Positive Symptoms Of Schizophrenia Research Articles

Using Cariprazine to Ameliorate Negative Symptoms and Metabolic Side Effects of Clozapine and Paliperidone - Clinical Cases.

IntroductionCariprazine is a third-generation antipsychotic approved in Europe in 2017 for the treatment of schizophrenia. It presents distinct pharmacodynamic properties, such as D3/D2 partial agonism, preferential binding to D3 receptors, antagonism at the serotonin 5-HT2A and 5-HT2B receptors, partial agonism at 5-HT1A receptors, and low affinity to other receptors (including noradrenergic, histaminergic, and cholinergic). It has demonstrated efficacy in the treatment of positive and negative symptoms of schizophrenia with a safe side effect and metabolic profile.MethodsHere, we describe one clinical case of a patient that benefited from an add-on of cariprazine to a regimen of clozapine; and two clinical cases of patients that benefited from the switch from clozapine and paliperidone long-acting injectable to cariprazine.Results and DiscussionThose cases illustrate how cariprazine can be used in patients with schizophrenia in the treatment of both positive and negative symptoms, and when aiming to ameliorate the metabolic burden associated with other treatments. However, further studies are needed to consubstantiate those findings.

Combined Low Dose of Ketamine and Social Isolation: A Possible Model of Induced Chronic Schizophrenia-Like Symptoms

IntroductionIdentifying a feasible model of chronic schizophrenia would be valuable for studying the possible underlying mechanism and to investigate emerging treatments. Our hypothesis starts from the observation that combining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like features; thus, it could probably be used as the first model of chronic schizophrenia that emphasizes the characteristic of having a multifactorial etiologyObjectivescreation of a complex animal model capable of exhibiting the multifactorial origin and manifestation of schizophrenia.Methodswe investigated the effects of ketamine administration combined with isolation in inducing schizophrenia-like symptoms in male albino rats and the brain reactive oxygen species levels.ResultsOur results showed that the number of lines crossings in the open field test, the number of open arm entries in the elevated plus maze, and the spontaneous alternations percentage in the Y-maze were significantly lower in the ketamine + isolation group compared to both the control and ketamine + social housing group (p < 0.05). Furthermore, the ketamine + isolation intervention significantly increased the MDA levels and decreased the GPx levels both in the hippocampus and the cortex of the rats. In addition, our premise of creating a model capable of exhibiting both positive and negative symptoms of schizophrenia was also based on adding the aripiprazole treatment to a group of ratsConclusionscombining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like featuresDisclosureNo significant relationships.

Pharmacogenetic testing in schizophrenia in real clinical practice: before or after antipsychotic -induced adverse drug reactions development?

IntroductionSchizophrenia is socially significant mental disorder characterized by early onset and high time and financial expenditure on treatment. Antipsychotics (APs) are highly effective against positive and negative symptoms, but at same time have a wide range of adverse drug reactions (ADRs). APs efficiency and safety are variable and depend on characteristics of genetically determined mechanisms (transportation, biotransformation, and elimination).ObjectivesInvestigation role of pharmacogenetic testing (PhGT) on example of clinical case of severe ADRs in 47-year-old woman with schizophrenia.MethodsPatient’s medical history analysis; clinical observation; biochemical serum analysis; therapeutic drug monitoring; PhGT.ResultsThe clinical case of a woman with schizophrenia who has been noted to be unresponsive to APs for some years after schizophrenia onset. She was found to be homozygous for nonfunctional SNVs CYP2D6*4 and CYP2C9*2, heterozygous for CYP1A1*2A, which was reason for complete shutdown of isoenzymes 2D6, 2C9 and 1A1 activity and development of ADRs in use of initial doses of several APs, as well as for an increase in severity of ADRs with schizophrenia positive symptoms aggravation with an even slower titration of APs daily dose not only with polytherapy, but also with monotherapy. So, not recommented APs for patient: aripiprazole, haloperidol, zuclopenthixol, cariprazine, quetiapine, paliperidone, risperidone, thioridazine, sertindole, asenapine, alimemazine, chlorpromazine, etc. (CYP2D6); haloperidol, clozapine, olanzapine, perphenazine, promazine (CYP2C9); carefully: haloperidol, olanzapine, perospirone (СYP1A1).ConclusionsThis rare case demonstrates PhGT importance before APs therapy, because the patient had very high risk AP – induced ADRs. She needed PhGt before APs use, but not after severe ADRs during 12 years.DisclosureNo significant relationships.

The effects of catechol-O-methyltransferase single nucleotide polymorphisms on positive and negative symptoms of schizophrenia: A systematic review and meta-analysis.

The catechol-O-methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding its role in clinical presentation. We aimed to elucidate the relationship between the single nucleotide polymorphisms (SNPs) in the COMT gene and the severity of positive and negative symptoms. In order to investigate the relationship, the PubMed, PubMed Central, Scopus, and Cochrane CENTRAL databases were screened for eligible articles. Thirty-eight studies, including 4443 adult patients with schizophrenia, were included in the quantitative analyses, and four studies were qualitatively assessed. Quantitative analyses were performed for acutely ill and clinically stable patient subgroups regarding the different genotypes of rs4680 SNP. Our results showed that the severity of negative symptoms was higher in patients who were rs4680 Met homozygous compared to Val/Met heterozygotes only in acutely ill samples. There was no other significant difference between genotypes. Meta-regression did not reveal any significant moderator effect on the difference in negative symptoms. General psychopathology, positive, negative, and total psychotic symptom levels also were similar between Val homozygotes and Met carriers. Nonetheless, there are some limitations in the study. First, SNPs except for rs4680 were under-researched because of the limited number of studies. Second, high heterogeneity across studies was the main concern. Our results suggested that the COMT rs4680 Met allele was associated with higher levels of negative symptoms within acutely ill patients. Future studies should focus on specific patient subgroups to reveal the moderating effects of SNPs.

Positive schizotypy is associated with amplified mnemonic discrimination and attenuated generalization

Tendency to experience inaccurate beliefs alongside perceptual anomalies constitutes positive schizotypal traits in the general population and shows continuity with the positive symptoms of schizophrenia. It has been hypothesized that the positive symptomatology of schizophrenia, and by extension, the odd beliefs and unusual perceptual experiences in the general population, are associated with specific alterations in memory functions. An imbalance between memory generalization and episodic memory specificity has been proposed on several counts; however, the direction of the imbalance is currently unclear. Here, we evaluated the association between positive schizotypy, and memory alterations related to hippocampal computations in a general population sample enriched for positive schizotypy. We found that memory generalization is attenuated while memory specificity is elevated in participants with more pronounced positive schizotypal traits. Our findings show that people who are prone to irrational beliefs and unusual experiences also show measurable alterations in memory and likely have difficulty grasping the global picture and rather be overpowered by fragments of information.

Structural brain imaging abnormalities correlate with positive symptom in schizophrenia

Accumulating evidence indicates neuroanatomical mechanisms underlying positive symptoms in schizophrenia; however, the exact structural determinants of positive symptoms remain unclear. This study aimed to investigate associations between positive symptoms and structural brain changes, including alterations in grey matter (GM) volume and cortical thickness, in patients with first-episode schizophrenia (FES). This study included 44 patients with FES and 48 healthy controls (HCs). Clinical symptoms of patients were evaluated and individual-level GM volume and cortical thickness were assessed. Patients with FES showed reduced GM volume in the right superior temporal gyrus (STG) and increased cortical thickness in the left inferior segment of the circular sulcus of the insula (S_circular_insula_inf) compared with HCs. Increased thickness of the left S_circular_insula_inf correlated positively with positive symptoms in patients with FES. Exploratory correlation analysis found that increased thickness of the left S_circular_insula_inf correlated positively with conceptual disorganization and excitement symptoms, and the right STG GM volume correlated negatively with hallucinations. This study suggests that GM abnormalities in the STG and altered cortical thickness of the S_circular_insula_inf, which were detected at the early stage of schizophrenia, may underlie positive symptoms in patients with FES.

Abnormal Brain Network Interaction Associated With Positive Symptoms in Drug-Naive Patients With First-Episode Schizophrenia.

Positive symptoms are marked features of schizophrenia, and emerging evidence has suggested that abnormalities of the brain network underlying these symptoms may play a crucial role in the pathophysiology of the disease. We constructed two brain functional networks based on the positive and negative correlations between positive symptom scores and brain connectivity in drug-naive patients with first-episode schizophrenia (FES, n = 45) by using a machine-learning approach (connectome-based predictive modeling, CPM). The accuracy of the model was r = 0.47 (p = 0.002). The positively and negatively associated network strengths were then compared among FES subjects, individuals at genetic high risk (GHR, n = 41) for schizophrenia, and healthy controls (HCs, n = 48). The results indicated that the positively associated network contained more cross-subnetwork connections (96.02% of 176 edges), with a focus on the default-mode network (DMN)-salience network (SN) and the DMN-frontoparietal task control (FPT) network. The negatively associated network had fewer cross-subnetwork connections (71.79% of 117 edges) and focused on the sensory/somatomotor hand (SMH)-Cingulo opercular task control (COTC) network, the DMN, and the visual network with significantly decreased connectivity in the COTC-SMH network in FES (FES < GHR, p = 0.01; FES < HC, p = 0.01). Additionally, the connectivity strengths of the right supplementary motor area (SMA) (p < 0.001) and the right precentral gyrus (p < 0.0001) were reduced in FES. To the best of our knowledge, this is the first study to generate two brain networks associated with positive symptoms by utilizing CPM in FES. Abnormal segregation, interactions of brain subnetworks, and impaired SMA might lead to salience attribution abnormalities and, thus, as a result, induce positive symptoms in schizophrenia.

Effects of tamoxifen alone and in combination with risperidone on hyperlocomotion, hippocampal structure and bone in ketamine-induced model of psychosis in rats

Background and aim of the workProtein kinase C activation with subsequent increase in oxidative stress (OXS) and reduction in brain derived neurotrophic factor (BDNF) are implicated in the pathophysiology of psychotic disorders and in osteoporosis. Accordingly PKC inhibitors such as tamoxifen could be a novel approach to psychotic illness and may reduce progression of osteoporosis. Since current antipsychotics such as risperidone have inconsistent effects on OXS and BDNF, combination with tamoxifen could be beneficial. Accordingly in this work, tamoxifen was used to investigate the impact of changes in OXS and BDNF on behavioral, hippocampus structural changes in a ketamine induced model of psychosis in rats. The impact of tamoxifen on the antipsychotic effects of risperidone and on its bone damaging effects was also determined.Ketamine was chosen, because it is a valid model of psychosis. Hippocampus was chosen, since hippocampal overactivity is known to correlate with the severity of symptoms in psychosis. Hippocampal overactivity contributes to hyperdopaminergic state in ventral tegmental area and increase in DA release in nucleus accumbens, these are responsible for positive symptoms of schizophrenia and hyperlocomotion in rodents. Hyperlocomotion is considered a corelate of positive symptoms of psychotic illness in rodents and is considered primary outcome to assess manic-like behavior.MethodsRats were divided into seven groups (ten rats each (1) non-ketamine control and (2) ketamine treated groups (a ketamine control, b risperidone/ketamine, c tamoxifen/ketamine, d Risp/Tamox/ketamine risperidone, tamoxifen/risperidone) to test if TAM exhibited behavioral changes or potentiated those of risperidone); (e clomiphene/ketamine and f clomiphene/risperidone/ketamine) to verify that estrogen receptor modulators do not exhibit behavioral changes or potentiates those of risperidone. In addition, thus, the effects of tamoxifen are not due to estrogen effects but rather due to protein kinase c inhibition. Drugs were given for 4 weeks and ketamine was given daily in the last week. Effects of drugs on ketamine-induced hyperlocomotion (open field test) and hippocampus and bone biochemical (MDA, GSH, BDNF) and histological changes (Nissel granules, GFAP positive astrocytes in hippocampus were determined).Electron microscopy scanning of the femur bone was done. Histomorphometric parameters measuring the: 1. Trabecular bone thickness and 2. The trabecular bone volume percentage.ResultsTamoxifen reduced hyperlocomotion, and improved hippocampus structure in ketamine-treated rats, by reducing OXS (reduced malondialdehyde and increased glutathione) and increasing BDNF. These effects might be related to (PKC) inhibition, rather than estrogen modulation, since the anti-estrogenic drug clomiphene had no effect on hyperlocomotion. Tamoxifen enhanced the beneficial effects of risperidone on hippocampal OXS and BDNF, augmenting its effectiveness on hyperlocomotion and hippocampal structure. It also reduced risperidone-induced OXS and the associated bone damage.ConclusionsPKC inhibitors, particularly tamoxifen, might be potential adjuncts to antipsychotics, by reducing OXS and increasing BDNF increasing their effectiveness while reducing their bone damaging effects.

The Comparison Between Positive and Negative Symptoms Severity in Prolonged Methamphetamine-induced Psychotic Disorder and Schizophrenia.

This study aims to compare the positive and negative symptoms of schizophrenia in patients who had psychotic symptoms more than one month after discontinuation of methamphetamine abuse. These factors were analyzed by the positive and negative syndrome scale (PANSS) questionnaire. Sixty participants were selected from patients referred to Iran Psychiatric Hospital with psychotic symptoms (delusions or hallucinations, disorganized behavior, and speech). The control group was 30 patients with schizophrenia based on a semi-structured interview according to DSMIV-TR (SCID). Thirty patients with a prolonged methamphetamine-induced psychotic disorder were also placed in the case group. For both groups of patients, questionnaires of PANSS, Brief Psychiatric Rating Scale (BPRS), and Global Assessment Of Functioning (GAF) were filled out after obtaining the companions' consent. The scale scores were compared between groups. We used the Mann-Whitney and the Chi-square test to evaluate the mean values of PANSS, BPRS, and GAF scores between the two groups. here was an insignificant difference in positive and general pathology scores between the two groups, but the total score of negative symptoms in the schizophrenia group was significantly higher than in the group of prolonged methamphetamine psychotic disorders (P=0.034). Average scores of uncooperativeness (0.008), difficulty in abstract thinking (0.004), motor retardation (0.002), unusual thought content (0.001), and hostility (0.011) in the schizophrenia group were significantly higher than those in the prolonged methamphetamine psychosis. The results showed that most of the disturbances in patients with schizophrenia might be more influenced by the expression of cognitive disabilities than those with methamphetamine psychosis. The difference in negative symptom scores suggests that schizophrenia and prolonged methamphetamine psychotic disorder can be two different disorders. General and positive symptoms scores don't have significant differences.Negative symptoms are much more in schizophrenia.Uncooperativeness, unusual thought content and, motor retardation have more scores in schizophrenia. In clinical practice, Schizophrenia and prolonged methamphetamine-induced psychotic disorder have some similar mental presentations. Additionally, in scientific literature, there is scarce evidence about these similarities. In this regard, this research was designed to investigate the aforementioned obscurity. Determination of similarities and differences between them helps us to address these disorders in terms of treatment and follow-up and awareness of their prognosis of them. This research is a case-control study in which we examine positive and negative psychotic symptoms in schizophrenia and prolonged methamphetamine-induced psychotic disorder. Researchers investigated psychotic symptoms with positive and negative syndrome scale (PANSS), brief psychiatric rating scale (BPRS), and global assessment of functioning (GAF) questionnaires. Moreover, results demonstrate general and positive symptoms scores don't have many differences but negative symptoms are much more in patients with schizophrenia than in patients with a prolonged methamphetamine-induced psychotic disorder. Also, other features like uncooperativeness, unusual thought content, motor retardation, difficulty in abstract thinking, and hostility have higher scores in schizophrenia than the others. In conclusion, this research showed that these disorders are two distinct disorders with some similarities in positive symptoms but not in all features. So, some studies can be designed about why there are similarities between them?

Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex

During early brain development, the subplate relays thalamocortical afferents to the overlying cortex. Disconnection of thalamic inputs to the prefrontal cortex by lesions of the subplate of the developing prefrontal cortex at early neonatal periods result in adult-onset behavioral abnormalities reminiscent of positive, negative, and cognitive symptoms of schizophrenia. Delayed maturation of γ-amino butyric acid (GABA) function may contribute to certain abnormalities of the prefrontal cortex and clinical manifestations of schizophrenia. Lesions to the subplate have also been implicated in developmental abnormalities of GABA neurotransmission in somatosensory and visual cortices. Therefore, we sought to examine the effects of subplate lesions in the developing prefrontal cortex of rats on the expression of GABA markers [parvalbumin and glutamic acid decarboxylase (GAD67)] and proteins responsible for GABAergic synaptic maturation [potassium-chloride cotransporter (KCC2) and sodium‑potassium-chloride cotransporter (NKCC1)]. Lesioned and control rats were sacrificed between postnatal days (P) 5 and 90 and immunolabeled for parvalbumin, GAD67, KCC2, and NKCC1 in the prelimbic area of the prefrontal cortex. We found decreased immunoreactivity of KCC2 on neuronal cell membranes at P11 compared to control rats. However, the overall immunoreactivity of KCC2 and NKCC1 did not differ between lesion and control animals at all time points studied. Lesioned rats also showed decreased expression of parvalbumin, but not GAD67. Our results indicate that mechanisms underlying trafficking and membrane binding of KCC2 may contribute to altered GABA receptor function during development in schizophrenia.

A Literature Mini-Review of Transcranial Direct Current Stimulation in Schizophrenia.

Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation method that utilizes the effect of low-current on brain tissue. In recent years, the effect of transcranial direct current stimulation has been investigated as a therapeutic modality in various neuropsychiatric indications, one of them being schizophrenia. This article aims to provide an overview of the potential application and effect of tDCS in treating patients with schizophrenia. A literature search was performed using the PubMed, Web of Science, and Google Scholar databases for relevant research published from any date until December 2021. Eligible studies included those that used randomized controlled parallel-group design and focused on the use of transcranial direct current stimulation for the treatment of positive, negative, or cognitive symptoms of schizophrenia. Studies were divided into groups based on the focus of research and an overview is provided in separate sections and tables in the article. The original database search yielded 705 results out of which 27 randomized controlled trials met the eligibility criteria and were selected and used for the purpose of this article. In a review of the selected trials, transcranial direct current stimulation is a safe and well-tolerated method that appears to have the potential as an effective modality for the treatment of positive and negative schizophrenic symptoms and offers promising results in influencing cognition. However, ongoing research is needed to confirm these conclusions and to further specify distinct application parameters.

Multiframe Evolving Dynamic Functional Connectivity (EVOdFNC): A Method for Constructing and Investigating Functional Brain Motifs.

The study of brain network connectivity as a time-varying property began relatively recently and, to date, has remained primarily concerned with capturing a handful of discrete static states that characterize connectivity as measured on a timescale shorter than that of the full scan. Capturing group-level representations of temporally evolving patterns of connectivity is a challenging and important next step in fully leveraging the information available in large resting state functional magnetic resonance imaging (rs-fMRI) studies. We introduce a flexible, extensible data-driven framework for the stable identification of group-level multiframe (movie-style) dynamic functional network connectivity (dFNC) states. Our approach employs uniform manifold approximation and embedding (UMAP) to produce a continuity-preserving planar embedding of high-dimensional time-varying measurements of whole-brain functional network connectivity. Planar linear exemplars summarizing dominant dynamic trends across the population are computed from local linear approximations to the two-dimensional 2D embedded trajectories. A high-dimensional representation of each 2D exemplar segment is obtained by averaging the dFNC observations corresponding to the n planar nearest neighbors of τ evenly spaced points along the 2D line segment representation (where n is the UMAP number-of-neighbors parameter and τ is the temporal duration of trajectory segments being approximated). Each of the 2D exemplars thus “lifts” to a multiframe high-dimensional dFNC trajectory of length τ. The collection of high-dimensional temporally evolving dFNC representations (EVOdFNCs) derived in this manner are employed as dynamic basis objects with which to characterize observed high-dimensional dFNC trajectories, which are then expressed as weighted combination of these basis objects. Our approach yields new insights into anomalous patterns of fluidly varying whole-brain connectivity that are significantly associated with schizophrenia as a broad diagnosis as well as with certain symptoms of this serious disorder. Importantly, we show that relative to conventional hidden Markov modeling with single-frame unvarying dFNC summary states, EVOdFNCs are more sensitive to positive symptoms of schizophrenia including hallucinations and delusions, suggesting that a more dynamic characterization is needed to help illuminate such a complex brain disorder.

Nicotine use in individuals with schizophrenia and its relation with clinical severity

Background: Schizophrenia is a major psychiatric disorder with diverse clinical presentations and comorbidities. Comorbid nicotine use worsens the clinical symptomatology, predisposes the individuals to other chronic illnesses, and is associated with poorer outcomes in schizophrenia. It is thus clinically essential to assess the presence of tobacco use, the severity of nicotine dependence, and its correlation with psychopathology in patients with schizophrenia. Aims and Objectives: (i) To describe the pattern of tobacco use and severity of nicotine dependence in schizophrenia patients. (ii) To compare the socio-demographic variables and symptom severity of schizophrenia between tobacco users and non-users. (iii) To determine the correlation between the severity of nicotine dependence and clinical and nicotine related variables in patients of schizophrenia. Materials and Methods: It was a cross-sectional observational study conducted in a tertiary care level psychiatric hospital in the northeast of India. The study included 100 male schizophrenia patients. Fagerstrom Test for Nicotine Dependence (FTND) and FTND - Smokeless Tobacco, and the Positive and Negative Syndrome Scale five-factor model was used for assessment of the severity of nicotine dependence and symptoms of Schizophrenia, respectively. Results: 70% of the study sample used some form of tobacco. The severity of nicotine dependence was significantly higher in patients using both forms of tobacco. Tobacco use was significantly associated with lower educational status, employment status, and positive symptoms of Schizophrenia. Finally, the severity of nicotine dependence was significantly correlated with the severity of positive and emotional symptoms of schizophrenia. Conclusion: Higher positive and emotional symptoms of schizophrenia predicted severity of nicotine use. Study needs to be replicated in larger population of patients suffering from schizophrenia.

Assessing the effects of antipsychotic medications on schizophrenia functional analysis: a postmortem proteome study.

Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.

Glutamate NMDA Receptor Antagonists with Relevance to Schizophrenia: A Review of Zebrafish Behavioral Studies.

Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Frequently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomotor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further characterize the major differences in behavior as compared to mammals.

Striatal dopamine synthesis capacity and its association with negative symptoms upon resolution of positive symptoms in first-episode schizophrenia and delusional disorder.

How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3months in first-episode SZ and DD patients. Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3months. All patients received an 18F-DOPA PET/MR scan at baseline. Baseline striatal DSC (Kocc;30-60) was inversely associated with negative symptoms at 3months in first-episode SZ patients (rs = - 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (β = - 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.

A meta-analytic review of transcranial direct current stimulation (tDCS) on general psychopathology symptoms of schizophrenia; immediate improvement followed by a return to baseline

Transcranial direct current stimulation (tDCS) is a promising tool for alleviating positive and negative symptoms of schizophrenia, but its role in functional outcome remains uncertain. This meta-analysis examined the effects of tDCS on general psychopathology symptoms (GPS) from the Positive and Negative Syndrome Scale (PANSS) because GPS are closely associated with daily functioning. Literature search using Medline and PsycINFO identified 8 randomized controlled trials with tDCS and PANSS. The GPS were significantly reduced after tDCS but there was no evidence for long-term treatment effects. Further research is needed to optimize the dosing of tDCS and to understand individual differences in treatment response.

Trace Amine-Associated Receptor 1 (TAAR1): Molecular and Clinical Insights for the Treatment of Schizophrenia and Related Comorbidities.

Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D2-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.

Cannabis and schizophrenia: characterisation of a risk factor in a sample of Moroccan patients hospitalised for psychosis

BackgroundIn addition to the biological plausibility widely described through a very large number of studies, the causal link between cannabis uses and schizophrenia disorders has become illicit internationally and given the scarcity of similar studies in Morocco. Our study consists of a prospective descriptive study in the psychiatric department of the Moulay ben Abdallah Hospital in Essaouira. The sample consisted of 95 patients diagnosed with schizophrenia according to the DSM5 criteria. The diagnostic assessment included the Positive and Negative Syndrome Scale to assess the severity of positive and negative symptoms of schizophrenia as well as the patient’s general psychopathology, the Clinician-Rated Dimensions of Psychosis Symptom Severity to assess the symptom severity of the psychotic dimensions according, and the Cannabis Abuse Screening Test to assess the extent of cannabis use.ResultsThe mean age of the patients recruited in the study was 33.7 ± 9.37 years with a clear male predominance (p < 0.0001). Cannabis users compared to non-users were younger and comprised only men. Cannabis users also have a lower educational and economic level than non-users. Furthermore, a clear dose effect of cannabis uses on the onset of positive and negative symptoms of schizophrenia. The temporality criterion is clear in our study, since the predictivity of the parameter: “age of onset of cannabis use” is highly significant (p = 0.000). These results suggest that cannabis use can be considered as the most illicit risk factor for the development and/or onset of schizophrenia.ConclusionsThese results suggest that there is a causal relationship between cannabis use and/or dependence (problematic use) and the onset and/or worsening of schizophrenic disorder. This means that problematic cannabis use can be considered as a real risk factor for the emergence and development of schizophrenic disorder.

Efficacy and safety of add-on sodium benzoate, a D-amino acid oxidase inhibitor, in treatment of schizophrenia: A systematic review and meta-analysis

The role of sodium benzoate, an NMDA receptor enhancer, in schizophrenia has been evaluated in a few clinical trials, but results are contradictory and inconclusive. The present meta-analysis has evaluated the efficacy and safety of add-on sodium benzoate for the treatment of schizophrenia. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from four relevant articles. PRISMA guidelines were followed in the selection, analysis, and reporting of findings. The random-effect model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool, and sensitivity analysis was done in case of high heterogeneity. Add-on sodium benzoate can improve positive symptoms of schizophrenia significantly (MD: -1.87; 95%CI: -3.25 to -0.48; p=0.008) but had no significant favourable effect on negative symptoms (p=0.84), general psychopathology (p=0.49), and total PANSS score (p=0.19) over the control. There was no significant improvement in GAF (p=0.43), CGI (p=0.58), cognitive function (p=0.46) and quality of life (p=0.73). Extrapyramidal symptoms were significantly higher (MD: 0.39; 95% CI:0.19-0.60; p=0.0002) in the sodium benzoate group in comparison to the control group; however, there was no significant difference in respect to other adverse events. Sodium benzoate can improve the positive symptoms of schizophrenia without any beneficial effect on other symptomatology, cognition, quality of life and functioning. Further studies are needed to evaluate long-term efficacy, safety and use in specific subgroups of patients.