Transcranial Magnetic Stimulation and Cranial Electrical Stimulation - Medical Clinical Policy Bulletins (2024)

Number:0469

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses transcranial magnetic stimulation and cranial electrical stimulation.

1. Medical Necessity

   Aetna considers transcranial magnetic stimulation (TMS)in a healthcare provider’s office medically necessary when the following criteria are met:

   • Administered by an FDAcleared device and utilized in accordance with the Food and Drug Administration (FDA) labeled indications;and
   • The member is age 18 years or older;and
   • The member has aconfirmed diagnosis by a psychiatrist ofsevere major depressive disorder (single or recurrent episode)without psychosisdocumented by standardized rating scales that reliably measure depressive symptoms (eg, Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.); severity of depression should be measured during the current depressive episode at baselinewith a validated depression rating scale, and changes from baseline with TMS treatment should be assessed using the same depression rating scale though the entire treatment course;and
   • The member has no contraindications to TMS (refer to contraindications below);and
   • The member has experienced inadequate response during the current depressive episode occurring within the past 5 years.Note: For purposes of this policy, the current depressive episode begins with the most recent onset of acute symptoms) with:
     
     • Two antidepressants from at least 2 different classes having different mechanisms of action (see Appendix) at the maximally tolerated labeled dose, each used for at least 8 weeks (to qualify as an adequate antidepressant drug trial, the individual’s dose during the failed trials should have been at or above the minimal effective therapeutic dose for that antidepressant);and
     • Augmentation therapy along with the primary antidepressant used for at least 8 weeks (see Appendix); if the augmenting agent is an antidepressant, the augmenting agent must be from a different class than the primary antidepressant. The augmenting agent should have been at or above the minimal effective therapeutic dose (which is typically the minimal labeled dose);and
       
       
   • Treatment consists of a maximum of 30 sessions (5 days a week for6 weeks) plus 6 tapering sessions (6 sessions over three weeks).Notes: Treatments beyond 36sessions(e.g., 30 treatment sessions followed by 6 tapering sessions) may be reviewed for medical necessity.There is a lack of evidence of the effectiveness of additional sessions beyond 36 to treat "late responders", to solidify response, or to attain remission.There is a lack of evidence that persons who fail to respond or become refractoryto one brand of repetitive transcranial magnetic stimulation (rTMS) device will respond to another brand of rTMS or deep TMS (dTMS)device;and
   • The TMS treatment is delivered by a device that is approved or cleared by the FDA for the treatment of major depressive disorder. Note: TMS treatment should generally follow the protocol and parameters specified in the manufacturer’s user manual, with modifications only as supported by the published scientific evidence base;and
   • The order for treatment (or retreatment) will be written by a psychiatrist (MD or DO) orbehavioral health nurse practionerwho will examine the patient and review the record and determine that TMS is indicated for use in a particular patient. In addition to patient selection, the psychiatrist should oversee initial patient motor threshold determinations, mapping and treatment parameter definitions and overall TMS treatment course planning for each patient.The psychiatrist must certify that the treatment will be given under direct supervision of this physician (i.e., the physician will be in the area and will be immediately available for each treatment).If the psychiatrist is not performing the daily TMS treatment sessions, then the psychiatrist should assign properly trained personnel who may perform the daily treatmentsessions. The psychiatrist is also responsible for theevaluation of the patient during the course of their TMS Therapy treatment;and
   • The TMS operator will be a clinical professional who is conducting TMS Therapy under the supervision of a physician,nurse practitioner or physician assistantwho is at the facility at the time of treatment. The TMSoperator should possess sufficient clinical expertise to monitor the patient during the conduct of a TMS treatment session. The operator must be able to observe the patient’s physical status for the potential occurrence of adverse events, and make routine adjustments as required and consistent with product labeling, or determine circ*mstances under which treatment interruption or treatment termination should be considered. The TMS operator should be present in the treatment room with the patient at all times. The operator must be qualified to monitor the patient for seizure activity and to provide seizure management care.

   Aetna considers TMS not medically necessary and experimental and investigational in persons withanyof the following contraindications to TMSbecause the safety and effectiveness in person with these contraindications has not been established:

   • Persons with abuse of substances with known abuse potential during the last 90 days;or
   • The memberis suicidal;or
   • The member has a metal implant in or around the head (eg, aneurysm coil or clip, metal plate, ocular implant, stent);or
   • The member has neurological conditions (eg, cerebrovascular disease, dementia, history of repetitive or severe head trauma, increased intracranial pressure or primary or secondary tumors in the central nervous system);or
   • There is presence of implanted devices, (eg, cardiac pacemaker or defibrillator, cochlear implant, deep brain stimulator, implantable infusion pump, spinal cord stimulator, vagus nerve stimulator, etc.);or
   • If the member has severe cardiovascular disease, he has been evaluated and cleared for TMS treatmentby a cardiologist.

   Aetna considers TMS re-treatment medically necessary for persons with depression relapse who meetallof the following criteria:

   • The member meets initiation criteria above;and
   • The member has relapsed following TMS despite other treatment approaches (e.g., psychotherapy, pharmacotherapy), as appropriate;and
   • The member had previously had at least a 50% reduction in depressive symptoms with TMS, as documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.), and this improvement was maintained for at least two months after the prior TMS treatment course; repeat TMS treatment within 60 days following the termination of the prior TMS course is considered not medically necessary.

   Aetna considers one TMS re-mapping during a course of TMS for depression medically necessary. Additional courses of re-mapping are considered medically necessary if the member is not responding to ensure the most accurate treatment location, or if there is concern that motor threshold may have changed (for example, because of a change in medication).Note: Re-mapping does not increase the medically necessary number of TMS sessions, as treatment is provided during remapping.

2. Experimental and Investigational

   Aetna considers the following procedures experimental and investigational because the effectiveness of these approaches has not been established:

   1. Adjunctive use of ketamine with transcranial magnetic stimulation (TMS)
   2. Combined TMS and electroencephalography (EEG) for evaluation of unconscious state (e.g., medication-induced unconscious state, minimally conscious state, and unresponsive wakefulness syndrome)
   3. Delivery of TMS using a non-standard protocol with increased hertz under sedation
   4. NavigatedTMS for motor function mapping and/or treatment planning of neurological diseases/disorders (e.g., amyotrophic lateral sclerosis, epilepsy, and resection of brain tumors)
   5. TMS maintenance therapy (i.e., treatment outside of the established 30 treatment sessions over 6 weeks plus six tapering sessions over 3 weeks)
   6. TMSfor the following conditions because its value and effectivenesshas not been established (not an all-inclusive list):
      • Alzheimer's disease
      • Amyotrophic lateral sclerosis
      • Anxiety disorders
      • Auditory verbal hallucinations
      • Bipolar disorder
      • Blepharospasm
      • Bulimia nervosa
      • Cerebellar ataxia
      • Cerebral palsy
      • Chronic pain including neuropathic pain (e.g., orofacial pain, and central post-stroke pain)
      • Communication and swallowing disorders (e.g., aphasia (including post-stroke aphasia), dysarthria, dysphagia (including post-stroke dysphagia), and linguistic deficits)
      • Complex regional pain syndrome
      • Concussion
      • Differential diagnosis of Alzheimer disease from frontotemporal dementia
      • Epilepsy (including status epilepticus)
      • Congenital hemiparesis
      • Dyslexia
      • Dystonia
      • Fibromyalgia
      • Functional neurological disorder
      • Insomnia
      • Levodopa-induced dyskinesia
      • Major depressive disorder with psychosis
      • Migraine
      • Mood disorders
      • Multiple sclerosis
      • Neurodevelopmental disorders (e.g., attention deficit/hyperactivity disorder, autism spectrum disorder, and tic disorders)
      • Neuropathic pain associated with spinal cord injury
      • Obsessive-compulsive disorder
      • Panic disorder
      • Parkinson disease
      • Peri-partum depression
      • Phantom pain associated with spinal cord injury
      • Post-traumatic stress disorder
      • Psychosis
      • Restless legs syndrome
      • Schizo-affective disorder
      • Schizophrenia
      • Smell and taste dysfunction (e.g., phantosmia and phantageusia)
      • Somatic symptom disorder (somatization disorder)
      • Spasticity
      • Stroke treatment (e.g., motor impairment, post-stroke hemiplegia, and post-stroke spasticity)
      • Substance addiction (substance use disorders)
      • Tourette syndrome (seeCPB 0480 - Tourette's Syndrome)
      • Tinnitus
      • Traumatic brain injury
      • Visual hallucinations after stroke.

   7. Cranial electrical stimulation (also known as cerebral electrotherapy, craniofacial electrostimulation, electric cerebral stimulation, electrosleep, electrotherapeutic sleep, transcerebral electrotherapy, transcranial electrotherapy, as well as the Fisher Wallace stimulator (formerly known as the Liss Body Stimulator) for any indication(not an all-inclusive list):

      See Also

      Clinical Payment and Coding PoliciesSearch Medical Policies and Clinical GuidelinesClinical Policy Bulletins – Health Care Professionals | Aetna
      • Alcoholism
      • Alzheimer's disease
      • Anxiety
      • Autism
      • Chemical dependency
      • Chronic pain
      • Dementia
      • Depression
      • Disorders of consciousness
      • Dyslexia
      • Headaches
      • Fibromyalgia
      • Insomnia
      • Mood and sleep disturbances
      • Neuropathic pain
      • Parkinson disease
      • Phantom pain associated with spinal cord injury
      • Progressive supranuclear palsy
      • Restless legs syndrome
      • Stroke treatment (e.g., motor impairment, post-stroke aphasia, and post-stroke hemiplegia)
      • Traumatic brain injury
      • Visual rehabilitation.

3. Related Policies

   • CPB 0480 - Tourette's Syndrome

Background

Transcranial magnetic stimulation (TMS) is a non-invasive method of induction of a focal current in the brain and transient modulation of the function of the targeted cerebral cortex. This procedure entails placement of an electromagnetic coil on the scalp; high-intensity electrical current is rapidly turned on and off in the coil through the discharge of capacitors. Depending on stimulation parameters (frequency, intensity, pulse duration, stimulation site), repetitive TMS (rTMS) to specific cortical regions can either increase or decrease the excitability of the affected brain structures.

Transcranial magnetic stimulation has been investigated in the treatment of various psychiatric disorders, especially depression. This procedure is usually carried out in an outpatient setting. In contrast to electroconvulsive therapy, TMS does not require anesthesia or analgesia. Furthermore, it does not affect memory and usually does not cause seizures. However, the available peer-reviewed medical literature has not established the effectiveness of rTMS in the treatment of psychiatric disorders other than major depression. In addition, more research is needed to ascertain the roles of various stimulation parameters of rTMS for its optimal outcome as well as its long-term effectiveness in the treatment of psychiatric disorders.

Depression

Martin et al (2003) conducted a systematic review of randomized controlled trials that compared rTMS with sham in patients with depression. The authors concluded that current trials are of low quality and provide insufficient evidence to support the use of rTMS in the treatment of depression. This is in accordance with the observations of Fitzgerald and colleagues (2002) who noted that TMS has a considerable role in neuropsychiatric research. It appears to have considerable potential as a therapeutic tool in depression, and perhaps a role in several other disorders, although widespread application requires larger trials and establishment of sustained response, as well as Gershon et al (2003) who stated that TMS shows promise as a novel anti-depressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success.

A health technology assessment prepared for the Ontario Ministry of Health and Long-Term Care (2004) concluded: “Due to several serious methodological limitations in the studies (Level 2to 4 evidence) that examined the effectiveness of rTMS in patients with MDD [major depressive disorder], to date, it is not possible to conclude that rTMS is effective or not effective for the treatment of MDD (treatment resistant or not treatment resistant MDD).”

Nemeroff (2007) stated that the role of non-pharmacological therapies such as electro-convulsive therapy (ECT), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and TMS in the treatment of patients with severe depression remain active avenues of investigation.

A randomized clinical trial (RCT) conducted for the National Coordinating Centre for Health Technology Assessment found that ECT is a more effective and potentially cost-effective antidepressant treatment than 3 weeks of rTMS (McLoughlin et al, 2007). A total of 46 patients with major depression were randomized to receive a 15-day course of rTMS (n = 24) or a course of ECT (n = 22). One patient was lost to follow-up at end of treatment and another 8 at 6 months. The end-of-treatment Hamilton Rating Scale for Depression (HRSD) scores were lower for ECT (95 % confidence interval (CI): 3.40 to 14.05, p = 0.002), with 13 (59 %) achieving remission compared with four (17 %) in the rTMS group (p = 0.005). However, HRSD scores did not differ between groups at 6 months. Beck Depression Inventory-II (BDI-II), visual analogue mood scales (VAMS), and Brief Psychiatric Rating Scale (BPRS) scores were lower forECT at end of treatment and remained lower after 6 months. Improvement in subjective reports of side-effects following ECT correlated with anti-depressant response. There was no difference between the2 groups before or after treatment on global measures of cognition. The NCCHTA study also evaluated the comparative costs ofECT and rTMS. The investigators reported that, although individual treatment session costs were lower for rTMS than ECT, the cost for a course of rTMS was not significantly different from that for a course of ECT as more rTMS sessions were given per course. Service costs were not different between the groups in the subsequent 6 months but informal care costs were significantly higher for the rTMS group (p = 0.04) and contributed substantially to the total cost for this group during the 6-month follow-up period. The investigators reported that there was also no difference in gain in quality adjusted life years (QALYs) for ECT and rTMS patients. The report noted that analysis of cost-effectiveness acceptability curves demonstrated that rTMS has very low probability of being more cost-effective than ECT.

The Australian Medical Services Advisory Committee (MSAC, 2007) found insufficient evidence of rTMS to support funding. The Australian MSAC considered the safety and effectiveness of rTMS for moderate to severe refractory treatment resistant depression compared to ECT andfound evidence that rTMS is safe and less invasive than ECT. However, MSAC also found limited evidence that rTMS may be less effective than ECT. A more recent MSAC review reached similar conclusions (MSAC, 2014): "After considering the available evidence in relation to safety, clinical effectiveness and cost-effectiveness, MSAC did not support public funding because of uncertain effectiveness and cost-effectiveness due to insufficient comparative data in treatment-resistant patients against current antidepressant treatments and uncertain costs."

OnOctober 8,2008, the U.S. Food and Drug Administration (FDA) cleared for marketing via the 510(k) processthe NeuroStar TMS (transcranial magnetic stimulation) Therapy system, which is specifically indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from1 prior anti-depressant medication at or above the minimal effective dose and duration in the current episode. A treatment course usually consists of 6 weeks of 40-min sessions (5 days a week). However, theevidence supporting NeuroStar's effectivenessis less clear than its safety profile. The FDA cleared the NeuroStar based on data that found patients did modestly better when treated with TMS than when they received a sham treatment. It was a study fraught with statistical questions that concerned the agency's own scientific advisers. For a more clear answer, the National Institutes of Health has an independent study under way that tracks 260 patients (Associated Press, 2008).

Randomized, controlled studies of rTMS compared to sham treatment have produced conflicting results (O'Reardon et al, 2007; Avery et al, 2008; Mogg et al, 2008).

In a double-blind, multi-site study, O'Reardon et al (2007) examined ifTMS over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. A total of 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted5 times per week with TMS at 10 pulses/sec, 120 % of motor threshold, 3,000 pulses/session, for 4 to 6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all3 scales at weeks 4 and 6. Remission rates were approximately 2-fold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well-tolerated with a low drop-out rate for adverse events (4.5 %) that were generally mild and limited to transient scalp discomfort or pain. The authors concluded that TMS was effective in treating major depression with minimal side effects reported.

Averyand colleagues(2008) described the results of an open-label extension study of active TMS in medication-resistant patients with MDD who did not benefit from an initial course of therapy in a previously reported 6-week, RCT of active versus sham TMS. Patients with DSM-IV-defined MDD were actively enrolled in the study from February 2004 through September 2005 and treated with left pre-frontal TMS administered 5 times per week at 10 pulses per second, at 120 % of motor threshold, for a total of 3,000 pulses/session. The primary outcome was the baseline to endpoint change score on the MADRS. In those patients who received sham in the preceding RCT (n = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0 (95 % CI: -14.0 to -19.9). Further, at 6 weeks, 36 (42.4 %) of these patients achieved response on the MADRS, and 17 patients (20.0 %) remitted (MADRS scoreless than10). For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (n = 73), the mean reduction in MADRS scores was -12.5 (95 % CI: -9.7 to -15.4), and response and remission rates were 26.0 % and 11.0 %, respectively, after 6 weeks of additional open-label TMS treatment. The authors concluded thatthis open-label study provides further evidence that TMS is a safe and effective treatment of MDD. Furthermore, continued active TMS provided additional benefit to some patients who failed to respond to 4 weeks of treatment, suggesting that longer courses of treatment may confer additional therapeutic benefit.

On the other hand, Mogg and co-workers (2008) noted that the effectiveness of rTMS for major depression is unclear. These investigators performed a RCT comparing real and sham adjunctive rTMS with 4-month follow-up. A total of 59 patients with major depression were randomly assigned to a 10-day course of either real (n = 29) or sham (n = 30) rTMS of the left DLPFC. Primary outcome measures were the 17-item HAMD and proportions of patients meeting criteria for response (50 % reduction in HAMD) and remission (HAMD8) after treatment. Secondary outcomes included mood self-ratings on Beck Depression Inventory-II and visual analog mood scales, Brief Psychiatric Rating Scale score, and both self-reported and observer-rated cognitive changes. Patients had 6-week and 4-month follow-ups. Overall, HAMD scores were modestly reduced in both groups but with no significant group x time interaction (p = 0.09) or group main effect (p = 0.85); the mean difference in HAMD change scores was -0.3 (95 % CI: -3.4 to 2.8). At end-of-treatment time-point, 32 % of the real group were responders compared with 10 % of the sham group (p = 0.06); 25 % of the real group met the remission criterion compared with 10 % of the sham group (p = 0.2); the mean difference in HAMD change scores was 2.9 (95 % CI: -0.7 to 6.5). There were no significant differences between the2 groups on any secondary outcome measures. Blinding was difficult to maintain for both patients and raters. The authors concluded that adjunctive rTMS of the left DLPFC could not be shown to be more effective than sham rTMS for treating depression.

Demirtas-Tatlidede et al (2008) examined the impact of rTMS throughout the long course of MDD and the effectiveness of rTMS in the treatment of depressive relapses. A total of 16 medication-free patients with refractory MDD (diagnosed according to DSM-IV) who initially had clinically significant anti-depressant responses to a 10-day course of 10-Hz rTMS were consecutively admitted to the protocol from 1997 to 2001 and were followed for 4 years. The cohort was studied during a total of 64 episodes of depressive relapse. Severity of depression was evaluated with the HAMD and the BDI prior to and after completion of each rTMS treatment course. Clinically significant response was defined as a reduction in HAMD score of at least 50 %. Safety was assessed by serial neurological examinations and neuropsychological evaluations. Approximately 50 % of the patients individually sustained a clinically significant response to the repeated courses of rTMS; the mean +/- SD decrease in HAMD scores was 64.8 % +/- 12.6 % (p < 0.0001), and, in BDI scores, 60.4 % +/- 20.6 % (p < 0.0001). Despite the lack of adjuvant anti-depressant medication, the mean interval between treatment courses was approximately 5 months, and the medication-free period ranged from 26 to 43 months. Transcranial magnetic stimulation was well-tolerated, and evaluations regarding the safety of the repeated applications of rTMS revealed no findings of concern. The authors concluded that repeated rTMS applications have demonstrated a reproducible anti-depressant effect in patients with refractory depression who initially showed a clinically significant benefit. The duration of effect varied across patients, but benefits were sustained for a mean of nearly 5 months. They stated that further studies with larger cohorts will be useful in determining the long-term effectiveness of rTMS maintenance therapy.

In a systematic review and meta-analysis, Lamand colleagues(2008)examined the effectiveness ofrTMS for treatment-resistant depression (TRD). The systematic review was conducted by identifying published RCTs of active rTMS, compared with a sham control condition in patients with defined TRD (i.e., at least1 failed trial). The primary outcome was clinical response as determined from global ratings, or 50 % or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in end point scores. Meta-analysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. A total of 24 studies (n = 1,092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17 % and a number-needed-to-treat of 6. The pooled response and remission rates were 25 % and 17 %, and 9 % and 6 % for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Drop-outs and withdrawals owing to adverse events were very low. The authors concluded that for patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggested that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD. This is in agreement with the observations of Daskalakisand colleaguesas well as Loo and associates. The former group of researchers (Daskalakis et al, 2008) stated thatmore studiesare needed to address the current limitations of rTMS and to optimize theeffectiveness of this promisingtherapeutic option in TRD. The latter group of investigators (Loo et al, 2008) noted that long-term effects of repeated rTMS sessions are as yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment. It is also interesting to note that Knapp andco-workers (2008) stated that ECT ismore cost-effective than rTMS in the treatment of severe depression.

Demitrack and Thase (2009) studied the clinical significance of the treatment effects seen with TMS in pharmaco-resistant major depression in their recently completed studies by comparing these outcomes with the results reported in several large, comprehensive published reference data sets of anti-depressant medications studied in both treatment-responsive and treatment-resistant patient populations. The efficacy of TMSreported in RCTs was comparable to that of anti-depressants studied in similarly designed registration trials and to the adjunctive use of atypical anti-psychotic medications in controlled trials of anti-depressant non-responders. The authors noted that these data may be helpful in treatment-planning decisions when using TMS in clinical practice.

In a prospective, multi-site, randomized, active sham-controlled (1:1 randomization) trial, George et al (2010) examined if daily left pre-frontal rTMS safely and effectively treats major depressive disorder. About 860 outpatients were screened, yielding 199 anti-depressant drug-free patients with unipolar non-psychotic major depressive disorder. These researchers delivered rTMS to the left pre-frontal cortex at 120 % motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 mins (3,000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88 % retention rate (90 % sham and 86 % active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1 % active rTMS and 5.1 % sham) (p = 0.02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95 % CI: 1.32 to 13.24). The number needed to treat was 12. Most remitters had low anti-depressant treatment resistance. Almost 30 % of patients remitted in the open-label follow-up (30.2 % originally active and 29.6 % sham). The authors concluded that the findings of this study suggested that daily left pre-frontal rTMS produced statistically significant and clinically meaningful anti-depressant therapeutic effects for unipolar depressed patients who are refractory toor intolerant of medications.

There are several limitations with the afore-mentioned study:

1. as a consequence of the extensive work in designing a sham system, which delayed the start of the trial, the study failed to enroll the projected 240 subjects suggested by the initial power analysis. This power issue may be the reason why the treatment condition effect on remission rate in the fully adherent sample analysis was not statistically significant. Treaters were able to guess randomization assignment better than chance, without much confidence, which was not explained by covarying for clinical benefit,
2. although the treatment effect was statistically significant on a clinically meaningful variable (remission), the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for 3 weeks or more, and
3. it is unclear how long the clinical benefit lasts once achieved.

Slotema et al (2010) examined if rTMS is effective for various psychiatric disorders. A literature search was performed from 1966 through October 2008 using PubMed, Ovid Medline, Embase Psychiatry, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and PsycINFO. The following search terms were used: transcranial magnetic stimulation, TMS, repetitive TMS, psychiatry, mental disorder, psychiatric disorder, anxiety disorder, attention-deficit hyperactivity disorder, bipolar disorder, catatonia, mania, depression, obsessive-compulsive disorder, psychosis, post-traumatic stress disorder, schizophrenia, Tourette's syndrome, bulimia nervosa, and addiction. Data were obtained from randomized, sham-controlled studies of rTMS treatment for depression (34 studies), auditory verbal hallucinations (AVH, 7 studies), negative symptoms in schizophrenia (7 studies), and obsessive-compulsive disorder (OCD, 3 studies). Studies of rTMS versus ECT (6 studies) for depression were meta-analyzed. Standardized mean effect sizes of rTMS versus sham were computed based on pre-treatment versus post-treatment comparisons. The mean weighted effect size of rTMS versus sham for depression was 0.55 (p < 0.001). Monotherapy with rTMS was more effective than rTMS as adjunctive to anti-depressant medication. Electro-convulsive therapy was superior to rTMS in the treatment of depression (mean weighted effect size -0.47,p = 0.004). In the treatment of AVH, rTMS was superior to sham treatment, with a mean weighted effect size of 0.54 (p < 0.001). The mean weighted effect size for rTMS versus sham in the treatment of negative symptoms in schizophrenia was 0.39 (p = 0.11) and for OCD, 0.15 (p = 0.52). Side effects were mild, yet more prevalent with high-frequency rTMS at frontal locations. While the authors concluded thatit is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms, they do not recommend rTMS for the treatment of OCD. Furthermore, the authors also stated that "[a]lthough the efficacy of rTMS in the treatment of depression and AVH may be considered proven, the duration of the effect is as yet unknown. Effect sizes were measured immediately after the cessation of rTMS treatment. There are indications that the effects of rTMS may last for several weeksto months. Future studies should assess symptom relief with longer follow-up periods to assess the cost-effectiveness of rTMS treatment, and to indicate its economic advantages and disadvantages .... Although rTMS cannot replace ECT in depressive patients, there may be subgroups in which rTMS can replace antidepressant medication".

The National Institute for Health and Clinical Excellence's interventional procedure overview of TMS for severe depression (2007) concluded that current evidence suggests there are no major safety concerns associated with TMS for severe depression, but there is no evidence that the procedure has clinically useful efficacy. Thus, TMS should be performed only in the context of research studies. Any future research should focus on factors including dose intensity, frequency and duration. Furthermore, the Institute for Clinical Systems Improvement's guideline on major depression in adults in primary care (2008) stated that results of research studies to date on rTMS for the treatment of MDD have been inconsistent and inconclusive.

The BCBS Association's Medical Advisory Panel (BCBSA, 2009) concluded that the use of rTMS in the treatment of depression does not meet the TEC criteria. The TEC assessment stated that an important limitation of the evidence is lack of information beyond the acute period of treatment. The TEC assessment noted that most of the clinical trials of rTMS evaluate the outcomes at the point of the last rTMS treatment, between 1 and 4 weeks, and thatvery few studies evaluated patients beyond this time period. Although meta-analyses are consistent with short-term antidepressant effects, the clinical significance of the effect is uncertain. The TEC assessmentstated that thelarge clinical trial of rTMS by O'Reardon et al(2007) thatwasreviewed in this assessment did not unequivocally demonstrate efficacy, as the principal endpoint was not statistically significant at 4 weeks, and some results were sensitive to the methods of analysis. The TEC assessment stated thatpatients in whom rTMS is indicated are usually treated with a second course of antidepressant therapy. The clinical trial by O'Reardon et al (2007), which was sham controlled without active treatment, can not determine whether rTMS would be more or less successful than this standard treatment. Referring to the study by George et al (2010), the TEC assessment also noted thata clinical trial sponsored by the National Institute of Mental Health has recruited subjects for another clinical trial of rTMS;however, this trial also appears to have only a short duration (3 weeks) in which the participants are randomized to rTMS or sham before crossovers or alternative treatments are offered.

An assessment by the California Technology Assessment Forum (CTAF, 2009)of rTMS for treatment-resistant depression concluded that rTMS does not meet CTAF technology assessment criteria. This report stated that there is insufficient evidence to conclude that rTMS improves net health outcomes for patients with treatment resistant depression,or that it is as effective as current alternatives (e.g., augmentation, ECT, or new drugs). The report noted that many of the individual studies of rTMSfor treatment-resistant depression randomized less than 20 patients and were under-powered to detect changes in net health outcomes, particularly remission of depression. The CTAF assessmentstated that thelargest and most recent clinical trials of rTMS for depression failed to demonstrate significant improvements on their primary outcome measures. The CTAF assessment noted, in addition, thatthere is no consensus on how to perform rTMS and a dearth of evidence on the efficacy of rTMS after cessation of therapy. "Undoubtedly because of the evidence that treatment does have some clinical effect, there is active ongoing research into rTMS. However, it is too early to conclude that rTMS improves net health outcomes for patients with treatment resistant depression, much less that it is as effective as current alternatives such as augmentation, new drugs, or ECT."

An assessment of rTMS by the Health Council of the Netherlands (2008) stated that efficacy studies should focus, in particular, on the use of rTMS to treat patients suffering from depression who are not responding well to medication. The assessment stated thatit would also be useful to study the longer term effects of rTMS therapy in depression.

An assessment of rTMS for depression by the Swedish Council on Technology Assessment in Health Care (SBU) (Brorrson et al, 2009) concluded that although the results of the studies are promising, they continue to regard the treatment as experimental. The assessment noted that one issue is that it is not known to what extent the treatment is effective in drug-resistant depression. The assessment also called for additional studies examining potential adverse effects of rTMS on memory.

An American Psychiatric Association practice guideline on major depression (2010, reaffirmed 2015) stated: "For patients whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered [I]. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective MAOI [II] after allowing sufficient time between medications to avoid deleterious interactions [I]. Transdermal selegiline, a relatively selective MAO B inhibitor with fewer dietary and medication restrictions, or transcranial magnetic stimulation could also be considered [II] . . . Based on the results of a multisite randomized sham-controlled clinical trial of high-frequency TMS over the left dorsolateral prefrontal cortex, TMS was cleared by the FDA in 2008 for use in individuals with major depressive disorder who have not had a satisfactory response to at least one antidepressant trial in the current episode of illness. However, another large randomized sham-controlled trial of TMS added to antidepressant pharmacotherapy showed no significant benefit of left dorsolateral prefrontal cortex TMS. In comparisons of actual TMS versus sham TMS, mostbut not allrecent meta-analyses have found relatively small to moderate benefits of TMS in terms of clinical response. Although the primary studies used in these meta-analyses are highly overlapping and the variability in TMS stimulus parameters and treat treatment paradigms complicates the interpretation of research findings, these meta-analyses also support the use of high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may be associated with a better acute response to TMS. In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT or comparable in efficacy to ECT, but in the latter studies TMS was more effective and ECT was less effective than is typically seen in clinical trials. A fewer number of studies have compared cognitive effects of TMS and ECT. One randomized trial found no significant difference between TMS and non-dominant unilateral ECT on performance on neuropsychological tests at 2 and at 4 weeks of treatment, although a small open-label trial reported a greater degree of memory difficulties with ECT than with TMS shortly after the treatment course."

In a review on “Transcranial magnetic stimulation in the management of mood disorders”, Allan et al (2011) presented an up-to-date meta-analysis of TMS in the treatment of depression. These investigators searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). They identified 1,789 studies; 31 were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. These researchers found a moderately sized effect in favor of TMS [Random Effects Model Hedges' g = 0.64, 95 % CI: 0.50 to 0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (less than or equal to 50 % reduction in depression scores) was 4.1 (95 % CI: 2.9 to 5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. A total of 9 studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges' g = -0.02, 95 % CI: -0.22 to +0.18) and no heterogeneity in outcome. The authors concluded that TMS appears to be an effective treatment; however, at 4 weeks' follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind RCTs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.

The BlueCross BlueShield Technology Evaluation Center (TEC)'s assessment on TMS for depression (2011) concludes that "[t]he available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives. Comparison to alternatives using other observational studies may not be valid due to unmeasured differences in severity of depression between studies and other differences in studies". It also states that "the current body of evidence can not determine in a rigorous way whether TMS would be as effective as a second course of antidepressant therapy. Other important gaps in current knowledge include whether TMS is effective as an adjunctive treatment to second-line drug therapy, the durability of TMS treatment, and the effectiveness of retreatment".

An Agency for Healthcare Research and Quality's review (Gaynes et al, 2011) reported that there is insufficient evidence to evaluate whether non-pharmacological treatments are effective for TRD. The review summarized evidence of the effectiveness of 4 non-pharmacological treatments:

1. ECT,
2. rTMS,
3. VNS, and
4. cognitive behavioral therapy (CBT) or inter-personal psychotherapy.

With respect to maintaining remission (or preventing relapse), there were no direct comparisons (evidence) involving ECT, rTMS, VNS, or CBT. With regard to indirect evidence, there were 3 fair trials compared rTMS with a sham procedure and found no significant differences, however, too few patients were followed during the relapse prevention phases in 2 of the 3 studies (20-week and 6-month follow-up) and patients in the 3rd study (3-month follow-up) received a co-intervention providing insufficient evidence for a conclusion. There were no eligible studies for ECT, VNS. or psychotherapy. The review concluded that that comparative clinical research on non-pharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain unanswered. Interpretation of the data is substantially hindered by varying definitions of TRD and the paucity of relevant studies. The greatest volume of evidence is for ECT and rTMS. However, even for the few comparisons of treatments that are supported by some evidence, the strength of evidence is low for benefits, reflecting low confidence that the evidence reflects the true effect and indicating that further research is likely to change our confidence in these findings. This finding of low strength is most notable in 2 cases: ECT and rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than pharmacotherapy. No trials directly compared the likelihood of maintaining remission for non-pharmacologic interventions. The few trials addressing adverse events, subpopulations,subtypes, and health-related outcomes provided low or insufficient evidence of differences between non-pharmacologic interventions. The most urgent next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing non-pharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures following a treatment attempt of adequate dose and duration in the current episode.

Using data from the AHRQ report, the Institute for Clinical and Economic Review (ICER, 2011) conducted a cost-effectiveness modeling study, assuming that transcranial electrical stimulation and electroconvulsive therapy have equivalent efficacy. The model predicted a cost-utility ratio of $216,468 per quality adjusted life year from a payer perspective and $321,880 per quality adjusted life year from a societal perspective.

An assessment by the University of Calgary Health Technology Assessment Unit (Leggett, et al., 2014) stated that, in adults with TRD, rTMS is more effective than no treatment but the optimal protocol remains unclear. Theassessment found that few studies have reported on the effectiveness of rTMS compared to ECT. The assessment stated that pooled estimates for response and remission provide conflicting results indicating rTMS may be more effective at achieving response but less effective at achieving remission. The assessment concluded that theeffectiveness of rTMS compared to ECT remains unclear. The assessment also concluded that theeffectiveness in youth and young adult populations is uncertain.

An assessment by the Galacian Health Technology Assessment Agency (AVALIA-T, 2014) reached similar conclusions: "Transcranial magnetic stimulation is not currently recommended as a treatment for depression, due to uncertainty about its clinical efficacy."

An assessment by the Alberta Health Technology Assessment Unit (2014) concluded that, in adults withtreatment resistant depression,repetitive transcranial magnetic stimulationis more effective than no treatment but the optimal protocol remains unclear. No statistically significant differences were found betweenrepetitive transcranial magenetic stimulationand electroconvulsive therapy; it is unclear which is most efficacious. The assessment alsofound that the effectiveness in youth and young adult populations is uncertain.

Hayes (2014) reported on a metaanalysis of controlled trials of TMS with sham stimulation. Most studies required patients to have 1 or more, and most typically two or more, previously failed trials of antidepressant medication. The post-treatment difference between transcranial magnetic stimulation and sham stimulation favored TMS; most differences were reported to be statistically significant, but the magnitude was generally small as measured by the MADRS scale and the various HAMD scales. No standard definition of clinically relevant improvement or a clinically relevant effect was identified in the literature. There is evidence of a strong placebo effect. A small quantity of data suggested that the durability of effect, i.e., the continued advantage of active transcranial magnetic stimulation over sham transcranial magnetic stimulation, may not last beyond 2 or 3 weeks after the end of treatment. Low quality evidence suggested that transcranial magnetic stimulation may be at least as effective as electroconvulsive therapy under certain circ*mstances, but under other circ*mstances, electroconvulsive may be superior; this evidence is of low quality because of unexplained inconsistency in study results. Low quality evidence suggested that if transcranial magnetic stimulation has any effect on quality of life or function, it is very small. The review found insufficient evidence on the use of transcranial magnetic stimulation as maintenance therapy after acute response.

An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2014) concluded that transcranial magnetic stimulation for depression does not meet the TEC criteria. The assessment stated that “adequately powered trials do not provide convincing evidence of improved health outcomes.” The assessment noted that meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large trials. The authors of the TEC assessment found that short-term randomized comparisons from 3 trials (2 reporting adequate power to detect effects and the third trial similar in size) do not provide consistent evidence that TMS improves remission of major depressive disorder compared with a sham procedure in patients failing 1 or more antidepressant trials. The authors stated that comparisons reported beyond the initial treatment period (3 weeks of TMS) in 2 of the trials (O’Reardon et al. 2007; George et al. 2010) are problematic given the planned crossover and dropouts. Analyses that take into account potential confounding introduced by crossovers were not reported. The assessment found no evidence comparing TMS with changing antidepressant or augmentation similar to the strategy employed in the Sequenced Treatment Alternatives to Relieve Depression (STAR-D)study (Rush et al. 2006).

The TECassessment included meta-analyses published from 2010 through the search date and trials enrolling more than 150 patients. The quality of meta-analyses was appraised using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) criteria. Randomized controlled trial quality was assessed using the U.S. Preventive Services Task Force criteria. Three randomized, controlled trials were identified that met inclusion criteria. Results from 2trialswere published at the time of the assessment-- George, et al. (2010) and O’Reardon, et al. (2007) -- and documents submitted to the FDA for the Brainsway device (subsequently published as Levkovitz, et al., 2015). The 2 published trials employed a so-called “duration adaptive design” or “forced dropout strategy” after 3 weeks of active TMS or sham. The TEC assessmentrated trial quality separately for results after 3 and 6 weeks of TMS: O’Reardon et al. (2007) was rated fair at 3 weeks and poor at 6 weeks. Response rates at three weeks for TMS versus sham were 20.6 percent and 11.6 percent at three weeks, which was statistically significant; however,the differences in remission rates at three weeks between TMS and sham were not statistically significant. There wasalso no statistically significant difference in remission rates atsix weeks.George et al. (2010) was rated good at 3 weeks and poor at 6 weeks. There was no statistically significant difference in remission rates between TMS and sham at three weeks. Although statistically significant differences in response and remission rates were reported at six weeks,trial quality for the 6-week results was rated poor because of crossover and dropouts during the second 3 weeks of treatment. Limited data are available from the Brainsway device trial that assessed outcomes at 4 and 16 weeks. Although there were significant differences between TMS and sham in per protocol and "modified intention to treat" analyses treatment differences between TMS and shamin the intention-to-treat (ITT) analysis were notsignificantly different.

The BlueCross BlueShield Assessment (2014) also looked at the result of the extension studies, finding that the response rates seen in the extension studies were difficult to interpret given the open-label nature of treatment and the lack of randomized comparator. Longer-term follow-up was examined in extension studies to the O’Reardon et al. (2007) and George et al. (2010) trials as well as in the meta-analysis by Allan et al. (2011). Patients in the O’Reardon et al. trial who did not respond (both active TMS and sham) were allowed to participate in an additional 6 weeks of repetitive TMS. The response and remission rates improved for both groups, and these outcome improvements occurred more frequently in the extension phase than in the original randomization phase. Another extension of this trial followed responders from either the initial randomized trial or the extension study above. Participants were followed 12 weeks for recurrence or additional TMS treatments, with a relapse rate of 12.9% with additional TMS treatment in 40.6%. The extension study to the George et al. (2010) trial enrolled 141 patients who failed to achieve remission in the original randomized phase of the trial. These participants were given additional TMS treatment for 6 weeks, but the TEC assessmentnoted that theseresults are difficult to interpret because the study lacked a control group. Any participant who remitted in the original trial or the extension study was eligible for inclusion into the third phase of the trial. Fifty patients underwent repetitive TMS tapering and were followed for 3 months. By the end of follow-up, 29 (58%) maintained remission, 2 (4%) were reclassified as partial responders, and 1 (2%) relapsed. The TEC assessmentstated that thestudy’s unblinded, nonrandomized design and high loss to follow-up prevent any conclusions about the efficacy of repetitive TMS. The TEC assessment concluded that, because of the lack of demonstrable efficacy in the randomized comparisons, the results of the longer follow-ups reported in O’Reardon et al. (O’Reardon et al. 2007) and George et al. (George et al. 2010) offer little toward establishing treatment benefit. The TEC assessment stated that thehigher response rates seen in the extension studies are difficult to interpret given the open-label nature of treatment and lack of randomized comparator.

The TEC assessment identified concerns about publication bias affecting the conclusions of the metaanalyses. Seven meta-analyses published in 2010 or later were identified. The 4 largest meta-analyses included between 24 and 34 trials. Besides differing by year of publication and available studies, the meta-analyses applied different selection criteria and analytic approaches. All meta-analyses examined clinical end points at the conclusion of TMS treatment (i.e., 1 to 5 weeks). Limited evidence on the durability of outcomes was reported in 1 analysis. The meta-analyses concluded that repetitive TMS is superior to sham for treating medication-resistant depression over the short term, and possibly over a longer term. A single meta-analysis satisfied all AMSTAR criteria, and it was the only analysis to assess trial quality (risk of bias). One meta-analysis suggested a possibility of publication bias, others did not report examining potential publication bias, and some found no indication to suspect it. A large majority of trials were small, and there was considerable overlap among the trials included in the meta-analyses. The only meta-analysis to satisfy all AMSTAR criteria included the 6-week results from O’Reardon et al. (2007), and it was conducted prior to the availability of the Brainsway results. The TEC assessment wasunable to identify published results for 11 completed trialsregistered on ClinicalTrials.gov; the published evidence is incomplete. Concerns by the authors of the TEC assessmentabout conclusions from the meta-analyses center on the potential for publication bias, and inclusion of the problematic 6-week results from 2 trials. The TEC assessment stated thatthe threeadequately powered trials do not provide convincing evidence of improved health outcomes. The meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large adequately poweredtrials. The TEC assessment stated that, although durability of any effects is relevant, absent demonstrable benefit compared with a sham, the question is of lesser or even little importance.

An assessment by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) stated that some studies of transcranial magnetic stimulation may show a benefit, but four health technology assessments have been unable to make conclusions. The assessment concluded that “evidence is generally inconsistent and of low quality.”

Dunner and colleagues (2014) evaluated the long-term effectiveness of TMS in naturalistic clinical practice settings following acute treatment for patients not benefiting from antidepressants. Adult patients with a primary diagnosis of unipolar, non-psychotic major depressive disorder (DSM-IV clinical criteria), who did not benefit from antidepressant medication, received TMS treatment in 42 clinical practices. A total of 257 patients completed a course of acute TMS treatment and consented to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. The study was conducted between March 2010 and August 2012. Compared with pre-TMS baseline, there was a statistically significant reduction in mean total scores on the Clinical Global Impressions-Severity of Illness scale (primary outcome), 9-Item Patient Health Questionnaire, and Inventory of Depressive Symptoms-Self Report (IDS-SR) at the end of acute treatment (all p < 0.0001), which was sustained throughout follow-up (all p < 0.0001). The proportion of patients who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. Among 120 patients who met IDS-SR response or remission criteria at the end of acute treatment, 75 (62.5 %) continued to meet response criteria throughout long-term follow-up. After the first month, when the majority of acute TMS tapering was completed, 93 patients (36.2 %) received re-introduction of TMS. In this group, the mean (SD) number of TMS treatment days was 16.2 (21.1). The authors concluded that TMS demonstrated a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. This was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS retreatment for symptom recurrence. The main drawbacks of this study were:

1. its observational, naturalistic design (no concurrent control group),
2. conclusions regarding the influence of concomitant treatments, including the role of TMS re-introduction, cannot be fully explored,and
3. analysis using an LOCF (last-observation-carried-forward) analysis method may exaggerate the consistency of the scores.

Silverstein et al (2015) systematically synthesized the literature on the neurobiological predictors of rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014), and PsycINFO (1806 [???] to 2014) were searched under set terms. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms. The authors concluded that significant methodological variability in rTMS treatment protocols limited the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow, and presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val hom*ozygotes of the brain-derived neurotrophic factor (BDNF) gene.

Noda et al (2015) systematically synthesized the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014) and PsycINFO (1806 [???] to 2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1,647 articles identified, 66 studies met both inclusion and exclusion criteria; rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limited the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggested that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. The authors concluded that more research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Serafini et al (2015) performed a systematic review of the current literature (PubMed/Medline, Scopus and ScienceDirect search) to examine the role of rTMS in improving neuro-cognition in patients with treatment-resistant depression (TRD). Studies were included according to the following criteria:

1. being an original paper in a peer-reviewed journal, and
2. having analyzed the effect of rTMS on neurocognitive functioning in TRD.

The combined search strategy yielded a total of 91 articles, of which, after a complete analysis, 22 fulfilled the inclusion criteria. Based on the main findings, most of the selected studies suggested the existence of a trend towards improvements in the neurocognitive profile using rTMS. Negative findings have also been reported. However, most studies were limited by their small sample size or included mixed samples, or the adopted single-blind designs potentially biased the blinding of the study design. The authors concluded that rTMS is a non-invasive brain stimulation that may be considered a valuable and promising technique for cognitive enhancement in TRD.

In an open-label study, McGirr et al (2015) the effectiveness and acceptability of an accelerated rTMS protocol for major depressive disorder (MDD). In this naturalistic trial, 27 patients with moderate-to-severe chronic and treatment-resistant MDD were treated with twice-daily HF-rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2 consecutive weeks (60,000 pulses). The primary outcomes were rates of clinical remission and response (16-item Quick Inventory of Depressive Symptomatology post-treatment score less than or equal to 6, and greater than or equal to 50 % reduction, respectively). Secondary outcomes were self-reported anxious symptoms, depressive symptoms and quality of life, and dropout rates as a proxy for acceptability. A total of 10 (37.0 %) patients met criteria for clinical remission and 15 (55.6 %) were classified as responders, with comparable outcomes for both moderate and severe MDD. Clinician-rated improvements in depressive symptoms were paralleled in self-reported depressive and anxious symptoms, as well as quality of life. No patient discontinued treatment. The authors concluded that an accelerated protocol involving twice-daily sessions of HF-rTMS over the left DLPFC for 2 weeks was effective in treatment-resistant MDD, and had excellent acceptability. They stated that additional research is needed to optimize accelerated rTMS treatment protocols and determine effectiveness using sham-controlled trials. The main drawbacks of this study were:

1. short treatment duration that might be lengthened with corresponding improvements in effectiveness,
2. limited duration of follow-up,
3. small sample size, and
4. an open-label design requiring randomized controlle