Jeffrey A. Lieberman

Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.

Pathomorphology of the limbic system has been described in post-mortem studies of schizophrenia. To determine whether this could be detected in living patients and was not secondary to the treatment or the chronicity of the disease itself, we measured the volumes of the hippocampus-amygdala complex and adjoining temporal horns of 34 patients in their first episode of schizophrenia and 25 normal volunteers using T1 weighted contiguous coronal magnetic resonance images of 3.1 mm width. The results demonstrate abnormal medial temporal lobe morphology in a subgroup of patients at the onset of their illness. There were clear laterality effects and sex differences: hippocampal tissue was significantly smaller only in the left hemisphere of male patients, whereas enlargement of the whole temporal horn or its anterior portion was present on the left side in both sexes. Dysfunction of the limbic mesiotemporal structures might explain some of the clinical features of the disease.

Hippocampus-Amygdala Volumes and Psychopathology in Chronic Schizophrenia

Volumes of the mesiotemporal structures (hippocampus-amygdala complex) were measured in 19 men who were chronic multiepisode schizophrenics and 18 age-matched healthy controls using T1-weighted contiguous coronal magnetic resonance images of 3.1-mm width. Using the level of the mammillary bodies as an anatomical landmark, the whole hippocampus-amygdala complex was divided into an anterior section (mainly containing amygdaloid tissue) and a posterior section (mainly containing the hippocampal formation). Total mesiotemporal tissue volume was reduced significantly in the patient group compared to controls (-11%), with significant reductions in both left (-20%) and right (-15%) hippocampal sections. Reduced limbic tissue volume was associated with increased severity of psychopathology. Severity of positive psychotic symptoms (Brief Psychiatric Rating Scale [BPRS] psychosis factor) was correlated significantly with right and left total mesiotemporal volumes (Spearman rhos = -0.61 p < 0.01). Negative symptom scores (BPRS anergia factor, Scale for Assessment of Negative Symptoms [SANS] global items) were not significantly correlated with any mesiotemporal tissue volumes. The data corroborate and extend previous findings of temporolimbic structure volume reduction in schizophrenia, and suggest that the positive psychotic symptoms of schizophrenia are associated with anatomic anomalies in mesiotemporal structure.

Mechanisms of action of atypical antipsychotic drugs: a critical analysis

Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.

Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia

This study examined relations of mesiotemporal lobe tissue volumes with neuropsychological (NP) functions in a sample of patients with first episode schizophrenia. Three contiguous compartments of the mesiotemporal lobe were measured on magnetic resonance images, comprising primarily amygdaloid, anterior hippocampal, and posterior hippocampal tissue volumes. NP measures were derived from a comprehensive battery. Decreased volume selectively in the anterior hippocampal formation was associated with lower scores on measures of executive and motor functions usually considered sensitive to the integrity of frontal lobe systems. Measures of other NP functions, and global intellectual ability, were not related to mesiotemporal volumes. The findings that morphologic abnormalities in the mesiotemporal lobe are associated with impairment of frontal lobe functions point to a defect in an integrated functional system that includes both frontal and mesiotemporal components. The findings are consistent with the hypothesis that neurodevelopmental defects affecting the morphology of the anterior hippocampal formation may be manifest later in life as impairments in fronto-limbic control. .

Psychobiologic correlates of treatment response in schizophrenia

In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity.

Clinical profile of clozapine: adverse reactions and agranulocytosis

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medications actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Depression in Hemodialysis Patients

Psychiatric evaluation of depression in medically ill patients using DSM-III-R or Research Diagnostic Criteria (RDC) is difficult because these diagnostic systems have not been validated for this population. Diagnosis of depression has been especially problematic in patients with end-stage renal disease (ESRD). This study found a 17.7% prevalence of RDC-defined minor depression and a 6.5% prevalence of major depression in 124 ESRD patients treated with hemodialysis. Vegetative symptoms of depression were less useful for discriminating between those with and without depression than were the psychological symptoms of suicidal ideation, depressed mood, and discouragement.

Increased prevalence of the cavum septum pellucidum in magnetic resonance scans and post-mortem brains of schizophrenic patients

A cavum septum pellucidum (CSP) has been regarded as an incidental finding of little clinical importance. However, an association between this developmental anomaly and a diagnosis of psychosis has previously been reported. We determined the prevalence of the CSP in parallel studies of brain scans obtained with magnetic resonance (MR) imaging and in the post-mortem brains of schizophrenic patients compared with normal controls. We found a significantly increased prevalence of the CSP in both the MR scans and post-mortem brains of schizophrenic patients compared with controls. In the MR study, 17 of 81 (21%) schizophrenic patients but only 1 of 46 (2%) control subjects had a CSP. In the post-mortem study, 17 of 28 (61%) schizophrenic patients and 12 of 39 (31%) normal controls had a CSP. The increased prevalence of a CSP in schizophrenic patients further indicates that anomalous development of the limbic system is an important aspect of this disorder.

Cerebellar volume asymmetries are related to handedness: A quantitative MRI study

Four cerebellar subregions were delineated (left, right; anterior, posterior), and their volumes measured on contiguous 3.1 mm coronal MR images in 15 dextral and 8 nondextral healthy control subjects. (1) Left and right cerebellar hemisphere volume asymmetries interacted with anterior-posterior level (anterior: right > left; posterior: left > right), following a pattern commonly found in the neocortex; (2) A significant handedness effect was found (P < or =0.01) on a composite index of cerebellar asymmetry, such that dextrals showed more asymmetry than nondextrals. These data suggest that the same pattern of asymmetries observed at the neocortical level is also present in the metencephalon. These asymmetries, possibly resulting from multiple developmental growth gradients acting on the metencephalon early in gestation, are associated with handedness differences in adulthood.

Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics.

Gender differences in neuroleptic-refractory chronic schizophrenic disorder patients were examined to determine whether a superior or equivalent antipsychotic response in women vs. men existed similar to that of the general schizophrenic population. Sixty-nine DSM-III schizophrenic patients (47 males and 22 females) were treated with clozapine using a standardized medication regime. The gender differences in these neuroleptic-nonresponsive chronic schizophrenic disorder patients differed from those previously observed in the general schizophrenic population in that an equivalent antipsychotic treatment response in females versus males was not found. These treatment-refractory women appear to be a severely ill subgroup of female schizophrenics with distinct onset of illness, course and treatment response characteristics.