Gessica Piras, Cristina Cadoni, Francesca Caria, Nicholas Pintori, Enrica Spano, Maksims Vanejevs, Anastasija Ture, Graziella Tocco, Nicola Simola, Maria Antonietta De Luca
Background: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted.
Methods: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties.
Results: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs.
Conclusions: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.
{"title":"Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.","authors":"Gessica Piras, Cristina Cadoni, Francesca Caria, Nicholas Pintori, Enrica Spano, Maksims Vanejevs, Anastasija Ture, Graziella Tocco, Nicola Simola, Maria Antonietta De Luca","doi":"10.1093/ijnp/pyae016","DOIUrl":"10.1093/ijnp/pyae016","url":null,"abstract":"<p><strong>Background: </strong>The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted.</p><p><strong>Methods: </strong>By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties.</p><p><strong>Results: </strong>2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs.</p><p><strong>Conclusions: </strong>This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11120233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Gärde, G J Matheson, K Varnäs, P Svenningsson, E Hedman-Lagerlöf, J Lundberg, L Farde, M Tiger
Background Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT) but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI-administration in primates and rodents respectively. The effect of SSRI treatment on 5-HT1B receptor binding in MDD subjects has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. Methods Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3-4 weeks of treatment with the SSRI escitalopram 10mg daily. Depression severity was assessed at time of PET and after 6-7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale (MADRS). Results We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (p = 0.036). Change in DBS [11C]AZ10419369 binding correlated with MADRS reduction after three (r = 0.78, p = 0.021) and seven (r = 0.94, p < 0.001) weeks’ treatment. Conclusions Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.
{"title":"Altered serotonin 1B receptor binding after escitalopram for depression is correlated with treatment effect","authors":"M Gärde, G J Matheson, K Varnäs, P Svenningsson, E Hedman-Lagerlöf, J Lundberg, L Farde, M Tiger","doi":"10.1093/ijnp/pyae021","DOIUrl":"https://doi.org/10.1093/ijnp/pyae021","url":null,"abstract":"Background Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT) but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI-administration in primates and rodents respectively. The effect of SSRI treatment on 5-HT1B receptor binding in MDD subjects has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. Methods Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3-4 weeks of treatment with the SSRI escitalopram 10mg daily. Depression severity was assessed at time of PET and after 6-7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale (MADRS). Results We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (p = 0.036). Change in DBS [11C]AZ10419369 binding correlated with MADRS reduction after three (r = 0.78, p = 0.021) and seven (r = 0.94, p &lt; 0.001) weeks’ treatment. Conclusions Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140826847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja, as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.
{"title":"Understanding the therapeutic action of antipsychotics: from molecular to cellular targets with focus on the islands of Calleja","authors":"Merve Direktor, Peter Gass, Dragos Inta","doi":"10.1093/ijnp/pyae018","DOIUrl":"https://doi.org/10.1093/ijnp/pyae018","url":null,"abstract":"The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja, as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140609015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samuel Pintos-Rodríguez, Irene Visos-Varela, Almudena Rodríguez Fernández, Maruxa Zapata-Cachafeiro, María Piñeiro-Lamas, María Teresa Herdeiro, Rosa María García Álvarez, Adolfo Figueiras, Ángel Salgado-Barreira
Background The association between use of antipsychotics and COVID-19 outcomes is inconsistent, which may be linked to use of these drugs in age-related diseases. Furthermore, there is little evidence as regards their effect in the non-geriatric population . We aim to assess the association between antipsychotic use and risk of disease progression and hospitalisation due to COVID-19 among the general population, stratifying by age. Methods We conducted a population-based, multiple case-control study to assess: (1) risk of hospitalisation, with cases being patients with a PCR(+)test who required hospitalisation and controls being subjects without a PCR(+) test; and (2) risk of progression to hospitalisation, with cases being the same as those used in the hospitalisation substudy and controls being non-hospitalised PCR(+) patients. We calculated adjusted odds-ratios (aOR) and 95% confidence intervals (CI), both overall and stratified by age. Results Antipsychotic treatment in patients <65 years was not associated with a higher risk of hospitalisation due to COVID-19 (aOR 0.94 [95%CI 0.69–1.27]) and disease progression among PCR(+) patients (aOR 0.96 [95%CI 0.70–1.33]). For patients aged ≥65 years, however, there was a significant, increased risk of hospitalisation (aOR 1.58 [95%CI 1.38–1.80]) and disease progression (aOR 1.31 [95%CI 1.12–1.55]). Conclusions The results of our large-scale real world data study suggest that antipsychotic use is not associated with a greater risk of hospitalisation due to COVID-19 and progression to hospitalisation among patients younger than 65 years. The effect found in the over-65-year age group might be associated with off-label use of antipsychotics.
{"title":"Outpatient antipsychotic use and severe COVID-19: avoiding the impact of age in a real-world data study","authors":"Samuel Pintos-Rodríguez, Irene Visos-Varela, Almudena Rodríguez Fernández, Maruxa Zapata-Cachafeiro, María Piñeiro-Lamas, María Teresa Herdeiro, Rosa María García Álvarez, Adolfo Figueiras, Ángel Salgado-Barreira","doi":"10.1093/ijnp/pyae020","DOIUrl":"https://doi.org/10.1093/ijnp/pyae020","url":null,"abstract":"Background The association between use of antipsychotics and COVID-19 outcomes is inconsistent, which may be linked to use of these drugs in age-related diseases. Furthermore, there is little evidence as regards their effect in the non-geriatric population . We aim to assess the association between antipsychotic use and risk of disease progression and hospitalisation due to COVID-19 among the general population, stratifying by age. Methods We conducted a population-based, multiple case-control study to assess: (1) risk of hospitalisation, with cases being patients with a PCR(+)test who required hospitalisation and controls being subjects without a PCR(+) test; and (2) risk of progression to hospitalisation, with cases being the same as those used in the hospitalisation substudy and controls being non-hospitalised PCR(+) patients. We calculated adjusted odds-ratios (aOR) and 95% confidence intervals (CI), both overall and stratified by age. Results Antipsychotic treatment in patients &lt;65 years was not associated with a higher risk of hospitalisation due to COVID-19 (aOR 0.94 [95%CI 0.69–1.27]) and disease progression among PCR(+) patients (aOR 0.96 [95%CI 0.70–1.33]). For patients aged ≥65 years, however, there was a significant, increased risk of hospitalisation (aOR 1.58 [95%CI 1.38–1.80]) and disease progression (aOR 1.31 [95%CI 1.12–1.55]). Conclusions The results of our large-scale real world data study suggest that antipsychotic use is not associated with a greater risk of hospitalisation due to COVID-19 and progression to hospitalisation among patients younger than 65 years. The effect found in the over-65-year age group might be associated with off-label use of antipsychotics.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140597127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathan T M Huneke, Cosmina Cross, Harry A Fagan, Laura Molteni, Naomi Phillips, Matthew Garner, David S Baldwin
Background Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed as many patients do not respond to current agents or experience unwanted side-effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalised anxiety in healthy volunteers. Methods Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic ‘lorazepam’ or ‘saline’. Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. Results Participants administered sham ‘lorazepam’ reported significant positive expectations of reduced anxiety (p = 0.001) but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (p’s > 0.350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. Conclusions Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function, or behaviour in line with a Bayesian predictive coding framework, attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.
{"title":"Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalised Anxiety","authors":"Nathan T M Huneke, Cosmina Cross, Harry A Fagan, Laura Molteni, Naomi Phillips, Matthew Garner, David S Baldwin","doi":"10.1093/ijnp/pyae019","DOIUrl":"https://doi.org/10.1093/ijnp/pyae019","url":null,"abstract":"Background Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed as many patients do not respond to current agents or experience unwanted side-effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalised anxiety in healthy volunteers. Methods Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic ‘lorazepam’ or ‘saline’. Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. Results Participants administered sham ‘lorazepam’ reported significant positive expectations of reduced anxiety (p = 0.001) but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (p’s &gt; 0.350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. Conclusions Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function, or behaviour in line with a Bayesian predictive coding framework, attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140603402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sumra Sajid, Hanga C Galfalvy, John G Keilp, Ainsley K Burke, J John Mann, Michael F Grunebaum
Objective Explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Method Data from a completed trial in suicidal, depressed participants (N=40) randomized to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Non-parametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset (N=28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (p = .064; p = .013 removing one outlier). Dehydronorketamine correlated with CADSS scores at 40 minutes (p = .034), 230 minutes (p = .014), and Day 1 (p=.012). Conclusion We did not find evidence that ketamine’s acute, transient dissociative or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.
{"title":"Acute Dissociation and Ketamine’s Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-controlled Trial","authors":"Sumra Sajid, Hanga C Galfalvy, John G Keilp, Ainsley K Burke, J John Mann, Michael F Grunebaum","doi":"10.1093/ijnp/pyae017","DOIUrl":"https://doi.org/10.1093/ijnp/pyae017","url":null,"abstract":"Objective Explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Method Data from a completed trial in suicidal, depressed participants (N=40) randomized to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Non-parametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset (N=28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (p = .064; p = .013 removing one outlier). Dehydronorketamine correlated with CADSS scores at 40 minutes (p = .034), 230 minutes (p = .014), and Day 1 (p=.012). Conclusion We did not find evidence that ketamine’s acute, transient dissociative or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum to: Anhedonia, Apathy, Pleasure, and Effort-Based Decision-Making in Adult and Adolescent Cannabis Users and Controls.","authors":"","doi":"10.1093/ijnp/pyae004","DOIUrl":"10.1093/ijnp/pyae004","url":null,"abstract":"","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10965023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atheeshaan Arumuham, Matthew M Nour, Mattia Veronese, Katherine Beck, Ellis Chika Onwordi, David J Lythgoe, Sameer Jauhar, Eugenii A Rabiner, Oliver D Howes
Background: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions.
Methods: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest.
Results: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups.
Conclusions: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.
{"title":"Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls.","authors":"Atheeshaan Arumuham, Matthew M Nour, Mattia Veronese, Katherine Beck, Ellis Chika Onwordi, David J Lythgoe, Sameer Jauhar, Eugenii A Rabiner, Oliver D Howes","doi":"10.1093/ijnp/pyae011","DOIUrl":"10.1093/ijnp/pyae011","url":null,"abstract":"<p><strong>Background: </strong>The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions.</p><p><strong>Methods: </strong>We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest.</p><p><strong>Results: </strong>We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups.</p><p><strong>Conclusions: </strong>These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Obituary - Prof Brian E. Leonard (1936-2023).","authors":"Timothy G Dinan, John F Cryan","doi":"10.1093/ijnp/pyae012","DOIUrl":"10.1093/ijnp/pyae012","url":null,"abstract":"","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joao Parente, Anna Carolyna Gianlorenco, Ingrid Rebello-Sanchez, Minkyung Kim, Jose Mario Prati, Chi Kyung Kim, Hyuk Choi, Jae-Jun Song, Felipe Fregni
Background: The discovery of effective treatments for major depressive disorder (MDD) may help target different brain pathways. Invasive vagus nerve stimulation (VNS) is an effective neuromodulation technique for the treatment of MDD; however, the effectiveness of the noninvasive technique, transauricular VNS (taVNS), remains unknown. Moreover, a mechanistic understanding of the neural effects behind its biological and therapeutic effects is lacking. This review aimed to evaluate the clinical evidence and the neural and anti-inflammatory effects of taVNS in MDD.
Methods: Two searches were conducted using a systematic search strategy reviewed the clinical efficacy and neural connectivity of taVNS in MDD in humans and evaluated the changes in inflammatory markers after taVNS in humans or animal models of depression. A risk of bias assessment was performed in all human studies.
Results: Only 5 studies evaluated the effects of taVNS in patients with depression. Although the studies demonstrated the efficacy of taVNS in treating depression, they used heterogeneous methodologies and limited data, thus preventing the conduct of pooled quantitative analyses. Pooled analysis could not be performed for studies that investigated the modulation of connectivity between brain areas; of the 6 publications, 5 were based on the same experiment. The animal studies that analyzed the presence of inflammatory markers showed a reduction in the level of pro-inflammatory cytokines or receptor expression.
Conclusions: Data on the clinical efficacy of taVNS in the treatment of MDD are limited. Although these studies showed positive results, no conclusions can be drawn regarding this topic considering the heterogeneity of these studies, as in the case of functional connectivity studies. Based on animal studies, the application of taVNS causes a decrease in the level of inflammatory factors in different parts of the brain, which also regulate the immune system. Therefore, further studies are needed to understand the effects of taVNS in patients with MDD.
{"title":"Neural, Anti-Inflammatory, and Clinical Effects of Transauricular Vagus Nerve Stimulation in Major Depressive Disorder: A Systematic Review.","authors":"Joao Parente, Anna Carolyna Gianlorenco, Ingrid Rebello-Sanchez, Minkyung Kim, Jose Mario Prati, Chi Kyung Kim, Hyuk Choi, Jae-Jun Song, Felipe Fregni","doi":"10.1093/ijnp/pyad058","DOIUrl":"10.1093/ijnp/pyad058","url":null,"abstract":"<p><strong>Background: </strong>The discovery of effective treatments for major depressive disorder (MDD) may help target different brain pathways. Invasive vagus nerve stimulation (VNS) is an effective neuromodulation technique for the treatment of MDD; however, the effectiveness of the noninvasive technique, transauricular VNS (taVNS), remains unknown. Moreover, a mechanistic understanding of the neural effects behind its biological and therapeutic effects is lacking. This review aimed to evaluate the clinical evidence and the neural and anti-inflammatory effects of taVNS in MDD.</p><p><strong>Methods: </strong>Two searches were conducted using a systematic search strategy reviewed the clinical efficacy and neural connectivity of taVNS in MDD in humans and evaluated the changes in inflammatory markers after taVNS in humans or animal models of depression. A risk of bias assessment was performed in all human studies.</p><p><strong>Results: </strong>Only 5 studies evaluated the effects of taVNS in patients with depression. Although the studies demonstrated the efficacy of taVNS in treating depression, they used heterogeneous methodologies and limited data, thus preventing the conduct of pooled quantitative analyses. Pooled analysis could not be performed for studies that investigated the modulation of connectivity between brain areas; of the 6 publications, 5 were based on the same experiment. The animal studies that analyzed the presence of inflammatory markers showed a reduction in the level of pro-inflammatory cytokines or receptor expression.</p><p><strong>Conclusions: </strong>Data on the clinical efficacy of taVNS in the treatment of MDD are limited. Although these studies showed positive results, no conclusions can be drawn regarding this topic considering the heterogeneity of these studies, as in the case of functional connectivity studies. Based on animal studies, the application of taVNS causes a decrease in the level of inflammatory factors in different parts of the brain, which also regulate the immune system. Therefore, further studies are needed to understand the effects of taVNS in patients with MDD.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10972554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49690436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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