The Institute of Mental Health (IMH), in collaboration with the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine), has embarked on two clinical pilots to study the efficacy of personalised Transcranial Magnetic Stimulation (TMS) in treating persons with treatment-resistant depression (TRD).

The trials, named APIC-TMS (Asia Pacific Individual Connectomics – Transcranial Magnetic Stimulation) and SPARK-D (Singapore’s Precision Approach for Relief from Depression), are catalysed by Temasek Foundation (TF) and the National Medical Research Council (NMRC) respectively, with a grant of S$1 million each.

Both clinical trials will run concurrently from March 2024 to 2026. Both trials will only recruit individuals who have undergone conventional psychiatric treatment for Major Depressive Disorder and failed to achieve remission, and they will be screened for suitability.

Singapore is the first country in Southeast Asia to conduct such clinical trials of personalised TMS, modelled after the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol¹. In pilots done with American subjects who had treatment-resistant depression, approximately 80% of patients achieved remission² with SAINT. The Singapore pilots will pair IMH’s clinical expertise in standard TMS with NUS Medicine’s expertise in brain MRI to personalise a treatment plan for each participant, study its efficacy and make recommendations on implementing this as a mainstream treatment.

Major Depressive Disorder and Treatment-Resistant Depression

Major Depressive Disorder, commonly known as “depression”, is the most common psychiatric disorder among adults in Singapore. The 2016 Singapore Mental Health Study showed that 6.3% of the Singapore adult population – or one in 16 adults (aged 18 and above) – has experienced the disorder at some point in their lifetime.

Persons diagnosed with depression may present with symptoms such as persistent sadness, insomnia (or sleeping more than normal), loss of interest, lethargy, irritability, poor concentration, and in severe cases, suicidal thoughts.

Depression is a treatable condition. Mild cases may be managed with psychotherapy, while moderate to severe cases are typically managed with antidepressant medication to alleviate the symptoms. However, some patients do not respond well to medication, failing two courses of different drug treatments – where a course would consist of adequate doses taken over a four to eight-week duration, and with adequate adherence during a major depressive episode. Such patients may see an alleviation but not a remission in their symptoms despite having been compliant with taking their antidepressants. Clinically, this is known as treatment-resistant depression (TRD).

There are no local studies on the prevalence of TRD. Figures from overseas literature vary with ranges between 12% – 55%³ and 40% – 70%⁴, depending on how the studies define TRD and the study methodologies.

Clinical Management of Treatment-Resistant Depression (TRD)

TRD is usually managed through a stepwise treatment approach that includes optimising medication dosage, switching to a different class of medications, and augmenting or combining treatments. Non-pharmacological treatments such as electroconvulsive therapy (ECT) and standard TMS are also recommended as appropriate options for persons with TRD.

IMH has been offering standard TMS treatment since 2015 for patients with TRD, under its Neurostimulation Service. TMS is a non-invasive medical procedure where an insulated coil is placed on a spot on the patient’s scalp where the prefrontal cortex resides. The coil generates brief magnetic pulses that directly stimulate specific areas of the brain involved in depression. For more details on the mechanism of action involved in TMS, please refer to Annex A.

Standard Transcranial Magnetic Stimulation (TMS) versus Personalised TMS

Standard TMS delivers stimulation to the same spot of the brain for all participants. It is typically applied by using a manually manipulated holder. On the other hand, personalised TMS – which will be used in the SPARK-D and APIC-TMS clinical trials – is more targeted and precise. It uses individualised functional magnetic resonance imaging (fMRI) to find the ideal location in each patient's brain that should be stimulated to treat his/her depression, and a high precision robot arm to target the stimulation. This spot is unique for each individual and to identify it, an algorithm developed by Research Fellow Ruby Kong and Associate Professor Thomas Yeo from the Centre for Sleep and Cognition at NUS Medicine and NUS College of Design and Engineering, will be used to perform advanced analytics on the individual brain scans.

The data from the fMRI scans is then integrated with an advanced neuro-navigation robotic arm to mount the magnetic coil on the precise spot on the patient’s head. Even if the patient moves during treatment, the robotic arm will keep the coil firmly trained on the spot so that stimulation can be precisely delivered without disruption for that patient.

ECT is the current gold standard treatment for TRD, with a remission rate of 50% – 60%⁵. That means, about half of patients who receive ECT will see a remission of symptoms, as fast as in 3 to 4 weeks while the other half may not. In comparison, other research has shown that TMS is able to achieve a lower remission rate of 33.6%⁶ after 6 weeks. However, the SAINT pilot has shown that remission rates improve significantly to about 80% with personalised TMS after 1 week.

Dr Tor Phern Chern, Senior Consultant, Department of Mood & Anxiety and Head of Neurostimulation Service, IMH, and Principal Investigator for both clinical trials said, “The severity of depression lies on a spectrum – many people will see their symptoms improve or remit with initial treatments such as medication and psychotherapy. But there are some whose conditions are treatment-resistant, and who require a longer treatment period to achieve remission or sufficient alleviation to resume day-to-day functioning. Published evidence from SAINT has shown us that personalised TMS can potentially bring about a paradigm shift in the management of treatment-resistant depression, going from a months-to-years long treatment to a rapid procedural one that delivers significant outcomes in a much shorter period. The success with SAINT – which enabled patients to participate more fully in their lives and that of their loved ones after treatment, or return to work and find more fulfilment – gives us confidence that similar outcomes may be achieved in Singapore. With these clinical trials, we hope to validate the efficacy of this precision modality in helping persons with treatment-resistant depression achieve remission and improve their quality of life.”

Assoc Prof Thomas Yeo, who is also Deputy Director of the Centre for Translational Magnetic Resonance Research at NUS Medicine and co-PI for the clinical trials, said, “Functional MRI is one of the few non-invasive approaches that can safely image the living human brain. By using this newly-developed machine-learning algorithm to clearly outline high-quality individualised brain networks from the limited quantity of functional MRI data, we are able to locate the exact spot unique to each patient, and stimulate it to treat their depression disorder as accurately as possible. These upcoming pilot trials provide a platform to demonstrate that the safety and efficacy from personalised transcranial magnetic stimulation can be assured for patients with treatment-resistant depression who are undergoing this procedure.”

Heng Li Lang, Head of Climate & Liveability at Temasek Foundation, added, "Major depressive disorder is a serious public health challenge. According to the Singapore Mental Health Study conducted in 2016, it affects one in 16 adults in Singapore. Temasek Foundation is committed to catalyse our support for breakthrough efforts in healthcare innovations such as this. The milestone pilot trials by IMH and NUS will be a transformative step to open up opportunities for patients with treatment-resistant depression, and their families. Temasek Foundation is heartened to partner both IMH and NUS on this journey, creating impactful work together with NMRC."

“The National Medical Research Council recognises the importance of advancing clinical practices in mental health through innovative research. Our investment in this study underscores our commitment to supporting research that has the potential to impact clinical practice and improve the quality of care for patients battling treatment-resistant depression,” said Professor Tan Say Beng, Executive Director, NMRC.

A cohort of 20 participants with treatment-resistant depression will be recruited for the APIC-TMS trial, and 70 for the SPARK-D trial. Participants will have to undergo fMRI scans as well as TMS. APIC-TMS will offer participants the personalised target, and SPARK-D will randomly assign patients to either the personalised target or the current standard one-size-fits all target. IMH is committed to patient safety and welfare by ensuring appropriate consent from the prospective participants in accordance with the Human Biomedical Research Act (HBRA).

For more information on the clinical trials, please refer to Annexes B and C.

Persons who wish to enquire about the pilot may email the IMH Neurostimulation Service at [email protected].