The patient was a 43-year-old male who had been suffering from recurrent depression since early adulthood and who had been diagnosed with bipolar disorder type I in 2017, following his first and only manic episode. Since then, he was suffering from severe intractable TRD. The patient had been a high functioning individual, holding a Ph.D and an executive position for many years before his manic episode. He was now without a job and presenting minimal functioning, living in his parent's basement. Treatment history included several years of psychotherapy and the unsuccessful trial of various antidepressants, antipsychotics, mood-stabilizers, and psychostimulants of adequate dosage and duration. The patient was also suffering from comorbid generalized anxiety disorder. Past medical history was significant for low testosterone treated with testosterone gel and restless leg syndrome previously treated with pramipexole.
The patient was initially referred for rTMS in January of 2019. At that time, baseline Montgomery-Asberg Depression Rating Scale (MADRS) was at 38 and Clinical Global Impression (CGI) at five. At baseline, the patient was receiving, quetiapine XR 300 mg HS, quetiapine 25 to 50 mg OD PRN, zolpidem 10 mg HS, clonazepam 1 mg AM and 2 mg HS, venlafaxine 262.5 mg OD and bupropion XL 150 mg OD. In February 2019, the patient underwent a first trial of rTMS in which he received two daily sessions (spaced by 45 min) of a 20 Hz, 3,000 pulses protocol (5 sec ON, 25 sec OFF) over the left dorsolateral prefrontal cortex (DLPFC) using the adjusted BeamF3 algorithm, delivered using a MagPro X100 device with a Cool-B70 coil (MagVenture, Farum, Denmark) at 120% of resting motor threshold (MT). Treatment was delivered every weekday for a total of 30 sessions over 3 weeks. The patient unfortunately did not show signs of improvement, scales remaining similar to baseline value (Figure 1). Of note during this phase of treatment was that the patient remained on 3 mg of clonazepam per day throughout treatment, which he was unable to wean off because of crippling anxiety.
The patient was referred to us again in September 2020 for ketamine given his hesitancy to proceed with ECT. After a slow decrease of his clonazepam over several months down to 0.25-0.5 mg HS, the patient underwent IV ketamine therapy, in January of 2021. The patient received three infusions, each week, of IV ketamine at 0.5 mg/kg over 60 min for 2 weeks. MADRS went from 30, at treatment initiation, down to 17 on the last day of treatment but went back up to 23, 1 week after treatment, and he experienced full relapse with MADRS at 35, 4 months later.
Given his refusal to proceed with ECT, we offered an intensive combined rTMS/ketamine therapy according to the below described protocol over a 2-week period. At the time, the patient was receiving the following medication regimen: quetiapine 50 mg TID, clonazepam 0.5 mg HS, bupropion XL 150 mg OD, trazodone 50-15 0 mg HS PRN, and pramipexole 0.25 mg HS. On each weekday afternoon, the patient received three daily sessions (50 min between each session) of standard intermittent theta burst stimulation (iTBS) at 600 pulses per session at 120% MT over the left DLPFC, located using the adjusted BeamF3 algorithm. Additionally, three mornings per week over those same 2 weeks, he received the same IV ketamine protocol as before (six sessions total). IV ketamine treatments and rTMS treatments were spaced by 4 h (ketamine in the morning, rTMS in the afternoon). The patient initially experienced partial improvement on his last day of treatment, MADRS decreasing from 35 to 23, Hamilton Depression Scale 17 (HAMD-17) scores from 28 to 11, Patient Health Questionnaire-9 (PHQ-9) scores from 21 to 7, Generalized Anxiety Disorder-7 (GAD-7) scores from 17 to 9 and CGI from 5 down to 4. Given the positive response, we continued with a 10-week consolidation phase, during which the patient received 2 days of rTMS (three sessions per day, spaced 50 min apart)administered every week for 6 weeks, and then 1 day per week (three sessions per day, spaced 50 min apart) for four additional weeks (48 treatment sessions total). Each rTMS session began with a 2 min, 600 pulse, 100% MT, right DLPFC continuous TBS (cTBS) treatment, directly followed by the above describe iTBS protocol. cTBS was delivered over the right DLPFC with the coil centered on the F4 EEG location (using the BeamF3 algorithm, but on the right-side of the head). During the consolidation phase of treatment, the patient received intramuscular (IM) racemic ketamine (same dosage as IV) once a week for 6weeks and then once every 2 weeks (eight sessions total). The IM ketamine was administered in the morning, and total dose (0.5 mg/kg) was split into two equivalent doses given 30 min apart. On days where patient received IM ketamine, ketamine was received in the mornings, and rTMS treatment was given in the afternoon (treatments spaced by 4 h). Throughout the consolidation phase, the patient continued to experience additional clinical improvement, eventually reaching full and sustained remission. During the consolidation phase, minor adjustments were done to his medication regimen: low dose pramipexole was added back to better control his restless leg syndrome, and clonazepam was increased back to 1.5 mg after the end of the consolidation phase to better control anxiety. At the end of the consolidation phase, the patient scored a four on MADRS, one on CGI a HAM- D-17 of five, PHQ-9 of one and GAD-7 of one. At the last follow-up, December 2021-close to 6 months after the last consolidation treatment-the patient had fully re-integrated his work functions, had moved out from his parent's home, and had a MADRS of two, CGI of one, HAM-D-17 of three, PHQ-9 of three, and GAD-7 of 0.
See Figure 1 for a summary of the three phases of treat. See Figure 2 for timeline of events. See Figure 3 for a graphical representation of MADRS and CGI scores over follow-up.