No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals☆
Introduction
Researches regarding the pathophysiology of schizophrenia have to a substantial extent focused on dysfunction of neurotransmission in the central nervous system (CNS) (Owen et al., 2016). People with schizophrenia show increased synthesis capacity, release and baseline synaptic concentrations of dopamine (Howes and Murray, 2014). Increased dopamine synthesis capacity seems to be present already in the prodromal phase and is correlated with severity of symptoms in people with schizophrenia (Howes et al., 2012). Also serotonergic dysfunction plays a role in the pathophysiology of schizophrenia. Altered serotonin receptor availability has been implicated in mood and anxiety disorders that resemble the negative symptoms of schizophrenia (Selvaraj et al., 2014). Also, there is some evidence that serotonin transporter reuptake inhibitors can treat negative symptoms of schizophrenia (Sommer et al., 2012). Recreational drugs that are structurally similar to and bind to the same receptors as serotonin distort perception and induce paranoia much like what is seen in patients with schizophrenia (Selvaraj et al., 2014). A number of studies have found concentrations of noradrenaline to be altered in serum and plasma in people with schizophrenia and to correlate with the severity of symptoms in these patients. Some studies have also shown that substances affecting noradrenaline signaling, such as clonidine, can have a therapeutic effect on symptoms of schizophrenia (Bjerkenstedt et al., 1985, Fitzgerald, 2014). The major metabolites of dopamine, serotonin and noradrenaline are homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively.
Metabolites of relevant neurotransmitters have been investigated in both plasma and cerebrospinal fluid (CSF). CSF analysis is however thought to be the most reliable way to estimate cerebral metabolism due to the close proximity between CSF and the CNS, the high turnover rate of CSF and a molecular complexity that is more manageable than that of serum or plasma (Schwarz and Bahn, 2008). Several studies have shown a correlation between CSF monoamine metabolite concentrations and schizophrenia. For example CSF HVA has been shown to be lower in patients with psychotic morbidity compared to healthy controls, whereas CSF MHPG has been reported to be higher in patients (Bjerkenstedt et al., 1985, Hsiao et al., 1993, Lindström, 1985, Wieselgren and Lindström, 1998). CSF monoamine metabolites have also been implied as intermediate phenotypes between glutamate- and dopamine-related genes and schizophrenia (Andreou et al., 2014, Andreou et al., 2015, Andreou et al., 2016).
There are several important covariates that might influence monoamine metabolite concentrations in CSF. For example, height and back-length of the subjects have been shown to influence HVA and 5-HIAA concentrations, age has been associated with CSF 5-HIAA and gender has been shown to affect the MHPG concentration (Andreou et al., 2012, Malone et al., 2003).
Studies have shown both that people with psychiatric conditions are more likely to smoke and that smokers are more likely to have a psychiatric diagnosis. Among patients with schizophrenia, the smoking prevalence has been estimated to 65–90% and there is evidence that this over-representation might to some extent be explained by shared genetics for schizophrenia and smoking dependence (Aubin et al., 2012). Nicotine interacts with neurotransmitter systems, notably the dopaminergic mesolimbic system, and prolonged nicotine use has been shown to up-regulate nicotinergic acetylcholine receptors in the mesolimbic system (Aubin et al., 2012).
Considering this, a correlation between regular tobacco use and monoamine metabolites in CSF may be anticipated. Few studies have investigated this connection to date. One study investigating men with post-traumatic stress disorder (PTSD) and healthy controls, found that smokers had about half of the concentrations of CSF HVA compared to non-smokers (Geracioti Jr et al., 1999). Another study found a negative correlation between cigarette smoking and 5-HIAA in CSF among depressed patients with suicidal behavior (Malone et al., 2003). Other researchers found the correlation between plasma 5-HIAA and CSF 5-HIAA to be diminished in smokers compared to non-smokers but did not find any difference in CSF 5-HIAA concentrations between smokers and non-smokers (Strawn et al., 2002). In a study investigating depressed patients a US research team reported lower CSF MHPG concentrations among smokers than non-smokers (Galfalvy et al., 2009).
Notably, several studies that have investigated the relationship between schizophrenia and CSF monoamine metabolite concentrations have failed to control for regular tobacco smoking (Andreou et al., 2015, Bjerkenstedt et al., 1985, Lindström, 1985, Wieselgren and Lindström, 1998). Thus, there is need for additional studies investigating these associations. In a replication attempt of previous studies claiming lower monoamine metabolite levels in smokers (Galfalvy et al., 2009, Geracioti Jr et al., 1999, Malone et al., 2003), we investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders and healthy non-psychotic human volunteers.
Section snippets
Study population
The present study was approved by the Stockholm Regional Ethics Committee (2016/2305–32). Informed consent was obtained from all the participating subjects. Subjects were included between 1973 and 1989 in studies analyzing different aspects of CSF monoamine metabolite concentrations among patients with schizophrenia or related psychosis and non-psychotic controls subjects as previously described (Andreou et al., 2015, Jönsson et al., 1996). Included in the present study were 269 subjects, 170
Descriptive statistics
A total of 269 subjects were included in the study. Out of these, 129 were smokers while 140 were non-smokers (Table 1). Smokers smoked an average of 14.6 cigarettes per day (SD = 6). There was no significant difference between smokers and non-smokers with regard to age, psychiatric morbidity, antipsychotic treatment, gender, height, back-length or weight (Table 1).
Comparative analyses
Smokers had slightly lower mean [SD] concentrations of HVA (168.4 [79.3] nmol/l), 5-HIAA (88.4 [36.4] nmol/l) and MHPG (41.0
Discussion
The present study was not able to demonstrate any significant effect of regular tobacco smoking on CSF HVA, 5-HIAA or MHPG concentrations in a large sample of healthy subjects and patients with psychotic disorders. This is at variance with most previous studies.
The lack of significant difference between smokers and non-smokers indicates that regular tobacco smoking has no major effect on monoamine metabolite concentrations in CSF. The present study had high power to finding moderate or large
Acknowledgements
We thank the patients and controls for their participation. We thank Alexandra Tylec, Kjerstin Lind, Sara Holmqvist and Charlotta Leandersson for technical assistance. The present study was financed by the Swedish Research Council (K2007-62×−15077-04-1, K2008-62P-20597-01-3, K2010-62×−15078-07-2, K2012-61×−15078-09-3), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Knut and Alice Wallenberg Foundation, and the
Conflict of interest
All authors declare that they have no conflicts of interest with regard to the present report.
Role of funding sources
None of the funding sources participated in the study design, the collection, analysis and interpretation of data, in writing of the report or in the decision to submit the article for publication.
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