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Effect of bilateral Transcranial Magnetic Stimulation (TMS) treatment in patients with unipolar major refractory depression and comorbid anxiety

By: Michael Kabar MD, Javier Tovar., Henry Díaz., Ángela Véliz., Jorge Leiva., Carla Delki


Recent studies indicate that 17.2% of the population suffers from depression in Peru [1]. To investigate the effects of TMS in this population, a total of 32 adults (53,1% women and 46,9% men; with an average age of 34,47; SD= 13,09) diagnosed with refractory major depression were treated at the Neurostimulation Institute of Lima with TMS for an average of 20.47 sessions during acute treatment (SD= 1.48). All patients met the criteria for non-psychotic unipolar depression as determined by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) assessment and their current medications were maintained during the study. The average length of time depressed was 7.59 years (SD= 6.23) and the average number of prior failed antidepressant trials was 2.75 (SD= 1.27). With the exception of one patient, all exhibited a significant level of anxiety as well (HARS >7).

The equipment used for the intervention was a Neuro-MSD from Neurosoft Company (Russia) with a double-cone coil and the software used for magnetic stimulator control was All sessions were performed by a trained psychiatrist in a private office.


Protocol of Treatment

Since its inception, several TMS protocols have been developed and many cortical areas have been modulated; nevertheless, the antidepressant effects of the standard 10 Hz, FDA approved TMS protocol, would achieve remission of depression in only one third of patients [2]. Consequently, new protocols must be studied in order to achieve a better rate of efficacy. One of the most recent ones –just approved by the FDA last month- is the Theta Burst Stimulation protocol, which has shown clinical effectiveness with shorter treatment sessions. Some studies have suggested that TBS has a similar or better effect in the treatment of depression compared to 10 Hz stimulation and that right side inhibition (1 Hz) of the PFDLC has the capacity to better improve the symptoms of anxiety and, potentially, improve the antidepressant response [3].


Therefore, in order to attempt a higher rate of response and remission and to decrease the number of sessions required for clinical efficacy of TMS, the protocol developed applied sequentially and during the same session, iTBS over the Dorsolateral Prefrontal Cortex (DLPFC) in the left hemisphere (triplet bursts with a pulse frequency of 50Hz, a burst frequency of 5Hz and 85% of motor threshold for a total of 3 minutes 47 seconds) , followed by inhibition of the DLPFC in the right hemisphere (continuous pulses with a burst frequency of 1Hz and 120% MT, during 25 minutes 59 seconds and a total of 1,560 pulses).


Measurement of Depression and Anxiety

Every patient filled out a PHQ-9 (Patient Health Questionnaire) and a Hamilton Anxiety Rating Scale before and after the treatment.



The outcome measures were the Patient Health Questionnaire (PHQ-9) and the Hamilton Anxiety Rating Scale (HARS). Both scales had appropriate internal consistency, both before (αPHQ-Pre = .84, αHARS-Pre = .83) and after (αPHQ-Post = .91; αHARS-Post = .92) treatment.


The results showed a prominent improvement on all assessments after the treatment. The changes were found to be statistically significant both for PHQ-9 scores (MdnPHQ-Pre = 15.00, MdnPHQ-Post = 7.00, p = .00). as well as HARS scores (MdnHARS-Pre = 28.00, MdnHARS-Post = 14.00, p = .00), with particularly stronger results in six participants.

Depression symptom response (at least a 50% PHQ-9 score reduction) was found in 16 patients (50.00%), while remission (PHQ-9 <5) was confirmed in 9 patients (28.00%). Anxiety symptom response (at least a 50% HARS score reduction) was found in 43.75% of the subjects, while remission (HARS <8) was achieved in 21.87%. So, results support that the usage of this protocol of TMS is effective.


The effectiveness was found in the reduction of both, somatic (MdnHARS-SA-Pre = 9.00, MdnHARS-SA-Post = 3.00, p = .00) and psychological (MdnHARS-PA-Pre = 18.50, MdnHARS-PA-Post = 9.00, p = .00) symptoms of comorbid anxiety. The decreases in scores in both PQH-9 and HARS (subscales included) were statistically significant. However, it appears that this protocol of TMS can be much more effective for the improvement of somatic anxiety symptoms (53.125% patients with response of symptoms), in contrast with the impact that the treatment has in the reduction of psychological anxiety symptoms (34,375% patients with response of symptoms).



This bilateral protocol applied to the patients with refractory major depression has shown adequate results for the improvement and remission of depressive symptoms and comorbid anxiety of patients with the diagnosis of Treatment-Refractory Major Depression.


With the obtained data it is not possible to determine if this protocol is more effective than other TMS protocols; nevertheless, in comparison with similar research in terms of sample number, the rate of effectiveness in the present study is slightly superior (42% of people responded to the treatment in Durmaz et al., (2017)) [4]. Such difference is possibly a result of the stimulation parameters used in this study, however, the design of it, limits the possibility of declaring causality between the variables. Posterior work must consider the inclusion of a sham-control group and a bigger sample size.


An additional result points out that women would have a better rate of response and remission, compared with men. This result corroborates what was found by Malik et al., (2016) [5] about women's capacity to respond better and relapse less often than men. Being the first study focusing on gender as differential factor in the response to the treatment, there's still a lot of research to do about it. The explanatory factors are not determined and (as mentioned by the authors) studies with larger populations and longer follow-ups are necessary.


Moreover, an anxiety measure was taken, which responds to the fact that both anxiety and depression are highly comorbid. Considering that our sample was taking randomly in terms of ages, number of prior antidepressant medication trials and number of years the disorder affected the patients, the rate of comorbidity depression-anxiety in this research is 96.87% which is very high in comparison with previous studies that stated a ratio between 40 and 70% [6][7][8][9].



[1] Instituto Nacional de Salud Mental (2013). Estudio Epidemiológico de Salud Mental en Lima Metropolitana y Callao Replicación 2012. Anales de Salud Mental. Volumen XXVIX, Suplemento 1.

[2] Carpenter, L., Janicak, P., Aaronson, S., Boyadjis, T., Brock, D., Cook, I., & Demitrack, M. (2012). Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depression and anxiety, 29(7), 587-596.

[3] Chung, S., Hoy, K., Fitzgerald, P. (2015). Theta-burst stimulation. A new form of TMS treatment for depression? Depression and Anxiety 32:182-192

[4] Durmaz, O., Ebrinc, S., Ates, M. A., & Algul, A. (2017). Evaluation of repetitive transcranial magnetic stimulation for treatment-resistant major depression and the impact of anxiety symptoms on outcome. Psychiatry and Clinical Psychopharmacology, 27(1), 14-18.

[5] Malik, A., Haque, Z., Ide, G., & Farley, A. (2016). Gender and age as factors in response and remission of depression treated with transcranial magnetic stimulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 9(5), e7.

[6] Fava, M., Rush, A. Alpert, J., Balasubramani, G., Wisniewski, S., Carmin, C., (2008). Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. American Journal of Psychiatry; 165(3):342–351.

[7] Wu, Z., Chen, J., Yuan, C., Hong, W., Peng, D., Zhang, C (2013). Difference in remission in a Chinese population with anxious versus nonanxious treatment-resistant depression: a report of OPERATION study. Journal of Affective Disorders; 150(3):834–839.

[8] Kessler, R. Merikangas, K., Wang, P. (2007) Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annual Review of Clinical Psychology;3:137–158.

[9] Lamers, F., van Oppen, P., Comijs, H., Smit, J., Spinhoven, P., van Balkom, A.J. (2011). Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). Journal of Clinical Psychiatry;72(3):341–348.

Notas Reunion Kabar

  • No se incluyó la pregunta 2 del PHQ-9 → CORROBORADO
  • Considerar depresión con ansiedad comorbida - Teoria


Estadistica -- Nuevas Variables -- 31 de 32 pacientes tienen ansiedad comorbilidad

Solo un paciente no tiene ansiedad

¿Cómo interpretar esa data? ¿Cuál fue la mejora de los 31 pacientes con ansiedad comorbida y cuál fue la mejora del único paciente sin ansiedad?

  • Considerar números de tratamientos fallidos
  • Considerar duración promedio de la enfermedad}


Tareas importantes

  • Poster -- No tiene restricción de palabras -- Conciso de todas maneras (Versión en ingles)
  • Revista de Neuropsiquiatria - Expandirse en su máxima expresión (Sin límites) (Versión en español)
  • 4.5 powerpoint -- Viaje Holanda -- Kabar viaja 3 de diciembre


V. Ingles -- 13 de octubre
V. Español -- 13 de octubre

Nota: Hay que verificar el post- post (Solo a pacientes que han llegado a remisión o han tenido respuesta) -- Aproximadamente en un añ