Effect of Intermittent and Continuous Theta Burst Stimulation on Sleep, Daytime Sleepiness, and Fatigue in Depression

Intermittent and continuous theta-burst stimulation (iTBS and cTBS respectively) are the newer modalities of conventional repetitive transcranial magnetic stimulation (rTMS) with documented noninferiority in improving mood in depressive disorders. The effect of both modalities on other significant depression symptoms has not been studied. In this feasibility study investigators aim primarily to assess the safety and therapeutic potential of iTBS over the left dorsolateral prefrontal cortex (lDLPFC) and cTBS over the right dorsolateral prefrontal cortex (rDLPFC) on sleep quality, sleep propensity, fatigue, and daytime sleepiness in patients with major and bipolar depression.

• iTBS (Device): Active iTBS over the left DLPFC to induce the long term potentiation of stimulated area.
• cTBS (Device): Active cTBS over the right DLPFC to induce the long term potentiation of stimulated area.
• Sham (Device): Sham iTBS or cTBS over the left or right DLPFC respectively for placebo.

Primary outcomes

• Beck Depression Inventory 2 [Before intervention - four weeks after finishing intervention.]: Inventory consisting of 21 items measuring cognitive, affective, somatic, and vegetative symptoms of depression. Each item is scored from 0 to 3, with a higher score denoting more severe depression. Items are related to the criteria from the Diagnostic and Statistical Manual of Mental Disorders-IV. The minimum value of the total score is 0 and the maximum is 63 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.
• Pittsburgh Sleep Quality Index [Before intervention - four weeks after finishing intervention.]: Pittsburgh Sleep Quality Index is a questionnaire to identify sleep disturbances. It consists of a combination of Likert-type and open-ended questions, which are later converted to scaled scores. Scores for each question range from 0 to 3, with higher scores indicating greater sleep disturbances. The minimum value of the total score is 0 and the maximum is 21 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.

Secondary outcomes

• Brief Psychiatric Rating Scale [Before intervention - four weeks after finishing intervention.]: An 18-item scale assessing negative symptoms, such as emotional withdrawal (e.g. withdrawal from relations), motor slowness and blunted affect. Each item is rated from 1 to 7 with 7-point Likert scaling, where 7 means the most severe disturbance. The minimum value of the total score is 18 and the maximum is 126 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.
• Epworth Sleepiness Scale [Before intervention - four weeks after finishing intervention.]: An eight-item scale. Each item refers to a situation such as driving a car or sitting quietly. The subject is asked to assess the chance of dosing in each situation, ranging from 0 (no chance) to 3 (dosing very likely). The minimum value of the total score is 0 and the maximum is 24 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.
• Fatigue Assessment Scale [Before intervention - four weeks after finishing intervention.]: A 10-item scale to assess the severity of fatigue. Each item is an expression describing the fatigue, such as: "I am bored by fatigue" or "Mentally I feel exhausted". Each item is answered using a Likert-type scale ranging from 1 (never) to 5 (always). The minimum value of the total score is 10 and the maximum is 50 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.
• Quality of Life in Depression Scale [Before intervention - four weeks after finishing intervention.]: A 34-item, self-reported scale to assess the impact of depression on the quality of life. The scale is scored binomially with higher scores indicating a lower quality of life. The minimum value of the total score is 0 and the maximum is 34 with higher scores meaning worse outcome. Change from the baseline to the measurement done after finishing intervention, to the measurement done two weeks after finishing intervention to the measurement done four weeks after finishing intervention.
• Sleep propensity non-rapid eye movement 1 sleep stage [Through study completion, an average of 1 year]: A 23-channel electroencephalography (EEG), 2-channel electrooculogram (EOG) and a chin electromyogram (EMG) recorded through 45 minutes in lying position with eyes closed. The recordings will then be divided into 30 second epochs. Each epoch will be assigned to particular sleep stage or wake, according to standards of sleep staging issued by the American Academy of Sleep Medicine \[Silber et al. 2007\]. The difference in the latency of non-rapid eye movement 1 sleep stage (the time from light off to the first epoch of the non-rapid eye movement 1 sleep stage) before and after intervention will be assessed.
• Sleep propensity non-rapid eye movement 2 sleep stage [Through study completion, an average of 1 year]: A 23-channel electroencephalography (EEG), 2-channel electrooculogram (EOG) and a chin electromyogram (EMG) recorded through 45 minutes in lying position with eyes closed. The recordings will then be divided into 30 second epochs. Each epoch will be assigned to particular sleep stage or wake, according to standards of sleep staging issued by the American Academy of Sleep Medicine \[Silber et al. 2007\]. The difference in the latency of non-rapid eye movement 2 sleep stage (the time from light off to the first epoch of the non-rapid eye movement 2 sleep stage) before and after intervention will be assessed.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* severe or moderate depressive episode (according to international classification of diseases (ICD)-10) without psychotic symptoms at the time of inclusion
* Diagnosis of major depression (F33.1 or F33.2) or bipolar disorder (F31.3 or F31.4).
* The score of the Athens Insomnia Scale five or more
* Unchanged antidepressive pharmacotherapy at least one month prior to inclusion

Exclusion Criteria:

* Contraindications to transcranial magnetic stimulation, including ferromagnetic elements in head, pregnancy and epilepsy
* Psychotic symptoms at the time of inclusion
* Suicidal ideations and/or attempts within three months prior to inclusion

• Silber MH, Ancoli-Israel S, Bonnet MH, Chokroverty S, Grigg-Damberger MM, Hirshkowitz M, Kapen S, Keenan SA, Kryger MH, Penzel T, Pressman MR, Iber C. The visual scoring of sleep in adults. J Clin Sleep Med. 2007 Mar 15;3(2):121-31. PMID 17557422

• Bogdan Stefanowski, MD, Principal investigator, Institute of Psychiatry and Neurology