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.

Neuropsychological functioning in MRI-derived subgroups of schizophrenia.

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<0.02) and nonverbal memory (p<0.07). 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.

Lithium ratio in vitro. Diagnosis and lithium carbonate response in psychotic patients.

The distribution of RBC lithium ratios in vitro in a recently hospitalized psychiatric population was found to be multimodal. Psychotic patients who had an antipsychotic response during open trials of lithium carbonate alone were identified with high sensitivity (89%), but low specificity (51%) before drug treatment, by lithium ratios that were in the extreme modes of the distribution (less than 0.30 or greater than 0.38). Diagnostic efficiency of the test was 61%. The DSM-III diagnosis of schizophreniform disorder demonstrated 90% diagnostic efficiency in predicting response/nonresponse during treatment with lithium carbonate alone. A subgroup of the psychotic disorders was similar to affective disorders with respect to course of illness, biological characteristics, and response to lithium carbonate.

Relation of clinical symptoms to apomorphine-stimulated growth hormone release in mood-incongruent psychotic patients.

The relationship between dopamine receptor agonist (apomorphine hydrochloride)-stimulated growth hormone (GH) release and psychotic symptoms was examined in 138 schizophrenic or schizoaffective inpatients (Research Diagnostic Criteria) and ten healthy normal volunteers. Patients were divided into three groups: those demonstrating an abnormally large GH response, an average GH response (mean GH response), or an abnormally low GH response. Abnormally large GH responses were associated with higher total psychosis scores. The increased psychosis scores observed in this group were due primarily to an increased incidence of thought disorder. Further analysis revealed a strong, positive correlation between thought disorder and the GH response. The apomorphine-stimulated GH response was also significantly related to duration of illness, an effect independent of age. Consistent with this last result, patients with a diagnosis of a DSM-III schizophreniform disorder demonstrated an elevated GH response.

Pharmacokinetics of red blood cell phenothiazine and clinical effects. Acute dystonic reactions.

Pharmacokinetics of the phenothiazine, butaperazine, were studied in relationship to acute dystonic reactions. Dystonias appeared on falling drug concentrations, more than one half-life after plasma and red blood cell (RBC) peak butaperazine concentrations. Red blood cell butaperazine kinetics differentiated better than did plasma butaperazine levels those subjects in whom dystonias would develop from those in whom they did not. We conclude that RBC phenothiazine levels may more clearly reflect drug concentration at critical brain sites than do simple plasma drug levels. Furthermore, dystonic reactions may be the result of differential sensitivity of two or more receptor systems to receptor blockade by antischizophrenic agents.

Phenothiazine levels in plasma and red blood cells. Their relationship to clinical improvement in schizophrenia.

A controlled study investigated the relationship between steady-state plasma and RBC concentrations of the phenothiazine derivative butaperazine maleate and the therapeutic response in 24 hospitalized schizophrenic patients who received constant maintenance doses of butaperazine during the first two weeks of treatment. Butaperazine concentrations in RBCs correlated significantly with clinical improvement in an inverted U-shaped pattern, whereas plasma levels of butaperazine were not significantly related to clinical response. Both plasma and RBC levels of butaperazine showed large interpatient variations. The level of RBC-bound drug might be a better peripheral correlate of drug levels in the brain than are drug levels in plasma. Thus, monitoring drug levels in RBCs might have an advantage over measured drug levels in plasma. These findings might not allow generalization to other antipsychotic agents.

Familial differences between rapid neuroleptic response psychosis and delayed neuroleptic response psychosis.

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.

Characteristics of phospholipid methylation in human erythrocyte ghosts: relationship(s) to the psychoses and affective disorders.

Recent studies have shown that patients with a schizophrenic-like illness have a significant deficit in erythrocyte ghost membrane (EGM) phosphatidylcholine (PC); patients with the most severe deficiency showed a marked decrease in Na+-Li+ counterflow activity (Hitzemann et al. 1984a and b). The present study was undertaken to see if the decrement in PC is associated with a decrease in phospholipid methylation activity. Phospholipid methylation in human EGMs is distinctly different from that in rat EGMs (Hirata and Axelrod 1980) in that the human activity is not Mg++-dependent, and apparent methyltransferase I activity is located in the external membrane surface. The patient population consisted of 20 DSM-III schizophrenics (SCZ), 13 DSM-III schizophreniform (SF) disorder patients, and 11 DSM-III manics (M). Twelve age- and sex-matched controls were used for the comparison group. Methylation activity was significantly decreased in all three patient groups, although the M group had significantly higher activity than the SF group. Twenty-four of the SCZ and SF patients entered a Li+ trial. The Li+ responder group (n = 8) showed significantly lower activity than the nonresponder group (n = 16). Overall, we conclude that the decrement in phospholipid methylation activity partially contributes to the decrement in PC levels.

RBC lithium transport in the psychoses.

In vitro and in vivo red blood cell (RBC) lithium (Li+) intracellular/extracellular ratios were determined in 93 DSM-III schizophrenics (SCZ) in 47 DSM-III schizophreniform disorder patients (SF), in 22 DSM-III bipolar manics (M), in 15 affective disorders patients with mood-incongruent psychotic features (AD-MIP), and in 40 normal controls. There were no significant differences among groups in the in vitro Li+ ratio. Similarly, there was no significant difference among patient groups in the in vivo Li+ ratio. Furthermore, there was no significant difference in the mean Li+ ratios between the Li+-responsive and nonresponsive schizophrenic-like subjects. However, the distribution of Li+ ratios (both in vitro and in vivo) in the Li+-responsive group was significantly abnormal, showing more ratios in the extremes of the distribution (a platykurtic distribution).

TSH response to TRH and haloperidol response latency in psychoses.

Thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) was measured in 19 acutely psychotic (DSM-III schizophrenia, 7; schizophreniform, 2; schizoaffective, 3; affective, mood-incongruent psychosis, 5; manic, mood-congruent psychosis, 2) drug-free patients prior to systematic trials of lithium and/or haloperidol. TSH response was not associated with sex, age, baseline T4, or baseline TSH. A reduced TSH response was associated with affective diagnosis and was a significant predictor of a positive, rapid response to neuroleptic treatment.

Growth hormone response to apomorphine and family patterns of illness.

Sixty-five psychotic probands were divided into three groups (low, intermediate, and high) on the basis of the GH response to the dopamine receptor agonist apomorphine. Two hundred and sixty-five first-degree relatives of the probands were diagnosed according to SADS-DSM-III methods, and the relatives of the three groups of probands were compared so as to detect familial differences in the incidence of DSM-III Axis I disorders, schizotypal personality disorder, and antisocial personality. Although the morbid risk of schizophrenic spectrum disorder was only 3.1% in the relatives of the high GH probands, the morbid risk for disorders of the schizophrenic spectrum was 17.0% and 10.7% in the relatives of the intermediate and low GH probands, respectively. These data provide preliminary evidence that there may be a psychotic subtype that is characterized by supersensitivity of the dopamine system that is familially, and perhaps genetically, distinct from the bulk of the schizophrenias.

Growth hormone response to apomorphine and diagnosis: a comparison of three diagnostic systems.

Our study takes a further look at the apomorphine test in the psychoses and affective disorders, with special reference to the use of different diagnostic systems. Patients meeting Research Diagnostic Criteria (RDC) for schizophrenia, schizoaffective disorder, or manic disorder were included. In addition to the RDC, diagnosis was also made using the DSM-III and ICD-9. All patients underwent an evaluation of peak GH response to apomorphine administration. The results show that RDC and ICD-9 are similar, in that for both systems, a high GH response correlates with a schizoaffective disorder and distinguishes those patients significantly from manic patients. The DMS-III brings in some new dimensions, in that schizophreniform disorder (6-month cut-off) is distinguished from schizophrenia. In addition, patients with affective symptoms and mood-incongruent psychoses are more closely related to schizophreniform disorder than to classical manic disorder.

Enlargement of cerebral third ventricle in psychotic patients with delayed response to neuroleptics.

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.

Nicotinic receptor desensitization and sensory gating deficits in schizophrenia.

BACKGROUND: Nicotinic receptor dysfunction is a possible mechanism of the abnormal sensory gating observed in schizophrenia with the P50 auditory event-related potential. Although nicotinic receptors normally desensitize after activation by acetylcholine or nicotine, pathologically increased desensitization might cause receptor dysfunction in schizophrenia. To examine this possibility, central cholinergic neuronal activity was diminished by allowing schizophrenic patients to sleep briefly, after which they experienced a transient period of normal P50 gating, consistent with receptor resensitization during the absence of cholinergic stimulation. A critical test of the mechanism is whether this resensitization is blocked by concurrent administration of nicotine, which would provide continuous receptor stimulation. METHODS: Six schizophrenic patients repeated the sleep experiment during nicotine exposure from a dermal patch, in a double-blind, placebo-controlled design. RESULTS: The normalization of P50 gating immediately postsleep was replicated in the placebo arm, but this effect was decreased in all six patients during exposure to nicotine. CONCLUSIONS: The results suggest that nicotinic receptor desensitization is responsible for the loss of P50 gating in schizophrenia.

Growth hormone levels and lithium ratios as predictors of success of lithium therapy in schizophrenia.

The authors previously found a high correlation between lithium response and clinical diagnostic criteria in a subgroup of schizophrenic-like patients who responded favorably to lithium therapy. In the present study the authors extend this research by using biological markers to predict and identify such patients. They examined growth hormone (GH) response to apomorphine administration and the in vitro lithium ratio in 31 patients before and after a 2-week lithium trial. Peak GH levels (greater than or equal to 20 ng/ml) and lithium ratios (greater than or equal to .39) were correlated with a positive response to lithium therapy. The authors discuss 1) the use of these two biological markers to predict the success of lithium therapy in schizophrenia and 2) biological abnormalities characteristic of lithium-responsive schizophrenic patients.

Down-regulation of central dopamine receptors in schizophrenia.

CSF homovanillic acid (HVA) levels reflecting central dopamine release and apomorphine-stimulated human growth hormone (HGH) secretion reflecting central dopamine receptor activity were concomitantly determined in 20 schizophrenic patients. There was a strong negative correlation between HVA and HGH levels: high dopamine release was associated with lower HGH responses to dopamine receptor activation by apomorphine. Studies are reviewed which suggest that the presently observed relationship reflects release-mediated down-regulation of central D2 receptors, the dopamine receptor subtype associated with the antipsychotic properties of neuroleptic medication.

Growth hormone catecholamines in affective disease.

The authors studied growth hormone (GH) release after insulin-induced hypoglycemia (HI) in relation to urinary MHPG, the major metabolite of central norepinephrine. There was a significant linear correlation of urinary MHPG levels and GH peaks after HI in unipolar depressed patients and in manic patients; however, GH peaks in manic patients shifted downward on the GH axis in comparison to the unipolar depressive patients. The authors suggest that such shifts in the GH response may occur as a result of abnormalities of other neurotransmitter systems also known to facilitate GH release.

Relation of CSF neurotensin concentrations to symptoms and drug response of psychotic patients.

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 for 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 11 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.

Predictors of response to lithium in patients with psychoses.

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.

Lithium response in good prognosis schizophrenia.

The authors report the results of a 2-week lithium trial using 31 patients meeting Research Diagnostic Criteria for schizophrenia or schizoaffective disorder who were also diagnosed according to DSM-III criteria. One-third of the patients showed reduction of their schizophrenic-like symptoms during the lithium trial. Seven of the 9 responders (78%) met DSM-III criteria not for schizophrenia but for a schizophreniform disorder. Such patients also met McCabe and associates' criteria for good prognosis schizophrenia. This study lends further support to the growing body of evidence which suggests that schizophreniform disorder and good prognosis schizophrenia may be affective disorders with atypical schizophrenic-like features. The authors cautiously suggest that a lithium trial may be indicated in this subgroup of patients.