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Case Report

Mania induced by varenicline

[version 1; peer review: 1 approved with reservations, 1 not approved]
PUBLISHED 13 Sep 2013
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Abstract

Varenicline is sometimes used in the treatment of smoking addiction. Side effects such as nausea, vomiting, and headaches have been well documented. In addition, depressed mood and suicidal thoughts relating to varenicline usage have been previously reported. We report a case of mania in a patient with refractory depression whose first manic episode developed under the use of varenicline in combination with original antidepressant medications.

Case report

Mr. L, a 55-year-old male, was diagnosed with major depressive disorder based on DSM-IV TR criteria in December 2010. The presenting symptoms included depressed mood, irritability, anxiety, somatic worries, difficulty falling asleep, ideations of death, anhedonia, and an impaired working ability for two months. Therefore, we prescribed standard antidepressant treatment, and also attended psychotherapeutic intervention sessions following his visit to our outpatient department.

He showed a poor response to both antidepressant monotherapy and combination therapy with a selective serotonin reuptake inhibitor (SSRI), serotonin/norepinephrine reuptake inhibitor (SNRI) and norepinephrine/dopamine reuptake inhibitor (NDRI) combined with lamotrigine. In detail, he received sertraline monotherapy (50 mg, 3 months), venlafaxine monotherapy (112.5 mg, 4 months), duloxetine monotherapy (30 mg, 2 months) and combination therapy of bupropion and lamotrigine (300 mg/50 mg, 6 months). Repetitive transcranial magnetic stimulation was also tried with only a partial antidepressant response. Finally, he maintained mild to moderate depression with the use of a melatonergic agent (agomelatine 25 mg) and lamotrigine (50 mg).

The patient reported being addicted to smoking for the past 40 years, 1 pack per day, with a Fagerstrom nicotine dependence score of 6. In March 2013, he was prescribed varenicline 0.5 mg/day for smoking cessation. He had been treated with agomelatine (25 mg/day) for three months prior to the initiation of varenicline treatment. After six days of varenicline treatment, there was no reported nausea or other side effects. The dosage of varenicline was subsequently titrated to 2 mg/day. During the first month of varenicline treatment, persistent elevated mood, high irritability and other symptoms of mania such as hyper-talkativity, grandiosity, decreased need for sleep were reported. In addition, increased verbal and physical aggressions toward strangers were noted for one week. Thus, varenicline-related mania was diagnosed and after discontinuation of varenicline, the manic symptoms disappeared rapidly within a few days. His mood returned back to its original status between mild to moderate depression.

Discussion

The occurrence of the mania in the present case seemed to be dose-dependent and the adverse effect rapidly disappeared after discontinuation of varenicline. Depressed mood and suicidal ideation have been listed in varenicline’s black box warning1. In addition, a previous case of aggressive behavior in a patient with schizophrenia induced by varenicline has been reported2. However, the mechanism by which varenicline could induce mania is not clear.

A prominent reduction in the expression of mRNA for several nicotinic subunit isoforms has been reported in bipolar disorders. Nicotinic cholinergic receptors play an important role in regulating the activity of GABA inhibitory interneurons3.

Selectively binding to the nicotinic acetylcholine α4β2 subunit may cause an imbalance of the inhibitory controls in the mood circuit, since the nicotinic acetylcholine receptor α7 and α4β2 subtypes have a different degree of GABAergic inhibition in target neurons4. Furthermore, an increase in nicotinic receptor α7-dependent signaling has been suggested to be critically involved in the pathophysiology of bipolar disorder from a study on post-mortem patients5. Varenicline seems to be safe in patients with bipolar disorders6, yet a few case reports have demonstrated a hypomanic or manic relapse in patients with identified bipolar disorders79. Varenicline is a partial agonist at the nicotinic acetylcholine α4β2 subunit and a full agonist at the α7 subunit10. Potent α7-dependent activation and weak α4β2-depedent activation caused by varenicline might lead to a central inhibitory dysfunction that might, in turn, lead to manic symptoms in patients with bipolar disorders or bipolar diathesis. Some patients with major depression may harbor bipolar disorders later, particularly if they show high resistance to antidepressant treatment11. Although central mechanisms of varenicline induced mania remain elusive, the present case report highlights the importance of monitoring for potential manic side effects with the use of varenicline in patients with major depression, especially when used in combination with antidepressants.

Consent

Written informed consent for publication of clinical details was obtained from the patient.

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 13 Sep 2013
  • Reader Comment 21 Mar 2016
    Omar González-Santiago, Universidad Autónoma de Nuevo León, Mexico
    21 Mar 2016
    Reader Comment
    It would be interesting to indicate specifically the time when the patient received each one of your antidepressants. Probably the patient is manifesting side effects of its antidepressants or may ... Continue reading
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Chang PT and Li CT. Mania induced by varenicline [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2013, 2:183 (https://doi.org/10.12688/f1000research.2-183.v1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 13 Sep 2013
Views
32
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Reviewer Report 10 Dec 2013
Jonathan Foulds, Public Health Services, Penn State University, Hershey, PA, USA 
Approved with Reservations
VIEWS 32
This article is a case report of a man who had been suffering from treatment-resistant depression who developed symptoms of mania. The main problem with this paper is that although the patient was prescribed varenicline for smoking cessation, the report ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Foulds J. Reviewer Report For: Mania induced by varenicline [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2013, 2:183 (https://doi.org/10.5256/f1000research.2318.r2637)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
38
Cite
Reviewer Report 19 Nov 2013
Eva Kralikova, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic 
Not Approved
VIEWS 38
Varenicline is commonly used in the treatment of tobacco dependence. Smokers have a very important and large psychiatric comorbidity. The paper presents no evidence that the status was caused by varenicline, including missing major publications on this topic - so ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Kralikova E. Reviewer Report For: Mania induced by varenicline [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2013, 2:183 (https://doi.org/10.5256/f1000research.2318.r2395)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 13 Sep 2013
  • Reader Comment 21 Mar 2016
    Omar González-Santiago, Universidad Autónoma de Nuevo León, Mexico
    21 Mar 2016
    Reader Comment
    It would be interesting to indicate specifically the time when the patient received each one of your antidepressants. Probably the patient is manifesting side effects of its antidepressants or may ... Continue reading
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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