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 disorders7–9. 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.
Author contributions
Conceived the case: Cheng-Ta Li. Analyzed the data: Ping-Tsun Chang and Cheng-Ta Li. Wrote the paper: Ping-Tsun Chang. Both authors critically revised the paper.
Competing interests
No competing interests were disclosed.
Grant information
The author(s) declared that no grants were involved in supporting this work.
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