Treatment resistance in depression is a common and compelling clinical condition. As there are several treatment methods including augmentation, combination, switching strategies in management of refractory depressed cases, stimulation methods are also one of these favorable options. Repetitive Transcranial Magnetic Stimulation (rTMS) is a wide spreading therapeutic tool approved by FDA in treatment of depression and has been shown to be effective as an add-on treatment to pharmacotherapy. There are different application methods of rTMS in clinical practice whereas high frequency(HF) to left dorsolateral prefrontal cortex (DLPFC) and low frequency (LF) to right DLPFC are the most studied methods in particular of depression treatment. Mechanism of antidepressant (AD) efficacy of rTMS still remains unclear but neuromodulation, neuroendocrinological and neurotransmitter pathways are likely responsible. Although neurobiology and underlying mechanisms of AD resistance in depression is not well known yet, inadequate response to several AD trials is considered to be a predictor of subsequent bipolar disorder. AD use in bipolar depression is another aspect in management of bipolar depression and is strongly debated. Beside to pharmacological AD interventions, there are some cases switches to hypomania/mania by rTMS application. Furthermore, current data with regard to long-term efficacy of rTMS is limited. In this report we present two cases of refractory depression that developed mania and hypomania in follow up one month after of rTMS course.
Case 1: Our first case was a 38 year-old female diagnosed to have non-psychotic depression and had been using venlafaxine 75-150 mg/day for nine months. Due to inadequate response to her current medication, left sided HF-rTMS course (including 20 Hz frequency, 1000 pulse/day, 15 sessions, applied to left DLPFC) was administered as an add-on treatment but her depressive symptoms didn’t improve in clinical follow-up. Hence, right-sided LF rTMS, another effective rTMS protocol has been applied to right DLPFC with 1 Hz frequency and 1000 pulse/day for 15 sessions but treatment response was not sufficient again. She has continued her treatment with receiving cognitive behavioral therapy in addition to her current medication. One month after her last rTMS course, she was admitted to our clinic with psychotic mania. She has been hospitalized with olanzapine 10 mg/day treatment and her AD treatment was stopped. In clinical follow up she was discharged with diagnosis of bipolar disorder in partial remission.
Case 2: The second case, a 24-year-old female, was diagnosed to have nonpsychotic depression under escitalopram 20 mg/day and olanzapine 5 mg/day medication for five months. Left sided HF-rTMS was applied with same protocol as previous case but similarly, response to TMS treatment was not sufficient. Nearly after one month of her last rTMS session, she was admitted to outpatient clinic with hypomanic symptoms. As escitalopram was ceased and olanzapine was titrated to 20 mg/day, her affective symptoms improved gradually. Both cases had neither family history nor history of manic/hypomanic episodes. ADs are known to have a potential of inducing mania/hypomania in bipolar patients. rTMS has been reported to have a similar potency as well. It was suggested that rTMS has delayed effects on mood in depressed patients. In these reported cases we can’t conclude whether manic/hypomanic symptoms developed in consequence of rTMS therapy or as a natural course of disease. There are some promising results supporting efficacy of rTMS in bipolar depression. Although rTMS is an effective therapeutic tool in depression, it could be suggested that rTMS resistant depressed patients, as similar to those pharmacotherapy resistant patients, should be evaluated as to be vulnerable to bipolar disorder and monitored in terms of manic shift.