Elsevier

Biological Psychiatry

Volume 73, Issue 3, 1 February 2013, Pages 211-218
Biological Psychiatry

Archival Report
Effects of Modafinil on Neural Correlates of Response Inhibition in Alcohol-Dependent Patients

https://doi.org/10.1016/j.biopsych.2012.06.032Get rights and content

Background

Impaired response inhibition is a key feature of patients with alcohol dependence. Improving impulse control is a promising target for the treatment of alcohol dependence. The pharmacologic agent modafinil enhances cognitive control functions in both healthy subjects and in patients with various psychiatric disorders. However, very little is known about the underlying neural correlates of improvements in response inhibition following modafinil.

Methods

We conducted a randomized, double-blind, placebo-controlled, crossover study using functional magnetic resonance imaging with a stop signal task to examine effects of a single dose of modafinil (200 mg) on response inhibition and underlying neural correlates in abstinent alcohol-dependent patients (AD) (n = 16) and healthy control subjects (n = 16).

Results

Within the AD group modafinil administration improved response inhibition (reflected by the stop signal reaction time [SSRT]) in subjects with initial poor response inhibition, whereas response inhibition was diminished in better performing subjects. In AD patients with initial poor response inhibition, modafinil-induced SSRT improvement was accompanied by greater activation in the thalamus and supplementary motor area (SMA) and reduced connectivity between the thalamus and the primary motor cortex. In addition, the relationship between baseline response inhibition and modafinil-induced SSRT improvement was mediated by these changes in thalamus and SMA activation.

Conclusions

These findings indicate that modafinil can improve response inhibition in alcohol-dependent patients through its effect on thalamus and SMA function but only in subjects with poor baseline response inhibition. Therefore, baseline levels of response inhibition should be taken into account when considering treatment with modafinil in AD.

Section snippets

Subjects

Twenty male subjects meeting DSM-IV (30) criteria for alcohol dependence (AD) were recruited from regional addiction treatment centers. In addition, 18 healthy control subjects (HC), matched on sex, education, and age, were included. Exclusion criteria can be found in the Supplemental Methods in Supplement 1. Four AD and two HC subjects were excluded from analyses due to either too many omission errors on go trials or excessive head motion during scanning. The remaining data from 32

Demographics and Clinical Assessments

Demographic, self-report, and substance use characteristics are presented in Table 1. The AD group did not differ from the HC group with regard to age, educational level, or IQ. Alcohol dependence subjects smoked significantly more cigarettes than HC subjects. We did not include smoking as a covariate in subsequent analyses, because smoking behavior was related to alcohol consumption during the past 6 months (r = .47, p = .01) and AUDIT scores (r = .54, p = .001). Therefore, including smoking

Discussion

This study demonstrates that modafinil can improve response inhibition by modulating activation in key regions involved in successful inhibition (SMA and thalamus) but only in alcohol-dependent patients that show poor initial response inhibition. In contrast, response inhibition in better performing subjects deteriorated after receiving modafinil. These observations are in line with findings of modafinil-induced improvements and deteriorations in response inhibition in subjects with low and

References (54)

  • M. Oscar-Berman et al.

    Alcohol: Effects on neurobehavioral functions and the brain

    Neuropsychol Rev

    (2007)
  • H. Bowden-Jones et al.

    Risk-taking on tests sensitive to ventromedial prefrontal cortex dysfunction predicts early relapse in alcohol dependency: A pilot study

    J Neuropsychiatry Clin Neurosci

    (2005)
  • C. Evren et al.

    Relationship of relapse with impulsivity, novelty seeking and craving in male alcohol-dependent inpatients

    Drug Alcohol Rev

    (2012)
  • S.E. Muller et al.

    Personality traits predict treatment outcome in alcohol-dependent patients

    Neuropsychobiology

    (2008)
  • H. Greely et al.

    Towards responsible use of cognitive-enhancing drugs by the healthy

    Nature

    (2008)
  • L. Joos et al.

    Modafinil in psychiatric disorders: The promising state reconsidered

    Tijdschr Psychiatr

    (2010)
  • B. Sahakian et al.

    Professor's little helper

    Nature

    (2007)
  • D.C. Turner et al.

    Cognitive enhancing effects of modafinil in healthy volunteers

    Psychopharmacology (Berl)

    (2003)
  • M.D. Hunter et al.

    Impact of modafinil on prefrontal executive function in schizophrenia

    Am J Psychiatry

    (2006)
  • L. Scoriels et al.

    Effects of modafinil on cognitive functions in first episode psychosis

    Psychopharmacology (Berl)

    (2011)
  • S.A. Spence et al.

    Modafinil modulates anterior cingulate function in chronic schizophrenia

    Br J Psychiatry

    (2005)
  • D.C. Turner et al.

    Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia

    Neuropsychopharmacology

    (2004)
  • A.C. Dean et al.

    Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans

    J Stud Alcohol Drugs

    (2011)
  • M. Zack et al.

    Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivity

    J Psychopharmacol

    (2009)
  • J.L. Evenden

    Varieties of impulsivity

    Psychopharmacology (Berl)

    (1999)
  • G.D. Logan et al.

    Impulsivity and inhibitory control

    Psychol Sci

    (1997)
  • D.M. Eagle et al.

    Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol

    Psychopharmacology (Berl)

    (2007)
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