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Miranda O, Fan P, Qi X, Wang H, Brannock MD, Kosten T, Ryan ND, Kirisci L, Wang L. Prediction of Adverse Events Risk in Patients with Comorbid Post- Traumatic Stress Disorder and Alcohol Use Disorder Using Electronic Medical Records by Deep Learning Models. RESEARCH SQUARE 2023:rs.3.rs-3299369. [PMID: 37790550 PMCID: PMC10543461 DOI: 10.21203/rs.3.rs-3299369/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Background Prediction of high-risk events in mental disorder patients is crucial. In our previous study, we developed a deep learning model: DeepBiomarker by using electronic medical records (EMR) to predict suicide related event (SRE) risk in post-traumatic stress disorder (PTSD) patients. Methods We applied DeepBiomarker2 through data integration of multimodal information: lab test, medication, co-morbidities, and social determinants of health. We analyzed EMRs of 5,565 patients from University of Pittsburgh Medical Center with a diagnosis of PTSD and alcohol use disorder (AUD) on risk of developing an adverse event (opioid use disorder, SREs, depression and death). Results DeepBiomarker2 predicted whether a PTSD + AUD patient will have a diagnosis of any adverse events (SREs, opioid use disorder, depression, death) within 3 months with area under the receiver operator curve (AUROC) of 0.94. We found piroxicam, vilazodone, dronabinol, tenofovir, suvorexant, empagliflozin, famciclovir, veramyst, amantadine, sulfasalazine, and lamivudine to have potential to reduce risk. Conclusions DeepBiomarker2 can predict multiple adverse event risk with high accuracy and identify potential risk and beneficial factors. Our results offer suggestions for personalized interventions in a variety of clinical and diverse populations.
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Krzystanek M, Martyniak E, Pałasz A, Skałacka K, Chwalba A, Wierzbiński P. Amantadine in Treatment of Dysthymia-The Pilot Case Series Study. Pharmaceuticals (Basel) 2023; 16:897. [PMID: 37375844 DOI: 10.3390/ph16060897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/28/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Dysthymia is a common chronic mood disorder in which isolated symptoms of depression persist for at least 2 years. Despite the many medications recommended for the treatment of dysthymia, no recommendations have yet been made for the treatment of patients who fail to achieve clinical improvement. This justifies attempts to identify second-line drugs for the treatment of dysthymia. In an open and naturalistic case study, five patients diagnosed with dysthymia in whom at least one antidepressant treatment was ineffective were treated with amantadine. In the age- and gender-matched external control group, patients were treated with sertraline at 100 mg/day. Depressive symptoms were assessed using HDRS-17. Two men and three women were treated with 100 mg amantadine for 3 months with 3-5 months follow-up. After 1 month of treatment with amantadine, a significant reduction in the intensity of depressive symptoms was achieved in all patients, and the clinical improvement increased over the next 2 months of treatment. No deterioration in well-being was observed in any patient after discontinuation of amantadine. The effect of amantadine treatment was comparable to that of sertraline treatment in patients with dysthymia who improved with this drug. The present study indicates that amantadine is an effective and well-tolerated drug in the treatment of dysthymia. Amantadine may be associated with a quick improvement in symptoms in the treatment of dysthymia. Treatment with this drug seems to be associated with good tolerability and persistency of the therapeutic effect after the discontinuation of the treatment.
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Affiliation(s)
- Marek Krzystanek
- Department and Clinic of Psychiatric Rehabilitation, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-635 Katowice, Poland
| | - Ewa Martyniak
- Department and Clinic of Psychiatric Rehabilitation, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-635 Katowice, Poland
| | - Artur Pałasz
- Department of Histology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | | | - Artur Chwalba
- Pharmacology Department, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-808 Zabrze Rokitnica, Poland
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DeBroff J, Omer N, Cohen B, Giladi N, Kestenbaum M, Shirvan JC, Cedarbaum JM, Gana‐Weisz M, Goldstein O, Orr‐Urtreger A, Mirelman A, Thaler A. The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease. Mov Disord Clin Pract 2023; 10:606-616. [PMID: 37070047 PMCID: PMC10105114 DOI: 10.1002/mdc3.13722] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 02/14/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023] Open
Abstract
Background Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. Objective To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Methods Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. Results The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Conclusions Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.
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Affiliation(s)
| | - Nurit Omer
- Sackler School of MedicineTel‐Aviv University
- Movement Disorders UnitNeurological Institute, Tel‐Aviv Medical Center
- Laboratory of Early Markers of NeurodegenerationNeurological Institute, Tel‐Aviv Medical Center
| | - Batsheva Cohen
- Laboratory of Early Markers of NeurodegenerationNeurological Institute, Tel‐Aviv Medical Center
| | - Nir Giladi
- Sackler School of MedicineTel‐Aviv University
- Movement Disorders UnitNeurological Institute, Tel‐Aviv Medical Center
- Sagol School of NeuroscienceTel‐Aviv University
| | - Meir Kestenbaum
- Sackler School of MedicineTel‐Aviv University
- Neurology departmentMeir HospitalKfar‐SabaIsrael
| | | | | | - Mali Gana‐Weisz
- Genomic Research Laboratory for NeurodegenerationTel‐Aviv Medical CenterTel‐AvivIsrael
| | - Orly Goldstein
- Genomic Research Laboratory for NeurodegenerationTel‐Aviv Medical CenterTel‐AvivIsrael
| | - Avi Orr‐Urtreger
- Sackler School of MedicineTel‐Aviv University
- Sagol School of NeuroscienceTel‐Aviv University
- Genomic Research Laboratory for NeurodegenerationTel‐Aviv Medical CenterTel‐AvivIsrael
| | - Anat Mirelman
- Sackler School of MedicineTel‐Aviv University
- Laboratory of Early Markers of NeurodegenerationNeurological Institute, Tel‐Aviv Medical Center
- Sagol School of NeuroscienceTel‐Aviv University
| | - Avner Thaler
- Sackler School of MedicineTel‐Aviv University
- Movement Disorders UnitNeurological Institute, Tel‐Aviv Medical Center
- Laboratory of Early Markers of NeurodegenerationNeurological Institute, Tel‐Aviv Medical Center
- Sagol School of NeuroscienceTel‐Aviv University
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Houpt AC, Schwartz SE, Coover RA. Assessing Psychiatric Comorbidity and Pharmacologic Treatment Patterns Among Patients With Neurofibromatosis Type 1. Cureus 2021; 13:e20244. [PMID: 35004058 PMCID: PMC8735883 DOI: 10.7759/cureus.20244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 11/17/2022] Open
Abstract
Background and objective Neurofibromatosis 1 (NF1) is a genetic disorder that is accompanied by psychiatric comorbidities such as depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) in more than half of the patients. However, there are limited data describing optimal treatment strategies for these conditions. This study aimed to address that gap in understanding and explore the neurobiological basis of psychiatric comorbidities in NF1. Materials and methods A retrospective cohort study was conducted among NF1 patients with a comorbid diagnosis of depression, anxiety, and/or ADHD. These disease states were chosen based on their relatively high reported prevalence in NF1 and shared pathophysiological mechanisms via monoaminergic dysfunction. Information regarding demographics, psychotherapeutic medication use, and clinical outcomes was gathered from electronic medical records. Relationships between patient- and medication-related factors and outcome measures were assessed using statistical analysis. Results The study population (n = 82) consisted of NF1 patients with a comorbid diagnosis of depression (76.8%), anxiety (53.7%), and/or ADHD (23.2%). The use of second-generation antipsychotic agent augmentation therapy or hydroxyzine monotherapy was associated with significantly more behavioral health (BH)-related emergency department (ED) visits, admissions, and inpatient days in the study population. Conversely, the use of bupropion augmentation therapy, buspirone augmentation therapy, and stimulants was associated with improved clinical outcomes, though these results were not statistically significant. Conclusions Based on our findings in this real-world study setting, patients with NF1 and psychiatric comorbidities appear to experience significant benefits from medications that enhance dopaminergic neurotransmission (e.g., bupropion, stimulants) when compared to drugs that oppose it (e.g., second-generation antipsychotics).
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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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Morrow K, Choi S, Young K, Haidar M, Boduch C, Bourgeois JA. Amantadine for the treatment of childhood and adolescent psychiatric symptoms. Proc AMIA Symp 2021; 34:566-570. [PMID: 34456474 DOI: 10.1080/08998280.2021.1925827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were prescribed amantadine and met study criteria to assess clinical responses and medication outcomes. More than 62% of patients experienced clinically significant symptom control and 83% achieved at least maintenance symptom control, while 11% discontinued amantadine for nonresponse and 6% stopped amantadine because of side effects. Among patients previously receiving other psychotropic medication, 42% and 28% of patients fully discontinued second- or third-generation antipsychotics or antidepressants, respectively. Patients responsive to amantadine who discontinued or reduced antipsychotic dose experienced a significant reduction in body mass index. Amantadine appears be an efficacious and safe alternative for treatment of a broad set of psychiatric symptoms in children and adolescents. Specifically, it may serve as an effective adjunct to stimulants for attention deficit/hyperactivity disorder-related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.
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Affiliation(s)
- Kyle Morrow
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
| | - Sun Choi
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
| | - Keith Young
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
| | - Makram Haidar
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
| | - Cassandra Boduch
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
| | - James A Bourgeois
- Department of Psychiatry, Baylor Scott & White Health, Temple, Texas.,Texas A&M University College of Medicine, Temple, Texas
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Shipley H, Flynn K, Tucker L, Wendt-Hornickle E, Baldo C, Almeida D, Allweiler S, Guedes A. Owner evaluation of quality of life and mobility in osteoarthritic cats treated with amantadine or placebo. J Feline Med Surg 2021; 23:568-574. [PMID: 33112193 PMCID: PMC10741303 DOI: 10.1177/1098612x20967639] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVES The aim of the study was to determine if amantadine improves owner-identified mobility impairment and quality of life associated with osteoarthritis in cats. METHODS Using a blinded, placebo-controlled, randomized, crossover design, 13 healthy client-owned cats with clinical and radiographic evidence of osteoarthritis and owner-identified mobility impairment were studied. Cats received 5 mg/kg amantadine or placebo q24h PO for 3 weeks each with no washout period in between. Locomotor activity was continuously assessed with a collar-mounted activity monitor system, and owners chose and rated two mobility-impaired activities using a client-specific outcome measures (CSOM) questionnaire on a weekly basis. Locomotor activity on the third treatment week was analyzed with two-tailed paired t-tests. The CSOM scores were analyzed using a mixed-effect model and the Bonferroni post-hoc test. Owner-perceived changes in quality of life were compared between treatments using the χ2 test. Statistical significance was set at P <0.05. RESULTS Mean ± SD activity counts during the third week of each treatment were significantly lower with amantadine (240,537 ± 53,880) compared with placebo (326,032 ± 91,759). CSOM scores assigned by the owners were significantly better with amantadine on the second (3 ± 1) and third (3 ± 1) weeks compared with placebo (5 ± 2 and 5 ± 1, respectively). A significantly greater proportion of owners reported improvement in quality of life with amantadine compared with placebo. CONCLUSIONS AND RELEVANCE Amantadine significantly decreased activity, but improved owner-identified impaired mobility and owner-perceived quality of life in cats with osteoarthritis. Amantadine appears to be an option for the symptomatic treatment of osteoarthritis in cats.
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Affiliation(s)
- Hilary Shipley
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
- Wisconsin Veterinary Referral Center,
Waukesha, WI, USA
| | - Kristi Flynn
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
| | - Laura Tucker
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
- Ontario Veterinary College, University
of Guelph, Guelph, ON, Canada
| | - Erin Wendt-Hornickle
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
| | - Caroline Baldo
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
| | - Daniel Almeida
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
| | - Sandra Allweiler
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
- Department of Clinical Sciences, College
of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
| | - Alonso Guedes
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN,
USA
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Danysz W, Dekundy A, Scheschonka A, Riederer P. Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. J Neural Transm (Vienna) 2021; 128:127-169. [PMID: 33624170 PMCID: PMC7901515 DOI: 10.1007/s00702-021-02306-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/13/2021] [Indexed: 12/30/2022]
Abstract
The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.
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Affiliation(s)
- Wojciech Danysz
- Merz Pharmaceuticals GmbH., Eckenheimer Landstraße 100, 60318, Frankfurt am Main, Germany
| | - Andrzej Dekundy
- Merz Pharmaceuticals GmbH., Eckenheimer Landstraße 100, 60318, Frankfurt am Main, Germany
| | - Astrid Scheschonka
- Merz Pharmaceuticals GmbH., Eckenheimer Landstraße 100, 60318, Frankfurt am Main, Germany
| | - Peter Riederer
- Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
- Department Psychiatry, University of Southern Denmark Odense, Vinslows Vey 18, 5000, Odense, Denmark.
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Possibility of a New Indication for Amantadine in the Treatment of Bipolar Depression-Case Series Study. Pharmaceuticals (Basel) 2020; 13:ph13100326. [PMID: 33096753 PMCID: PMC7589301 DOI: 10.3390/ph13100326] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 01/16/2023] Open
Abstract
Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as the repurposing of drugs used in other indications. In an open and naturalistic serious case study, 4 patients diagnosed with bipolar I disorder, chronically treated with a mood stabilizer, in whom at least two antidepressants were ineffective in the depressive phase, were treated with amantadine. The woman received 100 mg/day and 3 men received the target dose of 200 mg/day. All patients treated with amantadine improved their depressive symptoms after 1 week of treatment. None of them experienced side effects or manic switch. To reduce the risk of a manic switch, the treatment with amantadine was discontinued 2 weeks after the improvement of depressive symptoms, and no recurrence of depressive symptoms was observed. Amantadine may be a further therapeutic option for the treatment of acute bipolar depression. The drug in this indication may act quickly and be well tolerated. Confirmation of the antidepressant efficacy of amantadine in this indication requires replication of the results and conducting clinical trials.
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Marinescu I, Marinescu D, Mogoantă L, Efrem IC, Stovicek PO. SARS-CoV-2 infection in patients with serious mental illness and possible benefits of prophylaxis with Memantine and Amantadine. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2020; 61:1007-1022. [PMID: 34171050 PMCID: PMC8343601 DOI: 10.47162/rjme.61.4.03] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with serious mental illness are a high-risk category of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with schizophrenia are not participatory and have increased mortality and morbidity, patients with dementia cannot be cared for while depression, anxiety, bipolar tubing are associated with low immune status. Social stress is amplified by social isolation, amplifying depression and the mechanisms of decreased immunity. Hygiene measures and prophylactic behavior are impossible to put into practice in conditions of chronic mental illness. In coronavirus disease 2019 (COVID-19), the risk for severe development is associated with the presence of comorbidities and immune system deficiency. Prothrombotic status, cytokine storm and alveolar destruction are mechanisms that aggravate the evolution of patients, especially in the context in which they have dysfunction of the autonomic system. The activity of proinflammatory cytokines is accentuated by hyperglutamatergia, which potentiates oxidative stress and triggers the mechanisms of neural apoptosis by stimulating microglial activation. Activation of M1-type microglia has an important role in pathogenesis of major psychiatric disorders, such as major depression, schizophrenia or bipolar disorder, and may associate hippocampal atrophy and disconnection of cognitive structures. Memantine and Amantadine, N-methyl-D-aspartate (NMDA) glutamate receptor inhibitors, have demonstrated, through their pharmacological profile, psychotropic effects but also antiviral properties. In the conditions of the COVID-19 pandemic, based on these arguments, we suggest that they can be associated with the therapy with the basic psychotropics, Memantine or Amantadine, for the control of neuropsychiatric symptoms but also as adjuvants with antiviral action.
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Affiliation(s)
- Ileana Marinescu
- Doctoral School, Department of Internal Medicine, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Romania; ,
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Raupp-Barcaro IF, Vital MA, Galduróz JC, Andreatini R. Potential antidepressant effect of amantadine: a review of preclinical studies and clinical trials. ACTA ACUST UNITED AC 2018; 40:449-458. [PMID: 29898194 PMCID: PMC6899375 DOI: 10.1590/1516-4446-2017-2393] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 11/24/2017] [Indexed: 12/21/2022]
Abstract
Objective: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. Methods: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: “amantadine AND depress*”; “amantadine AND mood”; “amantadine AND animal models AND antidepres*”; and “amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference).” Results: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. Conclusion: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
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Affiliation(s)
- Inara F Raupp-Barcaro
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Maria A Vital
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - José C Galduróz
- Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Roberto Andreatini
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR, Brazil
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Strasburger SE, Bhimani PM, Kaabe JH, Krysiak JT, Nanchanatt DL, Nguyen TN, Pough KA, Prince TA, Ramsey NS, Savsani KH, Scandlen L, Cavaretta MJ, Raffa RB. What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities. J Clin Pharm Ther 2017; 42:147-154. [PMID: 28111761 DOI: 10.1111/jcpt.12497] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 11/29/2016] [Indexed: 12/18/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Abundant clinical data now confirm that ketamine produces a remarkable rapid-onset antidepressant effect - hours or days - in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life-saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self-limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid-onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery. METHODS A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid-acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included 'ketamine', 'antidepressant', 'mechanism of action', 'depression' and 'rapid acting', either individually or in combination. Information was sought that would include less well-known, as well as well-known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action. RESULTS Whether the mechanistic explanation for ketamine's rapid-onset antidepressant action is related to its well-known antagonism of the NMDA (N-Methyl-d-aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug-discovery sources reveals a wide variety of postulated mechanisms. WHAT IS NEW AND CONCLUSION The surprising discovery of ketamine's rapid-onset antidepressant effect is a game-changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug-discovery targets.
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Affiliation(s)
| | - P M Bhimani
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - J H Kaabe
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - J T Krysiak
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - D L Nanchanatt
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - T N Nguyen
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - K A Pough
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - T A Prince
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - N S Ramsey
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - K H Savsani
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - L Scandlen
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - M J Cavaretta
- Temple University School of Pharmacy, Philadelphia, PA, USA
| | - R B Raffa
- Temple University School of Pharmacy, Philadelphia, PA, USA.,University of Arizona College of Pharmacy, Tucson, AZ, USA
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13
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de Sousa RT, Zanetti MV, Brunoni AR, Machado-Vieira R. Challenging Treatment-Resistant Major Depressive Disorder: A Roadmap for Improved Therapeutics. Curr Neuropharmacol 2016; 13:616-35. [PMID: 26467411 PMCID: PMC4761633 DOI: 10.2174/1570159x13666150630173522] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 12/15/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Major
depressive disorder (MDD) is associated with a significant burden and costs to
the society. As remission of depressive symptoms is achieved in only one-third
of the MDD patients after the first antidepressant trial, unsuccessful
treatments contribute largely to the observed suffering and social costs of MDD.
The present article provides a summary of the therapeutic strategies that have
been tested for treatment-resistant depression (TRD). A computerized search on
MedLine/PubMed database from 1975 to September 2014 was performed, using the
keywords “treatment-resistant depression”, “major depressive disorder”,
“adjunctive”, “refractory” and “augmentation”. From the 581 articles retrieved,
two authors selected 79 papers. A manual searching further considered relevant
articles of the reference lists. The evidence found supports adding or switching
to another antidepressant from a different class is an effective strategy in
more severe MDD after failure to an initial antidepressant trial. Also, in
subjects resistant to two or more classes of antidepressants, some augmentation
strategies and antidepressant combinations should be considered, although the
overall response and remission rates are relatively low, except for fast acting
glutamatergic modulators. The wide range of available treatments for TRD
reflects the complexity of MDD, which does not underlie diverse key features of
the disorder. Larger and well-designed studies applying dimensional approaches
to measure efficacy and effectiveness are warranted.
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Affiliation(s)
| | | | | | - Rodrigo Machado-Vieira
- Laboratory of Neuroscience (LIM27), Department and Institute of Psychiatry, University of Sao Paulo, Brazil, Address: Instituto de Psiquiatria do HC-FMUSP, 3o andar, LIM-27, Rua Dr. Ovidio Pires de Campos, 785, Postal code 05403- 010, Sao Paulo, SP, Brazil
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14
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Villa A, Wolff A, Narayana N, Dawes C, Aframian DJ, Lynge Pedersen AM, Vissink A, Aliko A, Sia YW, Joshi RK, McGowan R, Jensen SB, Kerr AR, Ekström J, Proctor G. World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction. Oral Dis 2016; 22:365-82. [PMID: 26602059 DOI: 10.1111/odi.12402] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 11/11/2015] [Accepted: 11/14/2015] [Indexed: 12/11/2022]
Abstract
The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α-and β-adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.
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Affiliation(s)
- A Villa
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
| | - A Wolff
- Tel-Aviv Sourasky Medical Center and Saliwell Ltd., Harutzim, Israel
| | - N Narayana
- Department of Oral Biology, UNMC College of Dentistry, Lincoln, NE, USA
| | - C Dawes
- Department of Oral Biology, University of Manitoba, Winnipeg, MB, Canada
| | | | - A M Lynge Pedersen
- Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A Vissink
- University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - A Aliko
- Faculty of Dental Medicine, University of Medicine, Tirana, Albania.,Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Y W Sia
- McGill University, Montreal, QC, Canada
| | - R K Joshi
- DAPMRV Dental College, Bangalore, India
| | - R McGowan
- New York University College of Dentistry, New York, NY, USA
| | - S B Jensen
- Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A R Kerr
- New York University College of Dentistry, New York, NY, USA
| | - J Ekström
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - G Proctor
- Division of Mucosal & Salivary Biology, Dental Institute, King's College London, London, UK
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15
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Yu M, Zhang Y, Chen X, Zhang T. Antidepressant-like effects and possible mechanisms of amantadine on cognitive and synaptic deficits in a rat model of chronic stress. Stress 2016; 19:104-13. [PMID: 26466744 DOI: 10.3109/10253890.2015.1108302] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The aim of this study was to examine whether amantadine (AMA), as a low-affinity noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is able to improve cognitive deficits caused by chronic stress in rats. Male Wistar rats were divided into four groups: control, control + AMA, stress and stress + AMA groups. The chronic stress model combined chronic unpredictable stress (CUS) with isolated feeding. Animals were exposed to CUS continued for 21 days. AMA (25 mg/kg) was administrated p.o. for 20 days from the 4th day of CUS to the 23rd. Weight and sucrose consumption were measured during model establishing period. Spatial memory was evaluated using the Morris water maze (MWM) test. Following MWM testing, both long-term potentiation (LTP) and depotentiation were recorded in the hippocampal CA1 region. NR2B and postsynaptic density protein 95 (PSD-95) proteins were measured by Western-blot analysis. AMA increased weight and sucrose consumption of stressed rats. Spatial memory and reversal learning in stressed rats were impaired relative to controls, whereas AMA significantly attenuated cognitive impairment. AMA also mitigated the chronic stress-induced impairment of hippocampal synaptic plasticity, in which both the LTP and depotentiation were significantly inhibited in stressed rats. Moreover, AMA enhanced the expression of hippocampal NR2B and PSD-95 in stressed rats. The data suggest that AMA may be an effective therapeutic agent for depression-like symptoms and associated cognitive disturbances.
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Affiliation(s)
- Mei Yu
- a College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University , Tianjin , PR China
| | - Yuan Zhang
- a College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University , Tianjin , PR China
| | - Xiaoyu Chen
- a College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University , Tianjin , PR China
| | - Tao Zhang
- a College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University , Tianjin , PR China
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16
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Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015; 20:1057-68. [PMID: 26169973 DOI: 10.1038/mp.2015.91] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023]
Abstract
Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
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17
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Yang Y, Teja S, Baig K. Bilateral corneal edema associated with amantadine. CMAJ 2015; 187:1155-1158. [PMID: 25991839 DOI: 10.1503/cmaj.140542] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Affiliation(s)
- Yelin Yang
- Faculty of Medicine (Yang), University of Ottawa, Ottawa, Ont.; Department of Ophthalmology (Teja), University of British Columbia, Vancouver, BC; Eye Institute (Baig), University of Ottawa, Ottawa, Ont
| | - Salina Teja
- Faculty of Medicine (Yang), University of Ottawa, Ottawa, Ont.; Department of Ophthalmology (Teja), University of British Columbia, Vancouver, BC; Eye Institute (Baig), University of Ottawa, Ottawa, Ont
| | - Kashif Baig
- Faculty of Medicine (Yang), University of Ottawa, Ottawa, Ont.; Department of Ophthalmology (Teja), University of British Columbia, Vancouver, BC; Eye Institute (Baig), University of Ottawa, Ottawa, Ont.
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18
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The role of NMDA receptors in the pathophysiology and treatment of mood disorders. Neurosci Biobehav Rev 2014; 47:336-58. [PMID: 25218759 DOI: 10.1016/j.neubiorev.2014.08.017] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 08/08/2014] [Accepted: 08/28/2014] [Indexed: 12/31/2022]
Abstract
Mood disorders such as major depressive disorder and bipolar disorder are chronic and recurrent illnesses that cause significant disability and affect approximately 350 million people worldwide. Currently available biogenic amine treatments provide relief for many and yet fail to ameliorate symptoms for others, highlighting the need to diversify the search for new therapeutic strategies. Here we present recent evidence implicating the role of N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood disorders. The possible role of NMDARs in mood disorders has been supported by evidence demonstrating that: (i) both BPD and MDD are characterized by altered levels of central excitatory neurotransmitters; (ii) NMDAR expression, distribution, and function are atypical in patients with mood disorders; (iii) NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and (iv) conventional antidepressants/mood stabilizers can modulate NMDAR function. Taken together, this evidence suggests the NMDAR system holds considerable promise as a therapeutic target for developing next generation drugs that may provide more rapid onset relief of symptoms. Identifying the subcircuits involved in mood and elucidating the role of NMDARs subtypes in specific brain circuits would constitute an important step toward the development of more effective therapies with fewer side effects.
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19
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Abstract
High levels of several proinflammatory components of the immune system, such as interleukin-6, C-reactive protein, tumor necrosis factor (TNF)-α, or neopterin in patients suffering from major depression (MD) point to the involvement of an inflammatory process in the pathophysiology of MD. The direct and indirect effects of cytokines on neurotransmitter storage and release - mediated by microglia cells and astrocytes - are discussed. The tryptophan/kynurenine metabolism is one of the indirect mechanisms because the enzyme indoleamine 2,3-dioxygenase - a key enzyme of this metabolism in the central nervous system - is driven by pro- and anti-inflammatory cytokines and degrades serotonin. Moreover, neuroactive kynurenines such as kynurenic acid and quinolinic acid act on the glutamatergic neurotransmission as N-methyl-D-aspartate antagonists and agonists, respectively. Alterations of the serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may be involved in symptom generation. Epidemiological and clinical studies show a role for inflammation as a risk factor for MD. A large-scale epidemiological study in MD clearly demonstrates that severe infections and autoimmune disorders are lifetime risk factors for MD. The vulnerability-stress-inflammation model matches with this view as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. Further support comes from the therapeutic benefit of anti-inflammatory medications such as the cyclo-oxygenase-2 inhibitors, TNF-α antagonists and others, and the anti-inflammatory and immunomodulatory intrinsic effects of antidepressants.
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Affiliation(s)
- Norbert Müller
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany
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20
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Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 2012; 72:1313-33. [PMID: 22731961 DOI: 10.2165/11633130-000000000-00000] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
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Affiliation(s)
- Daniel C Mathews
- Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
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21
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Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 2012. [PMID: 22731961 DOI: 10.2165/11633130‐000000000‐00000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
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Affiliation(s)
- Daniel C Mathews
- Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
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22
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Howland RH. The use of dopaminergic and stimulant drugs for the treatment of depression. J Psychosoc Nurs Ment Health Serv 2012; 50:11-4. [PMID: 22263621 DOI: 10.3928/02793695-20120112-03] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The brain reward system consists of extensive neural pathways that mediate reward behavior such as pleasure and motivation. These pathways may be involved in the development of symptoms such as apathy, anhedonia, and cognitive dysfunction seen in patients with major depression. These pathways are served primarily, although not exclusively, by the chemical neurotransmitter dopamine, which has suggested a therapeutic role for drugs that influence dopamine activity. A small number of clinical trials using various dopaminergic and stimulant drugs for the treatment of major depression and bipolar depression have demonstrated some benefit when combined with standard antidepressant drugs. Based on this work, several ongoing trials are investigating the use of the stimulant drug lisdexamfetamine (Vyvanse®) as an adjunctive treatment for depression.
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Affiliation(s)
- Robert H Howland
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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23
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Bao AM, Ruhé HG, Gao SF, Swaab DF. Neurotransmitters and neuropeptides in depression. HANDBOOK OF CLINICAL NEUROLOGY 2012; 106:107-36. [PMID: 22608619 DOI: 10.1016/b978-0-444-52002-9.00008-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- A-M Bao
- Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
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24
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Kiss JP, Szasz BK, Fodor L, Mike A, Lenkey N, Kurkó D, Nagy J, Vizi ES. GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine. Neurochem Int 2011; 60:170-6. [PMID: 22197911 DOI: 10.1016/j.neuint.2011.12.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 12/03/2011] [Accepted: 12/09/2011] [Indexed: 01/18/2023]
Abstract
Accumulating evidence has indicated the involvement of glutamatergic neurotransmission in the pathophysiology of excitotoxicity and in the mechanism of action of antidepressants. We have previously shown that tricyclic desipramine and the selective serotonin reuptake inhibitor fluoxetine inhibit NMDA receptors (NMDARs) in the clinically relevant, low micromolar concentration range. As the different subtypes of NMDARs are markedly different in their physiological and pathological functions, our aim was to investigate whether the effect of antidepressants is subtype-specific. Using whole-cell patch-clamp recordings in rat cortical cell cultures, we studied the age-dependence of inhibition of NMDA-induced currents after treatment with desipramine and fluoxetine, as the expression profile of the NMDAR subtypes changes as a function of days in vitro. We also investigated the inhibitory effect of these antidepressants on NMDA-induced currents in HEK 293 cell lines that stably expressed rat recombinant NMDARs with GluN1a/GluN2A or GluN1a/GluN2B subunit compositions. The inhibitory effect of desipramine was not age-dependent, whereas fluoxetine displayed a continuously decreasing inhibitory profile, which was similar to the GluN1/GluN2B subtype-selective antagonist ifenprodil. In HEK 293 cells, desipramine equally inhibited NMDA currents in both cell lines, whereas fluoxetine showed an inhibitory effect only in cells that expressed the GluN1/GluN2B subtype. Our data show that fluoxetine is a selective inhibitor of GluN2B-containing NMDARs, whereas desipramine inhibits both GluN1/GluN2A and GluN1/GluN2B subtypes. As the clinical efficacy of these drugs is very similar, the putative NMDAR-associated therapeutic effect of antidepressants may be mediated only via inhibition of the GluN2B-containing subtype. The manifestation of the GluN1/GluN2B-selectivity of fluoxetine suggests the neuroprotective potential for this drug in both acute and chronic neurodegenerative disorders.
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Affiliation(s)
- Janos P Kiss
- Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
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25
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Holtzheimer PE. Advances in the Management of Treatment-Resistant Depression. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2010; 8:488-500. [PMID: 25960694 DOI: 10.1176/foc.8.4.foc488] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Treatment-resistant depression (TRD) is a prevalent, disabling, and costly condition affecting 1%-4% of the U.S. POPULATION Current approaches to managing TRD include medication augmentation (with lithium, thyroid hormone, buspirone, atypical antipsychotics, or various antidepressant medications), psychotherapy, and ECT. Advances in understanding the neurobiology of mood regulation and depression have led to a number of new potential approaches to managing TRD, including medications with novel mechanisms of action and focal brain stimulation techniques. This review will define and discuss the epidemiology of TRD, review the current approaches to its management, and then provide an overview of several developing interventions.
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Affiliation(s)
- Paul E Holtzheimer
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA
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26
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Abstract
Depressive disorders are highly prevalent and are a leading cause of disability, morbidity, and mortality worldwide; however, they often remain undertreated or untreated. This article provides a broad overview of the many strategies for treating depression. More than 24 antidepressant medications and depression-focused psychotherapies are available as first-choice options for treating depression. When patients have not had a satisfactory treatment response, the 2 main strategies are switching to an alternative antidepressant therapy or adding a second antidepressant therapy. A large number of medication combinations have been reported in the literature, and some have been shown to be effective in controlled studies. Nonstandard alternatives to conventional antidepressant treatments include exercise, light therapy, sleep deprivation, and various complementary and alternative therapies. For more chronic and refractory forms of depression, various neuromodulation therapies are available or are being investigated. Because depressive disorders are common in primary care and other medical settings, medical practitioners should be aware of the therapeutic armamentarium available for treating depression.
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Affiliation(s)
- Robert H Howland
- University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA.
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27
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Müller N, Myint AM, Schwarz MJ. Inflammatory biomarkers and depression. Neurotox Res 2010; 19:308-18. [PMID: 20658274 DOI: 10.1007/s12640-010-9210-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Revised: 06/28/2010] [Accepted: 07/01/2010] [Indexed: 11/28/2022]
Abstract
Antidepressants, predominantly serotonin- and/or noradrenaline reuptake inhibiting drugs have several shortcomings. The exact pathophysiological mechanisms leading to serotonergic-, noradrenergic- or dopaminergic dysfunction are still unclear. An inflammatory mechanism has been postulated and will be discussed here including possible therapeutic advantages of cyclooxygenase-2 (COX-2) inhibitors. Differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan-kynurenine metabolism resulting in an increased tryptophan and serotonin degradation and probably in an increased production of quinolinic acid might play a key role in major depression (MD). These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D: -aspartate agonism in MD. The immunological imbalance results in an increased prostaglandin E₂ production and probably also in an increased COX-2 expression. Although there is strong evidence for the view that the interactions of the immune system, IDO, the serotonergic system and the glutamatergic neurotransmission play a key role in MD, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc., have to be bridged by intense further research. There were already hints that anti-inflammatory therapy might have beneficial effects in MD. COX-2 inhibitors, however, have been tested in animal models and in preliminary clinical studies showing favourable effects compared to placebo in MD. The effects of COX-2 inhibition in the CNS as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further scientific evaluation including clinical studies in bigger samples of patients.
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Affiliation(s)
- Norbert Müller
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nußbaumstr. 7, 80336 München, Germany.
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Abstract
Antidepressant drugs represent one of the main forms of effective treatment for the amelioration of depressive symptoms. Most available antidepressants increase extracellular levels of monoamines. However, it is now recognized that monoamine levels and availability are only part of the story, and that antidepressants whose mechanism of action is mainly based on the modulation of monoaminergic systems may not be able to satisfy the unmet needs of depression. Therefore, a number of compounds, developed for their potential antidepressant activity, are endowed with putative mechanisms of action not affecting traditional monoamine targets. This article briefly reviews, within a mechanistic perspective, the pharmacological profiles of representative antidepressants from each class, including monoamine oxidase inhibitors, tricyclics, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors, antidepressants interacting with dopaminergic, melatonergic, glutamatergic, or neuropeptide systems. The undesirable side effects of currently used antidepressants, which can often be a reason for lack of compliance, are also considered.
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Ghasemi M, Raza M, Dehpour AR. NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test. J Psychopharmacol 2010; 24:585-94. [PMID: 19351802 DOI: 10.1177/0269881109104845] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.
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Affiliation(s)
- M Ghasemi
- Department of Pharmacology, School of Medicine, Medical Sciences, University of Tehran, Tehran, Iran
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Rogóz Z, Kubera M, Rogóz K, Basta-Kaim A, Budziszewska B. Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test. Pharmacol Rep 2010; 61:1050-60. [PMID: 20081240 DOI: 10.1016/s1734-1140(09)70167-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2009] [Revised: 10/16/2009] [Indexed: 12/16/2022]
Abstract
Considerable attention has been paid to a possible role of immunological dysregulation in the pathogenesis of depression. It has been reported that combined administration of antidepressant drugs and the non-competitive NMDA receptor antagonist amantadine reduces immobility time in the forced swimming test (FST). Moreover, preliminary clinical data show that such a combination of drugs has a beneficial effect on treatment-resistant depressed patients. Since immune activation and a pro-inflammatory response are clearly evident in treatment-resistant depression, the aim of the present study was to examine the effect of a combination of the antidepressant fluoxetine and amantadine on immunoendocrine parameters in rats subjected to the forced swimming test. The obtained results revealed synergistic antidepressant effects of the combined administration of fluoxetine (10 mg/kg) and amantadine (10 mg/kg) - drugs otherwise ineffective when given separately in the above doses. Antidepressant activity was accompanied with a significant decrease in the capacity of splenocytes to proliferate in response to concanavalin A. Moerover, fluoxetine and the combination of amantadine and fluoxetine reduced relative spleen weight in rats subjected to the FST, compared to rats treated with the vehicle. The combination of amantadine and fluoxetine enhanced the production of the negative immunoregulator interleukin-10 (but not interferon-gamma) in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with fluoxetine and amantadine. In summary, the antidepressive efficacy of a combination of fluoxetine and amantadine given in suboptimal doses may be related to the negative immunoendocrine effects of these drugs.
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Affiliation(s)
- Zofia Rogóz
- Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
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Gao SF, Bao AM. Corticotropin-Releasing Hormone, Glutamate, and γ-Aminobutyric Acid in Depression. Neuroscientist 2010; 17:124-44. [DOI: 10.1177/1073858410361780] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Stress response and depression have a significant impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. The monoamine hypothesis, which postulates dysfunctional noradrenergic and serotonergic systems as the underlying primary cause of depression, has been valuable for the development of conventional antidepressants, which can reverse these dysfunctional states to some degree. However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo—pituitary—adrenal (HPA) system might be the final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by γ-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.
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Affiliation(s)
- Shang-Feng Gao
- Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Ai-Min Bao
- Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China,
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Abstract
Treatment-resistant depression (TRD) presents major challenges for both patients and clinicians. There is no universally accepted definition of TRD, but results from the US National Institute of Mental Health's (NIMH) STAR*D (Sequenced Treatment Alternatives to Relieve Depression) programme indicate that after the failure of two treatment trials, the chances of remission decrease significantly. Several pharmacological and nonpharmacological treatments for TRD may be considered when optimized (adequate dose and duration) therapy has not produced a successful outcome and a patient is classified as resistant to treatment. Nonpharmacological strategies include psychotherapy (often in conjunction with pharmacotherapy), electroconvulsive therapy and vagus nerve stimulation. The US FDA recently approved vagus nerve stimulation as adjunctive therapy (after four prior treatment failures); however, its benefits are seen only after prolonged (up to 1 year) use. Other nonpharmacological options, such as repetitive transcranial stimulation, deep brain stimulation or psychosurgery, remain experimental and are not widely available. Pharmacological treatments of TRD can be grouped in two main categories: 'switching' or 'combining'. In the first, treatment is switched within and between classes of compounds. The benefits of switching include avoidance of polypharmacy, a narrower range of treatment-emergent adverse events and lower costs. An inherent disadvantage of any switching strategy is that partial treatment responses resulting from the initial treatment might be lost by its discontinuation in favour of another medication trial. Monotherapy switches have also been shown to have limited effectiveness in achieving remission. The advantage of combination strategies is the potential to build upon achieved improvements; they are generally recommended if partial response was achieved with the current treatment trial. Various non-antidepressant augmenting agents, such as lithium and thyroid hormones, are well studied, although not commonly used. There is also evidence of efficacy and increasing use of atypical antipsychotics in combination with antidepressants, for example, olanzapine in combination with fluoxetine (OFC) or augmentation with aripiprazole. The disadvantages of a combination strategy include multiple medications, a broader range of treatment-emergent adverse events and higher costs. Several experimental pharmaceutical treatment alternatives for TRD are also being explored in combination with antidepressants or as monotherapy. These less studied alternative compounds include pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate. In summary, despite an increasing variety of choices for the treatment of TRD, this condition remains universally undefined and represents an area of unmet medical need. There are few known approved pharmacological agents for TRD (aripiprazole and OFC) and overall outcomes remain poor. This might be an indication that depression itself is a heterogeneous condition with a great diversity of pathologies, highlighting the need for careful evaluation of individuals with depressive symptoms who are unresponsive to treatment. Clearly, more research is needed to provide clinicians with better guidance in making those treatment decisions--especially in light of accumulating evidence that the longer patients are unsuccessfully treated, the worse their long-term prognosis tends to be.
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Affiliation(s)
- Richard C Shelton
- Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats. Pharmacol Rep 2009; 61:924-9. [DOI: 10.1016/s1734-1140(09)70150-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 10/05/2009] [Indexed: 10/25/2022]
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Rakofsky JJ, Holtzheimer PE, Nemeroff CB. Emerging targets for antidepressant therapies. Curr Opin Chem Biol 2009; 13:291-302. [PMID: 19501541 DOI: 10.1016/j.cbpa.2009.04.617] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Accepted: 04/17/2009] [Indexed: 01/11/2023]
Abstract
Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF(1) receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).
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Affiliation(s)
- Jeffrey J Rakofsky
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 2004 Ridgewood Dr, Suite 218, Atlanta, GA 30322, United States.
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Abstract
Most depressed patients fail to achieve remission despite adequate antidepressant monotherapy, and a substantial minority show minimal improvement despite optimal and aggressive therapy. However, major advances have taken place in elucidating the neurobiology of depression, and several novel targets for antidepressant therapy have emerged. Three primary approaches are currently being taken: 1) optimizing the pharmacologic modulation of monoaminergic neurotransmission, 2) developing medications that target neurotransmitter systems other than the monoamines, and 3) directly modulating neuronal activity via focal brain stimulation. We review novel therapeutic targets for developing improved antidepressant therapies, including triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, dopamine receptor agonists, corticotropin-releasing factor-1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, N-methyl-D-aspartate receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Developments in therapeutic focal brain stimulation include vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, and deep brain stimulation.
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Affiliation(s)
- Paul E Holtzheimer
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle Northeast, Suite 4000, Atlanta, GA 30322, USA.
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Abstract
Metabolic encephalopathy is an acute disturbance in cellular metabolism in the brain evoked by conditions of hypoxia, hypoglycaemia, oxidative stress and/or inflammation. It usually develops acutely or subacutely and is reversible if the systemic disorder is treated. If left untreated, however, metabolic encephalopathy may result in secondary structural damage to the brain. Most encephalopathies are present with neuropsychiatric symptoms, one in particular being depression. However, mood disorders are often co-morbid with cardiovascular, liver, kidney and endocrine disorders, while increasing evidence concurs that depression involves inflammatory and neurodegenerative processes. This would suggest that metabolic disturbances resembling encephalopathy may underscore the basic neuropathology of depression at a far deeper level than currently realized. Viewing depression as a form of encephalopathy, and exploiting knowledge gleaned from our understanding of the neurochemistry and treatment of metabolic encephalopathy, may assist in our understanding of the neurobiology of depression, but also in realizing new ideas in the pharmacotherapy of mood disorders.
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Affiliation(s)
- Brian H Harvey
- Unit for Drug Research and Development, Division of Pharmacology, School of Pharmacy, North-West University, Potchefstroom, South Africa.
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Müller N, Schwarz MJ. A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders. Eur Arch Psychiatry Clin Neurosci 2008; 258 Suppl 2:97-106. [PMID: 18516521 DOI: 10.1007/s00406-008-2012-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The Kraepelinian classification of psychiatric disorders, in particular the dichotomy of dementia praecox and manic-depressive psychosis is under discussion since a long time. In recent years, not only new research in the fields of psychopathology and clinical outcome, but also findings of biological markers in the areas of neurophysiology, neuroendocrinology, psychoneuroimmunology, genetics, or psychopharmacology show a big overlap between both groups of disorders. This overlap of symptoms and markers of both disorders intensified the discussion and the proposals for new criteria for the classification of psychiatric disorders. By means of findings from the field of psychoneuroimmunology and inflammation it will be shown that different pathological mechanisms in depression and schizophrenia may lead to the same final common pathway of inflammation. These mechanisms include the immunological balance between type-1 and type-2 immune activation which influences the tryptophan-degradating enzyme indoleamine 2,3-dioxygenase (IDO) in the CNS in opposite ways, leading to an altered availability of tryptophan and serotonin, and a disturbance of the kynurenine metabolism with an imbalance in favor of the production of the NMDA-receptor agonist quinolinic acid in depression and of the NMDA-receptor antagonist kynurenic acid in schizophrenia. In both disorders, however, an increased production of prostaglandin E2 and increased expression of cyclo-oxygenase-2 reflect a slight inflammatory process taking place probably in different regions of the CNS. Albeit this common inflammatory pathway--inflammation is a general pathway of the body as answer to a lot of different noxae and pathogens--the Kraepelinian dichotomy is important with respect to pathological mechanisms and therapeutic approaches, not only for further research in understanding the exact pathological mechanisms but also for the development of preventive strategies in high risk individuals and in patients. Opposite pathways regarding the immune activation, the neurotoxic versus neuroprotective kynurenine metabolites and the agonistic versus antagonistic effects on the NMDA receptor and the glutamatergic neurotransmission show despite a possible therapeutic advantage of anti-inflammatory therapy in both disorders that the Kraepelinian dichotomy still has a significant value from a biologic-psychiatric point of view.
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Affiliation(s)
- Norbert Müller
- Hospital for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität, Nubbaumstr. 7, 80336, Munich, Germany.
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Szasz BK, Mike A, Karoly R, Gerevich Z, Illes P, Vizi ES, Kiss JP. Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system. Biol Psychiatry 2007; 62:1303-9. [PMID: 17659262 DOI: 10.1016/j.biopsych.2007.04.014] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2006] [Revised: 03/14/2007] [Accepted: 04/12/2007] [Indexed: 10/23/2022]
Abstract
BACKGROUND Data accumulated in the last decade indicate that N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of depression and the mechanism of action of antidepressants, although a direct inhibitory effect has been reported only in connection with tricyclic compounds, which interact with a wide range of receptors. METHODS Using whole-cell patch-clamp recording in rat cortical cell cultures, we investigated whether the selective serotonin reuptake inhibitor fluoxetine, which has a much better adverse effect profile, has a direct effect on NMDA receptors, and we compared its action to that of the tricyclic desipramine. RESULTS Both desipramine (concentration that causes 50% inhibition (IC(50)) = 3.13 microM) and fluoxetine (IC(50) = 10.51 microM) inhibited NMDA-evoked currents with similar efficacy in the clinically relevant low micromolar concentration range. However, in contrast to desipramine, the inhibition by fluoxetine was not voltage-dependent, and fluoxetine partially preserved its ability to associate with NMDA receptor in the presence of Mg(2+), suggesting different binding sites for the two drugs. CONCLUSIONS The fact that different classes of antidepressants were found to be low-affinity NMDA antagonists suggests that direct inhibition of NMDA receptors may contribute to the clinical effects of antidepressants.
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Affiliation(s)
- Bernadett K Szasz
- Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u.43, Budapest, Hungary
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Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 2007; 12:988-1000. [PMID: 17457312 DOI: 10.1038/sj.mp.4002006] [Citation(s) in RCA: 468] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes - counteracting this metabolism due to the lack of an enzyme of this metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
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Affiliation(s)
- N Müller
- Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, München, Germany.
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Carvalho AF, Cavalcante JL, Castelo MS, Lima MCO. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther 2007; 32:415-28. [PMID: 17875106 DOI: 10.1111/j.1365-2710.2007.00846.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND The large majority of depressed patients fail to remit on the first antidepressant prescribed. These patients with residual symptoms have higher relapse rates and poorer outcomes than those who remit. Treatment-resistant depression (TRD) is a therapeutic challenge for the clinician. Augmentation pharmacotherapy refers to the addition of drugs that are not standard antidepressants in order to enhance the effect of a classical antidepressant drug. The aim of this paper was to review the available evidence on the various augmenting agents that have been tested for efficacy in TRD. METHODS Electronic databases and relevant textbooks were searched and the information retrieved was integrated in this review. RESULTS Although augmentation strategies have been tested with various pharmacological agents, there are few controlled studies published. Lithium, triiodothyronine (T3), buspirone and pindolol have been most widely studied. Other agents include dopaminergic agents, atypical antipsychotics, psychostimulants, benzodiazepines/hypnotics, hormones and anticonvulsants. CONCLUSION The augmentation therapy with the best evidence was the lithium-antidepressant combination, especially in patients not responding to tricyclic agents. However, good results have also been reported with augmentation strategies involving T3 and buspirone.
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Affiliation(s)
- A F Carvalho
- Department of Medicine, Psychiatry Outpatient Clinics, Federal University of Ceará, Fortaleza, CE, Brazil.
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Ferraz MMD, Fontanella JC, Damasceno F, Silva de Almeida OMM, Ferraz MR. Chronic amantadine treatment enhances the sexual behaviour of male rats. Pharmacol Biochem Behav 2007; 86:616-21. [PMID: 17368735 DOI: 10.1016/j.pbb.2007.02.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Revised: 01/23/2007] [Accepted: 02/01/2007] [Indexed: 11/18/2022]
Abstract
The acute administration of amantadine (AMA), a dopaminomimetic and NMDA glutamatergic receptor antagonist also used as an anti-Parkinsonian agent, stimulates male rat sexual behaviour. However it remains unclear whether long term AMA supplementation might also provoke a similar increase in male rat sexual conduct. In the present study, male rats were administered AMA (5-50 mg/kg/day) or vehicle daily for 21 days and their sexual response was monitored weekly. Chronic treatment with AMA effectively increased the sexual response of male rats, similarly to what had been observed before with acute amantadine treatment. The main effect of chronic AMA treatment occurs in arousal and in ejaculatory response, whilst the excitatory component was not affected. The 21-day treatment with AMA did not lead to tolerance, suggesting that perhaps AMA could be used in male human patients to prevent sexual inhibition caused by anti-depressant and anti-psychotic agents.
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Affiliation(s)
- Marcia Martins Dias Ferraz
- Departamento de Farmacologia e Psicobiologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 20550-030, Brazil
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Nierenberg AA, Katz J, Fava M. A Critical Overview of the Pharmacologic Management of Treatment-Resistant Depression. Psychiatr Clin North Am 2007; 30:13-29. [PMID: 17362800 DOI: 10.1016/j.psc.2007.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Major depressive disorder is a frequent, serious disorder that usually responds partially to treatment and leaves many patients with treatment resistance. This article reviews and critically evaluates the evidence for the management of treatment-resistant depression and examines pharmacologic approaches to alleviate the suffering of patients who benefit insufficiently from initial treatment.
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Affiliation(s)
- Andrew A Nierenberg
- Depression Clinical and Research Program, Massachusetts General Hospital, 50 Staniford Street, Boston, MA 02114, USA.
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Howland RH. Glutamate-Modulating Drugs and the Treatment of Mental Disorders. J Psychosoc Nurs Ment Health Serv 2007; 45:11-4. [PMID: 17304980 DOI: 10.3928/02793695-20070101-04] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Robert H Howland
- University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pennsylvania 15213, USA.
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Abstract
Established treatments for depression are often effective. However, a significant number of patients show limited or no response. With advancements in the explanation of the underlying neurobiology of depression, several novel therapeutic approaches have been developed. Emerging drug targets include novel monoamine oxidase inhibitors, triple monoamine re-uptake inhibitors, omega-3 fatty acids, melatoninergic agonists and receptor antagonists for corticotropin-releasing factor(1), glucocorticoid, substance-P and NMDA. Developments in therapeutic focal brain stimulation include vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation. The role of psychotherapy, both as monotherapy and as adjunctive therapy, is an active avenue of investigation. Although data on these treatments are limited, preliminary results are encouraging. A major goal that remains to be achieved is the identification of predictors of response to the various antidepressant treatments that have diverse mechanisms of action.
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Affiliation(s)
- Paul E Holtzheimer
- Emory University School of Medicine, Department of Psychiatry and Behavioural Sciences, 1841 Clifton Rd NE, 4th floor, Atlanta, Georgia 30329, USA.
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Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. PSYCHOTHERAPY AND PSYCHOSOMATICS 2006; 75:139-53. [PMID: 16636629 DOI: 10.1159/000091771] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Most patients with major depressive disorder (MDD) do not reach symptom remission. These patients with residual symptoms have worse function and worse prognosis than those who remit. Several augmentation and combination treatments are used to either increase the chances of achieving remission or to eliminate/minimize residual depressive symptoms. Evidence for these pharmacological approaches rests primarily on open, uncontrolled studies, and there are clearly not enough controlled studies. Clinicians should carefully weigh these different treatment options to increase their patients' chances of achieving and sustaining remission from depression. This paper will review the pertinent studies and will propose a novel approach to improve practice involving the use of augmentation or combination strategies at the outset of initial treatment to primarily enhance the chances of remission through synergy and/or a broader spectrum of action. This novel approach could potentially enhance retention and/or increase remission rates since the lack of response with antidepressant monotherapy may lead many depressed patients with little or no benefit to drop out of treatment, precluding the subsequent use of augmentation or combination strategies altogether. In addition, the emergence of certain side-effects (e.g., agitation, insomnia) or the persistence of some initial baseline symptoms (e.g., anxiety, insomnia) may lead to premature discontinuation from monotherapy in the absence of concomitant use of augmenting pharmacological options targeting these symptoms.
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Affiliation(s)
- Maurizio Fava
- Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
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Owen JCE, Whitton PS. Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats. Brain Res 2006; 1117:206-12. [PMID: 16996043 DOI: 10.1016/j.brainres.2006.07.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2005] [Revised: 07/05/2006] [Accepted: 07/13/2006] [Indexed: 11/26/2022]
Abstract
NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.
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Affiliation(s)
- Jenny C E Owen
- The School of Pharmacy, Department of Pharmacology, 29-39 Brunswick Square, London WC1N 1AX, Great Britain UK
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Abstract
Major depression is a common, disabling, and often difficult-to-treat illness. Decades of research into the neurobiology and treatment of depression have greatly advanced our ability to manage this disorder. However, a number of challenges remain. A substantial number of depressed patients do not achieve full remission despite optimized treatment. For patients who do achieve resolution of symptoms, depression remains a highly recurrent illness, and repeated episodes are common. Finally, little is known about how depression might be prevented, especially in individuals at increased risk. In the face of these challenges, a number of exciting research efforts are currently under way and promise to greatly expand our knowledge of the etiology, pathophysiology, and treatment of depression. This review highlights these future prospects for depression research with a specific focus on lines of investigation likely to generate novel, more effective treatment options.
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Müller N, Schwarz MJ. Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. Expert Rev Neurother 2006; 6:1017-38. [PMID: 16831116 DOI: 10.1586/14737175.6.7.1017] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
This review focuses on possible causes and the impact of different immune states in schizophrenia and major depression. It discusses the fact that, in schizophrenia, an over-activation of the type 2 immune response may dominate, while the type 1 and the pro-inflammatory immune responses are over-activated in major depression. The consequence of these diverse immune states is the activation and, respectively, inhibition of different enzymes in tryptophan/kynurenine metabolism, which may lead to an overemphasis of N-methyl-D-aspartate (NMDA) receptor antagonism in schizophrenia and of NMDA-receptor agonism in depression, resulting in glutamatergic hypofunction in schizophrenia and glutamatergic hyperfunction in major depression. In addition, the activation of the type 1 and the pro-inflammatory immune responses in major depression result in increased serotonin degradation and a serotonergic deficit. While antipsychotics and antidepressants today mainly act on the dopaminergic-glutamatergic and the noradrenergic-serotonergic neurotransmission, anti-inflammatory and immune-modulating therapies might act more basically at the pathophysiological mechanism. The limitations of this concept, however, are critically discussed.
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Affiliation(s)
- Norbert Müller
- Ludwig-Maximilians-Universität München, Hospital for Psychiatry and Psychotherapy, 80336 München, Germany.
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Papakostas GI. Dopaminergic-based pharmacotherapies for depression. Eur Neuropsychopharmacol 2006; 16:391-402. [PMID: 16413172 DOI: 10.1016/j.euroneuro.2005.12.002] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2005] [Revised: 11/22/2005] [Accepted: 12/01/2005] [Indexed: 01/11/2023]
Abstract
The serendipitous discovery of the precursors of two of the major contemporary antidepressant families during the late 1950s, iproniazid for the monoamine oxidase inhibitors (MAOIs) and imipramine for the tricyclic antidepressants (TCAs), has guided the subsequent development of antidepressant compounds with predominantly serotonergic, noradrenergic or combined serotonergic and noradrenergic activity. Unfortunately, however, many depressed patients continue to remain symptomatic despite adequate treatment with pharmacologic agents currently available. When one reviews the list of pharmacologic agents currently approved for the treatment of Major Depressive Disorder (MDD), it is apparent that relatively few treatments with dopaminergic activity have been developed to date. Therefore, developing effective antidepressant treatments with pro-dopaminergic properties which also possess a relatively wide safety margin may further improve the standard of care for depression. In the present article we will briefly review studies focusing on the role of dopamine in depression followed by a comprehensive review of pharmacotherapies for depression with pro-dopaminergic activity.
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Affiliation(s)
- George I Papakostas
- Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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Owen JCE, Whitton PS. Chronic treatment with antidepressant drugs reversibly alters NMDA mediated regulation of extracellular 5-HT in rat frontal cortex. Brain Res Bull 2006; 70:62-7. [PMID: 16750484 DOI: 10.1016/j.brainresbull.2006.03.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2005] [Revised: 03/22/2006] [Accepted: 03/28/2006] [Indexed: 10/24/2022]
Abstract
Treatment of depression is largely based upon the monoamine theory of the illness. However, current therapies are only efficacious in 70-80% of patients indicating that other factors are involved. One mechanism could involve glutamatergic NMDA receptors since NMDA receptor antagonists have antidepressant like properties in paradigms of the illness. We have observed that the tricyclic clomipramine given chronically decreases NMDA mediated alterations in extracellular 5-hydroxytryptamine (5-HT). We have now studied whether this observation extends to other antidepressant drugs (AD's), reboxetine and parxoetine and also if the phenomenon is reversible after treatment is discontinued. To do this we have studied cortical extracellular 5-HT in rats using microdialysis. Acutely, none of the AD's altered extracellular 5-HT, while 100 microM NMDA infusion evoked an increase. All three AD's increased extracellular 5-HT after 14 days of treatment, however, at the same time the effects of NMDA on extracellular 5-HT were abolished. In vehicle only treated rats NMDA infusion still evoked a significant increase in extracellular 5-HT. This situation was unchanged after 3 days of drug washout with 5-HT levels remaining high and no response to NMDA infusion occurred. After 14 days of antidepressant washout, however, extracellular 5-HT levels in all three AD drug groups were around basal values. In these groups NMDA infusion now evoked an increase in extracellular 5-HT comparable to that seen in vehicle treated rats. If a reduction in NMDA receptor activity plays a role in AD drug action these observations could be of possible therapeutic significance.
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Affiliation(s)
- Jenny C E Owen
- The School of Pharmacy, Department of Pharmacology, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom
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