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This study examined neuropsychological functioning in two subgroups of patients with familial schizophrenia. Those who showed evidence of progressive ventricular enlargement observed across serial MRI scans (n=6) were compared with subjects whose ventricular volume remained static (n=10) over an average of 28 months. No differences were found in terms of age, education, ethnicity, level of psychotic symptomatology, DSM-IV subtype, age of onset, or duration of illness. Neurocognitively, the static ventricle group was impaired across more cognitive domains and had a larger percentage of subjects falling into the impaired range on a majority of measures, with the greatest differences on measures of attention (p

Objective: This study examined whether the practices of switching between classes of medications and prescription of concomitant medications differed between black and nonblack patients with bipolar disorders. Methods: In a retrospective cohort design, data from 1998 to 2004 for patients with diagnoses of bipolar disorders were obtained from a large claims database. Information was obtained on the number of prescriptions for four classes of medications (anticonvulsants, mood stabilizers, and first- and second-generation antipsychotics) as well as on medication switching (between drug classes), concomitant prescriptions, resource use, and outcomes (an emergency department visit or a hospitalization). Logistic models assessed the relationship between outcomes and switching or concomitant prescriptions. Results: The study population consisted of 1,113 adults who received at least one prescription from the four drug classes. Medication switching or concomitant prescriptions were documented for more than one-third of patients (36.6 percent). A significantly greater proportion of black patients received two or more medications from different drug classes (41.1 compared with 34.7 percent). The number of prescriptions was lower for black patients than for nonblack patients. Patients for whom switching or concomitant prescriptions were documented were significantly more likely to have an emergency department visit or a hospitalization, and race was a significant predictor of these outcomes. Conclusions: The prevalence of polypharmacy-medication switching and concomitant prescriptions-was high among patients with bipolar disorder, with a higher prevalence among black patients. Patients who experienced switching or concomitant prescriptions were more likely to visit the emergency department or to be hospitalized.

Evidence of immune activation has occasionally, but not consistently, been reported in schizophrenia. Investigations of cytokine abnormalities in serum, and occasionally in CSF, have yielded inconsistent results, which have been difficult to resolve. In such studies, schizophrenia has been assumed to consist of a single process rather than a group of disorders. This study assesses differences in the pro-inflammatory cytokine, interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) in two previously delineated subtypes of schizophrenics (‘delayed-responders’ (DR) (n=23) and ‘poor-responders’ (PR) (n=8)) during periods of neuroleptic-free psychotic exacerbation, and in a comparison group of normal controls (n=14). The two response subtypes were separated by subsequent treatment response (greater/less than 60% reduction of SAPS scores from baseline during 6 months of systematic treatment). The IL-6 assay, a sandwich enzyme-linked immunosorbent assay, was sensitive and reliable to detect IL-6 levels in the CSF of all subjects. CSF IL-6 was found to be significantly higher in the DR than the PR (P=0.017) and the controls (P=0.013). In addition to supporting the concept of heterogeneity in schizophrenia, this study also provides evidence that a central immune process may be occurring centrally in one subtype of schizophrenia.

Background Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. Method Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. Results At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. Conclusion Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.

Recent reports from serial brain scans suggest that the rate of ventricular expansion and/or brain atrophy may be accelerated in at least some schizophrenics. The authors assessed the effect of state changes upon such findings.Within-subject 3D MRIs were assessed for ventricular and brain volumes during periods of [partial] remission and of exacerbation of psychosis. Additional scans at comparable within-subject SAPS were used to assess rates of change in volumes that were independent of SAPS changes. Correlations of changes of ventricle and brain volumes vs. change of SAPS cores between scans revealed that ventricle volumes decreased during a period of psychotic exacerbation and increased at a time of [partial] remission (r(p)=-0.666; P0.0005); conversely, brain volumes increased during psychotic exacerbation and decreased at [partial] remission (r(p)=+0.448; P=0.032). Scans at comparable SAPS scores suggested that the majority of patients had rates of ventricular expansion comparable to controls (0.9+/-0.6 cc/year), though two patients appeared to have rates of ventricular increase of 4.5+/-2. 1 cc/year (Lilliefores P=0.036; K-means clustering F=17.75). Exacerbation of psychosis in schizophrenia is accompanied by evidence of brain swelling, especially of periventricular brain, with encroachment of brain substance upon ventricular volumes. Controlled for state changes, the majority of schizophrenics show rates of ventricular expansion or brain atrophy indistinguishable from controls.

The question of whether schizophrenic-like disorders are neurodevelopmental or degenerative in origin has been argued since the time of Kraepelin. The authors provide evidence for the existence of two etiologically distinct endophenotypes of the psychoses contained within the rubric of familial non-affective psychosis (schizophrenia), one atrophic and the other neurodevelopmental. The atrophic psychosis, identified by progressive ventricular enlargement throughout adult illness, evidences progressive impairment of interests, relationships, and withdrawal from latency through adolescence, with emergence of trait-like negative symptoms which are only marginally responsive to conventional neuroleptics. This psychosis also exhibits delayed response of positive symptoms during neuroleptic treatment, and may also proceed to a praecox dementia in later life. In contrast, a putative neurodevelopmental psychosis, associated with static ventricles during the course of adult illness, also demonstrates preadolescent impairments, but impairments which do not progress to marked negative symptoms. Conventional neuroleptics appear to have little effect (except sedation) on positive symptoms, but appear to induce negative symptomatology and partial disengagement from the burden of persistent psychotic thought processes in such static ventricle psychoses. Thus, separate patterns of illnesses with different prodromal features, different treatment response patterns, and different patterns of residual (negative) symptoms appear to characterize patients with psychosis who have expanding as opposed to stable cerebral-ventricles at doses of neuroleptic at 10 mg haloperidol equivalents/day.

The effectiveness of clozapine treatment in a treatment-refractory sample of older adult veterans with primary psychosis was examined.Data were collected over a five-year period for patients age 55 and older who were given clozapine because of a history of treatment-refractory or treatment-intolerant psychosis. At initiation of clozapine therapy, baseline demographic, clinical, and psychopathology data were collected. At baseline and quarterly, patients' psychopathology was rated with the Brief Psychiatric Rating Scale (BPRS), and involuntary movements were rated with the Abnormal Involuntary Movement Scale (AIMS).The 329 patients age 55 or older who received clozapine during the study period represented 10 percent of all patients on clozapine therapy in the VA system. Of the 312 patients for whom demographic information was available, 294 were men and 18 were women. Overall, patients improved on clozapine therapy, although wide variation in drug response was observed. Complete BPRS and AIMS data were available for 97 patients. The 55- to 64-year-old group had a mean improvement in total BPRS score of 19.8 percent, with 42.6 percent showing more than a 20 percent improvement; those age 65 and older had a mean improvement of 5.7 percent, with 17.2 percent showing an improvement greater than 20 percent. The 97 patients with complete AIMS data showed a mean improvement of 16.6 percent in total score.Clozapine is an important therapeutic agent for older adults with treatment-refractory psychosis. Patients between the ages of 55 and 64 may have a better response than those age 65 and older.

1. Using differential response to medications may help in resolving the central problem of heterogeneity of the psychoses, 2. A distinct subgroup of patients with a lithium responsive, nonaffective psychosis has been shown to have their core psychotic (nonaffective) symptoms respond to lithium alone. 3. The family histories of patients with lithium responsive, nonaffective psychoses suggests that there is less genetic loading for this subgroup of patients. 4. Research on the prodromal adjustment of lithium responsive, nonaffective psychosis patients has not been reported. 5. Lithium responsive patients showed significantly fewer negative symptoms than did those patients with a nonaffective psychosis who did not respond to lithium. 6. Patients with lithium responsive, nonaffective psychoses showed more extreme in vitro lithium ratios in the red blood cells and significantly less of all types of phospholipid methylation. 7. Patients with lithium responsive, nonaffective psychoses showed significantly greater reduction in symptoms during a physostigmine challenge test, but results from apomorphine challenge tests could not be replicated. 8. Aside from differential response to lithium, research on difference in treatment response and outcome for this group has not been reported. 9. Preliminary evidence may suggest that lithium responsive, nonaffective psychosis is a phenocopy of other psychotic disorders that is not associated with ventriculomegaly but is associated with stimulant abuse. 10. Lithium's effects on acetylcholine as well as effects on dopamine and serotonin may explain its efficacy with this subgroup of patients. 11. This review supports the existence of a distinct subgroup of patients with nonaffective psychoses who may have a separate disorder, but further research is necessary. 12. Lithium responsive nonaffective psychosis appears to be a separate, distinct psychotic phenocopy.

Whereas etiological heterogeneity of the various types of schizophrenia has been repeatedly proposed, relatively few attempts have been made to separate the component diseases. Using a strategy focusing on bimodal distributions within several relevant domains of schizophrenia, we demonstrate that currently available data on schizophrenia patients are consistent with the hypothesis that some of these patients have an ongoing neurodegenerative disease, whereas others do not. We review studies (longitudinal and cross-sectional) documenting progressive increases in ventricular size, accelerated loss of brain tissues, progressive delays in treatment response, and neurochemical (magnetic resonance spectroscopy) and neurophysiological (P300) indices, all of which are consistent with ongoing cerebral degeneration in a significant subgroup of schizophrenia patients. These lines of evidence converge on a conceptualization of schizophrenia as being composed of several etiologically distinct processes, with one subset of psychotic patients evidencing progressive brain degeneration. We conclude with a discussion of possible etiologies for this condition.

The authors describe their experience supervising and collaborating on projects that led to the first publications of several medical students and psychiatric residents. Rather than mandating a research project of all the residents, the faculty focus effort on the trainees with a sincere interest in writing a scholarly paper for publication. The authors break down the procedure of developing a published project into manageable steps that reflect and teach the scientific process. The mentoring required for these trainee-faculty publications is involved and time consuming, but the process is extremely rewarding. Four successful projects illustrate different levels of publication possibilities for trainees and demonstrate the positive effects the experiences had on their academic aspirations.

Several anatomic abnormalities in the brains of schizophrenics have frequently been reported. However, it remains unresolved whether such neuropathology is fully expressed and static at the onset of psychosis or whether further deterioration evolves during the course of illness. To address this important question, we obtained serial volumetric magnetic resonance images (MRI) of the cerebral ventricles of 18 patients with schizophrenic symptoms. Repeated blind measurements of total ventricular volume (TVV) revealed < 2% error of the segmentation method. Over a 2-3 year period, the rate of ventricular expansion (RVE) was 2.2 +/- 1.6 cm3/year in the patients and 0.7 +/- 0.6 cm3/year in controls. The RVE in the patients was not normally distributed, but clustered into two groups: a group similar to controls (n = 10; RVE, 0.9 +/- 0.5 cm3/year) and a group with a significantly greater rate of expansion (n = 8; RVE, 3.9 +/- 0.7 cm3/year) (P < 0.001). These results suggest that there are at least two subpopulations within the schizophrenias: one with relatively static ventricles and another with progressively enlarging ventricles. At least two distinct etiologic processes may thus underlie the clinical presentation of schizophrenic symptoms. Factors which might influence ventricular expansion (neuroleptic compliance, alcohol and recreational drug abuse, and some clinical correlates) could not account for differences between groups.

In an attempt to estimate dopamine production in psychotic patients, pHVA and pMHPG were assessed from morning blood samples of fasting, neuroleptic-free patients. The (pHVA/pMHPG) ratio was bimodally distributed. The upper mode delineated a cluster of psychotics with excess central dopamine activity. Despite a comparable duration of illness, the high ratio cluster had an earlier age of onset and a more complete subacute response during neuroleptic treatment than did lower ratio patients. Comparisons were made between these clusters and clusters defined by the distribution of pHVA alone. The data suggest a disorder of feedback control of central dopamine metabolism in the high pHVA/pMHPG cluster.

The distribution of drug-free plasma homovanillic acid (pHVA) concentrations was studied in a sample of psychotic patients, some of whom were selected for good prognostic features. Baseline pHVA was bimodally distributed, suggesting two different patient populations. The high-pHVA patients showed periods of better functioning and/or fewer symptoms 5 years before admission (p < .05) and had a more rapid (p < .05) and complete (p < .001) subacute neuroleptic response than lower-pHVA psychotics. High-pHVA psychotics did not differ in other aspects of demographics or clinical presentation from lower-pHVA psychotics. Compared to the general population, there were more psychotics in the families of high-pHVA patients (p < .005). Rapid antipsychotic response by high-pHVA psychotics is consistent with blockade of the effects of excess synaptic dopamine at D2 receptors for these patients. Results are discussed in the context of the syndromic heterogeneity of the psychoses.

Schizophrenic patients with an early age at onset of illness had low baseline levels of homovanillic acid (HVA) in serum compared with schizophrenic patients with a late age at onset. After adjustments were made for age at onset, there was a significant partial correlation between positive symptoms and serum HVA. The relationship between positive symptom scores and serum HVA was shifted to the left in the early onset patients, suggesting a relatively increased sensitivity of dopamine-associated response. Patients with severe negative symptoms also had an earlier age at onset and a trend toward lower serum HVA. This study found no difference between mean serum HVA values in schizophrenic patients and normal control subjects.

This study compared the course of illness of 36 patients who received a diagnosis of either DSM-III-R schizophreniform disorder or schizophrenia. Approximately 3.5 and 4.0 years after their index hospitalization, the two groups were compared for differences in positive and negative symptoms of psychosis, interpersonal and occupational role functioning, and other aspects of the deficit state. Multivariate data analyses indicate that the course of illness of the two groups is significantly different (p < .007), and the data also indicate that patient symptoms and functioning changed significantly over time (p < .008). The schizophreniform patients showed a low level of negative symptoms at both follow-ups; schizophrenics initially showed a higher level of negative symptoms, but these symptoms decreased significantly over time (p < .04). These data indicate that the course of DSM-III-R schizophreniform disorder is distinct from the course of schizophrenia.

Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was examined over a five-year period in the Veterans Affairs health care system. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for 522 patients, indicated a significant improvement, as did AIMS scores, which were available for 252 patients. Compared with individuals who showed a modest improvement, those with a more robust response to clozapine had higher initial BPRS scores and were three times more likely to have been suicidal in the month before starting clozapine therapy.

Psychiatric life histories of 487 first-degree family members of 24 lithium-responsive (mood-incongruent) psychotics, 54 lithium-nonresponsive (mood-incongruent) psychotics, and 18 lithium-responsive patients with bipolar (manic-depressive) disorder were contrasted. While the morbid risk of schizophrenic-spectrum was 11.1% in relatives of lithium-nonresponsive probands, the morbid risk for such disorders was only 2.4% in relatives of lithium-responsive (mood-incongruent) psychotics (P less than 0.05). This lithium-responsive illness appears to be familially, and perhaps genetically, distinct from the bulk of the schizophrenias.

1. 1. Clinical variables determining length of psychiatric hospitalization for psychotic inpatients were explored. Forty psychotic inpatients received a 14 day fixed dose neuroleptic trial. 2. 2. Neuroleptic responders ( 25 40 ) were discharged 15 ± 2 days after initiation of phannacotherapy. For neuroleptic non-responders ( 15 40 ) antipsychotic medication was then altered as clinically indicated. Patients requiring one change in medication (N = 8) were discharged after 27 ± 5 days; those requiring two medication adjustments (N = 4) were discharged after 33 ± 3 days and those requiring three alterations in phannacotherapy (N = 3) were discharged after 42 ± 12 days. 3. 3. Statistical analysis of clinical and diagnostic variables indicated that 84% of the variation in length of hospitalization was accounted for by the number of alterations in phannacotherapy required for symptom remission and discharge. It is suggested that length of hospitalization may be decreased by decreasing the length of time a clinician prescribes phannacotherapy that subsequently proves not effective. 4. 4. Bayesian analysis was employed to identify the minimum length of pharmacotherapy which accurately predicts subsequent antipsychotic response/non-response. During the fixed dose neuroleptic trial response/non-response could be accurately predicted for 65% of the patients by Day 3 of the trial while by Day 7 response/non-response could be predicted for 80% of the patients. 5. 5. The present data indicate that a three to seven day trial of antipsychotics may be sufficient for making phannacotherapy decisions as such a trial demonstrates a diagnostic efficiency similar to other predictive tests employed in clinical medicine.

Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity ( D m) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) ( n =8) were differentiated from poor responders (PR) ( n =5) according to previously defined criteria. Differences of D m at both baseline and following treatment were assessed using D m distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p

The accidental discovery (in the 1950s) and subsequent development of antipsychotic drugs have revolutionized the care of many patients with the schizophrenic psychoses. The first-generation antipsychotics, though effective for hallucinations, delusions, as well as a treatment of the disorder in two-thirds of patients with schizophrenia, burdened many patients with extrapyramidal effects (EPS), including dystonias, akathisia, and pseudo-Parkinsonian morbidity. Moreover, they had little or no effect on the most disabling, core symptoms associated with withdrawal of interests and interpersonal relationships. The second-generation antipsychotics, which began to appear in the late 1980s with the introduction of clozapine, had strikingly less morbidity, contributing little or no EPS and providing at least modest promise of reduction of negative symptoms and enhancement of some aspects of cognition. However, some second-generation antipsychotics have induced considerable weight gain, and appear to lower the threshold for the development of the metabolic syndrome, which increases cardio-vascular morbidity. The actual mechanism(s) of action of the antipsychotic drugs is still in dispute. Direct and indirect effects on dopamine transmission have been supported by much of the evidence. Direct blockade of dopamine hyperactivity and partial restoration deficient dopamine has been the standard explanation of their effects. However, dysfunctional intracellular signal transduction and dysfunction of myelin are emerging as competing pathologies upon which antipsychotics act. It is likely that the next generation of antipsychotics will act more directly and more specifically on such underlying neuropathology.

Research studies suggest that the left hemisphere is involved in the pathophysiology of dyslexia. Thus far, the exact location and nature of the purported lesion(s) remain a matter of contention. The present study describes the distribution of structural abnormalities as related to brain symmetry in the brains of dyslexic individuals. High-resolution three-dimensional magnetic resonance images (MRIs) were analyzed in 16 dyslexic men and 14 controls matched for sex, age, educational level, and handedness. A computerized image analysis system was used to assess the volumetric deformations required to match each brain with its left-right mirror image. The results showed significant abnormalities in five left hemisphere structures involving the extrapyramidal and limbic systems: amygdala, hippocampus proper, parahippocampal gyrus, putamen, and globus pallidus. The left hemisphere is thought to play a major role in the temporal analysis of information. This stream of temporal analysis is of importance in motor movements. Reading might have evolved as an exaptation to motor movements requiring the sequential analysis of information. ( J Child Neurol 2005;20:842—847).

Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein.Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n = 13) or a FGA (haloperidol; n = 6). Seven (untreated) control subjects were also assessed at a similar interval.During treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 +/- 11.4 cc (p.0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p = .983 and p = .932, respectively) at the time of reassessment.Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment.

Increased levels of lipid peroxidation products (thiobarbituric acid reactive substances [TBARS]) are reported in plasma/serum from patients with schizophrenia. CSF TBARS levels were assessed in 10 neuroleptic-free patients with schizophrenia and in 9 normal controls. Controlling for duration of storage, CSF TBARS content was significantly lower in patients with schizophrenia vs. controls (p

Thalamic volumes and psychotic symptoms were assessed during psychotic exacerbation and during antipsychotic drug treatment. Reduction of psychotic symptoms (SAPS) during four weeks of treatment was highly correlated with volumetric expansion as measured by magnetic resonance imaging in both left and right thalamus [r(s)=0.75 and r(s)=0.82, respectively (both P

Eleven drug-free patients with a DSM-IV diagnosis of schizophrenia who were in a period of psychotic exacerbation were treated with antipsychotics for 4 weeks. To evaluate treatment-associated changes in the basal ganglia and in psychotic symptomatology, the patients were studied with magnetic resonance imaging and with the Scale for the Assessment of Positive Symptoms. Serial assessments of striatal volumes and psychotic symptoms were performed at baseline and at 4 weeks of treatment; dual assessments of striatal volumes were also performed in 11 untreated normal controls. Patients and controls did not differ in striatal volumes at baseline, but the patients demonstrated a significant posttreatment increase in striatal tissues (caudate-putamen). An increase in left striatum was not associated with drug treatment itself, but with a reduction of positive symptoms.

Previous reports have described accelerated loss of cerebral white matter in schizophrenia. Others have reported changes of ventricle volumes in schizophrenic patients, with greatest increases following remission of psychotic symptoms. In this study changes in cerebral white matter volumes and psychotic symptoms were measured in 16 recently decompensated schizophrenic patients from neuroleptic-free baseline to 4 weeks later during treatment with antipsychotics. Serial white matter assessments were also performed in eight controls at similar intervals. Thirteen of 16 patients showed reduction of psychotic symptoms (reduction of SAPS scores by 24.4+/-12.6) during treatment. Three patients failed to respond (increase of SAPS scores by 15.7+/-13.8). Serial volumetric studies of cerebral white matter during the 4-week period showed a decrease of white matter volume in the responders by 8.2+/-8.2 cm(3) (P=0.003). Patients who failed to respond showed a non-significant increase in white matter during the same period by 11.4+/-11.7 cm(3). Absolute and percentage changes change in white matter volumes during the 4-week period were positively correlated with changes in SAPS scores (both P

Genome-wide linkage studies, examining the relationship between the schizophrenia syndrome(s) and possible susceptibility regions within the human genome have identified multiple regions within which linkage to the syndrome may be explored. No regions have been found to provide supportive evidence for linkage in all cohorts. These findings are consistent with the schizophrenia syndrome being genetically heterogeneous, with genetic susceptibility arising from multiple sites which are differentially distributed in from pedigree to pedigree. The authors present data from an autosomal-wide scan of 30 multiplex pedigrees, each with a mean of 4.1 members affected with a schizophrenia spectrum disorder with respect to regions of interest for linkage with the schizophrenia spectrum disease(s). Partial, though not significant replications of susceptibility sites at D1S518 ( P =0.029) described by Shaw et al. (1998 : Shaw, S.H., Kelly, M., Smith, A.B., Shields, G., Hopkins, P.J., Loftus, J., Laval, S.H., Vita, A., DeHert, M., Cardon, L.R., Crow, T.J., Sherrington, R., DeLisi, L.E., 1998. A Genome-wide search for schizophrenia susceptibility genes. Am. J. Med. Genet. (Neuropsychiatric Genet.) 81, 364–376.), and at D5S426 ( P =0.015) described by Silverman et al. (1996 : Silverman, J.M., Greenberg, D.A., Altstiel, L.D., Siever, L.J., Mohs, R.C., Smith, C.J., Zhou, G., Hollander, T.Y., Yang, X.-P., Kedache, M., Li, G., Zaccario, M.L., Davis, K.L., 1996. Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree. Am. J. Med. Genet. 67, 162–171.) were documented using multipoint non-parametric (NPL) statistics. Two additional novel regions worthy of further investigation were identified at D1S1150 ( P =0.004) and at D20S171 ( P =0.009). Previously reported genomic regions of interest for the schizophrenias are reviewed in the context of the same/flanking markers utilized with the present cohort of pedigrees. The data further suggests that only a fraction of pedigrees multiplex for schizophrenia link at any single susceptibility region.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule involved in cellular migration, synaptic plasticity, and CNS development. A 105- to 115-kDa isoform of N-CAM (cleaved N-CAM or cN-CAM) is increased in schizophrenia in hippocampus, prefrontal cortex, and CSF. We purified and partially characterized cN-CAM, a putative novel isoform, and confirmed that the first 9 amino acids were identical to exon 1 of N-CAM, without the signal sequence. Analysis of trypsin-digested cN-CAM fragments by matrix-assisted laser desorption ionization on a time-of-flight mass spectrometer (MALDI-TOF) yielded peptides that could be identified as being derived from the first 548 amino acid residues of the expected N-CAM amino acid sequence. Immunological identification with four specific N-CAM antisera directed toward cytoplasmic, secreted, variable alternative spliced exon, or GPI epitopes failed to indicate other known splice variants. Neuraminidase treatment of cN-CAM produced a minor alteration resulting in a faster migrating immunoreactive band, indicating partial glycosylation of cN-CAM. Membranous particles from cytosolic brain extract containing cN-CAM were obtained by ultracentrifugation; however, CSF contained few such particles. cN-CAM and synaptophysin were colocalized on these particles. Both cN-CAM and N-CAM 180 were present in synaptosomal preparations of human brain. Following incubation of synaptosomes or brain tissue without protease inhibitors, N-CAM 180 was degraded and cN-CAM was increased. A cN-CAM-like band was present in human fetal neuronal cultures, but not in fetal astrocyte cultures. Thus, cN-CAM represents a protease- and neuraminidase-susceptible fragment possibly derived by proteolytic cleavage of N-CAM 180. An enlargement in ventricular volume in a group of adult patients with schizophrenia over a 2-year interval was found to be correlated with CSF cN-CAM levels as measured at the time of the initial MRI scan (r = 0.53, P = 0.01). cN-CAM is associated with ventricular enlargement; thus, the release of N-CAM fragments may be part of the pathogenic mechanism of schizophrenia in vulnerable brain regions such as the hippocampus and prefrontal cortex. Alternatively, the increases in cN-CAM in schizophrenia may be a reflection of a more general abnormality in the regulation of proteolysis or of extracellular matrix stability.

A pattern of negative symptoms associated with a high rate of ongoing brain and ventricular instability has been described in a cohort of schizophrenia spectrum probands (patients with schizophrenia, schizoaffective disorder depressed and bipolar, and psychosis NOS) (Garver, D.L., Nair, T.R., Christensen, J.D., Holcomb, J., Ramberg, J., Kingsbury, S., 1999. Differential patterns of premorbid functioning, symptoms and neuroleptic response in stable and unstable ventricular-volume schizophrenia. Neuropsychopharmacology 20, in press). The present study contrasts the prevalence of negative symptoms in first- and second-degree relatives of probands with unstable ventricle volume (UnsVV) and stable ventricle volume (SVV). One hundred and sixteen first- and second-degree relatives of 10 probands were interviewed using the SANS, the ‘Characterization of Course: “Pattern of Symptoms” ’ [from Comprehensive Assessment of Symptoms and History (CASH)], SCID and SCID-II by interviewers blind to the status of the proband. Thirty-five of the 116 family members met DSM-IV criteria for schizophrenia, SA depressed, ‘Cluster A’ of the SCID-II (paranoid, schizotypal, schizoid personality disorder), psychosis NOS, or psychotic affective disorder. These 35 family members were defined as falling within a ‘schizophrenia spectrum’ as described by Farmer, A.E., McGuffin, P., Gottesman, I.I., 1987. Arch. Gen. Psychiatry 44, 634–641, but with the addition of DSM-IV affective psychosis. On that basis, the 35 members were considered ‘affected family members’ (AFMs). The remaining 81 family members were considered unaffected. The ‘predominant symptoms of illness‘ (during the past 2–3 years) for 25 of the 35 AFMs could be characterized according to the ‘Patterns of Symptoms‘ derived from the CASH. Twenty-five of the 35 AFMs were found to maintain a predominant symptom pattern during the course of illness, which could be characterized according to the ‘Pattern of Symptoms‘ as ‘predominantly positive‘ or ‘predominantly negative‘. Three of the probands had UnsVV; seven had SVV. Of the 35 AFMs, 11 were related to the UnsVV probands, and 24 were relatives of the SVV probands. The nine rated AFMs of the UnsVV probands showed a trend toward higher SANS scores (7.3±5.1) (mean±s.d.) than the 20 rated AFMs of SVV probands (4.3±5.1) ( p =0.08) at the time of the interview. Eighty-three per cent (eight of 10) of rated affected pedigree members of the pedigrees delineated by probands with UnsVV probands had a predominantly negative symptom course of illness, and 96% (23 of 24) of rated affected pedigree members of the pedigrees with SVV probands had a predominantly positive symptom course of illness during the preceding 2–3 years ( p =0.002). None of the 12 rated affected pedigree members within pedigrees having UnsVV probands were married at the time of the interview; 45% (14 of 31) of affected pedigree members having SVV probands were married ( p =0.004). A psychiatric disorder, characterized by unstable cerebral ventricles and predominant negative symptoms (including avoidance/failure of marital relationships) appears symptomatically to breed true in pedigrees containing schizophrenia-like illnesses.

An increased concentration of neural cell adhesion molecule (N-CAM) 105-115 kDa has been reported in patients with schizophrenia in both CSF and in post-mortem brain samples. To determine whether increased N-CAM is integral to the disease process or, alternatively, results from early treatment, CSF N-CAM was measured in a blind study of first episode (FE) patients, who were either neuroleptic-naïve (NN) or neuroleptic-treated (NT,100 mg Haldol equivalents), multi-episode (ME) patients, and controls. Overall, the FE patients displayed lower N-CAM concentrations as compared to controls (p = 0.043). This decrease in N-CAM in FE patients was seen only in the FE-NT group as compared to both controls (p = 0.0006). The FE-NT group also showed a lower CSF N-CAM compared to that in the FE-NN (p = 0.025) group. No difference in CSF N-CAM between the FE-NN and control group was found. ME patients showed an increased N-CAM as compared with FE patients (p = 0.018), but not as compared to controls (p = 0.93). Neuroleptic-naïve first-episode patients do not display a phenotypic increase in N-CAM. Thus, N-CAM is altered in first-episode patients following acute neuroleptic treatment and withdrawal, as compared to neuroleptic-naïve first-episode patients.

Evidence is increasing in support of the etiologic heterogeneity of schizophrenia. Five distinct diseases/disorders are suggested in this paper, and the relevant studies are reviewed. Familial forms of the disorder include a dopamine psychosis (supported by research documenting both altered dopamine activity and early neuroleptic response among some schizophrenic patients), a neurodegenerative psychosis (supported by investigations that document ongoing change in ventricular brain ratio, elevation of products of cell membrane catabolism within the central nervous system, and age-progressive third ventricle enlargement accompanied by delayed response to neuroleptics), and a neurodevelopmental psychosis (supported by evidence of static enlarged ventricles in some schizophrenic patients and neurological soft signs in high-risk offspring of schizophrenic individuals). Nonfamilial forms include a neurodevelopmental psychosis (supported by evidence of neurodevelopmental abnormalities triggered by neurotropic viruses, radiation, or anoxia) and a lithium-responsive psychosis (supported by evidence of a subgroup of psychotic patients who have low risk of either psychosis or mania in their pedigrees and respond to lithium).

Conversions between dissimilar antipsychotic agents can be problematic. Agents of low potency present risks of central depressant and autonomic side effects, whereas agents of high potency carry a higher risk of inducing acute extrapyramidal effects. Conversions between clozapine and other more typical antipsychotic drugs, including the new agent risperidone, 1 are increasingly common and may cause special problems. For example, over a dozen cases of worsening of psychotic symptoms after abrupt withdrawal from clozapine therapy have been reported 2-7 and at least five additional similar cases have been observed recently at our centers (D.M.G and R.J.B., unpublished data, June 1995). These reactions often evolved over several days and so were much more rapid than relapses after stopping treatment with standard agents, which average 50% risk over a 3- to 4-month period. 8,9 Moreover, several case reports 6,10,11 and cases observed at our centers (by D.M.G., D.L.G., and R.J.B. May 1995)

Objective This study sought to characterize a subset of patients with DSM-III schizophrenia or schizophreniform disorder who respond to lithium. Method Sixty-six psychotic patients were given a systematic therapeutic trial of lithium alone. Differences in demographic characteristics, symptoms, and family history of psychotic disorders between the responders and nonresponders to lithium were explored. Results Responders and nonresponders did not differ significantly in age, duration of illness, length of current episode, distribution of RDC and DSM-III diagnoses, or number of positive symptoms. However, the responders to lithium (N = 10) exhibited a paucity of negative symptoms and an absence of familial schizophrenic spectrum disorders. Conclusions These preliminary results suggest the possibility of pretreatment identification of psychotic patients for whom neuroleptic medication could be avoided by therapeutic intervention with lithium alone.

Objective : The authors' goal was to determine whether higher doses of haloperidol improve antipsychotic response. Method : During a 2-week, double-blind, randomized fixed-dose study, 24 psychotic patients were given 4, 10, or 40 mg/day of haloperidol. Results : No clinically relevant difference between groups in favor ofthe higher antipsychotic doses could be detected. Conclusions : Doses of 4 mg/day of haloperidol appear to be as effective as higher doses in the treatment of psychosis.

Patients with schizophrenia have been described as having deficits in the ability to recognize facial expressions of emotion. We report the results of a study on the effects of global psychopathology, positive and negative symptoms, diagnostic subtype, and antipsychotic medications, on the ability of subjects with schizophrenia to recognize facial affect. Eighteen SCID diagnosed patients with schizophrenia and ten matched controls were evaluated at a drug-free baseline for ability to identify facial expression expressed in a standardized series of photographs, with concurrent measures of global psychopathology, and positive and negative symptoms. At baseline patients were impaired in affect recognition relative to the normals, and impairment was not related to measures of psychopathology or positive or negative symptoms. Performance did not improve with antipsychotic treatment, and patients with paranoid schizophrenia had significantly better affect recognition abilities than non-paranoid patients.

1. 1. 10 male cocaine dependent patients and 10 sex matched controls were administered several behavioral measures of aggression including the Buss-Durkee Hostility Inventory, and The Brown-Goodwin Life History of Aggression. 2. 2. All subjects were also administered a buspirone neuroendocrine challenge as a measure of serotonin function. 3. 3. The cocaine dependent subjects were significantly more aggressive than the controls. 4. 4. There was a significant correlation between the growth hormone response to buspirone and behavioral measures of aggression in the cocaine dependent subjects, but not in the controls. 5. 5. There was no difference in the overall growth hormone response between the controls and cocaine dependent subjects, possibly due to differences in metabolism of buspirone. 6. 6. This study supports a role for serotonin in aggression in cocaine dependent subjects.

Recent data suggest that latency of neuroleptic response may be used to separate distinct subtypes of psychotic disorders. In this preliminary study we contrast family patterns of illness of rapid neuroleptic response psychotics and delayed neuroleptic response psychotics. The data show that first-degree relatives of delayed neuroleptic response psychotics evidence higher levels of psychiatric disorder than rapid responders: relatives of delayed neuroleptic response psychotics evidenced a morbid risk for schizophrenic-spectrum disorder that was more than twice as high as the morbid risk for such disorders among relatives of rapid neuroleptic response psychotics. Relatives of delayed neuroleptic responders that received a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder evidenced significantly more residual impairment than schizophrenic-spectrum relatives of rapid neuroleptic responders. These preliminary data indicate the possibility that latency of therapeutic response to neuroleptic medication may be used to discriminate two familially distinct psychotic disorders and they suggest that delayed neuroleptic response may characterize a familially transmitted poor-outcome disease.

Objective: The authors investigated the putative endogenous antipsychotic neurotensin in relation to both psychotic symptoms and patterns of response during treatment with an antipsychotic drug. Method: Twenty recently admitted patients with mood-incongruent psychoses underwent 1) interviews with the Schedule for Affective Disorders and Schizophrenia f or diagnostic evaluation and symptom profiles, 2) drug-free baseline measurements of CSF neurotensin and homovanillic acid, and 3) close monitoring of a therapeutic trial of haloperidol to determine latency of antipsychotic response. Results: A relative deficiency in CSF neurotensin was found in a subgroup of psychotic women whose clinical response to haloperidol was delayed for I 1 to 35 days after initiation of the neuroleptic. These patients had greater thought disorder, delusions-hallucinations, behavioral disorganization, and impaired functioning than did psychotic patients with higher CSF concentrations of neurotensin. Neurotensin concentrations increased during treatment with haloperidol. Conclusions: The study provides further evidence that there is diminished availability of neurotensin in some psychotic patients, with increases in neurotensin early in neuroleptic treatment. Exploration of neurotensin receptor agonists as a potentially novel class of antipsychotic compounds is suggested. (Am J Psychiatry 1991; 148:484-488)

Enlargement of the cerebral third ventricle appears to be a replicable finding in groups of patients with psychotic illnesses, and there is evidence for an association of third ventricle enlargement with poorer response to treatment. Third ventricle area and width were measured from computed tomography (CT) scans in 24 mood-incongruent psychotic patients and 14 controls age and gender matched to schizophrenic patients. Patients were treated with a fixed dose of haloperidol and classified as rapid responders (55% symptom reduction on New Haven Schizophrenic Index (NHSI) within 4.5 +/- 1.3 days) or delayed responders (55% symptom reduction on NHSI within 18.6 +/- 10.5 days). The significant enlargement of third ventricle area was isolated among the 12 delayed neuroleptic responders (19.3 +/- 9.0 mm2) compared with the 14 controls (11.7 +/- 4.8 mm2, p = 0.01), and 12 other mood-incongruent psychotics. Third ventricle width also showed a trend towards larger width in the delayed responders. There was a clear positive correlation between ventricular size and patient's age exclusively in the delayed responders (r = 0.78); a comparable relationship between ventricular size and age was not present in controls, or in the other psychotics. This finding is consistent with an age-related progressive degenerative process in the central nervous system (CNS) isolated to the neuroleptic-delayed responsive psychotics.

1. The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. 2. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments. 3. Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HT1 receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HT1 mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HT1 receptors. 6. Patient studies, employing a 5-HT1 mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HT1 receptors; and that chronic antidepressant treatment facilitates 5-HT1 receptor responsiveness in depressed patients. 7. New 5-HT1 selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HT1 receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta-1 receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-1 agonists, which like clinically proven antidepressants, decrease beta-1 receptor responsiveness with chronic treatment. 11. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment.

This study examined neuropsychological functioning in two subgroups of patients with familial schizophrenia. Those who showed evidence of progressive ventricular enlargement observed across serial MRI scans (n=6) were compared with subjects whose ventricular volume remained static (n=10) over an average of 28 months. No differences were found in terms of age, education, ethnicity, level of psychotic symptomatology, DSM-IV subtype, age of onset, or duration of illness. Neurocognitively, the static ventricle group was impaired across more cognitive domains and had a larger percentage of subjects falling into the impaired range on a majority of measures, with the greatest differences on measures of attention (pb0.02) and nonverbal memory (pb0.07). These results suggest that clinically meaningful differences between these two MRI-derived subgroups of patients with schizophrenia may exist, and further underscore the heterogeneity of the illness. © 2007 Elsevier B.V. All rights reserved.