Smoke, GPx activity and symptoms improvement in patients with drug-naive first-episode schizophrenia: A large-scale 12-week follow-up study

Highlights

• Two hundred and fifteen DNFE patients were recruited and received 12 weeks of risperidone monotherapy.

• Smokers showed greater improvement in negative symptoms relative to nonsmokers.

• Increased GPx activity was correlated with improvement in positive symptoms.

Abstract

The relationship between tobacco smoke and schizophrenia (SZ) is well established. Smoking is hypothesized to alleviate symptoms and reduce the adverse effects of antipsychotic medications in patients with SZ. However, the underlying biological mechanisms by which smoke improves symptoms in SZ remain unclear. The aim of this study was to investigate the effect of smoking on clinical symptoms and antioxidant enzyme activity after risperidone treatment in a 12-week prospective cohort study of drug-naïve first-episode (DNFE) SZ patients. Two hundred and fifteen DNFE patients were recruited and received 12 weeks of risperidone monotherapy. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of patient’s symptoms at baseline and post-treatment. Plasma GPx activity was also measured at baseline and at the end of 12 weeks. Smokers showed greater improvement in negative symptoms relative to nonsmokers with DNFE SZ. In addition, repeated ANCOVA analysis showed no significant interaction of time and group on GPx activity. Improvement in negative symptoms was not associated with changes in GPx activity. However, in nonsmokers, increased GPx activity was correlated with improvement in positive symptoms.

Introduction

Studies have shown that the prevalence of smoking in patients with chronic schizophrenia (SZ) is approximately 14%− 88%, almost twice that of the general population (Šagud et al., 2018, Ding and Hu, 2021). In addition, studies have reported that patients with SZ who smoke are also more likely to be heavier smokers compared to the general population (Williams et al., 2005). Until now, the relationship between smoking and SZ has been well established. However, the exact mechanisms underlying the effect of smoking on clinical symptoms are not yet fully understood.

Nicotine is the main addictive substance of cigarette (Changeux, 2010, Dome et al., 2010). Previous studies have shown that nicotine can be used as a self-medication for clinical symptoms of SZ through its neurobiological basis (e.g. interactive effect with the nicotinic acetylcholine) (Addington et al., 1998). In addition, nicotine can ameliorate some abnormalities in dopaminergic, glutamatergic and GABAergic pathways (Lucatch et al., 2018). Tobacco smoke contains a complex mixture of many chemicals, as well as high concentrations of free radicals and other oxidants that may cause oxidative damage to cell membranes and lipoproteins in vivo (Montuschi et al., 2000). The release of free radicals from macrophages can further increase free radicals and oxidants in tobacco smoke (MacNee, 2000, Kirkham and Rahman, 2006). Tobacco smoke can cause oxidative stress not only by enhancing free radicals in smoke, but also by weakening antioxidant enzymes (James et al., 2000). Indeed, there is accumulating evidence that smokers have impaired levels and activities of antioxidant enzyme (Ahmadi-Motamayel et al., 2017).

Notably, excessive free radical production or oxidative stress is also involved in the pathology of SZ, as evidenced by increased levels of reactive oxidative species and abnormal activities of antioxidants in SZ patients (Xiu et al., 2020, Cecerska-Heryć et al., 2021, Li et al., 2021, Liu et al., 2021a, Liu et al., 2021b, Murray et al., 2021). The brain is known to have a high oxygen consumption, about 20% of total basal oxygen consumption, and to have an increased rate of oxidative metabolism, making it more susceptible to oxidative stress (Macnee and Rahman, 1999). In healthy states, certain free radicals are known to have a beneficial role in activating the innate and acquired immune system (Knight, 2000). However, when the body is in a disease state such as SZ, an imbalance between free radicals and antioxidant enzymes (which favor free radicals) may lead to oxidative stress in cells. Free radicals may negatively affect key structures in the central nervous system (Sato et al., 2014). To combat the excessive accumulation of free radicals, it has been found that a complex set of endogenous antioxidants can be regulated. Glutathione Peroxidase (GPx), one of the free radical scavenger enzymes, forms the first line of antioxidant defense system against free radical-induced damage (Bošković et al., 2011). Abnormal levels and activity of GPx enzyme were indeed found in the serum, plasma and brain of patients with SZ (Xiu et al., 2020, Li et al., 2021, Liu et al., 2021a, Liu et al., 2021b, Goh et al., 2022).

The body’s antioxidant defense system is dynamic and responsive to abnormal redox balance (Wu et al., 2013). Based on previous studies, tobacco smoke has a dual effect on antioxidant enzyme activity and free radicals (Isik et al., 2007). Nicotine at reasonably low concentrations acts as an antioxidant and plays a critical role in neuroprotective effects, while high doses can cause neurotoxicity and oxidative stress (Guan et al., 2003). On the other hand, antipsychotics are known to partially alleviate psychotic symptoms by modulating antioxidant defense systems (Möller and Czobor, 2015). All these studies reveal a close relationship between nicotine and antioxidant enzymes, and an important role of free radicals in the pathophysiology of SZ. Specifically, a study by our group showed that smokers with chronic SZ had fewer positive and negative symptoms, which appeared to be associated with decreased oxidative stress and lipid peroxidation (Zhang et al., 2007). However, no studies have investigated the effect of tobacco smoke on antioxidant enzyme activity and clinical symptom improvement after antipsychotic treatment in patients with SZ. We hypothesize that smoking may contribute to the reduction of clinical symptoms in DNFE patients with SZ. In addition, a potential mechanism by which tobacco smoke alleviates symptoms may be related to changes in GPx activity. Therefore, to test our hypothesis, we explored (1) whether GPx activity was different in smokers and nonsmokers; (2) whether smoking has an effect on clinical symptom improvement after risperidone monotherapy for 12 weeks; and (3) whether the effect of smoking on symptom improvement is dependent on the changes in GPx activity.