Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Bar-Yosef, Tamara; Hussein, Wessal; Yitzhaki, Ofer; Damri, Odeya; Givon, Limor; Marom, Carmit; Gurman, Vlada; Levine, Joseph; Bersudsky, Yuly; Agam, Galila; Ben‐Shachar, Dorit

doi:10.1038/s41598-020-69207-4

Cited by 11 publications

(14 citation statements)

References 62 publications

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“…As indicated by Bar-Yosef et al, patient response to treatment was associated with mitochondrial parameters, approximately half of the mitochondrial parameters (respiratory parameters) were improved in patients with schizophrenia who were responsive, but these parameters returned to normal only in those who received long-term treatment. 62 Our results also indicated that parameters related to mitochondrial impairment in lymphocytes might be predictors of patient response. Nevertheless, no significant improvement was found in the mitochondrial damage in CD3, CD4, and CD8 lymphocytes after treatment, which might be due to the short follow-up duration (about 24 days) in this study.…”

Section: Discussionsupporting

confidence: 54%

Mitochondrial Damage of Lymphocytes in Patients with Acute Relapse of Schizophrenia: A Correlational Study with Efficacy and Clinical Symptoms

Hu¹,

Li²,

Zhao³

et al. 2022

NDT

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Objective Accumulating evidence has demonstrated that schizophrenia is associated with mitochondrial and immune abnormalities. In this pilot case–control study, we investigated the level of mitochondrial impairment in lymphocytes in patients with acute relapse of schizophrenia and explored the correlation between the level of mitochondrial damage and symptoms or treatment response. Methods Lymphocytic mitochondrial damage was detected using mitochondrial fluorescence staining and flow cytometry in 37 patients (at admission and discharge) and 24 controls. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Scale (CGI-S). Results The levels of mitochondrial damage in CD3+ T, CD4+ T, and CD8+ T lymphocytes of the patients with schizophrenia at admission were significantly higher than those of the controls (p<0.05) and did not return to normal at discharge (p>0.05). The mitochondrial damage of T cells significantly improved at discharge for responsive patients only, as compared with that at admission (P<0.05). However, no significant difference was found in mitochondrial damage in CD19+ B cells between patients and healthy controls, or between admission and discharge (p>0.05). Furthermore, the reduction in mitochondrial damage of CD3, CD4, and CD8 lymphocytes was positively correlated with the reduction of the score of the PANSS positive scale at discharge (p<0.05), while no significant correlation was found between the level of mitochondrial damage in lymphocytes and the scores of PANSS and CGI-S. Conclusion Acute relapse of schizophrenia might be associated with higher levels of mitochondrial damage in peripheral blood T lymphocytes. The degree of recovery of mitochondrial impairment in the T cells may be used as a predictor of treatment response in schizophrenia. As this is a pilot study, the conclusion still needs further verification in large-scale studies.

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Section: Discussionsupporting

confidence: 54%

Mitochondrial Damage of Lymphocytes in Patients with Acute Relapse of Schizophrenia: A Correlational Study with Efficacy and Clinical Symptoms

Hu¹,

Li²,

Zhao³

et al. 2022

NDT

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“…Future antipsychotic medication studies should include genetic and non-genetic biomarkers for the potential to develop antipsychotic-induced dopamine supersensitivity psychosis, aiDSP and treatment resistance, and various forms of oxidative stress and genetic metabolic responses, which may affect dropout rates, side effect profiles, and outcomes more generally. It is now possible to track longterm antipsychotic side effects such as cognitive decline and metabolic syndrome more precisely (Bar-Yosef et al, 2020;Cem Atbaşoglu, Schultz, & Andreasen, 2001;Joshi et al, 2021;Scaini et al, 2018). We, therefore, recommend that researchers follow biomarker adaptive antipsychotic medication clinical trial designs, in order to control for a myriad of molecular confounders and long-term side effects (Perkovic et al, 2017).…”

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confidence: 99%

Long-term effectiveness of antipsychotics

2021

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We welcome the comments by Drs Pierre et al. and Aftab regarding the Chicago Follow-up Study, especially in relation to our most recent publication in Psychological Medicine, 'Twenty-year effects of antipsychotics in schizophrenia and affective psychosis' (Harrow, Jobe, & Tong, 2021). By way of introduction we should provide some background regarding our study, which is a prospective naturalistic observational study of 20 years duration that includes six follow-up evaluations, having been funded almost continuously for over a 35 year period, 25 of those years by the National Institute of Mental Health, NIMH, in addition to 5 years of funding by the MacArthur Foundation and 4 years by the Center of Excellence in Mental Health. Our findings bring into question the current standard of practice that emphasizes long-term maintenance treatment with antipsychotic medication in patients with schizophrenia as the optimal strategy in all cases (American Psychiatric Association, 2020).First with reference to Dr Pierre et al.'s comments regarding the problem of reverse association, the proverbial chicken and egg question, we would point out that this kind of confound is difficult to control because the relevant variables are unanticipated and often discovered long after a study is completed (Carvalho et al., 2020;Marquis, Habicht, Lanata, Black, & Rasmussen, 1997). As a prospective long-term naturalistic study over 20 years, the Chicago Follow-up Study has made extraordinary efforts to sufficiently consider patients' heterogeneity and minimize biases.

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“…Effects of first- and second-generation antipsychotics were evaluated by an in vitro analysis of mitochondrial proteins in the lymphocytes of psychotic patients [ 270 ]. The hierarchical clustering dendrogram showed a separate cluster for first- and second-generation compounds, suggesting the possibility of exploiting mitochondrial function parameters as a tool for tailored drug treatment in patients with schizophrenia or bipolar disorder [ 270 ]. Olanzapine and risperidone were effective in decreasing mitochondrial maximal respiration [ 270 ].…”

Section: Antipsychotic Treatment Effects On Mitochondrial Function An...mentioning

confidence: 99%

“…The hierarchical clustering dendrogram showed a separate cluster for first- and second-generation compounds, suggesting the possibility of exploiting mitochondrial function parameters as a tool for tailored drug treatment in patients with schizophrenia or bipolar disorder [ 270 ]. Olanzapine and risperidone were effective in decreasing mitochondrial maximal respiration [ 270 ]. Olanzapine decreased levels of caspase 3 and MFN1, whereas risperidone significantly decreased OPA1 protein levels [ 270 ].…”

Section: Antipsychotic Treatment Effects On Mitochondrial Function An...mentioning

confidence: 99%

“…Olanzapine and risperidone were effective in decreasing mitochondrial maximal respiration [ 270 ]. Olanzapine decreased levels of caspase 3 and MFN1, whereas risperidone significantly decreased OPA1 protein levels [ 270 ]. Risperidone and haloperidol increased the expression of proteins involved in cell viability by raising the levels of both pro- and anti-apoptotic proteins BAX and Bcl-2, respectively [ 270 ].…”

Section: Antipsychotic Treatment Effects On Mitochondrial Function An...mentioning

confidence: 99%

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Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

et al. 2023

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Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants’ mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.

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Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Cited by 11 publications

References 62 publications

Mitochondrial Damage of Lymphocytes in Patients with Acute Relapse of Schizophrenia: A Correlational Study with Efficacy and Clinical Symptoms

Mitochondrial Damage of Lymphocytes in Patients with Acute Relapse of Schizophrenia: A Correlational Study with Efficacy and Clinical Symptoms

Long-term effectiveness of antipsychotics

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

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