Cortisol in schizophrenia: No association with tobacco smoking, clinical symptoms or antipsychotic medication
Introduction
Schizophrenia is a severe, heterogeneous chronic mental disorder with diverse clinical manifestations, influenced by various genetic risk factors and complex interplay between environmental risk factors such as stress exposure and gene–environment interactions. It affects about 1% of the population worldwide (Kahn et al., 2015). Patients with schizophrenia have dysregulated major system regulating the stress response, the hypothalamic–pituitary–adrenal (HPA) axis (Bradley and Dinan, 2010, Brenner et al., 2009, Girshkin et al., 2014, Girshkin et al., 2016, Walker et al., 2008), manifested in the form of both hyper- and hypofunction (Bradley and Dinan, 2010). Schizophrenic patients show altered response to stress compared to control subjects (Brenner et al., 2009, Girshkin et al., 2016). The HPA axis abnormalities in schizophrenia are indicated by elevated basal cortisol levels (Girshkin et al., 2014, Jakovljevic et al., 1998, Muck-Seler et al., 1999), non-suppression of cortisol after dexamethasone suppression test (DST) (Hori et al., 2012, Jakovljevic et al., 1998, Muck-Seler et al., 1999), and blunted cortisol awakening response (CAR) (Mondelli et al., 2010). Disrupted 24-h diurnal rhythm of cortisol secretion (Gallagher et al., 2007) and lower cortisol response to psychological stress (Brenner et al., 2009, Gispen-de Wied, 2000) were also reported. However, there are reports showing similar basal cortisol concentration between schizophrenia patients and controls (Bradley and Dinan, 2010). Some variations in the HPA axis are assumed (Murri et al., 2012) to be associated with severity of particular clinical symptoms evaluated by the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). However, our previous study did not confirm these findings (Pivac et al., 1997). Cortisol was reported to be associated with positive and depressive symptoms, excitement and disorganization in a small sample of first episode psychosis (Murri et al., 2012). Although schizophrenia is a neurodevelopmental disorder, the neural diathesis-stress model implicates the role of stress and HPA axis, and interaction with disturbed dopaminergic pathways, in the etiology of schizophrenia (Pruessner et al., 2016, Walker et al., 2008).
Smoking has been significantly associated with various neuropsychiatric disorders (Dome et al., 2010) and psychosocial stress (Slopen et al., 2013). The high incidence of tobacco smoking in schizophrenic patients (Sagud et al., 2009, Winterer, 2010) compared to the general population (de Leon and Diaz, 2005, Dome et al., 2010, Manzella et al., 2015) indicates their increased susceptibility to nicotine addiction.
In healthy subjects, elevated cortisol levels are associated with both passive and active tobacco smoking (Soldin et al., 2011). Cortisol levels were significantly higher in smokers than in non-smokers (Steptoe et al., 2004). These findings were confirmed in the large population cohorts of middle-aged (Badrick et al., 2007) and older (Direk et al., 2011) healthy subjects. Salivary cortisol levels were higher in current smokers than in non-smokers, but did not differ between former smokers and never-smokers (Badrick et al., 2007, Direk et al., 2011).
The primary hypothesis of this study was that smoking and/or intensity of nicotine addiction is significantly associated with salivary cortisol levels in patients with schizophrenia. As the effect of smoking on cortisol levels were evaluated in small number of patients with schizophrenia (Brenner et al., 2009, Hori et al., 2012, Iancu et al., 2007, Murri et al., 2012), we included a fairly large group of inpatients with schizophrenia. Given that smoking affects heart rate (Gillum, 1992) and heart rate is regulated by the autonomic nervous system, it was used in our study as an indicator of the cardiovascular system function. The second hypothesis of this study was that salivary cortisol levels are associated with various clinical symptoms of schizophrenia (Girshkin et al., 2014, Murri et al., 2012) and/or with antipsychotic medication (Bradley and Dinan, 2010). Therefore, we assessed the possible associations between salivary cortisol, symptoms of schizophrenia, and different antipsychotic medication.
Section snippets
Participants
The study included 196 inpatients with schizophrenia (51.30 ± 26.68 years old), diagnosed using the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1995) and recruited from the Psychiatric Hospital Vrapce, Zagreb, Croatia from January 2014 to December 2015. Schizophrenic patients were subdivided into 123 smokers (i.e. current smokers) and 73 non-smokers (i.e. never smokers and former smokers). All patients were Caucasians of Croatian origin. Besides the SCID, all patients were
Demographic data in patients with schizophrenia
Demographic data, as well as PANSS and FTND scores, and chlorpromazine equivalent doses, are shown in Table 1. Non-smokers were significantly older, had significantly longer duration of illness and received significantly lower doses of antipsychotic medication (calculated as chlorpromazine equivalent doses) than smokers. There were no significant differences in the distribution of male or female subjects or employment between smokers and nonsmokers. Smokers and non-smokers did not differ
Discussion
The results of the present study showed that 1) patients with schizophrenia who were non-smokers were older, had longer duration of schizophrenia, had more severe symptoms and were treated with lower doses of antipsychotics than smokers; 2) salivary cortisol was similar between smokers and non-smokers; and was not associated with smoking the first cigarette of that day, the number of cigarettes/day, or the intensity of physical addiction to nicotine; 3) salivary cortisol was not correlated with
Conclusions
The results of the present study revealed that salivary cortisol was not influenced by smoking, nicotine addiction intensity or clinical symptoms of schizophrenia. Our preliminary data showed no correlation between salivary cortisol and chlorpromazine equivalent doses. The data suggest that patients with schizophrenia differ from the general population in the HPA axis' responses to smoking and nicotine addiction. The differences might be explained by the HPA axis dysfunction in patients with
Authors contribution
Ed Domino and Nela Pivac developed the original idea and designed the study.
Nela Pivac, Suzana Uzun, Gordana Nedic Erjavec and Matea Nikolac Perkovic realized the experimental part of the study: clearly explained the research goals and described protocol in details to the patients; explained the importance of strict adherence to the sampling methods and heart rate measurement, and explained the inclusion/exclusion criteria, and emphasized the importance of strict adherence to the protocol.
Conflicts of interest
None.
Role of the funding source
This study was supported by the collaborative project “The association between stress, genetic variants of the catechol-O-methyltransferase (COMT) and mu opioid receptor gene (OPRM1) polymorphisms and tobacco smoking in patients with schizophrenia” lead by Nela Pivac and Ed Domino, among University of Michigan, Department of Pharmacology, Ann Arbor MI, USA, Ruđer Bošković Institute, Zagreb, Croatia and University Psychiatric Hospital Vrapče, Zagreb, Croatia. The funding source had no role in
Acknowledgements
The authors are grateful to Marina Gregurovic and other staff from Clinic for Psychiatry Vrapce, Zagreb, Croatia, for the help with patients. The study has been supported by CRO-USA collaborative project Pivac 1463002/1463002U, and in part by the University of Michigan Psychopharmacology Research Fund 361024.
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2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Furthermore, one RCT including 41 cases and 41 controls indicated that atypical AP significantly decreased serum cortisol levels compared to placebo (Wei et al., 2014). Meanwhile, two case series, one including 196 cases on clozapine and salivary cortisol (Erjavec et al., 2017) and the other 5 cases on sultopride with serum cortisol level (Miyachi et al., 1984), reported no difference of cortisol level after intervention. Among case-control studies, six articles, including 164 cases and 230 controls, reported no difference of cortisol-derived parameters between cases and controls (Birkenaes et al., 2009; Horodnicki et al., 1984; Lee et al., 2001; Rao et al., 1995; Sun et al., 2016; von Bardeleben et al., 1987).
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2020, Psychiatry ResearchCitation Excerpt :Beside alcohol and nicotine dependence, no other co-morbid substance abuse or dependence was present. Alcohol-dependent patients and healthy individuals were medication-free, while patients with schizophrenia received different antipsychotics (Nedic Erjavec et al., 2017). Subjects were classified as smokers (subjects smoking ≥10 cigarettes per day, i.e. current smokers, n = 514) and non-smokers (i.e. a group of never smokers and former smokers, n = 544).
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2018, PsychoneuroendocrinologyCitation Excerpt :Similarly, morning cortisol levels were heightened in patients, and seemed to increase with illness chronicity and severity (Girshkin et al., 2014), although results have been mixed (Brunelin et al., 2008; Chaumette et al., 2016; Girshkin et al., 2014; Marcelis et al., 2004; Pruessner et al., 2017; Yang et al., 2012; Yildirim et al., 2011; Zorn et al., 2017). In addition, there is evidence that antipsychotic medication use attenuates both basal and morning cortisol levels in psychosis (Chaumette et al., 2016; Girshkin et al., 2014), although some recent reports found no such effect (Girshkin et al., 2016; Nedic Erjavec et al., 2017). Whereas overall cortisol levels appear to be increased, cortisol reactivity is blunted in both chronic and first-episode psychosis (FEP) patients, as indicated by flattened cortisol awakening responses (CAR) (Berger et al., 2016) and blunted responses to experimental psycho-social stress(Ciufolini et al., 2014; Zorn et al., 2017), although there are indications of a publication bias (Zorn et al., 2017).
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Gordana Nedic Erjavec and Suzana Uzun equally contributed to this work.