Antipsychotic Medication and Oxidative Cell Stress: A Systematic Review
Objective: To look at (1) the association between antipsychotics and cell stress, (2) whether first-generation antipsychotics may show different effects than second-generation antipsychotics, and (3) whether recommendations can be made regarding medication.
Data Sources: We conducted a systematic review of 5 databases for all articles published until December 31, 2007: PubMed, Ovid MEDLINE, EMBASE, PsycINFO, and EBM Reviews. Under specific headings (eg, “heat shock proteins” and “oxidative stress”), a systematic search of these databases included such terms as HSP70 and homocysteine, and specific search strings were constructed. No limits were placed on the year or language of publication. References from pertinent articles or books were retrieved.
Study Selection: We included 42 articles of human studies from 2,387 references originally retrieved. We included only articles that (1) were quantitative; (2) referred only to human tissue, in vivo, or in vitro; (3) stated what tissue was examined; (4) identified what metabolites were measured; and (5) had references.
Data Extraction: All articles were assessed by 2 authors, which ensured that the inclusion criteria were met. The selected studies were too heterogeneous to be combined for any useful meta-analysis. Three authors, therefore, independently interpreted the data, using specified criteria to judge whether each study showed a beneficial, detrimental, or no effect on the markers measured.
Data Synthesis: The analysis revealed no conclusive association with direct or indirect markers of oxidative cell stress and antipsychotics. For every reviewed antipsychotic, we revealed differing research results showing a beneficial, detrimental, or no effect. This was true for in vivo as well as in vitro studies.
Conclusions: It remains unclear whether antipsychotics increase or reduce cell stress. Claims of neuroprotective properties of antipsychotics seem premature.
J Clin Psychiatry 2011;72(3):273–285
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: April 7, 2009; accepted September 16, 2009.
Online ahead of print: June 29, 2010 (doi:10.4088/JCP.09r05268yel).
Corresponding author: Peter Lepping, MD, Wrexham Academic Unit, Croesnewydd Rd, Wrexham, LL13 7TY, Wales, UK (firstname.lastname@example.org).
The use of antipsychotics in patients with schizophrenia is widespread and recommended.1 Furthermore, antipsychotic medication has recently been claimed to be neuroprotective,2–4 and its early use in first-onset psychosis has been advocated widely.5 In a recent major review Ng et al6 found consistent, robust, and multidimensional evidence that oxidative cell stress is involved in the pathogenesis of schizophrenia and bipolar affective disorder, with weaker evidence for its involvement in other mental disorders. They point out that “evidence for the interdependent relationships between oxidative pathways and those involving neurotransmitters, hormones and inflammatory mediators further enhance the plausibility of the oxidative stress hypothesis, and provide a unifying framework for the various conceptual theories of causality.”6(p867) We fully acknowledge that the etiology of schizophrenia is multifactorial, but Ng and colleagues’6 evidence points to oxidative stress as an important factor in the biologic aspects of etiology and mortality in patients with schizophrenia. We therefore decided to conduct a systematic review to look at (1) whether there is any evidence that antipsychotic medication is associated with or causes cell stress or has beneficial effects on cell stress, (2) whether first-generation antipsychotics show different effects than second-generation antipsychotics (including clozapine), and (3) whether any 1 medication can be shown to be particularly beneficial with regard to cell stress.
Long-term use of antipsychotic medication is associated with a number of adverse effects, such as neutropenia and agranulocytosis,7,8 hyperprolactinemia,9 cardiomyopathy,10,11 weight gain,12,13 and metabolic changes,14 which include insulin resistance and hypertension. Antipsychotic medication is also associated with an increased risk of developing type II diabetes, which exacerbates the already elevated risk of cardiovascular problems and diabetes in people who use antipsychotics long term.15 Although the development of neuroleptic malignant syndrome is associated with the use of all antipsychotic medication, it more commonly occurs with first-generation antipsychotics than with second-generation antipsychotics.16
The finding that oxidative stress is implicated in the etiology of major mental illness raises the possibility that oxidative cell stress arising from the bioactivation of antipsychotic drugs may impose an additional oxidative burden upon tissues that are already stressed and could result in cell death through apoptosis or necrosis. This process has been implicated in the pathogenesis of the metabolic syndrome.17 Furthermore, oxidative stress has been associated with agranulocytosis through the formation of chemically reactive nitrenium iron-containing metabolites11 and free radical formation.18 It is also known that people with schizophrenia who are on antipsychotic medication have less mature neutrophils compared to healthy unmedicated volunteers,7,8 implying an immunologic effect. This effect seems least significant for sulpiride, flupentixol, and fluphenazine but is highly statistically significant for olanzapine, risperidone, haloperidol, thioridazine, and trifluoperazine. In the case of olanzapine, the finding was slightly surprising given that it was previously considered to have little association with agranulocytosis.19 All this is accumulative evidence that oxidative stress is a possible mechanism for antipsychotic side effects.
Oxidative stress may also have an effect on vascular endothelium.20 Equally affected by oxidative cell stress are heat shock proteins (HSPs), which have a variety of protective intracellular duties and show increased expression in response to stress to protect cells from stress-induced damage.21 Heat shock proteins are known to be affected by peripheral vascular disease22 and cardiovascular disease,23 and oxidative stress has been suggested as a possible reason for this.23 Nothing is known about HSP levels in the context of antipsychotic medication usage. HSP70 is induced by many physiologic stresses including oxidative stress,21 and HSP32 is induced specifically by oxidative stress.24 While HSPs are traditionally regarded as intracellular proteins, it is now known that they are present extracellularly and are correlated to certain disease processes22,25,26 and in vitro cellular stress.27–30 Serum HSPs may be of use in the monitoring of disease should they be shown to be affected by antipsychotic drugs. Heat shock protein release from cells in culture is another method for monitoring stress induced by antipsychotics in in vitro studies. It is interesting to consider that schizophrenic patients are at increased risk of premature death due to cardiovascular disease, with a relative risk of 1.5 of patients dying from cardiovascular disease.31 If oxidative stress were a side effect of antipsychotic medication, it could help explain this worrying increase in cardiovascular disease.
DATA SOURCES AND EXTRACTION
We conducted a systematic review of 5 databases for all articles published until December 31, 2007—PubMed (produced 1,568 results), Ovid MEDLINE (produced 868 results), EMBASE (produced 1,008 results), PsycINFO (produced 88 results), EBM Reviews (produced 41 results). Under specific headings, eg, “heat shock proteins” and “oxidative stress,” a systematic search of these databases included such terms as HSP70 and homocysteine (Table 1), and specific search strings were constructed. No limits were placed on the year or language of publication. References from pertinent articles or books were retrieved using the following criteria: (1) only articles that were quantitative; (2) those that referred only to human tissue, in vivo, or in vitro; (3) articles that stated what tissue was examined; (4) articles that identified what metabolite/metabolites were measured; and (5) those that had references. We looked for homogeneity within the identified studies. Our aim was to pool any homogenous studies for a meta-analysis. In the case of heterogeneity, we planned to look at each substance individually. We pooled all the markers we were looking at into 3 categories:
• Category 1 combined all markers of direct oxidative stress, including malondialdehyde/thiobarbituric acid reactive substances, reactive oxygen species/reactive oxygen metabolites, hydrogen peroxide (H2O2), and O2. These are all a direct measure of oxidants (eg, H2O2) or the result of oxidative activity (eg, malondialdehyde).
• Category 2 consisted of indirect markers of oxidative stress, including superoxide dismutase, glutathione, glutathione peroxidase, catalase, essential polyunsaturated fatty acids, HSP antibodies and antioxidants. These are all induced by oxidative stress and are typically part of the cellular defense against oxidative stress.
• Category 3 consisted of other markers of immune response such as proinflammatory, anti-inflammatory, or markers of neutrophil shift or danger. These are also induced by oxidative stress, but are not part of an antioxidant defense but directly relate to the immune response.
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We assessed all selected studies and extracted all available data on any antipsychotic mentioned or combined data on first- or second-generation antipsychotics. We looked at the available in vitro data on human cells separately from the in vivo data. The lead author and 2 of the coauthors (J.H.H.W., P.L., and P.R.H.) individually assessed whether the substance had a beneficial (positive) or a detrimental (negative) effect on cells. Generally, a rise in direct or indirect markers of cell stress was interpreted as negative while a reduction was interpreted as positive. Among the immune markers, a reduction of proinflammatory markers, a rise in anti-inflammatory markers, a reduction in the neutrophil shift, and a reduction in hemolysis and danger markers were seen as positive. The opposite was interpreted as a negative effect.
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SELECTION of ARTICLES
Two reviewers (J.D. and R.M.) independently searched the 5 databases, finding 2,387 abstracts after the removal of duplicates (Figure 1). We wrote to all pharmaceutical companies manufacturing antipsychotics, requesting information regarding published or unpublished trials or work in progress on these drugs and their associations with cell stress. A database of these abstracts was created within a reference management software package (EndNote, Thomson-Reuters, New York, New York). We then applied the terms subject or patient to our database to exclude nonhuman data (Figure 1). This process excluded 1,853 articles from the identified abstracts, giving us a total of 534 abstracts. Further processing excluded 490 articles as they did not meet the inclusion criteria. In this group some had no references, others were similar articles written by the same authors with slightly different titles but submitted to different journals. They were treated as duplicates. Another substantial number of articles looked at related subjects such as tardive dyskinesia rather than schizophrenia or did not record any cell response.
All articles were assessed by 2 reviewers, which ensured that the inclusion criteria were met. A further 19 articles that contained no measurable parameters were excluded, leaving 25. Five articles were identified by manual literature search, 11 were added from the pharmaceutical industry, and 9 from the references within the identified articles bringing, the total up to 50 articles. Then 8 articles were identified as duplications and excluded, leaving a total of 42 included articles.
The selected studies were too heterogeneous to be combined for any useful meta-analysis. Some failed to give details for individual antipsychotics but combined a selection of first-generation antipsychotics.32–36 Some examined more than 1 cell stress marker.35,37–40 Many studies looked at more than 1 effect and more than 1 antipsychotic, which explains why the total number of reported effects for a particular drug or effect does not necessarily correspond with the total number of studies showing that effect. One study41 met the inclusion criteria but did not yield results at 2 different points in time and was therefore not included in the analysis. We show the referenced results for all individual antipsychotics in an interpreted format in Table 2. Table 3 shows a summary description of all included studies with their design, quality, and outcome. Table 4 shows the actual observed change for all studies and substances.
We excluded animal studies as they can be poor models for human cell behavior. Furthermore, we wanted to increase the relevance of the review to psychiatric practice by focusing on human cells.
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In summary, 11 studies32,34,35,38,42–48 looked at different first-generation antipsychotics and direct oxidative stress markers. Most of them used haloperidol. Two of the studies42,46 showed a beneficial effect; 5 studies,35,43,44,49,50 a detrimental effect; and 6 studies,32,34,38,42,45,48 no effect on cells. When we considered markers of indirect oxidative stress, 3 studies40,51,52 showed a beneficial effect; 6 studies,32,34,36,40,50,53 a detrimental effect; and 7 studies,33,35,37,38,43,47,54 no significant effect. Regarding markers for immune responses, 1 study55 showed a beneficial effect on inflammation and similar markers, 6 studies8,49,50,56–58 showed a detrimental effect, and 2 studies8,48 showed no effect. One of these studies was Delieu et al,8 which showed that chlorpromazine, trifluoperazine, thioridazine, flupenthixol, and sulpiride caused a neutrophil shift to less mature cells, while no such effect was seen with fluphenazine.
For the second-generation antipsychotics, the results were equally ambivalent. When we looked at direct oxidative stress markers, 3 studies59–61 showed a beneficial effect, 5 studies18,35,62–64 showed a detrimental effect, and 7 studies32,34,38,43,45,48,63 showed no significant effect. The 1 prospective randomized controlled study45 we identified showed a tendency toward a positive effect for clozapine, risperidone, and amisulpride but a tendency toward a negative effect for olanzapine compared to first-generation antipsychotics. However, when we did our own t tests using mean and standard deviations comparing day 21 with day 0 for all drugs, none of them were significant. Even those comparisons that appeared to be the most promising at face value between first-generation antipsychotics and olanzapine had a P value of P = .1 in both cases. Regarding markers of indirect cell stress, 5 studies40,52,59,65,66 showed a beneficial effect, 5 studies2,32,34,39,62 showed a detrimental effect, and 4 studies33,35,38,43,53 showed no significant effect. Looking at markers of inflammation, we found 2 studies55,67 that showed a beneficial effect (ie, reduced inflammatory markers), 7 studies8,49,57,58,68–70 that showed a detrimental effect, and 1 study48 that showed no effect. A neutrophil shift toward less mature cells was found with risperidone and olanzapine.8
In Vitro Studies
To summarize, no substance had exclusively beneficial or detrimental results across the board. First-generation antipsychotics do not come out better or worse than second-generation antipsychotics. With regard to the consequences of taking antipsychotics on cell stress and immune response markers, no definite conclusion can be drawn about potential harm or benefit from antipsychotic medication.
Given the recent independent research on second-generation antipsychotics and their relative risk for metabolic disturbance and weight gain as well as efficacy compared to first-generation antipsychotics, it is paramount that we gain more knowledge about potential risks and benefits of antipsychotic medication. Any suggestion from the data regarding beneficial effects on cell stress would have been highly welcomed. However, our results are inconclusive for every substance analyzed, with almost as many studies showing beneficial effects across the board as studies showing detrimental effects. We therefore cannot draw any conclusion as to whether antipsychotic medication increases the risk of cell stress, nor can we make any specific recommendation of 1 substance to be less likely to increase cell stress than another. It is not possible to conclude that antipsychotic medication does increase cell stress either, and no such assumption of increased metabolic risk should be drawn from our results.
There is now increasingly unambiguous evidence that oxidative stress is involved in the etiology of schizophrenia and bipolar affective disorder, probably also in major depression and other mental disorders.6 This evidence in itself demands further research in order to explore whether this new knowledge may lead to future treatment options. These include antioxidants and related substances,71 some of which have already been successfully tested in the treatment of schizophrenia. Another important clinical implication is for the claims of neuroprotective properties attributed particularly to expensive second-generation antipsychotics. This has led to calls for the early use of antipsychotic medication in newly diagnosed schizophrenic patients.5 Heat shock proteins are undoubtedly involved in diverse neuroprotective mechanisms,72 making a link between oxidative stress and neuroprotection very plausible. Our findings suggest that claims of neuroprotective properties of antipsychotics may well be premature given that we obtained very inconclusive results from the current literature. Unless it were proven that oxidative stress and neuroprotective properties of antipsychotic medication are unrelated, which is highly unlikely given the current breadth of evidence, any definite claims of neuroprotection should be treated with caution. This may also mean that we need to rethink neuroprotection as a potential benefit in the argument for the early use of second-generation antipsychotics in newly diagnosed schizophrenic patients. One in vitro study57 showed that haloperidol and clozapine cause a significant proinflammatory response in an activated system, indicating potential problems with inflammatory responses for patients on antipsychotic medication at times of infection or increased stress. This leaves open the possibility of varying responses according the current level of system activation.
Limitations of our study include the impossibility of making clear quality judgments about each study, as they do not fit into the usual quality assessment framework for randomized controlled trials. However, all included studies have a good or reasonable design and methodology for what they are intended to measure. Although they were all trials with human participants, the measured changes were usually in regard to blood markers and antipsychotics rather than changes in the participants themselves. The heterogeneity of the studies did not allow us to cluster any specific study designs, which rendered any comment on bias impossible.
There is a clear need for more prospective studies on humans in order to determine the risk on cells, including those involved in immune responses, that antipsychotic medication poses as well as any beneficial effects they may have. However, prior to this there is clearly a need for in vitro experiments using suitable cell culture systems looking at the potential cellular stress that may be induced by these compounds. There is also a case for the development and use of new, sensitive markers of cell stress to understand the metabolic effects of antipsychotic medication more fully. Such markers may include urine isoprostane73 and markers of protein glycation, oxidation, and nitration.74
Clinically, the importance of this study is that claims of neuroprotective properties of antipsychotic medication seem premature given the inconclusiveness of our results.
Drug names: aripiprazole (Abilify), clozapine (FazaClo, Clozaril, and others), haloperidol (Haldol and others), metoclopramide (Metozolv, Reglan, and others), molindone (Moban), olanzapine (Zyprexa), pimozide (Orap), prochlorperazine (Compro, Procomp, and others), quetiapine (Seroquel), risperidone (Risperdal, Risperdal Consta, and others), ziprasidone (Geodon).
Author affiliations: Glyndŵr University, Wrexham (Dr Lepping), and Departments of Psychiatry (Drs Lepping and Mellor) and Clinical Biochemistry (Dr Hudson), Betsi Cadwaladr University Health Board; School of Medical Sciences, Bangor University (Dr Delieu), Bangor, North Wales; and Chester Centre for Stress Research (Dr Williams) and Chester Centre for Stress Research (Dr Hunter-Lavin), University of Chester, Chester, England, United Kingdom. Dr Hunter-Lavin is no longer with Chester Centre for Stress Research.
Potential conflicts of interest: None reported.
Funding/support: None reported.
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