Effects of caffeine intake and smoking on neurocognition in schizophrenia

Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Effects of caffeine intake and smoking on neurocognition in schizophrenia Christian Núñez n, Christian Stephan-Otto, Jorge Cuevas-Esteban, Josep Maria Haro, Elena Huerta-Ramos, Susana Ochoa, Judith Usall, Gildas Brébion Parc Sanitari Sant Joan de Déu, Universitat de Barcelona, Sant Boi de Llobregat (Barcelona), C/Doctor Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain

art ic l e i nf o

a b s t r a c t

Article history: Received 3 February 2015 Received in revised form 30 October 2015 Accepted 15 November 2015

Although most studies support the beneficial effects of caffeine on neurocognition, its effects have never been assessed in psychiatric patients. In addition, results from studies in smokers are contradictory. Moreover, there are no data available about the neurocognitive effects of caffeine and tobacco together. We explored the concomitant effects of regular caffeine and tobacco intake on neurocognition in 52 schizophrenic patients and 61 healthy controls. Verbal fluency, processing speed, and working, visual and verbal memory were assessed. For each measurement, two tasks with two levels of complexity were administered. Our results showed that caffeine intake had beneficial effects on male schizophrenic patients only in complex tasks requiring deeper cognitive processing (semantic fluency, cognitive speed, working memory, and visual memory). Female patients and controls were unaffected. In contrast, smoking had a negative effect on male, but not on female, schizophrenic patients in semantic fluency. The effects of smoking in controls were inconsistent. In conclusion, our data showed, for the first time, beneficial effects of caffeine intake on neurocognition in male schizophrenic patients. These data suggest that further research of therapeutics based on caffeine is needed, as this could be beneficial for schizophrenic patients. In contrast, smoking appears to be detrimental. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Coffee Nicotine Processing depth Processing speed Verbal fluency Working memory

1. Introduction Caffeine and tobacco are among the most commonly consumed substances in the world. Moreover, it is well established that caffeine intake and smoking in schizophrenia is much more frequent than in the general population (Strassnig et al., 2006; Winterer, 2010). It is known that caffeine intake can be useful to reduce the cognitive decline after sleep deprivation (Snel and Lorist, 2011) and it also seems to protect against cognitive decline (Santos et al., 2010). In contrast to caffeine intake, most studies point to negative effects of smoking on global cognition and the hastened cognitive deterioration of current smokers over the years (Peters et al., 2008), as well as an increased risk of suffering from dementia (Peters et al., 2008). Some studies have tried to find whether there is a relationship between caffeine intake and performance in some specific cognitive functions. All of them have used healthy participants, and there are no data available for psychiatric patients. In addition, most of them are focused on the acute effects of caffeine administration rather than the effects of regular consumption. Visual n

Corresponding author. E-mail address: [email protected] (C. Núñez).

memory (Borota et al., 2014) and cognitive speed, measured with the Digit Symbol Substitution Test (DSST) (Mackay et al., 2002), were improved by acute administration of caffeine. When measuring working memory, Smillie and Gökçen (2010) found that only extrovert participants benefited from the administration of caffeine while performing a complex 3-back task, while those performing simpler tasks (1-back or 2-back) or introvert participants did not. In this sense, positive correlation has also been reported between acute administration of caffeine and performance in complex working memory tasks only in extrovert (Smith, 2013) and impulsive (Smith, 2002) participants, while the non-impulsive were impaired by caffeine (Smith, 2002). Some studies found a positive correlation between regular caffeine intake and semantic verbal fluency, in an animal naming task, with female participants (Vercambre et al., 2013). In contrast, Klaassen et al. (2013), using the Sternberg task, found impaired performance produced by administration of caffeine when the task requirements were higher. Others have failed to find any correlation between regular caffeine consumption and performance in the DSST or the Auditory Verbal Learning Test (Kyle et al., 2010). Studies with healthy participants do not permit the drawing of a clear conclusion about the effects of smoking. Most studies have failed to find an effect, either positive or negative, of regular

http://dx.doi.org/10.1016/j.psychres.2015.11.022 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Núñez, C., et al., Effects of caffeine intake and smoking on neurocognition in schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.11.022i

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smoking on verbal fluency in middle-aged and young adults (Wagner et al., 2013). Regarding working memory, it seems to be clear that regular smoking does not affect performance in simple tasks such as forward digit span, which requires only a small cognitive load (Wagner et al., 2013). Using more complex tasks which require a higher cognitive load, no differences were found in the letter-number sequencing task (Wagner et al., 2013). Nevertheless, other researchers have shown that smokers performed worse than non-smokers in the DSST (Starr et al., 2007; Wagner et al., 2013) and in the Auditory Verbal Learning Test (Wagner et al., 2013). In contrast, only a few studies have reported benefits from regular smoking. For example, Sabia et al. (2008) found that middle-aged former smokers performed better than never smokers in both semantic and phonemic fluency, although they did not find differences between current smokers and never smokers. In contrast to the data gathered with healthy participants, smoking seems to improve cognition to some extent in schizophrenia. Some studies with schizophrenic patients have found better performance in processing speed, assessed with the Stroop task, by regular smokers compared to never smokers (Wing et al., 2011), and by patients who were administered nicotine (Barr et al., 2008). Regular smoking (Morisano et al., 2013) and acute nicotine administration (Smith et al., 2002) were also associated to enhanced verbal memory. Jacobsen et al. (2004), applying a nicotine patch 6 h before a working memory assessment, found that high levels of nicotine were associated with a performance improvement in schizophrenic patients only in the 2-back dichotic condition, the most complex of their study, while smoking controls worsened their performance under the same conditions. Similarly, AhnAllen et al. (2008) found reduced reaction time in schizophrenic patients, but not in controls, after the administration of a nicotine patch during 3 h. Furthermore, smoking seems to improve visuospatial working memory (Sacco et al., 2005), selective attention (Hahn et al., 2012), and divided attention (Ahlers et al., 2014). On the other hand, schizophrenic regular smokers performed worse than schizophrenic non-smokers on visuospatial and immediate memory measures, according to Zhang et al. (2012). Iasevoli et al. (2013) failed to find any effect of regular smoking on cognitive speed using the symbol coding task, equivalent to the DSST, and they even found a trend towards worsened performance in the digit sequencing task and the category instances task, which measure working memory and semantic fluency, respectively (Iasevoli et al., 2013). Other studies evaluating the effects of acute nicotine administration did not find differences between nicotine or placebo administration on semantic fluency (Harris et al., 2004), and the letter-number task, measuring working memory (Barr et al., 2008). In studies comparing regular smokers and non-smokers, no differences were found in the TMT task, measuring processing speed (Morisano et al., 2013), and semantic fluency (Zhang et al., 2012). The general impression that smoking improves cognition in schizophrenic patients, added to further evidence of nicotine reducing negative symptomatology (Smith et al., 2002), supports the self-medication hypothesis of smoking in schizophrenia, which postulates that patients may smoke to experience these positive effects, and is a potential explanation of the high prevalence of smoking in schizophrenia (Ahlers et al., 2014; Hahn et al., 2012; Smith et al., 2002; Winterer, 2010). It has been proposed that some of the positive cognitive effects of smoking in schizophrenic patients may be mediated by D1 receptors in the prefrontal cortex (Ahlers et al., 2014; Hahn et al., 2012). Dopaminergic effects on D1 in the prefrontal cortex have been shown to follow an inverted-U shape (Vijayraghavan et al., 2007), in which the top of the inverted-U would represent the optimal D1 receptor activation, which would be associated with

better cognitive performance. Schizophrenic patients are thought to be in the non-optimal ascending left part of the inverted-U, and would be able to reach the top of the curve by means of tobacco consumption, which can stimulate dopamine release in the prefrontal cortex (Imperato et al., 1986). This could also account for the differential cognitive effects of smoking observed between schizophrenic patients and healthy controls, as the latter may be already located around the top of the curve and the release of dopamine by tobacco consumption would shift healthy controls to the non-optimal descending right part of the curve (Ahlers et al., 2014; Hahn et al., 2012). Some gender differences have been found regarding caffeine intake and smoking. Male schizophrenic patients smoke (Kim et al., 2013) and, among smokers, also consume more caffeine (Kim et al., 2013) than female schizophrenic patients. Benowitz et al. (2006) reported an accelerated metabolism of nicotine in women compared to men, probably because of the influence of estrogens over the CYP2A6 enzyme, the main responsible of nicotine metabolism. Botella and Parra (2003) found an increase in state anxiety in men, but not in women, after consuming caffeine. Moreover, caffeine seems to have a greater effect on men in reducing somnolence and inducing activation (Adan et al., 2008), suggesting that women are less sensitive to caffeine (Botella and Parra, 2003). With respect to metabolic issues, females are more affected by caffeine than males using the same doses, likely because of their reduced body weight and height (Carrillo and Benitez, 1996). Currently available data about the effects of caffeine intake and smoking on neurocognition are not clear and are sometimes contradictory. Moreover, most studies are focused on one substance only and few have examined the effects of caffeine intake and smoking together (see for example: Tanda and Goldberg, 2000; Powers et al., 2008), so the concomitant effects are generally not taken into account. This is especially relevant in schizophrenia studies, as most schizophrenic patients consume these substances simultaneously and do so more frequently than the general population. Another weakness of most studies is not taking into consideration the task difficulty; given that simple and complex tasks require different depth of processing (Craik and Tulving, 1975) that may change the cognitive load and may even involve distinct functional brain areas, caffeine intake and smoking may have differential effects depending on the task being performed. Therefore, our aim in this study was to explore the concomitant effects of regular caffeine intake and smoking on some neurocognitive functions, both in schizophrenic patients and controls, employing tasks with two levels of difficulty. Also, we explored gender differences within each group. Although the effects of caffeine on neurocognition have not been studied in the psychiatric population, we expected it to improve performance in both schizophrenic patients and controls, especially in those tasks requiring deeper cognitive processing. Furthermore, given the inconsistent data available about smoking, we sought to explore its effects on schizophrenic patients and controls.

2. Methods 2.1. Participants A total of 113 participants, 52 patients with schizophrenia, who were admitted to a large hospitalization unit of Parc Sanitari Sant Joan de Déu, and 61 healthy controls, were included in this study, which is part of a broader project. Inclusion criteria for patients were having schizophrenia (diagnosed according to DSM-IV-TR criteria), age between 18 and 65 years old and fluency in Spanish language. Exclusion criteria were

Please cite this article as: Núñez, C., et al., Effects of caffeine intake and smoking on neurocognition in schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.11.022i

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abuse of or dependence on alcohol or other substances (according to DSM-IV-TR) during the previous 6 months, a history of organic mental disease, intellectual disability, brain injury, dementia or severe physical illness. The control group was adjusted to the patient group by age and gender. However, education level, as well as the score on the vocabulary test TAP (Test de acentuación de palabras), a Spanish equivalent of the National Adult Reading Test (NART) used to assess premorbid verbal IQ, were significantly higher in the control group. The exclusion criteria for controls were having a mental illness, abuse of or dependence on alcohol or other substances during the previous 6 months, intellectual disability, dementia or severe physical illness. Participants were screened in a telephone interview to rule out current or recent alcohol or other substance abuse or dependence as well as other mental or non-mental illnesses. All participants provided informed consent before taking part in the study. 2.2. Clinical scales 2.2.1. Scale for the Assessment of Negative Symptoms Negative symptomatology in schizophrenic patients was assessed using the Spanish version of the Scale for the Assessment of Negative Symptoms (SANS). The attention item was discarded since attention disorders are considered as different from negative symptomatology. The other four items were added together to constitute the negative symptoms score (SANS-4). 2.2.2. Scale for the Assessment of Positive Symptoms Positive symptomatology in schizophrenic patients was assessed using the Spanish version of the Scale for the Assessment of Positive Symptoms (SAPS). 2.3. Neuropsychological scales 2.3.1. Semantic/phonemic verbal fluency To assess semantic verbal fluency, participants were given 60 s to say as many names of animals as they could. Phonemic verbal fluency was also assessed; in this case, participants had to say as many words starting with the letter P as they could in 60 s. Semantic fluency requires a deeper processing than phonemic fluency. 2.3.2. Cognitive/motor speed Cognitive speed was evaluated using the DSST, which is included in the WAIS-III. Participants were given a list of symbols associated with certain numbers. They had to fill in a list of numbers as fast as they could by drawing the corresponding symbol under each number for 90 s. The Digit Copy test, which is also included in the WAIS-III, was used to evaluate motor speed. Participants only had to copy the symbols presented in a list for 60 s. DSST constitutes the deeper processing measure. 2.3.3. Working/short-term memory The Letter-Number Sequencing (LNS) scale of the WAIS-III was used to evaluate working memory. Participants had to repeat a given sequence of numbers and letters that they had to reorder previously by placing first the numbers in ascending order and then the letters alphabetically. The Forward Digit Span (FDS) of the WAIS-III was used as a measure of short-term memory. In this case, participants had to repeat a given sequence of numbers in the same order as they were presented. In both cases, the total number of correct trials was recorded. The LNS task requires deeper processing than the FDS task.

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2.3.4. Visual memory 16 pictures from art galleries (8 colour and 8 black/white) were presented in groups of four pictures. After a 20-minute delay filled with other tasks, the 16 target pictures were mixed with 16 new pictures (8 colour and 8 black/white) and the participants had to recognize those that had been presented earlier. The Pr index of recognition accuracy (rate of correct recognitions minus rate of false recognitions) was computed for the colour and for the black/ white pictures. Colour picture recognition involves deeper processing than does black/white. 2.3.5. Verbal memory 2 lists of words were used to assess verbal memory; one of them contained 16 frequent words, while the other contained 16 rare words. 5 min after the first list was presented, during which time the participants had to perform a simple task, they were told to recognize all the words they could from a list of 32 words of the same kind (frequent or rare) as the first list. Then they were presented the second list and the procedure was repeated. The list order was counterbalanced. The Pr index of recognition accuracy (rate of correct recognitions minus rate of false recognitions) was computed for the frequent and for the rare lists. Rare word recognition requires deep processing, while frequent word recognition requires shallow processing. 2.4. Statistical analysis Regression analyses were conducted on the scores achieved by participants in each task. Performance predictors included in the analyses were caffeine intake (cups of coffee, tea or other caffeinated beverages per day reported by the participant) and tobacco intake (number of cigarettes per day reported by the participant), as well as the score obtained in the SANS-4 and years of duration of the illness (chronicity), when analyzing the patient group, to control for potential confounding effects. In the control group, the predictors were caffeine intake and tobacco intake. Analyses were performed independently for male and female participants. Other important confounders such as antipsychotic medication and the time of the last caffeine or tobacco intake were not assessed and their effects could not be analyzed. Multiple comparison adjustments were not performed given the exploratory nature of the study (Bender and Lange, 2001).

3. Results 3.1. Sample characteristics The sociodemographic and clinical characteristics of the sample are shown in Table 1. Schizophrenic male patients consumed significantly more caffeine than did female patients [t(50) ¼ 2.39, Po 0.025]; however, there were no caffeine intake differences between male and female controls or between patients and controls. Regarding tobacco, schizophrenic patients consumed significantly more than controls, both men [t(68) ¼4.95, P o0.001] and women [t(41) ¼ 4.60, P o0.001]. There were also significant differences between male and female patients [t(50) ¼1.99, P¼ 0.05] and between male and female controls [t(59) ¼ 2.36, Po 0.025]; in both cases, men consumed more tobacco than women. 3.2. Effects of caffeine intake and smoking Results of the regression analyses in patients are presented in Table 2. In male patients, caffeine intake had a significant positive effect on the deep measure of all the tasks except verbal memory.

Please cite this article as: Núñez, C., et al., Effects of caffeine intake and smoking on neurocognition in schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.11.022i

C. Núñez et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Table 1 Sociodemographic and clinical information of the schizophrenic and control sample. Schizophrenic patients

Age Caffeine intaked Tobacco intakee Education levelf Verbal IQ scoreg SANS-4 score SAPS score Chronicityh Age of onset

Healthy controls

P value

Male (n¼ 34)

Female (n¼ 18)

Male (n¼ 36)

Female (n¼ 25)

M vs. F SPa

M vs. F HCb

SP vs. HCc

Mean 47.41 2.66 21.66 3.12 16.91 26.65 30.62 21.85 25.56

Mean 44.39 1.61 12.44 3.67 17.11 18.56 30.50 13.72 30.67

Mean 46.89 2.21 5.17 4.61 21.06 – – – –

Mean 43.84 2.06 0.40 4.88 18.56 – – – –

ns o 0.025 0.05 ns ns o 0.05 ns o 0.025 o 0.05

ns ns o 0.025 ns 0.05 – – – –

ns ns o 0.001 o 0.001 o 0.01 – – – –

SD 10.52 1.53 17.20 1.41 5.92 12.70 17.57 12.01 7.50

SD 11.16 1.46 12.93 1.41 4.19 12.21 19.05 11.88 10.59

SD 8.40 1.69 9.95 1.18 4.62 – – – –

SD 10.05 1.52 2.00 1.30 5.05 – – – –

a

Male versus female schizophrenic patients. Male versus female healthy controls. c Schizophrenic patients versus healthy controls. d Cups of coffee, tea or other caffeinated beverages per day. e Number of cigarettes per day. f 1¼ no studies; 2¼ uncompleted primary studies; 3¼ completed primary studies; 4 ¼uncompleted high school; 5¼ completed high school; 6¼ uncompleted university studies; 7 ¼ completed university studies. g Assessed with TAP (Test de Acentuación de Palabras), Spanish equivalent of the National Adult Reading Test. h Years of duration of the illness. b

Smoking was negatively associated with semantic fluency. No significant association emerged in the female patient group. Post-hoc analyses were performed in the male patient sample to evaluate potential effects of age. Male patient sample was divided according to the median age of the group (M ¼46.5, IQR ¼16.25). There were no differences regarding caffeine or tobacco intake between the two subgroups (caffeine: P ¼0.956; tobacco: P ¼0.413). The results, presented in Table 3, showed that the positive effect of caffeine intake on the deep measures was still present in the younger subgroup of male patients, but not in the older subgroup. Likewise, smoking was negatively associated with

working memory in the younger, but not in the older, subgroup of male patients. In order to assess the potentially confounding effects of negative symptoms and duration of illness in these associations, the regression analyses were recomputed for the male patient sample, using only caffeine intake and tobacco intake as performance predictors. Results are presented in Table 4. The positive effect of caffeine intake was still present although weakened, while the negative effect of smoking was enhanced. Results of the regression analyses in controls are presented in Table 5. Caffeine intake did not have any significant effect either in

Table 2 Regression analyses in the male and female schizophrenic patients. Associations between task performance and caffeine intake, tobacco intake, negative symptomatology, and illness duration are expressed as β coefficients. Male schizophrenics (n¼ 34) Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

Caffeine nnnn

0.53 0.16 0.35n 0.25 0.39nn 0.07 0.40n 0.22  0.23 0.29

Chronicity

R2

F test

P value

 0.37  0.41n  0.18  0.36n  0.38n  0.19  0.09 0.21  0.11  0.57nnn

 0.10  0.07  0.45nnn  0.39nn  0.27  0.17  0.17  0.26 0.03 0.20

0.47 0.23 0.46 0.49 0.44 0.09 0.18 0.11 0.07 0.29

6.50 2.10 6.26 7.09 5.76 0.69 1.55 0.92 0.55 2.98

0.001 0.107 0.001 0.000 0.002 0.607 0.214 0.464 0.700 0.035

Smoking

SANS-4

nn

n

 0.39  0.12  0.26  0.17  0.22 0.08  0.02  0.04 0.17 0.11

Female schizophrenics (n¼ 18)

Caffeine

Smoking

SANS-4

Chronicity

R2

F test

P value

Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

0.06  0.01  .04  0.28  0.07 0.17  0.24  0.73  0.41  0.27

0.03 0.38  0.03 0.36 0.09 0.18  0.01 0.34 0.16  0.32

 0.30  0.18 0.11 0.17 0.26  0.12 0.02 0.38 0.43 0.16

 0.46  0.62n  0.79nnn  0.76nn  0.64n  0.24  0.52$  0.37  0.39 0.16

0.37 0.39 0.59 0.42 0.30 0.09 0.38 0.23 0.13 0.18

1.90 2.06 4.70 2.31 1.42 0.33 2.02 0.96 0.48 0.74

0.171 0.144 0.014 0.113 0.282 0.856 0.151 0.464 0.748 0.584

(D)¼ deep processing measure. (S)¼ shallow processing measure. $

P o0.08. Po 0.05. nn Po 0.025. nnn Po 0.01. nnnn Po 0.001. n

Please cite this article as: Núñez, C., et al., Effects of caffeine intake and smoking on neurocognition in schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.11.022i

C. Núñez et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ Table 3 Regression analyses in the male schizophrenic patients, separated by age groups according to the median age of this subgroup (M ¼ 46.5). Associations between task performance and caffeine intake, tobacco intake, negative symptomatology, and illness duration are expressed as β coefficients. Younger male sch. (n¼ 17)

Caffeine Smoking SANS-4 Chronicity R2

Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

0.66nnn

 0.32

 0.23

 0.06

0.53 3.37

0.046

0.40

 0.22

 0.20

0.05

0.21 0.80

0.550

 0.12

 0.03

 0.23

0.50 3.01

0.062

 0.34

 0.29

0.12

0.37 1.73

0.209

 0.41n

 0.05

 0.12

0.65 5.67

0.008

0.56n

0.00

 0.07

 0.12

0.34 1.52

0.257

0.50n

 0.42

 0.01

 0.23

0.45 2.46

0.102

0.08

 0.21

0.14

 0.27

0.14

0.50

0.740

0.04

 0.36

0.15

 0.08

0.15

0.54

0.712

0.30

 0.18

 0.46

0.19

0.31 1.32

0.317

Older male sch. (n¼17) Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

0.67nnn 0.48

$

0.74nnn

5

Table 4 Regression analyses in the male schizophrenic patients. Associations between task performance and caffeine and tobacco intake are expressed as β coefficients. Negative symptomatology and illness duration were not considered. Male schizophrenics (n¼34)

Caffeine

Smoking

R2

F test

P value

Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

0.47*** 0.09 0.31$ 0.18 0.32$ 0.03 0.38* 0.25  0.25 0.20

−0.48***  0.21 −0.42** −0.35$ −0.36* 0.00  0.08  0.08 0.16 0.07

0.30 0.04 0.19 0.11 0.16 0.00 0.13 0.06 0.06 0.05

6.74 0.63 3.53 1.94 2.88 0.02 2.34 0.92 1.02 0.87

0.004 0.538 0.041 0.160 0.071 0.982 0.114 0.410 0.374 0.430

F test P value

(D)¼ deep processing measure. (S)¼ shallow processing measure. $

Po 0.085. P o 0.05. nn Po 0.025. nnn Po 0.01. n

Table 5 Regression analyses in the male and female healthy controls. Associations between task performance and caffeine and tobacco intake are expressed as β coefficients. Male controls (n¼ 36)

Caffeine

Smoking

R2

F test

P value

0.02  0.22 0.04 0.04 0.10  0.30  0.22 0.09 0.21 0.27

0.11 0.10  0.23  0.14 0.12 0.28 0.07  0.04  0.17  0.13

0.01 0.05 0.05 0.02 0.03 0.13 0.04 0.01 0.06 0.07

0.23 0.77 0.83 0.33 0.49 2.35 0.76 0.12 0.96 1.30

0.796 0.472 0.444 0.724 0.619 0.111 0.474 0.889 0.395 0.287

0.41

 0.49

 0.45

0.13

0.33 1.50

0.262

Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

 0.17

0.01

 0.49

0.25

0.27 1.13

0.387

Female controls (n¼ 25)

Caffeine

Smoking

R2

F test

P value

0.00

 0.35

 0.21

 0.34

0.44 2.37

0.111

0.05

 0.05

 0.34

 0.55nn

0.58 4.07

0.026

0.07

0.00

 0.72nnn

 0.14

0.59 4.23

0.023

 0.37

0.26

 0.21

 0.21

0.29 1.25

0.342

Semantic fluency (D) Phonemic fluency (S) Cognitive speed (D) Motor speed (S) Working memory (D) Short-term memory (S) Visual memory (colour) (D) Visual memory (b/w) (S) Verbal memory (rare) (D) Verbal memory (freq.) (S)

 0.09  0.24  0.09  0.27  0.16  0.03  0.01  0.09  0.23  0.18

0.54nnn 0.09 0.09 0.00  0.11  0.19 −0.38$  0.28  0.55nnn  0.49nn

0.33 0.07 0.02 0.08 0.03 0.03 0.14 0.07 0.28 0.22

5.51 0.88 0.24 0.89 0.30 0.39 1.79 0.88 4.29 3.18

0.011 0.429 0.789 0.424 0.741 0.684 0.190 0.430 0.027 0.061

0.15

0.39

 0.10

0.02

0.21 0.81

0.543

0.37

0.06

0.24

 0.18

0.25 1.02

0.438

Caffeine Smoking SANS-4 Chronicity R2

F test P value

(D)¼ deep processing measure. (S)¼ shallow processing measure. $

Po 0.085 Po 0.025 Po 0.01

nn

nnn

 0.33

0.45

 0.38

 0.07

0.38 1.87

0.181

4. Discussion 0.41

0.28

 0.74nnn

 0.01

0.53 3.37

0.046

(D)¼ deep processing measure. (S)¼ shallow processing measure. $

P o0.085. Po 0.05. nn Po 0.025. nnn Po 0.01. n

the male or the female group. In female controls, smoking was positively associated with semantic verbal fluency, but negatively associated with both verbal memory and visual memory measures. No associations were seen in the male control group.

This is the first study to assess the neurocognitive effects of caffeine in schizophrenia, and also the first to analyze the concomitant effects on neurocognition of caffeine intake and smoking in schizophrenia. The data presented show a beneficial effect of caffeine intake and a negative effect of smoking for male schizophrenic patients. Smoking does not have any effect in male controls, while the effects in female controls are inconsistent. While controls were unaffected by caffeine, we found positive associations between caffeine and performance in some neurocognitive tasks in male schizophrenic patients, particularly in those tasks requiring deeper cognitive processing, namely semantic verbal fluency, cognitive speed, working memory and visual memory of colour pictures. No association was found for

Please cite this article as: Núñez, C., et al., Effects of caffeine intake and smoking on neurocognition in schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.11.022i

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verbal memory, as in the study of Kyle et al. (2010). All these results are in agreement with our hypotheses and with the results of other studies which have also found, although in healthy participants, beneficial effects of regular or acute consumption of caffeine on semantic verbal fluency (Vercambre et al., 2013), visual memory (Borota et al., 2014), processing speed (Mackay et al., 2002), and working memory (Smillie and Gökçen, 2010; Smith, 2002, 2013). Klaassen et al. (2013), however, found an impairment of working memory from acute caffeine administration. A possible explanation for this contradiction is the different kinds of tasks used to assess working memory; also, perhaps more importantly, the participants in the study by Klaassen et al. (2013) were all white-collar employees, probably having non-impulsive personalities, a factor known to interact negatively with caffeine when assessing performance in complex tasks (Smith, 2002). Also, unlike in our study, they did not assess the potential concomitant effects of smoking, which could have confounded the results. It is worth noting that the most important effect of caffeine on the central nervous system is the antagonism of adenosine receptors, especially A1 and A2A receptors, since these are highly expressed in the brain and can be activated by low adenosine concentrations (Ferré, 1997; Fredholm et al., 1999). It is well known that adenosine can have some direct or indirect effects on many neurotransmitter systems throughout the brain such as the serotoninergic, cholinergic, opioid and, more importantly for this study, the dopaminergic (Fredholm et al., 1999). It seems that there is an antagonistic interaction between A1 and D1 and also between A2A and D2 receptors (Ferré, 1997). This may explain why caffeine, by means of adenosine receptor antagonism, has similar effects to increased dopaminergic transmission (Ferré, 1997). Supporting this, Hsu et al. (2010) found increased levels of dopamine in striatum of mice after chronic caffeine administration. Given the inverted-U shaped dopaminergic effects on D1 receptors in the prefrontal cortex (Vijayraghavan et al., 2007), the antagonistic interaction between A1 and D1 could provide a potential explanation of why only schizophrenic patients, and not healthy controls, benefited from caffeine when performing complex cognitive tasks, similar to which has been already proposed for tobacco (Ahlers et al., 2014; Hahn et al., 2012). Schizophrenic patients would presumably be located in the non-optimal ascending left part of the inverted-U curve. Caffeine intake would stimulate dopamine release in the prefrontal region, by means of the antagonism of A1 receptors, therefore shifting schizophrenic consumers of caffeine to the top of the inverted-U curve, which is representative of an optimal D1 receptor activation, supposedly associated to a better cognitive function. Healthy consumers of caffeine would not benefit from its consumption as they would already be located at the top of the curve and caffeine would shift them to the non-optimal descending right part of the inverted-U. It is also known that nicotine can increase dopamine release in striatum (Brody et al., 2009) and that nicotine dependence is associated with low availability of D2 receptors, also in striatum (Fehr et al., 2008). It has been suggested that non-treated schizophrenics have elevated levels of dopamine in striatum, probably as a consequence of neurotransmitter reuptake dysfunction (Mateos et al., 2007). Thus, high consumption of caffeine and tobacco in schizophrenia, which is the case of the patients of this study, could lead to a lower number of D2 receptors in striatum through mechanisms of down-regulation, which is a molecular configuration similar to that seen in impulsive individuals (Trifilieff and Martinez, 2014). Supporting this, it has been suggested that schizophrenic patients possess more impulsive traits than healthy people, especially when there is a concomitant substance abuse (Zhornitsky et al., 2012). However, it seems that antipsychotics, especially clozapine, can partly reduce impulsivity (Spivak et al., 2003), probably because the blockade of the D2 receptors of the

striatum could lessen the effects of the increased dopaminergic levels. Altogether, this hypothesis of heightened impulsivity in schizophrenia could offer an alternative explanation of why our patients benefited from caffeine intake while controls did not, and also why the benefit was shown only in complex tasks requiring deeper processing, a condition in which caffeine is helpful for impulsive individuals (Smith, 2002). Furthermore, it is important to note that only male patients benefited from caffeine while female patients did not, probably because women are less impulsive than men (Cross et al., 2011). These results may also support other studies that found women being less sensitive to caffeine (Botella and Parra, 2003) and getting a lower activation from it (Adan et al., 2008) compared to men. However, differences may also be due to their significantly reduced consumption of caffeine compared to males. Finally, post-hoc analyses indicated that, among the male schizophrenic group of patients, only the younger subgroup was positively affected by caffeine intake. Although this finding needs to be replicated in larger samples, a linear inverse relationship between impulsivity and age has been proposed (Steinberg et al., 2008), which may fit with the hypothesis of caffeine benefiting only impulsive individuals, which in this case would be the younger subgroup of male patients of our study. Regarding tobacco, a positive association was seen between smoking and semantic verbal fluency, but only in female controls. This result partly agrees with the study of Sabia et al. (2008), although most studies have not found an association between smoking and semantic verbal fluency (Wagner et al., 2013). Moreover, a negative association between smoking and verbal memory was found in female controls. This association was found in both verbal memory tasks, and is in accordance with other studies (Starr et al., 2007). There was also a negative association between smoking and the deep measure for visual memory, although this only reached a trend level of significance. No associations were found for male controls. Metabolic differences between men and women regarding nicotine (Benowitz et al., 2006) may explain these results. In schizophrenic males, only semantic verbal fluency was negatively associated with tobacco intake, which is partly in accordance with Iasevoli et al. (2013), who found a negative association at a trend level of significance between smoking and semantic fluency in schizophrenics. However, Harris et al. (2004), assessing the effects of a nicotine gum on schizophrenics, did not find any association, probably because of the reduced sample size used in their study. Nevertheless, new associations emerged when we performed the analyses without taking into consideration negative symptomatology and duration of the illness. In this case, the tasks requiring deeper processing were negatively associated with smoking, except for visual and verbal memory tasks. No associations were seen between smoking and performance in female patients. These results do not agree with the processing speed studies of Wing et al. (2011) and Barr et al. (2008), perhaps because the task used was likely less complex than the one used in the present study, but partially agree with those of Jacobsen et al. (2004), who found beneficial effects of nicotine patches for schizophrenic patients in a working memory task, although they did not find differences between schizophrenic and healthy smokers, probably because they used a small sample. Nicotine is a very selective and specific ligand of nicotinic acetylcholine receptors. The two major subtypes of these receptors are α4β2 and α7 and they have different properties; α4β2 has a higher affinity for nicotine and both α4 and β2 subunits can be found in cortex and cerebellum, while α7 is expressed mainly in cortex, hippocampus and thalamus (Wang and Sun, 2005). Nicotine appears to modulate some neurotransmitter systems, especially dopaminergic and serotoninergic, in which antipsychotics

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exert their main effects. Some differences between schizophrenics and healthy people have been found regarding nicotinic receptors. A reduction in the expression and number of nicotinic receptors in schizophrenics compared to controls has been shown in post-mortem studies (Durany et al., 2000; Mexal et al., 2010). Terry et al. (2005) found that antipsychotic medication may cause a decrease in nicotinic receptors. Moreover, the normal up-regulation of nicotinic receptors caused by chronic smoking seems to be disrupted in schizophrenia (Breese et al., 2000), which may partly explain the reduced number of nicotinic receptors reported in post-mortem studies. These studies could also explain why schizophrenic patients of our study are presumably more affected by smoking than controls. As expected, patients with more severe negative symptomatology, measured with the SANS-4 scale, as well as those who have suffered from the illness for a longer time, performed worse on some neurocognitive tasks, regardless of whether these tasks involved a deeper cognitive process or not. This underlines the necessity of including these variables in the analysis to control possible confounding effects. However, there were other potential confounding factors that were not assessed in this study and, therefore, their effects could not be analyzed. One of them is the antipsychotic medication taken by patients, which, as previously mentioned, may be related to reduced impulsivity (Spivak et al., 2003) and a decrease of nicotinic receptors (Terry et al., 2005); also, antipsychotic medication may have metabolic interactions with caffeine (Carrillo and Benitez, 1996), and has been shown to have effects on cognition (Hori et al., 2006). Other important factor is the last time of caffeine or tobacco intake, as the variability in the abstinence periods between participants could influence the results (AhnAllen et al., 2008; Harris et al., 2004; Sacco et al., 2005). Given the beneficial effects of caffeine on neurocognition, more research is needed to determine whether a therapeutic approximation based on caffeine, or encouraging patients to consume it, could improve the quality of life of schizophrenic patients. Coffee therapy has been used in a small group of elderly patients with behavioural and psychological symptoms of dementia, a condition sometimes treated with antipsychotics; although cognition was not affected by the therapy, it succeeded in reducing neuropsychiatric symptoms, but more research is needed to elucidate whether it was the caffeine that was responsible for the improvement (Matsuda et al., 2012). On the other hand, contrary to some of the studies published and the self-medication hypothesis of smoking in schizophrenia (Ahlers et al., 2014; Hahn et al., 2012; Smith et al., 2002; Winterer, 2010), it seems that tobacco consumption has no beneficial effects on cognition, although it may be useful to maintain proper caffeine concentration in serum. Caffeine concentration appears to be increased in schizophrenic smokers compared to control smokers (Gandhi et al., 2010), probably due to a metabolic interaction between caffeine and some antipsychotics such as clozapine or olanzapine, as both caffeine and antipsychotics are metabolized by the CYP1A2 enzyme (Carrillo and Benitez, 1996). Smoking would diminish caffeine concentration by accelerating caffeine metabolism through the induction of the CYP1A2 enzyme (Carrillo and Benitez, 1996). However, even though the results of this study provide evidences against regular smoking, potential beneficial effects on cognition derived from acute administration of nicotine, by means of nicotine patches, gums, or intranasal sprays, as has been previously reported (AhnAllen et al., 2008; Barr et al., 2008; Jacobsen et al., 2004; Smith et al., 2002), can not be disregarded and need further research.

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4.1. Limitations There are some limitations in this study which should be considered in future research. First, the size of the group of patients is small, especially of the female subgroup. Secondly, the control group was not matched with the patient sample in terms of education level and verbal IQ, and there were also differences in tobacco intake between groups. Thirdly, this is an observational naturalistic study and the factors studied were not manipulated. Also, we did not objectively measure levels of caffeine and nicotine and we did not control the time of the last cigarette or caffeine consumption. Moreover, we did not differenciate between coffee, tea or other caffeinated beverages, which have different caffeine quantities. Finally, we did not consider the potential effects of medication in patients.

5. Conclusions In conclusion, our analysis of the concomitant effects of caffeine intake and smoking reveals the importance of caffeine intake in enhancing deeper cognitive abilities in chronic schizophrenic patients. It is also important to underline the influence of gender, as only male patients benefited from caffeine intake. On the other hand, smoking seems to impair performance, although the negative effect appears to be mostly accounted for by negative symptoms and duration of illness. These results are exploratory and require confirmation from future studies with larger samples matching schizophrenic patients and healthy controls by their amount of caffeine and tobacco consumption, and controlling for potential confounders such as age, antipsychotic medication, time of last consumption of caffeine or tobacco, and lifetime history of caffeine, tobacco and other substances use or abuse.

Conflicts of interest None of the authors declared conflicts of interest.

Funding This work was supported by a Miguel Servet contract (CP09/ 00292) and grant PI10/02479 from the Instituto de Salud Carlos III – Subdirección General de Evaluación y Fomento de la Investigación Sanitaria – co-funded by Fondo Europeo de Desarrollo Regional (FEDER), both to GB. The first author is funded by an FPI (BFU2010-19146) grant from the Spanish Government.

Acknowledgements We thank Mireia Pérez del Olmo and Lourdes Nieto for their contribution to the assessment of the participants, as well as Dr. Mercedes Roca and Montserrat Contel for helping with the recruitment of patients.

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