Abhijit Ramanujam, M.D. a psychiatrist and Regional Medical Director at Mindpath Health, formerly Community Psychiatry, provides a clinical review of an effective approach for treatment-resistant depression.

Repetitive transcranial magnetic stimulation (TMS) is a useful clinical tool that is effective in patients with treatment-resistant depression. This non-invasive treatment is an option for patients with depression who have not found relief from other treatments, such as psychotherapy and antidepressants.

TMS technology was developed in 1985 and has been gaining clinical interest since then. Two-thirds of TMS patients experienced either full remission of their depression symptoms or noticeable improvements.1 An out-patient procedure, TMS does not have serious side effects.

Mechanism of Action

Approved by the US Food and Drug Administration in 2008, TMS uses an alternating current passed through a metal coil placed against the scalp to generate rapidly alternating magnetic fields. These pass through the skull nearly unimpeded and induce electric currents that depolarize neurons in a focal area of the surface cortex.

The magnetic field generated by TMS is comparable to that of a standard magnetic resonance imaging device (MRI), measured at approximately 1.5 to 3 Teslas. However, the TMS field is focal (beneath the coil), whereas the MRI field is large and fills the room housing the MRI device.

One hypothesis on how TMS works is that the stimulation of discrete cortical regions alters pathologic activity within a network of gray matter brain regions, specifically those involved in mood regulation and connected to the targeted cortical sites.2 Functional imaging studies support this hypothesis by showing TMS can change activity in brain regions remote from the site of stimulation.3,4

TMS has many molecular effects comparable to electroconvulsive therapy (ECT), including increased monoamine turnover and normalization of the hypothalamic-pituitary axis.5 Additionally, in one neuroimaging study of depressed patients, a prefrontal serotonin deficiency at baseline normalized after treatment with TMS.

High-frequency stimulation is thought to excite the targeted neurons and is typically used to activate the left prefrontal cortex. Low-frequency stimulation appears to inhibit cortical activity and is usually directed at the right prefrontal cortex.

Consistent with this hypothesis, a review examined 66 studies in depressed patients who were treated with TMS targeting the dorsolateral prefrontal cortex. It found that high-frequency TMS generally increased regional cerebral blood flow, whereas low-frequency TMS generally decreased regional cerebral blood flow, which is reduced in a depressed brain.6


TMS is indicated for patients with unipolar major depression who have failed at least 1 antidepressant medication. In addition, TMS is indicated for patients who responded to a prior course of TMS.7

Use of TMS for treatment-resistant or refractory depression is consistent with treatment guidelines from the American Psychiatric Association, Canadian Network for Mood and Anxiety Treatments, and the Royal Australian and New Zealand College of Psychiatrists.

Patient Assessment

When conducting a patient assessment for TMS, the purpose of the evaluation is to confirm the primary diagnosis of treatment-resistant depression and determine whether the TMS intervention can be used safely. The assessment includes examinations of psychiatric history, general medical history, physical health, and mental status with emphasis upon depressive symptoms. This should emphasize risk factors for seizures and preexisting neurologic disease, such as epilepsy, intracranial masses, and vascular abnormalities.


TMS is contraindicated in patients with: increased risks for seizures, implanted metallic hardware (aneurysm clips, bullet fragments, etc), cochlear implants, implanted electrical devices (pacemakers, intracardiac lines, medication pumps, etc), and unstable general medical disorders. See the Sidebar for a 12-item questionnaire for TMS candidates.

Screening Questionnaire for TMS Candidates

  1. Do you have epilepsy or have you ever had a convulsion or seizure?
  2. Have you ever had a fainting spell or syncope?
  3. Have you ever had a head trauma that was diagnosed as a concussion or was associated with loss of consciousness?
  4. Do you have any hearing problems or ringing in your ears? Small eustachian tubes, some ringing?
  5. Do you have cochlear implants?
  6. Are you pregnant or is there any chance that you might be?
  7. Do you have metal in the brain, skull, or elsewhere in your body (for example, splinters, fragments, clips, etc)? If so, specify the type of metal.
  8. Do you have a cardiac pacemaker or intracardiac lines?
  9. Do you have a medication infusion device?
  10. Are you taking any medications? Please list them.
  11. Did you ever undergo TMS in the past? If so, were there any problems?
  12. Did you ever undergo an MRI in the past? If so, were there any problems?24


Multiple reviews have found consistent evidence that TMS provides a clinically relevant benefit to patients with treatment-resistant depression. In patients with acute major depression who have not responded to at least 1 antidepressant medication, numerous meta-analyses of randomized trials have found that TMS is superior to placebo treatment.8-11 It is not known if maintenance treatment with TMS for unipolar major depression is beneficial.

A meta-analysis of 34 randomized trials compared TMS with placebo treatment in 1383 patients with treatment-resistant major depression. It found that improvement was greater with active treatment.12 Add-on treatment with TMS was efficacious in patients who had not responded to an adequate antidepressant therapy. Response (for example, the reduction of baseline symptoms ≥ 50%) occurred in more patients who received active (47%) versus placebo (22%) TMS.12

TMS is less effective than ECT; however, TMS does not require general anesthesia, and it can be done in an outpatient setting. Unlike with ECT, patients with major depression do not experience impaired cognition with TMS.

Predictors of Response

No consistent predictors have been identified in meta-analyses. A 1-year, prospective observational study of 120 patients who responded or remitted with acute TMS found that the durability of response to TMS was not associated with age, sex, severity of depressive symptoms prior to TMS, nor the number of failed antidepressant trials prior to TMS.13

For treatment of major depression, TMS is less efficacious than ECT. Follow-up studies of patients with major depression who were treated acutely with TMS in randomized trials indicate that the short-term benefits of TMS are stable.14 With regard to longer-term benefits of TMS, prospective, observational studies lasting at least 6 months suggest that in patients with major depression who improve with acute TMS, relapse occurs in about 35%.15

For patients with unipolar major depression who improve with a course of TMS and subsequently deteriorate or relapse, reintroduction of TMS using the same stimulation parameters may be helpful.16 It is not known if maintenance treatment with TMS for unipolar major depression is beneficial, as few randomized trials using standard protocols have been conducted. However, in several small, observational studies of patients, the results suggest that maintenance TMS may, perhaps, be beneficial.7

Safety and Adverse Effects

TMS is generally safe and well-tolerated. As an example, a randomized trial of 301 patients found that study discontinuation due to adverse effects was comparable for active and placebo TMS (5% and 3%, respectively).17

The most serious adverse effect of TMS is a generalized tonic-clonic seizure. However, the risk of seizure appears to be comparable to that for antidepressant medications. Seizures probably occur in less than 0.1 to 0.5% of patients when safety guidelines are followed regarding patient selection and stimulation parameters. Seizures that have occurred were self-limited, required no medications, and did not recur.18 Factors that increase the risk of seizures can be found in the Table.

Factors That Increase Risk of Seizure

Patient factors, such as medications, blood alcohol concentration, schizophrenia, and a history of head injury

  • Personal and family (parent, sibling, or child) history of epilepsy
  • Preexisting neurological disorder (for example, prior head injury with loss of consciousness, prior brain surgery, or congenital brain malformation)
  • Medications that lower seizure threshold (bupropion, stimulants, tricyclic antidepressants, antipsychotics, and theophylline, etc)
  • Recent discontinuation of alcohol, benzodiazepines, or anticonvulsants
  • Sleep deprivation
  • TMS stimulation parameters
  • Higher frequency
  • Increased intensity
  • Shorter intertrain interval

Other side effects include hypomania and mania, described in randomized trials,17 as well as case reports of patients with major depression (both unipolar and bipolar) who were treated with TMS.19,20

However, the clinical significance is not known, because patients with bipolar major depression can switch to mood-elevated states in the absence of an antidepressant treatment. Treatment of unipolar major depression with TMS does not appear to increase suicidal ideation or behavior.21

Common Side Effects of TMS

Headache and scalp pain: A review of randomized trials in patients with major depression found that the incidence of headache with active treatment and placebo treatment was 28% and 16%, respectively. The incidence of scalp pain with active and placebo treatment was 39% and 15%, respectively. No migraine headaches have been reported. Headache and scalp pain may be more pronounced when higher stimulation frequencies and intensities are used. Topical lidocaine may reduce scalp pain. Reducing stimulation intensity can decrease scalp discomfort, but this can also reduce efficacy of treatment. For sensitive patients, the dose of TMS can be titrated up during the first week. Headache and scalp pain generally resolve over the first 2 weeks, although some patients may require an analgesic, such as acetaminophen or ibuprofen.22

Transient (< 4 hours) increase in auditory threshold: This is caused by repeated clicks that are produced as current passes through the stimulating magnetic coil and mechanically deforms the coil. Hearing loss is prevented with foam earplugs or noise protection ear coverings.

Vasovagal syncope: Management generally consists of reassurance.

Special Populations

Elderly: For elderly patients with major depression, TMS can be beneficial if the stimulation intensity is sufficient.17 Prefrontal atrophy in older patients can increase the distance between the coil and cortex to the point that lower-intensity stimulation, which typically penetrates to a depth of 2 to 3 cm, does not affect cortical activity. Increasing the intensity above the motor threshold can overcome the added distance.5

Poststroke depression: Depression frequently occurs after stroke, and TMS may help these patients.

Pregnancy and postpartum depression: For these patients with major depression, observational studies suggest that TMS may possibly be safe and effective. It appears unlikely that the fetus is directly affected by TMS because magnetic fields rapidly attenuate with distance.23


Concluding Thoughts

TMS is an exciting and promising therapy that can provide real and lasting relief for patients suffering from treatment-resistant depression. Conducted in an out-patient setting, TMS is a noninvasive procedure that is generally safe and well-tolerated. This provides patients with the flexibility to seek treatment in a way that does not disrupt their daily lives. TMS has an equally promising future, with studies exploring its expanded applications, as well as its use as an ongoing maintenance treatment.

Click here to see the full article with references in Psychiatric Times.

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