Comparison of Extrapyramidal Symptoms Among Outpatients With Schizophrenia on Long-Acting Injectable Antipsychotics.

BACKGROUND: Extrapyramidal symptoms (EPSs) are adverse effects of antipsychotics. Different risks of EPSs have been attributed to the 3 classes of antipsychotics. This study aimed to assess EPS in a clinical sample of schizophrenia patients who are on LAI and compare the severity of EPSs among the following 3 antipsychotic groups: (1) partial agonist, (2) second-generation antipsychotics, and (3) first-generation antipsychotics. METHODS: Ninety-two patients were recruited from the Schizophrenia Program Injection Clinic. Using the Extrapyramidal Symptom Rating Scale (ESRS), severity of EPS was assessed and information regarding factors associated with risk of EPS, including coprescriptions, comorbidities, and demographics, was obtained from medical charts. Group differences in ESRS scores and subscores were analyzed using 1-way analyses of variances. RESULTS: Among the 3 groups, there was no significant difference in total ESRS scores and subscores. Risperidone was associated with higher ESRS scores when compared with paliperidone, aripiprazole, and flupenthixol. Doses above maximum were commonly used in the paliperidone group, and there was no significant difference in total ESRS scores between the low, average, or above-maximum doses of paliperidone. CONCLUSIONS: Our results demonstrated a comparative risk of EPS across all 3 antipsychotic classes. Risperidone was associated with more EPS compared with other medications. A higher threshold for the "maximum dose" of paliperidone could be considered and higher doses used with the same cautions as low-average doses.

Retrospective review of use of adjunctive psychostimulants in patients with schizophrenia.

BACKGROUND: Adjunctive psychostimulants have been proposed as a potential treatment option for the management of cognitive and/or negative symptoms of schizophrenia. METHODS: The present study is a retrospective review of use of adjunctive psychostimulants among outpatients enrolled in our tertiary Schizophrenia Program between 2014 and 2019. We assessed response to treatment, adverse effects, and the impact of various clinical factors on treatment outcome. RESULTS: Of the 77 (out of 1,300) participants prescribed psychostimulants during the study period, 42.22% had chart-based evidence of significant improvement, 27.77% had minimal improvement, and 25.55% reported no change. The majority (61.9%) demonstrated improvement in attention, concentration, and/or other cognitive symptoms. Approximately one-third of cases had evidence of emergence of psychosis. Of the factors assessed, comorbid attention-deficit/hyperactivity disorder was associated with an increased likelihood of response, and higher doses of stimulants were associated with likelihood of emergence of psychosis. CONCLUSIONS: Adjunctive psychostimulants could be a potential treatment consideration to address cognitive deficits in selected patients with schizophrenia.

Effects of transcranial direct current stimulation on the auditory mismatch negativity response and working memory performance in schizophrenia: a pilot study.

Cognitive impairment has been proposed to be the core feature of schizophrenia (Sz). Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which can improve cognitive function in healthy participants and in psychiatric patients with cognitive deficits. tDCS has been shown to improve cognition and hallucination symptoms in Sz, a disorder also associated with marked sensory processing deficits. Recent findings in healthy controls demonstrate that anodal tDCS increases auditory deviance detection, as measured by the brain-based event-related potential, mismatch negativity (MMN), which is a putative biomarker of Sz that has been proposed as a target for treatment of Sz cognition. This pilot study conducted a randomized, double-blind assessment of the effects of pre- and post-tDCS on MMN-indexed auditory discrimination in 12 Sz patients, moderated by auditory hallucination (AH) presence, as well as working memory performance. Assessments were conducted in three sessions involving temporal and frontal lobe anodal stimulation (to transiently excite local brain activity), and one control session involving 'sham' stimulation (meaning with the device turned off, i.e., no stimulation). Results demonstrated a trend for pitch MMN amplitude to increase with anodal temporal tDCS, which was significant in a subgroup of Sz individuals with AHs. Anodal frontal tDCS significantly increased WM performance on the 2-back task, which was found to positively correlate with MMN-tDCS effects. The findings contribute to our understanding of tDCS effects for sensory processing deficits and working memory performance in Sz and may have implications for psychiatric disorders with sensory deficits.

Adjunctive methylphenidate extended release in patients with schizophrenia: Protocol of a single-centre fixed dose cross-over open-label trial to improve functional and cognitive outcomes.

Background: Cognitive symptoms, among the core symptoms of schizophrenia, are associated with poor functional outcome and burden of illness. To date, there is no effective pharmacological treatment for these symptom clusters. Augmentation with psychostimulants has been proposed as a potential treatment option. Objectives: The present study aims to assess off-label use of adjunctive methylphenidate extended release (ER) in patients with schizophrenia who are stable on antipsychotic medications, and to assess its efficacy on functioning and cognitive outcome. Methods: This is a single centre study at the Royal Ottawa Mental Health Centre. An open-label fixed dose controlled cross-over trial is planned. Eligible participants will be randomized into one of two arms of the study: 1) four weeks of add-on methylphenidate ER 36 mg, or 2) four weeks of treatment as usual. At 4 weeks, participants will switch arms. The duration of the study includes 8 weeks of treatment and a follow-up visit at 12 weeks. Primary outcome measures include tablet-based tests of functioning and cognition (VRFCAT and BAC) and will be administered at baseline and every 4 weeks. We are aiming to recruit a total of 24 participants. Expected outcomes: The proposed project intends to assess a potential treatment option for cognitive deficits of schizophrenia, for which there are no recommendations by current treatment guidelines. The novelty and significance of the current study is that it investigates this intervention and assess applicability of it in a "real world setting" in a tertiary care hospital.

Evidence review and clinical guidance for the use of ziprasidone in Canada.

While indicated for schizophrenia and acute mania, ziprasidone's evidence base and use in clinical practice extends beyond these regulatory approvals. We, an invited panel of experts led by a working group of 3, critically examined the evidence and our collective experience regarding the effectiveness, tolerability and safety of ziprasidone across its clinical uses. There was no opportunity for manufacturer input into the content of the review. As anticipated, ziprasidone was found to be effective for its indicated uses, although its utility in mania and mixed states lacked comparative data. Beyond these uses, the available data were either unimpressive or were lacking. An attractive characteristic is its neutral effect on weight thereby providing patients with a non-obesogenic long-term treatment option. Key challenges in practice include the need for dosing on a full stomach and managing its early onset adverse effect of restlessness. Addressing these issues are critical to its long-term success.

An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine.

BACKGROUND: Cognitive operations including pre-attentive sensory processing are markedly impaired in patients with schizophrenia (SCZ) but evidence significant interindividual heterogeneity, which moderates treatment response with nicotinic acetylcholine receptor (nAChR) agonists. Previous studies in healthy volunteers have shown baseline-dependency effects of the α7 nAChR agonist cytidine 5'-diphosphocholine (CDP-choline) administered alone and in combination with a nicotinic allosteric modulator (galantamine) on auditory deviance detection measured with the mismatch negativity (MMN) event-related potential (ERP). AIM: The objective of this pilot study was to assess the acute effect of this combined α7 nAChR-targeted treatment (CDP-choline/galantamine) on speech MMN in patients with SCZ (N = 24) stratified by baseline MMN responses into low, medium, and high baseline auditory deviance detection subgroups. METHODS: Patients with a stable diagnosis of SCZ attended two randomized, double-blind, placebo-controlled and counter-balanced testing sessions where they received a placebo or a CDP-choline (500 mg) and galantamine (16 mg) treatment. MMN ERPs were recorded during the presentation of a fast multi-feature speech MMN paradigm including five speech deviants. Clinical measures were acquired before and after treatment administration. RESULTS: While no main treatment effect was observed, CDP-choline/galantamine significantly increased MMN amplitudes to frequency, duration, and vowel speech deviants in low group individuals. Individuals with higher positive and negative symptom scale negative, general, and total scores expressed the greatest MMN amplitude improvement following CDP-choline/galantamine. CONCLUSIONS: These baseline-dependent nicotinic effects on early auditory information processing warrant different dosage and repeated administration assessments in patients with low baseline deviance detection levels.

Nicotine and the hallucinating brain: effects on mismatch negativity (MMN) in schizophrenia.

Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs.

The acute dose and baseline amplitude-dependent effects of CDP-choline on deviance detection (MMN) in chronic schizophrenia: A pilot study.

The detection of deviant auditory features is empirically supported as impaired in schizophrenia and has been shown to associate with functional outcome. Modulated by glutamate neurotransmission, this sensory process has also been shown to relate to the α7 nicotinic acetylcholine receptor (nAChR) system, a prioritized molecular target for the development of novel cognition targeted pharmacological treatments. This pilot study assessed the acute effects of CDP-Choline, a choline supplement with α7 nAChR agonist properties, on the mismatch negativity (MMN), an event-related potential index of the detection of an acoustic change, in a sample of individuals diagnosed with chronic schizophrenia. Utilizing a randomized, placebo-controlled, double-blind design, the dose-dependent (500 mg, 1,000 mg, 2,000 mg), baseline amplitude-dependent (low vs. high), and deviant feature-dependent effects of CDP-Choline on the MMN were examined. CDP-choline's effects interacted with dosage, deviance feature, and baseline amplitude with low baseline amplitude patients demonstrating enhanced MMNs, and high baseline amplitude patients demonstrating suppressed MMNs in response to CDP-Choline. These findings offer tentative support for the involvement of the α7 nAChR system in auditory MMN abnormalities in schizophrenia and supports further research assessing the effects of long-term treatment with CDP-Choline in the personalized treatment of auditory deviance processing impairments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Alterations of Resting EEG in Hallucinating and Nonhallucinating Schizophrenia Patients.

Auditory hallucinations (AHs) are a common symptom of schizophrenia and contribute significantly to disease burden. Research on schizophrenia and AHs is limited and fails to adequately address the effect of AHs on resting EEG in patients with schizophrenia. This study assessed changes in frequency bands (delta, theta, alpha, beta) of resting EEG taken from hallucinating patients (n = 12), nonhallucinating patients (n = 11), and healthy controls (n = 12). Delta and theta activity were unaffected by AHs but differed between patients with schizophrenia and healthy controls. Alpha activity was affected by AHs: nonhallucinators had more alpha activity than hallucinators and healthy controls. Additionally, beta activity was inversely related to trait measures of AHs. These findings contribute to the literature of resting eyes closed EEG recordings of schizophrenia and AHs, and indicate the role of delta, theta, alpha, and beta as markers for schizophrenia and auditory hallucinations.

Acute nicotine alteration of sensory memory impairment in smokers with schizophrenia.

CONTEXT: Patients with schizophrenia have a high rate of cigarette smoking and also exhibit profound deficits in sensory processing, which may in part be ameliorated by the acute actions of smoke-inhaled nicotine. The mismatch negativity (MMN), a preattentive event-related potential index of auditory sensory memory, is diminished in schizophrenia. The MMN is increased in healthy controls with acute nicotine. OBJECTIVE: To utilize the MMN to compare auditory sensory memory in minimally tobacco-deprived (3 hours) patients and matched tobacco-deprived smoking controls and to assess the effects of acute nicotine on MMN-indexed sensory memory processing in the patients. DESIGN: Event-related potentials were recorded in 2 auditory oddball paradigms, one involving tone frequency changes (frequency MMN) and one involving tone duration changes (duration MMN). Controls were assessed once under nontreatment conditions, and patients were assessed twice under randomized double-blind treatment conditions involving placebo and nicotine (8 mg) gum. SETTING: Outpatient mental health center. PATIENTS: Twelve smokers with schizophrenia and twelve control smokers. RESULTS: Compared with the controls, the patients showed reduced frequency-MMN (P < 0.001) and duration-MMN (P < 0.04) amplitudes. In addition to prolonging peak latency in duration MMN (P < 0.01), nicotine, relative to placebo, increased the amplitude of the patients' duration MMN (P < 0.01), but not their frequency MMN, to a level comparable with that seen in the controls. CONCLUSIONS: These preliminary findings demonstrate for the first time that acute nicotine can normalize temporal aspects of sensory memory processing in patients with schizophrenia, an effect that may be mediated by activation of α7 nicotinic acetylcholine receptors, the function of which is diminished in schizophrenia. These ameliorating actions of nicotine may have implications for understanding the close relationship between tobacco smoking and schizophrenia and for developing nicotinic pharmacotherapies to alleviate sensory memory impairments in schizophrenia.

Interaction of Background Noise and Auditory Hallucinations on Phonemic Mismatch Negativity (MMN) and P3a Processing in Schizophrenia.

Auditory hallucinations (AHs) are among the cardinal symptoms of schizophrenia (SZ). During the presence of AHs aberrant activity of auditory cortices have been observed, including hyperactivation during AHs alone and hypoactivation when AHs are accompanied by a concurrent external auditory competitor. Mismatch negativity (MMN) and P3a are common ERPs of interest within the study of SZ as they are robustly reduced in the chronic phase of the illness. The present study aimed to explore whether background noise altered the auditory MMN and P3a in those with SZ and treatment-resistant AHs. METHODS: MMN and P3a were assessed in 12 hallucinating patients (HPs), 11 non-hallucinating patients (NPs) and 9 healthy controls (HCs) within an auditory oddball paradigm. Standard (P = 0.85) and deviant (P = 0.15) stimuli were presented during three noise conditions: silence (SL), traffic noise (TN), and wide-band white noise (WN). RESULTS: HPs showed significantly greater deficits in MMN amplitude relative to NPs in all background noise conditions, though predominantly at central electrodes. Conversely, both NPs and HPs exhibited significant deficits in P3a amplitude relative to HCs under the SL condition only. SIGNIFICANCE: These findings suggest that the presence of AHs may specifically impair the MMN, while the P3a appears to be more generally impaired in SZ. That MMN amplitudes are specifically reduced for HPs during background noise conditions suggests HPs may have a harder time detecting changes in phonemic sounds during situations with external traffic or "real-world" noise compared to NPs.

Change in the Neural Response to Auditory Deviance Following Cognitive Therapy for Hallucinations in Patients With Schizophrenia.

Adjunctive psychotherapeutic approaches recommended for patients with schizophrenia (SZ) who are fully or partially resistant to pharmacotherapy have rarely utilized biomarkers to enhance the understanding of treatment-effective mechanisms. As SZ patients with persistent auditory verbal hallucinations (AVH) frequently evidence reduced neural responsiveness to external auditory stimulation, which may impact cognitive and functional outcomes, this study examined the effects of cognitive behavioral therapy for voices (CBTv) on clinical and AVH symptoms and the sensory processing of auditory deviants as measured with the electroencephalographically derived mismatch negativity (MMN) response. Twenty-four patients with SZ and AVH were randomly assigned to group CBTv treatment or a treatment as usual (TAU) condition. Patients in the group CBTv condition received treatment for 5 months while the matched control patients received TAU for the same period, followed by 5 months of group CBTv. Assessments were conducted at baseline and at the end of treatment. Although not showing consistent changes in the frequency of AVHs, CBTv (vs. TAU) improved patients' appraisal (p = 0.001) of and behavioral/emotional responses to AVHs, and increased both MMN generation (p = 0.001) and auditory cortex current density (p = 0.002) in response to tone pitch deviants. Improvements in AVH symptoms were correlated with change in pitch deviant MMN and current density in left primary auditory cortex. These findings of improved auditory information processing and symptom-response attributable to CBTv suggest potential clinical and functional benefits of psychotherapeutical approaches for patients with persistent AVHs.

Combining CDP-choline and galantamine, an optimized α7 nicotinic strategy, to ameliorate sensory gating to speech stimuli in schizophrenia.

Neural α7 nicotinic acetylcholine receptor (nAChR) expression and functioning deficits have been extensively associated with cognitive and early sensory gating (SG) impairments in schizophrenia (SCZ) patients and their relatives. SG, the suppression of irrelevant and redundant stimuli, is measured in a conditioning-testing (S1-S2) paradigm eliciting electroencephalography-derived P50 event-related potentials (ERPs), the S2 amplitudes of which are typically suppressed relative to S1. Despite extensive reports of nicotine-related improvements and several decades of research, an efficient nicotinic treatment has yet to be approved for SCZ. Following reports of SG improvements in low P50 suppressing SCZ patients and healthy participants with the α7 agonist, CDP-choline, this pilot study examined the combined modulatory effect of CDP-choline (500 mg) and galantamine (16 mg), a nAChR positive allosteric modulator and acetylcholinesterase inhibitor, on SG to speech stimuli in twenty-four SCZ patients in a randomized, double-blind and placebo-controlled design. As expected, in low P50 suppressors CDP-choline/galantamine (vs. Placebo) improved rP50 and dP50 scores by increasing inhibitory mechanisms as reflected by S2P50 amplitude reductions. Results also suggest a moderating role for auditory verbal hallucinations in treatment response. These preliminary findings provide supportive evidence for the involvement of α7 nAChR activity in speech gating in SCZ and support additional trials, examining different dose combinations and repeated doses of this optimized and personalized targeted α7 cholinergic treatment for SG dysfunction in subgroups of SCZ patients.

Mismatch negativity-indexed auditory change detection of speech sounds in early and chronic schizophrenia.

Auditory change detection, as indexed by the EEG-derived mismatch negativity, has been demonstrated to be dysfunctional in chronic schizophrenia using both pure-tone and speech (phoneme) sounds. It is unclear, however, whether reduced MMN amplitudes to speech sound deviants are observed within the first 5 years of the illness. The present study investigated MMNs elicited by across-vowel (phoneme) change in early schizophrenia (ESZ; Experiment 1) as well as chronic schizophrenia (CSZ; Experiment 2). In both experiments, clinical and control participants were presented the Finnish phoneme /e/ (standard; P = .90) and the Finnish phoneme /ö/ (deviant; P = .10) within an oddball paradigm. In experiment 2 we report significantly reduced MMN amplitudes in CSZ relative to HCs, but no differences were found when comparing ESZ and HC in experiment 1. Additionally, in our clinical samples, MMN amplitudes were correlated with symptom scores. These findings suggest that early detection of phonetic change may be impaired in chronic schizophrenia, but not early in the progression of the illness. As MMN reductions only emerged in patients with a longer course of illness, and appeared to change with symptom severity, this suggests a dynamic change in the early auditory processing of language over time in schizophrenia.

The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multi-feature paradigm.

OBJECTIVE: To examine pre-attentive acoustic change detection in schizophrenia patients with and without auditory hallucinations via mismatch negativity (MMN) extracted from a multi-feature paradigm. METHODS: This study examined the electroencephalograph (EEG)-derived MMN, recorded across 32 sites, in 12 hallucinating patients (HPs) with schizophrenia, 12 non-hallucinating patients (NPs) with schizophrenia and 12 healthy controls (HCs). MMN was recorded in response to a multi-feature MMN paradigm [Näätänen, R., et al., 2004. The mismatch negativity (MMN): towards the optimal paradigm. Clin. Neurophys. 115, 140-144] which employs frequency, duration, intensity, location and gap deviants. Differences in source localization were probed using standardized low resolution brain electromagnetic tomography (sLORETA). RESULTS: HPs showed significantly smaller MMNs to duration deviants compared to HCs and NPs, as well as smaller MMNs to intensity deviants compared to HCs. Regionalized differences between HCs and each of the patient groups were observed in response to frequency deviants. There were no significant group effects for location or gap deviants, or for MMN latency. Source localization using sLORETA showed no significant differences in MMN generator location across groups for any of the deviant stimuli. CONCLUSIONS: The often-reported robust MMN deficit to duration deviants may be specific to schizophrenia patients afflicted with auditory hallucinations. Furthermore, by using symptom-specific groups, novel deficits of pre-attentive auditory processing, such as that observed to intensity deviants in HPs, may be revealed. SIGNIFICANCE: The differential responding observed between both groups of patients with schizophrenia has implications for automatic processing within the auditory cortex of hallucinating patients and suggests that care must be taken when recruiting participants in studies involving schizophrenia to ensure consistent, replicable results.

Auditory hallucinations and the mismatch negativity: processing speech and non-speech sounds in schizophrenia.

BACKGROUND: In line with emerging research strategies focusing on specific symptoms rather than global syndromes in psychiatric disorders, we examined the functional neural correlates of auditory verbal hallucinations (AHs) in schizophrenia. Recent neuroimaging and behavioural evidence suggest a reciprocal relationship between auditory cortex response to external sounds versus that induced by AHs. METHODS: The mismatch negativity (MMN), a well established event-related potential (ERP) index of auditory cortex function, was assessed in 12 hallucinating patients (HP), 12 non-hallucinating patients (NP) and 12 healthy controls (HC). The primary endpoints, MMN amplitudes and latencies recorded from anterior and posterior scalp regions, were measured in response to non-phonetic and phonetic sounds. RESULTS: While schizophrenia patients as a whole differed from HCs, no significant between-group differences were observed when patients were divided into hallucinated and non-hallucinated subgroups but, compared to NPs and HCs, whose MMN amplitudes were greatest in response to across phoneme change at frontal but not temporal sites, MMN amplitudes in HPs at frontal sites were not significantly different to any of the presented stimuli, while temporal MMNs in HPs were maximally sensitive to phonetic change. SIGNIFICANCE: These findings demonstrate that auditory verbal hallucinations are associated with impaired pre-attentive processing of speech in fronto-temporal networks, which may involve defective attribution of significance that is sensitive to resource limitations. Overall, this research suggests that MMN may be a useful non-invasive tool for probing relationships between hallucinatory and neural states within schizophrenia and the manner in which auditory processing is altered in these afflicted patients.

Assessing the acute effects of CDP-choline on sensory gating in schizophrenia: A pilot study.

Deficient sensory gating (SG) in schizophrenia is associated with functional outcome and offers a therapeutic target as it is linked to the altered function/expression of the α7 nicotinic acetylcholine receptors (nAChRs). This study analyzed the effects of citicoline (CDP-choline), a supplement with α7 nAChRs agonist properties, on SG in a sample of schizophrenia (SZ) patients. Using a randomized, placebo-controlled, double-blind design the dose-dependent (500 mg, 1000 mg, 2000 mg) and baseline-dependent (deficient versus normal suppressors) effects of CDP-choline on SG were examined using the P50 event-related potential (ERP) index of SG. Overall analysis failed to demonstrate treatment effects but CDP-choline improved SG (500 mg) in the deficient SZ subgroup by increasing suppression of the S2 P50 amplitude. These findings tentatively support α7 nAChR dysfunction in the expression of SG deficits and suggest further trials to assess the effects of sustained α7 nAChR activation on SG with low doses of CDP-choline.

A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone.

OBJECTIVE: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. METHOD: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. RESULTS: Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. CONCLUSIONS: All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Association study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.

BACKGROUND: Brahma (BRM) is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG) repeat, the only known polymorphism in the coding region of the gene (SMARCA2). We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis. RESULTS: Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289) and unaffected controls (n = 273) in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin. CONCLUSION: Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.