Hypomanic episode in unipolar depression during transcranial direct current stimulation Non-invasive methods of brain stimulation are being increasingly investigated for the treatment of major depressive disorder (MDD). Transcranial direct current stimulation (tDCS), a promising treatment in which weak, constant, direct electric currents modify brain excitability by neuronal modulation of membrane resting potential and secondary synaptic changes, has shown encouraging results (1). To date, three randomised clinical trials using current tDCS methodology (2–4), and some open trials (5,6), have tested the efficacy of tDCS for treatment of MDD. These trials have mixed results, thus promoting further research in the field. In the context of tDCS clinical develop- ment, there are other equally important issues such as safety and potential adverse effects that need to be addressed. Because some adverse effects are rare and therefore not detected in small trials, it is important to report and discuss moderate or severe side effects such as hypomania. Recently, Arul-Anandam et al. (7) reported treatment-emergent hypomania during tDCS treatment. Here, we report a patient who also presented with hypomania after tDCS; however, unlike in Arul-Anandam et al.’s case study, our patient sustained hypomania for a longer period of time. And, we discuss the clinical and research implications of tDCS inducing hypomanic episodes in patients with mood disorders. A 58-year-old man who was referred to our team as a result of the symptoms of depression during the last 14 months. He was a suitable candidate for non-invasive stimulation therapy, as he recently had surgery for gastric cancer and could not tolerate antidepressants because of gastrointestinal effects. He was enrolled in the pilot phase of a larger, ongoing clinical trial of tDCS for MDD (8), which was approved by the Ethics Committee at Sao Paulo University (Hospital Universitario). Following the approved protocols, the anode electrode was placed over the left dorsolateral prefrontal cortex (DLPFC) located at F3 (according to the International EEG system 10-20) and the cathode over the right DLPFC (F4). The rubber elec- trodes consisted of 7 × 5 cm saline-soaked sponges fixed with a headband. Two mil- liamperes of current (current density = 0.6 A/m 2 ) was applied for 30 min. Initially, we planned to apply stimulation for 10 consecutive workdays, but, as we shall discuss, it was applied only for 5 days. We used a Portuguese-validated version of the Mini-International Neuropsychiatric Interview (M.I.N.I.) (9) to assess and confirm the following diagnoses: (a) an acute, 14-month-long depressive episode, in which the patient used sertraline 50 mg/day for 1 year and (b) six previous depressive episodes, as follows: (i) at age 21, lasting 8 months, no medications used; (ii) at age 34, lasting 1 year, used imipramine 75 mg/day for 2 months; (iii) at age 40, lasting 6 months, used fluoxetine 20 mg/day; (iv) at age 46, lasting 8 months, no medications used; (v) at age 52, lasting 3 months, no medications used and (vi) at age 54, lasting 6 months, used sertraline 50 mg/day. We did not confirm prior hypomanic episodes using DSM-IV criteria, which require at least three elation/expansiveness symptoms (or four if only irritable mood occurs) for more than 3 days. Instead, he had several episodes (about two per year since he was 18) lasting less than 48 h, in which he presented with dysphoric mood, insomnia, grandiose ideas and increased energy and activity. In addition, he had some periods lasting less than 1 week in which he presented with only increased irritability and energy. Importantly, he also reported the emergence of hypomanic symptoms after using imipramine, which was his first use of antidepressants. However, at that time (1985), his psychiatrist did not investigate whether he fulfilled the criteria for a hypomanic episode. His Hamilton (HDRS) and Montgomery-Asberg (MADRS) depression baseline severity scores were 23 and 35, respectively, suggesting a moderate-to-severe depressive episode. He had a Young Mania Rating Scale (YMRS) of 8, below the threshold of 12 that represents mania (see Fig. 1) (10). Five days after the onset of treatment, HDRS and MADRS scores substantially decreased, while YMRS increased (8–16). In fact, although he reported that he was sleeping better, had no more suicidal thoughts and had more energy, he felt distressed, angry and explosive, and he had increased sexual arousal and racing thoughts. He also spontaneously described his feelings and behaviours as in the same way when I was on Imipramine. Afterwards, sertraline was discontinued and neurostimulation was postponed for 1 week while the patient was re-evaluated and, because of remission of hypomania, tDCS was resumed at a lower current (1.5 mA instead of 2 mA). The patient’s endpoint scores showed remission of both depressive and manic symptoms (Fig. 1). One month after tDCS treatment, J. S. had sustained remission and lamotrigine was introduced 50 mg/day as a maintenance treatment for bipolar disorder not otherwise specified. Since then J. S. had presented no more manic or depressive symptoms (for 5 months). We reported a patient with depressive symptoms and no prior formal episodes of mania or hypomania, who developed a tDCS-induced transient hypomanic episode, which reverted only after discontinuation of treatment. Here, we discuss possible relationships between the hypomanic episode and tDCS use, as well as implications for tDCS safety and future trials. In addition, although the risk of treatment-emergent mania after 316