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Singh P, Srivastava A, Guin D, Thakran S, Yadav J, Chandna P, Sood M, Chadda RK, Kukreti R. Genetic Landscape of Major Depressive Disorder: Assessment of Potential Diagnostic and Antidepressant Response Markers. Int J Neuropsychopharmacol 2023; 26:692-738. [PMID: 36655406 PMCID: PMC10586057 DOI: 10.1093/ijnp/pyad001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation. METHODS We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values. RESULTS A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response. CONCLUSIONS The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.
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Affiliation(s)
- Priyanka Singh
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ankit Srivastava
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Delhi, India
| | - Sarita Thakran
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jyoti Yadav
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
| | - Puneet Chandna
- Indian Society of Colposcopy and Cervical Pathology (ISCCP), Safdarjung Hospital, New Delhi, India
| | - Mamta Sood
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Rakesh Kumar Chadda
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Zhang T, Rao Q, Lin K, He Y, Cai J, Yang M, Xu Y, Hou L, Lin Y, Liu H. CYP2C19-rs4986893 confers risk to major depressive disorder and bipolar disorder in the Han Chinese population whereas ABCB1-rs1045642 acts as a protective factor. BMC Psychiatry 2023; 23:69. [PMID: 36698099 PMCID: PMC9875448 DOI: 10.1186/s12888-022-04514-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 12/30/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Genetic risks may predispose individuals to major mood disorders differently. This study investigated the gene polymorphisms of previously reported candidate genes for major depressive disorder (MDD) and bipolar disorder (BPD) in the Han Chinese population. METHODS Twenty loci of 13 candidate genes were detected by MALDI-TOF mass spectrometry in 439 patients with MDD, 600 patients with BPD, and 464 healthy controls. The distribution of genotypes in alleles, Hardy-Weinberg equilibrium, and genetic association were analyzed using the PLINK software. The linkage of disequilibrium and haplotype analyses were performed using the Haploview software. RESULTS Out of the 20 loci analyzed, CYP2C19-rs4986893, ABCB1-rs1045642, and SCN2A-rs17183814 passed Bonferroni correction; their statistical powers were > 55%. The minor allele frequencies (MAF) of CYP2C19-rs4986893 in the MDD group (0.0547) and BPD group (0.0533) were higher than that of the control group (0.0259, P < 0.05), leading to the odds ratios (ORs) of MDD (2.178) and BPD (2.122), respectively. In contrast, the lower MAFs of ABCB1-rs1045642 were observed in both MDD (0.3599, OR = 0.726) and BPD (0.3700, OR = 0.758) groups than controls (0.4364, P < 0.05). The MDD group had a higher MAF of SCN2A-rs17183814 than controls (0.1743 vs. 0.1207, OR = 1.538, P < 0.05). Moreover, a G-A haplotype composed by CYP2C19-rs4986893 and -rs4244285 was associated with BPD (OR = 1.361, P < 0.01), and the A-G haplotype increased the risks to both MDD (OR = 2.306, P < 0.01) and BPD (OR = 2.332, P < 0.001). The CYP2C19 intermediate metabolizer and poor metabolizer (IM&PM) status was related to the raised risk of both MDD (OR = 1.547, P < 0.01) and BPD (OR = 1.808, P < 0.001). CONCLUSION Our data indicate that the impaired CYP2C19 metabolism caused by the haplotypes integrated by CYP2C19 alleles might confer the risk to MDD and BPD, whereas the ABCB1-rs1045642 T allele serves as a protective factor.
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Affiliation(s)
- Ting Zhang
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingmin Rao
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Kangguang Lin
- grid.410737.60000 0000 8653 1072Affective Disorder Department, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongyin He
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jintai Cai
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mengxin Yang
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ying Xu
- grid.410737.60000 0000 8653 1072Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Le Hou
- grid.410737.60000 0000 8653 1072Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yulong Lin
- Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Haiying Liu
- Clinical Laboratory, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
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Investigation of the Serotonergic Activity and the Serotonin Content in Serum and Platelet, and the Possible Role of the Serotonin Transporter in Patients with Depression. Behav Sci (Basel) 2022; 12:bs12060178. [PMID: 35735388 PMCID: PMC9220674 DOI: 10.3390/bs12060178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 02/05/2023] Open
Abstract
According to the monoamine hypothesis, the development of depression is associated with dysfunctions of the serotonergic system. Alterations in the serotonin transporter gene (5-HTTLPR), the serotonergic activity in the brain, and the content of serotonin (5-HT) have been related to depression and were examined separately by previous studies. This study investigates these parameters in 89 depressed patients and 89 healthy participants. We investigated the serotonergic activity measured by the loudness dependence of auditory evoked potentials (LDAEP). In addition to the examination of the serotonin content (serum and platelet), enzyme-linked immunosorbent assays (ELISA) were used and 5-HTTLPR genotypes were analyzed. We observed a lower serotonin content in patients compared to healthy participants. Further, we noticed a correlation between anxiety and depression-associated symptoms with serotonergic activity. Patients treated with SSRI/SNRI showed decreased contents of serum serotonin compared to patients without any psychotropic medication or other psychotropic medications. Since the serotonergic activity, peripheral serotonin content, and 5-HTTLPR were unrelated, the results suggest independent alterations of central and peripheral serotonergic systems in depression. In line with this finding, serotonergic activity was related to anxiety and depression symptoms. Furthermore, the applied medication seems to influence serum serotonin content in patients with depression.
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Miozzo R, Eaton WW, Bienvenu OJ, Samuels J, Nestadt G. The serotonin transporter gene polymorphism (SLC6A4) and risk for psychiatric morbidity and comorbidity in the Baltimore ECA follow-up study. Compr Psychiatry 2020; 102:152199. [PMID: 32911381 PMCID: PMC8442947 DOI: 10.1016/j.comppsych.2020.152199] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 07/23/2020] [Accepted: 08/06/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The human serotonin transporter (SERT) gene polymorphism (5HTTLPR) has been associated with multiple psychiatric disorders, including major depression, anxiety disorders, and substance use disorders. This study investigated the association between 5HTTLPR and psychiatric morbidity and comorbidity in a psychiatrist-examined population sample. METHODS 628 participants, mean age 48.3 years old, were assessed by psychiatrists using the Schedules for Clinical Assessment in Neuropsychiatry. Associations between 5HTTLPR and the prevalence, comorbidity, and time-to-diagnoses for 16 psychiatric conditions were evaluated, using several analytical approaches. RESULTS The SERT S allele was significantly associated with an increased lifetime prevalence of panic disorder. There was a "protective" association between SERT gene S allele carrier status and the risk of obsessive-compulsive disorder (OCD) in time-to-event analysis. Carriers of the S allele had a significant increased risk of two specific comorbid disorder pairs: major depressive disorder (MDD) and social phobia, and MDD and agoraphobia. Overall, there was no increased risk of receiving an initial or an additional diagnosis for a mental disorder in the SERT S allele carriers CONCLUSIONS: The findings suggest that the S allele carrier status is associated with an increased prevalence of panic disorder in a community sample. There was an increased risk for comorbidity in a more homogeneous subgroup of cases with MDD and social phobia, as well as or agoraphobia. Our findings suggest a specific effect of the SERT promoter gene polymorphism on a subgroup of individuals identifiable by their comorbidity.
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Affiliation(s)
- Ruben Miozzo
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States of America; Graduate Training Program in Clinic Investigation, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States of America.
| | - William W Eaton
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine. Baltimore, MD 21205,Department of Mental Health, Johns Hopkins Bloomberg School of Public Health. Baltimore, MD 21205
| | - O Joseph Bienvenu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine. Baltimore, MD 21205,Graduate Training Program in Clinic Investigation, Johns Hopkins Bloomberg School of Public Health. Baltimore, MD 21205,Department of Mental Health, Johns Hopkins Bloomberg School of Public Health. Baltimore, MD 21205
| | - Jack Samuels
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine. Baltimore, MD 21205,Department of Mental Health, Johns Hopkins Bloomberg School of Public Health. Baltimore, MD 21205
| | - Gerald Nestadt
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine. Baltimore, MD 21205,Department of Mental Health, Johns Hopkins Bloomberg School of Public Health. Baltimore, MD 21205
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Tahmasebivand M, Soltani F, Kouti L, Izadpanah M. Frequency and risk factors of polypharmacy and drug interactions among patients in general intensive care unit of Golestan Hospital, Ahvaz, southwest of Iran. AIMS MEDICAL SCIENCE 2020. [DOI: 10.3934/medsci.2020006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Wu X, Ding M, Liu Y, Xia X, Xu FL, Yao J, Wang BJ. hsa-miR-3177-5p and hsa-miR-3178 Inhibit 5-HT1A Expression by Binding the 3'-UTR Region in vitro. Front Mol Neurosci 2019; 12:13. [PMID: 30766477 PMCID: PMC6365703 DOI: 10.3389/fnmol.2019.00013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 01/14/2019] [Indexed: 12/20/2022] Open
Abstract
Abnormal expression of the 5-HT1A receptor, which is encoded by the HTR1A gene, leads to susceptibilities to neuropsychiatric disorders such as depression, anxiety, and schizophrenia. miRNAs regulate gene expression by recognizing the 3'-UTR region of mRNA. This study evaluated the miRNAs that might identify and subsequently determine the regulatory mechanism of HTR1A gene. Using the HEK-293, U87, SK-N-SH and SH-SY5Y cell lines, we determined the functional sequence of the 3'-UTR region of the HTR1A gene and predicted miRNA binding. Dual luciferase reporter assay and Western Blot were used to confirm the effect of miRNA mimics and inhibitors on endogenous 5-HT1A receptors. In all cell lines, gene expression of the -17 bp to +443 bp fragment containing the complete sequence of the 3'-UTR region was significantly decreased, although mRNA quantification was not different. The +375 bp to +443 bp sequence, which exhibited the most significant change in relative chemiluminescence intensity, was recognized by hsa-miR-3177-5p and hsa-miR-3178. In HEK-293 and U87 cells, hsa-miR-3177-5p significantly inhibited the 5-HT1A receptor expression, while a hsa-miR-3178 inhibitor up-regulated HTR1A gene expression in SK-N-SH and SH-SY5Y cells. By constructing the pmirGLO-vector with the mutated HTR1A gene, we further confirmed that hsa-miR-3177-5p recognized the HTR1A gene tgtacaca at +377 bp to +384 bp, and the +392 bp to +399 bp fragment cgcgccca was identified by hsa-miR-3178. hsa-miR-3177-5p and hsa-miR-3178 had significant inhibitory effects on expression of the HTR1A gene and 5-HT1A receptor and may directly participate in the development of neuropsychiatric diseases.
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Affiliation(s)
- Xue Wu
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Mei Ding
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Yi Liu
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Xi Xia
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Feng-Ling Xu
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Jun Yao
- School of Forensic Medicine, China Medical University, Shenyang, China
| | - Bao-Jie Wang
- School of Forensic Medicine, China Medical University, Shenyang, China
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Kao WT, Chang CL, Lung FW. 5-HTT mRNA level as a potential biomarker of treatment response in patients with major depression in a clinical trial. J Affect Disord 2018; 238:597-608. [PMID: 29957477 DOI: 10.1016/j.jad.2018.06.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/12/2018] [Accepted: 06/14/2018] [Indexed: 02/09/2023]
Abstract
OBJECTIVES To investigate whether the serotonin transporter (5-HTT or SERT or SLC6A4) mRNA level could be used as a biomarker of treatment response in patients with major depression treated with different antidepressants while controlling related factors. METHODS One hundred and nineteen patients with major depression were recruited; all genotyped for the 5-HTT polymorphism concerning 5-HTTLPR, rs25531, and STin2 VNTR, provided demographic data and completed relevant questionnaires. Duloxetine and paroxetine were administered over 32 weeks to these patients. The Hamilton depression rating scale (HDRS) and 5-HTT mRNA level were evaluated at baseline (Week 0), and at 8, 16, 24 and 32 weeks. RESULTS Improvement in depressive symptoms (HDRS score declined) and increasing in 5-HTT mRNA level were found with longer duration of antidepressant treatment in patients with major depression. Patients with more 5-HTTPR long-form alleles and STin2.12 alleles had poor antidepressant treatment response. Duloxetine may give a better treatment response than paroxetine. Using structural equation modeling (SEM), the 5-HTTLPR long-form had a direct positive association with the 5-HTT mRNA level and an indirect adverse relationship with the 5-HTT mRNA level through neuroticism and previous suicide attempts. CONCLUSION The 5-HTT mRNA level increased and correlated with the treatment response (HDRS score improvement) under 32-weeks antidepressants treatment clinical trial. We speculate that the 5-HTT mRNA level may be used as a potential biomarker of antidepressant treatment response.
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Affiliation(s)
- Wei-Tsung Kao
- Laboratories of Medical Research, Center for Faculty Development and Education, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Chen-Lin Chang
- Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, Taiwan
| | - For-Wey Lung
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan; Calo Psychiatric Center, Pingtung County, Taiwan.
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Oo KZ, Aung YK, Jenkins MA, Win AK. Associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence: A systematic review and meta-analysis. Aust N Z J Psychiatry 2016; 50:842-57. [PMID: 26979101 DOI: 10.1177/0004867416637920] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE The neurotransmitter serotonin is understood to control mood and drug response. Carrying a genetic variant in the serotonin transporter gene (5HTT) may increase the risk of major depressive disorder and alcohol dependence. Previous estimates of the association of the S allele of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence have been inconsistent. METHODS For the systematic review, we used PubMed MEDLINE and Discovery of The University of Melbourne to search for all relevant case-control studies investigating the associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence. Summary odds ratios (OR) and their 95% confidence intervals (CI) were estimated. To investigate whether year of publication, study population or diagnostic criteria used were potential sources of heterogeneity, we performed meta-regression analyses. Publication bias was assessed using Funnel plots and Egger's statistical tests. RESULTS We included 23 studies of major depressive disorder without alcohol dependence containing 3392 cases and 5093 controls, and 11 studies of alcohol dependence without major depressive disorder containing 2079 cases and 2273 controls. The summary OR for homozygote carriers of the S allele of 5HTTLPR polymorphism compared with heterozygote and non-carriers combined (SS vs SL+LL genotype) was 1.33 (95% CI = [1.19, 1.48]) for major depressive disorder and 1.18 (95% CI = [1.01, 1.38]) for alcohol dependence. The summary OR per S allele of 5HTTLPR polymorphism was 1.16 (95% CI = [1.08, 1.23]) for major depressive disorder and 1.12 (95% CI = [1.01, 1.23]) for alcohol dependence. Meta-regression models showed that the associations did not substantially change after adjusting for year of publication, study population and diagnostic criteria used. There was no evidence for publication bias of the studies included in our meta-analysis. CONCLUSIONS Our meta-analysis confirms that individuals with the homozygous S allele of 5HTTLPR polymorphism are at increased risks of major depressive disorder as well as alcohol dependence. Further studies are required to investigate the association between 5HTTLPR polymorphism and the comorbidity of major depressive disorder and alcohol dependence as well as gene × environmental interactions.
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Affiliation(s)
- Khine Zin Oo
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia The Park-Centre for Mental Health, Treatment, Research and Education, Wacol, QLD, Australia
| | - Ye Kyaw Aung
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia
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Lopizzo N, Bocchio Chiavetto L, Cattane N, Plazzotta G, Tarazi FI, Pariante CM, Riva MA, Cattaneo A. Gene-environment interaction in major depression: focus on experience-dependent biological systems. Front Psychiatry 2015; 6:68. [PMID: 26005424 PMCID: PMC4424810 DOI: 10.3389/fpsyt.2015.00068] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 04/21/2015] [Indexed: 12/27/2022] Open
Abstract
Major depressive disorder (MDD) is a multifactorial and polygenic disorder, where multiple and partially overlapping sets of susceptibility genes interact each other and with the environment, predisposing individuals to the development of the illness. Thus, MDD results from a complex interplay of vulnerability genes and environmental factors that act cumulatively throughout individual's lifetime. Among these environmental factors, stressful life experiences, especially those occurring early in life, have been suggested to exert a crucial impact on brain development, leading to permanent functional changes that may contribute to lifelong risk for mental health outcomes. In this review, we will discuss how genetic variants (polymorphisms, SNPs) within genes operating in neurobiological systems that mediate stress response and synaptic plasticity, can impact, by themselves, the vulnerability risk for MDD; we will also consider how this MDD risk can be further modulated when gene × environment interaction is taken into account. Finally, we will discuss the role of epigenetic mechanisms, and in particular of DNA methylation and miRNAs expression changes, in mediating the effect of the stress on the vulnerability risk to develop MDD. Taken together, we aim to underlie the role of genetic and epigenetic processes involved in stress- and neuroplasticity-related biological systems on the development of MDD after exposure to early life stress, thereby building the basis for future research and clinical interventions.
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Affiliation(s)
- Nicola Lopizzo
- IRCCS Fatebenefratelli San Giovanni di Dio , Brescia , Italy
| | - Luisella Bocchio Chiavetto
- IRCCS Fatebenefratelli San Giovanni di Dio , Brescia , Italy ; Faculty of Psychology, eCampus University , Novedrate, Como , Italy
| | - Nadia Cattane
- IRCCS Fatebenefratelli San Giovanni di Dio , Brescia , Italy
| | - Giona Plazzotta
- IRCCS Fatebenefratelli San Giovanni di Dio , Brescia , Italy
| | - Frank I Tarazi
- Department of Psychiatry and Neuroscience Program, McLean Hospital, Harvard Medical School , Belmont, MA , USA
| | - Carmine M Pariante
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London , London , UK
| | - Marco A Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan , Milan , Italy
| | - Annamaria Cattaneo
- IRCCS Fatebenefratelli San Giovanni di Dio , Brescia , Italy ; Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London , London , UK
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10
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Prediction of major depression in adolescents using an optimized multi-channel weighted speech classification system. Biomed Signal Process Control 2014. [DOI: 10.1016/j.bspc.2014.08.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Gillings MR. Were there evolutionary advantages to premenstrual syndrome? Evol Appl 2014; 7:897-904. [PMID: 25469168 PMCID: PMC4211719 DOI: 10.1111/eva.12190] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/01/2014] [Indexed: 01/24/2023] Open
Abstract
Premenstrual syndrome (PMS) affects up to 80% of women, often leading to significant personal, social and economic costs. When apparently maladaptive states are widespread, they sometimes confer a hidden advantage, or did so in our evolutionary past. We suggest that PMS had a selective advantage because it increased the chance that infertile pair bonds would dissolve, thus improving the reproductive outcomes of women in such partnerships. We confirm predictions arising from the hypothesis: PMS has high heritability; gene variants associated with PMS can be identified; animosity exhibited during PMS is preferentially directed at current partners; and behaviours exhibited during PMS may increase the chance of finding a new partner. Under this view, the prevalence of PMS might result from genes and behaviours that are adaptive in some societies, but are potentially less appropriate in modern cultures. Understanding this evolutionary mismatch might help depathologize PMS, and suggests solutions, including the choice to use cycle-stopping contraception.
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Affiliation(s)
- Michael R Gillings
- Department of Biological Sciences, Macquarie University Sydney, NSW, Australia
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12
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5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus. Brain Struct Funct 2014; 220:2373-85. [DOI: 10.1007/s00429-014-0782-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 04/15/2014] [Indexed: 12/16/2022]
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13
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Peñas-LLedó EM, LLerena A. CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics-guided clinical trials. Br J Clin Pharmacol 2014; 77:673-83. [PMID: 24033670 PMCID: PMC3971983 DOI: 10.1111/bcp.12227] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Accepted: 08/11/2013] [Indexed: 12/16/2022] Open
Abstract
Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under- or over-representation of certain CYP2D6 metabolic groups.
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Affiliation(s)
- Eva M Peñas-LLedó
- CICAB Clinical Research Centre, Extremadura University Hospital and Medical SchoolBadajoz
| | - Adrián LLerena
- CICAB Clinical Research Centre, Extremadura University Hospital and Medical SchoolBadajoz
- CIBERSAM, ISCIIIMadrid, Spain
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Williams MS. Platelets and depression in cardiovascular disease: A brief review of the current literature. World J Psychiatry 2012; 2:114-23. [PMID: 24175177 PMCID: PMC3782186 DOI: 10.5498/wjp.v2.i6.114] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 09/19/2012] [Accepted: 11/17/2012] [Indexed: 02/05/2023] Open
Abstract
Major depression is an independent risk factor for cardiovascular mortality and morbidity. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Several mechanisms have been proposed including increased platelet reactivity. This review focuses on the current literature that examines the platelet hypothesis of depression. To date studies show increased serotonin response, increased platelet serotonin receptor density, decreased serotonin transporter binding, and decreased platelet serotonin levels in individuals with depression. However other studies have shown no change in serotonin uptake. In addition to platelet serotonin specific pathways, other platelet pathways that have shown significant changes in depressed individuals include blunting of the platelet adenosine response, increased platelet thrombin response, increased glycoprotein Ib expression, increased P-selectin, β thromboglobulin, and platelet factor four, as well as decreased platelet brain derived neurotrophic factor. However there are other studies that show conflicting evidence of increased platelet activation as measured by integrin receptor α2bβ3. Other conflicting data include α adrenergic density and platelet response to augmented serotonin. The direction of future research in platelet functional changes in depression and coronary artery disease should continue to focus on serotonin specific pathways with emphasis on potential mechanisms of specific pathway changes.
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Affiliation(s)
- Marlene S Williams
- Marlene S Williams, Division of Cardiology, Johns Hopkins Bayview Medical Center, The Johns Hopkins University, Baltimore, MD 21224, United States
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15
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Ooi KEB, Lech M, Allen NB. Multichannel weighted speech classification system for prediction of major depression in adolescents. IEEE Trans Biomed Eng 2012. [PMID: 23192475 DOI: 10.1109/tbme.2012.2228646] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Early identification of adolescents at high imminent risk for clinical depression could significantly reduce the burden of the disease. This study demonstrated that acoustic speech analysis and classification can be used to determine early signs of major depression in adolescents, up to two years before they meet clinical diagnostic criteria for the full-blown disorder. Individual contributions of four different types of acoustic parameters [prosodic, glottal, Teager's energy operator (TEO), and spectral] to depression-related changes of speech characteristics were examined. A new computational methodology for the early prediction of depression in adolescents was developed and tested. The novel aspect of this methodology is in the introduction of multichannel classification with a weighted decision procedure. It was observed that single-channel classification was effective in predicting depression with a desirable specificity-to-sensitivity ratio and accuracy higher than chance level only when using glottal or prosodic features. The best prediction performance was achieved with the new multichannel method, which used four features (prosodic, glottal, TEO, and spectral). In the case of the person-based approach with two sets of weights, the new multichannel method provided a high accuracy level of 73% and the sensitivity-to-specificity ratio of 79%/67% for predicting future depression.
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Affiliation(s)
- Kuan Ee Brian Ooi
- School of Electrical and Computer Engineering, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
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16
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Luddington NS, Mandadapu A, Husk M, El-Mallakh RS. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. PRIMARY CARE COMPANION TO THE JOURNAL OF CLINICAL PSYCHIATRY 2012; 11:93-102. [PMID: 19617941 DOI: 10.4088/pcc.08r00656] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Accepted: 07/17/2008] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To determine the state of the art in understanding the role of genetic variation in the serotonin transporter (5-HTT) promoter region (5-HTTLPR) in the development of a depressive episode and in its response to treatment. DATA SOURCES PubMed and Ovid were used to search for articles published prior to December 2007 utilizing the key words serotonin transporter, 5-HTT, 5-HTTLPR, serotonin transporter gene, and SLC6A4. STUDY SELECTION All studies were reviewed, but case reports and small case series were excluded. DATA EXTRACTION All relevant articles were read by at least 2 of the coauthors and notes regarding study design, measures, data analysis, and findings were later used to construct the review. DATA SYNTHESIS A common genetic variant, the short allele, in which 44 base pairs are missing from the promoter of SLC6A4, is associated with a greater risk for developing a major depressive disorder in patients following exposure to adversity. This association appears to be most important in the early stages of the depressive disorder. Additionally, the likelihood of a positive response to antidepressant treatment may be reduced in these patients in terms of delayed response, greater adverse event load, or, in bipolar patients, mania induction and rapid cycling. CONCLUSIONS Selected genetic testing of patients with a recent history of significant adversity may be a reasonable tool that can enlighten treatment options and the course of illness. Ongoing work with the short allele of 5-HTT may also inform clinical guidelines of long-term treatment with antidepressants.
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Affiliation(s)
- Nicole S Luddington
- Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Kentucky, USA
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17
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5-HTTLPR polymorphism impacts task-evoked and resting-state activities of the amygdala in Han Chinese. PLoS One 2012; 7:e36513. [PMID: 22574175 PMCID: PMC3344896 DOI: 10.1371/journal.pone.0036513] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Accepted: 04/02/2012] [Indexed: 12/03/2022] Open
Abstract
Background Prior research has shown that the amygdala of carriers of the short allele (s) of the serotonin transporter (5-HTT) gene (5-HTTLPR) have a larger response to negative emotional stimuli and higher spontaneous activity during the resting state than non-carriers. However, recent studies have suggested that the effects of 5-HTTLPR may be specific to different ethnic groups. Few studies have been conducted to address this issue. Methodology/Principal Findings Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted on thirty-eight healthy Han Chinese subjects (l/l group, n = 19; s/s group, n = 19) during the resting state and during an emotional processing task. Compared with the s/s group, the l/l group showed significantly increased regional homogeneity or local synchronization in the right amygdala during the resting state (|t|>2.028, p<0.05, corrected), but no significant difference was found in the bilateral amygdala in response to negative stimuli in the emotional processing task. Conclusions/Significance 5-HTTLPR can alter the spontaneous activity of the amygdala in Han Chinese. However, the effect of 5-HTTLPR on the amygdala both in task state and resting state in Asian population was no similar with Caucasians. They suggest that the effect of 5-HTTLPR on the amygdala may be modulated by ethnic differences.
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18
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Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D, van Veen T, Willemsen G, DeRijk RH, de Geus EJ, Hoogendijk WJ, Sullivan PF, Penninx BW, Boomsma DI, Snieder H, Nolen WA. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 2011; 16:516-32. [PMID: 20351714 DOI: 10.1038/mp.2010.38] [Citation(s) in RCA: 205] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.
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Affiliation(s)
- F J Bosker
- Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Marin MF, Lord C, Andrews J, Juster RP, Sindi S, Arsenault-Lapierre G, Fiocco AJ, Lupien SJ. Chronic stress, cognitive functioning and mental health. Neurobiol Learn Mem 2011; 96:583-95. [PMID: 21376129 DOI: 10.1016/j.nlm.2011.02.016] [Citation(s) in RCA: 347] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Revised: 02/05/2011] [Accepted: 02/22/2011] [Indexed: 01/18/2023]
Abstract
This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimer's Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition.
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Affiliation(s)
- Marie-France Marin
- Center for Studies on Human Stress, Fernand-Seguin Research Center, Louis-H. Lafontaine Hospital, Canada
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20
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Clarke H, Flint J, Attwood AS, Munafò MR. Association of the 5- HTTLPR genotype and unipolar depression: a meta-analysis. Psychol Med 2010; 40:1767-1778. [PMID: 20380781 DOI: 10.1017/s0033291710000516] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND We sought to ascertain the strength of evidence for association between the 5-HTTLPR polymorphism and unipolar depression. METHOD We applied meta-analytic techniques to data from relevant published studies, and obtained an estimate of the likely magnitude of effect of any association. We also tested for possible publication bias, and explored the impact of various study design characteristics on the magnitude of the observed effect size. RESULTS Meta-analysis indicated evidence of a small but statistically significant association between the 5-HTTLPR polymorphism and unipolar depression [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03-1.12]. This remained significant when data from samples of European and East Asian ancestry were analyzed separately. In all cases there was evidence of significant between-study heterogeneity, although the observed associations were robust to the application of a random-effects framework. CONCLUSIONS Our results support the presence of a small effect of a polymorphism in the serotonin transporter promoter on susceptibility to depression. However, we caution that it is possible that the effect has an artifactual basis, rather than a biological origin.
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Affiliation(s)
- H Clarke
- Department of Experimental Psychology, University of Bristol, UK
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21
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Magnay JL, El-Shourbagy M, Fryer AA, O'Brien S, Ismail KM. Analysis of the serotonin transporter promoter rs25531 polymorphism in premenstrual dysphoric disorder. Am J Obstet Gynecol 2010; 203:181.e1-5. [PMID: 20462563 DOI: 10.1016/j.ajog.2010.02.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Revised: 11/16/2009] [Accepted: 02/16/2010] [Indexed: 11/27/2022]
Abstract
OBJECTIVE The objective of this study was to investigate whether the functional rs25531 promoter polymorphism in the serotonin transporter gene is associated with premenstrual dysphoric disorder. STUDY DESIGN The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27-46 years; mean, 37.7 years) and 52 healthy control subjects (age range, 22-48 years; mean, 36.2 years). The rs25531 polymorphism was genotyped in both groups. Because of its close proximity to rs25531, the 5-HTTLPR promoter polymorphism was also genotyped. Genotype and allele frequencies for rs25531 and for the composite 5-HTTLPR/rs25531 marker were analyzed by chi(2) test. RESULTS There was no significant association between any genotype and clinical category and no significant allele distribution profiles for rs25531 or 5-HTTLPR/rs25531 in either the premenstrual dysphoric disorder or the control groups. CONCLUSION These findings do not support a major role for rs25531, either in isolation or combined with 5-HTTLPR, in contributing to susceptibility to premenstrual dysphoria.
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22
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Association between major depressive disorder and a functional polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: a meta-analysis. Psychiatr Genet 2010; 20:49-58. [DOI: 10.1097/ypg.0b013e328335112b] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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23
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Hammoud DA, Endres CJ, Hammond E, Uzuner O, Brown A, Nath A, Kaplin AI, Pomper MG. Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV. Neuroimage 2009; 49:2588-95. [PMID: 19853044 DOI: 10.1016/j.neuroimage.2009.10.037] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Revised: 09/10/2009] [Accepted: 10/13/2009] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Site-selective imaging can provide significant insight into the mechanism of HIV-associated neurological disease. The goal of this study was to evaluate the involvement of serotonergic transmission in HIV-associated depression using [(11)C]DASB, a serotonin transporter (5-HTT)-specific radiopharmaceutical for positron emission tomography (PET). METHODS Nine depressed HIV+ subjects (HIV-D), 9 non-depressed HIV+ subjects (HIV-ND) and 7 healthy controls (HC) underwent an MRI scan and a [(11)C]DASB-PET scan. The outcome measure was 5-HTT binding potential normalized to non-displaceable tissue radioligand (BP(ND)). RESULTS HIV-ND subjects had lower mean regional 5-HTT BP(ND) estimates across regions compared to HC, while HIV-D subjects demonstrated higher mean regional binding values than HIV-ND subjects in most regions. Prior to correction for the false discovery rate, HIV-ND had significantly lower BP(ND) values compared to HC subjects in two regions (insula and anterior cingulate) and all HIV+ patients had significantly lower binding than HC in all regions except for the midbrain, thalamus and pons. After correction for the false discovery rate, only the insula showed significantly lower binding in HIV+ subjects compared to HC (P<0.0045). Despite a significant difference in the duration of illness between the HIV-D and HIV-ND groups, there was no definite correlation between the duration of illness and BP(ND). CONCLUSION Lower [(11)C]DASB binding in HIV+ patients compared to HC may reflect serotonergic neuronal loss as a component of generalized HIV-associated neurodegeneration. Higher mean regional BP(ND) values in HIV-D compared to HIV-ND subjects could reflect increased density of 5-HTT, leading to increased clearance of serotonin from the synapse, which could account, in part, for symptoms of depression. The lack of correlation between duration of illness and binding argues against these findings being the result of differential neurodegeneration only. Our findings suggest a possible role for dysregulated serotonergic transmission in HIV-associated depression.
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Affiliation(s)
- Dima A Hammoud
- Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, Bethesda, MD, USA
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24
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DiNunzio JC, Williams RO. CNS disorders--current treatment options and the prospects for advanced therapies. Drug Dev Ind Pharm 2009; 34:1141-67. [PMID: 18720140 DOI: 10.1080/03639040802020536] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The development of new pharmaceutical products has successfully addressed a multitude of disease states; however, new product development for treating disorders of the central nervous system (CNS) has lagged behind other therapeutic areas. This is due to several factors including the complexity of the diseases and the lack of technologies for delivery through the blood-brain barrier (BBB). This article examines the current state of six major CNS disease states: depression, epilepsy, multiple sclerosis (MS), neurodegenerative diseases (specifically Alzheimer's disease [AD]), neuropathic pain, and schizophrenia. Discussion topics include analysis of the biological mechanisms underlying each disease, currently approved products, and available animal models for development of new therapeutic agents. Analysis of currently approved therapies shows that all products depend on the molecular properties of the drug or prodrug to penetrate the BBB. Novel technologies, capable of enhancing BBB permeation, are also discussed relative to improving CNS therapies for these disease states.
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Affiliation(s)
- James C DiNunzio
- Division of Pharmaceutics, The University of Texas at Austin, Austin, TX 78712, USA.
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25
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Grossman I. ADME pharmacogenetics: current practices and future outlook. Expert Opin Drug Metab Toxicol 2009; 5:449-62. [DOI: 10.1517/17425250902902322] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Kiyohara C, Yoshimasu K. Molecular epidemiology of major depressive disorder. Environ Health Prev Med 2009; 14:71-87. [PMID: 19568851 DOI: 10.1007/s12199-008-0073-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2008] [Accepted: 12/16/2008] [Indexed: 11/26/2022] Open
Abstract
Major depressive disorder causes significant morbidity, affecting people's ability to work, function in relationships, and engage in social activities. Moreover, major depressive disorder increases the risk of suicidal ideation, attempted suicide and death by completed suicide. There is evidence that chronic stress can cause major depressive disorder. As for genetic factors, only minor susceptibility genes have been reliably identified. The serotonin system provides a logical source of susceptibility genes for depression, because this system is the target of selective serotonin reuptake-inhibitor drugs that are effective in treating depression. The 5-hydroxytryptamine (serotonin) transporter (5-HTT) has received particular attention because it is involved in the reuptake of serotonin at brain synapses. One common polymorphic variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which affects the promoter of the 5-HTT gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. The authors discussed the relationship between genetic polymorphisms and major depressive disorder, with special emphasis on the 5-HTTTLPR polymorphism. As the 5-HTTLPR polymorphism was significantly associated with an increased risk of major depressive disorder, the 5-HTT gene may be a candidate for a major depressive disorder susceptibility gene. As major depressive disorder is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for major depressive disorder. Hopefully, in the future we will be able to screen for major depressive disorder susceptibility by using specific biomarkers.
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Affiliation(s)
- Chikako Kiyohara
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan,
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The comparative distributions of the monoamine transporters in the rodent, monkey, and human amygdala. Brain Struct Funct 2008; 213:73-91. [PMID: 18283492 PMCID: PMC9741847 DOI: 10.1007/s00429-008-0176-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2007] [Accepted: 01/31/2008] [Indexed: 12/14/2022]
Abstract
The monoamines in the amygdala modulate multiple aspects of emotional processing in the mammalian brain, and organic or pharmacological dysregulation of these systems can result in affective pathologies. Knowledge of the normal distribution of these neurotransmitters, therefore, is central to our understanding of both the normal processes regulated by the amygdala and the pathological conditions associated with monoaminergic dysregulation. The monoaminergic transporters have proven to be accurate and reliable markers of the distributions of their substrates. The purpose of this review was twofold: First, to briefly recount the functional relevance of dopamine, serotonin, and norepinephrine transmission in the amygdala, and second, to describe and compare the distributions of the monoamine transporters in the rodent, monkey, and human brain. The transporters were found to be heterogeneously distributed in the amygdala. The dopamine transporter (DAT) is consistently found to be extremely sparsely distributed, however the various accounts of its subregional topography are inconsistent, making any cross-species comparisons difficult. The serotonin transporter (SERT) had the greatest overall degree of labeling of the three markers, and was characterized by substantial inter-species variability in its relative distribution. The norepinephrine transporter (NET) was shown to possess an intermediate level of labeling, and like the SERT, its distribution is not consistent across the three species. The results of these comparisons indicate that caution should be exercised when using animal models to investigate the complex processes modulated by the monoamines in the amygdala, as their relative contributions to these functions may differ across species.
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Surendiran A, Pradhan S, Adithan C. Role of pharmacogenomics in drug discovery and development. Indian J Pharmacol 2008; 40:137-43. [PMID: 20040945 PMCID: PMC2792612 DOI: 10.4103/0253-7613.43158] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Revised: 05/13/2008] [Accepted: 08/22/2008] [Indexed: 11/24/2022] Open
Abstract
Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of drug development and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and efficacy, have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for pharmacogenomic studies, where the effects of multiple genes are assessed with the study of entire genome.Pharmacogenetic studies can be used at various stages of drug development. The effect of drug target polymorphisms on drug response can be assessed and identified. In clinical studies, pharmacogenetic tests can be used for stratification of patients based on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical trials. This can also reduce attrition of drug compounds. Further, the variations in drug response can be better studied with the wider application of pharmacogenomic methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.
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Affiliation(s)
- A. Surendiran
- Department of Pharmacology, JIPMER, Puducherry, India
| | - S.C. Pradhan
- Department of Pharmacology, JIPMER, Puducherry, India
| | - C. Adithan
- Department of Pharmacology, JIPMER, Puducherry, India
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