Advances in schizophrenia.

Recent studies into the etiology of schizophrenia have yielded both promising leads and disappointing dead ends, indicating the multifactored and complex nature of the disorder. The focus has subsequently shifted back to refining the phenotype and identifying clinical and biological subtypes. Recent technological breakthroughs in genomics and proteomics hold promise for advancing our understanding of the molecular pathophysiology of schizophrenia.

The psychoses: cluster 3 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: In an effort to group mental disorders on the basis of etiology, five clusters have been proposed. Here we consider the validity of the cluster comprising selected psychotic and related disorders. METHOD: A group of diagnostic entities classified under schizophrenia and other psychotic disorders in DSM-IV-TR were assigned to this cluster and the bordering disorders, bipolar (BD) and schizotypal personality disorders (SPD), were included. We then reviewed the literature in relation to 11 validating criteria proposed by the DSM-V Task Force Study Group. RESULTS: Relevant comparisons on the 11 spectrum criteria are rare for the included disorders except for schizophrenia and the two border conditions, BD and SPD. The core psychosis group is congruent at the level of shared psychotic psychopathology and response to antipsychotic medication. BD and SPD are exceptions in that psychosis is not typical in BD-II disorder and frank psychosis is excluded in SPD. There is modest similarity between schizophrenia and BD relating to risk factors, neural substrates, cognition and endophenotypes, but key differences are noted. There is greater support for a spectrum relationship of SPD and schizophrenia. Antecedent temperament, an important validator for other groupings, has received little empirical study in the various psychotic disorders. CONCLUSIONS: The DSM-IV-TR grouping of psychotic disorders is supported by tradition and shared psychopathology, but few data exist across these diagnoses relating to the 11 spectrum criteria. The case for including BD is modest, and the relationship of BD to other mood disorders is addressed elsewhere. Evidence is stronger for inclusion of SPD, but the relationship with other personality disorders along the 11 criteria is not addressed and the absence of psychosis presents a conceptual problem. There are no data along the 11 spectrum criteria that are decisive for a cluster based on etiology, and inclusion of BD and SPD is questionable.

Dopamine agonist treatment of schizophrenia with N-propylnorapomorphine.

We administered N-propylnorapomorphine, a potent aporphine-family dopamine (DA) agonist, to schizophrenic patients with active psychotic symptoms. After acute administration a significant antipsychotic action of N-propylnorapomorphine, maximal at an oral dose of 19 mg, was noted. The antipsychotic action predominated in subjects with neuroleptic-responsive symptoms, not in neuroleptic-nonresponders. However, when N-propylnorapomorphine was administered on a subchronic dosage schedule, no antipsychotic effect occurred. These observations suggest a rapid-onset tolerance phenomenon of psychosis to N-propylnorapomorphine and are consistent with results from preclinical experiments. These data support the idea that the acute antipsychotic response of DA agonists is mediated by the DA autoreceptor but fail to provide evidence for the potential clinical usefulness of this treatment approach.

Brain gamma-aminobutyric acid abnormality in tardive dyskinesia. Reduction in cerebrospinal fluid GABA levels and therapeutic response to GABA agonist treatment.

A double-blind, placebo-controlled trial of gamma-vinyl gamma-aminobutyric acid (GVG) and 4,5,6,7-tetrahydroisoxazolo-(5,4-c) pyridine-3-ol (THIP) was carried out in drug-free schizophrenic patients with tardive dyskinesia. A significant decrease in dyskinetic symptoms occurred with the administration of GVG, associated with a twofold increase in cerebrospinal fluid levels of GABA; THIP produced a more moderate, yet consistent decrease in the involuntary movements. A pathophysiologic role for gamma-aminobutyric acid (GABA)-mediated neuronal transmission in tardive dyskinesia was explored by analyzing cerebrospinal fluid GABA concentrations in drug-free schizophrenic patients with and without tardive dyskinesia. A significant reduction in cerebrospinal fluid levels of GABA was observed in the dyskinetic schizophrenics compared with the nondyskinetic controls. These data compliment a growing body of experimental evidence suggesting a critical role for GABA-ergic neurons in the pathophysiology of tardive dyskinesia.

Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome.

A hypothesis of psychosis localization in schizophrenia was derived from studying metabolic alterations in rat brain in response to phencyclidine hydrochloride administration. Since phencyclidine and its selective agonist dizocilpine maleate (MK801) induced overlapping and long-lasting metabolic alterations predominantly in limbic areas, the hypothesis developed that schizophrenic patients with psychosis would evidence functional abnormalities in limbic circuits compared with normal controls. Accordingly, 12 actively psychotic, drug-free patients with schizophrenia and matched normal controls underwent functional brain scans using positron emission tomography and fluorodeoxyglucose. Regions of interest were identified on five matched axial slices in each patient and control subject, and average metabolic rates were calculated. Patients with schizophrenia showed a significantly lower regional cerebral metabolic rate of glucose in the hippocampus and the anterior cingulate cortex than did normal controls, but not in neocortical areas or in the extrapyramidal system. When the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary exploratory analysis suggested thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that different manifestations of schizophrenia may involve different neuronal circuits.

Smooth pursuit eye movements to extraretinal motion signals: deficits in relatives of patients with schizophrenia.

BACKGROUND: Although mounting evidence supports the idea that smooth pursuit abnormality marks the genetic liability to schizophrenia, the precise ocular motor mechanism underlying the abnormality remains unknown. Based on recent findings in schizophrenia, we hypothesize that subtle deficits in the ability to hold online and/or use extraretinal motion information underlie the pursuit abnormality in vulnerable individuals. METHODS: The hypothesis was tested in 69 first-degree, biological relatives of probands with schizophrenia; 26 relatives had schizophrenia spectrum personalities (SSP). Subjects recruited from the community (n=71; 29 with SSP), without a known family history of psychosis, constituted the comparison groups. The traditional smooth pursuit gain measure, which is a ratio of smooth pursuit eye velocity in response to both retinal and extraretinal motion signals and the target velocity, was obtained. In addition, newly developed measures of predictive smooth pursuit (ie, in the presence of only extraretinal motion signals) were obtained. The latter measures were evaluated after the current retinal motion signals were made unavailable by briefly making the target invisible. RESULTS: Relatives, particularly those with SSP, showed significantly poorer predictive pursuit response to extraretinal motion signals (F(2,136)=6.51, P<.005), compared with the community subjects. However, the traditional smooth pursuit gain in response to both retinal and extraretinal motion signals was not different between groups. CONCLUSIONS: These results suggest that relatives of patients with schizophrenia, particularly those with SSP, have specific deficits in predictive pursuit based on only extraretinal motion signals. Normal smooth pursuit gain in response to both retinal and extraretinal motion signals is likely due to compensation based on retinal motion information. The latter suggests normal retinal motion processing and smooth pursuit motor output.

Tobacco smoking increases square-wave jerks during pursuit eye movements.

Smooth-pursuit eye-movement (SPEM) abnormalities have been consistently observed in schizophrenia. The SPEM changes in schizophrenia are not thought to be an artifact of voluntary attention or medication, although a number of nondisease factors are known to affect SPEM. However, cigarette smoking has recently been reported to deteriorate SPEM in both smokers and nonsmokers. This finding is particularly relevant to schizophrenia, because schizophrenic patients smoke cigarettes considerably more than do normals, and none of the previous studies in this patient group have controlled for smoking. The current study was initiated to examine the effects of smoking on a number of oculomotor measures, including SPEM in smoker and nonsmoker normal volunteers. The results of this study suggest that cigarette smoking induces or significantly increases square-wave jerks, especially during smooth pursuit in normals. However, the effect is small and the global qualitative SPEM score is not affected. Other eye movements such as latencies for reflex and volitional saccades and saccadic distractibility are also unaffected by smoking. No differences were apparent between chronic smokers and nonsmokers under nonsmoking conditions in any of the eye-movement measures.

Increased saccadic distractibility in tardive dyskinesia: functional evidence for subcortical GABA dysfunction.

In mammals, GABAergic projections from the substantia nigra reticulata to the superior colliculus provide tonic inhibition to tectal neurons involved in the generation of saccades. Dysfunction of this pathway has been shown to produce saccadic "distractibility" in the experimental monkey. In two oculomotor paradigms, control of saccadic eye movements was tested in chronic schizophrenic patients with (n = 18) and without (n = 16) tardive dyskinesia (TD) and normal controls (n = 8). The three groups were matched by mean age; the TD and non-TD patient groups had similar duration of illness, benztropine and chlorpromazine equivalent doses and educational levels. A twofold increase in saccadic distractibility was observed in TD compared to non-TD schizophrenic patients, and both patient groups demonstrated a greater saccadic distractibility than normals. Furthermore, schizophrenic patients (both with and without TD) showed significantly increased latency for "volitional" saccades compared to the normal controls. These findings may provide further evidence for basal ganglia GABA dysfunction in tardive dyskinesia, as well as demonstrate oculomotor abnormalities in schizophrenic individuals.

Alterations in sleep polygraphy after neuroleptic withdrawal: a putative supersensitive dopaminergic mechanism.

Although a number of studies have reported sleep disturbances following neuroleptic withdrawal, a full description of such changes in sleep architecture is not available. Polysomnographic, plasma prolactin, and clinical measurements were carried out in a small number of patients on chronic neuroleptic treatment and after drug withdrawal. Preliminary findings show that in these chronically treated schizophrenic patients with and without tardive dyskinesia (TD), abrupt neuroleptic withdrawal induces reductions in total sleep, rapid eye movement (REM) sleep, and plasma prolactin. Furthermore, an increase in delta sleep was observed only in patients without TD. The REM suppression occurred significantly earlier in TD patients compared to the non-TD schizophrenic patients. These changes were transient, and both sleep measures and plasma prolactin stabilized during the 2-4 weeks after withdrawal to levels somewhere between the values observed during chronic treatment and withdrawal (week 1) periods. As the withdrawal-induced exaggerated changes mimicked the dopamine agonist effect on these sleep and hormonal measures, one can hypothesize that the observed changes are due to unmasking of supersensitive dopamine receptors following drug cessation. Normalization of these receptors and/or adaptational changes in other nondopaminergic system(s) can hypothetically explain the eventual stabilization of these measures during the following weeks.

Sleep polygraphy in schizophrenia: methodological issues.

The findings of sleep studies in schizophrenia have remained inconsistent in the literature as exemplified by the recent controversy regarding reduced rapid eye movements (REM) latency in these patients. These inconsistencies can partly be explained by major methodological shortcomings in studies evaluating sleep in schizophrenia. Lack of standardized scoring and diagnostic methods in the earlier studies and more recently, the effect of neuroleptic treatment or its withdrawal, have confounded the sleep results. Data are presented to illustrate the effect of the presence of tardive dyskinesia or active psychotic symptoms that further skew the sleep polygraphic measurements in these patients. Studies in drug-naive patients can circumvent some of these confounds but then these studies are weakened by sampling bias. Available data suggest that previous duration of neuroleptic treatment, duration of neuroleptic withdrawal, presence of tardive dyskinesia, and severity of psychotic symptoms should be considered when interpreting REM sleep measures in schizophrenic patients.

GABA agonist-induced changes in motor, oculomotor, and attention measures correlate in schizophrenics with tardive dyskinesia.

Saccadic distractibility, Stroop color-word scores, and serial dyskinesia assessments were obtained on 10 schizophrenic patients with tardive dyskinesia during a pharmacologic challenge with placebo or 7 mg muscimol, a potent, direct-acting GABA agonist. Although no significant difference in the measures was evident between conditions, a significant correlation was found between GABA agonist-induced changes in saccadic distractibility and dyskinesia scores where no correlation existed between these measures on placebo. Improvement in saccadic distractibility was also correlated with reduction in attention performance, as measured by Stroop. These effects are not due to sedation. The correlation between dyskinesia and saccadic distractibility is consistent with a model of parallel motor and oculomotor cortico-striatal-thalamic circuits in humans. This work supports the hypothesis that a dysfunction in GABA-mediated neurotransmission may be the basis for tardive dyskinesia.

Eye tracking disorder in schizophrenia is characterized by specific ocular motor defects and is associated with the deficit syndrome.

The objective was to determine the relationships between eye tracking disorder (ETD) in schizophrenia, specific ocular motor measures, and the deficit syndrome. Twenty-five normal comparison subjects and 53 schizophrenic patients had eye movements tested with infrared oculography using a sinusoidal target. Patients were assessed with the Schedule for the Deficit Syndrome. For the patients, the distribution of position root mean square error (a global measure of pursuit) was best fit by a mixture of two normal distributions. This information was used to divide the patients into two subgroups, those with and those without ETD. ETD was almost completely accounted for by several specific ocular motor measures and was significantly associated with the deficit syndrome. The finding that ETD was almost completely accounted for by specific measures bridges a gap of interpretation in this field. ETD and the deficit syndrome of schizophrenia may share a common pathophysiology of cerebral cortical-subcortical circuits.

Association between eye tracking disorder in schizophrenia and poor sensory integration.

OBJECTIVE: The authors tested the hypothesis that eye tracking disorder in schizophrenia is associated with neurological signs. METHOD: The subjects were 93 normal comparison subjects and 59 schizophrenic patients. They were evaluated with the Neurological Evaluation Scale, a standardized rating instrument that assesses sensory integration, motor coordination, sequencing of complex motor acts, and other neurological signs. Also, the schizophrenic patients' smooth-pursuit eye movements were tested in response to a 0.3-Hz sinusoidal target by means of infrared oculography. They were divided into those with (N=18) and without (N=41) eye tracking disorder by using a previously described method, which was based on mixture analysis of the distribution of position root mean square error. RESULTS: The patients with eye tracking disorder had significantly worse performance than the patients without eye tracking disorder with respect to sensory integration, and the effect size was moderate to large. In comparison with the normal subjects, both patient subgroups had significantly worse performance on all of the Neurological Evaluation Scale subscales. CONCLUSIONS: Although neurological signs are present generally in schizophrenia, poor sensory integration is particularly pronounced in patients with eye tracking disorder. A review of the literature shows that the two abnormalities have strikingly similar patterns of validators, including 1) familial aggregation, 2) premorbid presence, 3) syndromal specificity, 4) trait status, and 5) association with the deficit syndrome. Poor sensory integration and eye tracking disorder in schizophrenia may be various manifestations of a common, underlying pathophysiological process.

Relationship of awareness of dyskinesia in schizophrenia to insight into mental illness.

OBJECTIVE: The purpose of this study was to determine whether lack of awareness of motor dysfunction and lack of insight into mental dysfunction are related and to evaluate the longitudinal stability of lack of awareness of abnormal movements in schizophrenia. METHOD: Forty-three patients with schizophrenia and tardive dyskinesia participated in the study. The Scale of Unawareness of Mental Disorder was used to assess insight. All patients still meeting inclusion criteria after 2 years (N = 16) were reevaluated at follow-up. RESULTS: Twenty (46.5%) of the 43 patients had at least moderate unawareness of their tardive dyskinesia. Awareness of tardive dyskinesia was only modestly related to two of the five dimensions of insight into mental disorder assessed. Patients with the deficit syndrome showed significantly less awareness of their tardive dyskinesia than patients without the deficit syndrome. Lack of awareness of tardive dyskinesia was stable over time. CONCLUSIONS: Lack of awareness of tardive dyskinesia is a common feature in schizophrenia and is stable over time. Since patients are often unaware of dyskinesia, direct clinical examination is required to identify early tardive dyskinesia.

Eye movements in spectrum personality disorders: comparison of community subjects and relatives of schizophrenic patients.

OBJECTIVE: The purpose of the current study was to test the specificity of an association between eye tracking abnormality and schizophrenia spectrum personality symptoms in the family members of schizophrenic patients. The studies of biological markers for genetic vulnerability to schizophrenia, which test an association between a biological measure and schizophrenia spectrum personality symptoms, are constrained, since these personality symptoms may lack the specificity for a schizophrenic phenotype. An association between a behavioral measure and these personality symptoms in general can easily be false (i.e., not related to schizophrenic vulnerability). In contrast, a strong deviant finding in the relatives of schizophrenic patients with spectrum personality symptoms, in the presence of a relatively normal finding in spectrum subjects without a known history of schizophrenia, makes the biobehavioral measure an interesting candidate for such investigations. METHOD: Seventy-five subjects recruited from the community who did not have a family history of psychosis completed the study (24 of the 75 had significant schizophrenia spectrum personality symptoms). Thirty-two first-degree relatives of schizophrenic patients (13 with spectrum symptoms) completed the study. Subjects were 18-45 years old and had no DSM-III-R axis I diagnosis. RESULTS: Qualitative smooth pursuit eye movement score was significantly worse in relatives with the spectrum symptoms than in spectrum subjects without a family history of schizophrenia and the nonspectrum relatives. Schizotypal and schizoid symptoms explained a significant amount of the variance in the eye tracking measure in the relatives (31% and 20%, respectively) but not in the community subjects (less than 2%). Relatives of schizophrenic patients with and without the spectrum symptoms had significantly longer antisaccade latency, in spite of comparable latency for visually guided saccades, than the community subjects. CONCLUSIONS: Smooth pursuit abnormality in subjects with schizophrenia spectrum personality disorders is specifically associated with a family history of schizophrenia.

Spontaneous dyskinesia in subjects with schizophrenia spectrum personality.

OBJECTIVE: The study of spontaneous dyskinesia in schizophrenia is confounded by the widespread use of neuroleptics. The authors hypothesized that spontaneous dyskinesia would be present in subjects with schizophrenia spectrum personality (schizoid, paranoid, or schizotypal). They also tested the hypothesis that dyskinetic-like movements would increase after repeated dextroamphetamine challenge to the dopaminergic system. METHOD: Dyskinetic-like movements were assessed in 34 spectrum subjects and 22 normal subjects; nine subjects from each group were administered both placebo and repeated dextroamphetamine challenges. RESULTS: Spectrum subjects had more dyskinetic-like movements than normal subjects. Spontaneous dyskinesia was present in 12% of the spectrum subjects but was not seen in the normal subjects. Subjects with schizotypal personality had more dyskinetic-like movements than subjects with schizoid personality or normal subjects. Dyskinesia was present in 24% of the schizotypal subjects but not in the other groups. Dyskinetic movement scores correlated with positive symptom scores. With repeated amphetamine challenge, normal subjects showed a pattern of behavioral sensitization (an increase in dyskinetic-like movements), but spectrum subjects showed an abnormal response (fewer dyskinetic-like movements). CONCLUSIONS: Dyskinesia and dyskinetic-like movements are more common in subjects with schizophrenia spectrum personality (primarily schizotypal) than in normal subjects and are related to positive symptoms. A failure of normal behavioral sensitization mechanisms after dextroamphetamine challenge is seen in subjects with schizophrenia spectrum personality.

Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol.

OBJECTIVE: The functional pathways through which antipsychotic drugs act in the brain to decrease psychosis remain unknown, despite our knowledge that their site of initial action is through blockade of dopamine D2 receptors. The authors sought to define the brain regions that are functionally altered by neuroleptic drugs. METHODS: Regional cerebral glucose metabolism was studied in 12 subjects with schizophrenia while they were receiving a fixed dose of haloperidol, again 5 days after withdrawal of the drug, and a third time 30 days after withdrawal. Positron emission tomography with an [18F]fluorodeoxyglucose tracer was used in a within-subject design. RESULTS: The analysis demonstrated a decrease in glucose metabolism in the caudate and putamen 30 days after withdrawal, indicating that haloperidol treatment enhanced glucose utilization in these areas. The thalamus, bilaterally but only in anterior areas, showed the same response to haloperidol. Only in the frontal cortex and in the anterior cingulate had metabolism increased 30 days after withdrawal, indicating that in those two cortical areas haloperidol depressed glucose metabolism. In the 5-day drug free scans, no regions differed significantly from those in the haloperidol condition, despite numerical changes. CONCLUSIONS: It appears that 5 days of neuroleptic withdrawal are inadequate to escape the effects of neuroleptic drugs on regional cerebral glucose metabolism. The pattern and localization of changes in metabolic activity between the haloperidol condition and the 30-day drug-free condition suggest that haloperidol exerts its primary antidopaminergic action in the basal ganglia. It is proposed that the additional changes in the thalamus and cortex are secondary to this primary site of drug action, mediated through classically described striato-thalamo-cortical pathways.

Association of abnormal smooth pursuit eye movements with the deficit syndrome in schizophrenic patients.

OBJECTIVE: The authors' goal was to test the hypothesis that abnormal smooth pursuit eye movements in schizophrenic patients are associated with the deficit syndrome. METHOD: The eye movements of 24 normal comparison subjects, 32 patients with nondeficit schizophrenia, and 11 patients with deficit schizophrenia were tested with infrared oculography using foveapetal step-ramp targets. RESULTS: The group of schizophrenic patients had normal latency to pursuit onset, abnormally decreased open-loop acceleration and abnormally decreased velocity during the periods of closed-loop acceleration and steady-state pursuit. The subgroup of schizophrenic patients with the deficit syndrome had particularly poor performance during the periods of open- and closed-loop acceleration. CONCLUSIONS: Patients with schizophrenia have abnormal smooth pursuit eye movements in response to a step-ramp stimulus, and the defects are particularly pronounced in patients with the deficit syndrome. Abnormal smooth pursuit eye movements in schizophrenia and related disorders have been consistently linked with primary and enduring negative symptoms.

Clinical and neurobiological correlates of cytogenetic abnormalities in childhood-onset schizophrenia.

OBJECTIVE: Cytogenetic abnormalities are increased in schizophrenia, suggesting a possible etiologic contribution. However, their clinical and pathophysiologic roles in the disorder are unknown. To investigate this, a group of children and adolescents participating in a comprehensive study of childhood-onset schizophrenia were screened for chromosomal abnormalities, and their clinical and neurobiological correlates were examined. METHOD: Cytogenetic screening with the use of high-resolution banding, fluorescent in situ hybridization for chromosome 22q11 deletions, and molecular fragile X testing was undertaken in a group of 47 children and adolescents with very early onset of schizophrenia. Clinical, neurobiological (including brain morphometry), and risk factor measures of the subjects with cytogenetic abnormalities were compared with those of the remaining patients without cytogenetic anomalies. RESULTS: Five patients had previously undiagnosed cytogenetic abnormalities. Lower performance IQ and more pronounced premorbid developmental impairments were seen in this subgroup. Rates of obstetric complications, familial schizophrenia spectrum disorders, and familial eye tracking dysfunction were similar for the patients with and without cytogenetic abnormalities. CONCLUSIONS: Cytogenetic abnormalities appear to be increased in childhood-onset schizophrenia, suggesting an association with a very early age at onset. The data from the subgroup of patients with cytogenetic anomalies are consistent with a model in which a childhood onset of schizophrenia is due to a greater impairment of neurodevelopment secondary to the interaction of a number of factors, particularly genetic ones.

Clonazepam treatment of tardive dyskinesia: a practical GABAmimetic strategy.

Because of the efficacy of specific gamma-aminobutyric acid (GABA) agonists in tardive dyskinesia, the authors tested the benzodiazepine clonazepam in a 12-week, double-blind, placebo-controlled, randomized crossover trial in 19 chronically ill patients with tardive dyskinesia who were being treated with neuroleptics. They found a 35% decrease in dyskinesia ratings with clonazepam treatment. The six patients with predominantly dystonic symptoms showed greater benefit than the 13 patients with predominantly choreoathetoid dyskinesias. Tolerance developed to the antidyskinetic effect of clonazepam in the five patients whose long-term use of the drug was followed, but a 2-week clonazepam-free period recaptured its antidyskinetic effect.