1. Introduction 
Major depressive disorder (MDD) is a recurrent disabling disorder that is the most prevalent psychiatric disorder (12.7%) according to the Iranian mental health survey in 2011 (Sharifi et al., 2015). Given the risk of functional impairment, relational problems, and increased suicide risk associated with MDD (Rush et al., 2006) along with its recurrence and chronicity, the disease imposes a great burden on society (Rush, 2007). Meanwhile, a significant proportion of patients with MDD fail to respond to psychotropic medications (Rush et al., 2006). Data on the prevalence of treatment-resistant depression is limited; however, it is estimated that approximately one-third of patients with depression do not respond to standard treatment (Rush, 2007), and about one-fifth of them become refractory to treatment (Little, 2009).
Although pharmacological therapies in MDD have been improved in recent years, the management of treatment-resistant depression (TRD) has remained a challenge, and brain stimulation methods have emerged as potential alternatives (Little, 2009; Daly et al., 2010). Transcranial magnetic stimulation (TMS) is a non-invasive method initially introduced in 1985 to study neural networks (Barker et al., 1985). Repetitive transcranial magnetic stimulation (rTMS) has been particularly effective for TRD in recent years (Janicak et al., 2002; Ren et al., 2014; Mutz et al., 2018; Sehatzadeh et al., 2019) and was approved by the US Food and Drug Administration (FDA) as a therapy for TRD in 2008.
TMS uses electromagnetic fields to induce electrical currents in special areas of the brain, leading to excitation or inhibition of neural activity. In rTMS, repeated trains of pulses are generated and applied to the brain, resulting in prolonged alteration of cortical excitability. Dysfunction in the dorsolateral prefrontal cortex (DLPFC) is well-established in MDD, and rTMS is believed to show antidepressant effects by targeting these regions (Cao et al., 2018; Du et al., 2018). Normalization of DLPFC function is reported in patients with MDD after rTMS treatment (Cao et al., 2018; Du et al., 2018). 
The FDA protocol (2008) often takes 4 weeks to finish. TMS is an acceptable treatment for patients with MDD (McClintock et al., 2017; Horvath et al., 2010). However, given the cost and heavy traffic leading to major difficulties getting around in major metropolitan cities, it is anticipated that a proportion of cases will drop out prematurely. It is also thought that due to the cost and the number of sessions required for the treatment, dropouts may happen soon after improvement.
This study was conducted to evaluate the effect of left prefrontal rTMS on 22 patients with TRD using the FDA protocol (2008) (Horovath et al., 2008).

2. Materials and Methods 
Subjects
As seen in Table 1 a total of 24 depressed adults (female: 15) were initially included in the study. All subjects were referred by psychiatrists (except for two cases which were referrals from neurologists). The diagnosis of MDD was reconfirmed by the structured diagnostic interview for DSM-IV (SCID) done by our team’s psychiatrist, which resulted in the exclusion of 2 additional cases because they did not meet the required criteria for the trial. All participants, 18 years or older, had to have a history of at least one single failed treatment with an antidepressant. Clinical participants were excluded if they had a history of seizure or neurological disorders or taking medications known to lower seizure threshold (e.g. theophylline). Pregnancy and having ferromagnetic material in the body was also exclusionary. 

Procedures
All the procedures were performed by a cognitive psychologist trained and certified to work with the TMS instruments. All sessions were closely supervised by the psychiatrist and the study of the principal investigator (PI) throughout the sessions. A prospective, duration-adaptive design was implemented with three weeks of daily weekday treatments (fixed-dose phase), followed by continued treatment for up to another six weeks if needed. rTMS pulses were delivered to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second inter-train intervals) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. The patients continued their medications while receiving their rTMS treatment.

Outcome measures
All subjects were assessed initially and at two-week intervals using a battery of tests used by the National Network of Depression Centers (NNDC), including quick inventory of depressive symptomatology (QIDS_SR16), a 16-item questionnaire validated by rush et al. for scaling symptom severity of depression (Rush et al., 2003); patient health questionnaire (PHQ-9) which scores all nine criteria of DSM-IV from 0 to 3 to scale the severity of depression and treatment response (Kroenke et al., 2001), generalized anxiety disorder scale (GAD_7) assessing the degree of anxiety in the previous two weeks by asking 7 questions and scoring the answers from zero to two (Spitzer et al., 2006), work and social adjustment scale (WSAS) as a validated 5-item questionnaire measuring the impairment of daily functions resulted from a disorder (Mundt et al., 2002), global assessment of functioning (GAF) scale (DSM-IVTR) which is a 10-section questionnaire scoring patients in the range 0 to 100 and afterward assessing their ability of daily functioning (Hall, 1995). PHQ-9 (Ardestani et al., 2019), QIDS_SR16 (Hedayati et al., 2009), and GAD_7 (Omani-Samani et al., 2018) have been reported to have good reliability and validity.

Statistical analysis
Statistical analyses were conducted using IBM SPSS software, version 22. The significance level was determined as P<0.05. Since the distribution of variables showed abnormality in the one-sample Kolmogorov-Smirnov test, the non-parametric Wilcoxon signed ranks test was performed to compare data before and after the intervention. 

3. Results
Twenty-two patients were enrolled in the study; five patients dropped out before completing the first two weeks. Seventeen patients completed the two weeks and were assessed 2 weeks after a baseline of which only 6 patients completed the whole four weeks and the other 11 dropped out before the second assessment (Figure 1). 

As seen in Table 2, the baseline scores for QIDS, PHQ, GAD, and work and social adjustment scale (WSAS) were lower and GAF was higher in patients who dropped out in the first 2 weeks compared to those who stayed on treatment. However, the difference was not significant statistically and thus not considered a true finding.

A significant improvement in all the measures was observed in patients after 2 weeks (Table 3). 

For the next step, we separated the patients who dropped out after two weeks and patients who completed 4 weeks of treatment and repeated the analyses. Patients who dropped out after 2 weeks showed significant improvement in all measures (Table 4) while no such improvements were seen after the same 2 weeks in patients who continued treatment for 4 weeks. 

4. Discussion 
We found a significant improvement in depression symptoms after the rTMS course compared to the baseline. Similarly, anxiety symptoms were significantly decreased following the rTMS session. Also, we found improvement in functions as GAF and WSAS scores increased after two weeks. A high rate of comorbidity is observed between depression and anxiety disorders (Kessler et al., 2015). Unlike the well-established effect of the rTMS in depression, the data on the effects of the rTMS in anxiety disorders are not convincing. Most research on the efficacy of rTMS in the treatment of anxiety disorders is focused on post-traumatic stress disorder and obsessive-compulsive disorder, and the data on GAD are sparse (Bystritsky et al., 2008) . Dieffenbach et al reported an improvement in both anxiety and depressive symptoms in 32 patients with TRD after rTMS; anxiety symptoms had no attenuating effect on treatment response (Diefenbach et al., 2013). To evaluate the effect of rTMS on psychosocial outcomes, we utilized GAF and WSAS scales. Our findings reveal that rTMS has the potential to significantly improve psychosocial outcomes. A significant increase was observed in the GAF scale after rTMS sessions. Similarly, Anderson and colleagues reported an improvement in GAF scores in depressed patients after left DLPFC compared to a sham group (Anderson et al., 2007). The efficacy of rTMS in depression has been widely shown. According to a recent meta-analysis in 2018, rTMS on DLPFC results in a response rate of 3.75 times greater than sham (Mutz et al., 2018) . In 2013, a meta-analysis by Berlim et al reported rTMS to have clinically relevant antidepressant effects. It was also demonstrated that rTMS can be equally effective as both augmentation and monotherapy (Berlim et al., 2014). As seen in Figure 2, the patients who discontinued treatment after 2 weeks seemed to have significant improvement in their symptoms while patients who continued the sessions for at least 4 weeks did not have as much improvements in their anxiety and depressive symptoms.

We speculate those who discontinued after two weeks simply felt that they need no further treatment sessions because they already felt better. This is perhaps understandable because some patients were from low-income households and had to spend 4 hours per day for travel back and forth for each treatment session. In our study, we cannot identify markers that predict who will continue treatment beyond two weeks.
The observation of improved symptoms in our sample by the end of week two is consistent with studies that increased inferior frontal lobe activity in depressed adults who responded to TMS, compared to non-responders, is measurable after two weeks of treatment (Teneback et al., 1999). Recently, Fitzgerald B. et al published a new accelerated protocol performed in 6 days (three sessions per day) (Fitzgerald et al., 2018). This looks quite promising and will help better compliance in major metropolitan cities and especially in countries like Iran. Our results are consistent with the literature on compliance in clinical practice that emphasizes the importance of “hard” factors in considering compliance with particular clinical interventions (Jin et al., 2008). Of those factors, time commitment, therapy cost and income, and duration of the treatment period are critical. Other factors exist, such as patient’s health literacy, healthcare system, and lack of social support whose impacts on non-compliance with our study intervention cannot be disputed. Our study highlights the practical implications of using rTMS in a society, such as Iran while its efficacy has been replicated in many studies; however, our study shows that compliance with its protocol is not similar across the globe and is considerably affected by factors, such as time commitment, costs and income. This further emphasizes our need for accelerated protocols to improve our patients’ compliance.

5. Conclusion
We have replicated other studies showing that treatment of major depressive disorder using rTMS is very effective with no major side effects. However, our data highlight the importance of the application of more convenient protocols that require fewer sessions on fewer days to help with compliance and outcome particularly, in developing countries, such as Iran.

Limitations 
Some limitations should be considered for our study. The major limitation of the study was the lack of a sham group which made us unable to control for placebo effects. Additionally, patients recruited in the study were taking different medications, which could potentially influence response patterns to rTMS. Finally, similar to many other studies, it was unable to conclude about the durability of improved symptoms over time. Further studies addressing these limitations may deepen our understanding of the rTMS efficacy in TRD. 

Ethical Considerations
Compliance with ethical guidelines
This study complies with the principles of the declaration of Helsinki. The study protocol was approved by the local Ethics Committee of the Tehran University of Medical Sciences (Code: NCT01469325). Written informed consent was obtained from all patients. 

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
Conceptualization and supervision: Javad Alaghband rad; Investigation: All authors; Data collection: Parvaneh Farhadbeigi and Zahra Khazaei Pour; Data analysis: Mahtab Motamed, Parvaneh Farhad beigi and Zahra Khazaeipour; Writing the original manuscript: Mahtab Motamed and Zahra Khazaeipour; Methodology, Writing-review & editing: Javad Alaghband rad and Mahtab Motamed. 

Conflict of interest
The authors declared no conflict of interest. 

Acknowledgments
The authors thank those colleagues and staff at the Department of Psychiatry, Tehran University of Medical Sciences and Rad Clinic who helped with referring patients and providing administrative support.


References
Anderson, I. M., Delvai, N. A., Ashim, B., Ashim, S., Lewin, C., & Singh, V., et al. (2007). Adjunctive fast repetitive transcranial magnetic stimulation in depression. The British Journal of Psychiatry, 190, 533–534. [DOI:10.1192/bjp.bp.106.028019] [PMID]
Ardestani, M. S., Ashtiani, R. D., Rezaei, Z., Vasegh, S., & Gudarzi, S. S. (2019). Validation of Persian version of PHQ-9 for diagnosis of major depressive episode in psychiatric wards in IRAN. International Journal of Applied Behavioral Sciences, 5(2), 1-8. [Link]
Barker, A. T., Jalinous, R., & Freeston, I. L. (1985). Non-invasive magnetic stimulation of human motor cortex. Lancet, 1(8437), 1106–1107. [DOI:10.1016/S0140-6736(85)92413-4] [PMID]
Berlim, M. T., van den Eynde, F., Tovar-Perdomo, S., & Daskalakis, Z. J. (2014). Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychological Medicine, 44(2), 225–239. [DOI:10.1017/S0033291713000512] [PMID]
Bystritsky, A., Kaplan, J. T., Feusner, J. D., Kerwin, L. E., Wadekar, M., & Burock, M., et al. (2008). A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder. The Journal of Clinical Psychiatry, 69(7), 1092–1098. [DOI:10.4088/JCP.v69n0708] [PMID]
Cao, X., Deng, C., Su, X., & Guo, Y. (2018). Response and remission rates following high-frequency vs. Low-frequency repetitive transcranial magnetic stimulation (rTMS) over right DLPFC for treating major depressive disorder (MDD): A meta-analysis of randomized, double-blind trials. Frontiers in Psychiatry, 9, 413. [DOI:10.3389/fpsyt.2018.00413] [PMID]
Daly, E. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Gaynes, B. N., & Warden, D., et al. (2010). Health-related quality of life in depression: A STAR* D report. Annals of Clinical Psychiatry, 22(1), 43-55. [Link]
Diefenbach, G. J., Bragdon, L., & Goethe, J. W. (2013). Treating anxious depression using repetitive transcranial magnetic stimulation. Journal of Affective Disorders, 151(1), 365–368.[DOI:10.1016/j.jad.2013.05.094] [PMID]
Du, L., Liu, H., Du, W., Chao, F., Zhang, L., & Wang, K., et al. (2018). Stimulated left DLPFC-nucleus accumbens functional connectivity predicts the anti-depression and anti-anxiety effects of rTMS for depression. Translational Psychiatry, 7(11), 3. [DOI:10.1038/s41398-017-0005-6] [PMID]
Fitzgerald, P. B., Hoy, K. E., Elliot, D., Susan McQueen, R. N., Wambeek, L. E., & Daskalakis, Z. J. (2018). Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology, 43(7), 1565–1572. [DOI:10.1038/s41386-018-0009-9] [PMID]
Hall, R. C. (1995). Global assessment of functioning. A modified scale. Psychosomatics, 36(3), 267–275. [DOI:10.1016/S0033-3182(95)71666-8] [PMID]
Hedayati, S. S., Minhajuddin, A. T., Toto, R. D., Morris, D. W., & Rush, A. J. (2009). Validation of depression screening scales in patients with CKD. American Journal of Kidney Diseases, 54(3), 433–439. [DOI:10.1053/j.ajkd.2009.03.016] [PMID] [PMCID]
Horvath, J. C., Mathews, J., Demitrack, M. A., & Pascual-Leone, A. (2010). The neurostar TMS device: Conducting the FDA approved protocol for treatment of depression. Journal of Visualized Experiments, 45, e2345. [DOI:10.3791/2345]
Janicak, P. G., Dowd, S. M., Martis, B., Alam, D., Beedle, D., & Krasuski, J., et al. (2002). Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: Preliminary results of a randomized trial. Biological Psychiatry, 51(8), 659–667. [DOI:10.1016/S0006-3223(01)01354-3] [PMID]
Jin, J., Sklar, G. E., Min Sen Oh, V., & Chuen Li, S. (2008). Factors affecting therapeutic compliance: A review from the patient's perspective. Therapeutics and Clinical Risk Management, 4(1), 269–286. [DOI:10.2147/TCRM.S1458] [PMID] [PMCID]
Kessler, R. C., Sampson, N. A., Berglund, P., Gruber, M. J., Al-Hamzawi, A., & Andrade, L., et al. (2015). Anxious and non-anxious major depressive disorder in the World Health Organization World mental health surveys. Epidemiology and Psychiatric Sciences, 24(3), 210–226. [DOI:10.1017/S2045796015000189] [PMID] [PMCID]
Kroenke, K., Spitzer, R. L., & Williams, J. B. (2001). The PHQ-9: Validity of a brief depression severity measure. Journal of General Internal Medicine, 16(9), 606–613. [DOI:10.1046/j.1525-1497.2001.016009606.x] [PMID] [PMCID]
Little, A. (2009). Treatment-resistant depression. American Family Physician, 80(2), 167-172. [Link]
McClintock, S. M., Reti, I. M., Carpenter, L. L., McDonald, W. M., Dubin, M., & Taylor, S. F., et al. (2018). Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in The Treatment Of Depression. The Journal of Clinical Psychiatry, 79(1), 16cs10905. [DOI:10.4088/JCP.16cs10905] [PMID] [PMCID]
Mundt, J. C., Marks, I. M., Shear, M. K., & Greist, J. H. (2002). The work and social adjustment scale: a simple measure of impairment in functioning. The British Journal of Psychiatry, 180, 461–464. [DOI:10.1192/bjp.180.5.461] [PMID]
Mutz, J., Edgcumbe, D. R., Brunoni, A. R., & Fu, C. H. Y. (2018). Efficacy and acceptability of non-invasive brain stimulation for the treatment of adult unipolar and bipolar depression: A systematic review and meta-analysis of randomised sham-controlled trials. Neuroscience and Biobehavioral Reviews, 92, 291–303. [DOI:10.1016/j.neubiorev.2018.05.015] [PMID]
Omani-Samani, R., Maroufizadeh, S., Ghaheri, A., & Navid, B. (2018). Generalized anxiety disorder-7 (GAD-7) in people with infertility: A reliability and validity study. Middle East Fertility Society Journal, 23(4), 446-449. [DOI:10.1016/j.mefs.2018.01.013]
Ren, J., Li, H., Palaniyappan, L., Liu, H., Wang, J., Li, C., & Rossini, P. M. (2014). Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 51, 181–189.[DOI:10.1016/j.pnpbp.2014.02.004] [PMID]
Rush, A. J. (2007). Limitations in efficacy of antidepressant monotherapy. Journal of Clinical Psychiatry, 68(B), 8-10. [Link]
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., & Klein, D. N., et al. (2003). The 16-item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric evaluation in patients with chronic major depression. Biological Psychiatry, 54(5), 573–583. [DOI:10.1016/S0006-3223(02)01866-8] [PMID]
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., & Warden, D., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. The American Journal of Psychiatry, 163(11), 1905–1917. [DOI:10.1176/ajp.2006.163.11.1905] [PMID]
Sehatzadeh, S., Daskalakis, Z. J., Yap, B., Tu, H. A., Palimaka, S., & Bowen, J. M., et al. (2019). Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression: A meta-analysis of randomized controlled trials over 2 decades. Journal of Psychiatry & Neuroscienc, 44(3), 151–163. [DOI:10.1503/jpn.180056] [PMID]
Sharifi, V., Amin-Esmaeili, M., Hajebi, A., Motevalian, A., Radgoodarzi, R., & Hefazi, M., et al. (2015). Twelve-month prevalence and correlates of psychiatric disorders in Iran: The Iranian mental health survey, 2011. Archives of Iranian Medicine, 18(2), 76-84. [PMID]
Spitzer, R. L., Kroenke, K., Williams, J. B., & Löwe, B. (2006). A brief measure for assessing generalized anxiety disorder: The GAD-7. Archives of Internal Medicine, 166(10), 1092–1097.[DOI:10.1001/archinte.166.10.1092] [PMID]
Teneback, C. C., Nahas, Z., Speer, A. M., Molloy, M., Stallings, L. E., & Spicer, K. M., et al. (1999). Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. The Journal of Neuropsychiatry and Clinical Neurosciences, 11(4), 426-435. [Link]