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Carsten Korth - One of the best experts on this subject based on the ideXlab platform.
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Protein misassembly and aggregation as potential convergence points for non-genetic causes of Chronic Mental illness
Molecular Psychiatry, 2019Co-Authors: Nicholas J. Bradshaw, Carsten KorthAbstract:Chronic Mental Illnesses (CMI), such as schizophrenia or recurrent affective disorders, are complex conditions with both genetic and non-genetic elements. In many other Chronic brain conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia, sporadic instances of the disease are more common than gene-driven familial cases. Yet, the pathology of these conditions can be characterized by the presence of aberrant protein homeostasis, proteostasis, resulting in misfolded or aggregated proteins in the brains of patients that predominantly do not derive from genetic mutations. While visible deposits of aggregated protein have not yet been detected in CMI patients, we propose the existence of more subtle protein misassembly in these conditions, which form a continuum with the psychiatric phenotypes found in the early stages of many neurodegenerative conditions. Such proteinopathies need not rely on genetic variation. In a similar manner to the established aberrant neurotransmitter homeostasis in CMI, aberrant homeostasis of proteins is a functional statement that can only partially be explained by, but is certainly complementary to, genetic approaches. Here, we review evidence for aberrant proteostasis signatures from post mortem human cases, in vivo animal work, and in vitro analysis of candidate proteins misassembled in CMI. The five best-characterized proteins in this respect are currently DISC1, dysbindin-1, CRMP1, TRIOBP-1, and NPAS3. Misassembly of these proteins with inherently unstructured domains is triggered by extracellular stressors and thus provides a converging point for non-genetic causes of CMI.
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molecular linking of influenza infection to cellular pathology of protein misassembly the case of disrupted in schizophrenia 1 disc1
European Neuropsychopharmacology, 2018Co-Authors: Rita Marreiros, Suganya Selvarajah, Vishwanath R. Lingappa, Ingrid Prikulis, Andreas Mullerschiffmann, A R Moreira, S Sahu, I Soloviev, Carsten KorthAbstract:Chronic Mental Illnesses such as schizophrenia or recurrent affective disorders are heterogeneous in their biological causes behind the clinical, syndromatic diagnosis. Viral infection has been linked to Chronic Mental Illnesses both by direct mechanisms and indirect mechanisms through immune stimulation. For example, studies showed that intrauterine influenza infection could be a risk factor for Chronic Mental illness [1]. It is also established that viral infection can lead to a change in proteostasis impairing regulatory protein networks and leading to disease. The most dramatic consequences of disrupted proteostasis are the so-called protein misfolding diseases that show as a phenotypical hallmark, microscopically visible deposits of one or several proteins, and cell degeneration. More subtle forms of proteostatic imbalance exist where protein deposits are not microscopically visible and the neurons do not die but remain functionally impaired, for example in some forms of Chronic Mental illness such as schizophrenia [2]. We previously reported insoluble Disrupted-in-schizophrenia 1 (DISC1) protein in a subpopulation of patients with Chronic Mental illness [3]. This gene/protein is involved in vulnerability to Chronic Mental disorders, and was discovered mutant and segregating in a large Scottish pedigree with a chromosomal translocation leading to a 3′ truncation of the gene [4]. Subsequent genetic association studies in multiple populations of different ethnicities also support the involvement of this protein in Mental illness. For the present study, our hypothesis was that influenza infection could cause significant long-term impairments of specific proteostatic pathways leading to aggregated DISC1 protein in Chronic Mental illness patients [5]. Neuroblastoma cell lines expressing inducible full-length, non-mutant DISC1 protein were infected with WSN33 influenza (H1N1 strain). The effect of viral infection was investigated by immunocytochemistry, biochemical and functional assays. Furthermore, infected mice with WSN33 influenza where investigated for insoluble DISC1 deposits by immunohistochemistry. Antiviral drugs were tested in order to reverse the influenza-induced DISC1 aggregates. Influenza infection of cell lines induced DISC1 misassembly but not misassembly of the protein TDP43 known to be mislocalized in ALS, but not in Mental illness or influenza, and therefore serving as a control for specificity of DISC1 mis-assembly upon influenza infection in cellular models. Appearance of DISC1 deposits was dependent on infectious influenza virus titer, and the infection time. Functional consequences of influenza-induced DISC1 misassembly will be reported, as well as our investigations of influenza-infected mice that are still ongoing. We conclude that influenza infection leads to a very specific proteostatic change, including the misassembly of DISC1, which has functional consequences for dopamine homeostasis. Thus a selective reprogramming of cellular homeostasis, as measured by proteostasis, may be a novel molecular mechanism by which influenza infection can lead to brain disease.
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Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine
Open Biology, 2017Co-Authors: Seng Zhu, Carsten Korth, Saïda Abounit, Chiara ZurzoloAbstract:The disrupted-in-schizophrenia 1 (DISC1) gene was identified as a genetic risk factor for Chronic Mental Illnesses (CMI) such as schizophrenia, bipolar disorder and severe recurrent depression. Insoluble aggregated DISC1 variants were found in the cingular cortex of sporadic, i.e. non-genetic, CMI patients. This suggests protein pathology as a novel, additional pathogenic mechanism, further corroborated in a recent transgenic rat model presenting DISC1 aggregates. Since the potential role of aggregation of DISC1 in sporadic CMI is unknown, we investigated whether DISC1 undergoes aggregation in cell culture and could spread between neuronal cells in a prion-like manner, as shown for amyloid proteins in neurodegenerative diseases. Co-culture experiments between donor cells forming DISC1 aggregates and acceptor cells showed that 4.5% of acceptor cells contained donor-derived DISC1 aggregates, thus indicating an efficient transfer in vitro DISC1 aggregates were found inside tunnelling nanotubes (TNTs) and transfer was enhanced by increasing TNT formation and notably by dopamine treatment, which also induces DISC1 aggregation. These data indicate that DISC1 aggregates can propagate between cells similarly to prions, thus providing some molecular basis for the role of protein pathology in CMI.
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Viral capsid assembly as a model for protein aggregation diseases: Active processes catalyzed by cellular assembly machines comprising novel drug targets.
Virus Research, 2014Co-Authors: Rita Marreiros, Andreas Müller-schiffmann, Verian Bader, Suganya Selvarajah, Debendranath Dey, Vishwanath R. Lingappa, Carsten KorthAbstract:Abstract Viruses can be conceptualized as self-replicating multiprotein assemblies, containing coding nucleic acids. Viruses have evolved to exploit host cellular components including enzymes to ensure their replicative life cycle. New findings indicate that also viral capsid proteins recruit host factors to accelerate their assembly. These assembly machines are RNA-containing multiprotein complexes whose composition is governed by allosteric sites. In the event of viral infection, the assembly machines are recruited to support the virus over the host and are modified to achieve that goal. Stress granules and processing bodies may represent collections of such assembly machines, readily visible by microscopy but biochemically labile and difficult to isolate by fractionation. We hypothesize that the assembly of protein multimers such as encountered in neurodegenerative or other protein conformational diseases, is also catalyzed by assembly machines. In the case of viral infection, the assembly machines have been modified by the virus to meet the virus’ need for rapid capsid assembly rather than host homeostasis. In the case of the neurodegenerative diseases, it is the monomers and/or low n oligomers of the so-called aggregated proteins that are substrates of assembly machines. Examples for substrates are amyloid β peptide (Aβ) and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, prions in the prion diseases, Disrupted-in-schizophrenia 1 (DISC1) in subsets of Chronic Mental Illnesses, and others. A likely continuum between virus capsid assembly and cell-to-cell transmissibility of aggregated proteins is remarkable. Protein aggregation diseases may represent dysfunction and dysregulation of these assembly machines analogous to the aberrations induced by viral infection in which cellular homeostasis is pathologically reprogrammed. In this view, as for viral infection, reset of assembly machines to normal homeostasis should be the goal of protein aggregation therapeutics. A key basis for the commonality between viral and neurodegenerative disease aggregation is a broader definition of assembly as more than just simple aggregation, particularly suited for the crowded cytoplasm. The assembly machines are collections of proteins that catalytically accelerate an assembly reaction that would occur spontaneously but too slowly to be relevant in vivo . Being an enzyme complex with a functional allosteric site, appropriated for a non-physiological purpose (e.g. viral infection or conformational disease), these assembly machines present a superior pharmacological target because inhibition of their active site will amplify an effect on their substrate reaction. Here, we present this hypothesis based on recent proof-of-principle studies against Aβ assembly relevant in Alzheimer's disease.
Alec Sultana - One of the best experts on this subject based on the ideXlab platform.
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token economy for schizophrenia
Cochrane Database of Systematic Reviews, 2000Co-Authors: Tom Mcmonagle, Alec SultanaAbstract:Background A token economy is a behavioural therapy technique in which the desired change is achieved by means of tokens administered for the performance of predefined behaviours according to a program. Though token economy programmes were widespread in the 1970s they became largely restricted to wards where long-stay patients from institutions are prepared for transfer into the community and were particularly aimed at changing negative symptoms of schizophrenia - poor motivation, poor attention and social withdrawal. Objectives To review the effects of token economies for people with schizophrenia, or other serious or Chronic Mental Illnesses, compared with standard care. Search methods Electronic searches of Biological Abstracts (1985-1999), CINAHL (1982-1998), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register of Trials (February 1999), EMBASE (1980-1999) and PsycLIT (1987-1998) were supplemented with reference searches, personal contact with trial authors and hand searches. Selection criteria Randomised studies comparing a token economy regime (one in which change is achieved by means of use of non-monetary, non-consumable tokens) to standard care for those with schizophrenia or any other similar Chronic or serious Mental illness. Data collection and analysis Studies were reliably selected, quality rated and data extracted. For dichotomous data relative risk (RR) with 95% confidence intervals (CI) was estimated. Where possible, the number needed to treat statistic (NNT) was also calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. Main results Only three randomised controlled trials could be included in the analyses (total n=110). There were no usable data on target or non-target behaviour. One small study favoured the token economy approach for the outcome 'change in Mental state' on the SANS-CV with improvement in negative symptoms at three months (n=40, WMD -12.7, CI -21.44 to -3.96). Authors' conclusions The token economy approach may have effects on negative symptoms but it is unclear if these results are reproducible, clinically meaningful and are maintained beyond the treatment programme. Token economy remains worthy of careful evaluation in well designed, conducted and reported randomised trials.
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The Cochrane Library - Token economy for schizophrenia
Cochrane Database of Systematic Reviews, 2000Co-Authors: Tom Mcmonagle, Alec SultanaAbstract:Background A token economy is a behavioural therapy technique in which the desired change is achieved by means of tokens administered for the performance of predefined behaviours according to a program. Though token economy programmes were widespread in the 1970s they became largely restricted to wards where long-stay patients from institutions are prepared for transfer into the community and were particularly aimed at changing negative symptoms of schizophrenia - poor motivation, poor attention and social withdrawal. Objectives To review the effects of token economies for people with schizophrenia, or other serious or Chronic Mental Illnesses, compared with standard care. Search methods Electronic searches of Biological Abstracts (1985-1999), CINAHL (1982-1998), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register of Trials (February 1999), EMBASE (1980-1999) and PsycLIT (1987-1998) were supplemented with reference searches, personal contact with trial authors and hand searches. Selection criteria Randomised studies comparing a token economy regime (one in which change is achieved by means of use of non-monetary, non-consumable tokens) to standard care for those with schizophrenia or any other similar Chronic or serious Mental illness. Data collection and analysis Studies were reliably selected, quality rated and data extracted. For dichotomous data relative risk (RR) with 95% confidence intervals (CI) was estimated. Where possible, the number needed to treat statistic (NNT) was also calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. Main results Only three randomised controlled trials could be included in the analyses (total n=110). There were no usable data on target or non-target behaviour. One small study favoured the token economy approach for the outcome 'change in Mental state' on the SANS-CV with improvement in negative symptoms at three months (n=40, WMD -12.7, CI -21.44 to -3.96). Authors' conclusions The token economy approach may have effects on negative symptoms but it is unclear if these results are reproducible, clinically meaningful and are maintained beyond the treatment programme. Token economy remains worthy of careful evaluation in well designed, conducted and reported randomised trials.
Tom Mcmonagle - One of the best experts on this subject based on the ideXlab platform.
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token economy for schizophrenia
Cochrane Database of Systematic Reviews, 2000Co-Authors: Tom Mcmonagle, Alec SultanaAbstract:Background A token economy is a behavioural therapy technique in which the desired change is achieved by means of tokens administered for the performance of predefined behaviours according to a program. Though token economy programmes were widespread in the 1970s they became largely restricted to wards where long-stay patients from institutions are prepared for transfer into the community and were particularly aimed at changing negative symptoms of schizophrenia - poor motivation, poor attention and social withdrawal. Objectives To review the effects of token economies for people with schizophrenia, or other serious or Chronic Mental Illnesses, compared with standard care. Search methods Electronic searches of Biological Abstracts (1985-1999), CINAHL (1982-1998), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register of Trials (February 1999), EMBASE (1980-1999) and PsycLIT (1987-1998) were supplemented with reference searches, personal contact with trial authors and hand searches. Selection criteria Randomised studies comparing a token economy regime (one in which change is achieved by means of use of non-monetary, non-consumable tokens) to standard care for those with schizophrenia or any other similar Chronic or serious Mental illness. Data collection and analysis Studies were reliably selected, quality rated and data extracted. For dichotomous data relative risk (RR) with 95% confidence intervals (CI) was estimated. Where possible, the number needed to treat statistic (NNT) was also calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. Main results Only three randomised controlled trials could be included in the analyses (total n=110). There were no usable data on target or non-target behaviour. One small study favoured the token economy approach for the outcome 'change in Mental state' on the SANS-CV with improvement in negative symptoms at three months (n=40, WMD -12.7, CI -21.44 to -3.96). Authors' conclusions The token economy approach may have effects on negative symptoms but it is unclear if these results are reproducible, clinically meaningful and are maintained beyond the treatment programme. Token economy remains worthy of careful evaluation in well designed, conducted and reported randomised trials.
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The Cochrane Library - Token economy for schizophrenia
Cochrane Database of Systematic Reviews, 2000Co-Authors: Tom Mcmonagle, Alec SultanaAbstract:Background A token economy is a behavioural therapy technique in which the desired change is achieved by means of tokens administered for the performance of predefined behaviours according to a program. Though token economy programmes were widespread in the 1970s they became largely restricted to wards where long-stay patients from institutions are prepared for transfer into the community and were particularly aimed at changing negative symptoms of schizophrenia - poor motivation, poor attention and social withdrawal. Objectives To review the effects of token economies for people with schizophrenia, or other serious or Chronic Mental Illnesses, compared with standard care. Search methods Electronic searches of Biological Abstracts (1985-1999), CINAHL (1982-1998), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register of Trials (February 1999), EMBASE (1980-1999) and PsycLIT (1987-1998) were supplemented with reference searches, personal contact with trial authors and hand searches. Selection criteria Randomised studies comparing a token economy regime (one in which change is achieved by means of use of non-monetary, non-consumable tokens) to standard care for those with schizophrenia or any other similar Chronic or serious Mental illness. Data collection and analysis Studies were reliably selected, quality rated and data extracted. For dichotomous data relative risk (RR) with 95% confidence intervals (CI) was estimated. Where possible, the number needed to treat statistic (NNT) was also calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. Main results Only three randomised controlled trials could be included in the analyses (total n=110). There were no usable data on target or non-target behaviour. One small study favoured the token economy approach for the outcome 'change in Mental state' on the SANS-CV with improvement in negative symptoms at three months (n=40, WMD -12.7, CI -21.44 to -3.96). Authors' conclusions The token economy approach may have effects on negative symptoms but it is unclear if these results are reproducible, clinically meaningful and are maintained beyond the treatment programme. Token economy remains worthy of careful evaluation in well designed, conducted and reported randomised trials.
Karla Soares-weiser - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia
Cochrane Database of Systematic Reviews, 2018Co-Authors: Hanna Bergman, John Rathbone, Vivek Agarwal, Karla Soares-weiserAbstract:BACKGROUND: Since the 1950s antipsychotic medication has been extensively used to treat people with Chronic Mental Illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. OBJECTIVES: To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other Chronic Mental Illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. SEARCH METHODS: We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other Chronic Mental Illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. MAIN RESULTS: We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, Mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. AUTHORS' CONCLUSIONS: Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area.
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Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia.
The Cochrane database of systematic reviews, 2018Co-Authors: Hanna Bergman, John Rathbone, Vivek Agarwal, Karla Soares-weiserAbstract:Since the 1950s antipsychotic medication has been extensively used to treat people with Chronic Mental Illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other Chronic Mental Illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. We included reports if they assessed people with schizophrenia or other Chronic Mental Illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, Mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area.
Hanna Bergman - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia
Cochrane Database of Systematic Reviews, 2018Co-Authors: Hanna Bergman, John Rathbone, Vivek Agarwal, Karla Soares-weiserAbstract:BACKGROUND: Since the 1950s antipsychotic medication has been extensively used to treat people with Chronic Mental Illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. OBJECTIVES: To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other Chronic Mental Illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. SEARCH METHODS: We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other Chronic Mental Illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. MAIN RESULTS: We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, Mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. AUTHORS' CONCLUSIONS: Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area.
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Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia.
The Cochrane database of systematic reviews, 2018Co-Authors: Hanna Bergman, John Rathbone, Vivek Agarwal, Karla Soares-weiserAbstract:Since the 1950s antipsychotic medication has been extensively used to treat people with Chronic Mental Illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other Chronic Mental Illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. We included reports if they assessed people with schizophrenia or other Chronic Mental Illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, Mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area.