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Erkan O, Ozturk N, Ozdemir S. Impact of quetiapine on ion channels and contractile dynamics in rat ventricular myocyte. Eur J Pharmacol 2024; 976:176674. [PMID: 38810715 DOI: 10.1016/j.ejphar.2024.176674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/11/2024] [Accepted: 05/27/2024] [Indexed: 05/31/2024]
Abstract
Antipsychotic drugs often lead to adverse effects, including those related to the cardiovascular system. Of these, quetiapine is known to cause significant changes in the QT interval although the underlying mechanism remains mysterious, prompting us to examine its effects on cardiac electrophysiological properties. Therefore, we investigated the effect of quetiapine on contraction, action potential (AP), and the associated membrane currents such as L-type Ca2+ and K+ using the whole-cell patch clamp method to examine its impacts on isolated rat ventricular myocytes. Our results showed that (1) quetiapine reduces cell contractility in a concentration-dependent manner and (2) leads to a significant prolongation in the duration of AP in isolated ventricular myocytes. This effect was both concentration and frequency-dependent; (3) quetiapine significantly decreased the Ca2+, transient outward K+, and steady-state K+ currents. However, only high concentration of quetiapine (100 μM) could significantly change the activation and reactivation kinetics of L-type Ca2+ channels. This study demonstrates that QT extension induced by quetiapine is mainly associated with the prolongation of AP. Moreover, quetiapine caused a significant decrease in contractile force and excitability of ventricular myocytes by suppressing Ca2+ and K+ currents.
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Affiliation(s)
- Orhan Erkan
- Akdeniz University Faculty of Medicine Department of Biophysics, Antalya, Turkey
| | - Nihal Ozturk
- Akdeniz University Faculty of Medicine Department of Biophysics, Antalya, Turkey
| | - Semir Ozdemir
- Akdeniz University Faculty of Medicine Department of Biophysics, Antalya, Turkey.
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Khan MM, Khan ZA, Khan MA. Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration. World J Psychiatry 2024; 14:767-783. [PMID: 38984346 PMCID: PMC11230099 DOI: 10.5498/wjp.v14.i6.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024] Open
Abstract
Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
| | - Zaw Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
| | - Mohsin Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
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Khan MM. Role of de novo lipogenesis in insulin resistance in first-episode psychosis and therapeutic options. Neurosci Biobehav Rev 2022; 143:104919. [DOI: 10.1016/j.neubiorev.2022.104919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 10/07/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022]
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Kang M, Heo R, Park S, Mun SY, Park M, Han ET, Han JH, Chun W, Ha KS, Park H, Jung WK, Choi IW, Park WS. Inhibitory effects of the atypical antipsychotic, clozapine, on voltage-dependent K + channels in rabbit coronary arterial smooth muscle cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2022; 26:277-285. [PMID: 35766005 PMCID: PMC9247706 DOI: 10.4196/kjpp.2022.26.4.277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/10/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
To investigate the adverse effects of clozapine on cardiovascular ion channels, we examined the inhibitory effect of clozapine on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Clozapine-induced inhibition of Kv channels occurred in a concentration-dependent manner with an half-inhibitory concentration value of 7.84 ± 4.86 µM and a Hill coefficient of 0.47 ± 0.06. Clozapine did not shift the steady-state activation or inactivation curves, suggesting that it inhibited Kv channels regardless of gating properties. Application of train pulses (1 and 2 Hz) progressively augmented the clozapine-induced inhibition of Kv channels in the presence of the drug. Furthermore, the recovery time constant from inactivation was increased in the presence of clozapine, suggesting that clozapine-induced inhibition of Kv channels is use (state)-dependent. Pretreatment of a Kv1.5 subtype inhibitor decreased the Kv current amplitudes, but additional application of clozapine did not further inhibit the Kv current. Pretreatment with Kv2.1 or Kv7 subtype inhibitors partially blocked the inhibitory effect of clozapine. Based on these results, we conclude that clozapine inhibits arterial Kv channels in a concentrationand use (state)-dependent manner. Kv1.5 is the major subtype involved in clozapine-induced inhibition of Kv channels, and Kv2.1 and Kv7 subtypes are partially involved.
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Affiliation(s)
- Minji Kang
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Ryeon Heo
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Seojin Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Seo-Yeong Mun
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Minju Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Eun-Taek Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Jin-Hee Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Kwon-Soo Ha
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Hongzoo Park
- Institute of Medical Sciences, Department of Urology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
| | - Won-Kyo Jung
- Department of Biomedical Engineering and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan 48513, Korea
| | - Il-Whan Choi
- Department of Microbiology, College of Medicine, Inje University, Busan 48516, Korea
| | - Won Sun Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia.
AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ.
METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA).
RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = −0.4972, P = 0.001), PANSS-PSS (r = −0.4034, P = 0.028), and PANSS-NSS (r = −0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia.
CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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Jiang Y, Patton MH, Zakharenko SS. A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome. Front Neural Circuits 2021; 15:769969. [PMID: 34955759 PMCID: PMC8693383 DOI: 10.3389/fncir.2021.769969] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.
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Affiliation(s)
| | | | - Stanislav S. Zakharenko
- Division of Neural Circuits and Behavior, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
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Kessi M, Chen B, Peng J, Yan F, Yang L, Yin F. Calcium channelopathies and intellectual disability: a systematic review. Orphanet J Rare Dis 2021; 16:219. [PMID: 33985586 PMCID: PMC8120735 DOI: 10.1186/s13023-021-01850-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 05/04/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. MAIN BODY A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. CONCLUSION Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
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Affiliation(s)
- Miriam Kessi
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
- Kilimanjaro Christian Medical University College, Moshi, Tanzania
- Mawenzi Regional Referral Hospital, Moshi, Tanzania
| | - Baiyu Chen
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Jing Peng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Fangling Yan
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Lifen Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Fei Yin
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China.
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Rastogi A, Viani-Walsh D, Akbari S, Gall N, Gaughran F, Lally J. Pathogenesis and management of Brugada syndrome in schizophrenia: A scoping review. Gen Hosp Psychiatry 2020; 67:83-91. [PMID: 33065406 PMCID: PMC7537626 DOI: 10.1016/j.genhosppsych.2020.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/28/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
CONTEXT Excess cardiovascular morbidity and an increased prevalence of sudden cardiac death (SCD) contributes to premature mortality in schizophrenia. Brugada syndrome (BrS) is an important but underrecognized cause of SCD. It is more commonly seen in schizophrenia than in general population controls. METHODS We conducted a scoping review to describe the pathogenesis of BrS in schizophrenia and to identify the psychotropic medications that increase the risk of unmasking BrS and associated ventricular arrhythmias resulting in SCD. FINDINGS Schizophrenia and BrS share similar calcium channel abnormalities, which may result in aberrant myocardial conductivity. It remains uncertain if there is a genetic pre-disposition for BrS in a subset of patients with schizophrenia. However, the unmasking of Brugada ECG patterns with the use of certain antipsychotics and antidepressants increases the risk of precipitating SCD, independent of QT prolongation. CONCLUSIONS AND FUTURE DIRECTIONS Specific cardiology assessment and interventions may be required for the congenital or unmasked Brugada ECG pattern in schizophrenia. The current long-term standard of care for BrS is an implantable cardioverter defibrillator (ICD), but post-implantation psychological effects must be considered. Careful use of antipsychotic and other psychotropic medications is necessary to minimize proarrhythmic effects due to impact on cardiac sodium and calcium ion channels. When prescribing such drugs to patients with schizophrenia, clinicians should be mindful of the potentially fatal unmasking of Brugada ECG patterns and how to manage it. We present recommendations for psychiatrists managing this patient population.
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Affiliation(s)
- Anuj Rastogi
- Royal College of Surgeons in Ireland, School of Medicine, Dublin, Ireland.
| | - Dylan Viani-Walsh
- Royal College of Surgeons in Ireland, School of Medicine, Dublin, Ireland.
| | - Shareef Akbari
- Royal College of Surgeons in Ireland, School of Medicine, Dublin, Ireland.
| | - Nicholas Gall
- Department of Cardiology, King's College Hospital NHS Foundation Trust, United Kingdom.
| | - Fiona Gaughran
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience King's College London, United Kingdom.
| | - John Lally
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience King's College London, United Kingdom; Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland; St Vincent's Hospital Fairview, Dublin, Ireland; Department of Psychiatry, Mater Misericordiae University Hospital, Dublin, Ireland.
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Marks WN, Zabder NK, Cain SM, Snutch TP, Howland JG. The T-type calcium channel antagonist, Z944, alters social behavior in Genetic Absence Epilepsy Rats from Strasbourg. Behav Brain Res 2019; 361:54-64. [DOI: 10.1016/j.bbr.2018.12.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/30/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
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Lin CH, Lin CY, Wang HS, Lane HY. Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia. Sci Rep 2019; 9:3895. [PMID: 30846868 PMCID: PMC6405997 DOI: 10.1038/s41598-019-40691-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/21/2019] [Indexed: 01/24/2023] Open
Abstract
Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.
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Affiliation(s)
- Chieh-Hsin Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Yuan Lin
- Tsaotun Psychiatric Center, Ministry of Health and Welfare, Nantou, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,National Changhua University of Education, Changhua, Taiwan
| | - Hong-Song Wang
- Psychiatric department, Changhua Hospital, Ministry of Health & Welfare, Changhua, Taiwan
| | - Hsien-Yuan Lane
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. .,Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan. .,Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan.
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Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801. Psychopharmacology (Berl) 2018; 235:3339-3350. [PMID: 30251162 DOI: 10.1007/s00213-018-5040-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022]
Abstract
RATIONALE Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies. OBJECTIVES We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis. METHODS To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms. RESULTS Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay. CONCLUSIONS These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.
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Kanda Y, Okada M, Ikarashi R, Morioka E, Kondo T, Ikeda M. Bimodal modulation of store-operated Ca 2+ channels by clozapine in astrocytes. Neurosci Lett 2016; 635:56-60. [PMID: 27769892 DOI: 10.1016/j.neulet.2016.10.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 10/13/2016] [Accepted: 10/17/2016] [Indexed: 10/20/2022]
Abstract
Clozapine (Clz) and olanzapine (Olz) are second generation (atypical) antipsychotics, used widely for treating schizophrenia and bipolar disorder. These drugs share multiple sites of actions, however their mechanisms remain incompletely understood. Here, we analyzed the effects of these drugs on primary cultures of rat cortical astrocytes and C6 glioma cells using fura-2-based Ca2+ imaging. C6 cells, but not cortical astrocytes, express the serotonin 2A receptor subtype, which couples to phospholipase C. Clz (1μM) significantly blocked serotonin-induced Ca2+ transients in C6 cells, consistent with known antagonistic actions of Clz. Interestingly, at higher concentrations (>10μM), Clz but not Olz increased intracellular Ca2+ concentrations in both cortical astrocytes and C6 cells. This Clz-induced Ca2+ increase was concentration-dependent and completely blocked by removal of extracellular Ca2+ using ethylene glycol tetraacetic acid (EGTA). Furthermore, 2-aminoethyl diphenylborinate or SKF-96365, blockers for store-operated Ca2+ channels, significantly inhibited the Clz-induced Ca2+ increase. Therefore, we analyzed the effects of Clz and Olz during Ca2+ re-entry through store-operated Ca2+ channels, which was maximized following depletion of internal Ca2+ stores by thapsigargin and EGTA. The results demonstrated that Clz decreased Ca2+ re-entry through store-operated Ca2+ channels in cortical astrocytes and C6 cells whereas Olz failed to modulate the Ca2+ re-entry. These results suggest Clz-specific bimodal actions via store-operated Ca2+ channels in astrocytic cells. Since intracellular Ca2+ homeostasis in astrocytes is an important determinant for neighboring synaptic signal transmission, our results may explain Clz-specific adverse effects or differential actions between Clz and Olz reported in the treatment of psychiatric disorders.
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Affiliation(s)
- Yuzuki Kanda
- Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
| | - Miho Okada
- Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
| | - Rina Ikarashi
- Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
| | - Eri Morioka
- Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
| | - Takashi Kondo
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
| | - Masayuki Ikeda
- Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
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Rangel-Barajas C, Estrada-Sánchez AM, Barton SJ, Luedtke RR, Rebec GV. Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine. Neuropharmacology 2016; 113:502-510. [PMID: 27816502 DOI: 10.1016/j.neuropharm.2016.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/19/2016] [Accepted: 11/01/2016] [Indexed: 10/20/2022]
Abstract
The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30-50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.
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Affiliation(s)
- Claudia Rangel-Barajas
- Indiana University Bloomington, Department of Psychological and Brain Sciences, Program in Neuroscience, 1101 E. 10th St., Bloomington, IN 47405, USA
| | - Ana María Estrada-Sánchez
- Indiana University Bloomington, Department of Psychological and Brain Sciences, Program in Neuroscience, 1101 E. 10th St., Bloomington, IN 47405, USA; Intellectual and Developmental Disabilities Research Center, Semel Institute, Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Scott J Barton
- Indiana University Bloomington, Department of Psychological and Brain Sciences, Program in Neuroscience, 1101 E. 10th St., Bloomington, IN 47405, USA
| | - Robert R Luedtke
- University of North Texas Health Science Center, The Department of Pharmacology and Neuroscience, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
| | - George V Rebec
- Indiana University Bloomington, Department of Psychological and Brain Sciences, Program in Neuroscience, 1101 E. 10th St., Bloomington, IN 47405, USA.
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14
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Marks WN, Greba Q, Cain SM, Snutch TP, Howland JG. The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats. Neuroscience 2016; 332:121-9. [DOI: 10.1016/j.neuroscience.2016.06.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/25/2022]
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15
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Mizoguchi Y, Kato TA, Horikawa H, Monji A. Microglial intracellular Ca(2+) signaling as a target of antipsychotic actions for the treatment of schizophrenia. Front Cell Neurosci 2014; 8:370. [PMID: 25414641 PMCID: PMC4220695 DOI: 10.3389/fncel.2014.00370] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 10/20/2014] [Indexed: 11/18/2022] Open
Abstract
Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and neurotrophic factors when they are activated in response to immunological stimuli. Recent reports show that pathophysiology of schizophrenia is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling, which is mainly controlled by the endoplasmic reticulum (ER), is important for microglial functions such as release of NO and cytokines, migration, ramification and deramification. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of schizophrenia, while it remains unclear how typical or atypical antipsychotics affect intracellular Ca2+ mobilization in microglial cells. This mini-review article summarizes recent findings on cellular mechanisms underlying the characteristic differences in the actions of antipsychotics on microglial intracellular Ca2+ signaling and reinforces the importance of the ER of microglial cells as a target of antipsychotics for the treatment of schizophrenia.
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Affiliation(s)
- Yoshito Mizoguchi
- Department of Psychiatry, Faculty of Medicine, Saga University Saga, Japan
| | - Takahiro A Kato
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan ; Innovation Center for Medical Redox Navigation, Kyushu University Fukuoka, Japan
| | - Hideki Horikawa
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan
| | - Akira Monji
- Department of Psychiatry, Faculty of Medicine, Saga University Saga, Japan
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16
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Dwyer DS, Aamodt E, Cohen B, Buttner EA. Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs. Front Pharmacol 2014; 5:177. [PMID: 25120487 PMCID: PMC4112795 DOI: 10.3389/fphar.2014.00177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 07/09/2014] [Indexed: 02/02/2023] Open
Abstract
Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.
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Affiliation(s)
- Donard S. Dwyer
- Department of Psychiatry–Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-ShreveportShreveport, LA, USA
| | - Eric Aamodt
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center-ShreveportShreveport, LA, USA
| | - Bruce Cohen
- Department of Psychiatry, Harvard Medical SchoolBoston, MA, USA
- Mailman Research Center, McLean HospitalBelmont, MA, USA
| | - Edgar A. Buttner
- Mailman Research Center, McLean HospitalBelmont, MA, USA
- Department of Neurology–Department of Psychiatry, McLean Hospital, Harvard Medical SchoolBelmont, MA, USA
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17
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Lee H, Dvorak D, Fenton AA. Targeting Neural Synchrony Deficits is Sufficient to Improve Cognition in a Schizophrenia-Related Neurodevelopmental Model. Front Psychiatry 2014; 5:15. [PMID: 24592242 PMCID: PMC3924579 DOI: 10.3389/fpsyt.2014.00015] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 01/29/2014] [Indexed: 11/13/2022] Open
Abstract
Cognitive symptoms are core features of mental disorders but procognitive treatments are limited. We have proposed a "discoordination" hypothesis that cognitive impairment results from aberrant coordination of neural activity. We reported that neonatal ventral hippocampus lesion (NVHL) rats, an established neurodevelopmental model of schizophrenia, have abnormal neural synchrony and cognitive deficits in the active place avoidance task. During stillness, we observed that cortical local field potentials sometimes resembled epileptiform spike-wave discharges with higher prevalence in NVHL rats, indicating abnormal neural synchrony due perhaps to imbalanced excitation-inhibition coupling. Here, within the context of the hypothesis, we investigated whether attenuating abnormal neural synchrony will improve cognition in NVHL rats. We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats. These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.
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Affiliation(s)
- Heekyung Lee
- Graduate Program in Neural and Behavioral Science, Downstate Medical Center, State University of NewYork , Brooklyn, NY , USA
| | - Dino Dvorak
- Graduate Program in Biomedical Engineering, Downstate Medical Center, State University of New York and New York University Polytechnic School of Engineering , Brooklyn, NY , USA
| | - André A Fenton
- The Robert F. Furchgott Center for Neural and Behavioral Science, Downstate Medical Center, State University of New York , Brooklyn, NY , USA ; Center for Neural Science, New York University , New York, NY , USA
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18
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Gulsuner S, McClellan JM. De novo mutations in schizophrenia disrupt genes co-expressed in fetal prefrontal cortex. Neuropsychopharmacology 2014; 39:238-9. [PMID: 24317315 PMCID: PMC3857658 DOI: 10.1038/npp.2013.219] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Suleyman Gulsuner
- Department of Medicine, University of Washington, Seattle, WA, USA,Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Jon M McClellan
- Department of Psychiatry, University of Washington, Seattle, WA, USA,E-mail:
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Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H, Nimgaonkar VL, Go RCP, Savage RM, Swerdlow NR, Gur RE, Braff DL, King MC, McClellan JM. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 2013; 154:518-29. [PMID: 23911319 DOI: 10.1016/j.cell.2013.06.049] [Citation(s) in RCA: 420] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 06/03/2013] [Accepted: 06/28/2013] [Indexed: 11/28/2022]
Abstract
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
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Affiliation(s)
- Suleyman Gulsuner
- Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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20
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Choi KH. The design and discovery of T-type calcium channel inhibitors for the treatment of central nervous system disorders. Expert Opin Drug Discov 2013; 8:919-31. [DOI: 10.1517/17460441.2013.796926] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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21
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Egan MF, Zhao X, Smith A, Troyer MD, Uebele VN, Pidkorytov V, Cox K, Murphy M, Snavely D, Lines C, Michelson D. Randomized controlled study of the T-type calcium channel antagonist MK-8998 for the treatment of acute psychosis in patients with schizophrenia. Hum Psychopharmacol 2013; 28:124-33. [PMID: 23532746 DOI: 10.1002/hup.2289] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 11/08/2012] [Accepted: 01/02/2013] [Indexed: 11/06/2022]
Abstract
OBJECTIVE This study aimed to evaluate whether the T-type calcium channel antagonist MK-8998 was effective in treating acute psychosis in patients with schizophrenia. METHODS This was a randomized, double-blind, parallel-group study. After a placebo lead-in, acutely psychotic inpatients with schizophrenia were randomized to 4 weeks of MK-8998 12/16 mg daily (N = 86), olanzapine 10/15 mg daily (N = 47), or placebo (N = 83). The primary efficacy measure was score on the Positive and Negative Syndrome Scale (PANSS). RESULTS Out of 216 randomized patients, 158 completed the 4-week study: MK-8998 = 58 (67.4%), olanzapine = 38 (80.9%), and placebo = 62 (74.7%). The mean changes from baseline in PANSS score at week 4 for MK-8998 and olanzapine were not significantly different from placebo: MK-8998-placebo difference = -0.6 [95% confidence interval (CI): -7.0, 5.8], p = 0.9; olanzapine-placebo difference = -4.3 [95% CI: -11.7, 3.1), p = 0.3. A responder rate analysis (≥20% improvement from baseline in PANSS score) suggested an advantage of olanzapine over placebo (odds ratio = 2.20 [95% CI: 0.95, 5.09], p = 0.07) but no effect of MK-8998 over placebo (odds ratio = 1.28 [95% CI: 0.62, 2.64], p = 0.5). Treatments were generally well tolerated, but more patients reported adverse events for MK-8998 (47.7%) and olanzapine (48.9%) than placebo (37.3%). CONCLUSIONS MK-8998 was not effective in treating acutely psychotic inpatients with schizophrenia, as measured by PANSS score at week 4. Because of the limited efficacy of the active comparator, we cannot exclude the possibility that T-type calcium channel antagonists could prove to be effective in schizophrenia.
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Affiliation(s)
- Michael F Egan
- Merck Sharp & Dohme Corp., Whitehouse, Station, NJ, USA.
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22
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Li X, Li PCH. Strategies for the real-time detection of Ca2+ channel events of single cells: recent advances and new possibilities. Expert Rev Clin Pharmacol 2012; 3:267-80. [PMID: 22111609 DOI: 10.1586/ecp.10.16] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ca(2+) ion channels play key roles in cell physiology and they are important drug targets. The Ca(2+) channel events are mainly measurable by fluorescent and patch clamp methods. This review summarizes the recent advances of these techniques for the detection of Ca(2+) channel events and the prospect of their new directions in the near future. Conventional bulk fluorescent methods are amenable to high-throughput applications, but they are not real-time single-cell measurements, which provide kinetic data on individual cells and offer unparalleled sensitive data for rare cells. Recent advances on real-time single-cell fluorescent measurements are conducted on microfluidic chips with scalable cell-retention sites, integrated with electrical stimulation and fluorescent measuring features. Patch clamp techniques are real-time measurements conducted on single cells, but the measurements are of low throughput. Recent advances are conducted on microfluidic patch clamp chips for high-throughput applications. Future real-time single-cell Ca(2+) channel event measurements will be conducted in a multiparametric manner in an integrated and automated microfluidic chip.
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Affiliation(s)
- XiuJun Li
- University of California at Berkeley, CA 94720, USA
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Ohno-Shosaku T, Sugawara Y, Muranishi C, Nagasawa K, Kubono K, Aoki N, Taguchi M, Echigo R, Sugimoto N, Kikuchi Y, Watanabe R, Yoneda M. Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses. Brain Res 2011; 1421:66-77. [DOI: 10.1016/j.brainres.2011.08.073] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 08/31/2011] [Indexed: 11/28/2022]
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T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats. Neuropharmacology 2010; 62:1413-21. [PMID: 21110986 DOI: 10.1016/j.neuropharm.2010.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Revised: 11/08/2010] [Accepted: 11/17/2010] [Indexed: 11/23/2022]
Abstract
T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine's effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-fos expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-fos expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.
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