Mania induced by varenicline

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. Cheng-Ta Li ( ) Corresponding author: on5083@msn.com Chang PT and Li CT. How to cite this article: Mania induced by varenicline [version 1; referees: 1 approved with reservations, 1 not 2013, :183 (doi: ) approved] F1000Research 2 10.12688/f1000research.2-183.v1 © 2013 Chang PT and Li CT. This is an open access article distributed under the terms of the , Copyright: Creative Commons Attribution Licence which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the (CC0 1.0 Public domain dedication). Creative Commons Zero "No rights reserved" data waiver The author(s) declared that no grants were involved in supporting this work. Grant information: Competing interests: No competing interests were disclosed. 13 Sep 2013, :183 (doi: ) First published: 2 10.12688/f1000research.2-183.v1 Referee Status:

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 dosedependent and the adverse effect rapidly disappeared after discontinuation of varenicline.Depressed mood and suicidal ideation have been listed in varenicline's black box warning 1 .In addition, a previous case of aggressive behavior in a patient with schizophrenia induced by varenicline has been reported 2 .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 interneurons 3 .
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 neurons 4 .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 patients 5 .Varenicline seems to be safe in patients with bipolar disorders 6 , yet a few case reports have demonstrated a hypomanic or manic relapse in patients with identified bipolar disorders [7][8][9] .Varenicline is a partial agonist at the nicotinic acetylcholine α4β2 subunit and a full agonist at the α7 subunit 10 .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 treatment 11 .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.

Open Peer Review
Current Referee Status: 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 contains no information on any changes in his smoking around the time he was prescribed varenicline and thereafter…none!We are left to guess about this, and it is a reasonable guess that the patient significantly reduced his smoking.In that case why are the manic symptoms being attributed to varenicline rather than to smoking cessation?Some of the symptoms described (high irritability, decreased sleep) are known symptoms of nicotine withdrawal.There is also a lack of information on other drug/substance use that may help to interpret the patient's mood changes.For example, did he consume much caffeine?Caffeine metabolism slows down significantly on smoking cessation; could that have played a role?Overall there is insufficient provision of key information to help the reader interpret this potentially interesting case report.In addition, this report fails to cite recent key studies on large samples that are relevant to the question of whether varenicline may cause neuropsychiatric side effects (Gibbons & Mann ; ; ).

Foulds et al, Thomas et al, 2013
The paper needs to be revised to include a detailed description of the timing of symptoms relative to cigarette consumption and to address any other potential causes of mania.
I have read this submission.I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
I act as a consultant for Pfizer (manufacturer of varenicline) and other pharma Competing Interests: companies involved in smoking cessation.
Health Services, Penn State University, Hershey, PA, USA First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic