Search

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors, although their D(3), versus D(2) binding has not been clearly established in vivo in humans. However, the development of [(11)C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D(2) and D(3) receptors by comparing [(11)C]-(+)-PHNO in D(2)-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D(3)-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-naïve state and then again after ~2.5 weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BP(ND)) was obtained to derive estimates of drug occupancy in the identified brain regions. Antipsychotic treatment was associated with the expected occupancies in the D(2)-rich regions; unexpectedly though, patients showed a higher, rather than the expected lower, [(11)C]-(+)-PHNO BP(ND) in the GP and SN despite simultaneous evidence for ongoing D(2) blockade in the other regions (CAU and PUT). In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D(3) receptor occupancy, but instead possible D(3) up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D(3) binding in vivo. [(11)C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia and the action of antipsychotics. [ABSTRACT FROM AUTHOR]

Exposure to stress is known to affect biological aging as well as individuals' susceptibility to a wide variety of mental illnesses, such as schizophrenia. There is an established relationship between the onset of schizophrenia spectrum disorders (SSD) and biological aging. On the other hand, epigenetic modifications, such as DNA methylation (DNAm), are used as biomarkers for biological aging and were previously proven to be altered in schizophrenia. However, previous research did not consider the effect of psychosocial resilience to stress and its effect on aging in schizophrenia, which is what our study aims to address. For our pilot study, 65 schizophrenia patients were recruited and stress exposure and perception levels were assessed using the Social Readjustment Rating Scale (SRRS) and Perceived Stress Scale (PSS), respectively. Moreover, DNA was extracted from venous blood samples and 850,000 CpG loci were assessed for DNA methylation analysis. Average age of participants was 43.15 ± 13.32 years (55.4% male, 44.6% female). Linear regression plots showed significant correlation between SRRS and PSS scores as well as between biological and chronological ages (p < 0.05). The residuals from the two regression models were defined as the psychosocial resilience and DNAm age acceleration, respectively. Interestingly, DNAm age acceleration was inversely correlated with resilience to stress (p < 0.05). In conclusion, it appears that epigenetic age acceleration is associated with reduced resilience to stress in schizophrenia patients. Future studies should focus on establishing resilience effect on disease prognosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD., Competing Interests: Declaration of interests J.F.-G., M.J.D., A.J.-S., C.B.D., and A.M.S. are authors of a patent (application no. PCT/PT2021/050011; priority date: April 1, 2020) concerning the prevention of TrkB-FL cleavage as a therapeutic strategy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The risk of violence is higher in schizophrenia spectrum disorders (SSD) compared to the general population and it is a pressing and understudied issue. Several dispositional and environmental factors have been previously correlated with violence, however, there has been little success in assessing their ability to predict violence patterns across the life span. This study aims to assess violence prediction based on personality traits, psychological resilience, and life-course adversities in a non-forensic population of SSD patients. In a sample of 231 patients with SSD, we assessed violence using the Brown-Goodwin History of Lifetime Aggression Scale and conducted cross-sectional assessments of possible predictors such as childhood trauma, personality traits and resilience scores. We then utilized a logistic regression classification algorithm to predict different violence trajectories based on the proposed risk factors. Our model significantly predicted individuals with violence in both childhood and adulthood, as well as childhood-only violence (p < 0.001). However, the model did not show significance for adult-only violence (p = 0.604). In all given trajectories, female sex appeared to be protective against violence, while stressful life events appeared to contribute to it. These results suggest that distinct factors can better inform risk assessment of lifespan violence patterns for personalized interventions in SSD., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Assessing the number of past suicide attempts is vital in clinical and research settings, as it is a significant variable in assessing suicide risk. This study sought to compare the accuracy of the C-SSRS and the BSS in reporting past suicide attempts in schizophrenia spectrum disorders . Six hundred participants were recruited from the Centre for Addiction and Mental Health in Toronto, and completed the BSS and C-SSRS. A medical chart review was performed to determine the number of past suicide attempts. In addition, receiver operating characteristic curves were generated to compare the accuracy of both tests under various stratifications. Based on our findings, there were no significant differences (P = 0.8977) between the BSS and CSSRS in detecting a history of past suicide attempts. The BSS exhibited a sensitivity of 0.847 and a specificity of 0.841, while the C-SSRS had a slightly lower sensitivity of 0.795 and a slightly higher specificity of 0.889. Additionally, repeating the analysis to determine the accuracy of detecting multiple past suicide attempts, the BSS demonstrated a sensitivity of 0.704 and a specificity of 0.959, whereas the C-SSRS had a sensitivity of 0.787 and a specificity of 0.927. We further contrasted the two scales, stratified by different demographic variables such as age and sex. The accuracy of both tools, which is defined as the ability to identify true positive cases while minimizing false positives, increased as age increased, but these differences were not statistically significant. Therefore, both tools show a high level of accuracy in reporting past suicide attempt history and should be utilized to fit the specific needs of the research or clinical teams. These findings can inform clinical practice and future research, highlighting the importance of selecting assessment tools that fit the population's needs and context., Competing Interests: Declaration of competing interest The authors declare no competing interests. This study was funded by a standard research grant from the American Foundation for Suicide Prevention (AFSP)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Schizophrenia is a debilitating disease that is associated with higher rates of death by unnatural causes including suicide. Exposure to stressful events is an important risk factor for suicidal ideation (SI); however, the mechanisms that link stress, SI, and suicide remain unclear. Epigenetic processes are involved in both vulnerability to suicidal behavior and stress. Therefore, we sought to study the relationship between epigenetic modifications and suicidal behavior and stress., Methods: This pilot study was conducted on 39 patients diagnosed with schizophrenia (54% men and age 45.5 ± 12.7). We analyzed the effects of (a) stress exposure and (b) the mediation of DNA methylation [via an epigenetic wide association study (EWAS) of more than 450 000 CpG sites across the genome] on SI severity., Results: The top CpG site mediating the effect of global stress exposure on SI was cg27660192 located in an intergenic region on chromosome 11, exerting a facilitating effect on worsening SI through DNA hypomethylation., Conclusion: These preliminary results indicate that DNA methylation in peripheral tissues can shed light on the complex relationship between stress and SI in schizophrenia., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Bipolar disorder (BD) and schizophrenia (SCZ) are debilitating disorders that are associated with significant burden and reduced quality of life. In this study, we leveraged microarray data derived from both the Illumina HumanMethylation450 platform to investigate the epigenetic age of individuals with SCZ (n = 40), BD (n = 40), and healthy controls (n = 38), across five epigenetic clocks. Various statistical metrics were used to identify discrepancies between epigenetic and chronological age across the three groups. We observed a significant increase in epigenetic age compared to chronological age in the BD group. Mean epigenetic age acceleration was also higher in individuals with bipolar disorder compared to healthy controls across four different epigenetic clocks (p<0.05). Despite the study's relatively small sample size, these findings suggest that both individuals with bipolar disorder and schizophrenia may have epigenetic markers associated with a premature aging phenotype, which could be suggestive of negative outcomes associated with the disease. In our future studies, we hope to elucidate this finding further by elucidating the precise link between epigenetic age, symptomatology and disease progression., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: The relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug receptors has been often investigated. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and antipsychotic dosage. The primary aim of this pilot study was to investigate the association between antipsychotic dosage and genome-wide DNA methylation in patients with schizophrenia (SCZ)., Methods: Current dosage of antipsychotic medications was assessed in 136 patients with SCZ. Dosage was standardized using three different methods: chlorpromazine equivalent dose (CPZe), defined daily dose (DDD), and percentage of Lexicomp maximum dose (PM%). DNA methylation was measured in white blood cells. Antipsychotic dosage was the primary outcome variable in a model, including genome-wide methylation status as the main predictor., Results: This study did not show any association between DNA methylation and dosage variation for CPZe, PM%, and DDD. However, the probe cg271403389 was consistently associated with antipsychotic dosage across the three standardization methods. When looking at the genomic location of the most significant probes, we found that 15% were intergenic, 23% were in the distal promoter, 9% in the 3'untranslated region, 32% in the gene body, 3% in the 5' untranslated region, 15% in the proximal promoter, and 3% in the first exon., Discussion: This study shows the importance of investigating the relationship between DNA methylation and optimal antipsychotic dosage to personalize treatment in SCZ. Future studies require larger prescription databases to build on the results of this analysis., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p<.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed., Competing Interests: Declaration of Competing Interest The authors declare no financial conflicts of interest related to the study., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Childhood trauma in schizophrenia (SCZ) is associated with aberrant neurobiological downstream effects and cognitive deficits that markedly hinder patient outcome and functioning. However, the relationship between specific forms of childhood abuse and the tendency for certain personality traits in patients with SCZ has not been comprehensively studied yet. We recruited 374 SCZ patients and screened for history of physical abuse (PA), emotional abuse (EA), sexual abuse (SA), physical neglect (PN) and emotional neglect (EN) using the Childhood Trauma Questionnaire and measured personality traits using the NEO Five-Factor inventory. Using CTQ cut-off scores, the prevalence of EA, PA, SA, EN and PN was 60.7%, 42.0%, 37.7%, 64.2% and 54.3% respectively. Exposure to any form of childhood abuse was associated with increased neuroticism. Exposure to EA, SA, PN and EN was correlated with decreased agreeableness and conscientiousness scores. PN, EN and PA exposure was associated with decreased openness while EA, PN and EN exposure was associated with decreased extraversion. Furthermore, a positive correlation was found between all forms of childhood abuse and trait neuroticism whereas negative correlations were found between certain forms of childhood abuse and all other personality traits. Exposure to specific forms of childhood abuse was associated with specific personality traits in patients with SCZ., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: There have been a number of studies investigating antipsychotic adherence measured by electronic adherence monitoring (EAM) in patients with schizophrenia. However, no study has looked at overall adherence and both baseline and endpoint illness/symptom severity., Methods: We performed a secondary analysis of our previous study to examine antipsychotic adherence, as measured by EAM, and illness/symptom severity at baseline and endpoint in patients with schizophrenia. Adherence rates were defined as the proportion of adherent days over 3 months. Adherent days were defined as the subject having taken the medication at the prescribed time, with 2 tolerance margins operationally defined i.e., ±3 h and ±12 h. In addition, a dichotomous version of adherence was defined i.e., if he/she was adherent greater than 80% of the days. Illness severity and symptom severity were assessed using the Brief Psychiatric Rating Scale (BPRS) total score and the Clinical Global Impression - Severity of illness (CGI-S) scale score, respectively., Results: A total of 111 patients were enrolled in the study. Neither continuous or dichotomous adherence rates were significantly associated with baseline or endpoint illness/symptom severity (all Ps ≥ 0.05). The results remained unchanged when adjusting for clinico-demographic characteristics., Conclusion: Antipsychotic adherence, as measured by EAM, was not associated with illness/symptom severity at baseline and endpoint in patients with chronic schizophrenia, whose clinical status and adherence pattern were stabilized. This suggests that individuals may be able to achieve clinical stability in the face of maintenance antipsychotic treatment despite variations in adherence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75 NTR ). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH 2 , when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid β peptide (Aβ). Animals were treated for 20 days with KTP-NH 2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aβ administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH 2 treatment, Aβ-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aβ-injected rats that had been treated with KTP-NH 2 , which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aβ oligomers (200 nM) in the absence of KTP-NH 2 . Co-incubation with KTP-NH 2 (50 nM) rescued LTP toward control values. Similarly, Aβ caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH 2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH 2 treatment counteracts Aβ-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms., (Copyright © 2020 Belo, Martins, Shvachiy, Costa-Coelho, de Almeida-Borlido, Fonseca-Gomes, Neves, Vicente Miranda, Outeiro, Coelho, Xapelli, Valente, Heras, Bardaji, Castanho, Diógenes and Sebastião.)

Childhood trauma has been shown to increase the risk of suicide attempts in individuals with schizophrenia. However, previous literature has been limited by considerable heterogeneity within the category of suicide attempters. Here we tested the predictive effect of childhood maltreatment on lifetime suicide attempt in a homogeneous sample of 650 patients with schizophrenia spectrum disorders. Childhood trauma was assessed using the Childhood Trauma Questionnaire-Short Form and suicide history was measured using subjective and objective validated scales as well as medical chart reviews. We refined our sample into two homogenous groups: 1) suicide attempters: patients who had attempted suicide multiple times, with highly lethal results (medical hospitalization required) (n = 24); and 2) non-ideators: patients who had no personal history of suicide attempt or ideation, or family history of attempt (n = 25). Binary logistic regression models revealed that total childhood trauma (β = 0.002; OR: 1.07; 95% CI: 1.00-1.14) and emotional abuse (β = 0.04; OR: 1.38; 95% CI: 1.08-1.77), but not other trauma subtypes, significantly predicted lifetime multiple, high lethality suicide attempts after adjusting for demographic and clinical covariates. Thus, childhood trauma is a weak, independent risk factor for extreme suicide attempts in patients with schizophrenia spectrum disorders., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Patient input as part of health care has taken on increased importance recently. To look at whether patients with treatment resistant schizophrenia (TRS) are able to provide a valid self-assessment of symptoms, the present study investigated patient versus rater evaluation of clinical symptoms. Ninety-three patients diagnosed with TRS and treated with clozapine were recruited. Both patients and raters completed the 7-point Clinical Global Impression - Schizophrenia Version (CGI-SCH) scale, thereby providing evaluations for positive, negative, depressive, and cognitive symptoms as well as overall illness severity. Patients rated their clinical symptoms significantly lower than raters. A positive correlation was found between patients and raters for all symptom domains, while the strength of correlation varied. Age, gender and years of education did not impact the relationship between patient and rater scores. The conclusion is that patients provided valid information in self-assessments of symptoms when compared to raters, and this was consistent over time. In addition, the greatest heterogeneity between rater and patient ratings occurred with regard to cognitive symptoms. Patient assessments may help further engage individuals in their care and permit clinicians to identify where discrepancies exist. Addressing these issues offers opportunities for improved therapeutic alliance, education, and shared decision-making within treatment., (Copyright © 2019. Published by Elsevier B.V.)

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1 H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non-obese persons (9 female, mean age: 28.35 ± 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1 H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, β = .52, t = 2.55, p = .03; left: (r(12) = .63, β = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Aims: In the current study, we aimed to compare the prevalence of adverse lifetime events in treatment resistant and non-treatment resistant schizophrenia in a genome-wide association study., Materials & Methods: Our sample consisted of 84 Caucasian participants with schizophrenia spectrum disorders, assessed cross-sectionally to collect information regarding drug effectiveness and childhood trauma. Using a genome-wide association analysis, we tested single-nucleotide polymorphisms for their association with resistance to antipsychotics defined according to American Psychiatric Association criteria. Two models were tested: a main model and an interaction model with the childhood trauma., Results: Our analysis failed to demonstrate a significant relationship among 1,178,234 single-nucleotide polymorphisms and treatment-resistance in both the main model and in the childhood trauma interaction model., Conclusion: Even though we could not find any significant association, treatment resistance has clinical relevance and it may be determined by the interaction between biological and non biological factors.

Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3 R) have been quantified in the living human brain using the agonist radiotracer [(11) C]-(+)-PHNO. As an agonist radiotracer, [(11) C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [(11) C]-(+)-PHNO binding to D2/3 Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND ) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [(11) C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [(11) C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3 R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [(11) C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3 R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers., (© 2016 Wiley Periodicals, Inc.)

Objective: Antipsychotic polypharmacy (APP) is employed routinely, although it remains controversial because robust evidence supporting its efficacy is lacking. In addition, it is associated with increased costs, higher antipsychotic dosing, and greater risk of side effects. Surprisingly, no prospective, randomized, double-blind studies have addressed this issue; the present investigation set out to fill this gap in knowledge., Method: A 12-week, double-blind, randomized, placebo-controlled, single-site study was carried out in individuals with schizophrenia or schizoaffective disorder (DSM-IV) receiving a designated primary antipsychotic plus a secondary antipsychotic, with doses stabilized for each. Individuals were randomly assigned to APP (N = 17), reflecting current treatment, or antipsychotic monotherapy (APM) (N = 18), in which the secondary antipsychotic was discontinued. Assessments occurred weekly during month 1 and every 2 weeks during months 2 and 3; the primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Other measures included the Clinical Global Impressions (CGI) scale, Simpson-Angus Scale, and Barnes Akathisia Scale. The study was carried out between August 2006 and March 2011., Results: Withdrawal due to clinical deterioration occurred in 1 individual receiving APP (5.8%) and in 4 individuals in the APM group (22.2%). Overall, however, there was no indication of clinical worsening with APM, as measured using BPRS and CGI scale., Conclusions: Almost 80% (n = 14) of individuals with schizophrenia or schizoaffective disorder currently receiving APP could be safely transitioned to APM with no clinical deterioration. For those who do deteriorate, risk appears greatest in the first several months. From another perspective, results also indicate that a minority of individuals benefit from APP, and research focusing on identifying this group may represent the best strategy to curb excessive use of APP., Trial Registration: ClinicalTrials.gov identifier: NCT00493233., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Background: Using positron emission tomography (PET) it is possible to estimate endogenous dopamine (DA) occupying D2/3 receptors (D2/3R) in the living human brain. Persons with schizophrenia (SZ) (previously medicated and naïve) have increased endogenous DA occupying D2/3R in the caudate. It is unknown whether currently medicated patients demonstrate increased DA levels at D2/3R. Moreover, DA levels have not been estimated in SZ using agonist radiotracers, which may offer a more sensitive quantification over antagonists., Methods: Using the agonist radiotracer [(11)C]-(+)-PHNO, DA levels were estimated at D2/3R (ΔBP(ND)) in three patients with SZ (male, mean age=30±16). Patients were currently being treated long-term with Olanzapine (147±88 nmol/L). Results were compared to ten healthy controls (HCs)., Results: Medicated persons with SZ had greater ΔBP(ND) in the left caudate (U=2, Z=-2.20, p=.03) and right putamen (U=2, Z=-2.20, p=.03). No differences were observed in the ventral striatum or globus pallidus., Conclusions: It is possible to estimate endogenous DA at D2/3R in SZ patients currently taking antipsychotics. Despite medication, patients continue to have increased endogenous DA at D2/3R. This lends more biological support to the clinical observation that relapses in symptoms can occur in the face of complete antipsychotic discontinuation. Future studies with larger samples are warranted., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [(11)C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [(11)C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [(11)C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [(11)C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [(11)C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations.

Objective: To improve antipsychotic treatment in schizophrenia patients, many studies have investigated genetic polymorphisms associated with antipsychotic metabolizing enzymes and receptors. While these studies have typically focused on drug response, few have investigated genetic influences on antipsychotic dosage. This study set out to analyze the association between 134 SNPs in 38 candidate genes and antipsychotic dosage in schizophrenia patients., Methods: For our analysis, 300 patients with a diagnosis of either schizophrenia or schizoaffective disorder were recruited between the ages of 18 and 75. A cross-sectional assessment was used, in which data were collected from each participant through an interview and self-report questionnaire. Antipsychotic dose was standardized according to the chlorpromazine equivalents, defined daily dose and relative to the maximum dose specified in the product monograph. Participants were genotyped using a Customized Illumina Chip comprising 134 SNPs, and all markers were screened for nominal significance., Results: The analysis showed a nominally significant association with the GFRA1 gene., Conclusion: The common variants investigated in this study had no major influence on the antipsychotic dosage prescribed in study participants. It remains, though, that this strategy may prove valuable clinically and warrants further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily., Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design., Methods: Positron emission tomography (PET) scans with [(11)C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [(11)C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum., Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans., Conclusions: The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %)., Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298 , NCT00818298.

Objective: The goal of this research was to describe the relationship between treatment resistant schizophrenia, defined using the APA criteria and ethnic background in patients with schizophrenia spectrum disorders in a Canadian sample. A secondary goal was to analyze the number of antipsychotics failed due to side effects and number of antipsychotics failed due to non-response., Method: We included 497 patients diagnosed with schizophrenia spectrum disorders using the SCID. The medication history was extracted from the electronic health records. Data collection included demographics (sex, age, ethnicity), principal diagnosis according to SCID (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), duration of mental illness, number of psychiatric admissions and treatment information. If patients were on clozapine or polypharmacy treatment, this was recorded at the time of the SCID interview. Additional data, including prior antipsychotic history, were collected from the health records., Results: Thirty per cent of the patients were classified as resistant according to the APA criteria. There were significantly more white European subjects in the treatment resistant group (p=0.031). The duration of illness was significantly higher in the resistant group then in the non-resistant group (21.0 vs 15.1 years; p<0.001). Patients who were treatment resistant were more likely to be on polypharmacy compared with non-resistant patients (p=0.001; OR=2.424; 95%CI=1.446-4.065). When we considered the number of drug trials failed due to non response and drug trial failed because of side effects, we found a strong negative correlation in both white Europeans and non-white Europeans., Conclusions: White European ethnicity is associated with treatment resistant schizophrenia. In addition, patients with treatment-resistant schizophrenia were on polypharmacy at higher rate than non resistant patients., (Copyright © 2013. Published by Elsevier Inc.)

The treatment of patients with schizophrenia who fail to respond to antipsychotics is a major challenge and the proportion of treatment-resistant patients is estimated to be 20 to 40%. There are few genetic association studies that have compared resistant versus non-resistant schizophrenic patients; however, many genetic association studies focusing on antipsychotic response have been published. This contribution investigates the genetics of treatment-resistant schizophrenia, testing 384 candidate gene loci related to the neurobiology of the disease. First, we identified a subgroup of treatment-resistant patients in a sample of 240 schizophrenia patients using the American Psychiatric Association criteria and then we genotyped all patients using a custom Illumina Bead Chip comprising of 384 single nucleotide polymorphisms. We screened all markers for nominal significance and for statistical significance after multiple-testing correction. The most significant single nucleotide polymorphism was the rs2152324 marker in the NALCN gene (P=0.004); however, after the FDR correction, the P-value was not significant. Our analysis of 384 markers across candidate genes did not indicate any robust association with treatment-resistant schizophrenia. However, this phenotype can be assessed retrospectively in cross-sectional studies and these preliminary results point out the importance of choosing alternative phenotypes in psychiatric pharmacogenetics.

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.

Abnormal levels of amino acids have been reported in patients with schizophrenia and have also been investigated as a biomarker to monitor antipsychotic treatment, however results have been inconsistent. The purpose of the present review is to summarize the evidence in the literature of whether amino acid levels can be a biomarker and predict the treatment outcome in schizophrenia. The current review does not support amino acid concentration as a useful biomarker for monitoring antipsychotic response in patients with schizophrenia, although there is evidence that high levels of serum homocysteine and glutamate might be considered as a trait marker for schizophrenia. This review has also highlighted a considerable dearth of studies, specifically of studies evaluating antipsychotic side-effects.