Towards stage specific treatments: Effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia

https://doi.org/10.1016/j.pnpbp.2014.10.002Get rights and content

Highlights

  • We examined the duration of the illness as a key factor modulating the response to treatment with N-Acetyl cysteine (NAC) in schizophrenia.

  • Supportive evidence for the effectiveness on NAC in late stages of the illness is presented.

  • Stage specific approaches with novel therapies such as NAC may counteract the progression of schizophrenia at a particular point of time.

Abstract

Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomised in a double fashion to 24 weeks (placebo = 62; NAC = 59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into < 10 years, 10–< 20 years and > 20 years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effect related outcomes. The pattern of changes suggests that this mediator effect of duration of illness in response to treatment is more evident in those participants with 20 years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments.

Introduction

Schizophrenia is a chronic and often debilitating illness affecting approximately 1% of the world's population. In schizophrenia, stage of illness appears to influence course, outcome, prognosis and treatment response (Insel, 2010). Duration of illness has been shown to be a marker of poor prognosis (Emsley et al., 2007, Malla et al., 2011) and been associated with poorer outcome (Cuesta et al., 2012, Hill et al., 2012, Melle et al., 2008). Those people with chronic schizophrenia are characterised by non-remitting symptoms and functional decline over time suggestive of neuroprogression (Anderson et al., 2013a, Anderson et al., 2013b). While current therapies have some effectiveness, there are shortfalls in recovery.

Emerging neurobiological findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state provide evidence of deleterious neuropathologic progression of damage to key brain circuits (Anderson et al., 2013a, Anderson et al., 2013b). These appear mediated by oxidative stress regulation, inflammation, decreased neurotropic growth factors, apoptosis, mitochondrial dysfunction and impaired neuroplasticity. In that regard, neuroimaging studies have shown the existence of brain abnormalities which are apparent from the onset (Pantelis et al., 2003) and progressively change over the course of the illness (Arango et al., 2012, Sun et al., 2009) including during the progression from the ultra high-risk to the first episode phase (Pantelis et al., 2003). Oxidative and neuroinflammatory mechanisms are increasingly implicated in the development, maintenance and progression of schizophrenia (Wood et al., 2009, Anderson et al., 2013a, Anderson et al., 2013b, Cropley et al., 2013). Alterations in the redox regulation and increased inflammatory response in schizophrenia have been proposed as plausible underlying causes of the observed progressive deterioration. An altered antioxidant defense system has been documented, not only in individuals with schizophrenia but also in their siblings (see (Ng et al., 2008, Dean et al., 2009, Bitanihirwe and Woo, 2011) for a review). There has been significant interest in glutathione (GSH) which is the brain's primary antioxidant and is also involved in the modulation of glutamate (Berk, Ng et al., 2008). Specific decreases in GSH have been observed in those with early onset psychosis at the time of the first-episode (Mico et al., 2011). Furthermore, GSH reductions were related to a greater loss of cortical grey matter two years later (Fraguas et al., 2012), suggesting that oxidative damage is present at early stages of the illness and may play a key role on pathophysiological processes. Additionally, abnormalities in the glutamate system and dopamine transmission may also induce neuronal oxidative stress that is exaggerated by the existent GSH deficiency (Yao et al., 2001).

Altered glutamate and dopamine originate from various sources (Emsley et al., 2013). Dysregulation of the inflammatory response system has also been documented in schizophrenia (Altamura et al., 2013). Altered proinflammatory cytokines provoke glutamate hyperactivity leading to N-methyl-d-aspartate (NMDA) glutamate receptor activation, altered redox balance and oxidative stress accumulation which can modify dopamine release and function, potentially triggering the onset of psychosis and mediating relapses (Emsley et al., 2013, Hanson and Gottesman, 2005, Saetre et al., 2007). A trial of N-acetyl cysteine (NAC), a glutathione precursor, as an adjunctive treatment in schizophrenia has shown an attenuation of negative symptoms, general symptoms and overall functioning after 24 weeks of treatment (Berk et al., 2008a, Berk et al., 2008b) providing some support for a role of oxidative stress in schizophrenia. It is likely that NAC is exerting benefits beyond being a precursor to the GSH however, as it has properties that modulate glutamatergic, neurotropic and inflammatory pathways (Berk et al., 2013, Dean et al., 2012). Progressive changes in these pathways have been thought to underpin the staged process of neuroprogression observed in the disorder, and interact with oxidative factors.

A clinical staging model of psychosis initially proposed by Fava and Kellner (1993), and refined by McGorry and colleagues (Berk et al., 2011a, Berk et al., 2011b, Berk et al., 2011c, McGorry et al., 2006) allied to the early intervention paradigm, suggests that the more prompt the intervention, the better the response to treatment and thus the prognosis appears to be (Berk et al., 2010, McGlashan, 2006, McGorry et al., 2010). This has proposed a clinical framework on which particular interventions may counteract the progression of the illness at a particular point of time. This approach could potentially guide treatment and assist in predicting outcome by improving the timing of interventions according to specific markers of progression over time (Berk et al., 2010, Berk et al., 2011a, Berk et al., 2011b, Berk et al., 2011c, Lin et al., 2013, McGorry et al., 2006, McGorry et al., 2010). Clinical staging thus enables selection of treatments targeting those biomarkers that have been associated with distinct stages of the disorder (Cropley et al., 2013, Wood et al., 2009, Wood et al., 2011). According to this model, earlier and milder conditions would be distinguished from later and more impairing phenomena in terms of their biological and clinical features with progression from Stage 0 (at-risk state) to Stage 4 (chronic and treatment resistant conditions).

Duration of untreated psychosis has been associated with poorer clinical and functional outcomes (Perkins et al., 2005) and an increased risk of relapse (Alvarez-Jimenez et al., 2011) which is especially evident at follow-up (Schimmelmann et al., 2008). Duration and stage of the illness may thus moderate the extent of the improvement on severity of symptoms and functional outcomes with treatment.

The current manuscript aims to explore this particular issue in the context of the larger double blind, randomised, placebo controlled trial clinical trial to determine the role of duration of the illness on response to treatment and thus identify the particular group of patients who may receive the greatest benefit of a potentially neuroprotective agent (Dodd et al., 2013), NAC in this cohort. The operative hypothesis was that consistent with the early intervention paradigm, people at the early stages of their illness would derive most benefit from treatment with NAC.

Section snippets

Experimental/materials and methods

A detailed description on the study design and assessment procedures, as well as a complete description of the main study cohort, efficacy and outcome measures, has been published elsewhere (Berk et al., 2008a, Berk et al., 2008b, Berk et al., 2011a, Berk et al., 2011b, Berk et al., 2011c). In brief, this was a double blind, randomised, placebo controlled, adjunctive N-acetyl cysteine (NAC) trial conducted in four private and public psychiatry facilities in Victoria, Australia, and one public

Baseline clinical and sociodemographic characteristics

A sample of 121 participants diagnosed with schizophrenia (mean age 36.4 ± 10.4) were allocated to the placebo (N = 62) or NAC group (N = 59). The mean duration of the illness was 12.1 ± 9.0 years (range, 1–40 years) for the whole group of participants. The mean daily dose of antipsychotic on chlorpromazine equivalents (32.33) did not differ between the placebo group (625.6 ± 454.9 mg) and the NAC group (747.2 ± 483.1 mg) with clozapine (46%) and olanzapine (27%) being the primary antipsychotics used with no

Discussion

The operative hypothesis of this paper, that people at the early stages of their illness would derive more benefit from treatment with NAC, was not supported by these results. In contrast, these results point out to a particular advantage of NAC over placebo as an adjunctive treatment in those participants with more chronic illness, defined a-priori as a duration of over 20 years. Duration of the illness however appears to moderate the effect of NAC on positive symptoms and functioning in

Funding

This work was supported by the ‘Stanley Medical Research Institute’ and partially supported by the Spanish Ministry of Economy and Competitiveness, the Health Research Institute from the Hospital Gregorio Marañón (IiSGM) and Fundación Alicia Koplowitz. Trial Registration: The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12605000363684), www.anzctr.org.au.

Declaration of interest

MR-C has received a Sara Borrell Health Research Fellowship, a postdoctoral clinical research fellowship from the Institute of Health Carlos III, Spanish Ministry of Economy and Competitiveness, an Alicia Koplowitz Grant and an Alicia Koplowitz Fellowship for Short-Term Placements from the Alicia Koplowitz Foundation, and a IiSGM Fellowship Award for Short-term Placements from the Health Research Institute from the Hospital Gregorio Marañón (IiSGM), Madrid, Spain. MB has received grant support

Acknowledgements

The authors would also like to acknowledge service support, provided by ‘Barwon Health’, ‘the Bendigo Health Care Group’, ‘the Florey Institute for Neuroscience and Mental Health’ and ‘the CRC for Mental Health’.

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