The Effect of Combined Patching and Citalopram on Visual Acuity in Adults with Amblyopia: A Randomized, Crossover, Placebo-Controlled Trial.

Nonhuman animal models have demonstrated that selective serotonin reuptake inhibitors (SSRIs) can enhance plasticity within the mature visual cortex and enable recovery from amblyopia. The aim of this study was to test the hypothesis that the SSRI citalopram combined with part-time patching of the fellow fixing eye would improve amblyopic eye visual acuity in adult humans. Following a crossover, randomized, double-blind, placebo-controlled design, participants completed two 2-week blocks of fellow fixing eye patching. One block combined patching with citalopram (20 mg/day) and the other with a placebo tablet. The blocks were separated by a 2-week washout period. The primary outcome was change in amblyopic eye visual acuity. Secondary outcomes included stereoacuity and electrophysiological measures of retinal and cortical function. Seven participants were randomized, fewer than our prespecified sample size of 20. There were no statistically significant differences in amblyopic eye visual acuity change between the active (mean ± SD change = 0.08 ± 0.16 logMAR) and the placebo (mean change = -0.01 ± 0.03 logMAR) blocks. No treatment effects were observed for any secondary outcomes. However, 3 of 7 participants experienced a 0.1 logMAR or greater improvement in amblyopic eye visual acuity in the active but not the placebo blocks. These results from a small sample suggest that larger-scale trials of SSRI treatment for adult amblyopia may be warranted. Considerations for future trials include drug dose, treatment duration, and recruitment challenges. This study was preregistered as a clinical trial (ACTRN12611000669998).

Using fMRI to compare the effects of benzylpiperazine with dexamphetamine - Their differences during the Stroop paradigm.

RATIONALE: Benzylpiperazine (BZP) has been found to increase neural activation in the dorsal striatum when compared to placebo in response to a Stroop paradigm, in addition, subjective effects have been compared to dexamphetamine (DEX). Despite their similarities, the two have not been directly compared in respect to their effects on selective attention and inhibition. OBJECTIVES: To use a double-blind placebo-controlled crossover study to compare the acute effects of BZP and DEX on executive function using functional magnetic resonance imaging (fMRI) and an event-related Stroop task. METHODS: Eleven healthy participants aged 18-40 years undertook the Stroop task 90[Formula: see text]min after taking an oral dose of either BZP (200[Formula: see text]mg), DEX (20[Formula: see text]mg) or placebo. RESULTS: BZP induced a greater increase in activation than DEX in the inferior frontal gyrus (IFG) during the Stroop task. DEX increased BOLD signal in the thalamus and decreased it in the IFG in comparison to placebo. CONCLUSION: Despite BZP and DEX reportedly inducing similar subjective effects, there are different patterns of neural activation. We believe this differential activity is due to pharmacological differences in their receptor binding profiles and that subsequent inhibitory effects might be due to their direct effect on dopaminergic activity.

Extensive gray matter volume reduction in treatment-resistant schizophrenia.

BACKGROUND: Approximately one-third of people with schizophrenia are treatment-resistant and some do not achieve remission with clozapine, the gold-standard antipsychotic medication for treatment-resistant schizophrenia. This study compared global and regional brain volumes between treatment-respondent and treatment-resistant patients with schizophrenia, including a group of patients who were clozapine-resistant. METHODS: T1-weighted brain MRIs were obtained on a 3T scanner in 20 controls and 52 people with schizophrenia who were selected based on their symptomatic responses to antipsychotic medication: 18 responded well to first-line atypical antipsychotics (FLR), 19 were treatment-resistant but responsive to clozapine monotherapy (TR), and 15 were ultra-treatment-resistant and did not respond to clozapine (UTR). Treatment groups were matched for disease duration and current psychopathology. SIENAX and FSL-VBM were used to investigate differences in the global brain, gray matter (GM), white matter, ventricular cerebrospinal fluid volumes, and regional GM volumes. RESULTS: GM volume was significantly reduced in the TR and UTR groups compared with controls and the FLR group (p < 0.05). GM volume was significantly reduced in TR patients compared with FLRs in the superior, middle, and inferior temporal gyri, pre- and post-central gyri, middle and superior frontal gyri, right supramarginal gyrus, and right lateral occipital cortex. UTR patients showed reduced GM compared with FLRs in their right parietal operculum and left cerebellum. No significant volume differences were observed between TR and UTR groups. CONCLUSIONS: These differences are unlikely to be solely due to medication effects, and reduced GM volume in treatment-resistant schizophrenia may represent an accelerated disease course or a different underlying pathology.

Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia.

BACKGROUND: According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated. METHODS: Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects. RESULTS: Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η(2) = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η(2) = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected). CONCLUSIONS: Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.

Incorporating uncertainty within dynamic interoceptive learning.

Introduction: Interoception, the perception of the internal state of the body, has been shown to be closely linked to emotions and mental health. Of particular interest are interoceptive learning processes that capture associations between environmental cues and body signals as a basis for making homeostatically relevant predictions about the future. One method of measuring respiratory interoceptive learning that has shown promising results is the Breathing Learning Task (BLT). While the original BLT required binary predictions regarding the presence or absence of an upcoming inspiratory resistance, here we extended this paradigm to capture continuous measures of prediction (un)certainty. Methods: Sixteen healthy participants completed the continuous version of the BLT, where they were asked to predict the likelihood of breathing resistances on a continuous scale from 0.0 to 10.0. In order to explain participants' responses, a Rescorla-Wagner model of associative learning was combined with suitable observation models for continuous or binary predictions, respectively. For validation, we compared both models against corresponding null models and examined the correlation between observed and modeled predictions. The model was additionally extended to test whether learning rates differed according to stimuli valence. Finally, summary measures of prediction certainty as well as model estimates for learning rates were considered against interoceptive and mental health questionnaire measures. Results: Our results demonstrated that the continuous model fits closely captured participant behavior using empirical data, and the binarised predictions showed excellent replicability compared to previously collected data. However, the model extension indicated that there were no significant differences between learning rates for negative (i.e. breathing resistance) and positive (i.e. no breathing resistance) stimuli. Finally, significant correlations were found between fatigue severity and both prediction certainty and learning rate, as well as between anxiety sensitivity and prediction certainty. Discussion: These results demonstrate the utility of gathering enriched continuous prediction data in interoceptive learning tasks, and suggest that the updated BLT is a promising paradigm for future investigations into interoceptive learning and potential links to mental health.

A systematic review of brief respiratory, embodiment, cognitive, and mindfulness interventions to reduce state anxiety.

Introduction: Anxiety is one of the most prevalent mental health conditions worldwide, and psychotherapeutic techniques can be employed to help manage and mitigate symptoms. While the available therapies are numerous, key strategies often involve cognitive and/or embodiment techniques. Within body-centered methods, breathing-oriented approaches are particularly prevalent, using either attention towards or active control of breathing. As the perception of body states (i.e., interoception) is thought to be an integral component of emotion generation, these embodiment and breathing techniques may be key in addressing the miscommunication between the brain and body that is thought to exist with anxiety. Therefore, we conducted a systematic review and meta-analysis to assess the effects of acute administration of psychological interventions for state anxiety. Results: This systematic review was conducted in accordance with the PRISMA statement and registered prospectively in PROSPERO. A literature search for randomized controlled trials was conducted in PubMed, PsycINFO, and Scopus. We considered interventions that focused on cognitive, embodiment or breathing strategies, or a combination of these techniques. Twelve studies met our inclusion criteria, and study characteristics, quality and effect sizes were assessed. A single cognitive study was found to produce a moderate reduction in state anxiety, while moderate to large effects were found across studies assessing embodiment practices. In contrast, studies which utilized breathing-based interventions alone produced inconsistent results, with both attention towards and active control of breathing producing large to no effects depending on the technique employed. Finally, consistent moderate effects were found with combination techniques that involved passive attention (e.g., towards cognitions, body and/or breathing), with active combination techniques producing inconsistent results. Discussion: While study numbers are limited regarding brief interventions, cognitive and embodiment techniques are consistently helpful for reducing state anxiety, while breathing-based exercises need to consider the specific technique employed, and how successful this may be for each individual. Furthermore, combined practices such as mindfulness can also be successful, although care must be taken when introducing an active change to one or more elements. PROSPERO Systematic Review Registration Number: CRD42024507585 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024507585.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

Perceptual and Ventilatory Responses to Hypercapnia in Athletes and Sedentary Individuals.

Purpose: Hypercapnic chemosensitivity traditionally captures the ventilatory response to elevated pressures of carbon dioxide in the blood. However, hypercapnia also contributes to subjective breathing perceptions, and previously we demonstrated a closer matching of perception to changes in ventilation in athletes compared to controls. Here we investigated any potential underlying hypercapnic chemosensitivity differences between groups, and explored whether these measures relate to ventilatory and perceptual responses during exercise as well as trait levels of affect. Methods: A hypercapnic challenge, incremental maximal exercise test and affective questionnaires were completed by 20 endurance athletes and 20 age-/sex-matched sedentary controls. The hypercapnic challenge involved elevating end-tidal PCO2 by 0.8% (6.1 mmHg) and 1.5% (11.2 mmHg) for 3 min each (randomised), with constant end-tidal oxygen. Ventilatory and perceptual responses to hypercapnia were compared between groups, and within each group the relationships between hypercapnic chemosensitivity (slope analyses) and exercising ventilation and perceptions were calculated using Spearman's non-parametric correlations. Results: While absolute ventilation differences during hypercapnia and exercise were observed, no group differences were found across hypercapnic chemosensitivity (slope) measures. Correlation analyses revealed the anxiety hypercapnic response was related to maximal exercise anxiety, but only in sedentary individuals. Conclusion: Ventilatory and perceptual hypercapnic chemosensitivity do not differ between athletes and sedentary individuals. However, ventilatory and anxiety hypercapnic chemosensitivities were related to ventilatory and anxiety responses during exercise in untrained individuals only. Athletes may employ additional strategies during exercise to reduce the influence of chemosensitivity on ventilatory and perceptual responses.

Right frontal anxiolytic-sensitive EEG 'theta' rhythm in the stop-signal task is a theory-based anxiety disorder biomarker.

Psychiatric diagnoses currently rely on a patient's presenting symptoms or signs, lacking much-needed theory-based biomarkers. Our neuropsychological theory of anxiety, recently supported by human imaging, is founded on a longstanding, reliable, rodent 'theta' brain rhythm model of human clinical anxiolytic drug action. We have now developed a human scalp EEG homolog-goal-conflict-specific rhythmicity (GCSR), i.e., EEG rhythmicity specific to a balanced conflict between goals (e.g., approach-avoidance). Critically, GCSR is consistently reduced by different classes of anxiolytic drug and correlates with clinically-relevant trait anxiety scores (STAI-T). Here we show elevated GCSR in student volunteers divided, after testing, on their STAI-T scores into low, medium, and high (typical of clinical anxiety) groups. We then tested anxiety disorder patients (meeting diagnostic criteria) and similar controls recruited separately from the community. The patient group had higher average GCSR than their controls-with a mixture of high and low GCSR that varied with, but cut across, conventional disorder diagnosis. Consequently, GCSR scores should provide the first theoretically-based biomarker that could help diagnose, and so redefine, a psychiatric disorder.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Aberrant white matter microstructure in treatment-resistant schizophrenia✰.

Treatment response in schizophrenia divides into three subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS), and ultra-treatment-resistant schizophrenia (UTRS). White matter abnormalities could drive antipsychotic resistance but little work has investigated differences between TRS and UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were obtained using tract-based spatial statistics. Analysis of variance and post-hoc t-tests were conducted for each measure. Those with TRS had lower FA than healthy controls in superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). No post-hoc tests survived corrections for multiple comparisons and no differences in MD, AD or RD were observed. These data suggest that microstructural deficits in white matter could contribute to TRS but suggest that other mechanisms may be more relevant for UTRS.

Metabolic interactions with piperazine-based 'party pill' drugs.

OBJECTIVES: 'Party pills' have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions between 'party pills' constituents and other drugs metabolised by the same cytochrome P450 (CYP) isoenzymes. METHODS: The inhibitory effects of seven benzyl and phenyl piperazines were measured in microsomal incubation assays of probe substrates for five major CYP isoenzymes. In addition, the metabolism of benzylpiperazine and trifluoromethylphenylpiperazine, the two most commonly used constituents of 'party pills', was investigated using human liver microsomes assays and known inhibitors of CYP isoenzymes. KEY FINDINGS: All piperazine analogues tested showed significant inhibitory activity against most, if not all, isoenzymes tested. The metabolism of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) involved CYP2D6, CYP1A2 and CYP3A4. Furthermore, BZP and TFMPP inhibited each other's metabolism. CONCLUSIONS: Fluorophenylpiperazine, methoxyphenylpiperazine, chlorophenylpiperazine, methylbenzylpiperazine and methylenedioxybenzylpiperazine had significant inhibitory effects on CYP2D6, CYP1A2, CYP3A4, CYP2C19 and CYP2C9 isoenzymes but each piperazine had a different inhibitory profile. The metabolic interaction between BZP and TFMPP may have clinical implications, as these agents are often combined in 'party pills'.

Human Sensory LTP Predicts Memory Performance and Is Modulated by the BDNF Val66Met Polymorphism.

Background: Long-term potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to brain-derived neurotrophic factor (BDNF) Val66Met; a single-nucleotide polymorphism (SNP) implicated in memory function. Methods: Participants were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory. Results: The magnitude of LTP 40 min after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance. Conclusions: The current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.

Integrating Space, Time, and Orientation in Spiking Neural Networks: A Case Study on Multimodal Brain Data Modeling.

Recent progress in a noninvasive brain data sampling technology has facilitated simultaneous sampling of multiple modalities of brain data, such as functional magnetic resonance imaging, electroencephalography, diffusion tensor imaging, and so on. In spite of the potential benefits from integrating predictive modeling of multiple modality brain data, this area of research remains mostly unexplored due to a lack of methodological advancements. The difficulty in fusing multiple modalities of brain data within a single model lies in the heterogeneous temporal and spatial characteristics of the data sources. Recent advances in spiking neural network systems, however, provide the flexibility to incorporate multidimensional information within the model. This paper proposes a novel, unsupervised learning algorithm for fusing temporal, spatial, and orientation information in a spiking neural network architecture that could potentially be used to understand and perform predictive modeling using multimodal data. The proposed algorithm is evaluated both qualitatively and quantitatively using synthetically generated data to characterize its behavior and its ability to utilize spatial, temporal, and orientation information within the model. This leads to improved pattern recognition capabilities and performance along with robust interpretability of the brain data. Furthermore, a case study is presented, which aims to build a computational model that discriminates between people with schizophrenia who respond or do not respond to monotherapy with the antipsychotic clozapine.

Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia.

Schizophrenia may develop from disruptions in functional connectivity regulated by neurotransmitters such as dopamine and acetylcholine. The modulatory effects of these neurotransmitters might explain how antipsychotics attenuate symptoms of schizophrenia and account for the variable response to antipsychotics observed in clinical practice. Based on the putative mechanisms of antipsychotics and evidence of disrupted connectivity in schizophrenia, we hypothesised that functional network connectivity, as assessed using network-based statistics, would exhibit differences between treatment response subtypes of schizophrenia and healthy controls. Resting-state functional MRI data were obtained from 17 healthy controls as well as individuals with schizophrenia who responded well to first-line atypical antipsychotics (first-line responders; FLR, n=18), had failed at least two trials of antipsychotics but responded to clozapine (treatment-resistant schizophrenia; TRS, n=18), or failed at least two trials of antipsychotics and a trial of clozapine (ultra-treatment-resistant schizophrenia; UTRS, n=16). Data were pre-processed using the Advanced Normalization Toolkit and BrainWavelet Toolbox. Network connectivity was assessed using the Network-Based Statistics toolbox in Matlab. ANOVA revealed a significant difference in functional connectivity between groups that extended between cerebellar and parietal regions to the frontal cortex (p<0.05). Post-hoc t-tests revealed weaker network connectivity in individuals with UTRS compared with healthy controls but no other differences between groups. Results demonstrated distinct differences in functional connectivity between individuals with UTRS and healthy controls. Future work must determine whether these changes occur prior to the onset of treatment and if they can be used to predict resistance to antipsychotics during first-episode psychosis.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Quantitative EEG and Low-Resolution Electromagnetic Tomography (LORETA) Imaging of Patients Undergoing Methadone Treatment for Opiate Addiction.

Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal-interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference [MD] = 0.32, 95% CI = 0.09-0.55, P < .01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P = .01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT.

Investigation of the effects of 'piperazine-containing party pills' and dexamphetamine on interhemispheric communication using electroencephalography.

BACKGROUND: 'Piperazine-containing party pills' were marketed and sold as legal alternatives to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. The major constituents of these 'pills' were benzylphenylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). Despite their popularity, there is a paucity of knowledge about their central effects in humans. This study investigated their effects on human neural processing using electroencephalographic techniques. METHODS: A randomised, double-blind, placebo-controlled study investigated the effects of an acute dose of these compounds on the interhemispheric transfer of information (IHTT) using the Poffenberger task. Reaction time data were also collected. Healthy, right-handed males were given an oral dose of either BZP (n = 13) (200 mg), TFMPP (n = 15) (60 mg), a combination of BZP + TFMPP (n = 15) (100 mg/30 mg), dexamphetamine (n = 16) (20 mg), or placebo (n = 23) and tested both before and 120 min after drug administration. RESULTS: A mixed factorial repeated measures analysis of variance of absolute N160 latency and contrast analysis revealed that only TFMPP (F (1,77) = 17.30, p ≤ 0.001) significantly reduced the absolute N160 latency. Analysis of the IHTT revealed that only TFMPP (F (1,77) = 5.266, p ≤ 0.02) significantly reduced the IHTT, while BZP, BZP + TFMPP and dexamphetamine had no effect. Contrast analysis revealed that both TFMPP (F (1,77) = 17.30, p ≤ 0.001) and placebo (F (1,77) = 15.08, p ≤ 0.001) preserved the laterality of information transfer from one hemisphere to the other. Reaction time (p > 0.05) was not significantly affected by any of the drug treatments. CONCLUSIONS: The usual directional asymmetry (i.e. faster R-to-L transfer relative to L-to-R) observed in healthy control group was absent following the administration of either BZP, BZP + TFMPP or dexamphetamine. Surprisingly, lateralised hemispheric function was not affected by TFMPP. Our findings highlight how the administration of BZP, TFMPP and BZP + TFMPP leads to changes in the pattern of information transfer.

Varenicline improves motor and cognitive symptoms in early Huntington's disease.

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington's disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington's Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro®). Varenicline (1 mg twice daily) significantly improved performance in executive function and emotional recognition tasks. Our case reports describe no clinically significant adverse effects and suggest that varenicline improves aspects of cognitive function in patients with early HD. A randomized controlled study is now underway.

Acute effects of BZP, TFMPP and the combination of BZP and TFMPP in comparison to dexamphetamine on an auditory oddball task using electroencephalography: a single-dose study.

RATIONALE: Piperazine-based designer drugs such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been marketed and sold as legal alternatives to dexamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. When administered in combination, BZP + TFMPP have been reported to produce drug-drug synergism in rodents by stimulating the release of dopamine and serotonin. OBJECTIVES: This study was to evaluate the acute event-related potential effects of BZP, TFMPP or the combination of BZP + TFMPP compared with dexamphetamine in young healthy male adults. METHODS: A double-blind, randomised, placebo-controlled study investigated the effects of BZP, TFMPP, the combination of BZP + TFMPP, and dexamphetamine on the event-related potentials during an auditory oddball task. Healthy, right-handed males were given a single oral dose of either BZP (200 mg), TFMPP (60 mg), a combination of BZP + TFMPP (100/30 mg), dexamphetamine (20 mg) or placebo (lactose) and tested both before and 120 min after drug administration. RESULTS: A single dose of either TMFPP (t = -2.29, p = 0.03) or dexamphetamine (t = -2.33, p = 0.02) significantly reduced the P300 amplitude. A similar trend was also found in BZP. In contrast, BZP and TFMPP in combination has no effect. Neither P300 latency nor the mean reaction time was affected by any of the drug treatments. In addition, neither the P100 nor the P200 component was significantly affected following any of the drug treatments. CONCLUSIONS: A single oral dose of BZP or TFMPP, but not the combination of BZP/TFMPP, affected auditory sensory-evoked P300 potential in a manner similar to dexamphetamine.