Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder

Smith, Robert C.; Lindenmayer, Jean Pierre; Davis, John M.; Cornwell, James; Noth, Kathryn; Gupta, Sanjay; Sershen, Henry; Lajtha, Ábel

doi:10.1016/j.schres.2009.02.001

Cited by 91 publications

(73 citation statements)

References 26 publications

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“…In a recent randomized, placebo-controlled study, the a 4 b 2 agonist TC-1734 (AZD3480; isopronicline) was well-tolerated and robustly improved age-associated memory impairments as measured by assessment through the Cognitive Drug Research computerized test battery and a Subject Global Impression Scale of Cognition (SCI-Cog) (Dunbar et al, 2011) (see Table 3). Finally, varenicline, a clinically approved treatment for smoking cessation, with partial a 4 b 2 agonist and full a 7 agonist activity (Mihalak et al, 2006), significantly improved scores on verbal learning and memory tests, but not performance on visual-spatial or attentional performance or PANSS scores; these findings were consistent with previous preclinical data (Smith et al, 2009). However, in a more recent pilot study (n ¼ 6), varenicline did not improve P50 auditory gating in schizophrenia patients as compared with placebo, but elicited central side effects (Waldo et al, 2010), which were in line with the potential exacerbation of neuropsychiatric conditions (Kuehn, 2008).…”

Section: Preclinical Studies Of a 4 B 2 Nachr Agonistssupporting

confidence: 88%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

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Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

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Section: Preclinical Studies Of a 4 B 2 Nachr Agonistssupporting

confidence: 88%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

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“…Some reports find no worsening in psychiatric symptoms in people with schizophrenia (Hong et al, 2011;Smith et al, 2009;Evins and Goff, 2008), while one paper reports aggravation of psychotic symptoms with varenicline (Freedman, 2007). We did not observe any significant change in PANSS or SANS scores after adjunct varenicline treatment.…”

Section: Clinical and Safety Datacontrasting

confidence: 72%

“…Our findings are generally consistent with previous studies, which have reported beneficial effects of varenicline on cognition similar to those observed with nicotine. Smith et al (2009) found significant improvements in an open label study (N ¼ 12) in schizophrenia in some areas of cognition, particularly in the areas of verbal learning and memory. Others have also reported cognitive improvements in non-psychiatric populations in attention (Patterson et al, 2009) and working memory (Loughead et al, 2010;Patterson et al, 2009) that are similar to what is observed in animal studies (Rollema et al, 2007).…”

Section: Clinical and Safety Datamentioning

confidence: 91%

Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Shim

Jung

Jung³

et al. 2011

Neuropsychopharmacol

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The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the a4b2 and full agonist at the a7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2-8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline-placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p ¼ 0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p ¼ 0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p ¼ 0.008) and Stroop Interference (p ¼ 0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

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“…As mentioned above, there are similar case reports in the literature supporting an association between varenicline use and psychiatric adverse effects. However, there are also case series [19][20][21] and studies of patients 22,23 with chronic psychiatric disorders who showed significant improvement while taking varenicline in terms of smoking cessation without worsening of psychiatric symptoms. Furthermore, some authors also suggest that varenicline improves mood and cognition during smoking abstinence.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 In adults, uncontrolled studies in patients with bipolar depression or residual depressive symptoms also showed good tolerability of stimulants. [21][22][23][24][25] Concerning controlled studies in adults, only one small RCT (N=85) is available. Depressed bipolar patients treated with the stimulant modafinil in conjunction with a mood stabilizer did not show increased (hypo)manic symptoms.…”

Section: To the Editormentioning

confidence: 99%

Varenicline-Induced Psychosis

Cinemre

Akdag²,

Metin³

et al. 2010

CNS Spectr.

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Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder

Cited by 91 publications

References 26 publications

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Varenicline-Induced Psychosis

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