Kegg Pathway: Butyrophenone family

Endocrinology. 2008 May; 149(5): 2576-83
Zelena D, Domokos A, Barna I, Mergl Z, Haller J, Makara GB

In adulthood the hypothalamo-pituitary-adrenal axis is controlled by both CRH and arginine vasopressin (AVP). However, in neonates CRH secretion is very low, whereas AVP secretion is fully functional. This suggests that the role of AVP is more pronounced in young than in adult rats. We investigated the role of AVP by studying stress responses in 5, 10, and 20-d-old AVP-deficient Brattleboro rats. Two different stressors were applied: 24-h maternal separation and Hypnorm Grove Oxford UK injections. In heterozygous controls (that do express AVP), both stressors increased plasma ACTH and corticosterone. The ACTH stress response disappeared in AVP-deficient rats, demonstrating that during the perinatal period, the secretion of this hormone is controlled by AVP. Surprisingly, corticosterone responses remained intact in AVP-deficient rats. Similar findings were obtained after 1-, 4-, 12-, and 24-h long maternal separations. Thus, preserved corticosterone stress responses were not explained by changes in the timing of ACTH secretion. In vitro experiments suggested that the dissociation of ACTH and corticosterone stress responses can only be partly explained by higher ACTH responsiveness of the adrenal cortex in AVP-deficient rats. Together, our results show that in neonatal periods, AVP is crucial for the expression of ACTH stress responses, but neither AVP nor ACTH is necessary for the induction of corticosterone stress responses. Discrepant ACTH and corticosterone stress responses may reflect compensatory mechanisms activated by AVP deficiency, but disparate findings suggest that they rather depict a neonate-specific mechanism of hypothalamo-pituitary-adrenal-axis control.

Arzneimittelforschung. 2007; 57(10): 625-32
Awouters FH, Lewi PJ

The authors describe 40 years of antipsychotic drug research with Dr. Paul Janssen, which they have witnessed for a large part from first hand experience. The article describes the start of the Janssen Research and its early successes with antispasmodics and analgesics. The discovery of haloperidol followed from a serendipitous transition from analgesics to antipsychotics and culminated with the historical International Symposium on Haloperidol that was held in Beerse (Belgium) in 1959. The concept of the central role of dopamine receptor binding in schizophrenia has played a decisive part in focusing the Janssen Research on antipsychotics. Paul Janssen did not rest with haloperidol (CAS 52-68-8), but expanded it into the family of Butyrophenone antipsychotics, using Haase's handwriting test to clinically characterize the analogues. The emerging significance of serotonin antagonism in schizophrenia is discussed in the light of the discovery of pipamperone (CAS 1893-33-0), a forerunner of the modern so-called atypical neuroleptics. Continued research produced a novel chemical family of neuroleptics, exemplified by pimozide (CAS 2062-78-4) and fluspirilene (CAS 1841-19-6), and yielded selective serotonin 5HT2-antagonists. This research ultimately led to the discovery of risperidone (CAS 106266-06-2) and paliperidone (CAS 144598-75-4), compounds with inbuilt dopamine and serotonin antagonism. The authors discuss the lack of inhibition as a common trait of stereotyped behaviour in schizophrenia and the means of determining it by means of a computerized version of Bente's button press test. Finally the appropriate use of antipsychotics for optimal therapeutic result with minimal side effects is advocated.

Neurol Neurochir Pol. 2007 Sep-Oct; 41(5): 381-7
Janik P, Kalbarczyk A, Sitek M

BACKGROUND AND PURPOSE: Gilles de la Tourette syndrome (TS) is characterized by the presence of multiple motor and vocal tics, as well as other neuropsychiatric disorders. The aim of the study was to evaluate the frequency of particular clinical symptoms in patients diagnosed with TS. MATERIAL AND METHODS: A hundred twenty-six individuals were studied. A brief questionnaire including data from the medical history and neurological examination was used. RESULTS: TS was much more frequent in males (80%; 101/126) than in females. The mean age at onset was 7.6 (2-17) years. The onset of the disease was usually slow. Abrupt onset of the disease, usually after infection, was noted in 11% (12/114) of patients. The mean delay in diagnosis was 3.9 years. In most patients tics were moderate (64%; 81/126). Mild and severe intensity of tics were reported in 15% (19/126) and 21% (26/126) of patients, respectively. 77% (97/126) of individuals with TS had comorbidities. The mean comorbidity score was 2.79 per patient. Anger control problems, sleep difficulties, self-injurious behaviour and coprolalia were strongly associated with comorbidity. The most common reported comorbidity was attention deficit hyperactivity disorder (59%; 74/126). family history was positive in 46% (57/125) of patients, most often in TS patients with onset between ages 2 and 4 years (70%; 14/20). Haloperidol was the most commonly used medication in our cohort (60%; 57/95). 22% (27/122) of patients did not receive any symptomatic treatment. CONCLUSIONS: The appropriate diagnosis was delayed for about four years after the onset of the disease. Comorbidity and behavioural problems were frequent features of TS. Genetic factors can play an important role in the aetiology of TS.

J Fam Pract. 2007 Nov; 56(11): 944-6
Grover M, Edwards F, Hitchcock K, Stevens MM

Am J Geriatr Psychiatry. 2007 Nov; 15(11): 932-41
Hollis J, Grayson D, Forrester L, Brodaty H, Touyz S, Cumming R

OBJECTIVE: To establish the instantaneous relative risk (RR) of death associated with individual antipsychotic drugs, carbamazepine and sodium valproate for those 65 years and older. METHODS: Subjects dispensed antipsychotic drugs, sodium valproate or carbamazepine in 2003 or 2004 were analyzed as incident (N = 16,634) or prevalent (N = 9,831) users. Survival curves, mortality rates, and Cox proportional hazards models over two time periods were used to explore risk of death. The models were adjusted for age, sex, residential status, and psychotropic and medical drug dispensing. Olanzapine subjects were the reference group in the Cox regression. Subanalyses were performed for incident subjects with more than 30 days of follow-up and those dispensed cholinesterase inhibitors. RESULTS: In the adjusted Cox proportional hazards models, haloperidol dispensing was consistently associated with an increased risk of death compared with olanzapine users (relative risk [RR] for incident users: 2.26, 95% confidence intervals (CI): 2.08-2.47; Wald statistic: 345.36, df = 1, p < or =0.001). There was some evidence of decreased survival with dispensing of higher haloperidol doses, although confounding by medical comorbidity cannot be excluded. Chlorpromazine (RR: 1.39, 95% CI: 1.15-1.67; Wald statistic: 12.08, df = 1, p <0.001) and risperidone (RR: 1.23, 95% CI: 1.07-1.40; Wald statistic: 9.12, df = 1, p = 0.003) dispensing were associated with increased risk of death in incident users. CONCLUSION: These results should be interpreted cautiously because haloperidol and chlorpromazine are used in broader clinical contexts. However, in the absence of data from randomized trials, the safety profile of haloperidol should not be assumed to be benign. Antipsychotic drugs should not be studied as an aggregated group because their associated risks are not uniform.

Psychiatry Clin Neurosci. 2007 Oct; 61(5): 568-70
Katagai H, Yasui-Furukori N, Kikuchi A, Kaneko S

A 92-year-old woman who suffered from dementia with psychotic feature was admitted to a psychiatric ward. She refused to eat or take any medications. After 0.5 mg i.v. injection haloperidol, prolongation of QTc interval occurred in the electrocardiogram. Therefore two sessions of electroconvulsive therapy (ECT) were performed carefully after informed consent was obtained by her family. Almost no psychotic symptoms were observed after the first ECT. No cognitive side-effects were observed during and after the two ECT sessions. This demonstrates that ECT can be used as an alternative treatment when elderly dementia patients with psychotic feature cannot tolerate medication.

Eur J Neurosci. 2007 Oct; 26(7): 1853-61
Cui QL, Yung WH, Xue Y, Chen L

Substance P is a member of the neurokinin family. Previous studies have reported the existence of substance P and its high-affinity receptor, neurokinin-1 receptor, in globus pallidus. Employing in vivo extracellular recording combined with behavioural tests, the effects of substance P in globus pallidus of rats were studied. Micropressure ejection of the selective neurokinin-1 receptor agonist [Sar9,Met(O2)11] substance P increased the spontaneous firing rate of pallidal neurons in a concentration-dependent manner, with increases of 27.3% at 0.01, 33.4% at 0.03, 45.5% at 0.1, 38.4% at 0.3 and 36.4% at 1.0 mm. The selective neurokinin-1 receptor antagonist SR140333B prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. In behaving rats, we observed the postural effects of neurokinin-1 receptor activation in the globus pallidus. Consistent with electrophysiological results, unilateral microinjection of [Sar9,Met(O2)11] substance P (0.1 mm) led to a SR140333B-sensitive contralateral deflection in the presence of systemic haloperidol administration. Combining electrophysiological and behavioural findings, we concluded that substance P produces excitatory effects on globus pallidus neurons via neurokinin-1 receptors.

Clin Drug Investig. 2007; 27(9): 633-45
Cañas F, Pérez-Solá V, Díaz S, Rejas J,

OBJECTIVE: This study aimed to assess the cost effectiveness of ziprasidone versus haloperidol in sequential intramuscular (IM)/oral treatment of patients with exacerbation of schizophrenia in Spain. METHODS: A cost-effectiveness analysis from the hospital perspective was performed. Length of stay, study medication and use of concomitant drugs were calculated using data from the ZIMO trial. The effectiveness of treatment was determined by the percentage of responders (reduction in baseline Brief Psychiatric Rating Scale [BPRS] negative symptoms subscale >or=30%). Economic assessment included estimation of mean (95% CI) total costs, cost per responder and the incremental cost-effectiveness ratio (ICER) per additional responder. The economic uncertainty level was controlled by resampling and calculation of cost-effectiveness acceptability curves. RESULTS: A total of 325 patients (ziprasidone n = 255, haloperidol n = 70) were included in this economic subanalysis. Ziprasidone showed a significantly higher responder rate compared with haloperidol (71% vs 56%, respectively; p = 0.023). Mean total costs were euro3582 (95% CI 3226, 3937) for ziprasidone and euro2953 (95% CI 2471, 3436) for haloperidol (p = 0.039), mainly due to a higher ziprasidone acquisition cost. However, costs per responder were lower with ziprasidone (euro5045 [95% CI 4211, 6020]) than with haloperidol (euro5302 [95% CI 3666, 7791], with a cost per additional responder (ICER) for ziprasidone of euro4095 (95% CI -130, 22 231). The acceptability curve showed an ICER cut-off value of euro13 891 at the 95% cost-effectiveness probability level for >or=30% reduction in BPRS negative symptoms. CONCLUSIONS: Compared with haloperidol, ziprasidone was significantly better at controlling psychotic negative symptoms in acute psychoses. The extra cost of ziprasidone was offset by a higher effectiveness rate, yielding a lower cost per responder. In light of the social benefit (less family burden and greater restoration of productivity), the incremental cost per additional responder with sequential IM/oral ziprasidone should be considered cost effective in patients with exacerbation of schizophrenia in Spain.

J Obstet Gynaecol. 2007 Apr; 27(3): 310
Palanivelu LM

Bull Exp Biol Med. 2006 Aug; 142(2): 161-4
Dobryakova YV, Belyaeva YA, Stovolosov IS, Dubynin VA, Kamenskii AA

We studied the effect of D1/D2 antagonist haloperidol on maternal motivation in nursing albino rats. Haloperidol in a dose of 0.2 mg/kg significantly attenuated parental reactions and motor and exploratory activities. In a lower dose (0.1 mg/kg) the drug produced the same effect on maternal behavior (number of approaches to newborns) without reducing motor activity. The effect of low-dose haloperidol was different after naloxone treatment (0.2 mg/kg intranasally): the number of pup transfers increased significantly. The detected phenomenon indicates good prospects of combined treatment with agents modifying the cerebral dopaminergic and opioid systems as the method for correction of disorders in maternal behavior.

Am J Forensic Med Pathol. 2007 Mar; 28(1): 59-62
Kemp WL, Fitzgerald J, White CL

Medical examiners must decide whether or not a complete autopsy is warranted in evaluation of deaths that have been referred to their office. This decision is influenced by many factors. In most cases, the choice to perform only an external examination occurs in deaths where the decedent had previously documented potentially lethal natural disease or well-documented trauma. We report a patient who apparently died of the sequelae of a well-known complication of pharmacotherapy (neuroleptic malignant syndrome following Haldol administration). The death was referred to the medical examiner's office, where, based upon the history, an external examination was performed. Subsequently, the family requested an autopsy by the treating hospital. The autopsy established the diagnosis of progressive supranuclear palsy (PSP). The patient's presenting signs and symptoms were not typical of the disease; however, PSP most likely played a role in the neuroleptic malignant syndrome-like manifestations the patient exhibited following the Haldol administration. The results of the complete autopsy highlight its importance in identifying and enhancing our understanding of the underlying conditions in natural disease-based causes of death involving known therapeutic complications.

Exp Neurol. 2007 Feb; 203(2): 302-8
Saldaña M, Bonastre M, Aguilar E, Marin C

Tardive dyskinesia (TD) is a syndrome characterized by repetitive involuntary movements induced by the administration of typical neuroleptics such as haloperidol. TD generally persists after haloperidol withdrawal indicating that haloperidol produces long-lasting changes in brain function. In contrast to the typicals, atypical medications, such as clozapine, have very low rates of TD. The mechanisms underlying drug-induced TD are poorly understood. We have investigated the role of nigral expression of the bcl-2 family of proteins on haloperidol-induced neurotoxicity. Rats were treated for 21 days with the following drugs: haloperidol (1 mg/kg), clozapine (1 mg/kg) or saline. After a 3-day washout period, apomorphine-induced stereotyped behavior was scored. Western blotting was performed to evaluate the nigral expression of the dopamine transporter (DAT), bax, bcl-x(L) and bcl-2 proteins. Haloperidol administration, but not clozapine, increased stereotyped behavior (p<0.01) in association with a decrease in striatal DAT expression (p<0.05). Haloperidol and clozapine treatment significantly decreased the nigral expression of bax (p<0.05, p<0.01, respectively). Neither treatment modified bcx(L) expression. Haloperidol increased (p<0.05), whereas clozapine did not significantly modify the nigral expression of bcl-2. Our results suggest that the increase in bcl-2 expression in the haloperidol-treated animals might be a compensatory mechanism that may reflect cellular damage induced by haloperidol in the dopaminergic neurons in the pars compacta of the substantia nigra.

Aust N Z J Psychiatry. 2006 Nov-Dec; 40(11-12): 981-6
Hollis J, Touyz S, Grayson D, Forrester L

OBJECTIVES: To explore the odds ratios (ORs) of death associated with antipsychotic (AP) medications dispensed to elderly subjects. METHOD: Subjects were veterans and war widows 65 years and older dispensed an AP drug in 2001 in NSW or ACT. For all subjects, dispensing records for AP medication, benzodiazepines, lithium, carbamazepine, sodium valproate and antidepressant medication were extracted and combined with age, gender and date of death. A study date was allocated, either the date of death or a random date from 1.5.01 to 31.12.01. Subjects dispensed an AP in 2001, but not dispensed an AP or other psychotropic medication in the 120 days prior to their study date, formed a reference group. Psychotropic dispensing in the 120 days prior to the study date was analysed using nested logistic regression models to produce ORs of death associated with various AP drugs. The ORs for risperidone, olanzapine and pericyazine were compared. Haloperidol ORs were established for those dispensed the drug 0-30 days prior to study date or 31-120 days prior to the study date. RESULTS: The ORs associated with haloperidol, olanzapine, risperidone, pericyazine, thioridazine and chlorpromazine were significant when compared with the reference group. Odds ratios for all three haloperidol periods were significant when compared with olanzapine, risperidone and pericyazine 120 day ORs. Although there was a trend favouring olanzapine when compared with risperidone, the difference in the ORs failed to reach significance (p=0.066). CONCLUSIONS: Haloperidol is associated with significantly higher mortality rates than other AP medication but it is not clear whether this represents drug toxicity or the medical conditions for which it was dispensed. There was no evidence that the conventional AP pericyazine was associated with a higher mortality rate than olanzapine or risperidone.

Behav Brain Res. 2006 Nov 25; 175(1): 139-48
Pereira M, Ferreira A

The impairments in the maternal behavior of ovariectomized sensitized females, relative to lactating dams, resemble those deficits found in lactating females after treatment with the D1/D2 DA receptor antagonist haloperidol, which interferes with maternal motivation. Therefore, it could be speculated that these behavioral deficits found in sensitized females and haloperidol-treated dams are due to a reduced motivation to interact with pups. In support of this hypothesis, we have found that both sensitized and haloperidol-treated lactating females exhibited remarkably similar impairments in the expression of all active maternal behaviors relative to lactating dams. Furthermore, these deficits were overridden when they were allowed to interact with 12h-isolated pups (demanding pups). Interestingly, lactating dams also improved their maternal behavior in the presence of demanding pups, and clearly chose demanding more than non-demanding pups in a preference paradigm. These data support the idea that the behavioral deficits of sensitized and haloperidol-treated lactating females are due to a reduced behavioral activation in response to the incentive cues from pups compared to lactating dams, and not because of a motor inability to express maternal behavior. These findings ultimately suggest that pups modulate the activity of DA system involved in the regulation of maternal behavior.

J Indian Med Assoc. 2005 Dec; 103(12): 660-4
Guha P, Roy K, Sanyal D, Dasgupta T, Bhattacharya K

The association of hyperglycaemia and weight gain with the use of atypical antipsychotics has been documented. However, there is still not enough data from India. The fact that Indian patients usually have a lower body weight compared to European and American counterparts makes it difficult to extrapolate available data to the Indian context. The purpose of this study is: (a) To compare the prevalence of hyperglycaemia in schizophrenic patients taking olanzapine with those taking typical antipsychotics, and (b) to follow-up non-diabetic, non-obese schizophrenics on a stable regimen of antipsychotic monotherapy and determine the proportion of patients who develop weight gain, diabetes or impaired glucose tolerance; comparing the effects of olanzapine versus typical antipsychotics. Fifty-five schizophrenic patients attending psychiatry outpatients' department and on stable antipsychotic monotherapy for at least 6 weeks were included in the study. Those with a family or personal history of diabetes were excluded. There were 28 cases on olanzapine and 27 on either haloperidol or trifluoperazine. Fasting blood glucose estimation and body-mass Index (BMI) were recorded at baseline, at 6 weeks, and at 12 weeks. The two groups were comparable with respect to age, genderwise composition, and duration of illness. There was no significant difference in baseline glycaemic status or BMI. At the end of 12 weeks, olanzapine was not associated with any significant change in body weight, BMI or plasma fasting glucose. Duration of use of antipsychotic emerged as the only statistically significant risk factor for developing hyperglycaemia across both groups.

Brain Dev. 2006 Nov; 28(10): 625-32
Smeets EE, Julu PO, van Waardenburg D, Engerström IW, Hansen S, Apartopoulos F, Curfs LM, Schrander-Stumpel CT

We have used a novel neurophysiological technique in the NeuroScope system in combination with conventional electroencephalography (EEG) to monitor both brainstem and cortical activity simultaneously in real-time in a girl with Rett syndrome. The presenting clinical features in our patient were severe sleep disturbances, irregular breathing in the awake state dominated by Valsalva's type of breathing followed by tachypnoea and very frequent attacks of seizures and vacant spells. Our novel neurophysiological data showed that the patient was a Forceful Breather according to the breathing categories in Rett syndrome. She had frequent abnormal spontaneous brainstem activation (ASBA) preceded by severe attacks of hypocapnoea, which was caused by a combination of Valsalva's type of breathing and tachypnoea and all these together were responsible for the seizures and non-epileptic vacant spells. The ASBA was not detectable in conventional EEG and there were no epileptiform changes in the EEG during the seizures and vacant spells caused by the hypocapnic attacks, therefore these were pseudo-seizures. The record of brainstem activity confirmed that these were autonomic events, a kind of "brainstem epilepsy". We successfully treated the sleep disturbance with Pipamperone, a 5-hydroxytryptophan antagonist of receptor type 2 and we prevented the severe hypocapnoea during Valsalva's type of breathing and during tachypnoea using carbogen (a mixture of 5% carbon dioxide and 95% oxygen), which we gave by inhalation. Our treatment drastically reduced the autonomic events, promoted whole night sleep and significantly improved the quality of life in our patient. She can now participate in normal family activity which was previously impossible before treatment.

Epilepsia. 2006 Apr; 47(4): 793-8
Suzuki K, Miura N, Awata S, Ebina Y, Takano T, Honda T, Shindo T, Matsuoka H

PURPOSE: Some patients with nonconvulsive status epilepticus are known to exhibit catatonic stupor. Thus it is necessary to rule out ictal catatonia by electroencephalography in patients with catatonic stupor. However, few reports are available on epileptic seizures superimposed on catatonic stupor. METHODS: We report three cases of epileptic seizures superimposed on psychiatric catatonic stupor without a prominent predisposing factor, including high fever or encephalitis. None of the patients had a personal or family history of neurologic disease, including epilepsy. RESULTS: In all three patients, catatonic stupor persisted after resolution of the epileptic seizures with administration of phenytoin. In two of the three patients, catatonic stupor resolved with electroconvulsive therapy, which caused no marked adverse effects. CONCLUSIONS: Because it is possible that catatonic stupor itself predisposes patients to the development of epileptic seizures, electroencephalographic examinations in patients with catatonic stupor are indispensable for early recognition not only of nonconvulsive status epilepticus but also of epileptic seizures superimposed on catatonic stupor. Electroconvulsive therapy deserves consideration when catatonic stupor persists after resolution of epileptic seizures.

Drug Metab Dispos. 2006 Jul; 34(7): 1145-51
Kang HJ, Lee SS, Lee CH, Shim JC, Shin HJ, Liu KH, Yoo MA, Shin JG

Two neurotoxic pyridinium metabolites of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxybutyl]pyridinium ion (HPP(+)) and 4-(4-(chlorophenyl)-1-4-(fluorophenyl)-4-hydroxybutyl-pyridinium (RHPP(+)), are formed in the liver and found in the brain. To understand how these neurotoxic pyridinium metabolites are distributed in the brain, HPP(+) and RHPP(+) were evaluated as substrates for human organic cation transporters (hOCTs). Both HPP(+) and RHPP(+) were accumulated in Caco-2 cells, and these accumulations were significantly inhibited by pretreatment with the hOCT inhibitors verapamil, cimetidine, phenoxybenzamine, and corticosterone. The contribution of each hOCT was evaluated based on measurements of the intracellular concentrations of haloperidol metabolites in Madin Darby canine kidney (MDCK) cells transfected with hOCT1, hOCT2, or hOCT3. HPP(+) accumulated in hOCT-overexpressing MDCK cells in a concentration-dependent manner, with estimated K(m) values of 0.99, 2.79, and 2.23 microM and V(max) values of 282.1, 256.1, and 400.2 pmol/min/microg protein for hOCT1, hOCT2, and hOCT3, respectively. RHPP(+) accumulated in hOCT1- and hOCT3-overexpressing MDCK cells, with estimated K(m) values of 5.15 and 8.21 microM and V(max) values of 1230.9 and 1348.6 pmol/min/microg protein for hOCT1 and hOCT3, respectively. On the other hand, RHPP(+) did not accumulate in the hOCT2-expressing MDCK cells. These results suggest that HPP(+) and RHPP(+) are substrates for hOCTs, with the exception of RHPP(+) for hOCT2. Thus, hOCTs seem to contribute to the disposition of these toxic metabolites in human subjects, although further in vivo studies are required to elucidate the involvement of hOCTs in the disposition of haloperidol pyridinium metabolites.

Clin Evid. 2005 Dec; 1306-30
Lawrie S, McIntosh A, Nadeem Z

Synapse. 2006 Jun 1; 59(7): 394-402
Huerta I, McCullumsmith RE, Haroutunian V, Giménez-Amaya JM, Meador-Woodruff JH

The excitatory amino acid transporters (EAATs) are a family of plasma membrane proteins that maintain synaptic glutamate concentration by removing glutamate from the synaptic cleft. EAATs are expressed by glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4) throughout the brain. Glutamate reuptake is regulated, in part, by EAAT-interacting proteins that modulate subcellular localization and glutamate transport activity of the EAATs. Several lines of investigation support the hypothesis of glutamatergic abnormalities in schizophrenia. Previous work in our laboratory demonstrated increased expression of EAAT1 and EAAT2 transcripts in the thalamus, suggesting that alterations in synaptic glutamate levels may contribute to the pathophysiology of schizophrenia. Since EAAT-interacting proteins regulate EAAT function, directly impacting glutamatergic neurotransmission, we hypothesized that expression of EAAT-interacting proteins may also be altered in schizophrenia. Using in situ hybridization in subjects with schizophrenia and a comparison group, we detected increased expression of JWA and KIAA0302, molecules that regulate EAAT3 and EAAT4, respectively, in the thalamus in schizophrenia. In contrast, we did not find changes in the expression of transcripts for the EAAT2 and EAAT4 regulatory proteins GPS-1 and ARHGEF11. To address prior antipsychotic treatment in our schizophrenic subjects, we treated rats with haloperidol and clozapine for 4 weeks, and found changes in transcript expression of the EAAT-interacting proteins in clozapine-, but not haloperidol-, treated rats. These findings suggest that proteins associated with the regulation of glutamate reuptake may be abnormal in this illness, supporting the hypothesis of altered thalamic glutamatergic neurotransmission in schizophrenia.