Effects of Moderate-Dose Treatment With Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers With Schizophrenia or Schizoaffective Disorder

Maryland Psychiatric Research Center, Baltimore, MD 21228, USA.
Archives of general psychiatry (Impact Factor: 14.48). 08/2011; 68(12):1195-206. DOI: 10.1001/archgenpsychiatry.2011.83
Source: PubMed


The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder.
Because α4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans.
A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects.
Outpatient clinics.
A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention Varenicline.
Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention.
A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose).
Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits.

Download full-text


Available from: Robert P Mcmahon,
  • Source
    • "This study demonstrates that varenicline has a prominent impact on neuroplasticity in non-smoking humans, which is similar to that of nicotine application. As mentioned above, varenicline has also been explored for therapeutic application in patients with neuropsychiatric diseases (Kem 2000; Jensen et al. 2005; Mihalak et al. 2006; Hong et al. 2011; Liu et al. 2011; Shim et al. 2012; Zesiewicz et al. 2012; Anthenelli et al. 2013). It might be speculated that the impact of the drug on neuroplasticity is involved in the respective clinical effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nicotine alters cognitive functions in animals and humans most likely by modification of brain plasticity. In the human brain, it alters plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS), probably by interference with calcium-dependent modulation of the glutamatergic system. We aimed to test this hypothesis further by exploring the impact of the α4β2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity, induced by PAS and tDCS, respectively. We administered low (0.1 mg), medium (0.3 mg), and high (1.0 mg) single doses of varenicline or placebo medication before PAS or tDCS on the left motor cortex of 25 healthy non-smokers. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes up to 36 h after plasticity induction. Whereas low-dose varenicline had no impact on stimulation-induced neuroplasticity, medium-dose abolished tDCS-induced facilitatory after-effects, favoring focal excitatory plasticity. High-dose application preserved cathodal tDCS-induced excitability diminution and focal excitatory PAS-induced facilitatory plasticity. These results are comparable to the impact of nicotine receptor activation and might help to further explain the involvement of specific receptor subtypes in the nicotinic impact on neuroplasticity and cognitive functions in healthy subjects and patients with neuropsychiatric diseases.
    Cerebral Cortex 06/2014; 25(9). DOI:10.1093/cercor/bhu126 · 8.67 Impact Factor
  • Source
    • "Nicotine improves the deficits of schizophrenia patients in cognition (sensory gating) [3] [172] [173], working memory [152] [252] and attentional deficits [65], so that strong self-medication effects can be assumed for these deficits as well. Indeed, the nicotinic acetylcholine receptor agonist varenicline , which was specifically developed for smoking cessation, has been shown to improve cognitive impairments in people with schizophrenia [257] and possesses a unique treatment profile on core schizophrenia-related biomarkers [131]. The relationship between smoking and treatment with antipsychotic medication definitely plays an important role in this patient group: chronic nicotine intake can improve neurolepticinduced extrapyramidal symptoms [104] [191] and reduce the occurrence and severity of parkinsonism [63]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tobacco dependence is the most common substance use disorder in adults with mental illness. The prevalence rates for tobacco dependence are two to four times higher in these patients than in the general population. Smoking has a strong, negative influence on the life expectancy and quality of life of mental health patients, and remains the leading preventable cause of death in this group. Despite these statistics, in some countries smokers with mental illness are disadvantaged in receiving intervention and support for their tobacco dependence, which is often overlooked or even tolerated. This statement from the European Psychiatric Association (EPA) systematically reviews the current evidence on tobacco dependence and withdrawal in patients with mental illness and their treatment. It provides seven recommendations for the core components of diagnostics and treatment in this patient group. These recommendations concern: (1) the recording process, (2) the timing of the intervention, (3) counselling specificities, (4) proposed treatments, (5) frequency of contact after stopping, (6) follow-up visits and (7) relapse prevention. They aim to help clinicians improve the care, health and well-being of patients suffering from mental illness.
    European Psychiatry 01/2014; 29(2). DOI:10.1016/j.eurpsy.2013.11.002 · 3.44 Impact Factor
  • Source
    • "In a recent clinical trial, the α4β2 nAChR agonist varenicline did not improve PPI in a sample of smoking and non-smoking patients with schizophrenia or schizoaffective disorder (Hong et al. 2011a). However, varenicline reduced startle reactivity regardless of smoking status (Hong et al. 2011a). The notion that the α4β2 nAChR agonist varenicline did not enhance PPI speaks in favor of the idea that PPI is mainly modulated at the α3 nAChR subtype, possibly at the α3β2 or the α3β4 receptors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: RATIONALE: Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence. OBJECTIVES: We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI. METHODS: We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured. RESULTS: Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation. CONCLUSIONS: The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.
    Psychopharmacology 04/2013; 229(1). DOI:10.1007/s00213-013-3081-1 · 3.88 Impact Factor
Show more