The prevalence of smoking among people with psychosis is notoriously high, and smoking is often regarded as a form of self-medication, but a new analysis suggests smoking itself may play a causative role in the development of psychotic illness, new research shows. "[Our findings] suggest to clinicians that we should probably be more aggressive in how we manage smoking in people presenting with psychosis, in much the same way as we now consider managing cannabis use in people with psychosis," coauthor Sameer Jauhar, MD, an honorary consultant psychiatrist at the Maudsley Hospital, King’s College London, United Kingdom, told Medscape Medical News.
The study was published online July 9 in Lancet Psychiatry.
Self-Medication Hypothesis Debunked?
The analysis included 61 studies with data through 2014 involving 14,555 tobacco smokers and 273,162 nonsmokers. The studies included international populations, and two studies were from China, where smoking rates are lower than in Europe and North America.
The investigators hypothesized that if the high rate of smoking among people with psychosis was related to self-medication, then smoking rates could be expected to be normal at the time of the first psychotic episode and subsequently increase in reaction to the symptoms.
Instead, the analysis of case-control studies found that 57% of people with a first episode of schizophrenia were already smokers, for an overall odds ratio of 3.22 (95% confidence interval [CI], 1.63 - 6.33), with some evidence of publication bias.
A subanalysis of five longitudinal, prospective studies showed a more modest association, but daily smokers were still approximately twice as likely to develop new psychotic disorders as nonsmokers (relative risk, 2.18; 95% CI, 1.23 - 3.85).
In addition, those who smoked daily were found to develop psychotic illness approximately 1 year earlier than nonsmokers.
There was no significant difference in age of starting smoking between those who did, and did not, develop psychosis.
"We think that the earlier onset of psychosis and higher risk in smokers of developing psychosis (albeit based on few studies) calls into question the self-medication hypothesis," the authors wrote.
The findings collectively satisfy the Bradford Hill conditions, which include strength, consistency, specificity, and other factors, for evidence suggesting a causal relationship between smoking and psychosis, the authors conclude.
Although Dr Jauhar said he knew of no evidence linking smoking reduction or cessation with a reduction in psychosis, previous research by his team, published in the British Journal of Psychiatry, has shown some reduction in symptoms in those who quit.
"Our [previous study] suggested that positive psychotic symptoms were increased in those with nicotine dependence, [and] what was interesting in that article was that quitters and nonsmokers showed lesser severity of positive symptoms than those patients with nicotine dependence," he said.
"[However,] the other issue will be that if patients' symptoms do increase, there is a high probability that this will lead to treatment-seeking, so it may be difficult to look at."
Nicotine-Dopamine Connection?
In considering possible mechanisms that could cause psychosis, the authors note that previous epidemiologic and laboratory studies have shown evidence linking nicotine and the dopamine system, which would relate to a leading theory suggesting excess striatal dopamine to be a main cause of schizophrenia.
"In vivo, nicotine might increase dopamine release directlly...to a similar degree as other drugs of misuse," they wrote.
Nicotine could possibly also wreak havoc on D2 dopamine receptors, commonly implicated in psychosis, they added.
"Nicotine could cause a change in the dopamine system...through induction of supersensitivity of D2 receptors, which has been proposed as an explanatory mechanism for several risk factors for schizophrenia and as a common pathway for psychotic symptoms."
Finally, a key cluster of genes — CHRNA5, CHRNA3, and CHRNB5— on chromosome 15, which have been linked to schizophrenia in the largest genome-wide association study of the disease to date, also are associated with nicotine dependence and smoking behavior.
The authors acknowledge the study's important limitations, including the small number of longitudinal studies and the inability to determine use of other substances, such as cannabis.
"Future studies, particularly longitudinal and prospective studies with larger sample sizes, should investigate the relation between daily smoking, sporadic smoking, nicotine dependence, and development of psychotic disorders," they conclude.
Risk Factor?
In an accompanying editorial published along with the study, Helen L. Alderson, PhD, and Stephen M. Lawrie, MD, of the University of Edinburgh, United Kingdom, argue that the self-medication hypothesis and theory of smoking as a causative factor in psychosis are not necessarily mutually exclusive.
"The most likely explanation of these findings is that cigarette smoking is associated with an increased risk for schizophrenia," they write.
"Taking up, and continuing, smoking could be self-medication for anxiety, depression, or psychotic symptoms. It could also be shared with other risk factors for psychosis, such as family history, urban upbringing, or childhood adversity."
Along with regular cannabis use, the risk factors seem to have an additive effect to psychosis and age of onset, the authors add.
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They agree that further research should include large, longitudinal, prospective studies focusing on those risk factors.
"To say that smoking causes psychosis would be premature, but the time might not be too much longer before cigarette smoking is recognized as a risk factor for psychosis as well as anxiety and depression."
In further commenting on the study, Carol Tamminga, MD, professor and chair of the Department of Psychiatry at the University of Texas Southwestern School of Medicine, in Dallas, called into question several of the study's suggestions, including the role of D2 dopamine receptors.
"The stringent demonstration of the role of D2 dopamine receptors in psychosis has not been demonstrated, let alone that nicotine has the same kind of effect," she told Medscape Medical News.
"If this were true, then taking a cohort of 18-year-old adolescents and giving them nicotine would result in some degree of psychosis onset, more than placebo administrations."
In general, the analysis should caution against the use of its associational data to claim causality, she added.
"[The authors] do admit that the effect is weak, and any of us would add that it seems inconsistent."
"Cigarette smoking itself can have many other correlates which the authors mention but do not discuss, like the use of other addicting substances, probably poverty, and possibly early-life trauma. The authors really need to highlight these caveats."
The study received funding from NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust (SLaM) and King’s College London. The study authors, Dr Lawrie, and Dr Tamminga have disclosed no relevant financial relationships.
Lancet Psychiatry. Published online July 9, 2015. Full text, Editorial