Major depressive disorder (MDD) is a chronic and debilitating form of mental illness that is characterised by behavioural, affective, cognitive and somatic symptoms.
Research shows that the functional neuroanatomy of depression implicates the ventromedial and dorsolateral divisions of the prefrontal cortex (PFC) amongst other deeper brain regions. 
Several lines of compelling evidence implicate these brain regions including data from imaging studies that show connections to the ventromedial PFC (VMPFC) from the hypothalamus and the ventral striatum. These connections mediate activity associated with emotions, and motivation and reward, respectively. The VMPFC also receives projections from the amygdala, which is associated with threat detection and fear conditioning.
On the other hand, dysfunction in the dorsolateral PFC (DLPFC) is also related to depression. This area receives sensory projections from the eyes as well as also being involved in cognitive or executive functioning associated with working memory, goal-orientated actions and abstract reasoning. Together, dysfunction in the VMPFC and DLPFC play important neurocognitive and neurobehavioural roles in depression. (Read more about the differences between bipolar and unipolar depression)
Antidepressants are considered first line for the treatment of depression, however, even with modern generation agents a substantial proportion of patients fail to respond to first line and subsequent trials of therapy: it is usually estimated that ~ 10-20% of patients have minimal response to multiple medication trials. In the STAR*D trial which was the largest and longest depression treatment trial, there were 4 levels of study that tested a different medication or medication combination. The study found that while about 50% became symptom-free after 2 levels; after 4 levels 30% of patients did not reach remission. 
The consensus for defining treatment-resistant depression (TRD) is non-response to at least two different antidepressants from different classes.
Transcranial magnetic stimulation (TMS) has emerged as a novel neuromodulation technique in the management of depression. In this article, we review the evidence for TMS in depression.
Transcranial magnetic stimulation (TMS)
TMS involves placing a small coil near the scalp that when engaged generates a magnetic field that induces an electrical field in the brain’s outer cortex in regions that are close to the coil.
Over the last 20 years, a method called repetitive TMS (rTMS) has become widely used in clinical practice which occurs in a rhythmic and repetitive form. 
rTMS therapy is focused and so can be used to target discrete locations, such as the DLPFC, where it is typically used to deliver magnetic pulses at either a ‘high’ frequency of 10-20 Hertz or a ‘low’ frequency of ≤1 Hertz.
Low-frequency rTMS reduces neuronal excitability, whereas high-frequency rTMS increases cortical excitability.
The most common area targeted in depression is the DLPFC.
rTMS treatment results in increased neuronal activity in the (dorsolateral) prefrontal cortex, which through cortico-subcortical trans-synaptic connections (presumably through frontocingulate networks) suppresses hypothalamic and/or indirectly amygdala overactivity, resulting in CRH decreases and ultimately in decreased salivary cortisol concentrations. In line with successful pharmacological interventions, successful rTMS treatment results in normalization of the negative feedback system. (Baeken and Raedt)
There is also evidence for neurotransmitter changes after TMS treatment. 
Stimulation of the DLPFC has been shown to increase dopamine levels in the striatum.
There is also evidence that TMS over the left DLPFC modulates the GABA and glutamate systems which is correlated with response to treatment for depression.
Efficacy of Tms for Depression
A large number (>40) independently conducted sham-controlled trials have evaluated the efficacy of TMS treatment of TRD. These studies have been summarised in multiple meta-analyses that have consistently supported the antidepressant efficacy of repetitive TMS (rTMS).
rTMS has also been evaluated in a number of larger multi-site trials. Several of these will be described in the following section:
Study One – Neuronetics Trial
A multisite study across 23 sites globally (which including our site in Melbourne, Australia) was the first multi-site study to analyse the clinical outcomes of TMS-mediated excitation of the DLPFC. 
It included 301 patients with MDD who were diagnosed with a moderate level of resistance to antidepressant medication.
Patients were randomly allocated to one of two groups where they received either TMS therapy or a placebo (sham coil). Treatment was daily and lasted between four and six weeks.
TMS stimulation was set at a frequency of 10-Hertz, which was pulsed for four seconds and had intervals of 26 seconds between pulses. This was repeated 75 times per daily session.
Patients who responded to treatment then had their TMS treatment tapered across three weeks, which was then followed by antidepressant monotherapy and observations over 6 months.
Researchers employed MADRS analysis to score effect of treatment, and this analysis showed that after the initial TMS treatment regime there was an effect size of 0.39.
The primary outcome analysis was not significant although significant benefits were seen on multiple other outcome measures.
There was also benefit shown for those individuals who had previously failed just one depression medication regimen, and this finding led to device approval in the US in late 2007.
Study Two – NIMH Trial
A second multi-site trial (government agency funded) across four sites in the US involved 190 patients who had been diagnosed with MDD and again showed a moderate level of resistance to depression medication. 
Patients were randomised to receive either daily TMS to the left DLPFC or placebo, for between 3 and 6 weeks determined by a response. Stimulation was set at a frequency of 10-Hertz with pulses lasting four seconds and intervals of 26 seconds between pulses. This regimen was repeated 75 times per daily session.
To determine the efficacy of TMS treatment, researchers used HAMD24 scoring. Data showed that active TMS was reported to produce a clinically meaningful remission rate that was 4.2 times greater than when using the sham coil.
However, in real numbers, only 15% of patients reached remission with 4% in the placebo group also reaching a similar remission status.
Study Three – Brainsway Trial
This more recent study was across 20 sites globally and included 181 patients with MDD who had previously failed to respond to at most four different antidepressant treatment trials. 
Patients were randomly grouped to receive TMS to the left DLPFC or placebo for 5 sessions per week for 4 weeks.
This study used a proprietary ‘deep’ TMS coil that penetrates more deeply but also produces wider cortical stimulation
Stimulation was set at a frequency of 18-Hertz with a pulse duration of two seconds and intervals of 20 seconds between pulses.
This was repeated 55 times per daily session. After four weeks, patients were given a maintenance phase of twice-weekly TMS therapy sessions for 12 weeks.
After 5 weeks of treatment, the change in HAMD21 scores showed an improvement of 6.39 for TMS versus a 3.11 improvement with placebo. The response to treatment rate was a statistically significant 38.4% of patients at week-5 and 44.3% of patients at week-12.
Remission from depressive symptoms was a statistically significant 32.6% of patients at week-5. However, the remission rate at week 12 was a non-significant 31.8% when compared to placebo.
Durability of TMS in Depression
One of the major questions posed by researchers and clinicians is whether TMS treatment has long-lasting effects once the patient has been tapered off of TMS therapy and has begun more traditional antidepressant medication.
In one study, 10 out of 99 patients relapsed within a mean time of 23.5 weeks as estimated using a Kaplan-Meier analysis. 
Furthermore, 38 patients had worse symptoms although 32 of the 38 re-achieved symptoms benefits after a second round of TMS in conjunction with an adjunct antidepressant.
After 6 months, 50 out of the 99 patients maintained a remission-free status based on patient analysis with MADRS and HAMD24 questionnaires. Also, the majority of the patients who received TMS were also shown to have achieved significant improvements in quality of life.
In a follow-up study of those patients that took part in the NIMH trial, 62% of 120 patients maintained remission free status 12 months after TMS therapy. 
Overall most studies have put the durability of TMS to treat depression between 64 – 90 % over a 3 to 12 month period after TMS.
Safety of TMS for Depression
TMS is seen as being a safe procedure however the possibility of a seizure during TMS therapy is a small yet significant safety concern. In a study of 325 patients with an accumulative 10,000 treatment sessions, no seizures were observed. 
The most common adverse events with rTMS are headaches and scalp discomfort. Discontinuation rates in clinical trials are usually well below that seen with medication and are very low in our clinical programs. Switching is possible in bipolar patients.
Local and international experience has demonstrated that rTMS can safely be provided as an outpatient therapy with no restrictions required of the patient after attendance for treatment.
Clinical Practice Recommendations
rTMS is now recommended in all relevant depression treatment guidelines as an approach that should be considered in the standard care of patients with depression.
A recent publication by Perera and colleagues in 2016 outlines the recommended clinical practice essentials for TMS. 
The following pre and post-treatment guidelines briefly summarise some of the information regarding good clinical practice.
Pre-treatment involves planning a treatment regime that will provide the symptomatic relief of MDD only in patients who have failed to achieve a satisfactory improvement after receiving antidepressant medication.
Alternatively, TMS therapy can also be applied to patients who have had TMS therapy previously and have either benefitted from treatment or are currently experiencing a recurrence of depressive symptoms.
Safety considerations should include analysis of the chance of a seizure with all staff and physicians ably trained to respond to such an event.
Furthermore, training is device specific and is a compulsory requirement for all staff as well as showing a complete understanding of device-specific standard operating procedures for administering TMS therapy.
The cessation of rTMS treatment is likely to ideally involve the provision of a period of weaning off of therapy, usually with a decreasing schedule of sessions over a number of weeks.
Post-treatment planning after TMS therapy includes the requirement to evaluate how to minimise the risk of relapse in successfully treated patients.
This can include relevant antidepressant medication (and consideration of lithium) or additional TMS if depressive symptoms re-emerge. Evaluation should use relevant health questionnaires such as IDS-SRT and the BDI to determine what effect if any, TMS therapy had on depressive symptoms. Maintenance rTMS schedules do seem to have a meaningful benefit in reducing relapse.
Due to the resistant nature of depression, partial and non-responders are likely, and therefore non-responders may have treatment extended by 1-2 weeks.
An alternative approach in non-responders is to switch and conduct a trial of low-frequency stimulation applied to the right DLPFC, something that can be effective in a subgroup of patients.
Partial responders, on the other hand, may have their treatment extended beyond the initial 6 weeks if it is argued that they haven’t quite reached maximal benefit and will do so within 2 weeks.
rTMS treatment is currently being provided on both an inpatient and outpatient basis. Outpatient provision is considered safe and has the benefits of allowing slow weaning of therapy and reduced dislocation of patients from their home environment.
Updates on TMS
rTMS is an effective treatment for Major Depressive Disorder in people who have comorbid anxiety disorders. [Clarke E et al., 2019]
There is some debate as to the use of rTMS as a substitution treatment under the circumstances of ‘effective electroconvulsive therapy (ECT)’. [Malhi et al., 2019].
Two small case series [Cristancho et al., 2013] , [Noda et al., 2013] have found that rTMS may be successfully substituted (such that it maintains or improves clinical status) for maintenance ECT terminated due to tolerability issues.
Benzodiazepines are known to reduce response to rTMS while psychostimulants may enhance respinse. [Hunter et al., 2019]. The case to reduce benzodiazepines before rTMS is not clear. [Pridmore S, 2019]
In another small study, long-standing treatment resistant depression patients underwent 3 sessions per week deep (d) TMS added to a previously failed SSRI. 35.3% of patients remitted after 4 weeks with just 12 dTMS sessions and no drop outs. The only side effect was headache. [Tendler A et al., 2018]
TMS is a safe and effective computerised medical device that delivers non-invasive and focal magnetic stimulation to the DLPFC over a brief duration of time.
The pulsing magnetic fields induce electrical currents in these brain regions and over the course of 4 to 6 weeks can significantly increase a patient’s chances of achieving remission from depression.