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Randomized Controlled Trial
. 2015 Mar;29(3):300-11.
doi: 10.1177/0269881114562091. Epub 2014 Dec 16.

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation

Sherry A McKee  1 , Marc N Potenza  2 , Hedy Kober  3 , Mehmet Sofuoglu  4 , Amy F T Arnsten  5 , Marina R Picciotto  3 , Andrea H Weinberger  4 , Rebecca Ashare  6 , Rajita Sinha  3
Affiliations
Randomized Controlled Trial

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation

Sherry A McKee et al. J Psychopharmacol. 2015 Mar.

Abstract

Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.

Keywords: Guanfacine; Stroop; ad-libitum smoking; craving; fMRI; lapse; smoking cessation; stress.

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Conflict of interest statement

DECLARATION OF CONFLICT OF INTEREST

Dr. Arnsten and Yale receive royalties from the sales of Intuniv (extended-release guanfacine) for the treatment of pediatric ADHD. They do not receive royalties from the sales of generic guanfacine which is used to treat adults. Generic guanfacine was used in the current study. All other authors have no disclosures to report.

Dr. Sofuoglu is supported by the Veterans Administration Mental Illness Research, Education and Clinical Center (MIRECC). Dr. Sofuoglu served as an expert witness on behalf of Pfizer in lawsuits related to varenicline.

Dr. Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and advised Ironwood, Lundbeck, Shire and iNSYS; has received research support from the National Institutes of Health, Mohegan Sun Casino, the National Center for Responsible Gaming, and Psyadon pharmaceuticals; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse control disorders or other health topics; has consulted for law offices and gambling entities on issues related to impulse control disorders; provides clinical care in the Connecticut Department of Mental Health and Addiction Services Problem Gambling Services Program; has performed grant reviews for the National Institutes of Health and other agencies; has guest-edited or edited journals or journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts.

Drs. McKee, Kober, Sofuoglu, Picciotto, Weinberger, Ashare, and Sinha reported no conflicts of interest with this study.

Figures

Figure 1
Figure 1
Timeline of laboratory procedures to evaluate smoking-lapse during stress versus neutral imagery. Note: Assessment of cortisol and ACTH occurred at −30 min, −15 min, +10 min, +20 min, +40 min, and +60 min from the imagery procedure and remained fixed regardless of when the termination of the delay period occurred. Assessments of craving, emotion, physiologic reactivity, and nicotine withdrawal occurred at −15min, +5min, and termination of the delay.
Figure 2
Figure 2
Stress increases the ability to resist smoking (2A), ad-libitum smoking (2B), and tobacco craving (2C) during a human laboratory experiment and these effects are absent or reduced in guanfacine-treated subjects (guanfacine n=17; placebo n=16). (A): Stress (versus neutral imagery) reduced the ability to resist smoking in the placebo group, and this effect was absent in the guanfacine group. *p<.05 stress vs. neutral imagery within medication group. (B): Stress increased the number of cigarettes smoked in the placebo group, and this effect was absent in the guanfacine group. *p<.05 stress vs. neutral imagery within medication group. (C): Stress (versus neutral imagery) increased tobacco craving (change from pre to post-imagery) in the placebo group, and this effect was reduced in the guanfacine group. During the stress session, the increase in craving was greater in the placebo vs. guanfacine group. (*p<.05 stress vs. neutral imagery within medication group; and guanfacine vs. placebo within stress imagery). NOTE: The post-imagery timepoint occurs prior to the smoking lapse task.
Figure 3
Figure 3
Stress increases systolic blood pressure in placebo but not guanfacine-treated subjects (3A) and stress increases cortisol response in guanfacine but not placebo-treated subjects (3B). (A): Effect of medication (guanfacine vs placebo) and imagery (stress vs neutral) on systolic blood pressure during the smoking-lapse paradigm(guanfacine n=17; placebo n=16). Main effect of guanfacine on decreasing systolic blood pressure. Post-hoc analysis of change (pre to post imagery) demonstrated that stress vs. neutral imagery increased systolic blood pressure in placebo but not guanfacine-treated subjects (*p<.05 stress versus neutral imagery within medication). (B): Effect of medication (guanfacine vs placebo) and imagery (stress vs neutral) on cortisol levels during the smoking-lapse paradigm (guanfacine n=13; placebo n=14). Post-hoc analysis of change (pre to post-imagery) demonstrated that cortisol levels differed in guanfacine across stress and neutral imagery sessions but not in placebo-treated subjects (*p<.05 stress versus neutral imagery within medication) and differed across medication groups within stress condition (*p<.05 guanfacine vs. placebo within stress). NOTE: The post-imagery timepoint occurs prior to the smoking lapse task.
Figure 4
Figure 4
Guanfacine alters prefrontal activation to the incongruent stimuli in a Stroop task during the fMRI session (guanfacine n=9; placebo n=12). Guanfacine also attenuated demand on dorsal attention networks during the task. During this Stroop task, participants see color words (e.g., BLUE) presented in either congruent (blue) or incongruent color fill (green). Participants are asked to silently name the color fill while ignoring the word itself, and their ability to do so is thought to reflect attention, conflict resolution, and inhibitory control during incongruent stimuli presentations. Percent-signal-change values during incongruent (red) and congruent trials (green) are displayed in regions that showed significant between-group difference in the incongruent> congruent contrast in whole brain analysis (family-wise-error corrected p<.05). Figure shows increased activity in (A): Dorsal Cingulate/Sensorimotor area (SMA), (B): ventromedial prefrontal cortex (vmPFC), and (C): Superior Temporal Gyrus (STG)/Insula. Attenuated activity is shown in (D): Superior Parietal, and (E): Dorsal Prefrontal Cortex (dPFC).
Figure 5
Figure 5
Guanfacine reduces cigarette use and improves retention during a brief treatment phase (guanfacine n=9; placebo n=9). (A): Effect of medication (guanfacine vs placebo) on cigarette use during baseline (mean 30 day average), titration (mean of final titration week), and the 4-week treatment period (4-week average adjusted for baseline). Guanfacine significantly reduces cigarette use during the treatment phase (*p<.0005). (B): Effect of medication (guanfacine vs placebo) on retention in treatment during the 4-week quit attempt. Guanfacine significantly increases retention during the treatment phase (*p<.01).
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