Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

CSF homocysteine is not elevated in schizophrenia.

Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimer's disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients. We now studied two groups of schizophrenia patients (N=41) and controls (N=29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p=.041 for Study A and p=.52 for Study B).

Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees.

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, 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.

Characterization of human cleaved N-CAM and association with schizophrenia.

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.

Brain and ventricle instability during psychotic episodes of the schizophrenias.

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; P<0.0005); 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.

Review of quetiapine side effects.

The newest atypical antipsychotic medication to be approved by the U.S. Food and Drug Administration, quetiapine is a drug that awaits a wide range of clinical and head-to-head comparisons. Nevertheless, clinical trials currently available suggest that quetiapine has a beneficial side effect profile, particularly with regard,to extrapyramidal symptoms. To date, quetiapine has also proved effective in the treatment of schizophrenia, but its efficacy, while clearly superior to that of placebo, seems no greater than that of haloperidol or chlorpromazine. Clinical trials have supported the use of quetiapine in treating elderly patients. Further research is necessary to establish the clinical profile of quetiapine.

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.

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.

Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response.

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.

Negative symptoms of familial schizophrenia breed true in unstable (vs. stable) cerebral-ventricle pedigrees.

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.

CSF N-CAM in neuroleptic-naïve first-episode patients with schizophrenia.

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.

Heterogeneity of the psychoses: is there a neurodegenerative psychosis?

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.

Lithium and psychosis revisited.

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.

Mentoring psychiatric trainees' first paper for publication.

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.

Progression of cerebroventricular enlargement and the subtyping of schizophrenia.

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.

A biomodal distribution of plasma HVA/MHPG in the psychoses.

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 etiologic heterogeneity of schizophrenia.

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).

Etiologic heterogeneity of the psychoses: is there a dopamine psychosis?

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.

Risk factors for clozapine discontinuation among 805 patients in the VA hospital system.

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.