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.

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    • "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. "
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    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.
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    • "Varenicline is an effective smoking cessation agent (Coe et al. 2005), which is a high-affinity partial agonist to α 4 β 2 and full agonist to α 7 nAChRs (Mihalak et al. 2006). Varenicline is also suggested to have therapeutic effects in patients suffering from Alzheimer's disease (Kem 2000; Jensen et al. 2005), schizophrenia, depression during smoking abstinence (Hong et al. 2011; Liu et al. 2011; Shim et al. 2012; Anthenelli et al. 2013), and patients with ataxia (Zesiewicz et al. 2012). Studying the impact of varenicline on plasticity might thus not only be suited to explore the physiology of nicotinic receptor activation to a larger extent, but also help to comprehend its impact on clinical symptoms. "

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    • "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]. "
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