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Herrera B, Schall JD, Riera JJ. Agranular frontal cortical microcircuit underlying cognitive control in macaques. Front Neural Circuits 2024; 18:1389110. [PMID: 38601266 PMCID: PMC11005916 DOI: 10.3389/fncir.2024.1389110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 03/18/2024] [Indexed: 04/12/2024] Open
Abstract
The error-related negativity and an N2-component recorded over medial frontal cortex index core functions of cognitive control. While they are known to originate from agranular frontal areas, the underlying microcircuit mechanisms remain elusive. Most insights about microcircuit function have been derived from variations of the so-called canonical microcircuit model. These microcircuit architectures are based extensively on studies from granular sensory cortical areas in monkeys, cats, and rodents. However, evidence has shown striking cytoarchitectonic differences across species and differences in the functional relationships across cortical layers in agranular compared to granular sensory areas. In this minireview, we outline a tentative microcircuit model underlying cognitive control in the agranular frontal cortex of primates. The model incorporates the main GABAergic interneuron subclasses with specific laminar arrangements and target regions on pyramidal cells. We emphasize the role of layer 5 pyramidal cells in error and conflict detection. We offer several specific questions necessary for creating a specific intrinsic microcircuit model of the agranular frontal cortex.
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Affiliation(s)
- Beatriz Herrera
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
| | - Jeffrey D. Schall
- Centre for Vision Research, Centre for Integrative & Applied Neuroscience, Department of Biology and Psychology, York University, Toronto, ON, Canada
| | - Jorge J. Riera
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
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Guo X, Lin W, Zhong R, Han Y, Yu J, Yan K, Zhang X, Liang J. Factors related to the severity of obsessive-compulsive symptoms and their impact on suicide risk in epileptic patients. Epilepsy Behav 2023; 146:109362. [PMID: 37499582 DOI: 10.1016/j.yebeh.2023.109362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/29/2023]
Abstract
OBJECTIVE To explore relevant factors for the severity of obsessive-compulsive symptoms (OCSs) in adult epileptic patients and investigate whether the severity of OCSs is a mediator in the relationship between depressive/anxiety symptoms and suicide risk in epileptic patients. METHODS This was a cross-sectional study from a hospital in Northeast China. Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Neurological Disorders Depression Inventory for Epilepsy (NDDIE), Generalized Anxiety Disorder (GAD-7), and Nurses' Global Assessment of Suicide Risk (NGASR) were used to assess the severity of OCSs, depressive symptoms, anxiety symptoms, and suicide risk in epileptic patients, respectively. The independent factors of the severity of OCSs and their mediating effects in the relationship between depressive/anxiety symptoms and suicide risk were evaluated by regression analyses and mediator models, respectively. RESULTS NDDIE scores (β = 0.404, p < 0.001), GAD-7 scores (β = 0.247, p = 0.009), and polytherapy (β = 0.119, p = 0.032) were the independent factors of Y-BOCS scores. The Y-BOCS scores partially mediated the relationship between GAD-7 scores and NGASR scores (standardized coefficients of indirect effect = 0.109, Bootstrap 95% CI = 0.024 to 0.214). Still, they did not mediate the relationship between NDDIE scores and NGASR scores (standardized coefficients of indirect effect = 0.062, Bootstrap 95% CI = -0.024 to 0.169). CONCLUSIONS Depressive symptoms, anxiety symptoms, and polytherapy are independently associated with the severity of OCSs in epileptic patients. Depressive and anxiety symptoms mediate the effect of the severity of OCSs on suicide risk in epileptic patients completely.
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Affiliation(s)
- Xin Guo
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Weihong Lin
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Rui Zhong
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yujuan Han
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jieyang Yu
- Department of Pediatric Neurology, the First Hospital of Jilin University, Changchun, China
| | - Kangle Yan
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Xinyue Zhang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China.
| | - Jianmin Liang
- Department of Pediatric Neurology, the First Hospital of Jilin University, Changchun, China.
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Nematizadeh M, Ghorbanzadeh H, Moghaddam HS, Shalbafan M, Boroon M, Keshavarz-Akhlaghi AA, Akhondzadeh S. L-theanine combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci 2023; 77:478-485. [PMID: 37169515 DOI: 10.1111/pcn.13565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/19/2023] [Accepted: 05/08/2023] [Indexed: 05/13/2023]
Abstract
AIM The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and anti-depressant properties, on obsessive-compulsive disorder (OCD) symptoms in combination with fluvoxamine. METHODS Patients from either sex aged between 18 and 60 years diagnosed with OCD, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of more than 21 were enrolled in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either L-theanine (100 mg twice daily) and fluvoxamine (100 mg daily initially followed by 200 mg daily after week 5) or placebo and fluvoxamine. The primary outcome of interest in this study was the Y-BOCS total score decrease from baseline. RESULTS From a total of 95 evaluated patients, 50 completed our study; 30 were randomly assigned to each group. Multivariate analysis (ANOVA) showed a significant effect of time× $$ \times $$ treatment for L-theanine in obsession subscale (F = 5.51, P = 0.008) of the Y-BOCS score but not in the total and compulsion scores. Our results showed significantly more improvement in obsession subscale scores in L-theanine compared to placebo group (P = 0.007, Cohen's d = 0.82). Also, total Y-BOCS scores were lower in L-theanine compared to placebo group at week 5 (P = 0.039, Cohen's d = 0.60) and 10 (P = 0.008, Cohen's d = 0.80). However, there was no significant between-group differences in compulsion subscale scores. Complete response was also more frequent in the L-theanine group (P = 0.0001). CONCLUSION Findings in this study suggest L-theanine as a relatively safe and effective adjuvant therapy for moderate to severe OCD.
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Affiliation(s)
- Mehran Nematizadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Ghorbanzadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Sanjari Moghaddam
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Shalbafan
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Boroon
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir-Abbas Keshavarz-Akhlaghi
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Maraone A, Trebbastoni A, Di Vita A, D'Antonio F, De Lena C, Pasquini M. Memantine for Refractory Obsessive-Compulsive Disorder: Protocol for a Pragmatic, Double-blind, Randomized, Parallel-Group, Placebo-Controlled, Monocenter Trial. JMIR Res Protoc 2023; 12:e39223. [PMID: 37166948 PMCID: PMC10214117 DOI: 10.2196/39223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients' treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD. OBJECTIVE Our study's main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study's second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness. METHODS Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods. RESULTS Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal. CONCLUSIONS The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine's ability to improve concentration and attention mimics an antiobsessive effect. TRIAL REGISTRATION ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/39223.
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Affiliation(s)
| | | | | | | | - Carlo De Lena
- Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Rome, Italy
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Epping-Jordan MP, Girard F, Bessis AS, Mutel V, Boléa C, Derouet F, Bessif A, Mingard B, Barbier S, Paradis JS, Rocher JP, Lütjens R, Kalinichev M, Poli S. Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson's Disease. Cells 2023; 12:1004. [PMID: 37048075 PMCID: PMC10093229 DOI: 10.3390/cells12071004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Parkinson's disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients.
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Sherif MA, Fotros A, Greenberg BD, McLaughlin NCR. Understanding cingulotomy's therapeutic effect in OCD through computer models. Front Integr Neurosci 2023; 16:889831. [PMID: 36704759 PMCID: PMC9871832 DOI: 10.3389/fnint.2022.889831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 12/05/2022] [Indexed: 01/12/2023] Open
Abstract
Cingulotomy is therapeutic in OCD, but what are the possible mechanisms? Computer models that formalize cortical OCD abnormalities and anterior cingulate cortex (ACC) function can help answer this. At the neural dynamics level, cortical dynamics in OCD have been modeled using attractor networks, where activity patterns resistant to change denote the inability to switch to new patterns, which can reflect inflexible thinking patterns or behaviors. From that perspective, cingulotomy might reduce the influence of difficult-to-escape ACC attractor dynamics on other cortical areas. At the functional level, computer formulations based on model-free reinforcement learning (RL) have been used to describe the multitude of phenomena ACC is involved in, such as tracking the timing of expected outcomes and estimating the cost of exerting cognitive control and effort. Different elements of model-free RL models of ACC could be affected by the inflexible cortical dynamics, making it challenging to update their values. An agent can also use a world model, a representation of how the states of the world change, to plan its actions, through model-based RL. OCD has been hypothesized to be driven by reduced certainty of how the brain's world model describes changes. Cingulotomy might improve such uncertainties about the world and one's actions, making it possible to trust the outcomes of these actions more and thus reduce the urge to collect more sensory information in the form of compulsions. Connecting the neural dynamics models with the functional formulations can provide new ways of understanding the role of ACC in OCD, with potential therapeutic insights.
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Affiliation(s)
- Mohamed A. Sherif
- Department of Psychiatry, Brown University, Providence, RI, United States
- Carney Institute for Brain Science, Brown University, Providence, RI, United States
- Department of Psychiatry Lifespan Health System, Providence, RI, United States
| | - Aryandokht Fotros
- Department of Psychiatry, Brown University, Providence, RI, United States
- Department of Psychiatry Lifespan Health System, Providence, RI, United States
| | - Benjamin D. Greenberg
- Department of Psychiatry, Brown University, Providence, RI, United States
- Carney Institute for Brain Science, Brown University, Providence, RI, United States
- Butler Hospital, Providence, RI, United States
- United States Department of Veterans Affairs, Providence VA Medical Center, Providence, RI, United States
| | - Nicole C. R. McLaughlin
- Department of Psychiatry, Brown University, Providence, RI, United States
- Carney Institute for Brain Science, Brown University, Providence, RI, United States
- Butler Hospital, Providence, RI, United States
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Asch RH, Hillmer AT, Baldassarri SR, Esterlis I. The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 168:265-310. [PMID: 36868631 DOI: 10.1016/bs.irn.2022.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The role of glutamate system in the etiology and pathophysiology of psychiatric disorders has gained considerable attention in the past two decades, including dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Thus, mGlu5 may represent a promising therapeutic target for psychiatric conditions, particularly stress-related disorders. Here, we describe mGlu5 findings in mood disorders, anxiety, and trauma disorders, as well as substance use (specifically nicotine, cannabis, and alcohol use). We highlight insights gained from positron emission tomography (PET) studies, where possible, and discuss findings from treatment trials, when available, to explore the role of mGlu5 in these psychiatric disorders. Through the research evidence reviewed in this chapter, we make the argument that, not only is dysregulation of mGlu5 evident in numerous psychiatric disorders, potentially functioning as a disease "biomarker," the normalization of glutamate neurotransmission via changes in mGlu5 expression and/or modulation of mGlu5 signaling may be a needed component in treating some psychiatric disorders or symptoms. Finally, we hope to demonstrate the utility of PET as an important tool for investigating mGlu5 in disease mechanisms and treatment response.
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Affiliation(s)
- Ruth H Asch
- Department of Psychiatry, Yale University, New Haven, CT, United States.
| | - Ansel T Hillmer
- Department of Psychiatry, Yale University, New Haven, CT, United States; Department of Radiology and Biomedical Imaging, New Haven, CT, United States
| | - Stephen R Baldassarri
- Yale Program in Addiction Medicine, Yale University, New Haven, CT, United States; Department of Internal Medicine, Yale University, New Haven, CT, United States
| | - Irina Esterlis
- Department of Psychiatry, Yale University, New Haven, CT, United States; Department of Psychology, Yale University, New Haven, CT, United States; Clinical Neurosciences Division, U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
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S-ketamine exerts sex- and dose-dependent anti-compulsive-like effect as monotherapy or in augmentation to fluoxetine. Eur J Pharmacol 2022; 937:175382. [DOI: 10.1016/j.ejphar.2022.175382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/16/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022]
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Hadi F, Kashefinejad S, Kamalzadeh L, Hoobehfekr S, Shalbafan M. Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis. BMC Pharmacol Toxicol 2021; 22:69. [PMID: 34736541 PMCID: PMC8569963 DOI: 10.1186/s40360-021-00534-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 10/20/2021] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Obsessive-compulsive disorder (OCD) is among the most disabling neuropsychiatric conditions characterized by the presence of repetitive intrusive thoughts, impulses, or images (obsessions) and/or ritualized mental or physical acts (compulsions). Serotonergic medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are the first-line treatments for patients with OCD. Recently, dysregulation of glutamatergic system has been proposed to be involved in the etiology of OCD. We designed this systematic review and meta-analysis to evaluate clinical efficacy of glutamatergic medications in patients with OCD, according to the guidelines of Cochrane collaboration. METHOD We searched Medline, Scopus, and Cochrane library without applying any language filter. Two of the authors independently reviewed search results for irrelevant and duplicate studies and extracted data and assessed methodological quality of the studies. We transformed data into a common rubric and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 476 references in 3 databases, and after exclusion of irrelevant and duplicate studies, 17 studies with total number of 759 patients with OCD were included. In the present review we found evidence for several drugs such as memantine, N-acetylcysteine (NAC), Minocycline, L-carnosine and riluzole. Glutamaterigic drug plus SSRIs were superior to SSRI+ Placebo with regard to Y-BOCS scale [standardized mean difference (SMD = - 3.81 95% CI = - 4.4, - 3.23). CONCLUSION Augmentation of glutamatergic medications with SSRIs are beneficial in obsessive-compulsive patients, no harmful significant differences in any safety outcome were found between the groups.
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Affiliation(s)
- Fatemeh Hadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shayan Kashefinejad
- Mental Health Research Center, Psychosocial Health Research Institute, Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Leila Kamalzadeh
- Mental Health Research Center, Psychosocial Health Research Institute, Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Saba Hoobehfekr
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Shalbafan
- Mental Health Research Center, Psychosocial Health Research Institute, Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Brain and Cognition Clinic, Institute for Cognitive Sciences Studies, Tehran, Iran.
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Maraone A, Tarsitani L, Pinucci I, Pasquini M. Antiglutamatergic agents for obsessive-compulsive disorder: Where are we now and what are possible future prospects? World J Psychiatry 2021; 11:568-580. [PMID: 34631461 PMCID: PMC8474998 DOI: 10.5498/wjp.v11.i9.568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/25/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Recent data suggest that obsessive-compulsive disorder (OCD) is driven by an imbalance among the habit learning system and the goal-directed system. The frontostriatal loop termed cortico-striatal-thalamo-cortical (CSTC) circuitry loop is involved in habits and their dysfunction plays an important role in OCD. Glutamatergic neurotransmission is the principal neurotransmitter implicated in the CSTC model of OCD. Hyperactivity in the CSTC loop implies a high level of glutamate in the cortical-striatal pathways as well as a dysregulation of GABAergic transmission, and could represent the pathophysiology of OCD. Moreover, the dysregulation of glutamate levels can lead to neurotoxicity, acting as a neuronal excitotoxin. The hypothesis of a role of neurotoxicity in the pathophysiology of OCD clinically correlates to the importance of an early intervention for patients. Indeed, some studies have shown that a reduction of duration of untreated illness is related to an earlier onset of remission. Although robust data supporting a progression of such brain changes are not available so far, an early intervention could help interrupt damage from neurotoxicity. Moreover, agents targeting glutamate neurotransmission may represent promising therapeutical option in OCD patients.
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Affiliation(s)
- Annalisa Maraone
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Lorenzo Tarsitani
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Irene Pinucci
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Massimo Pasquini
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
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Abstract
Effective pharmacological and psychotherapeutic treatments are well established for obsessive-compulsive disorder (OCD). Serotonin reuptake inhibitors (SRIs) are first-line treatment and are of benefit to about half of patients. Augmentation of SRI treatment with low-dose neuroleptics is an evidence-based second-line strategy. Specialty psychotherapy is also used as both first-line and second-line treatment and can benefit many. However, a substantial number of patients do not respond to these treatments. New alternatives are urgently needed. This review summarizes evidence for these established pharmacotherapeutic strategies, and for others that have been investigated in refractory disease but are not supported by the same level of evidence. We focus on three neurotransmitter systems in the brain: serotonin, dopamine, and glutamate. We summarize evidence from genetic, neuroimaging, animal model, and other lines of investigation that probe these three systems in patients with OCD. We also review recent work on predictors of response to current treatments. While many studies suggest abnormalities that may provide insight into the pathophysiology of the disorder, most studies have been small, and non-replication of reported findings has been common. Nevertheless, the gradual accrual of evidence for neurotransmitter dysregulation may in time lead the way to new pharmacological strategies.
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Szalisznyó K, Silverstein DN. Computational Predictions for OCD Pathophysiology and Treatment: A Review. Front Psychiatry 2021; 12:687062. [PMID: 34658945 PMCID: PMC8517225 DOI: 10.3389/fpsyt.2021.687062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 06/01/2021] [Indexed: 01/29/2023] Open
Abstract
Obsessive compulsive disorder (OCD) can manifest as a debilitating disease with high degrees of co-morbidity as well as clinical and etiological heterogenity. However, the underlying pathophysiology is not clearly understood. Computational psychiatry is an emerging field in which behavior and its neural correlates are quantitatively analyzed and computational models are developed to improve understanding of disorders by comparing model predictions to observations. The aim is to more precisely understand psychiatric illnesses. Such computational and theoretical approaches may also enable more personalized treatments. Yet, these methodological approaches are not self-evident for clinicians with a traditional medical background. In this mini-review, we summarize a selection of computational OCD models and computational analysis frameworks, while also considering the model predictions from a perspective of possible personalized treatment. The reviewed computational approaches used dynamical systems frameworks or machine learning methods for modeling, analyzing and classifying patient data. Bayesian interpretations of probability for model selection were also included. The computational dissection of the underlying pathology is expected to narrow the explanatory gap between the phenomenological nosology and the neuropathophysiological background of this heterogeneous disorder. It may also contribute to develop biologically grounded and more informed dimensional taxonomies of psychopathology.
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Affiliation(s)
- Krisztina Szalisznyó
- Department of Neuroscience and Psychiatry, Uppsala University Hospital, Uppsala, Sweden.,Theoretical Neuroscience Group, Wigner Research Centre for Physics, Hungarian Academy of Sciences, Budapest, Hungary
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Ghasemi H, Nomani H, Sahebkar A, Mohammadpour AH. Anti-inflammatory Augmentation Therapy in Obsessive-compulsive Disorder: A Review. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180817999200520122910] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Obsessive-Compulsive Disorder (OCD) is considered as a serious disabling
psychiatric disorder, influencing 2-3% of the total general population, with an unknown etiology.
Methods:
A comprehensive literature search in electronic databases was performed to investigate
treatments targeting inflammation in patients suffering from OCD.
Results:
Recent studies display that inflammation processes and the dysfunction of the immune system
are likely to play a role in the pathophysiology of OCD, indicating that the disturbances in neurotransmitters
such as serotonin and dopamine cannot be alone involved in the development of
OCD. Therefore, it seems that medications with anti-inflammatory effects have the potential to be
evaluated as a new therapeutic strategy for OCD. However, this issue can be studied closely if OCD
etiological factors are thoroughly understood. The present review study aims at gathering all obtained
results concerning new treatments targeting inflammation in OCD patients. Reviewing the
conducted studies shows that the use of agents with anti-inflammatory properties, including some
NSAIDs, Minocycline and Atorvastatin, could lead to promising and intriguing results in the treatment
of OCD. Curcumin also showed good efficacy in the reduction of OCD-like behavior when it
has been used in an animal model. However, there is still no definitive and conclusive evidence for
any of the medications proposed.
Conclusion:
More future studies are needed to investigate anti-inflammatory treatment strategies for
OCD and its other subtypes such as Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS), and
Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection
(PANDAS).
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Affiliation(s)
- Hanie Ghasemi
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Homa Nomani
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amir Hooshang Mohammadpour
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Lustberg D, Iannitelli AF, Tillage RP, Pruitt M, Liles LC, Weinshenker D. Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder. Psychopharmacology (Berl) 2020; 237:1973-1987. [PMID: 32313981 PMCID: PMC7961804 DOI: 10.1007/s00213-020-05512-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 03/26/2020] [Indexed: 02/06/2023]
Abstract
RATIONALE Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated. OBJECTIVE To determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS), two animal models of OCD. METHODS We assessed NE-deficient (Dbh -/-) mice and NE-competent (Dbh +/-) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh -/- mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh -/- and control mice following both tasks. RESULTS Dbh -/- mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh -/- mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh -/- mice after MB and NS. CONCLUSION These findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.
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Affiliation(s)
- Daniel Lustberg
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA
| | - Alexa F Iannitelli
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA
| | - Rachel P Tillage
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA
| | - Molly Pruitt
- University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - L Cameron Liles
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA
| | - David Weinshenker
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA.
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15
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A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive-compulsive disorder: Mapping the way forward. COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2020; 19:1-39. [PMID: 30361863 DOI: 10.3758/s13415-018-00653-4] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety- and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive-compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of data.
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16
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Szechtman H, Harvey BH, Woody EZ, Hoffman KL. The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap. Pharmacol Rev 2020; 72:80-151. [PMID: 31826934 DOI: 10.1124/pr.119.017772] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.
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Affiliation(s)
- Henry Szechtman
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Brian H Harvey
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Erik Z Woody
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Kurt Leroy Hoffman
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
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17
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Marazziti D, Albert U, Mucci F, Piccinni A. The Glutamate and the Immune Systems: New Targets for the Pharmacological Treatment of OCD. Curr Med Chem 2019; 25:5731-5738. [PMID: 29119912 DOI: 10.2174/0929867324666171108152035] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/06/2017] [Accepted: 12/25/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND In the last decades the pharmacological treatment of obsessivecompulsive disorder (OCD) has been significantly promoted by the effectiveness of selective serotonin (5-HT) reuptake inhibitors (SSRIs) and the subsequent development of the 5-HT hypothesis of OCD. However, since a large majority of patients (between 40% and 60 %) do not respond to SSRIs or strategies based on the modulation of the 5-HT system, it is now essential to search for other possible therapeutic targets. AIMS The aim of this paper was to review current literature through a PubMed and Google Scholar search of novel hypotheses and related compounds for the treatment of OCD, with a special focus on the glutammate and the immune systems. DISCUSSION The literature indicates that glutamate, the main excitatory neurotransmitter, might play an important role in the pathophysiology of OCD. In addition, a series of clinical studies also supports the potential efficacy of drugs modulating the glutamate system. The role of the immune system alterations in OCD in both children and adults needs to be more deeply elucidated. In children, a subtype of OCD has been widely described resulting from infections driven by group A streptococcus β-hemolitic and belonging to the so-called "pediatric autoimmune neuropsychiatric disorders associated with streptococcus" (PANDAS). In adults, available findings are meager and controversial, although interesting. CONCLUSION The glutamate and the immune systems represent two intriguing topics of research that hold promise for the development of open novel treatment strategies in OCD.
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Affiliation(s)
- Donatella Marazziti
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Umberto Albert
- Rita Levi Montalcini Department of Neuroscience, University of Turin, Italy
| | - Federico Mucci
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Armando Piccinni
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
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18
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Wolmarans DW, Stein DJ, Harvey BH. A Psycho-Behavioral Perspective on Modelling Obsessive-Compulsive Disorder (OCD) in Animals: The Role of Context. Curr Med Chem 2019; 25:5662-5689. [PMID: 28545371 DOI: 10.2174/0929867324666170523125256] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 04/18/2017] [Accepted: 05/29/2017] [Indexed: 01/24/2023]
Abstract
Obsessive-compulsive disorder is a heterogeneous and debilitating condition, characterized by intrusive thoughts and compulsive repetition. Animal models of OCD are important tools that have the potential to contribute significantly to our understanding of the condition. Although there is consensus that pre-clinical models are valuable in elucidating the underlying neurobiology in psychiatric disorders, the current paper attempts to prompt ideas on how interpretation of animal behavior can be expanded upon to more effectively converge with the human disorder. Successful outcomes in psychopharmacology involve rational design and synthesis of novel compounds and their testing in well-designed animal models. As part of a special journal issue on OCD, this paper will 1) review the psychobehavioral aspects of OCD that are of importance on how the above ideas can be articulated, 2) briefly elaborate on general issues that are important for the development of animal models of OCD, with a particular focus on the role and importance of context, 3) propose why translational progress may often be less than ideal, 4) highlight some of the significant contributions afforded by animal models to advance understanding, and 5) conclude by identifying novel behavioral constructs for future investigations that may contribute to the face, predictive and construct validity of OCD animal models. We base these targets on an integrative approach to face and construct validity, and note that the issue of treatment-resistance in the clinical context should receive attention in current animal models of OCD.
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Affiliation(s)
- De Wet Wolmarans
- Division of Pharmacology, Center of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North West-University, Potchefstroom, South Africa
| | - Dan J Stein
- MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.,Department of Psychiatry and Mental Health, MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa
| | - Brian H Harvey
- Division of Pharmacology, Center of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North West-University, Potchefstroom, South Africa.,MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa
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19
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de Salles Andrade JB, Ferreira FM, Suo C, Yücel M, Frydman I, Monteiro M, Vigne P, Fontenelle LF, Tovar-Moll F. An MRI Study of the Metabolic and Structural Abnormalities in Obsessive-Compulsive Disorder. Front Hum Neurosci 2019; 13:186. [PMID: 31333428 PMCID: PMC6620433 DOI: 10.3389/fnhum.2019.00186] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 05/21/2019] [Indexed: 01/28/2023] Open
Abstract
Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness characterized by obsessions and/or compulsions. Its pathophysiology is still not well understood but it is known that the cortico-striatal-thalamic-cortical (CSTC) circuitry plays an important role. Here, we used a multi-method MRI approach combining proton magnetic resonance spectroscopy (H1-MRS) and diffusion tensor imaging (DTI) techniques to investigate both the metabolic and the microstructural white matter (WM) changes of the anterior cingulate cortex (ACC) in OCD patients as compared to healthy controls. Twenty-three OCD patients and 21 age-, sex-, and education-matched healthy volunteers participated in the study. Our 1H-MRS findings show increased levels of Glx in ACC in OCD. Further, significantly lower fractional anisotropy (FA) values were observed in OCD patients’ left cingulate bundle (CB) as compared to healthy controls. Finally, there was a negative correlation between FA in the left CB and level of obsessions, as well as the duration of the illness. Our findings reinforce the involvement of CSTC bundles in pathophysiology of OCD, pointing to a specific role of glutamate (glutamine) and WM integrity.
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Affiliation(s)
- Juliana B de Salles Andrade
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.,Institute of Biomedical Sciences (ICB), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Chao Suo
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Clayton, VIC, Australia
| | - Murat Yücel
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Clayton, VIC, Australia
| | - Ilana Frydman
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.,Obsessive, Compulsive, and Anxiety Spectrum Research Program, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marina Monteiro
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
| | - Paula Vigne
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.,Obsessive, Compulsive, and Anxiety Spectrum Research Program, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Leonardo F Fontenelle
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.,Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Clayton, VIC, Australia.,Obsessive, Compulsive, and Anxiety Spectrum Research Program, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Tovar-Moll
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.,Institute of Biomedical Sciences (ICB), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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20
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Rolls ET. The orbitofrontal cortex and emotion in health and disease, including depression. Neuropsychologia 2019; 128:14-43. [DOI: 10.1016/j.neuropsychologia.2017.09.021] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/04/2017] [Accepted: 09/20/2017] [Indexed: 12/16/2022]
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21
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Delgado-Acevedo C, Estay SF, Radke AK, Sengupta A, Escobar AP, Henríquez-Belmar F, Reyes CA, Haro-Acuña V, Utreras E, Sotomayor-Zárate R, Cho A, Wendland JR, Kulkarni AB, Holmes A, Murphy DL, Chávez AE, Moya PR. Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression. Neuropsychopharmacology 2019; 44:1163-1173. [PMID: 30622300 PMCID: PMC6462043 DOI: 10.1038/s41386-018-0302-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/01/2018] [Accepted: 12/15/2018] [Indexed: 12/12/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.
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Affiliation(s)
- Claudia Delgado-Acevedo
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Sebastián F Estay
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Instituto de Neurociencias, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Anna K Radke
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
- Department of Psychology and Center for Neuroscience and Behavior, Miami University, Oxford, OH, USA
| | - Ayesha Sengupta
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
| | - Angélica P Escobar
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Francisca Henríquez-Belmar
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Cristopher A Reyes
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Valentina Haro-Acuña
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Elías Utreras
- Functional Genomics Section and Gene Transfer Core, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
- Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile
| | - Ramón Sotomayor-Zárate
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
- Centro de Neurobiología y Fisiolopatogía Integrativa, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Andrew Cho
- Functional Genomics Section and Gene Transfer Core, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
| | - Jens R Wendland
- Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA
- Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, MA, 02139, USA
| | - Ashok B Kulkarni
- Functional Genomics Section and Gene Transfer Core, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
| | - Andrew Holmes
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
| | - Dennis L Murphy
- Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA
| | - Andrés E Chávez
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- Instituto de Neurociencias, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
| | - Pablo R Moya
- Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA.
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22
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Naderi S, Faghih H, Aqamolaei A, Mortazavi SH, Mortezaei A, Sahebolzamani E, Rezaei F, Akhondzadeh S. Amantadine as adjuvant therapy in the treatment of moderate to severe obsessive-compulsive disorder: A double-blind randomized trial with placebo control. Psychiatry Clin Neurosci 2019; 73:169-174. [PMID: 30488617 DOI: 10.1111/pcn.12803] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 11/20/2018] [Accepted: 11/25/2018] [Indexed: 12/15/2022]
Abstract
AIM The role of the glutamatergic system in the pathogenesis of obsessive-compulsive disorder (OCD) has been shown by numerous studies. The aim of the present randomized, double-blind, placebo-controlled, 12-week trial was to assess the efficacy and tolerability of amantadine as an adjuvant to fluvoxamine in the treatment of patients with moderate to severe OCD. METHODS One hundred patients diagnosed with moderate to severe OCD were randomized into two parallel groups to receive fluvoxamine (100 mg twice a day) plus placebo or fluvoxamine (100 mg twice a day) plus amantadine (100 mg daily) for 12 weeks. All patients received 100 mg/day fluvoxamine for 28 days followed by 200 mg/day for the rest of the trial, regardless of their treatment groups. Patients were evaluated for response to treatment using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and at Weeks 4, 10, and 12. The main outcome measure was to assess the efficacy of amantadine in improving the OCD symptoms. RESULTS Repeated-measure analysis of variance showed a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 3.84, d.f. = 1.50, P = 0.03) in the Y-BOCS total score and a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 5.67, d.f. = 1.48, P < 0.01) in the Y-BOCS Obsession subscale score between the two groups. CONCLUSION The results of this study suggest that amantadine may be effective as an augmentative agent in the treatment of moderate-to-severe OCD.
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Affiliation(s)
- Sina Naderi
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Heidar Faghih
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Aqamolaei
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Hosein Mortazavi
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhosein Mortezaei
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Sahebolzamani
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzin Rezaei
- Qods Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Paik SH, Choi MR, Kwak SM, Bang SH, Kim DJ. Decreased Serum Glutamate Levels in Male Adults with Internet Gaming Disorder: A Pilot Study. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2018; 16:276-281. [PMID: 30121977 PMCID: PMC6124868 DOI: 10.9758/cpn.2018.16.3.276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/29/2017] [Accepted: 06/27/2017] [Indexed: 02/03/2023]
Abstract
Objective Alteration in glutamatergic neurotransmission and dopaminergic dysfunction has been implicated in both the initiation and expression of addiction related behaviors. This pilot study was aimed to investigate the serum levels of glutamate and dopamine in adults with internet gaming disorder (IGD). Methods We measured serum levels of glutamate and dopamine in male participants with IGD (n=26) and age-matched healthy controls (n=25). Clinical interviews were performed to identify IGD and to rule out psychiatric comorbidities. Serum levels of glutamate and dopamine were examined by enzyme immunoassays using ELISA Kits. Results Serum levels of glutamate were lower among IGD than control (IGD: 24.184±12.303 μg/ml; control: 33.676±12.413μg/ml; t=2.742, p=0.008), while levels of dopamine did not differ between. Serum glutamate and dopamine levels did not correlate with gaming hours and exposure to game in the IGD group. But serum glutamate levels were positively correlated with the dopamine levels (r=0.360, p=0.013). Conclusion Our results suggest that altered glutamatergic neurotransmission may contribute to the pathophysiology of IGD.
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Affiliation(s)
- Soo-Hyun Paik
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mi Ran Choi
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su Min Kwak
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sol Hee Bang
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dai-Jin Kim
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Akouchekian S, Omranifard V, Moshfegh P, Maracy MR, Almasi A. The Effect of Atorvastatin on Obsessive-compulsive Symptoms of Refractory Obsessive-compulsive Disorder (Add-on Therapy). Adv Biomed Res 2018; 7:90. [PMID: 29930930 PMCID: PMC5991271 DOI: 10.4103/abr.abr_114_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Considering the effect of statins on the regulation of dopamine neurotransmitters and glutamates and importance of the treatment of obsessive-compulsive disorder (OCD) due to its relatively high prevalence and disability of available drugs in treatment of many patients, we came to the point to examine effectiveness of statins in patients with OCD. Materials and Methods This study is a double-blind randomized clinical trial, which is done in OCD clinic of Isfahan Shariati in 2014 for 1 year. The target population consists of 64 patients with OCD; one group is given a daily 40 mg atorvastatin tablets and the other group receives placebo. At baseline, 4- and 8-week severities of obsessive-compulsive symptoms are measured using Yale-Brown scale and compared in the two groups. Results The study results show a statistically significant difference between the two groups of intervention and control (P < 0.001). Furthermore, the results show the intervention effect at the end of the 4th week and 8th week (P < 0.001) that this change is evident in the 4th week but remained almost constant in the 8th week. Conclusion Overall, the evidences obtained from the study declare the effects of adding statins to treat obsessive-compulsive symptoms.
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Affiliation(s)
- Shahla Akouchekian
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Victoria Omranifard
- Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parivash Moshfegh
- Department of Psychiatry, Medical School, University of Medical Sciences, Isfahan, Iran
| | - Mohammad Reza Maracy
- Department of Epidemiology and Biostatistics, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Asiyeh Almasi
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Aouchekian S, Karimi R, Najafi M, Shafiee K, Maracy M, Almasi A. Effect of Religious Cognitive Behavioral Therapy on Religious Obsessive-compulsive Disorder (3 and 6 months Follow-up). Adv Biomed Res 2018; 6:158. [PMID: 29387669 PMCID: PMC5767803 DOI: 10.4103/abr.abr_115_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: Obsessive-compulsive disorder (OCD) is a chronic disorder that strongly affects one's life and social, emotional, and occupational functioning. Due to the effect of religious beliefs on phenomenology of OCD, in this paper, we assess the effectiveness of religious cognitive behavioral therapy (CBT) within 3 and 6 months follow-up. Materials and Methods: This study is a clinical trial with follow-ups which last 2 months consisting eight sessions of 1.5 h of religious CBT. The research is conducted in a group of 40, with pre- and post-test after 3 and 6 months. Used Yale-Brown OCD symptom scale, before, the end, after 3 months and after 6 months of intervention. Treatment is carried out by a psychiatrist and a clergyman through religious CBT. The trial is held in OCD clinic affiliated with Noor Hospital. Results are analyzed by ANOVA repeated measure with SPSS18. Results: The results showed a considerable decrease in OCD symptoms which remained almost persistent after 3 and 6 months (F = 3/54. P = 0/024). It also shows that religious CBT can leave substantial effect on OCD symptoms; permanency of this intervention after 3 and 6 months is noticeable (P < 0/001). In Conclusion this therapy could be helpful for OCD patients with religious content. Conclusion: RCBT have a positive effect on people with religious obsessive -compulsive.
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Affiliation(s)
- Shahla Aouchekian
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roya Karimi
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mostafa Najafi
- Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Katayon Shafiee
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Maracy
- Department of Epidemiologic and Statistical, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Asiyeh Almasi
- Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Abstract
SummaryWe present a narrative review of evidence-based treatment for obsessive–compulsive disorder (OCD), covering first-line pharmacological treatment, augmentation strategies, approaches for treatment-refractory OCD and the management of OCD in special populations (children and adolescents, pregnant and breast-feeding women, and elderly people).
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27
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Bird JS, Shah E, Shotbolt P. Epilepsy and concomitant obsessive-compulsive disorder. EPILEPSY & BEHAVIOR CASE REPORTS 2018; 10:106-110. [PMID: 30271707 PMCID: PMC6158956 DOI: 10.1016/j.ebcr.2018.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/12/2018] [Accepted: 07/06/2018] [Indexed: 04/09/2023]
Abstract
People with epilepsy (PWE) often suffer psychiatric symptoms which can impact them more than seizures. Affective and psychotic disorders are well recognized as occurring more frequently in PWE than the general population. Less is known about obsessive-compulsive disorder (OCD) in PWE, despite it being as disabling and distressing. We sought to explore the association between epilepsy and OCD with casereports by identifying ten PWE and concomitant OCD. Demographics, seizure classification, neurological, surgical, psychiatric and psychological treatment as well as quality of life were examined. A detailed analysis was performed for three of them, to explore the lived-experience of patients with the two conditions. This is followed by a discussion of how treatment for co-morbid epilepsy and OCD can be appropriately tailored to be patient specific and provide the greatest potential for improvement.
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Affiliation(s)
- Jacob S. Bird
- Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, Camberwell, London, SE5 8AB, United Kingdom of Great Britain and Northern Ireland
- South London and Maudsley NHS Trust, Maudsley Hospital, Denmark Hill, London SE5 8AZ, United Kingdom of Great Britain and Northern Ireland
- Corresponding author at: Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, Camberwell, London SE5 8AB, United Kingdom of Great Britain and Northern Ireland.
| | - Emiy Shah
- Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, Camberwell, London, SE5 8AB, United Kingdom of Great Britain and Northern Ireland
| | - Paul Shotbolt
- Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, Camberwell, London, SE5 8AB, United Kingdom of Great Britain and Northern Ireland
- South London and Maudsley NHS Trust, Maudsley Hospital, Denmark Hill, London SE5 8AZ, United Kingdom of Great Britain and Northern Ireland
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Şair A, Şair YB, Canazlar E, Sevinçok L. Remission of obsessive-compulsive symptoms following temporoparietal haemorrhage: a case report. PSYCHIAT CLIN PSYCH 2017. [DOI: 10.1080/24750573.2017.1410336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ahmet Şair
- Department of Neurology, Adnan Menderes University, Aydin, Turkey
| | - Yaşan Bilge Şair
- Department of Psychiatry, Adnan Menderes University, Aydin, Turkey
| | - Elif Canazlar
- Department of Psychiatry, Adnan Menderes University, Aydin, Turkey
| | - Levent Sevinçok
- Department of Psychiatry, Adnan Menderes University, Aydin, Turkey
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González LF, Henríquez-Belmar F, Delgado-Acevedo C, Cisternas-Olmedo M, Arriagada G, Sotomayor-Zárate R, Murphy DL, Moya PR. Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice. Biol Res 2017; 50:29. [PMID: 28927446 PMCID: PMC5605982 DOI: 10.1186/s40659-017-0138-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/11/2017] [Indexed: 12/23/2022] Open
Abstract
Background Obsessive–compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1–3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus—brain areas that are relevant to OCD. Results Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. Conclusions Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors. Electronic supplementary material The online version of this article (doi:10.1186/s40659-017-0138-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luis F González
- Laboratorio de Neuroquímica y Neurofarmacología, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.,Laboratorio de Neurogenética, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Francisca Henríquez-Belmar
- Laboratorio de Neurogenética, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.,Núcleo Milenio Nu-MIND Biology of Neuropsychiatric Disorders, Valparaíso, Chile
| | - Claudia Delgado-Acevedo
- Laboratorio de Neurogenética, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.,Núcleo Milenio Nu-MIND Biology of Neuropsychiatric Disorders, Valparaíso, Chile
| | - Marisol Cisternas-Olmedo
- Laboratorio de Neurogenética, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.,Núcleo Milenio Nu-MIND Biology of Neuropsychiatric Disorders, Valparaíso, Chile
| | - Gloria Arriagada
- Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Universidad Andres Bello, Viña del Mar, Chile
| | - Ramón Sotomayor-Zárate
- Laboratorio de Neuroquímica y Neurofarmacología, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Dennis L Murphy
- Laboratory of Clinical Science, National Institute of Mental Health, NIH, Bethesda, MD, 20892, USA
| | - Pablo R Moya
- Laboratorio de Neurogenética, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile. .,Núcleo Milenio Nu-MIND Biology of Neuropsychiatric Disorders, Valparaíso, Chile. .,Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Valparaíso, Chile.
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30
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Aripiprazole and Riluzole treatment alters behavior and neurometabolites in young ADHD rats: a longitudinal 1H-NMR spectroscopy study at 11.7T. Transl Psychiatry 2017; 7:e1189. [PMID: 28763063 PMCID: PMC5611734 DOI: 10.1038/tp.2017.167] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 05/20/2017] [Accepted: 05/30/2017] [Indexed: 01/13/2023] Open
Abstract
Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive compulsive disorder (OCD) are co-occurring neurodevelopmental diseases that share alterations of frontocortical neurometabolites. In this longitudinal study we investigated the behavioral and neurochemical effects of aripiprazole and riluzole treatment in juvenile spontaneously hypertensive rats (SHR), a model for ADHD. For neurochemical analysis we employed in vivo magnetic resonance spectroscopy (MRS). Spectra from voxels located at the central striatum and prefrontal cortex were acquired postnatally from day 35 to 50. In the SHR strain only, treatments reduced repetitive grooming and climbing behavior. The absolute quantification of cerebral metabolites in vivo using localized 1H-MRS at 11.7T showed significant alterations in SHR rats compared to controls (including glutamine, aspartate and total NAA). In addition, drug treatment reduced the majority of the detected metabolites (glutamate and glutamine) in the SHR brain. Our results indicate that the drug treatments might influence the hypothesized 'hyperactive' state of the cortico-striatal-thalamo-cortical circuitries of the SHR strain. Furthermore, we could show that behavioral changes correlate with brain region-specific alterations in neurometabolite levels in vivo. These findings should serve as reference for animal studies and for the analysis of neurometabolites in selected human brain regions to further define neurochemical alterations in neuropsychiatric diseases.
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Szechtman H, Ahmari SE, Beninger RJ, Eilam D, Harvey BH, Edemann-Callesen H, Winter C. Obsessive-compulsive disorder: Insights from animal models. Neurosci Biobehav Rev 2017; 76:254-279. [PMID: 27168347 PMCID: PMC5833926 DOI: 10.1016/j.neubiorev.2016.04.019] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 04/22/2016] [Accepted: 04/26/2016] [Indexed: 01/15/2023]
Abstract
Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.
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Affiliation(s)
- Henry Szechtman
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
| | - Susanne E Ahmari
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Richard J Beninger
- Departments of Psychology and Psychiatry, Queen's University, Kingston, ON, Canada.
| | - David Eilam
- Department of Zoology, Tel-Aviv University, Ramat-Aviv 69978, Israel.
| | - Brian H Harvey
- MRC Unit on Anxiety and Stress Disorders, Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Potchefstroom, South Africa.
| | - Henriette Edemann-Callesen
- Bereich Experimentelle Psychiatrie, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany.
| | - Christine Winter
- Bereich Experimentelle Psychiatrie, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany.
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Esalatmanesh S, Abrishami Z, Zeinoddini A, Rahiminejad F, Sadeghi M, Najarzadegan MR, Shalbafan MR, Akhondzadeh S. Minocycline combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci 2016; 70:517-526. [PMID: 27488081 DOI: 10.1111/pcn.12430] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 07/16/2016] [Accepted: 07/31/2016] [Indexed: 01/12/2023]
Abstract
AIM Several lines of evidence implicate glutamatergic dysfunction in the pathophysiology of obsessive-compulsive disorder (OCD), presenting this neurotransmitter as a target for the development of novel pharmacotherapy. The objective of this study was to assess the efficacy of minocycline as an augmentative agent to fluvoxamine in the treatment of patients with OCD. METHODS One hundred and two patients with the diagnosis of moderate-to-severe OCD were recruited to this study. A randomized double-blind trial was designed and patients received either L-carnosine or placebo as adjuvant to fluvoxamine for 10 weeks. The patients randomly received either minocycline 100 mg twice per day or placebo for 10 weeks. All patients received fluvoxamine (100 mg/day) for the first 4 weeks, followed by 200 mg/day for the rest of the trial, regardless of their treatment groups. Participants were evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The main outcome measure was to assess the efficacy of minocycline in improving the OCD symptoms. RESULTS General linear model repeated measures demonstrated significant effect for time × treatment interaction on the Y-BOCS total scores, F(1.49, 137.93) = 7.1, P = 0.003, and Y-BOCS Obsession subscale score, F(1.54, 141.94) = 9.72, P = 0.001, and near significant effect for the Y-BOCS Compulsion subscale score, F(1.27, 117.47) = 2.92, P = 0.08. A significantly greater rate of partial and complete response was observed in the minocycline group (P < 0.001). The frequency of side-effects was not significantly different between the treatment arms. CONCLUSION The results of this study suggest that minocycline could be a tolerable and effective adjuvant in the management of patients with OCD.
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Affiliation(s)
- Sophia Esalatmanesh
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Zoha Abrishami
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Atefeh Zeinoddini
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Rahiminejad
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Sadeghi
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad-Reza Shalbafan
- Mental Health Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Ortiz AE, Gassó P, Mas S, Falcon C, Bargalló N, Lafuente A, Lázaro L. Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive-compulsive disorder. World J Biol Psychiatry 2016; 17:394-404. [PMID: 26505676 DOI: 10.3109/15622975.2015.1111524] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The present study aimed to assess the relationship between variability in genes related to the pathophysiology of obsessive-compulsive disorder (OCD) and the concentration of different neurometabolites in the anterior cingulate cortex (ACC). METHODS We concomitantly assessed neurometabolite concentrations using 3-T (1)H-MRS and 262 single nucleotide polymorphism (SNPs) in 35 genes in 41 paediatric OCD patients. RESULTS There were significant associations, after Bonferroni correction, between the concentration of inositol, glutamate and glutamine, and total choline and five polymorphisms located in genes related to serotonin and glutamate (i.e., the vesicular monoamine transporter 1 gene, SLC18A1 [rs6586896]; the serotonin receptor 1B gene, HTR1B [rs6296 and rs6298]; and the glutamate receptor, ionotropic, AMPA1 gene, GRIA1 [rs707176 and rs2963944]). CONCLUSIONS The association observed between these polymorphisms and the neurometabolite concentrations could indicate the presence of a biological interaction between the serotonin and the glutamate pathways that could be involved in the pathophysiology of OCD. More studies with this methodology could increase our understanding of the aetiology and pathophysiology of OCD in children.
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Affiliation(s)
- Ana E Ortiz
- a Department of Child and Adolescent Psychiatry and Psychology , Institute of Neurosciences, Hospital Clínic , Barcelona , Spain
| | - Patricia Gassó
- b Department Anatomic Pathology, Pharmacology and Microbiology , University of Barcelona, Barcelona , Spain ;,f Institut D'investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) , Barcelona , Spain
| | - Sergi Mas
- b Department Anatomic Pathology, Pharmacology and Microbiology , University of Barcelona, Barcelona , Spain ;,f Institut D'investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) , Barcelona , Spain ;,g Centro De Investigación Biomédica En Red De Salud Mental (CIBERSAM) , Spain
| | | | - Nuria Bargalló
- c Magnetic Resonance Image Core Facility. IDIBAPS (Institut D'investigacions Biomèdiques August Pi I Sunyer) , Barcelona , Spain ;,d Image Diagnostic Center, Hospital Clínic , Barcelona , Spain ;,g Centro De Investigación Biomédica En Red De Salud Mental (CIBERSAM) , Spain
| | - Amalia Lafuente
- b Department Anatomic Pathology, Pharmacology and Microbiology , University of Barcelona, Barcelona , Spain ;,f Institut D'investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) , Barcelona , Spain ;,g Centro De Investigación Biomédica En Red De Salud Mental (CIBERSAM) , Spain
| | - Luisa Lázaro
- a Department of Child and Adolescent Psychiatry and Psychology , Institute of Neurosciences, Hospital Clínic , Barcelona , Spain ;,e Department Psychiatry and Clinical Psychobiology , University of Barcelona , Barcelona , Spain ;,f Institut D'investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) , Barcelona , Spain ;,g Centro De Investigación Biomédica En Red De Salud Mental (CIBERSAM) , Spain
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Abstract
Obsessive-compulsive disorder (OCD) is one of the most common comorbidities in bipolar disorder (BD). Clinicians often get perplexed in making treatment decisions when encountering comorbid OCD and BD as treatment of OCD by pharmacotherapy may induce or exacerbate mood instability and psychotherapeutic approaches for OCD may not be feasible in acute manic or depressive state of BD. In this study, we reviewed literature, whether existing guideline-based treatments of BD may be effective in OCD and whether newer agents will be of use for treating this comorbidity. We could find that treatment of such comorbid disorder is largely understudied. Adjuvant topiramate or olanzapine- selective serotonin reuptake inhibitor/clomipramine combination along with mood stabilizer is found to be effective for treating OCD in BD. Use of other conventional pharmacological agents and psychotherapy for treating comorbid OCD in BD lacks evidence and is limited to case reports. Our review also highlights the need for further studies regarding the treatment strategies in this highly prevalent comorbid disorder.
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Affiliation(s)
- Firoz Kazhungil
- Department of Psychiatry, Government Medical College, Kozhikode, Kerala, India
| | - E Mohandas
- Chief Consultant Psychiatrist, Sun Medical and Research Centre, Trissur, Kerala, India
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Khalkhali M, Aram S, Zarrabi H, Kafie M, Heidarzadeh A. Lamotrigine Augmentation Versus Placebo in Serotonin Reuptake Inhibitors-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Trial. IRANIAN JOURNAL OF PSYCHIATRY 2016; 11:104-14. [PMID: 27437007 PMCID: PMC4947218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Serotonin reuptake inhibitors are frequently used in first-line treatments for patients with obsessive-compulsive disorder. Nevertheless, many of these patients do not respond well to initial therapy. The hypothesis of glutamatergic dysfunction in specific brain regions has been proposed in the pathophysiology of obsessive-compulsive disorder. This study was designed to evaluate the possible efficacy of lamotrigine, a glutamatergic agent in Serotonin reuptake inhibitors-resistant patients with obsessive-compulsive disorder. METHOD This study was a 12-week, double blind, randomized, placebo-controlled trial of adjunctive fixed-doses of lamotrigine (100 mg) to Serotonin reuptake inhibitors therapy in obsessive-compulsive disorder. Eligible subjects who had a total Y-BOCS of 21 or above were randomly assigned to receive adjunctive treatment with either lamotrigine (n = 26), or placebo (n = 27). Response to lamotrigine was defined as clinical improvement (>25% decrease in the total Y-BOCS score), which was administered at weeks 0, 8 and 12. RESULTS At the endpoint (week 12), significant differences were observed in obsession, compulsion, and total Y-BOCS scores comparing lamotrigine to placebo (P = 0.01, 0.005 and 0.007 respectively). The mean reduction in obsession, compulsion and total scores in lamotrigine group was about 4.15, 4.50 and 8.73, respectively. Similarly, the mean reductions in the placebo group were 2.52, 2.56 and 5.07. Effect sizes for efficacy measureswerecalculatedbyCohen'sd, and it was calculated as 0.54 for the total YBOCS. CONCLUSION Our findings provide evidence that this augmentation is well tolerated and may be an effective strategy for patients with refractory obsessive-compulsive disorder.
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Affiliation(s)
| | - Setareh Aram
- Department of Psychiatry, Guilan University of Medical Sciences, Rasht, Iran.
| | - Homa Zarrabi
- Department of Psychiatry, Guilan University of Medical Sciences, Rasht, Iran.
| | - Moosa Kafie
- Department of Psychology, Guilan University, Rasht, Iran.
| | - Abtin Heidarzadeh
- Department of Community Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2016; 41:214-9. [PMID: 26931055 DOI: 10.1111/jcpt.12370] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 02/03/2016] [Indexed: 01/12/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE N-acetylcysteine (NAC) has been proposed as a potential therapy for obsessive-compulsive disorder (OCD) as it may regulate the exchange of glutamate and prevent its pre-oxidant effects. The aim of the present double-blind, placebo-controlled trial was to assess the efficacy and tolerability of NAC augmentation in moderate-to-severe (OCD) treatment. METHODS In this randomized, double-blind, two-centre, placebo-controlled, 10-week trial, patients with moderate-to-severe OCD were enrolled. Patients were randomized into two parallel groups to receive fluvoxamine (200 mg daily) plus placebo or fluvoxamine (200 mg daily) plus NAC (2000 mg daily). A total of 44 patients (22 in each group) were visited to evaluate response to therapy using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline, and at weeks 4, 8 and 10. Side effects were recorded using predesigned checklists upon each visit. RESULTS AND DISCUSSION Repeated-measures ANOVA showed a significant effect for time × treatment interaction (Greenhouse-Geisser corrected: F = 5·14, d.f. = 1·64, P = 0·012) in the Y-BOCS total score and a significant effect for time × treatment interaction (Greenhouse-Geisser corrected: F = 5·44, d.f. = 1·54, P = 0·011) in the Y-BOCS obsession subscale between the two groups. WHAT IS NEW AND CONCLUSION Our results showed that NAC might be effective as an augmentative agent in the treatment of moderate-to-severe OCD. TRIAL REGISTRATION Iranian Registry of Clinical Trials (www.irct.ir): IRCT201405271556N60.
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Affiliation(s)
- K Paydary
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - A Akamaloo
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - A Ahmadipour
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - F Pishgar
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - S Emamzadehfard
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - S Akhondzadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
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What Future Role Might N-Acetyl-Cysteine Have in the Treatment of Obsessive Compulsive and Grooming Disorders?: A Systematic Review. J Clin Psychopharmacol 2016; 36:57-62. [PMID: 26629962 DOI: 10.1097/jcp.0000000000000431] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Licensed pharmacological treatments for obsessive-compulsive disorders include selective serotonin reuptake inhibitors and tricyclic antidepressants. However, a large proportion of patients show minimal or no therapeutic response to these treatments. The glutamatergic system has been implicated in the etiology of obsessive-compulsive spectrum disorders, and it has been postulated that n-acetyl-cysteine (NAC) could have a therapeutic effect on these conditions through its actions on the glutamatergic system and the reduction of oxidative stress. A systematic review was conducted on the existing methodologically robust literature regarding the efficacy of NAC on obsessive-compulsive spectrum disorders in adults and children. Four randomized, double-blind placebo-controlled studies were identified, investigating the effects of NAC on obsessive-compulsive disorder, trichotillomania, and onychophagia. Results remain inconclusive, but NAC may still be useful as a treatment for obsessive-compulsive spectrum disorders on an individual level, particularly as the compound has a relatively benign side-effect profile. The dearth of methodologically robust work is clinically important: larger randomized controlled trials are required to inform of any meaningful clinical effectiveness, and to better determine which, if any, clinical populations might most benefit.
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Thorsen AL, van den Heuvel OA, Hansen B, Kvale G. Neuroimaging of psychotherapy for obsessive-compulsive disorder: A systematic review. Psychiatry Res 2015; 233:306-13. [PMID: 26228566 DOI: 10.1016/j.pscychresns.2015.05.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 10/20/2014] [Accepted: 05/11/2015] [Indexed: 10/23/2022]
Abstract
The symptoms of obsessive-compulsive disorder (OCD) include intrusive thoughts, compulsive behavior, anxiety, and cognitive inflexibility, which are associated with dysfunction in dorsal and ventral corticostriato-thalamocortical (CSTC) circuits. Psychotherapy involving exposure and response prevention has been established as an effective treatment for the affective symptoms, but the impact on the underlying neural circuits is not clear. This systematic review used the Medline, Embase, and PsychINFO databases to investigate how successful therapy may affect neural substrates of OCD. Sixteen studies measuring neural changes after therapy were included in the review. The studies indicate that dysfunctions in neural function and structure are partly reversible and state-dependent for affective symptoms, which may also apply to cognitive symptoms. This is supported by post-treatment decreases of symptoms and activity in the ventral circuits during symptom provocation, as well as mainly increased activity in dorsal circuits during cognitive processing. These effects appear to be common to both psychotherapy and medication approaches. Although neural findings were not consistent across all studies, these findings indicate that people with OCD may experience functional, symptomatic, and neural recovery after successful treatment.
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Affiliation(s)
- Anders Lillevik Thorsen
- OCD-team, Haukeland University Hospital, Bergen, Norway; Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
| | - Odile A van den Heuvel
- Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands; Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands
| | - Bjarne Hansen
- OCD-team, Haukeland University Hospital, Bergen, Norway; Department of Clinical Psychology, University of Bergen, Bergen, Norway
| | - Gerd Kvale
- OCD-team, Haukeland University Hospital, Bergen, Norway; Department of Clinical Psychology, University of Bergen, Bergen, Norway
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Pittenger C. Glutamatergic agents for OCD and related disorders. CURRENT TREATMENT OPTIONS IN PSYCHIATRY 2015; 2:271-283. [PMID: 26301176 PMCID: PMC4540409 DOI: 10.1007/s40501-015-0051-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pharmacotherapy remains inadequate for many patients with OCD; there is an urgent need for alternative pharmacological strategies. Convergent evidence suggests imbalance in glutamate, the brain's primary excitatory neurotransmitter, in some patients. This has motivated interest in glutamate modulators in patients who are unresponsive to standard pharmacotherapeutic approaches. While no glutamate modulator can be considered proven as an efficacious treatment of OCD, promising suggestions of benefit have been reported for memantine and riluzole. The evidence is thinner for N-acetylcysteine, but this agent's low cost and benign side effect profile make it a reasonable consideration in certain patients. Intriguing research on D-cycloserine and ketamine suggest potential benefit as well. It is notable that these agents all work by different, and in some cases opposite, mechanisms; this suggests that we have much to learn about the role of glutamate dysregulation in the etiology of OCD, and of glutamate modulators in its treatment.
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Affiliation(s)
- Christopher Pittenger
- Child Study Center Yale University 34 Park Street, W315 New Haven, CT 06519 203-974-7675 (phone) 203-974-7805 (fax)
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Pittenger C, Bloch MH, Wasylink S, Billingslea E, Simpson R, Jakubovski E, Kelmendi B, Sanacora G, Coric V. Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial. J Clin Psychiatry 2015; 76. [PMID: 26214725 PMCID: PMC4560666 DOI: 10.4088/jcp.14m09123] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population and is associated with significant morbidity. Many patients receive little benefit from the best available treatments, and even those who do respond often suffer from significant residual symptoms. Convergent evidence suggests that abnormalities in glutamate homeostasis and neurotransmission may contribute to OCD and that glutamate-modulating medications may be of benefit in patients whose symptoms are refractory to standard interventions. Small open-label trials of augmentation of serotonin reuptake inhibitor (SRI) pharmacotherapy with the glutamate modulator riluzole have suggested benefit in adults with refractory symptoms. We report a pilot randomized placebo-controlled trial of riluzole augmentation of ongoing SRI treatment in SRI-refractory patients. METHOD Outpatients (n = 27) and inpatients (n = 11) with DSM-IV OCD on stable SRI pharmacotherapy were randomized between November 2006 and December 2012 to receive riluzole 50 mg or placebo twice a day and followed for 12 weeks after a 2-week placebo lead-in phase. RESULTS Riluzole was well tolerated; 1 patient experienced moderate nausea, but none discontinued treatment due to side effects. While there was nominally greater Y-BOCS improvement in the riluzole group (our primary outcome) compared to placebo, it did not reach statistical significance. In the outpatient subsample, a trend suggesting benefit from riluzole augmentation for obsessions (P = .056, 2-tailed, uncorrected) was found in a secondary analysis. Among outpatients, more achieved at least a partial response (> 25% improvement) with riluzole than with placebo (P = .02 in a secondary analysis). CONCLUSIONS Riluzole may be of benefit to a subset of patients. Larger samples would be required to detect effects of the order suggested by the nominal improvement in our outpatient subsample. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00523718.
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Affiliation(s)
| | - Michael H. Bloch
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT,Yale Child Study Center, Yale University School of Medicine, New Haven, CT
| | - Suzanne Wasylink
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Eileen Billingslea
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Ryan Simpson
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Ewgeni Jakubovski
- Yale Child Study Center, Yale University School of Medicine, New Haven, CT
| | - Ben Kelmendi
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Gerard Sanacora
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Vladimir Coric
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
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Abstract
Established treatments for obsessive-compulsive disorder (OCD) are of benefit in approximately 3 of every 4 patients, but refractory disease remains distressingly common, and many treatment responders continue to experience considerable morbidity. This motivates a search for new insights into pathophysiology that may inform novel treatment strategies. Much recent work has focused on the neurotransmitter glutamate. Several lines of neurochemical and genetic evidence suggests that glutamate dysregulation may contribute to OCD, although much remains unclear. The off-label use of a number of pharmacological agents approved for other indications has been investigated in refractory OCD. We summarize investigations of memantine, riluzole, ketamine, D-cycloserine, glycine, N-acetylserine, topiramate, and lamotrigine. Evidence exists for benefit from each of these in some patients; though none has been proven effective with sufficient clarity to be considered part of standard care, these agents are options in individuals whose symptoms are refractory to better-established therapeutic strategies.
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Affiliation(s)
- Christopher Pittenger
- Departments of Psychiatry and Psychology, Child Study Center, and Interdepartmental Neuroscience Program, Yale University School of Medicine
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42
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Grados MA, Atkins EB, Kovacikova GI, McVicar E. A selective review of glutamate pharmacological therapy in obsessive-compulsive and related disorders. Psychol Res Behav Manag 2015; 8:115-31. [PMID: 25995654 PMCID: PMC4425334 DOI: 10.2147/prbm.s58601] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Glutamate, an excitatory central nervous system neurotransmitter, is emerging as a potential alternative pharmacological treatment when compared to gamma-aminobutyric acid (GABA)-, dopamine-, and serotonin-modulating treatments for neuropsychiatric conditions. The pathophysiology, animal models, and clinical trials of glutamate modulation are explored in disorders with underlying inhibitory deficits (cognitive, motor, behavioral) including obsessive–compulsive disorder, attention deficit hyperactivity disorder, Tourette syndrome, trichotillomania, excoriation disorder, and nail biting. Obsessive–compulsive disorder, attention deficit hyperactivity disorder, and grooming disorders (trichotillomania and excoriation disorder) have emerging positive data, although only scarce controlled trials are available. The evidence is less supportive for the use of glutamate modulators in Tourette syndrome. Glutamate-modulating agents show promise in the treatment of disorders of inhibition.
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Affiliation(s)
- Marco A Grados
- Division of Child and Adolescent Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Bloch MH, Storch EA. Assessment and management of treatment-refractory obsessive-compulsive disorder in children. J Am Acad Child Adolesc Psychiatry 2015; 54:251-62. [PMID: 25791142 PMCID: PMC4460245 DOI: 10.1016/j.jaac.2015.01.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 01/14/2015] [Accepted: 01/26/2015] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To review the assessment and treatment of treatment-refractory pediatric obsessive-compulsive disorder (OCD). METHOD A PubMed search was conducted to identify controlled trials in pediatric OCD. In addition, practice guidelines for the treatment of adults and children were further reviewed for references in treatment-refractory OCD across the lifespan. RESULTS Pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT) were found to be effective treatments for pediatric OCD. Evidence suggests that CBT is also effective even in pediatric patients with refractory OCD symptoms. Antipsychotic augmentation, raising SSRI dosage, and several glutamate-modulating agents have some evidence of efficacy in adults with treatment-refractory OCD but have not been studied in pediatric populations. CONCLUSION Several pharmacological treatment options exist for children with refractory OCD symptoms. However, little evidence-based data exist to guide treatment for our most challenging pediatric OCD patients. Further research is needed to evaluate the efficacy/side effect profile of commonly used interventions in treatment-refractory pediatric OCD.
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Hussain A, Dar MA, Wani RA, Shah MS, Jan MM, Malik YA, Chandel RK, Margoob MA. Role of lamotrigine augmentation in treatment-resistant obsessive compulsive disorder: a retrospective case review from South Asia. Indian J Psychol Med 2015; 37:154-8. [PMID: 25969599 PMCID: PMC4418246 DOI: 10.4103/0253-7176.155613] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Resistance to pharmacotherapy is one of the major challenges in the management of obsessive-compulsive disorder (OCD). OCD being a quite prevalent disorder, this resistance adds to the disability. Different strategies are being employed to counter this resistance, one of them being augmentation with glutamatergic modulators. Lamotrigine is being used for same since the recent past with mixed results. OBJECTIVE The aim was to study the role of lamotrigine augmentation in serotonin reuptake inhibitor (SRI) resistant OCD patients. METHODOLOGY AND RESULTS This study was carried by studying the case sheets of SRI resistant cases having already completed the treatment. A total of 22 cases sheets over 2 years met the study criteria with a mean age of mean age of 34.14 years. Over a period of 16 weeks, with a mean lamotrigine dose of 150 mg/day, 20 out of 22 patients had shown a significant response. The mean decrease in Yale-Brown Obsessive Compulsive Scale score was 67.23% with a baseline score of 28.87. There was a similar change on different domains of World Health Organization quality of life (P = 0.00564). CONCLUSION Lamotrigine augmentation to on-going treatment with SRIs may be an effective move in case of SRI resistant OCD patients.
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Affiliation(s)
- Arshad Hussain
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Mansoor Ahmad Dar
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Rayees Ahmad Wani
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Majid Shafi Shah
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Mohd Muzzaffar Jan
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Yasir A Malik
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Rajesh Kumar Chandel
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Mushtaq Ahmad Margoob
- Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
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Terbeck S, Akkus F, Chesterman LP, Hasler G. The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies. Front Neurosci 2015; 9:86. [PMID: 25852460 PMCID: PMC4364244 DOI: 10.3389/fnins.2015.00086] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 02/27/2015] [Indexed: 12/30/2022] Open
Abstract
In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches—from basic neurobiological approaches to human studies—might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.
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Affiliation(s)
- Sylvia Terbeck
- School of Psychology, Faculty of Health and Human Sciences, University of Plymouth Plymouth, UK
| | - Funda Akkus
- Division of Molecular Psychiatry, Translational Research Center, Psychiatric University Hospital, University of Bern Bern, Switzerland
| | | | - Gregor Hasler
- Division of Molecular Psychiatry, Translational Research Center, Psychiatric University Hospital, University of Bern Bern, Switzerland
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Goltseker K, Yankelevitch-Yahav R, Albelda NS, Joel D. Signal attenuation as a rat model of obsessive compulsive disorder. J Vis Exp 2015:52287. [PMID: 25650700 PMCID: PMC4354519 DOI: 10.3791/52287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
In the signal attenuation rat model of obsessive-compulsive disorder (OCD), lever-pressing for food is followed by the presentation of a compound stimulus which serves as a feedback cue. This feedback is later attenuated by repeated presentations of the stimulus without food (without the rat emitting the lever-press response). In the next stage, lever-pressing is assessed under extinction conditions (i.e., no food is delivered). At this stage rats display two types of lever-presses, those that are followed by an attempt to collect a reward, and those that are not. The latter are the measure of compulsive-like behavior in the model. A control procedure in which rats do not experience the attenuation of the feedback cue serves to distinguish between the effects of signal attenuation and of extinction. The signal attenuation model is a highly validated model of OCD and differentiates between compulsive-like behaviors and behaviors that are repetitive but not compulsive. In addition the measures collected during the procedure eliminate alternative explanations for differences between the groups being tested, and are quantitative, unbiased and unaffected by inter-experimenter variability. The major disadvantages of this model are the costly equipment, the fact that it requires some technical know-how and the fact that it is time-consuming compared to other models of OCD (11 days). The model may be used for detecting the anti- or pro-compulsive effects of pharmacological and non-pharmacological manipulations and for studying the neural substrate of compulsive behavior.
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Affiliation(s)
| | | | - Noa S Albelda
- School of Psychological Sciences, Tel-Aviv University
| | - Daphna Joel
- School of Psychological Sciences, Tel-Aviv University; Sagol School of Neuroscience, Tel-Aviv University;
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Tunca Z, Kıvırcık Akdede B, Özerdem A, Alkın T, Polat S, Ceylan D, Bayın M, Cengizçetin Kocuk N, Şimşek S, Resmi H, Akan P. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry 2014; 30:198-204. [PMID: 25543333 DOI: 10.1016/j.eurpsy.2014.11.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 11/14/2014] [Accepted: 11/14/2014] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. METHODS BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non-patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. RESULTS While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive-compulsive disorder were positively correlated. CONCLUSION Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania.
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Affiliation(s)
- Z Tunca
- Dokuz Eylul University, Medical School, Izmir, Turkey.
| | | | - A Özerdem
- Dokuz Eylul University, Medical School, Izmir, Turkey
| | - T Alkın
- Dokuz Eylul University, Medical School, Izmir, Turkey
| | | | | | | | | | | | - H Resmi
- Dokuz Eylul University, Medical School, Izmir, Turkey
| | - P Akan
- Dokuz Eylul University, Medical School, Izmir, Turkey
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Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson's disease dementia. Neuropharmacology 2014; 91:43-56. [PMID: 25499022 DOI: 10.1016/j.neuropharm.2014.11.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 11/05/2014] [Accepted: 11/28/2014] [Indexed: 01/24/2023]
Abstract
Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD.
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Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder. Int J Neuropsychopharmacol 2014; 17:1915-22. [PMID: 24833114 DOI: 10.1017/s1461145714000716] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.
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Wang HR, Woo YS, Bahk WM. Potential role of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Psychiatry Clin Neurosci 2014; 68:723-32. [PMID: 24735021 DOI: 10.1111/pcn.12186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/26/2014] [Accepted: 04/11/2014] [Indexed: 11/29/2022]
Abstract
We reviewed the extant literature to evaluate the current evidence regarding the efficacy and safety of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Relevant literature was accessed using the Cochrane database, embase and PubMed on 29 October 2013. Prospective studies examining the efficacy of anticonvulsants in obsessive-compulsive and related disorders were included. Case reports, case series, and retrospective studies were excluded. A total of 10 studies were included in this review. The studies of obsessive-compulsive disorder, except for two negative studies, showed favorable efficacy results of anticonvulsants. In one study on body dysmorphic disorder, levetiracetam showed favorable efficacy. In two lamotrigine studies for pathologic skin-picking, the efficacy findings were inconsistent. In one trichotillomania study, topiramate had reduced hair-pulling symptoms. Despite limited evidence, our review suggests that anticonvulsants have a potential role in the treatment of obsessive-compulsive and related disorders.
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Affiliation(s)
- Hee Ryung Wang
- Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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