Cardiovascular effects of 0.5 milligrams per kilogram oral d-amphetamine and possible attenuation by haloperidol.

In a series of earlier studies, an oral dose of 0.5 mg/kg d-amphetamine was administered to 81 patients with schizophrenia and eight normal control subjects. Seven more subjects with schizophrenia received placebo. Blood pressure and pulse rate were monitored before and 3 hours after drug administration. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in normal control subjects as blood pressure began to decrease. Significant negative correlations between systolic blood pressure and pulse rate occurred at 2 and 3 hours, suggesting that the early cardiovascular response to amphetamine is an increase in blood pressure that recruits reflex control of heart rate. Eighteen of these subjects had hypertensive responses. Six subjects received 5 mg haloperidol intramuscularly, and 12 others had their blood pressure monitored until normalization. Haloperidol led to a more rapid decline of some but not all indices of blood pressure, suggesting that amphetamine-induced hypertension may have a dopaminergic component.

Akathisia and exacerbation of psychopathology: a preliminary report.

Akathisia has previously been reported to exacerbate psychopathology and to be associated with noncompliance, suicidality, and violence. One previous study found brisk decrements in psychopathology after acute treatment of akathisia with intramuscular biperiden. This study assessed changes in akathisia and psychopathology in 19 patients after separate one-day treatments with intramuscular benztropine and oral propranolol. Benztropine and propranolol led to clinically meaningful and statistically significant decrements in ratings of subjective and objective measures of akathisia and in psychopathology scores. Changes in psychopathology correlated significantly with changes in subjective measures of akathisia after benztropine and with subjective and objective measures of akathisia after propranolol. Changes in akathisia accounted for 9%-42% of the variance in changes in psychopathology. After treatment, statistically significant decrements in Brief Psychiatric Rating Scale (BPRS) positive symptoms were noted, and individual items not directly related to the akathisia syndrome, such as conceptual disorganization, hallucinatory behavior, and unusual thought content declined, although not significantly. These findings, taken together with the results of a similar previous study, indicate that the effect of akathisia in exacerbating psychopathology is large. If suspected, akathisia should be treated promptly.

Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms.

BACKGROUND: Previous research has provided evidence for brain abnormalities in schizophrenia, but their relationship to specific clinical symptoms and syndromes remains unclear. METHODS: With an all-male demographically similar sample of 53 schizophrenic patients and 29 normal control subjects, cerebral gray and white matter volumes (adjusted for intracranial volume and age were determined for regions in the prefrontal lobe and in the superficial and mesial temporal lobe using T1-weighted magnetic resonance imaging with 2.8-mm coronal slices. RESULTS: As a group, schizophrenic patients had wide-spread bilateral decrements in gray matter in the pre-frontal (7.4%) and temporal lobe regions (8.9%), but not in white matter in these regions. In the temporal lobe, gray matter reductions were found bilaterally in the superior temporal gyrus (6.0%), but not in the hippocampus and parahippocampus. While there were no overall group differences in white matter volumes, widespread decrements in prefrontal white matter in schizophrenic patients (n = 53) were related to higher levels of negative symptoms (partial r[49] = -0.42, P = .002), as measured by the Scale for the Assessment of Negative Symptoms. A post hoc analysis revealed that schizophrenic patients with high negative symptoms had generalized prefrontal white matter reductions (11.4%) that were most severe in the orbitofrontal subregion (15.1%). CONCLUSIONS: These results suggest that gray matter deficits may be a fairly common structural abnormality of schizophrenia, whereas reductions in prefrontal white matter may be associated with schizophrenic negative symptoms.

Impaired prepulse inhibition of acoustic startle in schizophrenia.

BACKGROUND: Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. METHODS: PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. RESULTS: Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. CONCLUSIONS: These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Fine volumetric analysis of the cerebral ventricular system in schizophrenia: further evidence for multifocal mild to moderate enlargement.

We used traditional volumetric regional analysis and a finer anterior-posterior (AP) profile volumetric analysis to examine the cerebral ventricular system in an all-male, demographically matched sample of schizophrenia patients (n = 73) and normal controls (n = 29) using 2.8-mm-thin coronal T1-weighted magnetic resonance images from a 1.5 tesla scanner. Traditional regional analysis was performed on various regions using absolute volumes after adjusting for intracranial volume (ICV) and age. The fine AP profile analysis was done by intrasubject "stacking" of contiguous coronal cross-sectional volumes (adjusted for ICV and age) across the AP plane, intersubject AP alignment of all slices relative to the mammillary bodies, and plotting of slice volumes along the AP plane with 95 percent t-test-based confidence intervals. Schizophrenia subjects had mild to moderate multifocal ventricular enlargement (overall effect size d = 0.48), which was especially prominent in the right posterior temporal horn and, more generally, in the central to posterior portions of the lateral and third ventricles. Schizophrenia subjects also had milder enlargement in the left frontal horn, but no significant differences were found in the anterior temporal horns and the right frontal horn. Post hoc analyses of demographic, clinical, and neuropsychological variables did not account for much variance in the ventriculomegaly observed in the schizophrenia group. The lack of a single locus in the observed ventricular enlargement, the nonsignificant results from schizophrenia subtypes based on regional distributions, and the strong positive correlations among the ventricular regions for the schizophrenia group suggest that the ventriculomegaly seen in this chronic population reflects a single brainwide disease process leading to a multifocal or patchy loss of integrity in brain structure.

Structural magnetic resonance image averaging in schizophrenia.

OBJECTIVE: Intersubject averaging of structural magnetic resonance (MR) images has been infrequently used as a means to study group differences in cerebral structure throughout the brain. In the present study, the authors used linear intersubject averaging of structural MR images to evaluate the validity and utility of this technique and to extend previous research, conducted using a different approach to image averaging, in which reduction in thalamic size and abnormalities in perithalamic white matter tracts in the brains of schizophrenic patients were reported by Andreasen et al. METHOD: A 1.5-T MR scanner was used to obtain high-resolution, whole brain T1-weighted structural MR images for an age-matched sample of 25 schizophrenic patients and 25 normal control subjects. A "bounding box" procedure was used to create a single "averaged" brain for the schizophrenic group and for the control group. Differences in signal intensity between the two average brains were examined on a pixel-wise basis through use of one-tailed effect size maps. RESULTS: Effect size maps revealed widespread patchy signal intensity differences between the two groups in both cortical and periventricular areas, including major white matter tracts. The signal intensity differences were consistent with cortical thinning/sulcal widening and ventricular enlargement. No differences were found within thalamus or in immediately surrounding white matter. Effect size maps for differences (schizophrenic minus normal subjects) had only small values. CONCLUSIONS: These results are consistent with diffuse structural brain abnormalities of both gray and white matter in schizophrenic populations such as the one in this study.

Prognostic significance of spontaneous echo contrast in the thoracic aorta: relation with accelerated clinical progression of coronary artery disease.

OBJECTIVES: The purposes of this study were to identify the incidence of aortic smoke in an unselected cohort of patients and to determine the utility of this measurement as a clinical marker for future coronary events and long-term cardiac prognosis. BACKGROUND: Although spontaneous echo contrast detected within the cardiac chambers has been associated with an increased risk of thromboembolism, less is known about "smoke" within the thoracic aorta and its relation to progression of coronary artery disease. METHODS: We prospectively assessed 118 unselected, consecutive male patients (mean age 67 years, range 29 to 86) who underwent transesophageal echocardiography (TEE). The presence of aortic smoke was identified by swirling echodense shadows distinct from high gain artifact. A positive result required confirmation by two of three independent observers. RESULTS: Aortic smoke without dissection was found in 25 of the patients (21%). Indications for TEE, coronary risk factors, the incidence of reduced left ventricular ejection fraction and mitral insufficiency and known coronary artery disease severity collectively did not differ significantly at baseline between the groups with and without smoke. Follow-up averaged 20.4 months (range 18 to 24) and was 100% complete for mortality and 98% complete for morbidity. The presence of aortic smoke was an independent predictor of myocardial infarction (16.0% vs. 2.2%, p < 0.005) and cardiac death (20.0% vs. 1.1%, p < 0.0001). These statistics remained significant after covarying for age, ejection fraction < 50%, hypertension, diabetes, aortic dimension, the presence of an atheromatous plaque and smoke in the left atrium. CONCLUSIONS: Spontaneous echo contrast detected within the thoracic aorta by transesophageal echocardiography is a common and important clinical marker that is strongly associated with an increased risk for future myocardial infarction and cardiac mortality. Future studies will attempt to define the pathophysiology of this relation and assess whether aggressive revascularization strategies and antithrombotic therapy may aid in the reduction of this risk.

Blunted change in cerebral glucose utilization after haloperidol treatment in schizophrenic patients with prominent negative symptoms.

OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences.

Amphetamine and negative symptoms of schizophrenia.

The purpose of this study was to assess further the effect of amphetamine on negative symptoms of schizophrenia. Thirty-seven schizophrenic males meeting DSM-III criteria were rated with the Brief Psychiatric Rating Scale, the Abrams and Taylor Scale, and the Abnormal Involuntary Movements Scale before and after double-blind administration of either amphetamine (n = 26) or placebo (n = 11). Our results indicated that amphetamine administration generally did not improve negative symptoms, even when accounting for changes in positive symptoms. However, greater baseline negative symptoms were associated with a modest diminution after amphetamine treatment. Therefore, amphetamine may modestly improve negative symptoms in those schizophrenics in whom this symptomatology is more severe.

Relationship between hypomania and personality disorders before and after successful treatment.

OBJECTIVE: To examine the effect of hypomanic states on maladaptive personality traits and personality disorders, the authors evaluated personality traits and disorders of patients during an episode of hypomania and after successful somatic treatment. METHOD: The authors used the Structured Interview for DSM-III Personality Disorders to study 66 outpatients who had a lifetime diagnosis of bipolar disorder and who met the minimum Research Diagnostic Criteria for hypomania. All patients had a knowledgeable informant separately undergo the Structured Interview for DSM-III Personality Disorders during the patient's hypomanic state. Outpatients who successfully recovered from the hypomanic episode (N = 47) and their informants were read-ministered the interview 4-8 weeks after the initial assessment. RESULTS: During the hypomanic state, informants generally reported higher levels of maladaptive personality traits among patients than patients themselves. For the patients who recovered successfully from the hypomanic episode, a reduction in all maladaptive personality traits except schizoid and dependent traits was reported by both patients and their informants; however, the decrease reported by patients generally was much greater than that reported by informants. In addition, schizoid traits actually increased after successful treatment according to patient reports but were unchanged according to informant reports. CONCLUSIONS: Hypomania may be associated with an exacerbation of maladaptive personality traits, which may be attenuated after successful treatment. Even with the attainment of euthymic mood, however, about 50% of the cohort had at least one personality disorder, which suggests that a high degree of comorbidity may exist between bipolar disorders and maladaptive personality traits or personality disorders.

Patients' and informants' reports of personality traits during and after major depression.

The influence of major depression on patients' and informants' reports of personality traits was examined using the Structured Interview for DSM-III Personality Disorder, both before and after successful antidepressant or placebo treatment (N = 58). According to patients' reports, Cluster A and C traits decreased significantly from pre- to posttreatment, but Cluster B traits were unchanged, excluding an increase in histrionic traits. According to informants' reports, Cluster A and B traits did not change from pre- to posttreatment, but Cluster C traits decreased significantly after treatment, not including passive-aggressive traits. Moreover, informants generally reported much higher levels of maladaptive personality traits than patients themselves. These results suggest that informants should be used in future research on personality disorders until better assessment techniques are developed.

Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology.

The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crow's type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however.

Masculinity, femininity, and subjective experiences of depression.

In this study, the relations of masculinity, femininity, and gender with various depressive experiences were examined in a sample of normal young men and women. The results indicated that greater masculinity generally was associated with lower levels of different depressive experiences in men and women. Greater femininity was related to advantageous outcomes for various depressive experiences in a relatively weaker and gender-specific fashion, but also was associated with greater anaclitic depression in men and women. The variable of gender alone was either weakly related or unrelated altogether to various depressive experiences. These results suggest that culturally defined gender-role characteristics may be more important than gender with respect to different aspects of depressive experiences in normal young adults.

Personality traits during depression and after clinical recovery.

We investigated whether and how acute depressive symptoms affect the self-report of maladaptive personality traits. Sixty-eight acutely depressed patients underwent the Structured Interview for DSM-III Personality Disorder (SIDP) before and after pharmacological treatment, allowing us to determine whether self-reported maladaptive personality traits are different during depression and after successful clinical recovery. After the initial SIDP administration (during an episode of major depression), patients received desipramine treatment (dose range 150-300 mg/day) over a course of 4-5 weeks before readministration of the SIDP. For those who recovered from their depression (n = 39), cluster III trait scores were significantly lower than those assessed at baseline, and there was a lower frequency of cluster III categorical diagnoses for a personality disorder after treatment than before treatment. Recovered patients also had significantly lower cluster I personality trait scores after treatment as compared with baseline ratings. For those who did not recover from their depression after treatment (n = 29), cluster I trait scores were in fact higher than those measured at baseline, but there were no differences in categorical diagnoses before and after treatment. Cluster II personality traits and categorical diagnoses were not different between those who did and did not recover from their depression. Thus, depression may have a significant effect on the assessment of cluster I and cluster III personality traits. It is possible that cluster I and III 'personality traits' may be interwoven with depressive features and therefore subject to state influences, whereas cluster II personality traits may entail enduring, long-term characteristic modes of thinking, feeling, and behaving.

Lithium prophylaxis of bipolar illness. The value of combination treatment.

Using a longitudinal life-table analysis, we assessed the efficacy of lithium alone, administered within the context of a naturalistic clinical setting, by calculating the probability of patients remaining free of an affective episode (manic or depressive) over a five-year course. In addition, for those who suffered a manic or depressive relapse, we attempted to analyse the subsequent course of patients who suffered a manic/hypomanic or depressive relapse and were then restabilised on lithium plus either a neuroleptic, carbamazepine, or a benzodiazepine, or lithium plus an antidepressant. Lithium alone offered an average 83% probability against an affective relapse after one year, 52% after three years, and 37% after five years. For patients who failed on lithium alone, it appeared that combination treatment offered greater protection against subsequent affective relapse than the initial course on lithium alone.

Persistent psychosis after reduction in pre- and post-synaptic dopaminergic function.

The purpose of this study was to evaluate the hypothesis that neuroleptic non-response in the face of "adequate" DA post-synaptic receptor blockade reflects failure of regulatory mechanisms to decrease DA pre-synaptic activity. Eight chronic schizophrenics, meeting rigorous criteria for neuroleptic non-response, were treated for four weeks with alpha-methylparatyrosine as an adjunct to their previously stable neuroleptic dose. Treatment with AMPT produced a prompt decrease in plasma HVA that was, on average, 72% lower at the end of the study. While there was also strong clinical evidence of reduction in central dopaminergic activity (both a significant reduction in dyskinetic movements and increase in extrapyramidal symptoms), there was virtually no change in severity of psychotic symptoms. Thus, in this group of non-responders, psychotic symptoms persisted despite both extensive dopamine post-synaptic receptor blockade and marked reduction of presynaptic activity. These symptoms may not be directly DA dependent.

Elevated PLA2 activity in schizophrenics and other psychiatric patients.

We measured serum phospholipase A2 (PLA2) activity in 39 schizophrenics, 26 psychiatric controls, and 26 normal controls using a radioenzymatic assay with phosphatidylcholine as precursor. Serum PLA2 activity was significantly higher in schizophrenics (p = 0.002) and other psychiatric (including substance abusing) patients (p = 0.032) than in normal controls. Enzyme activity did not differ between the schizophrenic patients and psychiatric controls. Fifty-one percent of the schizophrenics and 46% of psychiatric controls had PLA2 values above the highest value for normal controls. In the psychiatric control group higher than normal PLA2 activities were observed in all diagnostic categories, including major depression, bipolar disorder, posttraumatic stress disorder (PTSD), and substance abuse. In the context of others' findings of increased circulating PLA2 in infectious and inflammatory conditions, these increases must be viewed as disease nonspecific. The significance of these changes and their relationship to other acute-phase protein changes needs to be clarified in future research.

Plasma homovanillic acid in neuroleptic responsive and nonresponsive schizophrenics.

Changes in plasma homovanillic acid (HVA) were investigated in neuroleptic responsive and nonresponsive schizophrenics in order to delineate parameters of dopamine regulation, which may underlie differences in neuroleptic responsivity. Nineteen schizophrenics were treated with haloperidol for 6 weeks. HVA was sampled at baseline, 24 hr after initial neuroleptic dose, and after 6 weeks of treatment. Subjects were pretreated with debrisoquin in order to reduce the peripheral production of HVA. The responders had an initial rise in HVA at 24 hr after first neuroleptic dose, followed by a decline back to baseline over the 6 weeks of treatment. The nonresponders' HVA failed to rise at 24 hr after first neuroleptic dose. At 6 weeks of treatment their HVA had fallen to significantly below baseline. Thus, a rise in HVA 24 hr after the first dose of neuroleptic predicted treatment response; a fall in HVA at 6 weeks to below pretreatment values was associated with neuroleptic nonresponse.

A placebo-controlled trial of L-dopa/carbidopa in early cocaine abstinence.

Thirty patients with primary cocaine dependence who had used cocaine within the past 24 hours and were being admitted to a detoxification ward were rated for signs and symptoms of cocaine abstinence and craving. They then received four doses of either L-dihydroxy-phenylalanine/carbidopa (100 mg/25 mg) or placebo over the next day. Ratings were repeated in the late afternoon of the day of admission and after the final morning dose the next day. No significant differences in abstinence scores were found between the two treatment groups. The lack of drug-placebo differences appeared to be mainly due to rapid clearing of abstinence symptoms in the placebo-treated patients.

Negative symptoms and hypofrontality in chronic schizophrenia.

Frontal lobe dysfunction is widely suspected to underlie negative symptoms of schizophrenia. This hypothesis is based largely on long-standing observations of the similarities between the effects of frontal lobe lesions and negative symptoms. However, there is little direct evidence specifically for such an association in schizophrenic patients. We measured the relationship between decreased relative prefrontal cortex glucose metabolism (hypofrontality) using positron emission tomography and evaluated the severity of negative symptoms in 20 chronic schizophrenics who underwent scanning while not receiving neuroleptic drugs. We found a close relationship between negative symptoms and prefrontal hypometabolism, particularly in the right dorsolateral convexity. This association was regionally specific. Furthermore, there was no evidence that this relationship was an artifact of age, cerebral atrophy, or severity of positive symptoms.