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Cigarette smoking prevalence in psychiatric disorders (PDs) such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) is two to three times higher than in the general population in which the rate is approximately 20%.[1, 2] Clinical estimates of smoking prevalence range from 58–88% for individuals with SZ, 51–70% for those with BD,[4-7] and 40–60% for those with MDD.[7, 8] This pattern has been found to persist across cultures, even after controlling for age, gender, country, and interaction between country and mental illness. Furthermore, both epidemiological[1, 10] and clinical studies[11-17] have suggested a reduced likelihood of smoking cessation in people with PDs.
There is evidence for widespread neurocognitive deficits (executive functioning, attention and working memory function) in people with PDs, particularly those with SZ. Previous studies have demonstrated that individuals with SZ exhibited significant deficits in executive function, attention, and concentration, working memory, verbal learning and memory, processing speed, and visuospatial working memory (VSWM). Similarly, there is evidence for neuropsychological dysfunction in both BD and MDD. BD is associated with impairments in processing speed, working memory, verbal fluency and episodic memory, verbal memory, and executive function, while MDD is associated with deficits in episodic memory, verbal recall and recognition, executive function,[28, 30, 31] sustained attention, and visuospatial learning and memory.[28, 30] In comparison to patients with BD and MDD, however, those with SZ seem to have more profound neuropsychological impairments.[32, 33] Recent studies comparing the neuropsychological profiles of persons with SZ and BD (in a euthymic phase) have either reported similar profiles patterns but more severe impairments in SZ or more widespread and severe cognitive deficits in SZ compared with BD.[35, 36] In MDD, deficits in executive function are less severe than SZ, while deficits in sustained attention are more severe and stable in SZ than in BD and MDD, where deficits are more “state-dependent.”
There is increasing evidence that cigarette smoking and/or nicotine administration improves selected aspects of cognitive dysfunction in SZ (reviewed in references [38-40]). In contrast, the cognitive-enhancing effects in non-psychiatric controls are less clear. Some studies have demonstrated enhancements following acute nicotine administration, while others have reported no effects or even detrimental effects (for review, see references 41 [41, 42]). Moreover, recent studies have indicated that in non-psychiatric controls chronic smoking is associated with worse cognitive function, particularly in higher-order domains,[43-45] which may be due to the detrimental effects of acute nicotine or that poor cognitive function acts as a risk factor for the initiation of smoking. It has been suggested that cognitive enhancement in SZ as a result of smoking might be specific to the domains of working memory, attention, and information processing.[46, 47] The cognitive-enhancing effects of smoking on neurocognitive performance in SZ have been observed in both cross-sectional (ie, smokers vs. non-smokers) and longitudinal studies (ie, smoking vs. abstinent conditions and nicotine challenge paradigms) and span tasks associated with sustained[47-52] and selective attention, working memory,[24, 47, 51, 54, 55] response inhibition, processing speed,[49, 50, 54] prepulse inhibition,[56-58] and sensorimotor gating.[46, 59, 60]
The high rates of smoking in BD and MDD are often attributed to an attempt to self-medicate affective symptoms and elevated monoamine oxidase (MAO)-A levels associated with the MDD.[61-63] However, little is known about whether smoking modulates cognition in BD or MDD. This is an important issue given that MDD and BD are associated with both high rates of smoking and poor cognitive performance. To our knowledge, the only study to be conducted to date demonstrated in a small sample of smokers and non-smokers with bipolar illness (I and II) that smoking status did not significantly alter neuropsychological task performance on measures of psychomotor speed, attention, memory, learning, and executive function. Accordingly, in the present study, we used a cross-sectional design to evaluate the effects of smoking status on neuropsychological task performance in subjects with SZ, BD, and MDD.
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The current study was a preliminary cross-sectional investigation of the effects of cigarette smoking on neurocognitive function across several psychiatric diagnoses. Participants with SZ performed significantly worse than controls on several neurocognitive tests (CVLT-II, TMT, and VSWM), while participants with BD or MDD did not differ significantly from controls on any task; these findings are consistent with the literature reporting more profound neurocognitive deficits in SZ than in BD and MDD.[32, 33]
With regard to interactions of smoking status and diagnosis, there was an association between better performances on three CVLT-II tasks (STCR and LTCR, recognition/discriminability) and the presence of smoking in individuals with SZ, after co-varying for group differences in age, gender, and years of education. Better performance was observed in smokers with SZ when asked to recall verbal information after either a short or long delay with the benefit of semantic prompting (STCR and LTCR), and in recognizing previously presented verbal information when given a forced-choice (CVLT-II recognition). Furthermore, in the non-psychiatric control group, there was an association between being a smoker and worse performance on a CVLT-II task that measured the effects of proactive interference (List B). Interestingly, smoking status was not associated with altered cognitive performance in patients with BD or MDD. Given the small size of the smoking status MDD and BD sub-groups these findings should be interpreted with caution. Nevertheless, our finding of a lack of an effect of BD subjects is similar to the results of Law et al. There is no preexisting literature on the effects of smoking on neurocognitive performance in MDD with which to contrast the current results.
It is notable that we did not observe effects of smoking on tasks that have previously been shown to be sensitive to tobacco effects, such as attention and spatial working memory reported in previous cross-sectional studies comparing smokers and non-smokers with SZ.[24, 50, 53] Methodological, statistical, and population differences between this and other studies may explain these discrepancies. Nonetheless, our results suggest a degree of specificity in cigarette-smoking modulation of neurocognitive deficits in individuals with SZ compared to BD and MDD. If confirmed, these findings could have significant treatment implications for smokers with co-morbid PDs who wish to quit. Targeting cognitive deficits has been proposed as a promising avenue for smoking cessation treatment in SZ,[40, 78, 79] however, our findings suggest this may not be an appropriate strategy for BD and MDD smokers, and therefore other treatment approaches should be explored.
Limitations of this study included: (1) secondary analysis of data derived from three studies on cognition in persons with SZ, BD, and major depression versus controls conducted over a 5-year period; (2) power to detect differences between smoking and non-smoking BD and MDD groups were limited by the small samples sizes of these subgroups (in some cases with N's <10 subjects in the BD and MDD subgroups); and (3) cross-sectional design of the study insofar as comparison of smoking status effects. That the psychiatric groups were on psychotropic medications which could impact cognitive function could be considered a limitation, nevertheless, this is likely to be the most clinically relevant situation for these populations and is therefore important to study. Further studies are needed to evaluate the effects of cigarette smoking on cognitive performance in these affective disorders. These should include larger sample sizes, incorporate longitudinal designs (to evaluate the effects of smoking abstinence and reinstatement on cognition), and evaluate the association between cognition and smoking cessation treatment outcomes (association between baseline cognitive performance on quit rates in BD and MDD[78, 79]). Another potential avenue of research is to examine the effects of smoking history (ie, current, former, and never smokers) in BD and MDD as recent studies in SZ have identified subtle differences between former and never smokers which may be masked by grouping subjects together as non-smokers.[50, 80]
In conclusion, the results of this preliminary study suggest that the improved cognitive abilities associated with cigarette smoking are specific to SZ, such that smoking status does not alter cognitive performance in BD and MDD.
This work was supported in part by Grants K02-DA-16611, R01-DA-13672, and R01-DA-14039 from the National Institutes on Drug Abuse, Bethesda, MD (Dr. George); an NARSAD Independent Investigator Award (Dr. George); an operating grant (MOP#115145) from the Canadian Institutes of Health Research (Dr. George); the Endowed Chair in Addiction Psychiatry at the University of Toronto (Dr. George); an NARSAD Young Investigator Award (Dr. Sacco); and Centre for Addiction and Mental Health Foundation Research Fellowships (Drs. Morisano and Wing).
We thank Angelo Termine, Jennifer Vessicchio, LCSW, Melissa Dudas, Aisha Seyal, Taryn Allen, Erin Reutenauer, and Marc Potenza, MD, PhD for their assistance with study procedures.
Declaration of Interest
Drs. Morisano, Sacco, and Wing, and Ms. Arenovich have no conflicts to report. Dr. George reports that he has received grant support from Pfizer, Inc., and has received consulting fees from Pfizer, Evotec, Eli Lilly, Janssen-Ortho, Astra-Zeneca, and Novartis in the past 2 years. The authors alone are responsible for the content and writing of this paper.