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Hatoum AS, Gorelik AJ, Blaydon L, Huggett SB, Chi T, Baranger DAA, Miller AP, Johnson EC, Agrawal A, Bogdan R. Psychiatric genome-wide association study enrichment shows promise for future psychopharmaceutical discoveries. COMMUNICATIONS MEDICINE 2025; 5:176. [PMID: 40379965 PMCID: PMC12084526 DOI: 10.1038/s43856-025-00877-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/22/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Innovation in psychiatric therapeutics has stagnated on known mechanisms. Psychiatric genome-wide association studies (GWAS) have identified hundreds of genome-wide significant (GWS) loci that have rapidly advanced our understanding of disease etiology. However, whether these results can be leveraged to improve clinical treatment for specific psychiatric disorders remains poorly understood. METHODS In this proof-of-principal evaluation of GWAS clinical utility, we test whether the targets of drugs used to treat Attention Deficit Hyperactivity Disorder (ADHD), Bipolar Disorder (BiP), Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), Schizophrenia (SCZ), Substance Use Disorders (SUDs), and insomnia (INS), are enriched for GWAS meta-analysis findings. RESULTS The genes coding for treatment targets of medications used to SCZ, BiP, MDD, and SUDs (but not ADHD, PTSD, GAD, or INSOM) are enriched for GWS loci identified in their respective GWAS (ORs: 2.78-27.63; all ps <1.15e-3). Enrichment is largely driven by the presence of a GWS locus or loci within a gene coding for a drug target (i.e., proximity matching). Broadly, additional annotation (i.e., functional: Combined Annotation Dependent Depletion [CADD] scores, regulomeDB scores, eQTL, chromatin loop, and gene region; statistical: effect size of genome-wide significant SNPs; Z-score of SNPs; number of drug targets implicated by GWAS), with the exception of weighting by the largest SNP effect size, does not further improve enrichment across disorders. Evaluation of prior smaller GWAS reveal that more recent larger GWAS improve enrichment. CONCLUSIONS GWAS results may assist in the prioritization of medications for future psychopharmaceutical research.
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Affiliation(s)
- Alexander S Hatoum
- Washington University in St. Louis, Department of Psychological & Brain Sciences, St. Louis, MO, USA.
- Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA.
- Washington University School of Medicine, AI and Health Institute, St. Louis, MO, USA.
| | - Aaron J Gorelik
- Washington University in St. Louis, Department of Psychological & Brain Sciences, St. Louis, MO, USA
| | - Lauren Blaydon
- Washington University in St. Louis, Department of Psychological & Brain Sciences, St. Louis, MO, USA
| | | | - Tingying Chi
- St. Louis Behavioral Medicine Institute, St. Louis, WA, USA
| | - David A A Baranger
- Washington University in St. Louis, Department of Psychological & Brain Sciences, St. Louis, MO, USA
- Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
| | - Alex P Miller
- Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
- Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN, USA
| | - Emma C Johnson
- Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
| | - Arpana Agrawal
- Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
- Washington University School of Medicine, AI and Health Institute, St. Louis, MO, USA
| | - Ryan Bogdan
- Washington University in St. Louis, Department of Psychological & Brain Sciences, St. Louis, MO, USA
- Washington University School of Medicine, AI and Health Institute, St. Louis, MO, USA
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Briganti G, Lechien JR. Voice Quality as Digital Biomarker in Bipolar Disorder: A Systematic Review. J Voice 2025:S0892-1997(25)00004-9. [PMID: 39818493 DOI: 10.1016/j.jvoice.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/18/2025]
Abstract
BACKGROUND Voice analysis has emerged as a potential biomarker for mood state detection and monitoring in bipolar disorder (BD). The systematic review aimed to summarize the evidence for voice analysis applications in BD, examining (1) the predictive validity of voice quality outcomes for mood state detection, and (2) the correlation between voice parameters and clinical symptom scales. METHODS A PubMed, Scopus, and Cochrane Library search was carried out by two investigators for publications investigating voice quality in BD according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements. Studies were assessed using the modified methodological index for non-randomized studies (MINORS). RESULTS Of the 400 identified publications, 16 studies met the inclusion accounting for 575 BD patients. Machine learning approaches were implemented in 87.5% of studies, with classification accuracies ranging from 70.9% to 96.9%. Manic state detection showed the strongest predictive validity [area under the curve (AUC) up to 0.89], while depression detection demonstrated moderate performance (AUC: 0.66-0.78). Individual-specific models outperformed population-level approaches (correlation coefficients: 0.78 versus 0.44). Voice quality showed significant correlations with standardized clinical scales, particularly Young Mania Rating Scale and Hamilton Depression Rating Scale (normalized root mean square errors: 1.985 and 3.945, respectively). Prosodic features were examined in 81.25% of studies, with pitch consistently elevated during manic episodes. MINORS varied from 10 to 14, with notable limitations in sample size calculations and blinding procedures. CONCLUSIONS Voice quality is a promising biomarker in BD, particularly for manic state detection and individualized monitoring. While controlled settings showed strong performance, naturalistic applications yielded more modest results. Future research should focus on standardizing protocols across different environments and conducting large-scale longitudinal studies with robust methodological controls.
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Affiliation(s)
- Giovanni Briganti
- Unit of Computational Medicine and Neuropsychiatry, Faculty of Medicine, Pharmacy and Biomedical Sciences, University of Mons (UMONS), Mons, Belgium; Department of Clinical Sciences, Faculty of Medicine, University of Liège, Liège, Belgium; Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Jérôme R Lechien
- Department of Surgery, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMons), Mons, Belgium; Division of Laryngology and Bronchoesophagology, Department of Otolaryngology Head Neck Surgery, EpiCURA Hospital, Baudour, Belgium; Department of Otolaryngology-Head and Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Paris, France; Department of Otolaryngology, Elsan Hospital, Paris, France.
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Zinellu A, Tommasi S, Sedda S, Mangoni AA. Arginine metabolomics in mood disorders. Heliyon 2024; 10:e27292. [PMID: 38515671 PMCID: PMC10955251 DOI: 10.1016/j.heliyon.2024.e27292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 02/12/2024] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
Alterations of nitric oxide (NO) homeostasis have been described in mood disorders. However, the analytical challenges associated with the direct measurement of NO have prompted the search for alternative biomarkers of NO synthesis. We investigated the published evidence of the association between these alternative biomarkers and mood disorders (depressive disorder or bipolar disorder). Electronic databases were searched from inception to the June 30, 2023. In 20 studies, there was a trend towards significantly higher asymmetric dimethylarginine (ADMA) in mood disorders vs. controls (p = 0.072), and non-significant differences in arginine (p = 0.29), citrulline (p = 0.35), symmetric dimethylarginine (SDMA; p = 0.23), and ornithine (p = 0.42). In subgroup analyses, the SMD for ADMA was significant in bipolar disorder (p < 0.001) and European studies (p = 0.02), the SMDs for SDMA (p = 0.001) and citrulline (p = 0.038) in European studies, and the SMD for ornithine in bipolar disorder (p = 0.007), Asian (p = 0.001) and American studies (p = 0.005), and patients treated with antidepressants (p = 0.029). The abnormal concentrations of ADMA, SDMA, citrulline, and ornithine in subgroups of mood disorders, particularly bipolar disorder, warrant further research to unravel their pathophysiological role and identify novel treatments in this group (The protocol was registered in PROSPERO: CRD42023445962).
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Affiliation(s)
- Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Sara Tommasi
- Department of Clinical Pharmacology, Southern Adelaide Local Health Network, Australia
- Discipline of Clinical Pharmacology, Flinders University, Adelaide, Australia
| | - Stefania Sedda
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Arduino A. Mangoni
- Department of Clinical Pharmacology, Southern Adelaide Local Health Network, Australia
- Discipline of Clinical Pharmacology, Flinders University, Adelaide, Australia
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Gonzalez-Torres C, Mulsant BH, Husain MI, Alda M, Young RC, Ortiz A. Challenges in defining treatment-resistant mania in adults: A systematic review. Bipolar Disord 2024; 26:7-21. [PMID: 37963496 PMCID: PMC10922285 DOI: 10.1111/bdi.13383] [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] [Indexed: 11/16/2023]
Abstract
OBJECTIVES To review the definitions of treatment-resistant mania (TRM) in the literature and propose criteria for an operationalized definition. METHODS A systematic search of five databases (MEDLINE, EMBASE, PsychInfo, Cochrane Central, and CINAHL) and data extraction of eligible articles. RESULTS In total, 47 articles addressing the concept of TRM were included, comprising 16 case reports, 11 case series, 3 randomized clinical trials, 8 open-label clinical trials, 1 experimental study, 7 narrative reviews, and 1 systematic review. While reviews discussed several challenges in defining TRM, definitions varied substantially based on different criteria for severity of mania, duration of mania, and use of specific therapeutic agents with minimal dosages and duration of treatment. Only a handful of the reviewed articles operationalized these criteria. CONCLUSION While the concept of TRM has been discussed in the literature for over three decades, we could not find an agreed-upon operationalized definition based on specific criteria. We propose and discuss a possible definition that could be used by clinicians to guide their practice and by researchers to assess the prevalence of TRM and develop and test interventions targeting TRM.
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Affiliation(s)
- Christina Gonzalez-Torres
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Benoit H. Mulsant
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - M. Ishrat Husain
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Martin Alda
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
- National Institute of Mental Health, Klecany, Czech Republic
| | - Robert C. Young
- Department of Psychiatry, Weil Cornell Medicine, New York, New York, US
| | - Abigail Ortiz
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Daniels SD, Boison D. Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence. Neuropharmacology 2023; 241:109756. [PMID: 37820933 PMCID: PMC10841508 DOI: 10.1016/j.neuropharm.2023.109756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 09/25/2023] [Accepted: 10/07/2023] [Indexed: 10/13/2023]
Abstract
Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms of several antimanic and antiseizure therapies including lithium, valproate, carbamazepine, and ECT suggest a fundamental pathogenic role of adenosine deficit in bipolar mania to match the established role of adenosine deficit in epilepsy. The depletion of adenosine-derivatives within the purine cycle is expected to result in a compensatory increase in oxopurines (uric acid precursors) and secondarily increased uric acid, observed in both bipolar mania and epilepsy. Cortisol-based inhibition of purine conversion to adenosine-derivatives may be reflected in observed uric acid increases and the well-established contribution of cortisol to both bipolar mania and epilepsy pathology. Cortisol-inhibited conversion from IMP to AMP as precursor of both ATP and adenosine may represent a mechanism for treatment resistance common in both bipolar mania and epilepsy. Anti-cortisol therapies may therefore augment other treatments both in bipolar mania and epilepsy. Evidence linking (i) adenosine deficit with a decreased need for sleep, (ii) IMP/cGMP excess with compulsive hypersexuality, and (iii) guanosine excess with grandiose delusions may converge to suggest a novel theory of bipolar mania as a condition characterized by disrupted purine metabolism. The potential for disease-modification and prevention related to adenosine-mediated epigenetic changes in epilepsy may be mirrored in mania. Evaluating the purinergic effects of existing agents and validating purine dysregulation may improve diagnosis and treatment in bipolar mania and epilepsy and provide specific targets for drug development.
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Affiliation(s)
- Scott D Daniels
- Hutchings Psychiatric Center, New York State Office of Mental Health, Syracuse, NY, 13210, USA
| | - Detlev Boison
- Dept. of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA.
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Aliphon B, Dai T, Moretti J, Penrose-Menz M, Mulders WHAM, Blache D, Rodger J. A repeated measures cognitive affective bias test in rats: comparison with forced swim test. Psychopharmacology (Berl) 2023; 240:2257-2270. [PMID: 36450831 DOI: 10.1007/s00213-022-06281-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 11/17/2022] [Indexed: 12/05/2022]
Abstract
RATIONALE There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. OBJECTIVES This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. METHODS Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4 weeks with no intervention, or for 2 weeks of chronic restraint stress (CRS), followed by 2 weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. RESULTS In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2 weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. CONCLUSIONS Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders.
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Affiliation(s)
- Benjamin Aliphon
- School of Biological Sciences, University of Western Australia, Crawley, Australia
- School of Human Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia
| | - Twain Dai
- School of Biological Sciences, University of Western Australia, Crawley, Australia
| | - Jessica Moretti
- School of Biological Sciences, University of Western Australia, Crawley, Australia
- Perron Institute for Neurological and Translational Sciences, University of Western Australia, Nedlands, Australia
| | - Marissa Penrose-Menz
- School of Biological Sciences, University of Western Australia, Crawley, Australia
| | - Wilhelmina H A M Mulders
- School of Human Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia
| | - Dominique Blache
- School of Agriculture and Environment, Institute of Agriculture, University of Western Australia, Crawley, Australia
| | - Jennifer Rodger
- School of Biological Sciences, University of Western Australia, Crawley, Australia.
- Perron Institute for Neurological and Translational Sciences, University of Western Australia, Nedlands, Australia.
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7
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Gałuszko-Wȩgielnik M, Jakuszkowiak-Wojten K, Wiglusz MS, Cubała WJ, Pastuszak M. Central nervous system-related safety and tolerability of add-on ketamine to standard of care treatment in treatment-resistant psychotic depression in patients with major depressive disorder and bipolar disorder. Front Neurosci 2023; 17:1214972. [PMID: 37496742 PMCID: PMC10366536 DOI: 10.3389/fnins.2023.1214972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023] Open
Abstract
Background Psychotic treatment-resistant depression represents a complex and challenging form of mood disorder in clinical practice. Despite its severity, psychotic depression is frequently underdiagnosed and inadequately treated. Ketamine has demonstrated rapid and potent antidepressant effects in clinical studies, while exhibiting a favorable safety and tolerability profile. Although there is limited literature available on the use of ketamine in psychotic TRD, reports on its efficacy, safety, and tolerability profile are of great interest to clinicians. The aim of this study is to investigate the relationship between dissociative symptomatology and psychomimetic effects in inpatients with treatment-resistant major psychotic depression and treatment-resistant bipolar psychotic depression, who receive intravenous ketamine treatment alongside psychotropic medication, both during and after treatment. Materials and methods A total of 36 patients diagnosed with treatment-resistant unipolar (17 patients) or bipolar (18 patients) depression with psychotic features were treated with eight intravenous infusions of 0.5 mg/kg ketamine twice a week over 4 weeks. Ketamine was given in addition to their standard of care treatment. The severity of depressive symptoms was evaluated using the MADRS, while dissociative and psychomimetic symptoms were assessed using the CADSS and BPRS, respectively. Results There were no statistically significant changes observed in MADRS, CADSS, and BPRS scores within the study group during ketamine infusions. However, significant improvements in MADRS, CADSS, and BPRS scores were observed during ketamine infusions in both the unipolar and bipolar depression groups. Conclusion This study provides support for the lack of exacerbation of psychotic symptoms in both unipolar and bipolar depression.
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Kamalapathy PN, Wang KY, Puvanesarajah V, Raad M, Hassanzadeh H. Presence and Severity of Mental Illness Is Associated With Increased Risk of Postoperative Emergency Visits, Readmission, and Reoperation Following Outpatient ACDF: A National Database Analysis. Global Spine J 2023; 13:1267-1272. [PMID: 34212775 PMCID: PMC10416597 DOI: 10.1177/21925682211026913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
STUDY DESIGN Retrospective cohort study. OBJECTIVE The purpose was to compare rates of postoperative ED visits, readmission, and reoperation between patients with and without preexisting mental illness undergoing outpatient anterior cervical discectomy and fusion (ACDF). METHODS A retrospective review of the Mariner Database was conducted on patients who underwent ACDF between 2010 and 2017. Exclusion criteria included same day revision surgery and patients with a history of spine infection, trauma, or neoplasm. Patients were grouped into 3 categories: those with existing history of anxiety and/or depression, those with severe mental illness, and those without any history of mental illness. Severe mental illness was defined as a combination of diagnosis including schizophrenia, bipolar disorder, and/or psychotic disorder. Outcome measures were analyzed by comparing groups using multivariate logistic regression. Significance was set at P < 0.05. RESULTS Patients with anxiety/depression and patients with severe mental illness both had significantly increased risk of ED visits and readmission at 30-day and 90-day intervals. Compared to patients without mental illness, patients with severe mental illness (OR 1.93, P < 0.001) had significantly increased rates of reoperation at 90-days and 1-years postoperatively. Patients with anxiety/depression did not have increased rates of reoperation relative to patients without anxiety/depression at any time interval (P > 0.05). CONCLUSION Anxiety/depression as well as more severe psychiatric disease such as Schizophrenia and Bipolar disorder were significantly associated with increased healthcare utilization following outpatient ACDF. Patients with preexisting mental illness undergoing outpatient ACDF should be carefully evaluated preoperatively and closely followed postoperatively to reduce risk of adverse events.
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Affiliation(s)
| | - Kevin Y. Wang
- Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Varun Puvanesarajah
- Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Micheal Raad
- Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Hamid Hassanzadeh
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA
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Tripathi U, Mizrahi L, Alda M, Falkovich G, Stern S. Information theory characteristics improve the prediction of lithium response in bipolar disorder patients using a support vector machine classifier. Bipolar Disord 2023; 25:110-127. [PMID: 36479788 DOI: 10.1111/bdi.13282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM Bipolar disorder (BD) is a mood disorder with a high morbidity and death rate. Lithium (Li), a prominent mood stabilizer, is often used as a first-line treatment. However, clinical studies have shown that Li is fully effective in roughly 30% of BD patients. Our goal in this study was to use features derived from information theory to improve the prediction of the patient's response to Li as well as develop a diagnostic algorithm for the disorder. METHODS We have performed electrophysiological recordings in patient-derived dentate gyrus (DG) granule neurons (from a total of 9 subjects) for three groups: 3 control individuals, 3 BD patients who respond to Li treatment (LR), and 3 BD patients who do not respond to Li treatment (NR). The recordings were analyzed by the statistical tools of modern information theory. We used a Support Vector Machine (SVM) and Random forest (RF) classifiers with the basic electrophysiological features with additional information theory features. RESULTS Information theory features provided further knowledge about the distribution of the electrophysiological entities and the interactions between the different features, which improved classification schemes. These newly added features significantly improved our ability to distinguish the BD patients from the control individuals (an improvement from 60% to 74% accuracy) and LR from NR patients (an improvement from 81% to 99% accuracy). CONCLUSION The addition of Information theory-derived features provides further knowledge about the distribution of the parameters and their interactions, thus significantly improving the ability to discriminate and predict the LRs from the NRs and the patients from the controls.
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Affiliation(s)
- Utkarsh Tripathi
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
| | - Liron Mizrahi
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
| | - Martin Alda
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Gregory Falkovich
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Shani Stern
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
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Włodarczyk A, Dywel A, Cubała WJ. Safety and Tolerability of the Acute Ketamine Treatment in Treatment-Resistant Depression: Focus on Comorbidities Interplay with Dissociation and Psychomimetic Symptoms. Pharmaceuticals (Basel) 2023; 16:173. [PMID: 37259323 PMCID: PMC9966368 DOI: 10.3390/ph16020173] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/20/2023] [Accepted: 01/22/2023] [Indexed: 11/25/2023] Open
Abstract
There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety concerns arise regarding adverse drug reactions in specific subpopulations. The aim of this study was to investigate the safety of intravenous ketamine treatment in relation to dissociative and psychotic measures in TRD inpatients with Major Depressive Disorder (MDD) and Bipolar depression (BP) with comorbidities. In total, 49 inpatients with MDD or BP were treated with ketamine following the registered naturalistic observational protocol in a tertiary reference unit for mood disorders (NCT04226963). This dataset represents an intermittent analysis of an observational study performed for interim modeling of observational learning. The observations were applied to the inhomogeneous TRD population in a single site with no blinding and were limited to acute administration. The presence of epilepsy was significantly associated with an elevation in the BPRS over time (p = 0.008). Psychotic symptomatology with BPRS scores for comorbid conditions excluding epilepsy turned out to be insignificant (p = 0.198) regardless of the diagnosis. However, for a subgroup of patients with epilepsy (n = 6), a substantial fluctuation was seen across all administrations in the time course of the study. The study results contribute to the literature on the safety and tolerability profile of CNS adverse drug reactions in short-term treatment with intravenous ketamine as an add-on intervention to current standard-of-care psychotropic medication in TRD-MDD and TRD-BP inpatients with comorbidities. The careful consideration of comorbidities and concomitant medication is needed with ketamine administration along with close-clinical supervision at every visit.
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Affiliation(s)
- Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland
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Changes in T-Cell Subpopulations and Cytokine Levels in Patients with Treatment-Resistant Depression-A Preliminary Study. Int J Mol Sci 2022; 24:ijms24010479. [PMID: 36613927 PMCID: PMC9820349 DOI: 10.3390/ijms24010479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
Although there is some evidence for the involvement of cytokines and T cells in the pathophysiology of treatment-resistant depression (TRD), the nature of this relationship is not entirely clear. Therefore, we compared T-cell subpopulations and serum cytokine levels in TRD patients to find relationships between their immunological profiles, clinical presentation, and episode severity. Blood samples from TRD patients (n = 20) and healthy people (n = 13) were collected and analyzed by flow cytometry. We analyzed the percentages of helper and cytotoxic T cells according to the expression of selected activation markers, including CD28, CD69, CD25, CD95, and HLA-DR. The serum levels of inflammatory cytokines IL12p70, TNF-α, IL-10, IL-6, IL-1β, and IL-8 were also determined. TRD patients had a lower percentage of CD3+CD4+CD25+ and CD3+CD8+CD95+ cells than healthy people. They also had lower serum levels of IL-12p70 and TNF-α, whereas IL-8 levels were significantly higher. Receiver operating characteristic (ROC) analysis demonstrated that serum IL-8 values above 19.55 pg/mL were associated with a 10.26 likelihood ratio of developing TRD. No connections were found between the MADRS score and immunological parameters. These results show that TRD patients have reduced percentages of T cells expressing activation antigens (CD25 and CD95) and higher serum concentrations of proinflammatory and chemotactic IL-8. These changes may indicate reduced activity of the immune system and the important role of IL-8 in maintaining chronic inflammation in the course of depression.
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Shan J, Tian H, Zhou C, Wang H, Ma X, Li R, Yu H, Chen G, Zhu J, Cai Z, Lin C, Cheng L, Xu Y, Liu S, Zhang C, Luo Q, Zhang Y, Jin S, Liu C, Zhang Q, Lv L, Yang L, Chen J, Li Q, Liu W, Yue W, Song X, Zhuo C, China; MODMD Group of China (CMODG). Prevalence of Heavy Menstrual Bleeding and Its Associated Cognitive Risks and Predictive Factors in Women With Severe Mental Disorders. Front Pharmacol 2022; 13:904908. [PMID: 35910343 PMCID: PMC9326357 DOI: 10.3389/fphar.2022.904908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022] Open
Abstract
There has been limited studies examining treatment-induced heavy menstrual bleeding (HMB) in women with severe mental illnesses. The aim of this study was to examine HMB prevalence and HMB-associated factors in young women (18–34 years old) diagnosed with bipolar disorder (BP), major depressive disorder (MDD), or schizophrenia (SCZ) who have full insight and normal intelligence. Eighteen-month menstruation histories were recorded with pictorial blood loss assessment chart assessments of HMB. Multivariate analyses were conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Drug effects on cognition were assessed with the MATRICS Consensus Cognitive Battery (MCCB). HMB prevalence were: BP, 25.85%; MDD, 18.78%; and SCH, 13.7%. High glycosylated hemoglobin (HbA1c) level was a strong risk factor for HMB [BP OR, 19.39 (16.60–23.01); MDD OR, 2.69 (4.59–13.78); and SCZ OR, 9.59 (6.14–12.43)]. Additional risk factors included fasting blood sugar, 2-h postprandial blood glucose, and use of the medication valproate [BP: OR, 16.00 (95%CI 12.74–20.22); MDD: OR, 13.88 (95%CI 11.24–17.03); and SCZ OR, 11.35 (95%CI 8.84–19.20)]. Antipsychotic, antidepressant, and electroconvulsive therapy use were minor risk factors. Pharmacotherapy-induced visual learning impairment was associated with HMB [BP: OR, 9.01 (95%CI 3.15–13.44); MDD: OR, 5.99 (95%CI 3.11–9.00); and SCZ: OR, 7.09 (95%CI 2.99–9.20)]. Lithium emerged as a protective factor against HMB [BP: OR, 0.22 (95%CI 0.14–0.40); MDD: OR, 0.30 (95%CI 0.20–0.62); and SCZ: OR, 0.65 (95%CI 0.33–0.90)]. In SCZ patients, hyperlipidemia and high total cholesterol were HMB-associated factors (ORs, 1.87–2.22). Psychiatrist awareness of HMB risk is concerningly low (12/257, 2.28%). In conclusion, prescription of VPA should be cautioned for women with mental illness, especially BP, and lithium may be protective against HMB.
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Affiliation(s)
- Jianmin Shan
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Hongjun Tian
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Chunhua Zhou
- Department of Pharmacology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Haibo Wang
- Peking University Clinical Research Institute, Peking University First Hospital, Beijing, China
| | - Xiaoyan Ma
- MECT Center, Sleep Disorder Center, Tianjin Anding Hospital, Tianjin, China
| | - Ranli Li
- MECT Center, Sleep Disorder Center, Tianjin Anding Hospital, Tianjin, China
| | - Haiping Yu
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Guangdong Chen
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Jingjing Zhu
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Ziyao Cai
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Chongguang Lin
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Langlang Cheng
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
| | - Yong Xu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Sha Liu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Congpei Zhang
- Inpatient Department of Harbin First Psychiatry Hospital, Harbin, China
| | - Qinghua Luo
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunshu Zhang
- Inpatient Department of Hebei Mental Health Center, Baoding, China
| | - Shili Jin
- Inpatient Department, Shandong Daizhuang Hospital, Jining, China
| | - Chuanxin Liu
- Institute of Psychiatry, Jining Medical University, Jinning, China
| | - Qiuyu Zhang
- Institute of Psychiatry, Jining Medical University, Jinning, China
| | - Luxian Lv
- Department of Psychiatry, Henan Psychiatry Hospital, Xinxiang, China
| | - Lei Yang
- Key Laboratory of Mental Health, Ministry of Health (Peking University) and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Jiayue Chen
- Department of Psychiatry, The First Hospital Affiliated to Harbin Medical University, Harbin, China
| | - Qianchen Li
- Department of Pharmacology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wei Liu
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Wei Liu, ; Weihua Yue, ; Xueqin Song, ; Chuanjun Zhuo,
| | - Weihua Yue
- Department of Psychiatry, The First Hospital Affiliated to Harbin Medical University, Harbin, China
- *Correspondence: Wei Liu, ; Weihua Yue, ; Xueqin Song, ; Chuanjun Zhuo,
| | - Xueqin Song
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Wei Liu, ; Weihua Yue, ; Xueqin Song, ; Chuanjun Zhuo,
| | - Chuanjun Zhuo
- Department of Psychiatry, Tianjin Fourth Center Hospital, Tianjin, China
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Laboratory of Psychiatric-Neuroimaging-Genetic and Cor-morbidity, Tianjin Mental Health Center of Tianjin Medical University, Tianjin Anding Hospital, Tianjin, China
- *Correspondence: Wei Liu, ; Weihua Yue, ; Xueqin Song, ; Chuanjun Zhuo,
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Dion-Albert L, Bandeira Binder L, Daigle B, Hong-Minh A, Lebel M, Menard C. Sex differences in the blood-brain barrier: Implications for mental health. Front Neuroendocrinol 2022; 65:100989. [PMID: 35271863 DOI: 10.1016/j.yfrne.2022.100989] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/07/2022] [Accepted: 02/19/2022] [Indexed: 12/13/2022]
Abstract
Prevalence of mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are increasing at alarming rates in our societies. Growing evidence points toward major sex differences in these conditions, and high rates of treatment resistance support the need to consider novel biological mechanisms outside of neuronal function to gain mechanistic insights that could lead to innovative therapies. Blood-brain barrier alterations have been reported in MDD, BD and SZ. Here, we provide an overview of sex-specific immune, endocrine, vascular and transcriptional-mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders. We also identify pitfalls in current literature and highlight promising vascular biomarkers. Better understanding of how these adaptations can contribute to mental health status is essential not only in the context of MDD, BD and SZ but also cardiovascular diseases and stroke which are associated with higher prevalence of these conditions.
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Affiliation(s)
- Laurence Dion-Albert
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, Canada
| | - Luisa Bandeira Binder
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, Canada
| | - Beatrice Daigle
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, Canada
| | - Amandine Hong-Minh
- Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate, Dublin 2, Ireland
| | - Manon Lebel
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, Canada
| | - Caroline Menard
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, Canada.
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Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability. Int Clin Psychopharmacol 2022; 37:46-53. [PMID: 34864756 DOI: 10.1097/yic.0000000000000383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Unsatisfactory responses to bipolar disorder treatments have necessitated novel therapeutic approaches. Evidence of levetiracetam's effectiveness in mania was reported in previous studies. This study evaluated its efficacy, safety and tolerability as an adjunct to quetiapine in mania. Forty-four patients with Young Mania Rating Scale (YMRS) score ≥20 entered and were randomized to receive levetiracetam plus quetiapine or placebo plus quetiapine for 6 weeks. Patients were assessed using the YMRS and Beck Scale for Suicidal Ideations (BSSI) at baseline and weeks 2, 4 and 6. Changes in the scores, remission rates and response to treatment were compared between the groups. Forty patients completed the trial. The general linear model (GLM) repeated measures demonstrated a significant effect for time × treatment interaction on the YMRS score during the trial (P = 0.04). A greater reduction in YMRS scores was seen in the levetiracetam group compared with the placebo group from baseline to week 4 (P = 0.045). Response to treatment was significantly better in the levetiracetam group (P = 0.046). No significant effect for time × treatment interaction on BSSI score was seen in GLM repeated measures. Finally, there was no significant difference in the frequency of adverse events. Adjunctive levetiracetam is effective, safe and well-tolerated in patients with mania. Further high-quality, large-scale trials are recommended.
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15
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Madireddy S, Madireddy S. Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder. Int J Mol Sci 2022; 23:ijms23031844. [PMID: 35163764 PMCID: PMC8836876 DOI: 10.3390/ijms23031844] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/26/2021] [Accepted: 12/30/2021] [Indexed: 01/10/2023] Open
Abstract
Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive–behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.
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Affiliation(s)
- Sahithi Madireddy
- Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Correspondence:
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16
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Zhuo C, Chen G, Lin C, Ping J, Zhu J, Wang L, Jin S, Liu C, Zhang Q, Yang L, Li Q, Zhou C, Cheng L, Tian H, Song X. Risk-to-befit ratios of consecutive antidepressants for heavy menstrual bleeding in young women with bipolar disorder or major depressive disorder. Front Psychiatry 2022; 13:1012644. [PMID: 36386987 PMCID: PMC9650378 DOI: 10.3389/fpsyt.2022.1012644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/06/2022] [Indexed: 11/24/2022] Open
Abstract
The occurrence of heavy menstrual bleeding (HMB) induced by pharmacological agents has been reported in young adult women. This study aimed to investigate a possible association between the occurrence rates of HMB and different treatment methods such as antidepressant agents alone and in combination with other pharmacological agents. The examined cohort included young women (age 18-35 years, n = 1,949) with bipolar disorder (BP) or major depressive disorder (MDD). Menstruation history for 24 months was recorded and evaluated according to pictorial blood loss assessment charts of HMB. Multivariate analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals. The examined antidepressant agents had varying ORs for patients with BP vs. those with MDD. For example, the ORs of venlafaxine-induced HMB were 5.27 and 4.58 for patients with BP and MDD, respectively; duloxetine-induced HMB, 4.72 and 3.98; mirtazapine-induced HMB, 3.26 and 2.39; fluvoxamine-induced HMB, 3.11 and 2.08; fluoxetine-induced HMB, 2.45 and 1.13; citalopram-induced HMB, 2.03 and 1.25; escitalopram-induced HMB, 1.85 and 1.99; agomelatine-induced HMB, 1.45 and 2.97; paroxetine-induced HMB, 1.19 and 1.75; sertraline-induced HMB, 0.88 and 1.13; reboxetine-induced HMB, 0.45 and 0.45; and bupropion-induced HMB, 0.33 and 0.37, in each case. However, when antidepressant agents were combined with valproate, the OR of HMB greatly increased, with distinct profiles observed for patients with BP vs. those with MDD. For example, the ORs of HMB induced by venlafaxine combined with valproate were 8.48 and 6.70 for patients with BP and MDD, respectively; for duloxetine, 5.40 and 4.40; mirtazapine, 5.67 and 3.73; fluvoxamine, 5.27 and 3.37; fluoxetine, 3.69 and 4.30; citalopram, 5.88 and 3.46; escitalopram, 6.00 and 7.55; agomelatine, 4.26 and 5.65; paroxetine, 5.24 and 3.25; sertraline, 4.97 and 5.11; reboxetine, 3.54 and 2.19; and bupropion, 4.85 and 3.46, in each case. In conclusion, some antidepressant agents exhibited potential risks of inducing HMB. Therefore, a combined prescription of antidepressant agents and valproate should be carefully considered for young women with HMB.
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Affiliation(s)
- Chuanjun Zhuo
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China.,Key Laboratory of Multiple Organs Damage in Patients With Metal Disorder, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China.,Department of Psychiatry, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China.,Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Laboratory of Psychiatric-Neuroimaging-Genetic and Comorbidity, Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China
| | - Guangdong Chen
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Chongguang Lin
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Jing Ping
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Jingjing Zhu
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Lina Wang
- Laboratory of Psychiatric-Neuroimaging-Genetic and Comorbidity, Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China
| | - Shili Jin
- Inpatient Department, Shandong Daizhuang Hospital, Jining, China
| | - Chuanxin Liu
- College of Mental Disorder, Jining Medical University, Jining, China
| | - Qiuyu Zhang
- Key Laboratory of Multiple Organs Damage in Patients With Metal Disorder, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China
| | - Lei Yang
- Key Laboratory of Multiple Organs Damage in Patients With Metal Disorder, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China
| | - Qianchen Li
- Key Laboratory of Multiple Organs Damage in Patients With Metal Disorder, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China
| | - Chunhua Zhou
- Department of Pharmacology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Langlang Cheng
- Department of Psychiatry, Wenzhou Seventh Peoples Hospital, Wenzhou, China
| | - Hongjun Tian
- Key Laboratory of Multiple Organs Damage in Patients With Metal Disorder, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin, China
| | - Xueqin Song
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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17
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Arıkan MK, Günver G, İlhan R, Öksüz Ö, Metin B. Gamma oscillations predict treatment response to aripiprazole in bipolar disorder. J Affect Disord 2021; 294:159-162. [PMID: 34298220 DOI: 10.1016/j.jad.2021.07.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/25/2021] [Accepted: 07/11/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Treatment of Bipolar Disorder (BD) is a challenging issue. Aripiprazole monotherapy is a recommended option for the treatment of mania in BD. The electrophysiological markers of treatment response to aripiprazole could be potentially identified by quantitative Electroencephalography (qEEG). METHODS Twenty-four patients with BD were analysed retrospectively. Based on the percentage reduction in Young Mania Rating Scale, they were classified as responders (N = 14) and non-responders (N = 10) to aripiprazole monotherapy. Their resting-state qEEG recordings were examined. Spectral power across all frequency bands were calculated. Absolute powers for all frequency bands were compared between these groups. RESULTS Independent sample Mann-Whitney U test revealed that patients who did not respond to aripiprazole had greater gamma power than aripiprazole treatment responders. CONCLUSIONS Based on the present findings, it can be proposed that excess in gamma power could be the electrophysiological biomarkers of unresponsiveness to aripiprazole treatment in BD.
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Affiliation(s)
| | - Güven Günver
- Istanbul University, Department of Biostatistics, Istanbul, Turkey
| | - Reyhan İlhan
- Kemal Arıkan Psychiatry Clinic, Istanbul, Turkey
| | - Özden Öksüz
- Yeditepe University, Department of Neuroscience, Istanbul, Turkey
| | - Baris Metin
- Uskudar University, NPIstanbul Brain Hospital, Department of Neurology, Istanbul, Turkey
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Kamalapathy P, Kurker KP, Althoff AD, Browne JA, Werner BC. The Impact of Mental Illness on Postoperative Adverse Outcomes After Outpatient Joint Surgery. J Arthroplasty 2021; 36:2734-2741. [PMID: 33896669 DOI: 10.1016/j.arth.2021.04.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/15/2021] [Accepted: 04/02/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND The effect of pre-existing mental illness on outpatient surgical outcomes is not well characterized. The objective of this study was to evaluate the association between pre-existing mental illness diagnosis and postoperative complications after outpatient total knee (TKA) and total hip arthroplasty (THA) and 2) compare with inpatient total joint arthroplasty (TJA). METHODS The Mariner Claims Database was used to capture patients undergoing outpatient TJA from 2010 to 2017. Patients were grouped into three categories: those with an existing history of anxiety and/or depression, those with severe mental illness, and those without history of mental illness. Additional subgroup analysis compared those with severe mental illness undergoing outpatient vs inpatient TJA. Outcomes were analyzed using multivariable logistic regression (P < .05). RESULTS Patients undergoing outpatient TJA with prior history of anxiety and/or depression or severe mental illness had an increased risk of emergency department (ED) visits (TKA, P < .001; THA, P = .014) within 90 days compared with those without history of mental illness. Severe mental illness was also associated with increased risk of medical complications at 90 days (TKA, P < .001; THA, P = .006). When compared with those undergoing inpatient surgery, patients undergoing outpatient TKA with severe mental illness were at increased risk of periprosthetic infection (P = .005) and ED visit (P = .003) within 90 days of surgery. CONCLUSION Anxiety/depression and severe mental illness are associated with higher rates of ED visits after outpatient TJA. Patients with severe mental illness also experienced more adverse events, whereas those with anxiety and/or depression had similar rates compared with control. A higher rate of adverse outcomes was seen after TKA in patients with severe mental illness when surgery was performed in the outpatient setting vs those that had surgery as an inpatient. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Pramod Kamalapathy
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
| | - Kristina P Kurker
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
| | - Alyssa D Althoff
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
| | - James A Browne
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
| | - Brian C Werner
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
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19
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Włodarczyk A, Cubała WJ, Gałuszko-Węgielnik M, Szarmach J. Dissociative symptoms with intravenous ketamine in treatment-resistant depression exploratory observational study. Medicine (Baltimore) 2021; 100:e26769. [PMID: 34398056 PMCID: PMC8294865 DOI: 10.1097/md.0000000000026769] [Citation(s) in RCA: 4] [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: 10/21/2020] [Accepted: 07/05/2021] [Indexed: 01/04/2023] Open
Abstract
There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety and tolerability concerns arise regarding adverse drug reactions and specific subpopulations. This paper aims to investigate the relationship between dissociative and psychometric measures in course of intravenous ketamine treatment in TRD inpatients with major depressive disorder and bipolar disorder.This study result represents safety data in a population of 49 inpatients with major depressive disorder and bipolar disorder subjects receiving eight 0.5 mg/kg of ketamine intravenous infusions, with a duration of 40 min each, as an add-on treatment to standard-of-care pharmacotherapy, registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). The safety psychometrics assessed dissociation and psychomimetic symptomatology with the Clinician-Administered Dissociative States Scale (CADSS) the Brief Psychiatric Rating Scale (BPRS).The significant differences in CADSS scores between measurements in course of the treatment were observed (P = .003). No significant differences between BPRS measurements were made after infusions. In each case, both BPRS and CADSS values dropped to the "absent" level within 1 hour from the infusion. Neither CADSS nor BPRS scores were associated with the treatment outcome.The study demonstrates a good safety profile of intravenous ketamine as an add-on intervention to current psychotropic medication in TRD. The abatement of dissociation was observed in time with no sequelae nor harm. The study provides no support for the association between dissociation and treatment outcome.This study may be underpowered due to the small sample size. The protocol was defined as a study on acute depressive symptomatology without blinding.
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20
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Gammon D, Cheng C, Volkovinskaia A, Baker GB, Dursun SM. Clozapine: Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric Disorders? Biomolecules 2021; 11:1030. [PMID: 34356654 PMCID: PMC8301879 DOI: 10.3390/biom11071030] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022] Open
Abstract
Clozapine is superior to other antipsychotics as a therapy for treatment-resistant schizophrenia and schizoaffective disorder with increased risk of suicidal behavior. This drug has also been used in the off-label treatment of bipolar disorder, major depressive disorder (MDD), and Parkinson's disease (PD). Although usually reserved for severe and treatment-refractory cases, it is interesting that electroconvulsive therapy (ECT) has also been used in the treatment of these psychiatric disorders, suggesting some common or related mechanisms. A literature review on the applications of clozapine and electroconvulsive therapy (ECT) to the disorders mentioned above was undertaken, and this narrative review was prepared. Although both treatments have multiple actions, evidence to date suggests that the ability to elicit epileptiform activity and alter EEG activity, to increase neuroplasticity and elevate brain levels of neurotrophic factors, to affect imbalances in the relationship between glutamate and γ-aminobutyric acid (GABA), and to reduce inflammation through effects on neuron-glia interactions are common underlying mechanisms of these two treatments. This evidence may explain why clozapine is effective in a range of neuropsychiatric disorders. Future increased investigations into epigenetic and connectomic changes produced by clozapine and ECT should provide valuable information about these two treatments and the disorders they are used to treat.
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Affiliation(s)
- Dara Gammon
- Saba University School of Medicine, Saba, The Netherlands; (D.G.); (A.V.)
| | - Catherine Cheng
- Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2B7, Canada; (C.C.); (G.B.B.)
- Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada
| | - Anna Volkovinskaia
- Saba University School of Medicine, Saba, The Netherlands; (D.G.); (A.V.)
| | - Glen B. Baker
- Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2B7, Canada; (C.C.); (G.B.B.)
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Serdar M. Dursun
- Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2B7, Canada; (C.C.); (G.B.B.)
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
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21
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Poyurovsky M, Papach P, Weizman A. Beneficial Effect of a Relatively Low Dose of Clozapine in a Bipolar Depression Patient With Comorbid Obsessive-Compulsive Disorder and Severe Suicidality. Clin Neuropharmacol 2021; 43:169-170. [PMID: 32947431 DOI: 10.1097/wnf.0000000000000406] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Michael Poyurovsky
- Maale HaCarmel Mental Health Center, Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Maale HaCarmel Mental Health Center, Tirat Carmel, Israel Felsenstein Medical Research Institute, Petach Tikva, Israel, Sackler Faculty of Medicine, Tel-Aviv University
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22
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Myöhänen TT, Mertens F, Norrbacka S, Cui H. Deletion or inhibition of prolyl oligopeptidase blocks lithium-induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A. Basic Clin Pharmacol Toxicol 2021; 129:287-296. [PMID: 34196102 DOI: 10.1111/bcpt.13632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/15/2021] [Accepted: 06/27/2021] [Indexed: 11/27/2022]
Abstract
Alterations in prolyl oligopeptidase (PREP) activity have been connected, for example, with bipolar and major depressive disorder, and several studies have reported that lack or inhibition of PREP blocks the effects of lithium on inositol 1,4,5-triphosphate (IP3 ) levels. However, the impact of PREP modulation on other intracellular targets of lithium, such as glycogen synthase kinase 3 beta (GSK3b) or protein kinase B (Akt), has not been studied. We recently found that PREP regulates protein phosphatase 2A (PP2A), and because GSK3b and Akt are PP2A substrates, we studied if PREP-related lithium insensitivity is dependent on PP2A. To assess this, HEK-293 and SH-SY5Y cells with PREP deletion or PREP inhibition (KYP-2047) were exposed to lithium, and thereafter, the phosphorylation levels of GSK3b and Akt were measured by Western blot. As expected, PREP deletion and inhibition blocked the lithium-induced phosphorylation on GSK3b and Akt in both cell lines. When lithium exposure was combined with okadaic acid, a PP2A inhibitor, KYP-2047 did not have effect on lithium-induced GSK3b and Akt phosphorylation. Therefore, we conclude that PREP deletion or inhibition blocks the intracellular effects of lithium on GSK3b and Akt via PP2A activation.
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Affiliation(s)
- Timo T Myöhänen
- Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Helsinki, Finland.,Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Turku, Finland.,School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Freke Mertens
- Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Helsinki, Finland
| | - Susanna Norrbacka
- Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Helsinki, Finland
| | - Hengjing Cui
- Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Helsinki, Finland.,Department of Pharmacy, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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23
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Chen Q, Zhou Y, Lv H, Ma C. Adjuvant psychotherapy in early-stage bipolar disorder: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25443. [PMID: 33832148 PMCID: PMC8036117 DOI: 10.1097/md.0000000000025443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE There is no systematic review or meta-analysis to evaluate the efficacy of adjuvant psychotherapy in early-stage bipolar disorder. Therefore, the goal of this meta-analysis is to examine the evidence supporting psychotherapy as an efficacious approach to treating bipolar disorder. METHODS Seven electronic databases including Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library were searched in March 2021 by two independent reviewers. Data extraction was performed independently, and any conflict was resolved before final analysis. Only randomized clinical trials were included in this study. The trial entails 1 primary outcome measure (relapse) and several secondary outcome measures: time to relapse, relapse rate, days missed at work/school (record, interview), and social functioning level. The risk of bias assessment of the included studies was performed by 2 authors independently using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS We hypothesized that combined psychotherapy and pharmacological interventions would be superior to pharmacological interventions alone regarding the time to relapse into a manic or depressive episode. CONCLUSION This study expects to provide credible and scientific clinical evidence for the efficacy and safety of combined psychotherapy and pharmacological interventions in the treatment of bipolar disorder. OSF REGISTRATION NUMBER 10.17605/OSF.IO/ZGS6W.
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Affiliation(s)
| | | | - Huifen Lv
- Department of psychiatry, Hangzhou Seventh People's Hospital, Zhejiang, China
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24
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Szarmach J, Cubała WJ, Włodarczyk A, Gałuszko-Węgielnik M. Somatic Comorbidities and Cardiovascular Safety in Ketamine Use for Treatment-Resistant Depression. ACTA ACUST UNITED AC 2021; 57:medicina57030274. [PMID: 33809766 PMCID: PMC8002231 DOI: 10.3390/medicina57030274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 01/15/2023]
Abstract
Background and Objectives: There is evidence for ketamine efficacy in treatment-resistant depression (TRD). Several safety and tolerability concerns arise that some psychotropic agents may provide blood pressure or/and heart rate alterations. The aim of this study is to review blood pressure measurements in course of the treatment with ketamine on treatment refractory inpatients with somatic comorbidities in the course of MDD and BP. Materials and Methods: The study population of 49 patients comprised MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of treatment-resistant mood disorders (NCT04226963). Results: The conducted analysis showed that among people suffering from hypertension there is a higher increase in systolic blood pressure (RR) after infusion 2 (p = 0.004) than among people who do not suffer from hypertension. Patients with hypertension have a higher increase in diastolic RR compared to those not suffering from hypertension (p = 0,038). Among the subjects with diabetes mellitus, significant differences occurred for infusions 2 (p = 0.020), 7 (p = 0.020), and 8 (p = 0.035) for heart rate (HR), compared to subjects without diabetes mellitus. A higher increase in diastolic RR was noted in the group of subjects suffering from diabetes mellitus (p = 0.010) compared to those who did not. In the hyperlipidemic patients studied, a significantly greater decrease in HR after infusion 5 (p = 0.031) and systolic RR after infusion 4 (p = 0.036) was noted compared to nonpatients. People after a stroke had significantly higher increases in diastolic RR after infusions 4 (p = 0.021) and 6 (p = 0.001) than those who did not have a stroke. Patients suffering from epilepsy had a significantly greater decrease in systolic RR after the 8th infusion (p = 0.017) compared to those without epilepsy. Limitations: The study may be underpowered due to the small sample size. The observations apply to inhomogeneous TRD population in a single-site with no blinding and are limited to the acute administration. Conclusions: This study supports evidence for good safety and tolerability profile for short-term IV ketamine use in TRD treatment. However, risk mitigation measures are to be considered in patients with metabolic and cardiovascular comorbidities.
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25
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Iannaccone T, Sellitto C, Manzo V, Colucci F, Giudice V, Stefanelli B, Iuliano A, Corrivetti G, Filippelli A. Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters. Pharmaceuticals (Basel) 2021; 14:204. [PMID: 33804537 PMCID: PMC8001195 DOI: 10.3390/ph14030204] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 12/18/2022] Open
Abstract
Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient's genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.
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Affiliation(s)
- Teresa Iannaccone
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
| | - Carmine Sellitto
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
| | - Valentina Manzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
| | - Francesca Colucci
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
| | - Valentina Giudice
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
| | - Berenice Stefanelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
| | - Antonio Iuliano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
| | - Giulio Corrivetti
- European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy;
| | - Amelia Filippelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (T.I.); (V.M.); (F.C.); (V.G.); (B.S.); (A.I.); (A.F.)
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
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26
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Griffiths K, Millgate E, Egerton A, MacCabe JH. Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis. Psychol Med 2021; 51:376-386. [PMID: 33602358 DOI: 10.1017/s0033291721000246] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06-0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.
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Affiliation(s)
- Kira Griffiths
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Edward Millgate
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Alice Egerton
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - James H MacCabe
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
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Włodarczyk A, Cubała WJ, Gałuszko-Węgielnik M, Szarmach J. Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression. Ther Adv Psychopharmacol 2021; 11:20451253211011021. [PMID: 34046159 PMCID: PMC8138297 DOI: 10.1177/20451253211011021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 03/27/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine's safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP). METHODS A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol. RESULTS No antidepressants were associated with psychomimetic symptomatology except for citalopram (p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed. CONCLUSIONS Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.ClinicalTrials.gov identifier: NCT04226963.
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Affiliation(s)
- Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7 St. Build. 25, Gdańsk, pomorskie 80-952, Poland
| | - Wiesław J Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Pomorskie, Poland
| | - Maria Gałuszko-Węgielnik
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Pomorskie, Poland
| | - Joanna Szarmach
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Pomorskie, Poland
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28
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Wilkowska A, Włodarczyk A, Gałuszko-Węgielnik M, Wiglusz MS, Cubała WJ. Intravenous Ketamine Infusions in Treatment-Resistant Bipolar Depression: An Open-Label Naturalistic Observational Study. Neuropsychiatr Dis Treat 2021; 17:2637-2646. [PMID: 34421299 PMCID: PMC8373304 DOI: 10.2147/ndt.s325000] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Bipolar disorder is a chronic and recurrent condition often associated with treatment resistance and suicidality. There is an unmet need for effective treatment in this group of patients. Ketamine has been demonstrated to have antidepressant and antisuicidal properties in unipolar depression. Most of the available studies concern unipolar depression. Here, we present the efficacy and safety of IV ketamine as an add-on treatment in patients with bipolar I and bipolar II depression. PATIENTS AND METHODS Thirteen patients with treatment-resistant bipolar depression (TRBD) received eight IV infusions of 0.5 mg/kg ketamine twice a week over four weeks. This is an open-label naturalistic observational study. Ketamine is an add-on treatment. Depressive symptoms were measured with the Montgomery-Asberg Depression Rating Scale (MADRS), and manic symptoms were measured with the Young Mania Rating Scale (YMRS). Psychomimetic symptoms were assessed with the Clinician-Administered Dissociative States Scale (CADSS) and the Brief Psychiatric Rating Scale (BPRS). RESULTS The rates of response and remission after the seventh infusion of ketamine were 61.5% and 46.2%, respectively. A significant antisuicidal effect was observed in responders at the 7th infusion. Suicidality was measured with item 10 on the MADRS scale. The average time to respond was between 21.1 and 23.2 days to remission. There was an increase in the CADSS scores during the treatment compared to baseline and follow-up, but no differences between responders and non-responders were observed. No affective switch was observed according to the YMRS scale scores. Ketamine treatment was associated with a transient increase in arterial blood pressure. No serious adverse events, however, were observed. CONCLUSION This report presents the preliminary results of IV ketamine effectiveness and safety in treatment-resistant bipolar depression. The findings suggest that it is a feasible, safe and well-tolerated treatment option in this group of patients. There is a definite need for more studies in this field.
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Affiliation(s)
- Alina Wilkowska
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | | | - Mariusz S Wiglusz
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław J Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Wilkowska A, Wiglusz MS, Gałuszko-Wegielnik M, Włodarczyk A, Cubała WJ. Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression. Front Psychiatry 2021; 12:704330. [PMID: 34733182 PMCID: PMC8558390 DOI: 10.3389/fpsyt.2021.704330] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient's lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.
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Affiliation(s)
- Alina Wilkowska
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | | | | | - Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław Jerzy Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Zhuo C, Ji F, Tian H, Wang L, Jia F, Jiang D, Chen C, Zhou C, Lin X, Zhu J. Transient effects of multi-infusion ketamine augmentation on treatment-resistant depressive symptoms in patients with treatment-resistant bipolar depression - An open-label three-week pilot study. Brain Behav 2020; 10:e01674. [PMID: 32621379 PMCID: PMC7428494 DOI: 10.1002/brb3.1674] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/29/2020] [Accepted: 05/08/2020] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment-resistant bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi-infusion ketamine augmentation in patients with TRBPD. METHODS The present three-week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi-infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD). RESULTS Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment. CONCLUSIONS Multi-infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.
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Affiliation(s)
- Chuanjun Zhuo
- Department of Psychiatry, School of Mental Health, Jining Medical University, Jining, China.,Department of Psychiatry and Imaging-Genetics and Co-morbidity (PNGC-Lab), Tianjin Anding Hospital, Tianjin Mental Health Center, Mental Health Teaching Hospital, Tianjin Medical University, Tianjin, China.,Department of Psychiatry Wenzhou Seventh People's Hospital, Wenzhou, China
| | - Feng Ji
- Department of Psychiatry, School of Mental Health, Jining Medical University, Jining, China
| | - Hongjun Tian
- Department of Psychiatry and Imaging-Genetics and Co-morbidity (PNGC-Lab), Tianjin Anding Hospital, Tianjin Mental Health Center, Mental Health Teaching Hospital, Tianjin Medical University, Tianjin, China
| | - Lina Wang
- Department of Psychiatry and Imaging-Genetics and Co-morbidity (PNGC-Lab), Tianjin Anding Hospital, Tianjin Mental Health Center, Mental Health Teaching Hospital, Tianjin Medical University, Tianjin, China
| | - Feng Jia
- Department of Psychiatry and Imaging-Genetics and Co-morbidity (PNGC-Lab), Tianjin Anding Hospital, Tianjin Mental Health Center, Mental Health Teaching Hospital, Tianjin Medical University, Tianjin, China
| | - Deguo Jiang
- Department of Psychiatry Wenzhou Seventh People's Hospital, Wenzhou, China
| | - Ce Chen
- Department of Psychiatry Wenzhou Seventh People's Hospital, Wenzhou, China
| | - Chunhua Zhou
- Department of Pharmacy, First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaodong Lin
- Department of Psychiatry Wenzhou Seventh People's Hospital, Wenzhou, China
| | - Jingjing Zhu
- Department of Psychiatry Wenzhou Seventh People's Hospital, Wenzhou, China
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Huilei X, Siyu C, Jianghua X, Jidong R, Yi R. Clinical utility of pharmacogenetic testing in the treatment of bipolar disorder of Chinese patients. Pharmacogenomics 2020; 21:761-770. [PMID: 32597302 DOI: 10.2217/pgs-2020-0050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: The purpose of this study was to evaluate the clinical utility of pharmacogenetic (PGx) testing in the treatment of bipolar disorder in the Chinese population. Patients & methods: Compare efficacy and side effects, measured by the Clinical Global Impression Efficacy Index scale (CGI-EI), of PGx-guided treatment (n = 100) to that of the traditional treatment (n = 100). Results: Compared with the traditional treatment, PGx-guided treatment reduced the number of medications used for patients, also achieving better efficacy at 4, 8 and 12 weeks. In the analysis of side effects, the PGx-guided group significantly reduced the side effects. Conclusion: Our study suggests that PGx testing results-guided treatment is superior to the traditional treatment of bipolar disorder in the Chinese population.
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Affiliation(s)
- Xu Huilei
- Nanchong Psychosomatic Hospital, Nanchong, 637700, China
| | - Chen Siyu
- Nanchong Psychosomatic Hospital, Nanchong, 637700, China
| | - Xu Jianghua
- Nanchong Psychosomatic Hospital, Nanchong, 637700, China
| | - Ren Jidong
- Nanchong Psychosomatic Hospital, Nanchong, 637700, China
| | - Ren Yi
- Nanchong Psychosomatic Hospital, Nanchong, 637700, China
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Poweleit EA, Colestock M, Kantemneni EC, Strawn JR, Patino LR, DelBello MP, Ramsey LB. Cariprazine in Youth with Bipolar and Psychotic Disorders: A Retrospective Chart Review. J Child Adolesc Psychopharmacol 2020; 30:267-272. [PMID: 31825249 DOI: 10.1089/cap.2019.0106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Objective: To examine the potential effectiveness and tolerability of cariprazine in pediatric bipolar and psychotic disorders. Methods: We retrospectively reviewed the electronic health records of patients <21 years of age prescribed cariprazine to treat bipolar and psychotic disorders. Adverse effects, tolerability, therapeutic response (Clinical Global Impression-Improvement [CGI-I]), and severity of illness (Clinical Global Impression-Severity [CGI-S]) were determined through manual chart review. Results: We identified 16 patients aged 6-20 years who were treated with cariprazine (initial dose: 1.5 mg/day, interquartile range [IQR], 1.5-1.5; endpoint dose: 3 mg/day, IQR, 1.5-4.5). No serious adverse events were reported, but the most commonly reported side effect was weight gain (n = 3, 19%). Of the 14 patients for whom baseline and endpoint body mass index (BMI) data were available, neither changes in BMI (p = 0.391; 0.54 kg/m2, IQR, -0.33 to 1.38) nor BMI percentile (p = 0.71; 0.36%, IQR, -0.49 to 3.97) significantly differed between baseline and endpoint. However, patients receiving ≥4.5 mg/day had a significantly greater BMI increases during the course of treatment compared with those receiving ≤3 mg/day (p = 0.034; -1.14 kg/m2, IQR, -3.65 to 0.53 vs. 1.01 kg/m2, IQR, 0.17-4.88). CGI-S scores (p = 0.016; 4.5, IQR, 4-5 vs. 4, IQR, 3-4) significantly differed from baseline to endpoint. The response rate was 44% (n = 7/16), with responders being prescribed higher doses (p = 0.005; 6 mg/day, IQR, 4.875-6 vs. 3 mg/day, IQR, 3-4.125). Conclusions: Cariprazine may be well tolerated and effective for pediatric bipolar and psychotic disorders; however, compared with higher doses, total daily doses ≤3 mg/day appear to be more tolerable. Prospective controlled studies to further evaluate cariprazine in youth are needed.
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Affiliation(s)
- Ethan A Poweleit
- Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Michaela Colestock
- Molecular, Cellular, and Biochemical Pharmacology, Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Eashwar C Kantemneni
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Jeffrey R Strawn
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Luis R Patino
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Melissa P DelBello
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Laura B Ramsey
- Divisions of Research in Patient Services and Clinical Pharmacology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Grover S, Chakrabarti S, Sahoo S. Prevalence and clinical correlates of residual symptoms in remitted patients with bipolar disorder: An exploratory study. Indian J Psychiatry 2020; 62:295-305. [PMID: 32773873 PMCID: PMC7368443 DOI: 10.4103/psychiatry.indianjpsychiatry_760_19] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/30/2020] [Accepted: 04/10/2020] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE This cross-sectional study aimed to evaluate the prevalence and factors associated with residual symptoms (both depressive and manic) in subjects with bipolar disorder (BD). MATERIALS AND METHODS A total of 844 subjects diagnosed BD with an illness of 2 years' duration and minimum of two lifetime episodes and in clinical remission were evaluated for residual symptoms using Hamilton Depression Rating Scale (HAM-D) and Young Mania Rating Scale (YMRS). Based on the severity of residual symptoms, the study groups were divided into four groups. RESULTS Sixty-nine percent of the subjects had residual depressive symptoms (i.e., HAM-D score in the range of 1-7) and 59% had residual manic symptoms (i.e., YMRS score in the range of 1-7). The most common residual depressive symptom was psychic anxiety (34%) followed by impaired insight (29%). The most common manic symptom was poor insight (31%) followed by sleep disturbances (25%). Subjects with both sets of residual symptoms had onset of BD at a relatively young age, when compared to those with only residual depressive symptoms. Presence of any comorbid physical illness and substance abuse disorder was significantly higher in those with both sets of residual symptoms. CONCLUSIONS The present study suggests that a substantial proportion of patients with BD have residual symptoms of both types. Comorbid physical illness and substance use were associated with residual symptoms. Identification and management of residual symptoms are highly essential to improve the overall outcome of patients with BD.
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Affiliation(s)
- Sandeep Grover
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Subho Chakrabarti
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Swapnajeet Sahoo
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Lv Q, Hu Q, Zhang W, Huang X, Zhu M, Geng R, Cheng X, Bao C, Wang Y, Zhang C, He Y, Li Z, Yi Z. Disturbance of Oxidative Stress Parameters in Treatment-Resistant Bipolar Disorder and Their Association With Electroconvulsive Therapy Response. Int J Neuropsychopharmacol 2020; 23:207-216. [PMID: 31967315 PMCID: PMC7177162 DOI: 10.1093/ijnp/pyaa003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 12/17/2019] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Electroconvulsive therapy (ECT) is an effective option for treatment-resistant bipolar disorder (trBD). However, the mechanisms of its effect are unknown. Oxidative stress is thought to be involved in the underpinnings of BD. Our study is the first, to our knowledge, to report the association between notable oxidative stress parameters (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT], and malondialdehyde [MDA]) levels and ECT response in trBD patients. METHODS A total 28 trBD patients and 49 controls were recruited. Six-week ECT and naturalistic follow-up were conducted. SOD, GSH-Px, CAT, and MDA levels were measured by enzyme-linked immunosorbent assay, and the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale were administered at baseline and the end of the 6th week. MANCOVA, ANCOVA, 2 × 2 ANCOVA, and a multiple regression model were conducted. RESULTS SOD levels were lower in both trBD mania and depression (P = .001; P = .001), while GSH-Px (P = .01; P = .001) and MDA (P = .001; P = .001) were higher in both trBD mania and depression compared with controls. CAT levels were positively associated with 17-item Hamilton Depression Rating Scale scores in trBD depression (radjusted = 0.83, P = .005). MDA levels in trBD decreased after 6 weeks of ECT (P = .001). Interestingly, MDA levels decreased in responders (P = .001) but not in nonresponders (P > .05). CONCLUSIONS Our study indicates that decreased SOD could be a trait rather than a state in trBD. Oxidative stress levels are associated with illness severity and ECT response. This suggests that the mechanism of oxidative stress plays a crucial role in the pathophysiology of trBD.
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Affiliation(s)
- Qinyu Lv
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiongyue Hu
- Qingdao Mental Health Center, Qingdao, China
| | | | - Xinxin Huang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minghuan Zhu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruijie Geng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Cheng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenxi Bao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingyi Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongguang He
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zezhi Li
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghui Yi
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Fountoulakis KN, Yatham LN, Grunze H, Vieta E, Young AH, Blier P, Tohen M, Kasper S, Moeller HJ. The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder. Int J Neuropsychopharmacol 2020; 23:230-256. [PMID: 31802122 PMCID: PMC7177170 DOI: 10.1093/ijnp/pyz064] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/26/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Resistant bipolar disorder is a major mental health problem related to significant disability and overall cost. The aim of the current study was to perform a systematic review of the literature concerning (1) the definition of treatment resistance in bipolar disorder, (2) its clinical and (3) neurobiological correlates, and (4) the evidence-based treatment options for treatment-resistant bipolar disorder and for eventually developing guidelines for the treatment of this condition. MATERIALS AND METHODS The PRISMA method was used to identify all published papers relevant to the definition of treatment resistance in bipolar disorder and the associated evidence-based treatment options. The MEDLINE was searched to April 22, 2018. RESULTS Criteria were developed for the identification of resistance in bipolar disorder concerning all phases. The search of the literature identified all published studies concerning treatment options. The data were classified according to strength, and separate guidelines regarding resistant acute mania, acute bipolar depression, and the maintenance phase were developed. DISCUSSION The definition of resistance in bipolar disorder is by itself difficult due to the complexity of the clinical picture, course, and treatment options. The current guidelines are the first, to our knowledge, developed specifically for the treatment of resistant bipolar disorder patients, and they also include an operationalized definition of treatment resistance. They were based on a thorough and deep search of the literature and utilize as much as possible an evidence-based approach.
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Affiliation(s)
- Konstantinos N Fountoulakis
- 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Lakshmi N Yatham
- Department of Psychiatry, University of British Columbia, Mood Disorders Centre of Excellence, Djavad Mowafaghian Centre for Brain Health, Vancouver, Canada
| | - Heinz Grunze
- Psychiatrie Schwäbisch Hall & Paracelsus Medical University, Nuremberg, Germany
| | - Eduard Vieta
- Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - Allan H Young
- Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK
| | - Pierre Blier
- The Royal Institute of Mental Health Research, Department of Psychiatry, University of Ottawa, Ottawa, Canada
| | - Mauricio Tohen
- Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Siegfried Kasper
- Department of Psychiatry and Psychotherapy, Medical University Vienna, MUV, AKH, Vienna
- Center for Brain Research, Medical University Vienna, MUV, Vienna, Austria
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Costa MH, Kunz M, Nierenberg AA, Deckersbach T, Berk M, Magalhaes PVS. [Not Available]. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2020; 65:245-252. [PMID: 31958979 PMCID: PMC7385420 DOI: 10.1177/0706743719900460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective: The potential of clozapine in severe bipolar disorder is suggested by its
efficacy in refractory schizophrenia, but the evidence is limited thus far.
This report utilizes data from the standard care pathway of the Systematic
Treatment Enhancement Program to examine the clinical impact of clozapine in
bipolar disorder, comparing it to two groups, one that received olanzapine
and an additional group that received neither drug. Method: A total of 4,032 outpatients were available for this analysis. Groups for
longitudinal analyses are based on the medication used at each visit.
Outcomes assessed were clinical status, symptoms subscales,
hospitalizations, and death. We utilized mixed models and generalized
estimating equations to adjust for baseline differences and investigate
longitudinal differences in symptoms, clinical status, and hospitalization
rates between groups. Results: During the study, 1.1% (n = 43) of the patients used
clozapine at any time. Those on clozapine had significantly fewer manic and
depressive symptoms during follow-up as compared with those on neither
clozapine nor olanzapine, while those on olanzapine had more symptoms. The
use of clozapine was not associated with an increased risk of
hospitalization. No deaths were recorded for clozapine group during the
trial. Conclusions: Although prescribed to very few patients, the impact of clozapine was
notable, with fewer symptoms in patients who had more severe illnesses at
baseline. Clozapine could prove to be as successful an intervention for
late-stage bipolar disorder as it has been in schizophrenia.
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Affiliation(s)
- Marta H Costa
- Graduate Program in Psychiatry and Behavioral Sciences, Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Mauricio Kunz
- Graduate Program in Psychiatry and Behavioral Sciences, Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Andrew A Nierenberg
- Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Thilo Deckersbach
- Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia.,Orygen, The Centre of Excellence in Youth Mental Health, Department of Psychiatry and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia
| | - Pedro V S Magalhaes
- Graduate Program in Psychiatry and Behavioral Sciences, Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: A randomized clinical trial. J Affect Disord 2020; 261:145-152. [PMID: 31630035 DOI: 10.1016/j.jad.2019.10.021] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/18/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The goal of this study was to reduce treatment resistance and enhance antidepressant response in patients with treatment-resistant bipolar depression (TRBDD) by modulating inflammatory activation. METHODS Forty-seven TRBDD patients completed a randomized, double-blind, placebo (PBO)-controlled two-arm study using celecoxib (CBX), a cyclooxygenase 2 (COX-2) inhibitor, in combination with escitalopram (ESC). The Hamilton Depression (17-Item) and the Hamilton Anxiety Rating Scales were used to quantify symptom severity. Self-rating instruments included BDI, BAI and QLES-Q questioner. An adverse events inventory was used, and the possibility of bleeding diathesis was monitored. Complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (APTT) were determined. Comparison of mood scores between the CBX and PBO groups were conducted using a mixed ANOVA and an Independent Sample Student t-test. RESULTS The CBX adjunctive treatment produced significantly more responders and remitters than the PBO arm. Compared to the PBO group (n = 20), the CBX group (n = 27) experienced lower depression severity through the entire course of the study, showing significant decrease in depression and anxiety scores as early as week 1. Except for initial mild nausea, no adverse events were reported and study medications were well tolerated. CONCLUSIONS Modulation of the inflammatory response through targeted inhibition of the enzyme COX-2 by means of CBX reduces TRBDD and augments and accelerates treatment response in an efficacious and safe manner. Future studies should replicate these findings and additionally investigate whether prolonged administration of CBX is required to maintain remission by adding a discontinuation phase to the study design. TRIAL REGISTRATION Clinicaltrials.gov ID: NCT01479829.
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Affiliation(s)
- Angelos Halaris
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA.
| | - Adriana Cantos
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
| | - Katherine Johnson
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
| | - Michael Hakimi
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
| | - James Sinacore
- Department of Public Health SciencesParkinson School of Health Sciences & Public Health, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
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Szarmach J, Cubała WJ, Włodarczyk A, Gałuszko-Węgielnik M. Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression. Neuropsychiatr Dis Treat 2020; 16:2539-2551. [PMID: 33154641 PMCID: PMC7605942 DOI: 10.2147/ndt.s273287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/19/2020] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Ketamine exhibits antidepressant properties in treatment-resistant depression (TRD) with some concern over its cardiovascular safety and tolerability issues. This paper reports on the cardiovascular safety in short-term intravenous ketamine treatment in TRD inpatients with major depressive disorder (MDD) and bipolar disorder (BP). MATERIALS AND METHODS The observational study population comprises 35 MDD and 14 BP subjects treated with intravenous ketamine. RESULTS Blood pressure (RR) and heart rate (HR) values returned to baseline within 1.5-hours post infusion with no sequelae for all study subjects. Six time points were analyzed for each infusion: 0', 15', 30', 45', 60' and 90' for RR and HR. After the infusion significant peaks in systolic (p = 0.004) and diastolic (p = 0.038) RR were seen. In concomitant medication with selective serotonin reuptake inhibitors (SSRIs), higher RR peaks (p = 0.020; p = 0.048) were seen as compared to other subjects. The decrease in HR was greater (p = 0.02) in the absence of concomitant medication with mood stabilizers as compared to subjects receiving mood stabilizing medication accompanied by the observation of a greater decrease in diastolic RR among those taking mood stabilizers (p = 0.009). LIMITATIONS The study may be underpowered due to the small sample size. The observations apply to an inhomogeneous TRD population in a single-site, pilot study, with no blinding and are limited to the acute administration. CONCLUSION The study demonstrates good safety and tolerability profile of intravenous ketamine as add-on intervention to current psychotropic medication in TRD, regardless of the MDD or BP type of mood disorders. The abatement of elevated RR and BP scores was observed in time with no sequelae nor harm. Still, cardiovascular risks appear to be more pronounced in subjects with comorbid arterial hypertension and diabetes mellitus.
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Affiliation(s)
- Joanna Szarmach
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław Jerzy Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Fornaro M, Fusco A, Novello S, Mosca P, Anastasia A, De Blasio A, Iasevoli F, de Bartolomeis A. Predictors of Treatment Resistance Across Different Clinical Subtypes of Depression: Comparison of Unipolar vs. Bipolar Cases. Front Psychiatry 2020; 11:438. [PMID: 32670098 PMCID: PMC7326075 DOI: 10.3389/fpsyt.2020.00438] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/28/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study. METHODS A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression. RESULTS The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not. LIMITATIONS Small sample size and high rate of comorbidity. CONCLUSIONS Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.
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Affiliation(s)
- Michele Fornaro
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy.,Polyedra Research Group, Teramo, Italy
| | - Andrea Fusco
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
| | - Stefano Novello
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
| | - Pierluigi Mosca
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
| | | | - Antonella De Blasio
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
| | - Felice Iasevoli
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
| | - Andrea de Bartolomeis
- Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy
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Kamintsky L, Cairns KA, Veksler R, Bowen C, Beyea SD, Friedman A, Calkin C. Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression. Neuroimage Clin 2019; 26:102049. [PMID: 31718955 PMCID: PMC7229352 DOI: 10.1016/j.nicl.2019.102049] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/05/2019] [Accepted: 10/21/2019] [Indexed: 11/29/2022]
Abstract
Bipolar disorder affects approximately 2% of the population and is typically characterized by recurrent episodes of mania and depression. While some patients achieve remission using mood-stabilizing treatments, a significant proportion of patients show progressive changes in symptomatology over time. Bipolar progression is diverse in nature and may include a treatment-resistant increase in the frequency and severity of episodes, worse psychiatric and functional outcomes, and a greater risk of suicide. The mechanisms underlying bipolar disorder progression remain poorly understood and there are currently no biomarkers for identifying patients at risk. The objective of this study was to explore the potential of blood-brain barrier (BBB) imaging as such a biomarker, by acquiring the first imaging data of BBB leakage in bipolar patients, and evaluating the potential association between BBB dysfunction and bipolar symptoms. To this end, a cohort of 36 bipolar patients was recruited through the Mood Disorders Clinic (Nova Scotia Health Authority, Canada). All patients, along with 14 control subjects (matched for sex, age and metabolic status), underwent contrast-enhanced dynamic MRI scanning for quantitative assessment of BBB leakage as well as clinical and psychiatric evaluations. Outlier analysis has identified a group of 10 subjects with significantly higher percentages of brain volume with BBB leakage (labeled the "extensive BBB leakage" group). This group consisted exclusively of bipolar patients, while the "normal BBB leakage" group included the entire control cohort and the remaining 26 bipolar subjects. Among the bipolar cohort, patients with extensive BBB leakage were found to have more severe depression and anxiety, and a more chronic course of illness. Furthermore, all bipolar patients within this group were also found to have co-morbid insulin resistance, suggesting that insulin resistance may increase the risk of BBB dysfunction in bipolar patients. Our findings demonstrate a clear link between BBB leakage and greater psychiatric morbidity in bipolar patients and highlight the potential of BBB imaging as a mechanism-based biomarker for bipolar disorder progression.
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Affiliation(s)
- Lyna Kamintsky
- Department of Medical Neuroscience, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, B3H 4R2, Canada
| | - Kathleen A Cairns
- Nova Scotia Health Authority, Mood Disorders Clinic, 5909 Veterans Memorial Lane, Halifax, NS, B3H 2E2, Canada
| | - Ronel Veksler
- Department of Physiology and Cell Biology, Medicine, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Chris Bowen
- Biomedical Translational Imaging Centre (BIOTIC), QEII Health Sciences Centre, and Department of Diagnostic Radiology, Dalhousie University, 1796 Summer Street, Halifax, NS, B3H 3A7, Canada
| | - Steven D Beyea
- Biomedical Translational Imaging Centre (BIOTIC), QEII Health Sciences Centre, and Department of Diagnostic Radiology, Dalhousie University, 1796 Summer Street, Halifax, NS, B3H 3A7, Canada
| | - Alon Friedman
- Department of Medical Neuroscience, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, B3H 4R2, Canada; Department of Physiology and Cell Biology, Medicine, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| | - Cynthia Calkin
- Departments of Psychiatry and Medical Neuroscience, Dalhousie University, Mood Disorders Clinic, 5909 Veterans Memorial Lane, Halifax, NS, B3H 2E2, Canada
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Cepeda MS, Kern DM, Nicholson S. Treatment resistant depression in women with peripartum depression. BMC Pregnancy Childbirth 2019; 19:323. [PMID: 31477032 PMCID: PMC6721276 DOI: 10.1186/s12884-019-2462-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/16/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Peripartum depression is a leading cause of disease burden for women and yet there is little evidence as to how often peripartum depression does not respond to treatment and becomes treatment resistant depression. We sought to determine the incidence of treatment resistant depression (TRD) in women with peripartum depression. METHODS Population based retrospective cohort study using a large US claims database. Peripartum depression was defined as having a depression diagnosis during pregnancy or up to 6 months after the end of pregnancy. We included women with prevalent or incident depression. The outcome was the development of TRD within 1 year after the diagnosis of peripartum depression. TRD was defined as having 3 distinct antidepressants or 1 antidepressant and 1 antipsychotic in 1 year. Women with peripartum depression may not be exposed to pharmacological treatments early in pregnancy, therefore we created two groups: 1. women with peripartum depression, and 2. women with peripartum depression diagnosed 3 months before a live birth delivery or within 6 months after that delivery. RESULTS There were 3,207,684 pregnant women, of whom 2.5% had peripartum depression. Of these women half had incident depression during pregnancy. Five percent of women with peripartum depression developed TRD within 1 year of the depression diagnosis. The risk of developing TRD was 50% higher in women with prevalent depression than in women with incident peripartum depression (P < 0.0001). Results were similar in women with peripartum depression diagnosed later in their pregnancy. Women who went on to develop TRD had more substance use disorders, anxiety, insomnia and painful conditions. CONCLUSIONS TRD occurs in approximately 5% of women with peripartum depression. The risk of TRD is higher in pregnant women with a history of depression. Women who went on to develop TRD had more psychiatric comorbidities and painful conditions than women who did not.
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Affiliation(s)
- M. Soledad Cepeda
- Janssen Research and Development, 1125 Trenton Harbourton Rd, Titusville, NJ 08560 USA
| | - David M. Kern
- Janssen Research and Development, 1125 Trenton Harbourton Rd, Titusville, NJ 08560 USA
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Broder MS, Greene M, Chang E, Hartry A, Yan T, Yermilov I. Atypical antipsychotic adherence is associated with lower inpatient utilization and cost in bipolar I disorder. J Med Econ 2019; 22:63-70. [PMID: 30376745 DOI: 10.1080/13696998.2018.1543188] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIMS This study explored the association between medication adherence to oral atypical antipsychotics (AAP) and both psychiatric hospitalization and associated costs in bipolar I disorder (BD-I) in a real-world setting. MATERIALS AND METHODS This retrospective study used the Truven Health MarketScan Medicaid, Commercial, and Medicare Supplemental Claims Databases. Adults were identified if they had BD-I and initiated an AAP treatment during the study identification period (July 1, 2015-June 30, 2016 for Medicaid, July 1, 2015-March 31, 2016 for Commercial and Medicare Supplemental) and had ≥6-month continuous enrollment before (baseline) and after (follow-up) the first day of treatment. Medication adherence was measured by the proportion of days covered (PDC) and grouped as: fully-adherent (PDC ≥80%), partially-adherent (40% ≤ PDC <80%), and non-adherent (PDC <40%). Logistic and linear regression models were conducted to estimate the risk of psychiatric hospitalization and costs during the 6-month follow-up period. RESULTS The final sample consisted of 5,892 (32.0%) fully-adherent, 4,246 (23.1%) partially-adherent, and 8,250 (44.9%) non-adherent patients. The adjusted rate of psychiatric hospitalization during the follow-up period was lower in the fully-adherent (6.0%) vs partially- (8.3%) or non-adherent (8.8%) groups (p < 0.001). Using the fully-adherent cohort as the reference group, the odds of psychiatric hospitalization were significantly higher for the partially-adherent (OR = 1.42; 95% CI = 1.23-1.64) and non-adherent (1.51; 1.33-1.71) cohorts. The mean adjusted psychiatric hospitalization cost over 6 months among hospitalized patients was lower for the fully-adherent cohort ($11,748), than the partially-adherent ($15,051 p = 0.002) or non-adherent cohorts ($13,170, not statistically significant). LIMITATIONS The medication adherence measures relied on prescription claims data, not actual use. CONCLUSIONS In the treatment of BD-I, better medication adherence to AAP was associated with fewer psychiatric hospitalizations. Among hospitalized patients, fully-adherent patients had statistically significantly lower psychiatric costs than partially-adherent ones. These findings suggest that improving adherence to AAP in BD-I may be a valuable goal from both clinical and economic perspectives.
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Affiliation(s)
- Michael S Broder
- a Partnership for Health Analytic Research (PHAR), LLC , Beverly Hills , CA , USA
| | - Mallik Greene
- b Otsuka Pharmaceutical Development & Commercialization, Inc. , Princeton , NJ , USA
| | - Eunice Chang
- a Partnership for Health Analytic Research (PHAR), LLC , Beverly Hills , CA , USA
| | | | - Tingjian Yan
- a Partnership for Health Analytic Research (PHAR), LLC , Beverly Hills , CA , USA
| | - Irina Yermilov
- a Partnership for Health Analytic Research (PHAR), LLC , Beverly Hills , CA , USA
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Wilkowska A, Cubała WJ. Clozapine As Transformative Treatment In Bipolar Patients. Neuropsychiatr Dis Treat 2019; 15:2901-2905. [PMID: 31632038 PMCID: PMC6790347 DOI: 10.2147/ndt.s227196] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 09/19/2019] [Indexed: 01/21/2023] Open
Abstract
Clozapine is an atypical antipsychotic used in treatment-resistant bipolar disorder. There is evidence for its anti-suicidal, anti-aggressive properties and efficacy in substance use comorbidities. Despite guidelines, the drug is used in 1.5% of bipolar patients only. Considering its effectiveness in treatment-resistant cases as well as its epigenetic effects it may become transformative treatment in bipolar disorder impacting the clinical course and psychosocial burden of the disease.
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Affiliation(s)
- Alina Wilkowska
- Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław J Cubała
- Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
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Capote HA, Rainka M, Westphal ES, Beecher J, Gengo FM. Ropinirole in Bipolar Disorder: Rate of Manic Switching and Change in Disease Severity. Perspect Psychiatr Care 2018; 54:100-106. [PMID: 28105645 DOI: 10.1111/ppc.12205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 11/01/2016] [Accepted: 11/25/2016] [Indexed: 01/11/2023] Open
Abstract
PURPOSE To determine the effects of ropinirole on manic switching and disease severity in bipolar disorder. DESIGN AND METHODS A cross-sectional survey was conducted in 23 bipolar depressed patients using ropinirole combination therapy (Young Mania Rating Scale [YMRS], Bipolar Inventory of Symptoms Scale [BISS]). Retrospective Clinical Global Impression of Change (CGI-C) and CGI-S (Severity) were captured via chart review. FINDINGS One patient (4.3%) experienced induction of mania (YMRS). All patients responded or partially responded to ropinirole (CGIs). YMRS and BISS mania scores were correlated. PRACTICE IMPLICATIONS Ropinirole has a low rate of manic switching and significantly reduces bipolar depression severity.
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Affiliation(s)
- Horacio A Capote
- Director, Neuropsychiatry Division, Dent Neurologic Institute, Buffalo, New York, USA
| | - Michelle Rainka
- Clinical Pharmacist, Research Division, Dent Neurologic Institute, Buffalo, New York, USA
| | - Erica S Westphal
- Research Associate, Dent Neurologic Institute, Buffalo, New York, USA
| | - Jonathan Beecher
- Research Intern, Dent Neurologic Institute, Buffalo, New York, USA
| | - Francis M Gengo
- Director of Research Division, Dent Neurologic Institute, Buffalo, New York, USA
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Li DJ, Tseng PT, Chen YW, Wu CK, Lin PY. Significant Treatment Effect of Bupropion in Patients With Bipolar Disorder but Similar Phase-Shifting Rate as Other Antidepressants: A Meta-Analysis Following the PRISMA Guidelines. Medicine (Baltimore) 2016; 95:e3165. [PMID: 27043678 PMCID: PMC4998539 DOI: 10.1097/md.0000000000003165] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Bupropion is widely used for treating bipolar disorder (BD), and especially those with depressive mood, based on its good treatment effect, safety profile, and lower risk of phase shifting. However, increasing evidence indicates that the safety of bupropion in BD patients may not be as good as previously thought. The aim of this study was to summarize data on the treatment effect and safety profile of bupropion in the treatment of BD via a meta-analysis. Electronic search through PubMed and ClinicalTrials.gov was performed. The inclusion criteria were: (i) studies comparing changes in disease severity before and after bupropion treatment or articles comparing the treatment effect of bupropion in BD patients with those receiving other standard treatments; (ii) articles on clinical trials in humans. The exclusion criteria were (i) case reports/series, and (ii) nonclinical trials. All effect sizes from 10 clinical trials were pooled using a random effects model. We examined the possible confounding variables using meta-regression and subgroup analysis. Bupropion significantly improved the severity of disease in BD patients (P < 0.001), and the treatment effect was similar to other antidepressants/standard treatments (P = 0.220). There were no significant differences in the dropout rate (P = 0.285) and rate of phase shifting (P = 0.952) between BD patients who received bupropion and those who received other antidepressants. We could not perform a detailed meta-analysis of every category of antidepressant, nor could we rule out the possible confounding effect of concurrent psychotropics or include all drug side effects. Furthermore, the number of studies recruited in the meta-analysis was relatively small. Our findings reconfirm the benefits of bupropion for the treatment of bipolar depression, which are similar to those of other antidepressants. However, the rate of phase shifting with bupropion usage was not as low compared to other antidepressants as previously thought, which should serve to remind clinicians of the risk of phase shifting when prescribing bupropion to BD patients regardless of the suggestions of current clinical practice guidelines.
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Affiliation(s)
- Dian-Jeng Li
- From the Kaohsiung Municipal Kai-Syuan Psychiatric Hospital (D-JL), Kaohsiung; Department of Psychiatry (P-TT, C-KW), Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home; Department of Neurology (Y-WC), E-Da Hospital; Department of Psychiatry (P-YL), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine; and Institute for Translational Research in Biomedical Sciences (P-YL), Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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