal mean serum T to castrate range (less than 2 nmol/L). Serum bioactive LH levels also showed a marked decrease in the 5.0-mg group similar to that seen in immunoreactive LH levels. Amplitude of immunoreactive LH pulses was markedly reduced in the 5.0-mg group on day 21. A 1.5-mg dose of Nal-Glu transiently suppressed serum immunoreactive LH levels on day 1. There was a subsequent escape on the rest of the days sampled. Serum immunoreactive FSH levels were not significantly changed over the 21-day treatment period. Serum T levels were transiently suppressed only on day 1 paralleling immunoreactive LH suppression. No adverse systemic side effects occurred. Thus, the 5.0-mg dose of this GnRH antagonist provides a pharmacological means of markedly suppressing the hypothalamic-pituitary-gonadal axis and, therefore, has potential as a male contraceptive.

Group self-identification and adolescent cigarette smoking: a 1-year prospective study.

As an extension of previous work, we analyzed the longitudinal relations between group self-identification and adolescent cigarette smoking. The predictive precedence of cigarette smoking and identification with 6 different types of peer groups was examined. Results indicated that 7th-grade group self-identification predicted 8th-grade cigarette smoking, whereas 7th-grade cigarette smoking did not predict 8th-grade group self-identification. Group self-identification also was compared with 7 other psychosocial variables as predictors of smoking 1 year later. The pattern of results suggests that group self-identification is about as good a predictor of smoking as other psychosocial variables, and that group self-identification is more than a mere proxy of other psychosocial variables.

Comparative effects of two different delivery systems on gonadotropin-releasing hormone (GnRH) antagonist-induced suppression of gonadotropins and testosterone in man.

The Nal-Glu gonadotropin-releasing hormone (GnRH) antagonist, when given in daily subcutaneous (SC) doses of 5 mg or higher, maximally suppresses serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to near undetectable levels and induces azoospermia in normal men; lower doses (1.5 and 3.0 mg) are less effective. Cost and convenience are important considerations in contraceptive development. Studies with GnRH agonists suggest that constant delivery is more effective in suppressing gonadal function than equal doses by single daily injection. In this study, we examined whether the constant infusion (CI) of a submaximal suppressive dose (1.5 mg) of Nal-Glu would be more effective in suppressing the pituitary-gonadal axis than its repeated single daily injections (SDI). This (1.5 mg) dose was selected because the 5 mg dose given once daily SC for 21 days led to maximal suppression of LH, FSH, and testosterone (T) levels, whereas 1.5 mg once daily for 21 days gave only partial suppression. It was felt that if continuous infusion was considerably more effective than intermittent administration of this submaximal dose, then the development of long-acting sustained release delivery systems for contraceptives based on GnRH antagonist analogs would allow both reduced cost and enhanced convenience. One and a half mg of Nal-Glu was administered SC either as a SDI or CI over 24 hours for 21 days to two groups of five normal men. Three measurements of serum LH, FSH, and T were performed before antagonist injection and 1, 2, 4, 8, 12, 16, and 24 hours after Nal-Glu injection on days 0, 1, 7, 21.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognitive performance and mood in patients with chronic insomnia during 14-day use of flurazepam and midazolam.

The 99 chronic insomniacs examined in the present multicenter study were given three cognitive tasks (reading comprehension, addition, and digit symbol substitution test [DSST]) as well as the Hopkins Symptom Checklist (HSCL) and the Profile of Mood States (POMS) in order to evaluate the effects of flurazepam (Dalmane) 15 and 30 mg, midazolam 15 mg, and placebo on cognitive performance and mood. Subjective evaluation of performance was also obtained. A significant person in the patient's life was also asked to evaluate the patient's mood before and during the 14-day treatment interval. After a 20-day washout, next-day performance and mood were evaluated after placebo nights -1 and 0 (baseline) and after treatment nights 1, 2 (early interval), 7 (middle interval), and 13 and 14 (late interval). Analysis of variance (ANOVA) on changes from baseline indicated no significant between-groups treatment effects for reading comprehension or any of the mood variables at any interval. Patients on flurazepam 30 mg performed less well compared with other groups even though, after completion of the tasks, this group believed that they performed as well as those on the other regimens. Performances by flurazepam 15 mg, midazolam, and placebo groups were similar. Significant others tended to rate high-dose flurazepam patients more negatively. High-dose flurazepam patients had a significant change on the DSST and addition tasks due to treatment after the first night, and change in performance remained significantly impaired for the DSST task relative to that of the other groups thereafter.