Genetic insights into childhood-onset schizophrenia: The yield of clinical exome sequencing.

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset prior to 13 years of age. Although genetic factors play a role in COS etiology, only a few causal variants have been reported to date. This study presents a diagnostic exome sequencing (ES) in 37 Israeli Jewish families with a proband diagnosed with COS. By implementing a trio/duo ES approach and applying a well-established diagnostic pipeline, we detected clinically significant variants in 7 probands (19 %). These single nucleotide variants and indels were mostly inherited. The implicated genes were ANKRD11, GRIA2, CHD2, CLCN3, CLTC, IGF1R and MICU1. In a secondary analysis that compared COS patients to 4721 healthy controls, we observed that patients had a significant enrichment of rare loss of function (LoF) variants in LoF intolerant genes associated with developmental diseases. Taken together, ES could be considered as a valuable tool in the genetic workup for COS patients.

Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study.

Schizophrenia is a common, severe, and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell-free DNA (cfDNA) fragments are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129), and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area under the curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier, or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.

Callous-Unemotional Traits and Face-Emotion Recognition as Mediators in Conduct Problems of Children With ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk for conduct problems (CP), as well as with callous-unemotional traits (CUt) and lower accuracy in face emotional recognition (FER). It is unclear, however, whether CUt and low accuracy in FER contribute to the risk for CP in ADHD. The present study investigated the possibility of such contribution. METHODS: This pilot study's participants included 31 children aged 7-17 years, diagnosed with ADHD, and treated in a psychiatric outpatient clinic. The parents rated their children on the ADHD Rating Scale, Inventory of Callous-Unemotional Traits, and the Child Behavior Checklist-Conduct Problems scale. Participants completed the Hebrew version of the children's Reading the Mind in the Eyes Test (cRMET)-a Theory of Mind measure. A bootstrapped multiple mediator model was used, adjusting for age and gender. RESULTS: ADHD symptoms were associated with CP. This association was not mediated by CUt or cRMET. CUt was associated with CP independent of ADHD symptom severity. CONCLUSIONS: ADHD symptoms and CUt both should be considered when assessing risk for CP and devising a treatment plan, in children with ADHD. Current results did not confirm the hypothesis that cRMET and CUt mediate between ADHD symptoms and CP. More studies employing larger samples, longitudinal design, and other emotion recognition measures are needed.

Comparable reliability and acceptability of telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

OBJECTIVE: This study aims to compare the reliability and acceptability of psychiatric interviews using telepsychiatry and face-to-face modalities in the emergency room setting. METHODS: In this prospective observational feasibility study, psychiatric patients (n = 38) who presented in emergency rooms between April and June 2020, went through face-to-face and videoconference telepsychiatry interviews in a non-randomised varying order. Interviewers and a senior psychiatry resident who observed both interviews determined diagnosis, recommended disposition and indication for involuntary admission. Patients and psychiatrists completed acceptability post-assessment surveys. RESULTS: Agreement between raters on recommended disposition and indication for involuntary admission as measured by Cohen's kappa was 'strong' to 'almost perfect' (0.84/0.81, 0.95/0.87 and 0.89/0.94 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively). Partial agreement between the raters on diagnosis was 'strong' (Cohen's kappa of 0.81, 0.85 and 0.85 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively).Psychiatrists' and patients' satisfaction rates, and psychiatrists' perceived certainty rates, were comparably high in both face-to-face and telepsychiatry groups. CONCLUSIONS: Telepsychiatry is a reliable and acceptable alternative to face-to-face psychiatric assessments in the emergency room setting. Implementing telepsychiatry may improve the quality and accessibility of mental health services.Key pointsTelepsychiatry and face-to-face psychiatric assessments in the emergency room setting have comparable reliability.Patients and providers report a comparable high level of satisfaction with telepsychiatry and face-to-face modalities in the emergency room setting.Providers report a comparable level of perceived certainty in their clinical decisions based on telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset before 13 years of age. There is rising evidence that genetic factors play a major role in COS etiology, yet, only a few single gene mutations have been discovered. Here we present a diagnostic whole-exome sequencing (WES) in an Israeli Jewish female with COS and additional neuropsychiatric conditions such as obsessive-compulsive disorder (OCD), anxiety, and aggressive behavior. Variant analysis revealed a de novo novel stop gained variant in GRIA2 gene (NM_000826.4: c.1522 G > T (p.Glu508Ter)). GRIA2 encodes for a subunit of the AMPA sensitive glutamate receptor (GluA2) that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. GluA2 subunit mutations are known to cause variable neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, epilepsy, and OCD. Our findings support the potential diagnostic role of WES in COS, identify GRIA2 as possible cause to a broad psychiatric phenotype that includes COS as a major manifestation and expand the previously reported GRIA2 loss of function phenotypes.

The association of non-suicidal self-injurious and suicidal behaviors with religiosity in hospitalized Jewish adolescents.

Religiosity may be a potent protective factor against self-injurious and suicidal behaviors. However, no previous study has addressed this relationship in adolescent psychiatric population. This study aimed to examine the association between religiosity and non-suicidal self-injurious (NSSI) and suicidal behaviors, among hospitalized Jewish adolescents. This is a cross-sectional study of 60 hospitalized Jewish adolescents in two mental health centers. They were evaluated for religiosity, NSSI, and suicidal behaviors. The following religiosity measures were found to be protective against NSSI: a higher degree of adherence to religious practices (extrinsic measure) (beta = -0.083, p = .006), a higher level of belief in religious principles (intrinsic measure) (beta = -0.063, p = .008) and a self-reported higher religious affinity (χ2 = 7.64, p = .022). The severity of suicidal ideation inversely correlated with the extrinsic measure (standardized beta = -0.2, t = -2.5, p = .015) and with self-reported degree of religious affinity (analysis of variance, F = 3.5, p = .035). History of transition in religious affinity was associated with worse suicidal ideation (3.77 ± 1.8 vs. 2.26 ± 1.99, t = -3.25, p = .004) and with suicide attempts (OR = 3.89 (95% CI: 1.08 - 14.03), p = .004); however, these relationships were mediated by history of abuse. This study provides first evidence of a protective effect of some religiosity measures on NSSI and suicidal behaviors in hospitalized Jewish adolescents.

Toward risk adjustment in mental health in Israel: calculation of risk adjustment rates from large outpatient and inpatient databases.

BACKGROUND: In 2015, mental health services were added to the Israeli National Health Insurance package of services. As such, these services are financed by the budget which is allocated to the Health Plans according to a risk adjustment scheme. An inter-ministerial team suggested a formula by which the mental health budget should be allocated among the Health Plans. Our objective in this study was to develop alternative rates based on individual data, and to evaluate the ones suggested. METHODS: The derivation of the new formula is based on our previous study of all psychiatric inpatients in Israel in the years 2012-2013 (n = 27,446), as well as outpatients in one psychiatric clinic in the same period (n = 6115). Based on Ministry of Health and clinic data we identified predictors of mental health services consumption. Age, gender, marital status and diagnosis were used as risk adjusters to calculate the capitation rates for outpatient care and inpatient care, respectively. All prices of services were obtained from the Ministry of Health tariffs. These rates were modified to include non-users using restricted models. RESULTS: The mental health capitation scales are typically "humped" with regard to age. The rates for ambulatory care varied from a minimum 0.19 of the average consumption for males above the age of 85 to a maximum of 1.93 times the average for females between the ages of 45-54. For inpatient services the highest rate was 409.25 times the average for single, male patients with schizophrenia spectrum diagnoses, aged 45-54. The overall mental health scale ranges from 2.347 times the average for men aged 45-54, to 0.191 for women aged 85+. The modified scale for the entire post-reform package of benefits (including both mental health care and physical health care) is increasing with age to 4.094 times the average in men aged over 85. The scale is flatter than the pre-reform scale. CONCLUSIONS: The risk adjustment rates calculated for outpatient care are substantially different from the ones suggested by the inter-ministerial team. The inpatient rates are new, and indicate that for patients with schizophrenia, a separate risk-sharing arrangement might be desirable. Adopting the rates developed in this analysis would decrease the budget shares of Clalit and Leumit with their relatively older populations, and increase Maccabi and Meuhedet's shares. Future research should develop a risk-adjustment scheme which covers directly both mental and physical care provided by the Israeli Health Plans, using their data.

Commentary: seclusion and mechanical restraint of psychiatric patients in Israel - an update.

Recently, Miodownik et al. reported in this journal the results of a study on seclusion and mechanical restraint of psychiatric patients in Israel (Isr J Health Policy Res 8:9, 2019). The study was a retrospective examination over a year of one inpatient ward in a psychiatric hospital. They found negative associations between length of use of coercive measures and the diagnosis of schizophrenia, being single, and the presence of academic nurses. Positive associations were found between length of use of coercive measures and the use of antipsychotic medications, violence towards oneself, and the use of restraint compared to seclusion. Interesting and important as they are, these results were obtained from data gathered in 2014. As the authors note, since then there has been a dramatic change in the official policy of the Israeli Ministry of Health on this topic and in the practice of seclusion and mechanical restraint in Israel. This commentary reviews and comments on the current situation.

[IDENTIFYING PREDICTORS OF MENTAL HEALTH SERVICES CONSUMPTION IN ISRAEL].

INTRODUCTION: The budget for health services in Israel was recently increased to cover mental health. It was suggested to divide funds for psychiatric hospitalization between the HMOs based on their share of insured members. For ambulatory care, it was suggested to add risk adjustment based on age only to the capitation formula used for allocating health care funds. This simplistic measure encourages risk selection and discrimination of costly individuals. AIMS: To identify predictors of mental health services consumption in Israel, in order to implement them in the capitation formula. METHODS: Data were gathered on 27,446 individuals hospitalized in psychiatric wards in Israel in 2012-2013, and 6115 outpatients treated during this period in one mental health clinic. The association between demographic and clinical variables with services consumption was studied. RESULTS: The average annual expenses per person on mental health were NIS 50,000 for hospitalization, NIS 1,700 for ambulatory care and NIS 7,000 for all services. Adult age and schizophrenia spectrum diagnoses predicted increased expenditure on all services. Being a male, single, Jewish and living in the economic periphery predicted increased expenditure mainly on hospitalization. Regression analysis using these variables explained up to 30% of variance. CONCLUSIONS: It is possible to predict, at least partially, mental health consumption in Israel based on clinical and demographic variables. DISCUSSION: Limitations of the study call or re-analysis using full databases, which are available only to the state authorities. Predictors of mental health consumption in Israel can be used for the risk adjustment of allocating funds for services.

Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.

OBJECTIVE: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability. METHODS: Identification of the responsible gene by whole exome sequencing and homozygosity mapping. RESULTS: Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12 p.R839X is <0.00001 worldwide. Genotyping PCDH12 p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12 p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability. CONCLUSIONS: Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.

Transitioning home: A four-stage reintegration hospital discharge program for adolescents hospitalized for eating disorders.

PURPOSE: Treatment for adolescents with eating disorders (ED) is multidimensional and extends after hospitalization. After participating in a four-step reintegration plan, treatment success including post-discharge community and social reintegration were examined from perspectives of patients, family members, and healthcare providers. DESIGN AND METHODS: Six pairs of patients and parents, and seven parents without their children were interviewed 2 to 30 months following discharge. RESULTS: All but two adolescents were enrolled in, or had completed school. Five worked in addition to school, and three completed army or national service. Twelve were receiving therapeutic care in the community. PRACTICE IMPLICATIONS: Adolescents with ED can benefit from a systematic reintegration program, and nurses should incorporate this into care plans.

Severe methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia.

IMPORTANCE: Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy. OBSERVATIONS: Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients. CONCLUSIONS AND RELEVANCE: Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation.

Do tardive dyskinesia and L-dopa induced dyskinesia share common genetic risk factors? An exploratory study.

Tardive dyskinesia (TD) in schizophrenia patients treated with antipsychotic medications and L-dopa induced dyskinesia (LID) among Parkinson's disease (PD) affected individuals share similar clinical features. Both conditions are induced by chronic exposure to drugs that target dopaminergic receptors (antagonists in TD and agonists in LID) and cause pulsatile and nonphysiological stimulation of these receptors. We hypothesized that the two motor adverse effects partially share genetic risk factors such that certain genetic variants exert a pleiotropic effect, influencing susceptibility to TD as well as to LID. In this pilot study, we focused on 21 TD-associated SNPs, previously reported in TD genome-wide association studies or in candidate gene studies. By applying logistic regression and controlling for relevant clinical risk factors, we studied the association of the SNPs with LID vulnerability in two independent pharmacogenetic samples. We included a Jewish Israeli sample of 203 PD patients treated with L-dopa for a minimum of 3 years and evaluated the existence or absence of LID (LID+ = 128; LID- = 75). An Italian sample was composed of early LID developers (within the first 3 years of treatment, N = 187) contrasted with non-early LID developers (after 7 years or more of treatment, N = 203). None of the studied SNPs were significantly associated with LID susceptibility in the two samples. Therefore, we were unable to obtain proof of concept for our initial hypothesis of an overlapping contribution of genetic risk factors to TD and LID. Further studies in larger samples are required to reach definitive conclusions.

Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease.

Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS), and extensive Nigro-Striatal (NS) degeneration, manifested by reduced uptake of [(123)I]FP-CIT, is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small "proof of concept" study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

Involvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition.

OBJECTIVE: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific member of the protein tyrosine phosphatase (PTP) family that has been implicated in learning and memory. In this study, we examined the association of the protein tyrosine phosphatase non-receptor 5 (PTPN5) gene, which encodes for STEP, with both schizophrenia and cognitive functioning in the Israeli Jewish population. METHODS: A schizophrenia (SZ) case-control study of 868 participants was carried out (286 patients and 582 controls). Eleven PTPN5 tagging single-nucleotide polymorphisms (SNPs) were selected and single markers and haplotype association analyses were carried out. A cognitive variability study included 437 healthy women who completed a computerized cognitive battery. We performed univariate associations between the SNPs and cognitive performance. The possible functional role of these variants was examined by studying their association with gene expression levels in the brain. RESULTS: In the SZ study, we found a nominal association in the whole sample between rs4075664 and SZ. Male patients with SZ showed a more significant association for three SNPs (rs4075664, rs2278732, and rs4757710). Haplotypes of the studied SNPs were associated with SZ both in the overall sample and within the male subsample. Expression analysis provided some support for the effects of the associated SNPs on PTPN5 expression level. The cognitive variability study showed positive associations between PTPN5 SNPs and different cognitive subtests. Principal component analysis showed an 'attention index' neurocognitive component that was associated with two SNP pairs (rs10832983 × rs10766504 and rs7932938 × rs4757718). CONCLUSION: The results imply a model in which PTPN5 may play a role in normal cognitive functioning and contribute to aspects of the neuropathology of SZ.

Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample.

Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10⁻6) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10⁻6) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.

DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population.

It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134×10⁻7) and six additional nominally significant association signals with p<1×10⁻5. One of the top single nucleotide polymorphisms (p<1×10⁻5) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61×10⁻8), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population.

Alteration in RGS2 expression level is associated with changes in haloperidol induced extrapyramidal features in a mutant mouse model.

Antipsychotic induced Parkinsonism (AIP) is a common adverse effect of antipsychotic drug treatment among schizophrenia patients. Two previous studies showed association of the rs4606 SNP in the 3' untranslated region of the regulator of G protein signaling 2 gene (RGS2) with susceptibility to AIP. Since rs4606 reportedly influences expression of RGS2, we applied a translational approach and studied the effect of chronic (24 days) exposure to haloperidol on AIP-like features in mice carrying a mutation that causes lower Rgs2 gene expression. Haloperidol and vehicle treated male mice heterozygous (HET) or homozygous (HOM) for the mutation, or wild type (WT), were evaluated for open field locomotion, catalepsy duration, pole test performance and rota-rod latency to fall. We showed that in haloperidol treated mice lower Rgs2 expression is associated with better performance on the open field, catalepsy and rota-rod tests but not the pole test. Results were most consistent for the 0.2 mg/kg/d haloperidol dose. These observations support the possible involvement of RGS2 in mechanisms underlying susceptibility to AIP.