A CHRNA5 allele related to nicotine addiction and schizophrenia.

Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could hypothesize that genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (P = 0.001) and control smokers (P = 0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (P = 0.022) and African-American (P = 0.006) nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies.

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.

Children and adolescents with psychotic disorder not otherwise specified: a 2- to 8-year follow-up study.

Although psychotic phenomena in children with disruptive behavior disorders are more common than expected, their prognostic significance is unknown. To examine the outcome of pediatric patients with atypical psychoses, a group of 26 patients with transient psychotic symptoms were evaluated with clinical and structured interviews at the time of initial contact (mean age, 11.6 +/- 2.7 years) and at follow-up 2 to 8 years later. Measures of functioning and psychopathology were also completed at their initial assessment. Risk factors associated with adult psychotic disorders (familial psychopathology, eyetracking dysfunction in patients and their relatives, obstetrical complications, and premorbid developmental course in the proband) had been obtained at study entry. On follow-up examination (mean age, 15.7 +/- 3.4 years), 13 patients (50%) met diagnostic criteria for a major axis I disorder: three for schizoaffective disorder, four for bipolar disorder, and six for major depressive disorder. The remaining 13 patients again received a diagnosis of psychotic disorder not otherwise specified (NOS), with most being in remission from their psychotic symptoms. Among this group who had not developed a mood or psychotic disorder, disruptive behavior disorders were exceedingly common at follow-up and were the focus of their treatment. Higher initial levels of psychopathology, lower cognitive abilities, and more developmental motor abnormalities were found in patients with a poor outcome. Obstetrical, educational, and family histories did not differ significantly between the groups. Through systematic diagnostic evaluation, children and adolescents with atypical psychotic disorders can be distinguished from those with schizophrenia, a difference with important treatment and prognostic implications. Further research is needed to delineate the course and outcome of childhood-onset atypical psychoses, but preliminary data indicate improvement in psychotic symptoms in the majority of patients and the development of chronic mood disorders in a substantial subgroup.

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.

Defining the schizophrenia phenotype.

Schizophrenia is a complex disease with multifactorial etiology. The schizophrenia phenotype has been traditionally defined by chronic psychosis and functional deterioration. However, the boundary of the phenotype is likely to be more extensive than the one defined by chronic psychosis. This is highlighted by the findings of subtle, schizophrenia- like deficits in the nonschizophrenic, first-degree relatives of schizophrenic patients. Subtle clinical signs and symptoms, cognitive impairment particularly in attention and memory, and neurophysiologic deficits such as in sensory gating and smooth-pursuit eye movements all define aspects of the schizophrenia phenotype.

Ketamine effects on eye movements.

In order to determine if the N-methyl-D-aspartate antagonist ketamine would reproduce eye movement dysfunction in schizophrenia, we studied 12 normal control subjects with low dose (0.1 mg/kg) bolus injection of ketamine in a double-blind placebo-controlled study. Oculomotor measures were obtained during smooth pursuit that included closed loop gain and measures of gain during masking conditions. Measures during initiation of smooth pursuit included latency, open loop acceleration and velocity. Ketamine disrupted closed loop gain and open loop acceleration but not measures during the masking conditions. The ketamine partly reproduced some abnormalities seen in schizophrenia but not measures that may be more specifically linked to familial abnormalities found in family members of subjects with schizophrenia.

Saccadic eye movement abnormalities in relatives of patients with schizophrenia.

Recent studies note abnormalities in saccadic eye movements of relatives of patients with schizophrenia. The current study examined which aspects of the saccadic system are affected, whether these saccadic abnormalities are associated with schizophrenia spectrum personality symptoms (SSP), and whether such an association is dependent on a family history of schizophrenia. Furthermore, the study examined what proportion of relatives have the saccadic abnormality(ies). Fifty-five first-degree relatives with no DSM-III-R Axis I diagnosis participated in the study. Twenty-one of these relatives experienced SSP symptoms and 34 had no Axis II diagnosis. Sixty-two subjects with no Axis I diagnosis were recruited from the community. Twenty-five experienced SSP symptoms and 37 had no Axis II diagnosis. Prosaccades (saccades toward the target) and antisaccades (saccades made in the opposite direction of the target jump) were examined. Relatives, particularly those with SSP, had difficulties with the antisaccade task as suggested by higher error rates and longer antisaccade latency. Prosaccades were not different in relatives compared to the community subjects, although the effects of field were different in the two groups on some measures. The antisaccade latency was 'abnormal' in only a small proportion (1.6%) of community subjects compared to 14.9% of all relatives (35.3% of SSP relatives and 3.3% of non-SSP relatives). Relatives of patients with schizophrenia have deficits in aspects of the saccadic system involved in generating internally driven saccades and inhibition of unwanted saccades. These deficits implicate frontal ocular motor neuronal circuitry involving frontal cortical and basal ganglia areas. These deficits are associated with SSP symptoms, but not in the absence of a blood relationship to schizophrenia. The relatively high prevalence rate of the abnormality in at-risk subjects may have relevance for use of these measures in linkage analysis.

Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors.

OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined. METHOD: Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments. RESULTS: Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.

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.

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.

Smooth pursuit eye movements to extra-retinal motion signals: deficits in patients with schizophrenia.

In order to understand mechanisms underlying the smooth pursuit abnormality(ies) in schizophrenia, new methods, which independently evaluated predictive smooth pursuit responses to extra-retinal motion signals, were developed and tested. The study compared responses to only extra-retinal motion signals in normal volunteers (n = 25), and individuals with a chronic (n = 21) and a recent onset (n = 18) schizophrenia. Subject groups with chronic schizophrenia and recent onset schizophrenia had significantly poorer predictive pursuit than normal subjects in response to only extra-retinal motion signals. The poor predictive pursuit was evident even at low target velocity when the closed-loop pursuit gain was normal in patients with schizophrenia. Ten of the 18 recent onset patients were drug-free at the time of testing and had no or minimum previous exposure to anti-psychotic medications. Re-analyses of the data showed that on most measures of predictive pursuit, drug-free patients were not significantly different from patients who received anti-psychotic drug treatment. Both patient groups had significantly poorer predictive pursuit than normal subjects. These results suggest that a deficit in processing extra-retinal motion may underlie the abnormal smooth pursuit response in schizophrenia. At low target velocities, patients with schizophrenia were able to compensate for the low extra-retinal gain by increasing the gain of response to the retinal slip velocity. This indicates that patients were able to process retinal slip velocity and generate smooth pursuit eye movements, but experienced a specific deficit in processing and/or integrating extra-retinal motion information for the smooth pursuit response.

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.

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.

The relationship between smooth pursuit eye movements and tardive dyskinesia in schizophrenia.

OBJECTIVE: To examine the relationship between smooth pursuit eye movements and tardive dyskinesia (TD) in schizophrenia. METHODS: Forty schizophrenic patients with TD and 25 non-TD patients had smooth pursuit eye movements tested with infrared oculography. In addition to the diagnosis of TD (present or absent), each patient had ratings of severity of TD. RESULTS: There was no significant or strong association between TD and poor smooth pursuit eye movements. CONCLUSION: The results stand in contrast to those of several previous studies, which were based on limited methodology. However, this study was not able to exclude definitively the possibility that TD is associated with poor smooth pursuit, perhaps with a small to moderate effect. Furthermore, these conclusions are limited to simple eye tracking protocols in which distractions are minimized. The question of whether or not TD is associated with poor smooth pursuit in schizophrenia needs to be resurrected.

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.

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.

The Maryland Psychiatric Research Center scale and the characterization of involuntary movements.

The Maryland Psychiatric Research Center involuntary movement scale (MPRC scale) has been used in the evaluation of 1107 patients referred for drug-induced movement disorders. The scale has increased discrimination of body area and severity compared to other scales. Validity was examined using principal component analyses, pharmacologic response studies and associations with AIMS, global judgement and motor diagnosis. Reliability was examined using Cronbach's alpha, intraclass correlation coefficient (ICC) between raters and test-retest measurements. The prevalence of dyskinetic and parkinsonian signs at several levels of severity are reported. Total dyskinesia was strongly correlated with AIMS score, r = 0.97. Inter-rater reliability was 0.81-0.90 for total dyskinesia score. Receiver Operating Characteristic (ROC) analysis shows a total dyskinesia score of 4 or above to predict tardive dyskinesia, consistent with RDC-TD criteria. Hand dyskinesia showed a high prevalence comparable to that of oral dyskinesias. The MPRC scale is a valid, sensitive and reliable instrument for the rating of neuroleptic-induced dyskinetic and parkinsonian syndromes and may offer advantages over other scales in neurophysiologic research and brain imaging with its ease of use, uniform structure and greater discrimination of anatomic place and severity in the rating of involuntary movements.

Accuracies of saccades to moving targets during pursuit initiation and maintenance.

The overall goals of the studies presented here were to compare (1) the accuracies of saccades to moving targets with either a novel or a known target motion, and (2) the relationships between the measures of target motion and saccadic amplitude during pursuit initiation and maintenance. Since resampling of position error just prior to saccade initiation can confound the interpretation of results, the target ramp was masked during the planning and execution of the saccade. The results suggest that saccades to moving targets were significantly more accurate if the target motion was known from the early part of the trial (e.g., during pursuit maintenance) than in the case of novel target motion (e.g., during pursuit initiation); both these types of saccades were more accuate than those when target motion information was not available. Using target velocity in space as a rough estimate of the magnitude of the extra-retinal signal during pursuit maintenance, the saccadic amplitude was significantly associated with the extra-retinal target motion information after accounting for the position error. In most subjects, this association was stronger than the one between retinal slip velocity and saccadic amplitude during pursuit initiation. The results were similar even when the smooth eye motion prior to the saccade was controlled. These results suggest that different sources of target motion information (retinal image velocity vs internal representation of previous target motion in space) are used in planning saccades during different stages of pursuit. The association between retinal slip velocity and saccadic amplitude is weak during initiation, thus explaining poor saccadic accuracy during this stage of pursuit.

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.