Mr. X was a 67-year-old man with nicotine dependence (45 packs-years), alcohol dependence in early full remission, and dysthymic disorder in remission. He was maintained on venlafaxine XR (225 mg per day) and quetiapine XR (50 mg per day + an additional 25 mg twice daily as needed) with no recent treatment regimen modification. Past psychiatric history was significant for recurrent unipolar major depressive episodes and cocaine abuse. Past substance use history included daily alcohol use since age 35. The number of standard drinks per day increased over the years but averaged 14–20 in the two years preceding his sobriety period. Cocaine was used once per month from the age of 35 to 45 and approximately two times per year thereafter until his sobriety period. He reported no other recent regular substance use. The patient had been stable psychiatrically with no alcohol or cocaine use for seven months. There was no personal or family history of bipolar disorder, but prior long-term substance use history remains a potential confounding factor.

For smoking cessation, bupropion SR coupled with nicotine replacement therapy (NRT) (14 mg patch daily) and therapeutic groups were used. In March 2012, bupropion SR (150 mg per day) was prescribed for three days and a preplanned quit date was set for day 4. As the treatment began, the patient noticed some feelings of excitement, which were amplified when the dose was increased to 150 mg twice daily on the fourth day of treatment. From that point on, he reported the onset of euphoria, racing thoughts, and decreased need for sleep. He subsequently relapsed to alcohol and cocaine use (on days 7 and 8) with minimization of the consequences of substance use. He mentioned no suicidality or psychotic symptoms. The patient met his therapist during the smoking cessation group on day 5, who noticed a change in the patient’s affect and describing him as more anxious, tense, and keyed up. Subjectively, on that day, the patient noticed being more anxious and having less ability to concentrate, which could be early nicotine withdrawal symptoms or early hypomanic symptoms. When seen by his psychiatrist 11 days after treatment initiation, the patient had decided to stop substance use and bupropion for two days. He was getting back to his baseline level, reporting some residual anxiety. Venlafaxine and NRT were maintained, while his quetiapine XR dose was increased to 100 mg per day regularly; bupropion was discontinued. One week later, the patient’s mood was stable, and he had not used any substances.