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Xu F. Efficacy of Cognitive Behavioural Therapy in Controlling Negative Symptoms in Schizophrenic Patients: A Systematic Review and Meta-Analysis. INTERNATIONAL JOURNAL OF PSYCHOLOGY 2025; 60:e70045. [PMID: 40194927 DOI: 10.1002/ijop.70045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 01/11/2025] [Accepted: 03/29/2025] [Indexed: 04/09/2025]
Abstract
The aim of this meta-analysis was to assess the effectiveness of cognitive behavioural therapy (CBT) in reducing negative symptoms in patients with schizophrenia. The search period was from the beginning of the database creation to 30 September 2022. An initial search of 169 articles was conducted through database searches and other means. After applying inclusion and exclusion criteria, seven randomised controlled studies were included in the final analysis. The intervention group included a total of 293 patients with schizophrenia, and the control group included 291 patients with schizophrenia. Meta-analysis showed that there was a statistically significant difference in negative symptom reduction between the CBT intervention group [SMD = -0.26,95% CI (-0.45, -0.07), p = 0.006] and the control group. We analysed the effectiveness of CBT based on previous studies and found that CBT was effective in improving negative symptoms in patients with schizophrenia.
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Affiliation(s)
- Feifei Xu
- School of Psychology, Zhejiang Normal Uinversity, Jinhua, China
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2
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Holter KM, Klausner MG, Hite MH, Moriarty CT, Barth SH, Pierce BE, Iannucci AN, Sheffler DJ, Cosford NDP, Bimonte-Nelson HA, Raab-Graham KF, Gould RW. 17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats. Mol Psychiatry 2025:10.1038/s41380-025-02996-0. [PMID: 40185905 DOI: 10.1038/s41380-025-02996-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
Low 17β-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu2/3) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.
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Affiliation(s)
- Kimberly M Holter
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - McKenna G Klausner
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Mary Hunter Hite
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Carson T Moriarty
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Samuel H Barth
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Bethany E Pierce
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Alexandria N Iannucci
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Douglas J Sheffler
- Cancer Molecular Therapeutics Program. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Nicholas D P Cosford
- Cancer Molecular Therapeutics Program. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | | | - Kimberly F Raab-Graham
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Robert W Gould
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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Holter KM, Klausner M, Hite MH, Moriarty C, Barth S, Pierce B, Iannucci A, Sheffler D, Cosford N, Bimonte-Nelson H, Raab-Graham KF, Gould RW. 17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.10.637465. [PMID: 39990384 PMCID: PMC11844370 DOI: 10.1101/2025.02.10.637465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Low 17β-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu2/3) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power equally regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.
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Mu E, Gurvich C, Kulkarni J. Estrogen and psychosis - a review and future directions. Arch Womens Ment Health 2024; 27:877-885. [PMID: 38221595 PMCID: PMC11579214 DOI: 10.1007/s00737-023-01409-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 12/02/2023] [Indexed: 01/16/2024]
Abstract
The link between sex hormones and schizophrenia has been suspected for over a century; however, scientific evidence supporting the pharmacotherapeutic effects of exogenous estrogen has only started to emerge during the past three decades. Accumulating evidence from epidemiological and basic research suggests that estrogen has a protective effect in women vulnerable to schizophrenia. Such evidence has led multiple researchers to investigate the role of estrogen in schizophrenia and its use in treatment. This narrative review provides an overview of the effects of estrogen as well as summarizes the recent work regarding estrogen as a treatment for schizophrenia, particularly the use of new-generation selective estrogen receptor modulators.
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Affiliation(s)
- Eveline Mu
- HER Centre Australia, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
| | - Caroline Gurvich
- HER Centre Australia, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Jayashri Kulkarni
- HER Centre Australia, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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Xu F, Xu S. Cognitive-behavioral therapy for negative symptoms of schizophrenia: A systematic review and meta-analysis. Medicine (Baltimore) 2024; 103:e39572. [PMID: 39252302 DOI: 10.1097/md.0000000000039572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Cognitive-behavioral intervention techniques are increasingly demonstrating their efficacy in preventing relapses and managing problems in patients with schizophrenia. There is still variation in its effectiveness for negative symptoms, such as mood-related symptoms and motivation to engage socially. METHODS A systematic search was conducted in PubMed, Web of Science for English literature on cognitive-behavioral therapy (CBT) interventions in patients with schizophrenia. The search included randomized controlled trials and nonrandomized controlled trials. The search period extended from the inception of the databases to September 30, 2022. Two researchers independently performed quality assessment and data extraction based on predefined inclusion and exclusion criteria. RESULTS Discrepancies were resolved through discussion or consultation with a third researcher. Initially, 169 articles were retrieved through database searches and other means. After applying the inclusion and exclusion criteria, 10 randomized controlled studies were included in the final analysis. The intervention group comprised a total of 680 patients with schizophrenia, while the control group included 686 patients with schizophrenia. Meta-analysis results demonstrated a statistically significant difference in negative symptom reduction between the CBT intervention group (WMD = -1.19, 95% CI [-1.73, -0.66], P < .0001) and the control group. CONCLUSION We have analyzed the effectiveness of CBT based on our previous research, CBT was found to effectively improve negative symptoms in individuals diagnosed with schizophrenia.
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Affiliation(s)
- Feifei Xu
- School of Psychology, Zhejiang Normal University, Jinhua, China
- Intelligent Laboratory of Child and Adolescent Mental Health and Crisis Intervention of Zhejiang Province, Zhejiang Normal University, Jinhua, China
| | - Sheng Xu
- School of Humanities and International Education Exchange, Anhui University of Chinese Medicine, HeFei, China
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Amerio A, Magnani L, Arduino G, Fesce F, de Filippis R, Parise A, Costanza A, Nguyen KD, Saverino D, De Berardis D, Aguglia A, Escelsior A, Serafini G, De Fazio P, Amore M. Immunomodulatory Effects of Clozapine: More Than Just a Side Effect in Schizophrenia. Curr Neuropharmacol 2024; 22:1233-1247. [PMID: 38031778 PMCID: PMC10964093 DOI: 10.2174/1570159x22666231128101725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 12/01/2023] Open
Abstract
Recent evidence suggests a possible relationship between the immune system and schizophrenia spectrum disorders (SSDs), as neuroinflammation appears to play a role in major psychiatric conditions. Neuroinflammation is as a broad concept representing a physiological protective response to infection or injury, but in some cases, especially if chronic, it may represent an expression of maladaptive processes, potentially driving to clinical dysfunction and neurodegeneration. Several studies are concurrently highlighting the importance of microglia, the resident immune cells of the central nervous system, in a huge number of neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's diseases, as well as SSDs. A more fundamental phenomenon of maladaptive coupling of microglia may contribute to the genesis of dysfunctional brain inflammation involved in SSDs, from the onset of their neurophenomenological evolution. Clozapine and other antipsychotic drugs seem to express a provable immunomodulant effect and a more specific action on microglia, while neuroactive steroids and nonsteroidal anti-inflammatory drugs may reduce some SSDs symptoms in add-on therapy. Given these theoretical premises, this article aims to summarize and interpret the available scientific evidence about psychotropic and anti-inflammatory drugs that could express an immunomodulant activity on microglia.
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Affiliation(s)
- Andrea Amerio
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Luca Magnani
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Gabriele Arduino
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Fabio Fesce
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Renato de Filippis
- Psychiatry Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Alberto Parise
- Department of Geriatric-Rehabilitation,, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Alessandra Costanza
- Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Geneva, Switzerland
- Department of Psychiatry, Faculty of Biomedical Sciences, University of Italian Switzerland (USI) Lugano, Switzerland
| | - Khoa D. Nguyen
- Department of Microbiology and Immunology, Stanford University, Palo Alto, CA, USA
- Tranquis Therapeutics, Palo Alto, CA, USA
| | - Daniele Saverino
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine (DiMeS), Section of Human Anatomy, University of Genoa, Genoa, Italy
| | - Domenico De Berardis
- NHS, Department of Mental Health, Psychiatric Service for Diagnosis and Treatment, Hospital “G. Mazzini”, Teramo, Italy
| | - Andrea Aguglia
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Andrea Escelsior
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Gianluca Serafini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Pasquale De Fazio
- Psychiatry Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Mario Amore
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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González-Rodríguez A, Cobo J, Seeman MV. Improving treatment of women with schizophrenia: a review of the recent literature. EXPLORATION OF MEDICINE 2023:985-1000. [DOI: 10.37349/emed.2023.00189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/13/2023] [Indexed: 03/05/2025] Open
Abstract
Effective clinical management of women with schizophrenia is therapeutically challenging. While there have been recent advances in the understanding of neurobiological, hormonal, and female reproductive cycle factors that play a decisive role in the development and progression of schizophrenia in women, this knowledge has not yet been fully translated into treatment practice. The aim was to apply the best evidence available to optimally treat women with schizophrenia at various periods of the lifespan. A narrative review was conducted of recent advances (2018–2023) in aspects of schizophrenia in women that demand sex-specific treatment. Sex steroids impact antipsychotic absorption, distribution, metabolism, elimination, passage through the blood-brain barrier, and blood flow rate to the brain. For these reasons, premenopausal women with schizophrenia, as compared to male age peers, require lower doses of most antipsychotic drugs and suffer comparatively more adverse events (metabolic, sexual, and cardiovascular) at similar doses. Apart from pharmacologic treatment, women have specific reproductive planning needs and need protection from sexual exploitation and domestic abuse. In addition, when pregnant, schizophrenia women show a high risk of gestational diabetes and pre-eclampsia/eclampsia that requires prevention. Prevention is also needed against long-term health hazards for their offspring. Another period of therapeutic challenge specific to women is menopause. The collected evidence points to women-specific recommendations for both biological and psychosocial treatment strategies for schizophrenia.
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Affiliation(s)
- Alexandre González-Rodríguez
- Department of Mental Health, Mutua Terrassa University Hospital, Fundació Docència i Recerca Mutua Terrassa, University of Barcelona, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 08221 Terrassa, Spain
| | - Jesús Cobo
- Department of Mental Health, Parc Tauli University Hospital, Autonomous University of Barcelona (UAB), Instituto de Investigación e Innovación Parc Taulí (I3PT), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 08208 Sabadell, Spain
| | - Mary V. Seeman
- Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada
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Barker LC, Vigod SN. Reproductive Health Among Those with Schizophrenia Spectrum Disorders: An Overview of Considerations Related to the Premenopausal Period, Pregnancy and Postpartum, and the Menopausal Transition, with a Focus on Recent Findings. Curr Psychiatry Rep 2023; 25:793-802. [PMID: 37906350 DOI: 10.1007/s11920-023-01472-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2023] [Indexed: 11/02/2023]
Abstract
PURPOSE OF REVIEW Schizophrenia spectrum disorders (SSD) impact many aspects of reproductive health for women and non-binary and transgender individuals assigned female at birth. In this narrative review, we highlight considerations and recent research related to (1) the premenopausal period, (2) pregnancy and postpartum, and (3) the menopausal transition. RECENT FINDINGS Most recent research has focused on pregnancy and the postpartum period, and specifically on elucidating perinatal risk factors, adverse obstetrical and neonatal outcomes (and modifiable contributors such as smoking), long-term child health, and psychotropic medications (with reassuring results related antipsychotic-associated gestational diabetes mellitus and neurodevelopmental outcomes). Much less recent focus has been on menstruation and menopause, although some research has highlighted the relative worsening of illness peri-menstrually and peri-menopausally. Despite the many important reproductive considerations for those with SSD, many aspects including menstruation and menopause have received very little attention. Further research is needed on how to best support women, non-binary, and transgender people assigned female at birth with SSD throughout the lifespan.
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Affiliation(s)
- Lucy C Barker
- Department of Psychiatry, University of Toronto, Toronto, Canada.
- Women's College Hospital, 76 Grenville Street, Toronto, ON, M5S 1B2, Canada.
| | - Simone N Vigod
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Women's College Hospital, 76 Grenville Street, Toronto, ON, M5S 1B2, Canada
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Brand BA, Willemse EJM, Hamers IMH, Sommer IE. Evidence-Based Recommendations for the Pharmacological Treatment of Women with Schizophrenia Spectrum Disorders. Curr Psychiatry Rep 2023; 25:723-733. [PMID: 37864676 PMCID: PMC10654163 DOI: 10.1007/s11920-023-01460-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2023] [Indexed: 10/23/2023]
Abstract
PURPOSE OF REVIEW Despite clear evidence that sex differences largely impact the efficacy and tolerability of antipsychotic medication, current treatment guidelines for schizophrenia spectrum disorders (SSD) do not differentiate between men and women. This review summarizes the available evidence on strategies that may improve pharmacotherapy for women and provides evidence-based recommendations to optimize treatment for women with schizophrenia. RECENT FINDINGS We systematically searched PubMed and Embase for peer-reviewed studies on three topics: (1) sex differences in dose-adjusted antipsychotic serum concentrations, (2) hormonal augmentation therapy with estrogen and estrogen-like compounds to improve symptom severity, and (3) strategies to reduce antipsychotic-induced hyperprolactinemia. Based on three database studies and one RCT, we found higher dose-adjusted concentrations in women compared to men for most antipsychotics. For quetiapine, higher concentrations were specifically found in older women. Based on two recent meta-analyses, both estrogen and raloxifene improved overall symptomatology. Most consistent findings were found for raloxifene augmentation in postmenopausal women. No studies evaluated the effects of estrogenic contraceptives on symptoms. Based on two meta-analyses and one RCT, adjunctive aripiprazole was the best-studied and safest strategy for lowering antipsychotic-induced hyperprolactinemia. Evidence-based recommendations for female-specific pharmacotherapy for SSD consist of (1) female-specific dosing for antipsychotics (guided by therapeutic drug monitoring), (2) hormonal replacement with raloxifene in postmenopausal women, and (3) aripiprazole addition as best evidenced option in case of antipsychotic-induced hyperprolactinemia. Combining these strategies could reduce side effects and improve outcome of women with SSD, which should be confirmed in future longitudinal RCTs.
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Affiliation(s)
- Bodyl A Brand
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Neuro Imaging Center 3111, Deusinglaan 2, 9713 AW, Groningen, the Netherlands.
| | - Elske J M Willemse
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Neuro Imaging Center 3111, Deusinglaan 2, 9713 AW, Groningen, the Netherlands
| | - Iris M H Hamers
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Neuro Imaging Center 3111, Deusinglaan 2, 9713 AW, Groningen, the Netherlands
| | - Iris E Sommer
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Neuro Imaging Center 3111, Deusinglaan 2, 9713 AW, Groningen, the Netherlands
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Dróżdż W, Wiciński M, Szota AM, Szambelan M, Radajewska I, Popławski I, Wojciechowski P. Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia-A Systematic Review. J Clin Med 2023; 12:4012. [PMID: 37373704 PMCID: PMC10299654 DOI: 10.3390/jcm12124012] [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: 04/14/2023] [Revised: 05/18/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
The aim of this review is to appraise the data from available randomized clinical trials (RCT) regarding the possible combinations of neuroleptic and non-antipsychotic treatment which could enhance antipsychotic therapy efficacy whilst simultaneously addressing somatic symptoms in individuals with schizophrenia. A systematic search of the PubMed database up to February 2022 was conducted. Inclusion criteria: randomized controlled trials using augmentation therapy in chronic schizophrenia in adults, written in English, and only studies with psychometric assessments of schizophrenia were incorporated. Exclusion criteria: non-clinical, first episode of schizophrenia, patients on medication other than antipsychotics augmented, and not adjunctive therapy. Overall, 37 studies of 1931 patients with schizophrenia who received a combination of antipsychotic medication with other drugs were selected. A statistically significant reduction of negative and positive symptoms of schizophrenia, measured with the PANSS scale, when using a combination of antipsychotic treatment along with aspirin, simvastatin, N-acetylcysteine, or pioglitazone was found. A combination of antipsychotic medication with aspirin, simvastatin, N-acetylcysteine, or pioglitazone seems to be effective in the reduction of symptoms of schizophrenia in adults, but long-term studies are required to confirm this effect.
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Affiliation(s)
- Wiktor Dróżdż
- Department of Psychiatry, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (W.D.); (I.R.)
| | - Michał Wiciński
- Department of Pharmacology and Therapy, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (M.W.); (M.S.); (I.P.); (P.W.)
| | - Anna Maria Szota
- Department of Psychiatry, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (W.D.); (I.R.)
| | - Monika Szambelan
- Department of Pharmacology and Therapy, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (M.W.); (M.S.); (I.P.); (P.W.)
| | - Izabela Radajewska
- Department of Psychiatry, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (W.D.); (I.R.)
| | - Igor Popławski
- Department of Pharmacology and Therapy, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (M.W.); (M.S.); (I.P.); (P.W.)
| | - Paweł Wojciechowski
- Department of Pharmacology and Therapy, Ludwig Rydygier Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń, Curie Skłodowskiej Street 9, 85-094 Bydgoszcz, Poland; (M.W.); (M.S.); (I.P.); (P.W.)
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Li Z, Wang Y, Wang Z, Kong L, Liu L, Li L, Tang Y. Estradiol and raloxifene as adjunctive treatment for women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Acta Psychiatr Scand 2023; 147:360-372. [PMID: 36585771 DOI: 10.1111/acps.13530] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/13/2022] [Accepted: 12/26/2022] [Indexed: 01/01/2023]
Abstract
OBJECTIVES We conducted a comprehensive meta-analysis of all available trials to evaluate the efficacy and safety of estrogen and selective estrogen receptor modulators as adjunctive treatment for women with schizophrenia. METHODS Multiple databases were searched from the inception until March 2022. Only randomized, double-blind, placebo-controlled studies (randomized controlled trials) were included. Mean differences (MDs) and their 95% confidence intervals (CIs) were calculated using random effects models. RESULTS The meta-analysis included six estradiol versus placebo studies (n = 724) and seven raloxifene versus placebo studies (n = 419), covering a total of 1143 patients. Adjunctive estradiol outperformed the placebo in terms of the Positive and Negative Syndrome Scale (PANSS) total score (MD = -7.29; 95% CI = -10.67 to -3.91; I2 = 59.1%; p < 0.001; k = 9; N = 858), positive symptom score (MD = -1.54; 95% CI = -3.04 to -0.72; I2 = 45.8%; p < 0.001; k = 7; N = 624), negative symptom score (MD = -1.9; 95% CI = -1.77 to -0.34; I2 = 37.6%; p < 0.05; k = 14; N = 1042), and general psychopathology score (MD = -4.27; 95% CI = -7.14 to -1.41; I2 = 76.3%; p < 0.005; k = 7; N = 624). Adjunctive raloxifene outperformed the placebo in terms of the PANSS total score (MD = -6.83; 95% CI = -11.69 to -1.97; I2 = 67.8%; p = 0.006; k = 8; N = 432) and general psychopathology score (MD = -3.82; 95% CI = -6.36 to -1.28; I2 = 65.3%; p < 0.005; k = 8; N = 432). CONCLUSIONS Our meta-analysis showed that estradiol and raloxifene are effective and safe adjunctive treatments that improve schizophrenia symptoms in women. Moreover, the effects of estradiol and raloxifene differed in terms of timing and dosage. Both are promising adjunctive treatments that merit further study.
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Affiliation(s)
- Zijia Li
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yucheng Wang
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, People's Republic of China
- School of Public Health, China Medical University, Shenyang, People's Republic of China
| | - Zhe Wang
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Lingtao Kong
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Linzi Liu
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Liu Li
- Shenyang Women's and Children's Hospital, Shenyang, People's Republic of China
| | - Yanqing Tang
- Department of Psychiatry and Geriatrics, The First Hospital of China Medical University, Shenyang, People's Republic of China
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12
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Correll CU, Solmi M, Cortese S, Fava M, Højlund M, Kraemer HC, McIntyre RS, Pine DS, Schneider LS, Kane JM. The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents. World Psychiatry 2023; 22:48-74. [PMID: 36640403 PMCID: PMC9840514 DOI: 10.1002/wps.21056] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2022] [Indexed: 01/15/2023] Open
Abstract
Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.
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Affiliation(s)
- Christoph U Correll
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA
- Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA
| | - Marco Solmi
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada
- Department of Mental Health, Ottawa Hospital, Ottawa, ON, Canada
- Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
| | - Samuele Cortese
- Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
- Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK
- Solent NHS Trust, Southampton, UK
- Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK
- Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA
| | - Maurizio Fava
- Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Mikkel Højlund
- Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, Odense, Denmark
- Mental Health Services in the Region of Southern Denmark, Department of Psychiatry Aabenraa, Aabenraa, Denmark
| | - Helena C Kraemer
- Department of Psychiatry and Behavioral Sciences, Stanford University, Cupertino, CA, USA
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Department of Pharmacology, University of Toronto, Toronto, ON, Canada
- Brain and Cognition Discovery Foundation, Toronto, ON, Canada
| | - Daniel S Pine
- Section on Developmental Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA
| | - Lon S Schneider
- Department of Psychiatry and Behavioral Sciences, and Department of Neurology, Keck School of Medicine, and L. Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - John M Kane
- Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA
- Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA
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13
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Khan MM. Role of de novo lipogenesis in insulin resistance in first-episode psychosis and therapeutic options. Neurosci Biobehav Rev 2022; 143:104919. [DOI: 10.1016/j.neubiorev.2022.104919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 10/07/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022]
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14
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González-Rodríguez A, Monreal JA, Seeman MV. The Effect of Menopause on Antipsychotic Response. Brain Sci 2022; 12:1342. [PMID: 36291276 PMCID: PMC9599119 DOI: 10.3390/brainsci12101342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/28/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022] Open
Abstract
Background: It has been hypothesized that, whenever estrogen levels decline, psychosis symptoms in women increase. At menopause, this can happen in two main ways: (a) the loss of estrogen (mainly estradiol) can directly affect central neurotransmission, leading to increase in schizophrenia-related symptoms, and (b) the loss of estrogen can decrease the synthesis of enzymes that metabolize antipsychotic drugs, thus weakening their efficacy. Aims and Methods: The aim of this narrative review was to investigate the second possibility by searching PubMed and ClinicalTrials.gov for studies over the last two decades that investigated the metabolism of antipsychotics and their efficacy before and after menopause in women or that studied systemic and local estrogen level effects on the pharmacokinetics and pharmacodynamics of individual antipsychotic drugs. Results: The evidence suggests that symptom level in women with schizophrenia rises after menopause for many reasons beyond hormones but, importantly, there is an estrogen-dependent loss of efficacy related to antipsychotic treatment. Conclusion: Effective clinical intervention is challenging; nevertheless, several promising routes forward are suggested.
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Affiliation(s)
- Alexandre González-Rodríguez
- Department of Mental Health, Mutua Terrassa University Hospital, Fundació Docència i Recerca Mutua Terrassa, University of Barcelona (UB), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 08221 Terrassa, Spain
| | - José A. Monreal
- Department of Mental Health, Mutua Terrassa University Hospital, Fundació Docència i Recerca Mutua Terrassa, University of Barcelona (UB), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 08221 Terrassa, Spain
- Institut de Neurociències, Universitat Autònoma de Barcelona, 08221 Terrassa, Spain
| | - Mary V. Seeman
- Department of Psychiatry, University of Toronto, Toronto, ON M5P 3L6, Canada
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15
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Influence of Menstrual Cycle Length and Age at Menarche on Symptoms, Cognition, Social Cognition, and Metacognition in Patients with First-Episode Psychosis. WOMEN 2022. [DOI: 10.3390/women2020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
A protective effect has traditionally been attributed to estrogen in psychotic disorders. The aim of this study was to investigate cumulative lifetime estrogen by assessing the menstrual cycle length, age at menarche, and years of difference between the onset of psychotic symptoms and the age of menarche, measuring their effects on symptoms, cognition, social cognition, and metacognition. As it was not possible to directly measure cumulative estrogen levels over the lifetime of a patient, the study sample was composed of 42 women with first-episode psychosis; estrogen levels were inferred by the menstrual cycle length, age at menarche, and years of difference between the onset of psychotic symptoms and menarche. All patients were assessed with a battery of questionnaires using the BDI, PSYRATS, PANSS, STROOP, TAVEC, WSCT, IPSAQ, and BCIS questionnaires. The results related to menstrual cycle length showed a relationship with memory; specifically, shorter cycles with semantic strategies (p = 0.046) and longer cycles with serial strategies in the short term (p = 0.005) as well as in the long term (p = 0.031). The results also showed a relationship with perseverative errors (p = 0.035) and self-certainty (p = 0.049). Only personalized bias (p = 0.030) was found to be significant in relation to the age at menarche. When analyzing the differences in years of difference between the age at menarche and the onset of psychotic symptoms, the results indicated lower scores in women with a smaller difference between both events in memory (short-term (p = 0.050), long-term (p = 0.024), intrusions (p = 0.013), and recognition (p = 0.043)) and non-perseverative errors (p = 0.024). No relationship was found between symptoms and menstrual characteristics. The investigatory outcomes seem to indicate a relationship between estrogen cumulative effects and the memory domain. More in-depth investigations in the field are necessary in order to improve personalized treatment in women with psychosis.
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16
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Schmidt PJ, Wei SM, Martinez PE, Ben Dor RR, Guerrieri GM, Palladino PP, Harsh VL, Li HJ, Wakim P, Nieman LK, Rubinow DR. The short-term effects of estradiol, raloxifene, and a phytoestrogen in women with perimenopausal depression. Menopause 2021; 28:369-383. [PMID: 33470755 PMCID: PMC9022873 DOI: 10.1097/gme.0000000000001724] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). METHODS Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. RESULTS Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. CONCLUSIONS This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).
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Affiliation(s)
- Peter J. Schmidt
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Shau-Ming Wei
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Pedro E. Martinez
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Rivka R. Ben Dor
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Gioia M. Guerrieri
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Paula P. Palladino
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Veronica L. Harsh
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Howard J. Li
- Section on Behavioral Endocrinology, National Institute of Mental Health, NIH, DHHS, Bethesda, MD
| | - Paul Wakim
- Biostatistics and Clinical Epidemiology Service, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Lynnette K. Nieman
- Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD
| | - David R. Rubinow
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC
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17
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Brand BA, de Boer JN, Oude Ophuis SB, Slot MI, De Wilde B, Catthoor KC, Goverde AJ, Bakker PR, Marcelis MC, Grootens KP, Luykx JJ, Heringa SM, Weickert CS, Sommer IE, Weickert TW. Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol. Contemp Clin Trials Commun 2020; 20:100681. [PMID: 33364517 PMCID: PMC7750317 DOI: 10.1016/j.conctc.2020.100681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/28/2020] [Accepted: 11/22/2020] [Indexed: 12/14/2022] Open
Abstract
Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.
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Key Words
- AE, Adverse event
- AF, alkaline phosphatase
- ALAT, alanine aminotransferase
- ANOVA, analysis of variance
- ANSS, positive and negative syndrome scale
- APTT, activated partial thrombin time
- ASAT, aspartate aminotransferase
- Antipsychotic medication
- BACS, Brief Assessment of Cognition in Schizophrenia
- BDI, Beck's Depression Inventory
- BNSS, Brief Negative Symptom scale
- CRP, C-reactive protein
- DHEA, dehydroepiandrosterone
- DNA, Deoxyribonucleic acid
- DSMB, Data Safety Monitoring Board
- EQ-5D-5L, Euro Quality of Life 5 Dimensions 5 Levels
- Estrogen
- FSH, follicle stimulating hormone
- GGZ Centraal, Psychiatric Center Geestelijke Gezondheidszorg Centraal
- GGzE, Geestelijke Gezondheidszorg Eindhoven
- HDL, high-density lipoprotein
- ICH-GCP, the International Conference on Harmonization – Good Clinical Practice
- IMCJE, International Committee of Medical Journal Editors
- LDL, low-density lipoprotein
- LHT, lithium heparin tube
- MINI, Mini International Neuropsychiatric Interview Plus
- PSP, Personal and Social Performance
- QALYs, Quality Adjusted Life Years
- Raloxifene
- Randomised controlled trial
- RvA, Reinier van Arkel Institute for Mental Health Care
- SAE, Serious Adverse Event
- SCT, sodium citrate tube
- SERM, selective estrogen receptor modulator
- SHBG, sex hormone-binding globulin
- SMD, standard mean difference
- SST, serum separator tube
- SUSAR, Suspected Unexpected Serious Adverse Reaction
- Schizophrenia
- TALD, Thought And Language Disorder scale
- ULN, upper limit of normal
- UMCG, University Medical Center Groningen
- UMCU, University Medical Center Utrecht
- WOCBP, Women of child bearing potential
- ZNA, Ziekenhuis Netwerk Antwerpen
- eGFR, estimated glomerular filtration rate
- iMTA-MCQ, institute for Medical Technology Assessment's Medical Consumption Questionnaire
- iMTA-PCQ, institute for Medical Technology Assessment's Productivity Cost Questionnaire
- psychotic disorder NOS, psychotic disorder not otherwise specified
- β-HCG, beta-human chorionic gonadotropin
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Affiliation(s)
- Bodyl A. Brand
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Janna N. de Boer
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Sebastianus B.J. Oude Ophuis
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
| | - Margot I.E. Slot
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
| | | | - Kirsten C.E.E.R. Catthoor
- Ziekenhuis Netwerk Antwerpen (ZNA), Antwerp, Belgium
- The Collaborative Antwerp Psychiatric Research Institute (CAPRI), Antwerp, Belgium
| | - Angelique J. Goverde
- Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands
| | - P. Roberto Bakker
- Arkin, Institute for Mental Health, Amsterdam, the Netherlands
- Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Machteld C. Marcelis
- Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
- Institute for Mental Health Care Eindhoven (GGzE), Eindhoven, the Netherlands
| | - Koen P. Grootens
- Reinier van Arkel Institute for Mental Health Care (RvA), ‘s Hertogenbosch, the Netherlands
| | - Jurjen J. Luykx
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
- Ziekenhuis Netwerk Antwerpen (ZNA), Antwerp, Belgium
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center, Utrecht, Utrecht University, Utrecht, the Netherlands
- Outpatient Second Opinion Clinic, GGNet Mental Health, Warnsveld, the Netherlands
| | - Sophie M. Heringa
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
- Isala, Department of Medical Psychology, Zwolle, the Netherlands
| | - Cynthia Shannon Weickert
- Neuroscience Research Australia, Randwick, New South Wales, Australia
- State University of New York, Upstate Medical University, Syracuse, NY, USA
| | - Iris E.C. Sommer
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, the Netherlands
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Thomas W. Weickert
- Neuroscience Research Australia, Randwick, New South Wales, Australia
- State University of New York, Upstate Medical University, Syracuse, NY, USA
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18
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Jeppesen R, Christensen RHB, Pedersen EMJ, Nordentoft M, Hjorthøj C, Köhler-Forsberg O, Benros ME. Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis. Brain Behav Immun 2020; 90:364-380. [PMID: 32890697 DOI: 10.1016/j.bbi.2020.08.028] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/07/2020] [Accepted: 08/28/2020] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking. METHOD Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes. RESULTS Seventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon. CONCLUSIONS Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.
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Affiliation(s)
- Rose Jeppesen
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
| | - Rune H B Christensen
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
| | - Emilie M J Pedersen
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
| | - Merete Nordentoft
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; iPSYCH The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
| | - Carsten Hjorthøj
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; iPSYCH The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; University of Copenhagen, Department of Public Health, Section of Epidemiology, Denmark
| | - Ole Köhler-Forsberg
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Michael E Benros
- Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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19
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Huerta-Ramos E, Labad J, Cobo J, Núñez C, Creus M, García-Parés G, Cuadras D, Franco J, Miquel E, Reyes JC, Marcó-García S, Usall J. Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Eur Arch Psychiatry Clin Neurosci 2020; 270:729-737. [PMID: 31728631 DOI: 10.1007/s00406-019-01079-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 10/24/2019] [Indexed: 12/13/2022]
Abstract
We assessed the utility of raloxifene (60 mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight began the clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60 mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.
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Affiliation(s)
- Elena Huerta-Ramos
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain. .,Fundació Sant Joan de Déu, Barcelona, Spain. .,Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain. .,Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
| | - Javier Labad
- Corporació Sanitària Parc Taulí, Barcelona, Spain
| | - Jesus Cobo
- Corporació Sanitària Parc Taulí, Barcelona, Spain
| | - Christian Núñez
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain.,Fundació Sant Joan de Déu, Barcelona, Spain.,Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | | | | | - Daniel Cuadras
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain.,Fundació Sant Joan de Déu, Barcelona, Spain.,Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | | | - Eva Miquel
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain
| | | | - Silvia Marcó-García
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain.,Fundació Sant Joan de Déu, Barcelona, Spain.,Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | | | - Judith Usall
- Parc Sanitari Sant Joan de Déu, C/Antoni Pujadas, 42. Sant Boi de Llobregat, 08830, Barcelona, Spain.,Fundació Sant Joan de Déu, Barcelona, Spain.,Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Institut de Recerca Sant Joan de Déu, Barcelona, Spain
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20
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Advances in the Conceptualization and Study of Schizophrenia in Later Life: 2020 Update. Clin Geriatr Med 2020; 36:221-236. [DOI: 10.1016/j.cger.2019.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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21
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Seiler N, Nguyen T, Yung A, O'Donoghue B. Terminology and assessment tools of psychosis: A systematic narrative review. Psychiatry Clin Neurosci 2020; 74:226-246. [PMID: 31846133 DOI: 10.1111/pcn.12966] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 12/05/2019] [Indexed: 12/20/2022]
Abstract
AIM Phenomena within the psychosis continuum that varies in frequency/duration/intensity have been increasingly identified. Different terms describe these phenomena, however there is no standardization within the terminology. This review evaluated the definitions and assessment tools of seven terms - (i) 'psychotic experiences'; (ii) 'psychotic-like experiences'; (iii) 'psychotic-like symptoms'; (iv) 'attenuated psychotic symptoms'; (v) 'prodromal psychotic symptoms'; (vi) 'psychotic symptomatology'; and (vii) 'psychotic symptoms'. METHODS EMBASE, MEDLINE, and CINAHL were searched during February-March 2019. Inclusion criteria included 1989-2019, full text, human, and English. Papers with no explicit definition or assessment tool, duplicates, conference abstracts, systematic reviews, meta-analyses, or no access were excluded. RESULTS A total of 2238 papers were identified and of these, 627 were included. Definitions and assessment tools varied, but some trends were found. Psychotic experiences and psychotic-like experiences were transient and mild, found in the general population and those at-risk. Psychotic-like symptoms were subthreshold and among at-risk populations and non-psychotic mental disorders. Attenuated psychotic symptoms were subthreshold but associated with distress, risk, and help-seeking. Prodromal psychotic symptoms referred to the prodrome of psychotic disorders. Psychotic symptomatology included delusions and hallucinations within psychotic disorders. Psychotic symptoms was the broadest term, encompassing a range of populations but most commonly involving hallucinations, delusions, thought disorder, and disorganization. DISCUSSION A model for conceptualizing the required terms is proposed and future directions needed to advance this field of research are discussed.
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Affiliation(s)
- Natalie Seiler
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,The University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Tony Nguyen
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,The University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Alison Yung
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Brian O'Donoghue
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
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22
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Vila È, Huerta-Ramos E, Núñez C, Usall J, Ramos B. Specificity proteins 1 and 4 in peripheral blood mononuclear cells in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Eur Arch Psychiatry Clin Neurosci 2019; 269:941-948. [PMID: 30167782 DOI: 10.1007/s00406-018-0938-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/09/2018] [Indexed: 12/23/2022]
Abstract
Accumulating evidence suggests that Specificity Protein 1 (SP1) and 4 (SP4) transcription factors are involved in the pathophysiology of schizophrenia. The therapeutic use of selective oestrogen modulators such as raloxifene added to antipsychotic drugs in the treatment of postmenopausal women with schizophrenia has been investigated in a few clinical trials, which reported an improvement in negative, positive, and general psychopathological symptoms. We aimed to investigate the possible association between peripheral SP protein levels and symptom improvement in postmenopausal women with schizophrenia treated with adjuvant raloxifene. In a subgroup of 14 postmenopausal women with schizophrenia from a 24-week, randomized, parallel, double-blind, placebo-controlled clinical trial (NCT015736370), we investigated changes in SP1 and SP4 protein levels in peripheral blood mononuclear cells. Participants were randomized to either 60 mg/day adjunctive raloxifene or placebo. Psychopathological symptoms were assessed at baseline and at week 24 with the Positive and Negative Syndrome Scale (PANSS). The expression of SP proteins was evaluated by immunoblot, and changes in PANSS scores and protein levels were compared at baseline and after 24 weeks of treatment. An improvement in symptoms was observed in the intervention group, but not in placebo group. Post-treatment protein levels of SP4, but not SP1, correlated with improvements in general and total PANSS subscales in the raloxifene intervention group. A reduction in SP4 levels was found after raloxifene treatment. These results suggest that SP4 may be involved in raloxifene symptom improvement in postmenopausal women and could be a potential candidate for future studies investigating blood-based biomarkers for raloxifene effectiveness.
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Affiliation(s)
- Èlia Vila
- Psiquiatria Molecular, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain
| | - Elena Huerta-Ramos
- Intervencions en Salut Mental, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain
- Parc Sanitari Sant Joan de Déu, Doctor Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Spain
- Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain
- Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain
| | - Christian Núñez
- Intervencions en Salut Mental, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain
- Parc Sanitari Sant Joan de Déu, Doctor Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Spain
- Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain
| | - Judith Usall
- Intervencions en Salut Mental, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain.
- Parc Sanitari Sant Joan de Déu, Doctor Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Spain.
- Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
- Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain.
| | - Belén Ramos
- Psiquiatria Molecular, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain.
- Parc Sanitari Sant Joan de Déu, Doctor Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Spain.
- Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
- Dept. de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
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23
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Çakici N, van Beveren NJM, Judge-Hundal G, Koola MM, Sommer IEC. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med 2019; 49:2307-2319. [PMID: 31439071 PMCID: PMC6763537 DOI: 10.1017/s0033291719001995] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 07/04/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). METHODS PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. RESULTS Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. CONCLUSIONS Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.
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Affiliation(s)
- N. Çakici
- Department of Psychiatry and Amsterdam Neuroscience, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Antes Center for Mental Health Care, Albrandswaardsedijk 74, 3172 AA, Poortugaal, the Netherlands
| | - N. J. M. van Beveren
- Antes Center for Mental Health Care, Albrandswaardsedijk 74, 3172 AA, Poortugaal, the Netherlands
- Department of Psychiatry, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
- Department of Neuroscience, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - G. Judge-Hundal
- Antes Center for Mental Health Care, Albrandswaardsedijk 74, 3172 AA, Poortugaal, the Netherlands
- Department of Psychiatry and Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Deusinglaan 2, 9713AW Groningen, the Netherlands
| | - M. M. Koola
- Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, 2300I St NW, Washington, DC 20052, USA
| | - I. E. C. Sommer
- Department of Psychiatry and Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Deusinglaan 2, 9713AW Groningen, the Netherlands
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Laird S, Ney LJ, Felmingham KL, Gogos A. Hormonal Contraception and the Brain: Examining Cognition and Psychiatric Disorders. CURRENT PSYCHIATRY RESEARCH AND REVIEWS 2019. [DOI: 10.2174/1573400515666190521113841] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background:The combined oral contraceptive pill (OC), containing synthetic estrogens and progestins, is used by millions of women worldwide, yet little is known about its effects on cognition or on psychiatric disorders. The progestin component of OCs determines their androgenicity, i.e. whether the OC has androgen binding components with masculinising effects or antiandrogenic components with feminising effects.Objective:The present review discusses the literature surrounding OC use and cognition in healthy women. Given the important role that sex hormones play in psychiatric disorders, we also consider the influence of OCs on symptoms of schizophrenia, post-traumatic stress disorder, depression, bipolar disorder, anxiety disorders and indirectly, sleep quality.Results:Research has shown that while there are no differences between OC users and non-users, androgenic OCs enhance visuospatial ability and anti-androgenic OCs enhance verbal fluency. Little is known about OCs effects on other cognitive domains, such as memory and executive function. There is little research examining OC use in schizophrenia, post-traumatic stress disorder, bipolar disorder and anxiety disorders. There is some evidence that OC use is associated with depression, however the exact causality of this association remains to be verified.Conclusion:We maintain that future studies need to address several methodological limitations, such as separating OCs based on androgenicity to avoid the masking effects that occur when various OCs are considered as one group. As this review highlights several significant effects of OC use on the brain, the implications of OC use needs to be considered in future research.
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Affiliation(s)
- Stephanie Laird
- School of Psychological Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Luke J. Ney
- School of Medicine (Psychology), University of Tasmania, Sandy Bay, TAS, Australia
| | - Kim L. Felmingham
- School of Psychological Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Andrea Gogos
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
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25
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Cho M, Lee TY, Kwak YB, Yoon YB, Kim M, Kwon JS. Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials. Aust N Z J Psychiatry 2019; 53:742-759. [PMID: 30864461 DOI: 10.1177/0004867419835028] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Recent evidence suggests that adjuvant anti-inflammatory agents could improve the symptoms of patients with schizophrenia. However, the effects of the adjuvant anti-inflammatory agents on cognitive function, general functioning and side effects have not yet been systematically investigated. The present meta-analysis aimed to explore the effects of anti-inflammatory agents in patients with schizophrenia comprehensively. METHOD We performed a literature search in online databases, including PubMed, EMBASE and the Cochrane Database of Systematic Reviews. Randomized, placebo-controlled double-blind studies that investigated clinical outcomes including psychopathology, neurocognition, general functioning and extrapyramidal side effects were included. The examined anti-inflammatory agents included aspirin, celecoxib, omega-3 fatty acids, estrogen, selective estrogen receptor modulator, pregnenolone, N-acetylcysteine, minocycline, davunetide and erythropoietin. RESULTS Sixty-two double-blind randomized clinical trials studying 2914 patients with schizophrenia met the inclusion criteria for quantitative analysis. Significant overall effects were found for anti-inflammatory agents for reducing total, positive and negative symptom scores in the Positive and Negative Syndrome Scale. Cognitive improvements were significant with minocycline and pregnenolone augmentation therapy. General functioning was significantly enhanced by overall anti-inflammatory agents. There were no significant differences in side effects compared with placebo. Baseline total Positive and Negative Syndrome Scale score and illness duration were identified as moderating factors in the effects of anti-inflammatory augmentation on psychiatric symptom improvements. CONCLUSION The comparative evaluation of efficacy and safety supported the use of anti-inflammatory adjuvant therapy over the use of antipsychotics alone. However, future studies could focus on patients with homogeneous clinical profile to figure out more detailed effects of anti-inflammatory therapy.
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Affiliation(s)
- Myeongju Cho
- 1 College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae Young Lee
- 2 Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Yoo Bin Kwak
- 3 Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Youngwoo Brian Yoon
- 3 Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Minah Kim
- 2 Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jun Soo Kwon
- 2 Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea.,3 Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
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26
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González-Rodríguez A, Seeman MV. The association between hormones and antipsychotic use: a focus on postpartum and menopausal women. Ther Adv Psychopharmacol 2019; 9:2045125319859973. [PMID: 31321026 PMCID: PMC6610461 DOI: 10.1177/2045125319859973] [Citation(s) in RCA: 23] [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: 11/17/2018] [Accepted: 04/01/2019] [Indexed: 12/17/2022] Open
Abstract
During the postpartum and menopausal periods of women's lives, there is a well-established and significant drop of circulating estrogens. This may be the reason why both these periods are associated with an increased risk for onset or exacerbation of psychiatric disorders. Whether symptoms are mainly affective or mainly psychotic, these disorders are frequently treated with antipsychotic medications, which calls for an examination of the relationship between hormone replacement and antipsychotic agents at these time periods. The aim of this narrative review is to summarize what is known about the association of hormones and antipsychotics in the postnatal period and at menopause. In the review, we focus on estrogen and oxytocin hormones and include, for the most part, only papers published within the last 10 years. Both estradiol and oxytocin have at various times been implicated in the etiology of postpartum disorders, and estrogens, sometimes combined with progesterone, have been tested as potential treatments for these conditions. The role of estradiol as an adjunct to antipsychotics in the prevention of postpartum relapses is currently controversial. With respect to oxytocin, studies are lacking. Psychosis in menopausal and postmenopausal women has been successfully treated with estrogens and selective estrogen-receptor modulators, mainly raloxifene, in addition to antipsychotics. Some symptoms appear to respond better than others. No oxytocin study has specifically targeted postmenopausal women. Because of feedback mechanisms, there is a theoretical danger of therapy with exogenous hormones interfering with endogenous secretion and disturbing the balance among inter-related hormones. When used with antipsychotics, hormones may also affect the metabolism and, hence, the brain level of specific antipsychotics. This makes treatment with antipsychotics plus hormones complicated. Dose, timing and route of intervention may all prove critical to efficacy. While much remains unknown, this literature review indicates that, within standard dose ranges, the combination of hormones and antipsychotics for postnatal and menopausal women suffering severe mental distress can be beneficial, and is safe.
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Affiliation(s)
| | - Mary V. Seeman
- Department of Psychiatry, University of Toronto,
260 Heath Street West, Suite 605, Toronto, Ontario M5P 3L6, Canada
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27
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Abstract
Women undergo developmental and cyclic changes in hormonal exposures that affect brain function and mental health. Some women are more vulnerable to the effects of these hormonal exposures, for reasons that remain to be determined. Evidence to date indicates that anxiety and mood disorders are the most sensitive to hormonal fluctuations in women but there is also growing evidence for a protective effect of female reproductive hormones on schizophrenia. The hormonal exposures of the menstrual cycle, pregnancy, the postpartum period, lactation, and menopause are quite different and may be associated with at least partially distinct symptom profiles.
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Affiliation(s)
- Margaret Altemus
- VA Connecticut Health Care System, Women's Clinic, Building 2, Room 7-165, 950 Campbell Avenue, New Haven, CT 06516, USA.
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28
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Zhao K, So HC. Drug Repositioning for Schizophrenia and Depression/Anxiety Disorders: A Machine Learning Approach Leveraging Expression Data. IEEE J Biomed Health Inform 2019; 23:1304-1315. [DOI: 10.1109/jbhi.2018.2856535] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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29
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Owens SJ, Weickert TW, Purves-Tyson TD, Ji E, White C, Galletly C, Liu D, O'Donnell M, Shannon Weickert C. Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia. MOLECULAR NEUROPSYCHIATRY 2019; 5:28-41. [PMID: 31019916 PMCID: PMC6465742 DOI: 10.1159/000495062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 11/01/2018] [Indexed: 12/25/2022]
Abstract
Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene's effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.
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Affiliation(s)
- Samantha J. Owens
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
| | - Thomas W. Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
| | - Tertia D. Purves-Tyson
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
| | - Ellen Ji
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
| | - Christopher White
- Department of Endocrinology, Prince of Wales Hospital, Randwick, New South Wales, Australia
| | - Cherrie Galletly
- Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
- Northern Adelaide Local Health Network, Adelaide, South Australia, Australia
| | - Dennis Liu
- Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
- Northern Adelaide Local Health Network, Adelaide, South Australia, Australia
| | - Maryanne O'Donnell
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
| | - Cynthia Shannon Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
- Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, New York, USA
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30
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The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review. J Psychiatr Res 2019; 108:57-83. [PMID: 30055853 DOI: 10.1016/j.jpsychires.2018.07.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 06/13/2018] [Accepted: 07/12/2018] [Indexed: 01/28/2023]
Abstract
Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia.
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Fraguas D, Díaz-Caneja CM, Pina-Camacho L, Umbricht D, Arango C. Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis. Schizophr Bull 2019; 45:57-68. [PMID: 29370436 PMCID: PMC6293224 DOI: 10.1093/schbul/sbx192] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We conducted a meta-regression analysis of all double-blind, randomized, placebo-controlled clinical trials (DBRCTs) reporting effects of drug and placebo on negative symptoms in people with stable schizophrenia and predominant or prominent negative symptoms to assess predictors of placebo response in these individuals. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews and meta-analyses to conduct a systematic literature search to identify DBRCTs assessing treatment efficacy on negative symptoms, as primary outcome, in patients with stable schizophrenia and predominant or prominent negative symptoms. We used Cohen's d, with 95% CIs, as the effect size measure for placebo response, based on negative symptom change scores from baseline to endpoint (range 4 to 24 wk) in the placebo-treated group. We included 18 DBRCTs from 17 publications, assessing the effect of 13 drugs vs placebo on negative symptoms and comprising 998 patients, in the meta-regression analyses. Overall, drugs showed greater efficacy than placebo in reducing negative symptoms, with small effect size (Cohen's d: 0.208, P = .020). Placebo response was significant (P < .001) and clinically relevant (Cohen's d: 2.909), but there was significant heterogeneity and high risk of publication bias. Multivariable meta-regression analyses showed that larger numbers of arms in the trial, larger numbers of study sites and industry sponsorship were significant moderators of placebo response in this population. Our results suggest that some clinical trial design and operational factors affect the level of placebo response in such studies, thus highlighting the need for designs better suited to assess these outcomes.
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Affiliation(s)
- David Fraguas
- Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM. Madrid, Spain
| | - Covadonga M Díaz-Caneja
- Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM. Madrid, Spain
| | - Laura Pina-Camacho
- Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM. Madrid, Spain
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Daniel Umbricht
- Neuroscience, Ophthalmology, Rare Diseases, Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Celso Arango
- Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM. Madrid, Spain
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Seeman MV. Women who suffer from schizophrenia: Critical issues. World J Psychiatry 2018; 8:125-136. [PMID: 30425943 PMCID: PMC6230925 DOI: 10.5498/wjp.v8.i5.125] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/24/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Many brain diseases, including schizophrenia, affect men and women unequally - either more or less frequently, or at different times in the life cycle, or to varied degrees of severity. With updates from recent findings, this paper reviews the work of my research group over the last 40 years and underscores issues that remain critical to the optimal care of women with schizophrenia, issues that overlap with, but are not identical to, the cares and concerns of men with the same diagnosis. Clinicians need to be alert not only to the overarching needs of diagnostic groups, but also to the often unique needs of women and men.
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Affiliation(s)
- Mary V Seeman
- Department of Psychiatry, University of Toronto, Institute of Medical Science, Toronto, ON M5P 3L6, Canada
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Khan MM. Translational Significance of Selective Estrogen Receptor Modulators in Psychiatric Disorders. Int J Endocrinol 2018; 2018:9516592. [PMID: 30402099 PMCID: PMC6196929 DOI: 10.1155/2018/9516592] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/10/2018] [Accepted: 09/02/2018] [Indexed: 12/11/2022] Open
Abstract
Accumulating data from various clinical trial studies suggests that adjuvant therapy with ovarian hormones (estrogens) could be effective in reducing cognitive deficit and psychopathological symptoms in women with psychiatric disorders. However, estrogen therapy poses serious limitations and health issues including feminization in men and increased risks of thromboembolism, hot flashes, breast hyperplasia, and endometrium hyperplasia when used for longer duration in older women (aged ≥ 60 years) or in women who have genetic predispositions. On the other hand, selective estrogen receptor modulators (SERMs), which may (or may not) carry some risks of hot flashes, thromboembolism, breast hyperplasia, and endometrial hyperplasia, are generally devoid of feminization effect. In clinical trial studies, adjuvant therapy with tamoxifen, a triphenylethylene class of SERM, has been found to reduce the frequency of manic episodes in patients with bipolar disorder, whereas addition of raloxifene, a benzothiophene class of SERM, to regular doses of antipsychotic drugs has been found to reduce cognitive deficit and psychological symptoms in men and women with schizophrenia, including women with treatment refractory psychosis. These outcomes together with potent neurocognitive, neuroprotective, and cardiometabolic properties suggest that SERMs could be the potential targets for designing effective and safer therapies for psychiatric disorders.
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Affiliation(s)
- Mohammad M. Khan
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Zawia, P.O. Box 16418, Az-Zawiyah, Libya
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Paipa N, Stephan-Otto C, Cuevas-Esteban J, Núñez-Navarro A, Usall J, Brébion G. Second-to-fourth digit length ratio is associated with negative and affective symptoms in schizophrenia patients. Schizophr Res 2018; 199:297-303. [PMID: 29503231 DOI: 10.1016/j.schres.2018.02.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 11/27/2022]
Abstract
BACKGROUND Higher levels of circulating oestrogens in women and testosterone in men have been shown to have a protective effect against the clinical manifestations of schizophrenia, mostly with respect to negative symptomatology. Certain studies suggest that they also have a protective effect against the neuropsychological impairment observed in the disease. We investigated whether greater prenatal exposure to estrogens in women and to testosterone in men, reflected by the 2D:4D ratio, was similarly associated with decreased negative symptomatology and improved neuropsychological functioning in patients. METHOD 51 schizophrenia patients and 50 healthy participants were administered a neuropsychological battery. The 2D:4D ratio was measured in all participants. Positive, negative, and affective symptoms were assessed in patients. Regression analyses were conducted separately in male and female subgroups. RESULTS No associations with positive symptoms were revealed. In male patients, the 2D:4D ratio was positively associated with avolition and inversely associated with anxiety. In female patients, it was inversely associated with alogia, and tended to be positively associated with depression. No association between higher prenatal concentration of the relevant sex hormone and improved neuropsychological performance emerged in patients. CONCLUSIONS Higher concentrations of prenatal testosterone in male patients, and prenatal oestrogens in female patients, are associated with a decrement in certain aspects of negative symptomatology. In addition, prenatal sex hormone concentration seems to be associated with predisposition to anxiety in male patients, and to depression in female patients.
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Affiliation(s)
- Nataly Paipa
- Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain
| | - Christian Stephan-Otto
- Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Jorge Cuevas-Esteban
- Servei de Psiquiatria, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Araceli Núñez-Navarro
- Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain
| | - Judith Usall
- Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Gildas Brébion
- Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
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Soria V, González-Rodríguez A, Huerta-Ramos E, Usall J, Cobo J, Bioque M, Barbero JD, García-Rizo C, Tost M, Monreal JA, Labad J. Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis. Psychoneuroendocrinology 2018; 93:8-19. [PMID: 29680774 DOI: 10.1016/j.psyneuen.2018.04.012] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 03/24/2018] [Accepted: 04/11/2018] [Indexed: 01/05/2023]
Abstract
Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause of functional disability. There is limited efficacy of pharmacological interventions for improving the cognitive deficits in these disorders. As pro-cognitive pharmacological treatments are lacking, hormones or drugs that target the endocrine system may become potential candidates for 'repurposing' trials aiming to improve cognition. We aimed to study whether treatment with drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis and sex steroids can improve cognition in patients with schizophrenia, MDD or BD. A systematic search was performed using PubMed (Medline), PsychInfo and clinicaltrials.gov, and a narrative synthesis was included. The systematic review identified 12 studies dealing with HPA-related drugs (mifepristone [n = 3], cortisol synthesis inhibitors [ketoconazole, n = 2], dehydroepiandrosterone [n = 5], fludrocortisone [n = 2]) and 14 studies dealing with sex steroids (oestradiol [n = 2], selective oestrogen receptor modulators [raloxifene, n = 7], pregnenolone [n = 5]). Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone). A replication of positive findings by at least two clinical trials was found for mifepristone in BD and raloxifene and pregnenolone in schizophrenia. The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.
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Affiliation(s)
- Virginia Soria
- Department of Psychiatry, Bellvitge University Hospital, Universitat de Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain
| | - Alexandre González-Rodríguez
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain
| | - Elena Huerta-Ramos
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Research and Development Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Judith Usall
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Research and Development Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Jesús Cobo
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain
| | - Miquel Bioque
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan David Barbero
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain
| | - Clemente García-Rizo
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Meritxell Tost
- Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain
| | - José Antonio Monreal
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain
| | | | - Javier Labad
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Mental Health, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, I3PT, Sabadell, Barcerlona, Spain.
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Zhu XM, Zheng W, Li XH, Cai DB, Yang XH, Ungvari GS, Ng CH, Wang XP, Kulkarni J, Grigg J, Ning YP, Xiang YT. Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Schizophr Res 2018; 197:288-293. [PMID: 29395611 DOI: 10.1016/j.schres.2018.01.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 11/26/2017] [Accepted: 01/17/2018] [Indexed: 01/16/2023]
Abstract
OBJECTIVE Raloxifene, a selective estrogen receptor modulator, has been used in treating postmenopausal women with schizophrenia with inconsistent results. This meta-analysis of randomized, double-blind, placebo-controlled trials (RCTs) examined its efficacy and safety for postmenopausal women with schizophrenia. METHOD Standardized mean differences (SMDs) and risk ratio (RR) together with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS The meta-analysis included 5 RCTs (n = 240) comparing raloxifene (n = 125, 60 or 120 mg/day) with placebo (n = 115). Adjunctive raloxifene outperformed placebo with regard to the Positive and Negative Syndrome Scale (PANSS) total psychopathology [n = 240, SMD:-0.64 (95%CI:-0.90, -0.37), P < 0.00001; I2 = 0%], positive symptoms [n = 240, SMD:-0.49 (95%CI:-0.81, -0.16), P = 0.003; I2 = 29%], negative symptoms [n = 240, SMD:-0.43 (95%CI:-0.68, -0.17), P = 0.001; I2 = 0%], and general psychopathology scores [n = 240, SMD:-0.66 (95%CI:-0.92, -0.39), P < 0.00001; I2 = 0%]. Both groups had similar rates of adverse events and discontinuation (n = 159, RR: 1.32 (95%CI: 0.65, 2.70), P = 0.44, I2 = 0%). CONCLUSION Adjunctive raloxifene appears to be effective and safe in improving psychotic symptoms for postmenopausal women with schizophrenia. Review registration: CRD 42017059946.
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Affiliation(s)
- Xiao-Min Zhu
- Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Wei Zheng
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Xiao-Hong Li
- The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Dong-Bin Cai
- Clinics of Chinese Medicine, The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin-Hu Yang
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Gabor S Ungvari
- The University of Notre Dame Australia/Graylands Hospital, Perth, Australia
| | - Chee H Ng
- Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
| | - Xiao-Ping Wang
- Mental Health Institute of the Second Xiangya Hospital, Hunan Province Technology Institute of Psychiatry & Key Laboratory of Psychiatry, Mental Health of Hunan Province, Central South University, China
| | - Jayashri Kulkarni
- Monash Alfred Psychiatry Research Centre, Alfred Hospital, Melbourne, Australia; Monash University Central Clinical School, Monash University, Melbourne, Australia
| | - Jasmin Grigg
- Monash Alfred Psychiatry Research Centre, Alfred Hospital, Melbourne, Australia; Monash University Central Clinical School, Monash University, Melbourne, Australia
| | - Yu-Ping Ning
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
| | - Yu-Tao Xiang
- Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China.
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Abstract
INTRODUCTION Reduced estrogen levels at menopause mean a loss of the neuroprotection that is conferred, from puberty until menopause, on women with schizophrenia. The postmenopausal stage of schizophrenia requires therapeutic attention because women with this diagnosis almost invariably experience increased symptoms and increased side effects at this time. So far, few targeted therapies have been successfully developed. AREAS COVERED This non-systematic, narrative review is based on the relevant published literature indexed in PubMed. A digital search was combined with a manual check of references from studies in the field of gender differences, menopause and schizophrenia. Aside from the inclusion of a few early classic papers, the review focuses on 21st century basic, psychopharmacologic, and clinical literature on the treatment of women with schizophrenia after menopause. EXPERT OPINION Beyond a relatively low dose threshold, all antipsychotic medications have adverse effects, which become more prominent for women at the time of menopause. Estrogen modulators may not help all symptoms of schizophrenia but are, nevertheless, relatively safe and, when used as adjuncts, help to keep antipsychotic doses low, thus reducing the side effect burden. The field is currently moving towards precision medicine and individual genetic profiles will help to determine the efficacy of available treatments in the future.
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Affiliation(s)
| | - Mary V Seeman
- b Department of Psychiatry , University of Toronto , Toronto , Canada
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Seeman MV, González-Rodríguez A. Use of psychotropic medication in women with psychotic disorders at menopause and beyond. Curr Opin Psychiatry 2018; 31:183-192. [PMID: 29528895 DOI: 10.1097/yco.0000000000000410] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Drugs have been extensively prescribed for the treatment of psychotic symptoms in schizophrenia and related disorders, as well as for the management of psychotic features in delirium, dementia and affective disorders. The aim of this narrative review is to focus on the recent literature on drug treatment in women with psychosis at the transition to menopause and subsequently. RECENT FINDINGS The recent literature emphasizes the following points: the efficacy of antipsychotic medication in psychosis is largely confined to the alleviation of delusions and hallucinations; menopause and ageing alter the kinetics and dynamics of drug action; drugs other than antipsychotics are currently being tested to address the cognitive, affective and negative symptoms of psychotic illnesses; menopausal symptoms add to comorbidities and require simultaneous treatment, raising the probability of deleterious drug interactions; antipsychotic drugs have many side effects and contribute to high mortality rates in the older psychosis population. SUMMARY A major implication for research is that antipsychotic drugs with a wider range of action and with fewer side effects are urgently needed. The clinical implications of the pharmacotherapy of psychotic illness are: older women's needs must be assessed through a comprehensive history and review of systems and physical and mental examination. To avoid adverse effects, drug dosages are best kept low and polypharmacy avoided wherever possible. It is important to frequently reassess older patients, as their pharmacotherapy requirements change with age and with comorbidity.
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Affiliation(s)
- Mary V Seeman
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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Abstract
A crisis looms as research and clinical programs have not kept pace with dramatic increases in the number of older adults with schizophrenia. This article provides an overview of the advances in the conceptualization and study of schizophrenia in later life. Theoretic and clinical models in psychiatry and gerontology are integrated. Specifically, recovery is examined in the context of aging, how clinical dimensionality affects diagnoses in older adults, how various features of schizophrenia are implicated in models of accelerated and paradoxic aging, and how outcome in later life is a more dynamic and heterogeneous than assumed previously.
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Wang Q, Dong X, Wang Y, Li X. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a meta-analysis of randomized controlled trials. Arch Womens Ment Health 2018; 21:31-41. [PMID: 28849318 DOI: 10.1007/s00737-017-0773-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 08/21/2017] [Indexed: 12/21/2022]
Abstract
The aim of this study is to meta-analytically assess the efficacy and safety of adjunctive raloxifene for postmenopausal women with schizophrenia. Six studies with 440 patients, including 225 (51.14%) patients on raloxifene and 215 (48.86%) on placebo who completed 13.71 ± 5.09 weeks of treatment, were included in this study. Meta-analysis of Positive and Negative Syndrome Scale total scores and positive, negative, and general symptom scores [standard mean difference (SMD) -0.22 to -0.55, 95% confidence interval (CI) -1.01 to -0.02, p = 0.04-0.01; I 2 = 74-79%] revealed an advantage of adjunctive raloxifene treatment over placebo treatment. There was no significant difference regarding discontinuation rate [risk ratio (RR) = 1.38, p = 0.51] and adverse drug reactions (RR = 1.27, p = 0.57) between the two groups. This meta-analysis showed that adjunctive raloxifene appears to be efficacious and safe for postmenopausal women with schizophrenia. Moreover, raloxifene may be efficacious for patients with less severe symptoms. Future studies with a large sample size are needed to confirm these findings.
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Affiliation(s)
- Qi Wang
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjingbei Street, Shenyang, Liaoning, 110001, China
| | - Xiaomei Dong
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjingbei Street, Shenyang, Liaoning, 110001, China
| | - Yan Wang
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjingbei Street, Shenyang, Liaoning, 110001, China
| | - Xiaobai Li
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjingbei Street, Shenyang, Liaoning, 110001, China.
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Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C. Considering the role of adolescent sex steroids in schizophrenia. J Neuroendocrinol 2018; 30. [PMID: 28941299 DOI: 10.1111/jne.12538] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 09/06/2017] [Accepted: 09/20/2017] [Indexed: 12/29/2022]
Abstract
Schizophrenia is a disabling illness that is typically first diagnosed during late adolescence to early adulthood. It has an unremitting course and is often treatment-resistant. Many clinical aspects of the illness suggest that sex steroid-nervous system interactions may contribute to the onset, course of symptoms and the cognitive impairment displayed by men and women with schizophrenia. Here, we discuss the actions of oestrogen and testosterone on the brain during adolescent development and in schizophrenia from the perspective of experimental studies in animals, human post-mortem studies, magnetic resonance imaging studies in living humans and clinical trials of sex steroid-based treatments. We present evidence of potential beneficial, as well as detrimental, effects of both testosterone and oestrogen. We provide a rationale for the necessity to further elucidate sex steroid mechanisms of action at different ages, sexes and brain regions to more fully understand the role of testosterone and oestrogen in the pathophysiology of schizophrenia. The weight of the evidence suggests that sex steroid hormones influence mammalian brain function, including both cognition and emotion, and that pharmaceutical agents aimed at sex steroid receptors appear to provide a novel treatment avenue to reduce symptoms and improve cognition in men and women with schizophrenia.
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Affiliation(s)
- S J Owens
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia
- Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - C E Murphy
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia
- Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - T D Purves-Tyson
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia
- Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - T W Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia
- Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - C Shannon Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia
- Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
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de Boer J, Prikken M, Lei WU, Begemann M, Sommer I. The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis. NPJ SCHIZOPHRENIA 2018; 4:1. [PMID: 29321530 PMCID: PMC5762671 DOI: 10.1038/s41537-017-0043-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/18/2017] [Accepted: 12/18/2017] [Indexed: 12/20/2022]
Abstract
Recognizing the robust sex differences in schizophrenia prevalence, the selective estrogen receptor modulator (SERM) raloxifene is a likely candidate for augmentation therapy in this disorder. Therefore, a systematic search was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Randomized controlled trials investigating the effect of raloxifene in schizophrenia spectrum disorders were included in the quantitative analyses. Outcome measures were psychotic symptom severity, depression, and cognition. Meta-analyses were performed using Comprehensive Meta-Analysis software. A random-effects model was used to compute overall weighted effect sizes in Hedges’ g. Nine studies were included, investigating 561 patients with a schizophrenia spectrum disorder. Raloxifene was superior to placebo in improving total symptom severity (N = 482; Hedge’s g = .57, p = 0.009), as well as positive (N = 561; Hedge’s g = 0.32, p = 0.02), negative (N = 561; Hedge’s g = 0.40, p = 0.02), and general (N = 526; Hedge’s g = 0.46, p = 0.01) subscales, as measured by the Positive and Negative Syndrome Scale. No significant effects were found for comorbid depression and cognitive functioning. Altogether, these results confirm the potential of raloxifene augmentation in the treatment of schizophrenia.
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Affiliation(s)
- Janna de Boer
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University & Brain Center Rudolf Magnus, Utrecht, The Netherlands.
| | - Merel Prikken
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University & Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Wan U Lei
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University & Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Marieke Begemann
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University & Brain Center Rudolf Magnus, Utrecht, The Netherlands
| | - Iris Sommer
- Department of Neuroscience and Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
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McGregor C, Riordan A, Thornton J. Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms. Front Neuroendocrinol 2017; 47:19-33. [PMID: 28673758 DOI: 10.1016/j.yfrne.2017.06.003] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 06/25/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023]
Abstract
Schizophrenia is a complex neuropsychiatric illness with marked sex differences. Women have later onset and lesser symptoms, which has led to the hypothesis that estrogens are protective in schizophrenia. Cognitive dysfunction is a hallmark of the disease and the symptom most correlated with functional outcome. Here we describe a number of mechanisms by which estrogens may be therapeutic in schizophrenia, with a focus on cognitive symptoms. We review the relationship between estrogens and brain derived neurotrophic factor, neuroinflammation, NMDA receptors, GABA receptors, and luteinizing hormone. Exploring these pathways may enable novel treatments for schizophrenia and a greater understanding of this devastating disease.
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Affiliation(s)
- Claire McGregor
- Department of Neuroscience, Oberlin College, 119 Woodland St, Oberlin, OH 44074, USA.
| | - Alexander Riordan
- Department of Neuroscience, Oberlin College, 119 Woodland St, Oberlin, OH 44074, USA
| | - Janice Thornton
- Department of Neuroscience, Oberlin College, 119 Woodland St, Oberlin, OH 44074, USA
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Abstract
Women undergo developmental and cyclic changes in hormonal exposures that affect brain function and mental health. Some women are more vulnerable to the effects of these hormonal exposures, for reasons that remain to be determined. Evidence to date indicates that anxiety and mood disorders are the most sensitive to hormonal fluctuations in women but there is also growing evidence for a protective effect of female reproductive hormones on schizophrenia. The hormonal exposures of the menstrual cycle, pregnancy, the postpartum period, lactation, and menopause are quite different and may be associated with at least partially distinct symptom profiles.
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Affiliation(s)
- Margaret Altemus
- VA Connecticut Health Care System, Women's Clinic, Building 2, Room 7-165, 950 Campbell Avenue, New Haven, CT 06516, USA.
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Abstract
OBJECTIVE The aim of this review is to examine three questions: What are the risks and benefits of treating women with schizophrenia with hormone therapy (HT) at menopause? Should the antipsychotic regimen be changed at menopause? Do early- and late-onset women with schizophrenia respond differently to HT at menopause? METHODS MEDLINE databases for the years 1990 to 2016 were searched using the following interactive terms: schizophrenia, gender, menopause, estrogen, and hormones. The selected articles (62 out of 800 abstracts) were chosen on the basis of their applicability to the objectives of this targeted narrative review. RESULTS HT during the perimenopause in women with schizophrenia ameliorates psychotic and cognitive symptoms, and may also help affective symptoms. Vasomotor, genitourinary, and sleep symptoms are also reduced. Depending on the woman's age and personal risk factors and antipsychotic side effects, the risk of breast cancer and cardiovascular disease may be increased. Antipsychotic types and doses may need to be adjusted at menopause, as may be the mode of administration. CONCLUSIONS Both HT and changes in antipsychotic management should be considered for women with schizophrenia at menopause. The question about differences in response between early- and late-onset women cannot yet be answered.
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Affiliation(s)
- Amnon Brzezinski
- 1Department of Obstetrics and Gynecology, The Hebrew University-Hadasssah Medical Center, Jerusalem, Israel 2Ben-Gurion University Medical School, Beer-Sheba, Israel 3Department of Psychiatry, University of Toronto, Canada
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Joseph J, Depp C, Shih PAB, Cadenhead KS, Schmid-Schönbein G. Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Front Neurosci 2017; 11:155. [PMID: 28396623 PMCID: PMC5366345 DOI: 10.3389/fnins.2017.00155] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/10/2017] [Indexed: 12/14/2022] Open
Abstract
Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia.
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Affiliation(s)
- Jamie Joseph
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
| | - Colin Depp
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
- Department of Psychology, VA San Diego Healthcare SystemSan Diego, CA, USA
| | - Pei-an B. Shih
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
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Riecher-Rössler A. Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses. Lancet Psychiatry 2017; 4:63-72. [PMID: 27856396 DOI: 10.1016/s2215-0366(16)30379-0] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 07/07/2016] [Accepted: 07/25/2016] [Indexed: 02/07/2023]
Abstract
Interest is growing in the potential effect of gonadal hormones, prolactin, and the hypothalamic-pituitary-gonadal axis in schizophrenic psychoses. Many studies from clinical, epidemiological, and fundamental research have confirmed that oestradiol, the main component of oestrogens, can have protective effects in schizophrenic psychoses. Furthermore, many patients with schizophrenic psychoses-even in the untreated prodromal stages-have hyperprolactinaemia and gonadal dysfunction, with oestrogen deficiency in women and testosterone deficiency in men. The understanding of the pathogenetic mechanisms underlying these findings could contribute to a better understanding of the aetiopathogenesis of schizophrenic psychoses and improve therapeutic approaches. In this Series paper, we aim to review methodologically sound studies in this area, propose a theory to explain these findings in the context of psychosis, and suggest therapeutic strategies and implications for further research.
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Affiliation(s)
- Anita Riecher-Rössler
- Center for Gender Research and Early Detection, University of Basel Psychiatric Clinics, Basel, Switzerland.
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Naguy A, Fatehi S. Schizophrenia in Women-A Different Phenotype? Arch Womens Ment Health 2016; 19:1153. [PMID: 27565803 DOI: 10.1007/s00737-016-0662-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 08/22/2016] [Indexed: 11/25/2022]
Affiliation(s)
- Ahmed Naguy
- Child/Adolescent Psychiatrist, Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH), Jamal Abdul-Nassir St, Shuwaikh, State of Kuwait.
| | - Shima Fatehi
- Child Psychologist, ASD Clinic, Al-Manara Centre, KCMH, Shuwaikh, State of Kuwait
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Khan MM. Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia. CNS Drugs 2016; 30:589-601. [PMID: 27193386 DOI: 10.1007/s40263-016-0343-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Raloxifene is a selective estrogen receptor modulator that has been approved for treating osteoporosis and breast cancer in high-risk postmenopausal women. However, recent evidence suggests that raloxifene adjunct therapy improves cognition and reduces symptom severity in men and women with schizophrenia. In animal models, raloxifene increases forebrain neurogenesis and enhances working memory and synaptic plasticity. It may consequently repair the neuronal and synaptic connectivity that is disrupted in schizophrenia. It also reduces oxidative stress and neuroinflammation, which are potent etiological factors in the neuropathology of schizophrenia. Furthermore, in postmenopausal women, raloxifene reduces the risks for atherosclerosis, diabetes mellitus, and weight gain, which are serious adverse effects associated with long-term antipsychotic treatment in schizophrenia; therefore, it may improve the safety and efficacy of antipsychotic drugs. In this review, recent insights into the neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene in relation to therapeutic outcomes in schizophrenia are discussed.
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Affiliation(s)
- Mohammad M Khan
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Zawia, Jamal Abdul Nassre Street, P.O. Box 16418, Az-Zawiyah, Libya.
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Abstract
Interest in the negative symptoms of schizophrenia has increased rapidly over the last several decades, paralleling a growing interest in functional, in addition to clinical, recovery, and evidence underscoring the importance negative symptoms play in the former. Efforts continue to better define and measure negative symptoms, distinguish their impact from that of other symptom domains, and establish effective treatments as well as trials to assess these. Multiple interventions have been the subject of investigation, to date, including numerous pharmacological strategies, brain stimulation, and non-somatic approaches. Level and quality of evidence vary considerably, but to this point, no specific treatment can be recommended. This is particularly problematic for individuals burdened with negative symptoms in the face of mild or absent positive symptoms. Presently, clinicians will sometimes turn to interventions that are seen as more “benign” and in line with routine clinical practice. Strategies include use of atypical antipsychotics, ensuring the lowest possible antipsychotic dose that maintains control of positive symptoms (this can involve a shift from antipsychotic polypharmacy to monotherapy), possibly an antidepressant trial (given diagnostic uncertainty and the frequent use of these drugs in schizophrenia), and non-somatic interventions (e.g., cognitive behavioral therapy, CBT). The array and diversity of strategies currently under investigation highlight the lack of evidence-based treatments and our limited understanding regarding negative symptoms underlying etiology and pathophysiology. Their onset, which can precede the first psychotic break, also means that treatments are delayed. From this perspective, identification of biomarkers and/or endophenotypes permitting earlier diagnosis and intervention may serve to improve treatment efficacy as well as outcomes.
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