 |
|
Effects of Cigarette Smoking on Spatial Working Memory and Attentional Deficits in Schizophrenia
Involvement of Nicotinic Receptor Mechanisms
Kristi A. Sacco, PsyD;
Angelo Termine, BS;
Aisha Seyal, BS;
Melissa M. Dudas, BS;
Jennifer C. Vessicchio, LCSW;
Suchitra Krishnan-Sarin, PhD;
Peter I. Jatlow, MD;
Bruce E. Wexler, MD;
Tony P. George, MD
Arch Gen Psychiatry. 2005;62:649-659.
ABSTRACT
| |
Background Cigarette smoking rates in schizophrenia are higher than in the general population.
Objectives To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking–related cognitive enhancement.
Design Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d).
Participants Twenty-five smokers with schizophrenia and 25 control smokers.
Setting Outpatient mental health center.
Main Outcome Measures Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores.
Results In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment.
Conclusions Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.
INTRODUCTION
Schizophrenia is associated with wide-ranging deficits in neurocognitive function, including attention, verbal learning and memory, executive function, and spatial working memory.1-2 Many of these deficits are associated with dysfunction of the prefrontal cortex, are evident during periods of symptom remission, and significantly affect quality of life even in optimally treated patients.3 Furthermore, antipsychotic drugs, especially neuroleptics, may contribute to neurocognitive deficits in schizophrenia.4
In animal studies, spatial working memory and executive cognitive task performance have been shown to be dependent in part on prefrontal cortical dopamine function.5-6 Dopamine release in cortical regions is enhanced by nicotine administration,7-10 and conversely, nicotine withdrawal has been associated with reductions in dopamine function.8, 11-12 Correspondingly, there is evidence to suggest that nicotine administration can improve attentional and working memory deficits in schizophrenia,13-15 while abstinence may worsen spatial working memory deficits.16 Therefore, individuals with schizophrenia may be vulnerable to cigarette smoking as a means of self-administering nicotine to remediate cognitive deficits,15-16 which may partly explain why smoking rates are higher in schizophrenia (58%-88%) compared with the general population (approximately 23%).17-21
Furthermore, nicotine and smoking have been shown to remediate deficits in attention such as P50 auditory evoked potential gating deficits.22-23 Moreover, there is genetic evidence to suggest that the  7 subunit of the nicotinic acetylcholine receptor (nAChR) is associated with P50 gating deficits in this disorder24 and that polymorphisms in the 7 nAChR subunit promoter region are linked to severity of P50 gating deficits in individuals with schizophrenia and their first-degree relatives. In addition, postmortem studies have demonstrated that tritiated nicotine binding is reduced in schizophrenic compared with healthy control brain regions, including the striatum, thalamus, hippocampus, and prefrontal cortex.25
More direct evidence linking particular cognitive deficits with particular neuroreceptors can be gathered by in vivo manipulation of receptors with appropriate agonists and antagonists. While there are few pharmacological agents available for use besides nicotine to study nAChR function in human subjects, mecamylamine hydrochloride (MEC) is a ganglionic blocker approved for the treatment of mild to moderate hypertension and a nonselective nAChR antagonist.26 In vitro studies have suggested that MEC is a noncompetitive antagonist (at the ion channel site) of several nAChR subtypes in the low-micromolar (0.5-5.0) range, including 4 2, 34, 32, and 7.27 In addition, MEC may block effects of nicotine by reducing its transport into the brain.28 Mecamylamine does not disrupt the rodent analogue of P50 responses (N40 responses), and studies in humans have shown that it does not alter P50 deficits,29 suggesting that MEC does not antagonize 7 nAChRs.30 The role of nAChRs in mediating the effects of nicotine14-15 and smoking-related16 cognitive enhancement in patients with schizophrenia and in cigarette smokers without psychiatric disorders, however, has not been convincingly established. Evidence to solidly implicate nAChR involvement in mediating such cognitive enhancement would provide justification for the development of nAChR agents in the treatment of neurocognitive deficits associated with schizophrenia.
Accordingly, the purpose of this study was to: (1) establish the effects of short-term cigarette smoking and abstinence on neuropsychological function in subjects with schizophrenia and nonpsychiatric control subjects, and (2) to determine the involvement of central nAChRs in mediating the effects of cigarette smoking on these cognitive tasks by pretreating subjects with MEC.
METHODS
SUBJECTS
Seventy-five smokers with schizophrenia and 80 control smokers were screened for study participation. After baseline evaluations, 32 smokers with schizophrenia and 28 control smokers were enrolled in this study. Twenty-five smokers with schizophrenia and 25 control smokers who completed the entire study were judged to be free of protocol violations. Seven smokers with schizophrenia and 3 controls were excluded because of an inability to abstain from smoking overnight for a single test session, leading to withdrawal of informed consent (3 smokers with schizophrenia); housing problems (1 smoker with schizophrenia); a positive urine toxicology screen for drugs of abuse (1 smoker with schizophrenia, 2 controls); positive alcohol breathalyzer results (1 control); and unwillingness to complete study procedures (2 smokers with schizophrenia). Patients were recruited from the Connecticut Mental Health Center in New Haven, while controls were recruited from the community using newspaper advertisements and flyers. Written informed consent was obtained from all participants and the protocol was approved by the Yale Medical School Human Investigation Committee.
Subjects were screened using the Structured Clinical Interview for DSM-IV Axis I Disorders.31 Subjects meeting criteria for schizophrenia or schizoaffective disorder were included in the schizophrenia group. Subjects with schizophrenia were outpatients who were judged to be psychiatrically stable by the study psychiatrist (T.P.G.) and another trained professional (J.C.V. or K.A.S.) and were prescribed a stable dose of antipsychotic medication (typical or atypical) for at least 3 months prior to study assessments. Controls demonstrated no current Axis I disorder on the Structured Clinical Interview for DSM-IV Axis I Disorders; those with a history of major depression or drug and alcohol abuse in remission for at least 1 year were included if they satisfied other study criteria. Intellectual ability was assessed using the Shipley Institute of Living Scale32 from which an estimated Full Scale Wechsler Adult Intelligence Scale-Revised IQ score was derived33; subjects were required to have an estimated IQ of greater than 80 to be eligible for study participation.
All subjects were cigarette smokers meeting criteria that included smoking more than 15 cigarettes per day, which was assessed using a self-reported, 7-day timeline follow-back measuring number of cigarettes smoked per day,34 expired breath carbon monoxide levels of more than 10 ppm, and plasma cotinine levels of more than 150 ng/mL. Subjects were classified as nicotine dependent using DSM-IV criteria35 and as defined by a score of more than 5 on the Fagerstrom Test for Nicotine Dependence.36
PROCEDURES
Weekly test sessions spanned 3 consecutive days per week during 3 separate test weeks and included 4 laboratory sessions (day 1, day 2, day 3 morning, day 3 afternoon) (Figure 1). Subjects (>90%) completed the 3 weekly test sessions over the course of 3 consecutive weeks, or at a maximum during a 2-month period, with no more than 3 intervening weeks between experimental testing weeks. Day 1 consisted of the administration of study medication along with psychiatric rating scales (psychiatric group) and nicotine dependence and withdrawal measures. On the first day of testing (day 2 morning), subjects underwent the neurocognitive test battery while being permitted to smoke during hourly smoke breaks. Subjects remained abstinent on the evening of day 2 after 8 PM in order to undergo the neurocognitive battery during short-term abstinence on the following morning (day 3). Once smoking abstinence was verified on the morning of day 3 (approximately 9 AM, using the criterion of expired breath carbon monoxide levels <10 ppm), they were eligible to proceed with day 3 testing. Following completion of the day 3 morning session, smokers recommenced smoking as needed for satiety and were instructed to "smoke until you are satisfied." The final neurocognitive battery was administered during the afternoon session (day 3). Subjects were paid $25 for completing each day 2 morning session and $100 if they successfully remained abstinent from smoking overnight and successfully completed the day 3 morning and afternoon sessions. If they were not successful in quitting overnight, subjects were paid $5 and given 1 additional opportunity the following week. This 20:1 ratio of contingent reinforcement for achieving overnight abstinence was effective in more than 90% of schizophrenic and control test sessions, consistent with previous reports on the use of contingent reinforcement in persons with schizophrenia.37-38 All subjects were administered MEC study medication (0, 5, and 10 mg/d) counterbalanced across 3 separate test weeks (Figure 1). For subjects with schizophrenia, psychotropic medications were held during testing sessions.
|
|
|
|
Figure 1. Single subject study timeline for smokers with schizophrenia and control smokers.
|
|
|
Tobacco craving was measured using the Tiffany Questionnaire for Smoking Urges.39 Changes in mood were assessed using the Beck Depression Inventory.40 Psychotic symptoms were rated at each session in the patient group using the Positive and Negative Syndrome Scale.41 Study medication–related adverse events were assessed using the Adverse Events Checklist.42
NEUROPSYCHOLOGICAL TEST BATTERY
Before administration of the test sessions, all subjects were given a training session conducted by the study neuropsychologist (K.A.S.) to ensure understanding of each task. Administration of the visuospatial working memory (VSWM) task, Stroop Color-Word Test (SCWT), and Word Serial Position Test (WSPT) was done using PsyScope 1.143 (Carnegie Mellon University, Pittsburgh, Pa) on a Macintosh G4 computer (Apple, Cupertino, Calif), while the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) were administered on a Pentium III personal computer (Dell Computer, Round Rock, Tex).
Visuospatial Working Memory Task
The VSWM task16 is a delayed-response spatial working memory task that assesses working memory for nonverbal (object) visuospatial stimuli. It presents the subject with an object at a particular location on the computer screen (screen 1), then presents a "distractor task" screen, which entails a sham performance task ("tic-tac-toe"; screen 2), appearing for variable fixed intervals (eg, delay 30 or 60 seconds), followed by a final screen that prompts the subject to identify where the original object had been located (screen 3). Performance is reported as the averaged "distance from target" in centimeters for 16 trials at each delay condition, with higher scores indicating more impaired VSWM performance.1
Continuous Performance Test
The Connors’ CPT-X44 (MS-DOS version; Multi-Health Systems Inc, North Tonawanda, NY) is designed to measure sustained attention, concentration, response inhibition, and impulsivity. Subjects press the space bar as quickly as possible after each of a series of similar visual stimuli except when presented with the letter X. Commonly reported outcome measures include: percentage of hits, percentage of commission errors, reaction time for hits (in milliseconds), a measure of overall attentiveness (d'), and hit rate reaction time standard error variability.
Word Serial Position Test
The WSPT is a verbal memory test known to be deficient in schizophrenia and related to frontal cortical activation during functional magnetic resonance imaging.45 Each of 36 trials begins with 4 nouns spoken with 1 second between words. One word is then repeated after a delay of 1, 5, or 9 seconds. Subjects are instructed to remember the 4 words in the order presented and indicate the serial position of the repeated word by pushing the appropriate number on the keyboard.
Stroop Color-Word Test
The SCWT measures subjects’ ability to shift their perceptual set to conform to changing conditions requiring mental control, response inhibition, response flexibility, and selective attention with the occurrence of perceptual interference.46 Participants report the color ink in which the names of colors are printed. The difference in response time (in milliseconds) when the ink is a different color than the color name compared with a response time when the ink is the color name is "Stroop interference." Performance of the SCWT activates the anterior cingulate cortex.47 Stroop interference is impaired in many neuropsychiatric disorders including schizophrenia.48
Wisconsin Card Sorting Test
The WCST49 assesses executive functions, including cognitive flexibility in response to feedback, and performance on this task is known to be impaired in schizophrenia and thought to relate to dorsolateral prefrontal cortex function.50 A total of 128 cards are presented and the test requires participants to sort the cards on the basis of the color, shape, or number of figures. The only feedback provided to the subject is whether responses are correct or incorrect. Common outcomes are categories completed, percentage of total errors, percentage of perseverative errors, and percentage of nonperseverative errors.
STUDY MEDICATION PROCEDURES AND PLASMA NICOTINE DETERMINATION
Mecamylamine hydrochloride as 2.5-mg tablets and matching placebo were obtained from Layton BioSciences, Inc (Sunnyvale, Calif) under an investigational new drug protocol (58 680) for use in neuropsychiatric disorders. Medication was administered as 2 tablets twice daily under double-blind conditions. Subjects were administered the first, third, fifth, and sixth doses in the outpatient laboratory by a trained research assistant, and the second and fourth doses of the study medication were given to subjects as take-home doses after the day 1 and 2 procedures were completed.
Venous plasma, to measure levels of nicotine and its metabolite cotinine, was obtained on day 2 (9 AM) and repeated on day 3 (9 AM and 1 PM, 1 hour after cigarette smoking reinstatement). Nicotine and cotinine concentrations (in nanograms per milliliter) were determined by reverse-phase high-pressure liquid chromatography. The procedure, adapted from Hariharan and VanNoord,51 was modified to enable an aqueous micro back-extraction clean-up step in place of solvent evaporation. Briefly, following addition of an internal standard, 2-phenylimidazole, nicotine and cotinine were extracted from alkalinized serum with a 40:60 mixture of dichloromethane hexane. Between-day precision coefficients of variation, at concentrations of 200 ng/mL (cotinine) and 20 ng/mL (nicotine), were 6.6% and 6.3%, respectively.
STATISTICAL METHODS
Demographic and clinical variables were compared between groups with independent samples t test or  2 analyses. Baseline differences in cognitive performance between groups were evaluated with independent t tests. There were 3 primary experimental questions: (1) Do smoking abstinence and reinstatement have different effects on cognition in patients and controls? This was evaluated for each neuropsychological test during the placebo test week with a 2-way (diagnosis x session) analysis of variance (ANOVA). (2) Does MEC pretreatment alter the effects of reinstatement? Percentage enhancement produced by smoking reinstatement (calculated as day 3 afternoon session–day 3 morning session/day 3 morning session x 100%) was calculated in the schizophrenic and control group sessions for each drug dose condition and compared using 2-way (diagnosis x dose) ANOVA. For pairwise post hoc comparisons within sessions (day 2 morning, day 3 morning, day 3 afternoon) using a 1-way ANOVA model, a Bonferroni-corrected = .05/3 = 0.0167 was used to define statistical significance. (3) Does MEC itself alter cognitive performance at baseline in smokers with schizophrenia and control smokers? One-way ANOVAs in both schizophrenic and control smoker groups were performed to determine MEC dose effects in the baseline session (day 2), with Bonferroni-corrected post hoc analyses. All statistical analyses were performed using SPSS software version 12.0 for Windows (SPSS Inc, Chicago, Ill), and statistical significance in the ANOVA models was defined with P<.05.
RESULTS
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF SAMPLE
Demographic and clinical variables are presented in Table 1. There were no differences between groups in age, sex, race, or cigarette smoking. Patients had significantly higher cotinine levels and plasma cotinine level–cigarettes per day ratio at baseline than the control group. Subjects with schizophrenia also demonstrated significantly lower Shipley IQ scores (P<.001), less education (P = .005), and higher depression scores on the Beck Depression Inventory (P<.001).
|
|
|
|
Table 1. Demographic and Clinical Characteristics of 25 Smokers With Schizophrenia and 25 Control Smokers*
|
|
|
BASELINE NEUROPSYCHOLOGICAL PERFORMANCE
After completion of the training session, smokers with schizophrenia exhibited significant (P<.05) deficits compared with control smokers on the CPT (hit rate percentage, reaction time, variability index, attentional index), VSWM task (60-second delay condition), WCST (percentage of total errors, percentage of perseverative errors, percentage of perseverative responses), the WSPT (percentage of correct responses), and the SCWT (neutral and congruent conditions) (Table 2). There were trends toward group differences on CPT commission rate (P = .06), VSWM 30-second delay (P = .09), and WCST categories completed (P = .08). These baseline neuropsychological data, compared with data from the study testing sessions, suggest that smokers with schizophrenia and controls had achieved asymptotic performance on the VSWM task and CPT prior to beginning testing sessions.
|
|
|
|
Table 2. Baseline Comparisons of Smokers With Schizophrenia and Control Smokers on Various Neuropsychological Tasks*
|
|
|
EFFECTS OF SMOKING ABSTINENCE AND REINSTATEMENT ON PLASMA NICOTINE LEVELS AND TOBACCO CRAVING
P lasma nicotine levels were higher in smokers with schizophrenia vs control smokers at baseline (day 2 morning session) in the placebo condition (mean ± SD, smokers with schizophrenia, 32.4 ± 16.3 ng/mL vs controls, 22.2 ± 11.6 ng/mL; t47 = 2.56; P<.05) (Figure 2), decreased to undetectable levels with abstinence in both groups (P<.01), and returned to levels comparable with baseline (day 2 morning session) with reinstatement of smoking in both groups (day 3 afternoon session) (Figure 2). There was no significant effect of MEC administration on plasma nicotine levels (Figure 2) at either baseline (day 2 morning session) or after smoking reinstatement (day 3 afternoon session). In the placebo condition, there was a significant increase in tobacco craving on the Tiffany Questionnaire of Smoking Urges during short-term abstinence in the day 3 afternoon session and reversal of abstinence-induced increases in craving with smoking reinstatement during the day 3 afternoon session in both smokers with schizophrenia and control smokers (data not shown). These effects on the Tiffany Questionnaire of Smoking Urges were not modified by MEC administration (data not shown).
|
|
|
|
Figure 2. Effects of smoking abstinence, reinstatement, and mecamylamine hydrochloride (MEC) dose (in milligrams per day) on plasma nicotine levels in smokers with schizophrenia (n = 25) (A) and control smokers (n = 25) (B).
|
|
|
VISUOSPATIAL WORKING MEMORY TASK
Effect of Smoking Abstinence and Reinstatement in the Placebo Condition
There was a significant diagnosis x session interaction in the placebo condition (F2,144 = 4.53; P<.01). In smokers with schizophrenia (n = 25), we observed a main effect of session on VSWM 30-second delay performance in the placebo (0 mg/d) condition (1-way ANOVA, F2,72 = 7.21; P<.01). Post hoc analysis indicated that the schizophrenic group demonstrated significant impairment in VSWM 30-second delay performance after short-term (overnight) smoking abstinence during the day 3 morning session and significant reversal of abstinence-induced VSWM impairment with smoking reinstatement during the day 3 afternoon session (P<.01) (Figure 3A). In the control group (n = 25), no main effect of session on VSWM 30-second delay performance was observed in the placebo condition (1-way ANOVA, F2,72 = 0.27; P = .76) (Figure 3B).
Effects of MEC Pretreatment on Smoking-Induced Changes in VSWM 30-Second Delay Performance
The diagnosis x dose interaction for VSWM percentage enhancement during smoking reinstatement was significant (F2,143 = 7.85; P<.01) (Figure 4A). In smokers with schizophrenia, there was a mean ± SD 31.4% ± 21.8% enhancement of VSWM performance in the day 3 afternoon session compared with the day 3 morning session in the placebo condition, which was robustly reduced by MEC pretreatment at 5 (mean ± SD, –8.9% ± 49.9%; P<.01) and 10 mg/d (mean ± SD, –14.5% ± 53.8%; P<.01) (1-way ANOVA for MEC dose, F2,71 = 8.02; P<.01) (Figure 4A). In controls, smoking reinstatement produced an impairment (mean ± SD, –16.9% ± 58.1%) of VSWM performance in the day 3 afternoon session compared with the day 3 morning session, which was not significantly altered by MEC pretreatment at 5 (mean ± SD, 2.1% ± 51.3%) and 10 mg/d (mean ± SD, 5.4% ± 35.5%) (1-way ANOVA for MEC dose, F2,72 = 1.50; P = .23) (Figure 4A).
|
|
|
|
Figure 4. Effects of mecamylamine hydrochloride dose on percentage enhancement of visuospatial working memory (VSWM) 30-second delay performance (A) and Continuous Performance Test (CPT) hit rate (B) in smokers with schizophrenia and control smokers. Percentage enhancement for VSWM 30-second delay performance was calculated as [(day 3 morning session)–day 3 afternoon session/day 3 morning session] x 100%, while that for CPT hit rate was calculated as [(day 3 afternoon session)–day 3 morning session/day 3 afternoon session] x 100%. Asterisk indicates P<.01 vs 5 mg of mecamylamine hydrochloride per day and P<.01 vs 10 mg mecamylamine hydrochloride per day in the schizophrenia group and P<.01 vs control group.
|
|
|
Effect of MEC Pretreatment on Baseline VSWM 30-Second Delay Performance
Pretreatment with MEC at 5 mg/d did not alter baseline (day 2 morning session) VSWM performance compared with the placebo condition (P = .91) in smokers with schizophrenia but led to a nonsignificant reduction of abstinence-induced impairment (day 3 morning session) compared with the placebo condition (P = .10) (Figure 3A). However, pretreatment with MEC at 10 mg/d impaired baseline performance compared with the 0 mg/d condition (P<.05) (Figure 3A), an effect that persisted with smoking abstinence and reinstatement. There were no effects of MEC pretreatment on baseline performance in the control group (Figure 3B). The order of MEC dose in the counterbalanced sequence (eg, 0, 5, or 10 mg/d in the first test week) did not significantly influence the pattern of results with VSWM in either smokers with schizophrenia or controls (data not shown), suggesting no significant carryover effects between test weeks.
Effects of Smoking Abstinence, Reinstatement, and MEC Pretreatment on VSWM 60-Second Delay Performance
There were no significant changes in the 60-second delay condition of the VSWM task with short-term smoking abstinence and reinstatement and no effects of MEC dose (data not shown).
CONTINUOUS PERFORMANCE TEST
Effect of Smoking Abstinence and Reinstatement in the Placebo Condition
The diagnosis x session interaction in the placebo condition was not significant for CPT hit rate (F2,144 = 0.44; P = .64). However, in smokers with schizophrenia (n = 25), there was a trend toward a main effect of session in the placebo condition (0 mg/d) (1-way ANOVA, F2,72 = 4.91; P = .09). Post hoc testing revealed that within the 3 test sessions in the placebo condition in smokers with schizophrenia, overnight smoking abstinence (day 3 morning session) produced a nonsignificant decline in performance (P = .13) compared with baseline (day 2 morning session) (Figure 5A), while smoking reinstatement (day 3 afternoon session) reversed abstinence-induced performance deficits (day 3 morning session) (P = .03). In the control group, there was a significant effect of session (F2,72 = 3.28; P<.05) following a pattern similar to that in the patients with schizophrenia. Post hoc analyses demonstrated impairment in CPT hit rate after overnight abstinence (P<.05) and reversal of this abstinence-induced deficit with smoking reinstatement (P<.05) (Figure 5B).
|
|
|
|
Figure 5. Effects of mecamylamine hydrochloride (MEC) administration and manipulation of smoking status on Continuous Performance Test (CPT) hit rate percentage in smokers with schizophrenia (n = 25) (A) and control smokers (n=25) (B). Asterisk indicates P<.05 vs 0 mg of MEC per day (day 3 afternoon session).
|
|
|
Effects of MEC Pretreatment on Smoking-Induced Changes in CPT Hit Rate
The diagnosis x dose interaction for CPT hit rate was nonsignificant (F2,138 = 1.51; P = .22). In the placebo condition, smokers with schizophrenia demonstrated a mean ± SD 2.5% ± 5.0% enhancement of CPT hit rate, which was dose-dependently (Figure 4B) reduced by pretreatment with MEC at 5 (mean ± SD, 0.6% ± 2.9%; P = .28) and 10 mg/d (mean ± SD, –0.3 ± 3.3%; P = .05) (1-way ANOVA for dose, F2,66 = 3.19; P<.05). Controls demonstrated a mean ± SD 1.2% ± 3.2% enhancement of CPT hit rate, which, in contrast to the schizophrenia group, did not differ significantly with MEC pretreatment at 5 (mean ± SD, 0.9% ± 2.9%) or 10 mg/d (mean ± SD, 0.9% ± 3.1%) (1-way ANOVA for dose, F2,72 = 0.11; P = .90) (Figure 4B).
Effect of MEC Pretreatment on Baseline CPT Hit Rate Performance
In both the schizophrenia and control groups, pretreatment with MEC at the 5 and 10 mg/d doses did not alter baseline (day 2 morning session) CPT hit rate performance compared with the placebo (0 mg/d) condition (Figure 5A and B). Similar to VSWM, the order of MEC dose in the counterbalanced sequence did not significantly influence the pattern of results of the CPT hit rate in either group (data not shown).
Other CPT Outcome Measures
There were no significant effects of smoking abstinence, reinstatement, or MEC dose on other measures of the CPT-X, including commission errors, reaction time variability index, and attentional index (d') (data not shown).
EFFECTS OF ATYPICAL ANTIPSYCHOTIC DRUGS AND ANTIMUSCARINIC DRUGS ON NEUROPSYCHOLOGICAL OUTCOMES
In subgroup analyses of smokers with schizophrenia (n = 25), we found no significant differences in either atypical (n = 18) vs typical (n = 7) antipsychotic agents or antimuscarinic (n = 14) vs nonantimuscarinic (n = 11) drugs on either (1) baseline VSWM 30-second delay or CPT hit rate performance or (2) the effects of smoking abstinence, reinstatement, or MEC dose on these outcome measures (data not shown).
SCWT, WSPT, AND WCST
There were no significant changes in Stroop interference, the WSPT percentage of correct responses, or WCST categories completed or percentage of perseverative errors with short-term smoking abstinence and reinstatement and no effects of MEC dose (data not shown).
POSITIVE AND NEGATIVE SYNDROME SCALE
There were no significant changes in positive or negative symptoms with short-term smoking abstinence and reinstatement and no effects of MEC dose (data not shown).
ADVERSE EVENTS RELATED TO STUDY MEDICATION
Adverse effects reported by smokers with schizophrenia and control smokers (respectively) taking study medications included: headache (20.3% vs 25.6%), constipation (18.9% vs 18.6%), sedation (28.4% vs 34.9%), dry mouth (14.9% vs 32.6%), difficulty concentrating (35.1% vs 16.3%), and orthostatic hypotension (18.9% vs 17.4%). With the exception of dry mouth and difficulty concentrating (P<.01 for both), differences between diagnostic groups were not significant.
COMMENT
Our results suggest that cigarette smoking has selective effects on VSWM 30-second delay performance and sustained attention performance on the CPT in schizophrenia. Calculated effect sizes (Cohen d52) for overnight smoking abstinence effects ranged from d = 0.40 for CPT hit rate to d = 1.01 for VSWM 30-second delay, suggesting that there are clinically significant effects3 of smoking abstinence on neuropsychological performance. Similarly, smoking reinstatement produced effect sizes for cognitive enhancement of d = 0.58 for CPT hit rate and d = 0.90 for VSWM 30-second delay. Neither antipsychotic drug class (eg, atypical vs typical agents) nor exposure to antimuscarinic agents modified these neuropsychological outcomes. Interestingly, the longer spatial working memory delay (VSWM 60-second delay) was unaffected by smoking and MEC administration, and this may relate to the observation that longer delay durations are not specific to prefrontal cortex mechanisms and recruit hippocampal mechanisms.53 Accordingly, differences in the neuroanatomical substrates of long vs short delay in our VSWM task may explain differences we observed with smoking and MEC administration. Our results suggest that cigarette smoking may be an attempt to remediate neurocognitive deficits associated with schizophrenia, as previously proposed for psychophysiological,22, 54-56 working memory,14-16,57 and attentional13-14 deficits in schizophrenia. These observations suggest that neurocognitive deficits in schizophrenia may constitute a vulnerability factor for the initiation and maintenance of cigarette smoking.16, 18, 58-59 An important caveat is that the present study is a model of abstinence-induced cognitive deficits in schizophrenia, and further studies are needed to determine the direct effects of nicotine on endogenous neurocognitive deficits without confounding effects of tobacco withdrawal. Nonetheless, since the majority of patients with schizophrenia are daily smokers, we believe that our findings have substantial clinical relevance.
In the present study, reversal of abstinence-related deficits in VSWM and sustained attention in subjects with schizophrenia by smoking reinstatement was blocked by pretreatment with MEC. This is the first evidence that the effects of smoking on cognitive function in patients with schizophrenia are mediated by stimulation of central nAChRs.
Baseline impairment of VSWM 30-second delay performance was observed in patients receiving the highest MEC dose (10 mg/d). Several other studies have reported dose-dependent impairment of cognitive performance in healthy and elderly subjects receiving MEC.60-61 In contrast, we did not observe that MEC administration impaired VSWM 30-second delay in control smokers. This suggests that smokers with schizophrenia are more sensitive to MEC at higher doses of the drug, and this could relate to reduced tritiated nicotine binding to high-affinity nAChRs in the schizophrenic brain.25 Interestingly, smoking abstinence did not appear to alter VSWM 30-second delay performance in control smokers matched for nicotine dependence level with the schizophrenic sample (Figure 3B). This suggests a differential response to smoking in the control as compared with the schizophrenic group.16 The disparate effects of acute smoking on VSWM 30-second delay in subjects with schizophrenia compared with controls may relate to impairments in the functional upregulation of high-affinity nAChRs,25 such that the presence of exogenous nicotine derived from cigarette smoking is required to sustained performance in subjects with schizophrenia.62 Since subjects with schizophrenia were prescribed antipsychotic agents and control subjects were not, it is possible that antipsychotic agents could interact with nAChR systems either directly by binding to nAChRs63-65 or indirectly by increasing prefrontal cortex and hippocampal acetylcholine levels66 to alter nAChR-mediated neurotransmission, leading to diagnosis-based performance differences in VSWM. Future studies in medication-naïve and nonsmoking patients with schizophrenia, as well as other mentally ill populations (eg, bipolar disorder), are needed to test the specificity of these findings to schizophrenia.
Continuous Performance Test hit rate was impaired in both subjects with schizophrenia and controls with overnight smoking abstinence and reversed by smoking reinstatement. No consistent effects of smoking or MEC administration were found on other CPT measures, suggesting that the positive effects of smoking in these patients were confined sustained attention and not impulsivity or risk taking. Sustained attention is considered the most basic of attentional processes on which other derivative attentional and neuropsychological (eg, working memory, learning, executive functioning) measures are based.67 Selective effects of a nicotine patch on CPT hit rate were also found in subjects with schizophrenia by Depatie et al.13
The effects of smoking reinstatement on reversal of CPT hit rate decrements were dose-dependently blocked by MEC administration in smokers with schizophrenia but not control smokers, suggesting involvement of nAChR stimulation in the attention-enhancing effects of smoking in those with schizophrenia and dysregulation of nAChR systems in this disorder.25 Accordingly, blockade of smoking-related CPT hit rate enhancement by MEC pretreatment in subjects with schizophrenia suggests that attentional function in schizophrenia is selectively modulated by cigarette smoking secondary to dysregulation of (high-affinity) nAChRs. The CPT hit rate performance levels in both smokers with schizophrenia and control smokers were prone to "ceiling effects" (Figure 5), but this would not explain the differential effects of MEC administration during smoking reinstatement. This observation will require further study, including the use of nicotine or nAChR agonists, in nonsmoking subjects with schizophrenia as compared with control subjects, to rule out the confounding effects of nicotine withdrawal on cognitive function. Interestingly, the effects of smoking on attentional outcomes on this version of the CPT (CPT-X) in these studies is also consistent with rodent studies of the effects of nicotine on attention using the CPT analogue, the 5-choice serial reaction time test.68
Both smokers with schizophrenia and control smokers completed a training session prior to beginning study procedures to familiarize them with the various neuropsychological tests. Our findings (Table 2) (Figure 4 and Figure 5) suggest that for VSWM 30-second delay and CPT hit rate percentage, both patients and controls achieved asymptotic performance on these tasks, further strengthening our conclusions that the effects on VSWM 30-second delay and CPT performance we observed were directly related to smoking status changes and MEC administration rather than learning effects with repeated test performance. Furthermore, we have shown that after similar training in nonsmoking subjects with schizophrenia and controls (where there are no confounding effects of smoking on test performance), there is little evidence of learning effects on VSWM 30-second delay and CPT performance with repeated task administration (K.A.S. and T.P.G., unpublished data, June 2004), consistent with these subjects having attained asymptotic task performance.
We observed that subjects with schizophrenia had significantly higher plasma nicotine and cotinine levels compared with controls and a significantly higher ratio of plasma cotinine to cigarettes smoked per day, an index of nicotine extracted per cigarette smoked,69 consistent with findings of Olincy et al.70 Interestingly, the lack of effect of MEC administration on plasma nicotine concentration, tobacco craving, and smoking consumption in both smokers with schizophrenia and control smokers is consistent with the notion that subjective effects of cigarette smoking are not mediated by nAChR stimulation but by non-nicotine components of cigarette smoke such as tar.71-73 Non-nicotine contributions to smoking-related cognitive enhancement in subjects with schizophrenia have been suggested in a study using nicotine-free cigarettes.15 Further studies in our smoking abstinence and reinstatement model of the relative contributions of nicotinic vs non-nicotinic contributions to cognition are warranted.
Taken together, our findings suggest a critical role for central nAChRs in mediating smoking-related enhancement of VSWM and sustained attention in schizophrenia. Furthermore, these findings may have implications for understanding factors that may predispose to the initiation and maintenance of nicotine and tobacco use in schizophrenia, where high rates of comorbid smoking have been shown in both clinical19, 58, 74 and epidemiological75-76 samples and patients are predisposed to smoking cessation treatment failure.21, 42, 76-80 The implication of nAChR systems in cigarette smoking–related cognitive enhancement suggests that nicotine, or nAChR agonists devoid of the harmful effects of tobacco and smoking,81 may be beneficial for pharmacological treatment of cognitive dysfunction associated with schizophrenia.
AUTHOR INFORMATION
Correspondence: Tony P. George, MD, Department of Psychiatry, Yale University School of Medicine, Room S-109, Substance Abuse, Connecticut Mental Health Center, New Haven, CT 06519 (tony.george{at}yale.edu).
Submitted for Publication: May 12, 2004; final revision received September 28, 2004; accepted October 7, 2004.
Funding/Support: This study was supported in part by grants R01-DA-14039, R01-DA-13672, and K02-DA-16611 from the National Institute on Drug Abuse, Bethesda, Md (Dr George), and a National Alliance for Research of Schizophrenia and Depression Young Investigator Award (Dr George). Mecamylamine hydrochloride (Inversine) and matching placebo tablets were supplied by Layton BioScience, Inc, Sunnyvale, Calif.
Acknowledgment: We thank Thomas Bregartner, BA, Deanna Sahady, BS, Cory Head, BA, Margaret Fonder, BS, Brigid S. Boland, BS, Nicolette Franck, BA, Paige Harazin, BA, Lindsay Nordell, BA, Anne Kim, BS, Sara Dolan, MA, Tanzim Ludhi, Katie Bannon, BA, Kevin Pohl, RPh, Xavier D. Lara, MD, and Marc N. Potenza, MD, PhD, for assistance with study procedures and Alan Feingold, PhD, for biostatistical consultation.
Author Affiliations: Program for Research in Smokers with Mental Illness (PRISM) (Drs Sacco and George; Mr Termine; and Mss Seyal, Dudas, and Vessicchio), Division of Substance Abuse (Dr Krishnan-Sarin), Department of Psychiatry (Drs Sacco, Wexler, and George), Department of Laboratory Medicine (Dr Jatlow), Yale University School of Medicine, New Haven, Conn.
REFERENCES
| |
1. Keefe RS, Lees Roitman SE, Harvey PD, Blum CS, DuPre RL, Prieto RM, Davidson M, Davis KL. A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia. Schizophr Res. 1995;17:25-33.
FULL TEXT
|
ISI
| PUBMED
2. Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992;49:975-982.
FREE FULL TEXT
3. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321-330.
FREE FULL TEXT
4. Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry. 2004;55:1013-1022.
FULL TEXT
|
ISI
| PUBMED
5. Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry. 1999;46:650-661.
FULL TEXT
|
ISI
| PUBMED
6. Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol. 1997;11:123-131.
7. George TP, Verrico CD, Picciotto MR, Roth RH. Nicotinic modulation of mesoprefrontal dopamine systems: pharmacologic and neuroanatomic characterization. J Pharmacol Exp Ther. 2000;295:58-66.
FREE FULL TEXT
8. George TP, Verrico CD, Roth RH. Effects of repeated nicotine pre-treatment on mesoprefontal dopaminergic and behavioral responses to acute footshock stress. Brain Res. 1998;801:36-49.
FULL TEXT
|
ISI
| PUBMED
9. Vezina P, Blanc G, Glowinski J, Tassin JP. Nicotine and morphine differentially activate brain dopamine in prefrontalcortical and subcortical terminal fields: effects of acute and repeated injections. J Pharmacol Exp Ther. 1992;261:484-490.
FREE FULL TEXT
10. Hildebrand BE, Panagis G, Svennson TH, Nomikos GG. Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area. Neuropsychopharmacology. 1999;21:560-574.
FULL TEXT
|
ISI
| PUBMED
11. Fung YK, Schmid MJ, Anderson TM, Lau Y-S. Effects of nicotine withdrawal on central dopaminergic systems. Pharmacol Biochem Behav. 1996;53:635-640.
FULL TEXT
|
ISI
| PUBMED
12. Hildebrand BE, Nomikos GG, Panagis G, Hertel P, Schilstrom B, Svennson TH. Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome. Brain Res. 1998;779:214-225.
FULL TEXT
|
ISI
| PUBMED
13. Depatie L, Driscoll GA, Holahan A-LV, Atkinson V, Thavundayil JX, Ying Kin NN, Samarthji L. Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study. Neuropsychopharmacology. 2002;27:1056-1070.
FULL TEXT
|
ISI
| PUBMED
14. Levin ED, Wilson W, Rose J, McEvoy J. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology. 1996;15:429-436.
FULL TEXT
|
ISI
| PUBMED
15. Smith RC, Singh A, Infante M, Khandat A, Kloos A. Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology. 2002;27:479-497.
FULL TEXT
|
ISI
| PUBMED
16. George TP, Vessicchio JC, Termine A, Sahady DM, Head CA, Pepper WT, Kosten TR, Wexler BE. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology. 2002;26:75-85.
FULL TEXT
|
ISI
| PUBMED
17. Ziedonis DM, Williams JM. Management of smoking in people with psychiatric disorders. Curr Opin Psychiatry. 2003;16:305-315.
FULL TEXT
|
ISI
18. Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence and schizophrenia: clinical phenomenon and laboratory findings. Am J Psychiatry. 1998;155:1490-1501.
FREE FULL TEXT
19. George TP, Vessicchio JC, Termine A. Nicotine and tobacco use in schizophrenia. In: Meyer JM, Nasrallah HA, eds. Medical Illness in Schizophrenia. Washington, DC: American Psychiatric Press, Inc; 2003.
20. CDC. Cigarette smoking among adults—United States, 2002. MMWR Morb Mortal Wkly Rep. 2004;53:427-431.
PUBMED
21. McChargue DE, Gulliver SB, Hitsman B. Would smokers with schizophrenia benefit from a more flexible approach to smoking treatment? Addiction. 2002;97:785-793.
FULL TEXT
|
ISI
| PUBMED
22. Adler LE, Hoffer LD, Wiser A, Freedman R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856-1861.
FREE FULL TEXT
23. Adler LE, Hoffer LD, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R. Schizophrenia, sensory gating and nicotinic receptors. Schizophr Bull. 1998;24:189-202.
24. Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997;94:587-592.
FREE FULL TEXT
25. Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000;23:351-364.
FULL TEXT
|
ISI
| PUBMED
26. Young JM, Shytle RD, Sanberg PR, George TP. Mecamylamine: new therapeutic uses and toxicity risk profile. Clin Ther. 2001;23:532-565.
FULL TEXT
|
ISI
| PUBMED
27. Papke RL, Sanberg PR, Shytle RD. Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes. J Pharmacol Exp Ther. 2001;297:646-656.
FREE FULL TEXT
28. Zevin S, Jacob P III, Benowitz NL. Nicotine-mecamylamine interactions. Clin Pharmacol Ther. 2000;68:58-66.
FULL TEXT
|
ISI
| PUBMED
29. Freedman R, Adler LE, Bickford P, Byerley W, Coon H, Cullum CM, Griffith JM, Harris JG, Leonard S, Miller C, Myles-Worsely M, Nagamoto HT, Rose G, Waldo M. Schizophrenia and nicotinic receptors. Harv Rev Psychiatry. 1994;2:179-192.
ISI
| PUBMED
30. Luntz-Leybman V, Bickford PC, Freedman R. Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res. 1992;587:130-136.
FULL TEXT
|
ISI
| PUBMED
31. First MB, Spitzer RI, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV Axis I Disorders. 4th ed. New York, NY: Biometrics Research, New York State Psychiatric Institute; 1996:886.
32. Shipley WC, Burlington CC. A convenient self-administered scale for measuring intellectual impairment in psychotics. Am J Psychiatry. 1941;97:1313-1325.
FREE FULL TEXT
33. Zachary RA, Paulson MJ, Gorsuch RL. Estimating WAIS IQ from the Shipley Institute of Living Scale using continuously adjusted age norms. J Clin Psychol. 1985;41:820-831.
ISI
| PUBMED
34. Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: assessing normal drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J Addict. 1988;83:393-402.
FULL TEXT
|
ISI
| PUBMED
35. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994:886.
36. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86:1119-1127.
FULL TEXT
|
ISI
| PUBMED
37. Tidey JW, Higgins ST, Bickel WK, Steingard S. Effects of response requirement and the availability of an alternate reinforcer on cigarette smoking by schizophrenics. Psychopharmacology (Berl). 1999;145:52-60.
FULL TEXT
| PUBMED
38. Roll JM, Higgins ST, Steingard S, McGinley M. Use of monetary reinforcement to reduce the cigarette smoking of persons with schizophrenia: a feasibility study. Exp Clin Psychopharmacol. 1998;6:157-161.
FULL TEXT
|
ISI
| PUBMED
39. Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on smoking urges. Br J Addict. 1991;86:1467-1476.
FULL TEXT
|
ISI
| PUBMED
40. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77-100.
41. Kay SR, Fiszbein A, Opler L. The Positive and Negative Syndrome Scale for schizophrenia. Schizophr Bull. 1987;13:261-276.
42. George TP, Vessicchio JC, Termine A, Bregartner TA, Feingold A, Rounsaville BJ, Kosten TR. A placebo-controlled study of bupropion for smoking cessation in schizophrenia. Biol Psychiatry. 2002;52:53-61.
FULL TEXT
|
ISI
| PUBMED
43. Cohen JD, MacWhinney B, Flatt M, Provost J. PsyScope: a new graphic interactive environment for designing psychology experiments. Behav Res Methods Instrum Comput. 1993;25:257-271.
ISI
44. Connors CK. The Continuous Performance Test (CPT). Odessa, Fla: Psychological Assessment Resources, Inc; 1995.
45. Wexler BE, Stevens AA, Bowers AA, Sernyak MJ, Goldman-Rakic PS. Word and tone working memory deficits in schizophrenia. Arch Gen Psychiatry. 1998;55:1093-1096.
FREE FULL TEXT
46. Lezak MD. Neuropsychological Assessment. 3rd ed. New York, NY: Oxford University Press; 1995.
47. Swick D, Jovanovic J. Anterior cingulate cortex and the Stroop task: neuropsychological evidence for topographic specificity. Neuropsychologia. 2002;40:1240-1253.
FULL TEXT
|
ISI
| PUBMED
48. Hepp H, Maier S, Hermle L, Spitzer M. The Stroop effect in schizophrenic patients. Schizophr Res. 1996;22:187-195.
FULL TEXT
|
ISI
| PUBMED
49. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G. Wisconsin Card Sorting Test Manual. Odessa, Fla: Psychological Assessment Resources Inc; 1993.
50. Goldberg TE, Weinberger DR. Probing prefrontal function in schizophrenia with neuropsychological paradigms. Schizophr Bull. 1988;14:179-183.
51. Hariharan M, VanNoord TJ. A high performance liquid chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem. 1988;34:724-729.
FREE FULL TEXT
52. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
53. Clark RE, West AN, Zola SM, Squire LR. Rats with lesions of the hippocampus are impaired on the delayed nonmatching-to-sample task. Hippocampus. 2001;11:176-186.
FULL TEXT
|
ISI
| PUBMED
54. Avila MT, Sherr JD, Hong E, Myers CS, Thaker GK. Effects of nicotine on leading saccades during smooth pursuit eye movements in smokers and nonsmokers with schizophrenia. Neuropsychopharmacology. 2003;28:2184-2191.
ISI
| PUBMED
55. Olincy A, Ross RG, Young DA, Roath M, Freedman R. Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacology. 1998;18:175-185.
FULL TEXT
|
ISI
| PUBMED
56. Olincy A, Johnson LL, Ross RG. Differential effects of cigarette smoking on performance of a smooth pursuit and a saccadic eye movement task in schizophrenia. Psychiatry Res. 2003;117:223-236.
FULL TEXT
|
ISI
| PUBMED
57. Harris JG, Kongs S, Allensworth D, Martin L, Tregellas J, Sullivan B, Zerbe G, Freedman R. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology. 2004;29:1378-1385.
FULL TEXT
|
ISI
| PUBMED
58. de Leon J. Smoking and vulnerability for schizophrenia. Schizophr Bull. 1996;22:405-409.
59. Leonard S, Gault J, Hopkins J, Logel J, Viazon R, Short M, Drebing C, Berger R, Venn D, Sirota P, Zerbe G, Olincy A, Ross RG, Adler LE, Freedman R. Promoter variants in the alpha-7 nicotinic acetylcholine receptor subunit gene are associated with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry. 2002;59:1085-1096.
FREE FULL TEXT
60. Eissenberg T, Griffiths RR, Stitzer ML. Mecamylamine does not precipitate withdrawal in cigarette smokers. Psychopharmacology (Berl). 1996;127:328-336.
FULL TEXT
| PUBMED
61. Newhouse PA, Potter A, Corwin J, Lenox R. Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsychopharmacology. 1994;10:93-107.
ISI
| PUBMED
62. Leonard S, Giordano L. Are differential behavioral responses to smoking and smoking cessation in schizophrenia related to nicotine receptor level? Neuropsychopharmacology. 2002;27:1082-1083.
FULL TEXT
|
ISI
| PUBMED
63. Simosky JK, Stevens KE, Adler LE, Freedman R. Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl). 2003;165:386-396.
PUBMED
64. Nguyen Q-T, Miledi R. Inhibition of skeletal muscle nicotinic receptors by the atypical antipsychotic clozapine. Neuropharmacology. 2002;42:662-669.
FULL TEXT
|
ISI
| PUBMED
65. Lee MJ, Breese CR, Strook ML, Leonard S. The effect of nicotine and haloperidol co-treatment on nicotinic receptor levels in rat brain. Brain Res Mol Brain Res. 2001;86:115-124.
PUBMED
66. Ichikawa J, Li Z, Dai J, Meltzer HY. Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor antagonism. Brain Res. 2002;956:349-357.
FULL TEXT
|
ISI
| PUBMED
67. DeGangi G, Porges S. Neuroscience Foundations of Human Performance. Rockville, Md: American Occupational Therapy Association; 1990.
68. Hahn B, Shoiab M, Stolerman IP. Nicotine-induced enhancement of attention in the five-choice serial reaction time task: the influence of task demands. Psychopharmacology (Berl). 2002;162:129-137.
FULL TEXT
| PUBMED
69. SRNT Subcommittee on Biochemical Verification. Biochemical verification of tobacco use and cessation. Nicotine Tob Res. 2002;4:149-159.
70. Olincy A, Young DA, Freedman R. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry. 1997;42:1-5.
FULL TEXT
|
ISI
| PUBMED
71. Rose JE, Westman EC, Behm FM, Johnson MP, Goldberg JS. Blockade of smoking satisfaction using the peripheral nicotinic antagonist trimethaphan. Pharmacol Biochem Behav. 1999;62:165-172.
FULL TEXT
|
ISI
| PUBMED
72. Westman EC, Behm FM, Rose JE. Dissociating the nicotine and airway sensory effects of smoking. Pharmacol Biochem Behav. 1996;53:309-315.
FULL TEXT
|
ISI
| PUBMED
73. Dallery J, Houtsmuller EJ, Pickworth WB, Stitzer ML. Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking. Psychopharmacology (Berl). 2003;165:172-180.
PUBMED
74. Hughes JR, Hatsukami DK, Mitchell JE, Dahlgreen LA. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:993-997.
FREE FULL TEXT
75. Kelly C, McCredie RG. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland. Am J Psychiatry. 1999;156:1751-1757.
FREE FULL TEXT
76. Lasser K, Boyd JW, Woolhander S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: a population-based prevalence study. JAMA. 2000;284:2606-2610.
FREE FULL TEXT
77. George TP, Zeidonis DM, Feingold A, Pepper WT, Satterburg CA, Winkel J, Rounsaville BJ, Kosten TR. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry. 2000;157:1835-1842.
FREE FULL TEXT
78. Addington J, el-Guebaly N, Campbell W, Hodgins DC, Addington D. Smoking cessation treatment for patients with schizophrenia. Am J Psychiatry. 1998;155:974-976.
FREE FULL TEXT
79. Dudas MM, Sacco KA, George TP. Psychopharmacological treatments for nicotine addiction in schizophrenia. Essent Psychopharmacol. 2003;5:171-186.
80. Evins AE, Mays VK, Rigotti NA, Tisdale T, Cather C, Goff DC. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tob Res. 2001;3:397-403.
81. Decker MW, Meyer MD, Sullivan JP. The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control (review). Expert Opin Investig Drugs. 2001;10:1819-1830.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
The Role of Pharmacogenetics in Treating Central Nervous System Disorders
Patnaik et al.
Exp. Biol. Med. 2008;233:1504-1509.
ABSTRACT
| FULL TEXT
Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia
Freedman et al.
Am. J. Psychiatry 2008;165:1040-1047.
ABSTRACT
| FULL TEXT
Schizophrenia, Psychiatric Genetics, and Darwinian Psychiatry: An Evolutionary Framework
Pearlson and Folley
Schizophr Bull 2008;34:722-733.
ABSTRACT
| FULL TEXT
{alpha}7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1
Mathew et al.
Hum Mol Genet 2007;16:2921-2932.
ABSTRACT
| FULL TEXT
Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia
Gray and Roth
Schizophr Bull 2007;33:1100-1119.
ABSTRACT
| FULL TEXT
Recent Advances in the Development of Novel Pharmacological Agents for the Treatment of Cognitive Impairments in Schizophrenia
Buchanan et al.
Schizophr Bull 2007;33:1120-1130.
ABSTRACT
| FULL TEXT
Elevations of Endogenous Kynurenic Acid Produce Spatial Working Memory Deficits
Chess et al.
Schizophr Bull 2007;33:797-804.
ABSTRACT
| FULL TEXT
Successful Tobacco Dependence Treatment in Schizophrenia
Williams and Foulds
Am. J. Psychiatry 2007;164:222-227.
FULL TEXT
Why Do So Many Patients with Schizophrenia Smoke?
JWatch Psychiatry 2005;2005:7-7.
FULL TEXT
|
, P = .10 vs 0 mg of MEC per day (day 3 afternoon session); 
, P<.05 vs 0 mg of MEC per day.
