Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology.

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.

Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome.

Negative symptoms have been associated with poor response to neuroleptics, enlarged ventricles, cognitive impairment, and poor outcome in schizophrenia. These associations appear, however, to be dependent on the phase of study, suggesting that acute-phase (phasic) negative symptoms may be pathophysiologically distinct from enduring negative symptoms that persist through the residual phase. To compare correlates of enduring and phasic negative symptoms, we studied 60 drug-free schizophrenic patients (DSM-III-R and SADS/RDC) at baseline, 4 weeks after neuroleptic treatment, and assessed the 1 year outcome. We rated positive and negative symptoms at baseline and 4 weeks after treatment. At baseline, premorbid function, neuropsychological function, ventricle-brain ratio (VBR) and symptom response to an anticholinergic agent were assessed, and a two-night sleep EEG and 1mg dexamethasone suppression test (DST) were conducted. Phasic negative symptoms were defined as the change in negative symptoms (baseline to 4 weeks) and enduring negative symptoms as severity of negative symptoms at 4 weeks. Patients had varying proportions of phasic and enduring symptoms; the two did not define distinct subgroups. Phasic negative symptoms were significantly correlated with global treatment response, positive symptom treatment response, response to anticholinergic agent, baseline post-dexamethasone cortisol, and shortened REM latency. Enduring negative symptoms were significantly correlated with residual positive symptoms and global psychopathology, VBR, poor performance on neuropsychological testing, decreased slow-wave sleep, poor premorbid function, and poor 1 year outcome. These data suggest that phasic negative symptoms and enduring negative symptoms may be caused by different pathophysiological mechanisms.

Superior temporal gyrus in schizophrenia: a volumetric magnetic resonance imaging study.

The left superior temporal gyrus (STG) has been reported to be smaller in patients with schizophrenia. The volume of the STG has been found to correlate negatively with severity of hallucinations and thought disorder. In this study, we measured the STG volume of 20 normal controls and 20 patients with schizophrenia using 3 mm contiguous coronal T1 magnetic resonance images. We found that patients had a significantly smaller left anterior STG, and that the volume of this region negatively correlated with the severity of hallucinations. The left posterior STG was not significantly smaller in patients than in controls, but its volume negatively correlated with severity of thought disorder. We also found that the left anterior STG was smaller than the right STG in patients but not in controls. The STG has at least three histologically distinct areas, each with different connections to the rest of the brain. These data are consistent with the proposition that dysfunction of the primary auditory cortex in the anterior and middle STG and auditory association cortex in the posterior STG may play a role in the production of auditory perceptual abnormalities and poor organization of thought respectively.

Symptom correlates of global measures of severity in schizophrenia.

There is an increasing need for practical instruments that can rapidly and accurately assess the effectiveness of treatments for mental illness in clinical settings. Symptom rating scales used in clinical research are too complex and time-consuming to be useful in these settings. In contrast, single-item global measures of severity such as the Clinical Global Impression-severity scale (CGI) and the Global Assessment of Function scale (GAF) are brief and easy to complete, but little is known about their relationship with the specific symptoms of severe mental illnesses. In this study, we examine the extent to which CGI and GAF scores reflect the severity and the change in severity of positive, negative, depressive, and agitation symptoms in a sample of 102 schizophrenia inpatients at the University of Michigan Medical Center. At admission, positive symptoms were the strongest correlates of both CGI and GAF scores, followed by negative symptoms, and agitation. Depressive symptoms did not correlate significantly with either global measure. The three symptom scores together explained 58% of the variation in CGI and 39% of the variation in GAF. A similar pattern of association was found for the scores measured at discharge and for the relationships between the change in global measures and change in specific symptom clusters. Thus, by demonstrating that single-item global measures, particularly the CGI, can be reasonably good indicators of psychopathology, this study suggests that these measures may be practical tools for routine monitoring of the effectiveness of treatments for severe mental illness in community settings.

Combined electroconvulsive therapy and clozapine in treatment-resistant schizophrenia.

1. To assess the efficacy and safety of combining electroconvulsive therapy (ECT) and clozapine in patients with treatment-resistant schizophrenia, the authors reviewed use of this combination in four treatment-resistant schizophrenic inpatients and one inpatient with schizophrenia who was intolerant of clozapine doses needed to control her psychosis. 2. The combination of clozapine and bilateral ECT was modestly effective in two treatment-resistant patients and markedly effective in three patients. There was significant overall improvement in patients' Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) scores (p < 0.005 and p < 0.0004, respectively), however in patients where marked symptomatic improvement was noted, effects were not sustained. 3. One of the patients that showed dramatic yet transient improvement followed by relapses received maintenance ECT but relapsed despite this. 4. The authors saw no adverse effects in connection with the combination of ECT and clozapine. 5. Supplementing clozapine with a course of bilateral ECT appears to be safe and is effective in some patients with refractory schizophrenia, however its beneficial effects may be short-lived. The long-term impact of ECT on the course of schizophrenia in patients incompletely responsive to clozapine is not fully elucidated.

Electroconvulsive treatment of a bipolar adolescent postcraniotomy for brain stem astrocytoma.

This is the first reported use of electroconvulsive treatment (ECT) in an adolescent with bipolar mania who had been treated with craniectomy for an intracranial neoplasm. The reported case is of a 16-year-old girl with a history of brain stem glioma (pontomesencephalic astrocytoma) diagnosed at 13 years of age. She presented in a psychiatric emergency room with suicidal ideation, depressed mood, irritability, olfactory hallucinations, early insomnia, grandiosity, and guilt. Her symptoms failed to respond to a trial of an antidepressant, mood stabilizer alone, and mood stabilizer in conjunction with a neuroleptic. The decision to use ECT was based on suicidal ideation, extreme disinhibition, and danger to self and others. Significant improvement in mood and remission in psychosis were noted after the eighth treatment. Comparison of 2-week pre-ECT and 3-month post-ECT cognitive testing revealed no change in IQ. This report highlights rapid response and the ability to tolerate ECT in an adolescent diagnosed with bipolar disorder, who had also been treated with radiation and craniotomy.

Landmark-based morphometric analysis of first-episode schizophrenia.

BACKGROUND: The goal of this investigation was to utilize landmark-based shape analysis and image averaging to determine the sites and extent of specific structural changes in first-episode schizophrenia. METHODS: Neuroanatomic structures identified on midsagittal magnetic resonance imaging (MRI) scans were compared between 20 patients with schizophrenia and 22 normal control subjects. The difference between averaged landmark configurations in the two groups was visualized as a shape deformation by a thin-plate spline and through averaged MRI images for both groups. RESULTS: A shape difference was found to be statistically significant; by inspection, it is contrast between differences in two closely abutting regions, involving primarily the posterior corpus callosum and upper brain stem--the "focus" is the relation between them. CONCLUSIONS: The findings are consistent with prior studies suggesting involvement in schizophrenia of the corpus callosum and the limbic structures contributing to the corpus callosum; the possibility of local pathology primarily involving the brain stem cannot be excluded. The methods of landmark-based shape analysis and image averaging utilized in this study can complement the "region-of-interest" method of investigating morphometric abnormalities by characterizing the spatial relationships among structural brain abnormalities in schizophrenia.

Pharmacologic treatment of first-episode schizophrenia: early intervention is key to outcome.

The early recognition and management of a first episode of schizophrenic illness is a difficult task, with identification complicated by a broad differential diagnosis, lack of definitive data on the prognostic implications of premorbid/prodromal symptoms, and, until recently, treatment limited to pharmacologic agents with severe adverse effects. The first psychotic episode in patients with schizophrenia is the most responsive to treatment in terms of both rate and degree. However, first-episode patients are also more likely to develop motor side effects, even at lower medication doses, than multiepisode patients. Considerable evidence supports the assertion that early treatment can improve outcome and possibly prevent the development of full-blown illness in high-risk individuals. There is evidence that atypical antipsychotic medications are effective in the treatment of first-episode schizophrenia and are well tolerated. The improved tolerability associated with the newer antipsychotic medications, including a lower risk for motor side effects and possible lower risk for development of tardive dyskinesia, has swung the risk-benefit balance in favor of early and aggressive treatment. By intervening early and providing long-term maintenance treatment, the course of schizophrenic illness may be altered in the coming years with overall decreased deterioration and chronicity and overall improved functioning resulting in lower societal costs.

Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension.

OBJECTIVE: The authors sought to replicate and extend previous observations of improvement in some EEG sleep measures during the course of antipsychotic treatment in schizophrenia patients. METHOD: Fourteen medication-free patients with schizophrenia underwent 2 nights of sleep EEG monitoring before and after 3-4 weeks of treatment with clinically determined doses of haloperidol or thiothixene. RESULTS: Measures of sleep continuity improved consistently. REM latency increased, although five of 14 patients continued to exhibit short REM latencies (less than 60 minutes). Stage 3 sleep increased during neuroleptic treatment, while stage 4 sleep did not change. CONCLUSIONS: These data demonstrate partial improvement of some but not all EEG sleep measures in schizophrenic patients through the course of neuroleptic treatment. They suggest that shortened REM latency and disturbed sleep continuity might represent reversible state abnormalities, while reduced slow-wave sleep may represent a more persistent trait abnormality in schizophrenia.

Do atypical antipsychotic medications favorably alter the long-term course of schizophrenia?

Schizophrenia is characterized by the greatest degree of clinical deterioration in the first decade following onset of psychosis; in fact, deterioration begins even prior to the onset of frank psychotic symptomatology. While somewhat controversial, it appears that effective early antipsychotic treatment might limit the extent of such deterioration. The newer, atypical antipsychotics such as clozapine, risperidone, olanzapine and quetiapine appear to have antipsychotic efficacy at least equal to the traditional neuroleptics, but with a much more favorable side effect profile. Clozapine is also effective in treating neuroleptic-refractory schizophrenic patients. Data suggest that in comparison to conventional agents, treatment with atypical antipsychotics may be associated with a more benign course of schizophrenic illness. Whether these atypical antipsychotics are associated with greater efficacy in limiting clinical deterioration in schizophrenic illness than traditional neuroleptics is, however, unclear. The following questions will be addressed in this paper: (i) Do atypical antipsychotics differ from traditional neuroleptics in modifying the natural course of symptomatology in schizophrenic illness? (ii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of neurobiological and cognitive abnormalities in schizophrenic illness? (iii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of psychosocial dysfunction in schizophrenic illness? (iv) Are there differences between typical and atypical antipsychotics with regard to their effects on the cost of care and resource utilization? The implications of the answers to these questions for the long-term treatment of schizophrenia will be discussed.

Does neuroanatomy predict ECT response?

1. Structural neuropathologic abnormalities have been associated with severe psychiatric illnesses, including bipolar disorder, major depressive disorder, and schizophrenia. In the latter, ventricular enlargement has been variably associated with symptom severity and poor treatment response. In patients with severe depressive disorders, the relationship between cortical and subcortical pathology and ventricle enlargement, symptom severity, and response to treatment is far from clear. 2. The present study investigated the relationship between structural CNS pathology, symptom severity and treatment response in patients undergoing ECT. It was hypothesized that patients with greater neuroanatomic abnormalities would demonstrate greater initial symptom severity and poorer response to ECT. 3. The subjects were 57 patients with unipolar or bipolar depression admitted for ECT treatment. Symptom severity was quantified using the Hamilton Depression Rating Scale (HRSD) at baseline and post-ECT. 4. Lateral and third ventricle-brain ratio (LVBR, 3VBR) were determined from CT scans and cortical atrophy was rated by a faculty neuroradiologist. 5. Contrary to our first hypothesis, structural pathology was not associated with baseline symptom severity. In terms of treatment response, the number of treatments required to achieve benefit was correlated with larger 3VBR; CT variables were not related to total post-treatment or change in HRSD score. Third ventricle enlargement may be an index of generalized pathology or regional brainstem abnormalities that influence ECT response rate by limiting individual seizure efficacy or neurochemical responsiveness, thereby necessitating a greater number of ECT treatments, without significant impact on overall response.

Biological predictors of suicidality in schizophrenia.

The objective of this study was to determine whether polysomnographic rapid eye movement (REM) sleep abnormalities and cortisol response to the dexamethasone suppression test (DST) differentiate between schizophrenic patients with and without a history of suicidal behaviour. We assessed a sample of 96 schizophrenic in-patients at the end of a 2-week medication-free period with the DST, polysomnography, and an extensive clinical assessment battery. Patients exhibiting suicidal behaviour were significantly more likely to have increased total REM time and increased total REM activity. We found no significant relationship between suicidal behaviour and DST non-suppression. This study confirms a previous finding suggesting an association between REM sleep abnormalities and suicidal behaviour in schizophrenia. It is postulated that this observed association may be related to serotonergic dysfunction in schizophrenia.

Biological predictors of 1-year outcome in schizophrenia in males and females.

This paper describes a prospective study designed to ascertain the predictive value of biological factors associated with schizophrenia in males and females. In a sample of 59 medication-free schizophrenic inpatients (41 males; 18 females), we assessed the correlation of four factors--rapid eye movement (REM) sleep latency, delta (slow-wave) sleep, dexamethasone suppression test (DST) cortisol levels, and ventricle-brain ratio (VBR)--with several dimensions of outcome at 1-year post-discharge. In the total sample, shorter REM latency was associated with poor outcome on all dimensions measured: rehospitalization, employment, social activity, symptomatology, and global functioning. However, none of the other biological factors were associated with any measure of outcome. The predictive value of REM latency appeared to be gender-specific; in general, the relationships between reduced REM latency and poor outcome were consistently noted in females, but were not significant in males. These results suggest that a common, possibly gender-related, pathophysiological mechanism might underlie both abnormal REM latency and poor outcome. The findings underscore the importance of considering gender differences in studies of schizophrenia.

VBR in schizophrenia: relationship to family history of psychosis and season of birth.

Ventricular enlargement has been consistently demonstrated in schizophrenia using both CT and MRI. Despite this, the structural changes that underlie increased ventricle-brain ratio (VBR) and its relationship to environmental factors (intrauterine viral exposure, obstetric complications, etc.) and family history of schizophrenia remain poorly defined. Increased VBR has been shown in some studies to correlate with an absence of family history of schizophrenia and with Winter-Spring birth. In an attempt to obtain a clearer picture of the contribution of environmental and genetic factors to VBR, we studied 54 patients with DSM III-R schizophrenia. VBR was determined from head CT scans via computerized planimetry. Family history of psychosis and non-psychotic mood disorder was determined with the family informant method. Season of birth was encoded in several ways, including season, trimester and dichotomously. Patients without a family history of psychosis had significantly larger VBR than patients with such a history; family history of mood disorder was not related to VBR. Season of birth was not predictive of VBR. Family history of psychosis and season of birth were not related to each other. These results are in line with prior work demonstrating an association between increased VBR and sporadic (non-familial) schizophrenia. We did not find a relationship between VBR and season of birth, which suggests that risk of perinatal viral exposure and other seasonal environmental factors may not account for the ventricular enlargement in non-familial schizophrenia observed in our sample.