الفهرس 
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Abstract
Repetitive transcranial magnetic stimulation rTMS is a non-invasive focal cortical stimulation technique involving modulating the cortical excitability. It uses powerful, focused magnetic field pulses to induce electrical currents in target brain areas. First discovered by Michael Faraday in 1881.
Major depressive disorder (MDD) is one of the most common medical disorders worldwide, its pathology involve significant dysfunction within distributed fronto-limbic networks.
Treatment resistant depression (TRD) represents one of the most important clinical challenges. Many studies revealed that the personal and societal burdens of depression are disproportionately greater among patients who do not respond to antidepressant therapies.
Currently, 60–70% of MDD patients will ultimately respond to trials of standard medications and psychotherapy treatments, therefore, there are about 30% of MDD patients not responding to the available antidepressant treatments. The TRD patients commonly have a significant decline in their daily functioning associated with an increased risk of functional impairment and mortality.
No single uniform definition for treatment resistance in the pharmacotherapy of unipolar depression .That term is mostly used in case of insufficient improvement of depressive symptoms after receiving antidepressant drugs in advised dose and duration.
Historically, the degree of resistance was defined according to the number of treatment failures with antidepressants from different classes assuming a hierarchy of efficacy of the various classes of antidepressants. In the current study participants failed to respond to at least two trials of antidepressants with therapeutic dose and adequate duration.
The Food and Drug Administration (FDA) has approved rTMS for the treatment of both MDD and TRD in adolescent and adult populations since 2008.
It is commonly accepted that a patient had non response when the improvement is less than 25% in a rating psychometric scale, such as Hamilton Depression Rating Scale (HDRS), a partial response to treatment would be a 25-49% improvement on rating scores, response corresponds to an improvement of at least 50% on depression scores, whereas remission is a state in which only minimal symptoms are present as manifested by HDRS ≤7.
rTMS modulate cortical excitability beyond the stimulation train, implicating some form of neural plasticity. rTMS, via repeated activation of the target region, may change the spontaneous neural activity in proximal and distal brain regions, subsequently altering their functional connectivity. This is observed at the network level, with emerging evidence suggesting a causal role for rTMS in regulating both within and between network connectivity.
The primary brain region targeted with rTMS for depression has been the DLPFC, which has demonstrated direct anatomical connectivity to several fronto-limbic regions related to depressive symptomatology, via white matter pathways with depression-associated microstructural abnormalities. The DLPFC is therefore in a prime position to directly modulate the activity in these distal brain regions and to affect changes in the pathways connecting them.
The current study is an interventional prospective comparative study, the clinical sample of this study consists of a statistically significant number of patients (60) fulfilling the diagnosis of Major depressive disorder using the DSM- IV criteria currently in relapse (30 in the intervention group A and 30 in the control group B). The sample was collected from December 2015 till September 2017 .The participants were divided into two groups;
group A: the active intervention group (a group of 30 patients who received a course of rTMS sessions ranging from 10 to 30 sessions as add on therapy to their medications and /or psychotherapy).
group B: the control group (a group of 30patients who continued only on their previous medications and /or psychotherapy).
DROP outs: Three patients started in the intervention arm yet they did not reach to the tenth session.
All subjects involved in the study were subjected to:
1-Structured clinical interview for DSM-IV Axis I Disorder (SCID-I)
2-Hamilton rating scale for depression
3-The Wechsler Memory Scale fourth edition
The intervention in the current study was in the form of standard repetitive transcranial magnetic stimulation (rTMS) sessions that were delivered using figure of eight coil .The 30 patients included received at least 10 sessions with a maximum of 30 sessions in the frequency of five sessions per week on the left DLPFC. The first treatment session included initial motor threshold determination by increasing the output of the stimulator by 5% until a visible twitch in the right first dorsal interosseous (FDI). The intensity of the magnetic stimulus was set at 90% of the resting motor threshold. The magnetic stimulation coil was positioned on the scalp 5 cm anterior to the optimal site to elicit a motor twitch in FDI muscle (by visual inspection) in the parasagittal plane.
The used protocol lasts 37 minutes, the frequency is 10 Hz, has a total of 75 pulse trains with 40 pulse per train (total 3000 pulse per session) and is run at 26 sec intertrain interval. using butterfly coil MCF –B65 of MagVenture device .
Assessment was done at baseline , at the fourth week(after 20 sessions ), at sixth week (after 30 sessions ) of treatment sessions and 1month after completion of the sessions (follow up) by the same assessment tools mentioned above.
The main findings of this study were:
Regarding the clinical characteristics of MDD: The mean duration of illness was 9.6 (+ 4.73 SD) for group A and 10.53 (+ 5.89 SD) for group B .The mean age of onset was 31.63(+ 6.3 SD) for group A and 33.97 (+ 7.69 SD) for group B. The mean number of episodes was 3.9 for both groups A (+ 2.12 SD) & B (+1.45 SD). The mean Hamilton score at base line assessment was 22.5 (+ 3.88 SD) for group A and 21.9 (+2.8 SD) for group B. The mean for drug trials was 2.27 (+ 0.52SD)
In the current study, the clinically significant response (as defined by a reduction in the HDRS by ≥ 50 ) was achieved in 30% of the participants in participants received rTMS course as add on therapy to their medications versus none of the controls with a statistically significant difference between both groups (P value 0.0001) and a number needed to treat (NNT) was 3.3 to achieve a response . Remission (as defined by HDRS ≤ 7) was achieved in only 10% of participants received rTMS and in none of the controls with no statistically significant difference between both groups and NNT was 10 patients to reach the remission.
The improvement was significantly correlated with the increase of the numbers of rTMS sessions with a mean number of sessions in the existing study of 26.3, yet not significantly correlated with other variables including the age of the patient, the duration of the MDD, the age at onset, the number of episodes, the depression severity or the number of medications trials.
The percent of change in the WMS subsets between the study participants was statistically significant for digit span backward (P value 0.011) and associative learning (P value 0.001) subsets of the Wechsler memory scale and non statistically significant for other subsets of the WMS.
rTMS is accepted and well tolerated by participants in the existing study with no serious side effects reported. Only 16.7 % complained of headache and 16.7% complained of scalp discomfort yet no seizures or serious side effects induced by rTMS were reported in the current study.
Finally, rTMS could be considered as a line of management in TRD patients as an add on therapeutic modality with other lines of management including antidepressant medications or psychotherapy, without serious side effects. It needs more attention in research and clinical practice.