Understanding Treatment-Resistant Depression: Exploring Alternative Therapies

Treatment-resistant depression (TRD) affects people who do not respond to conventional therapies after at least two adequate antidepressant trials. Alternative treatments such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), vagus nerve stimulation (VNS), ketamine infusions, and psilocybin have shown promise in addressing TRD by targeting underlying biological, psychological, and lifestyle factors. These innovative therapies, often tailored to individual needs, offer hope and improved quality of life for those struggling with TRD when traditional approaches fall short.

What is Treatment-Resistant Depression?

Major Depressive Disorder is a highly prevalent mental health condition, and about 30% of people with this illness are resistant to conventional treatments. Once two adequate antidepressant trials have been unsuccessful, the illness is termed treatment-resistant depression (TRD) also called refractory depression. 

When someone doesn’t respond well to treatment for depression, we take a step-by-step approach to help. First, we confirm the diagnosis to make sure the symptoms aren’t caused by something else. Next, we adjust the doses of their current medication to see if that helps. If needed, we may switch to a different type of antidepressant.

If these steps don’t work, we explore additional treatments by adding other medicines to boost the effect of the antidepressants. These include:

• Lithium, which is often used for mood stabilisation.
• Thyroid hormone (T3), can improve how the brain responds to medication.
• Certain antipsychotics like quetiapine, aripiprazole, olanzapine, or risperidone, are effective in improving depression when combined with antidepressants.

Multiple somatic or brain stimulation therapy modalities have been investigated and applied in the treatment. 

Alternate therapies for depression that help cope with TRD

Electroconvulsive treatment or ECT

Electroconvulsive treatment is a non-invasive brain stimulation technique that causes increased activity in relevant areas of the brain after producing a generalised seizure of 30-60. ECT is delivered as a series of high-frequency electrical pulses 2–3 weekly for 6–18 sessions. A Consortium for Research in ECT (CORE) report revealed that over half of the subjects improved within the first week. ECT remains the most effective option to treat TRD, especially in situations where a patient’s life may be at risk. A depressive episode with catatonic or psychotic symptoms has a greater likelihood of responding to a course of ECT. It is considered effective for treatment-resistant depression.

ECT in India

ECT is regulated by guidelines from the Indian Psychiatric Society (IPS) and the Mental Healthcare Act, of 2017. The regulation clearly states the use of ECT to be done only with the client’s consent and under proper clinical administrative care. 

However, it has been a sensitive topic owing to concerns about safety and ethics in the Indian context. The use of ECT, especially in an involuntary setting has raised eyebrows with suggestions for alternatives, stricter regulations and more transparency. ECT can be found in almost every hospital under the Max speciality hospital group. Other medical centres/hospitals that provide ECT in India are:

• Cadabams Hospital, Karnataka
• Vibhas & Vishakha Psychiatry Hospital & Rehabilitation Centre, Virar West
• Unlimited Potentialities, Borivali West
• Swaminarayan Clinic & Nursing Home, Borivali East

Repetitive Transcranial Magnetic Stimulation (rTMS)

Repetitive Transcranial Magnetic Stimulation (rTMS) is a relatively new type of brain stimulation therapy. It uses magnetic pulses delivered through a coil placed on the scalp to stimulate specific brain cells. This process is non-invasive, meaning it doesn’t involve surgery, and it doesn’t cause seizures. The treatment usually targets an area of the brain called the dorsolateral prefrontal cortex (DLPFC) using a handheld magnetic coil.

rTMS has been approved as a treatment for people with treatment-resistant depression (TRD) by health authorities such as Health Canada (since 2002), the US FDA (since 2008), and similar organisations in Europe, Australia, and Israel. Research shows that rTMS can help improve symptoms of depression, partly by restoring normal activity in the prefrontal part of the brain.

Key findings about rTMS include:

• A study in 2014 found that 29.3% of people with TRD responded to rTMS, nearly twice as effective as antidepressants after multiple failed treatments (16.8%).
• A recent analysis in the Journal of Clinical Psychiatry showed rTMS was five times more likely to help patients achieve remission compared to a placebo.
• rTMS also has fewer side effects that lead to stopping treatment compared to antidepressants.

Also read: What is the difference between depression and chronic depression?

Repetitive Transcranial Magnetic Stimulation (rTMS) in India

Repetitive Transcranial Magnetic Stimulation (rTMS) has gained popularity in India over the recent years. Top mental health institutions also add it as part of their treatment options. While it is a better alternative to ECT as it involves no anaesthesia or hospitalisation, it is slightly costly with each session costing around Rs. 6000 - Rs 7000.

Deep TMS

The second way to use repetitive Transcranial Magnetic Stimulation (rTMS) is by applying the treatment with specially designed coils that can target deeper areas of the brain. These coils include types like double-cone coils, Hesel-coils (H-coils), and halo coils, which allow the magnetic pulses to reach further into the brain's cortex.

Another recent advancement in rTMS is called Theta-Burst Stimulation (TBS). This method seems to be more effective at promoting changes in brain activity (known as brain plasticity) compared to standard rTMS. TBS delivers quick bursts of 3 magnetic pulses at a high frequency of 50 times per second, repeated 5 times every second.

TBS can be given in two ways:

• Intermittent TBS: Short bursts of stimulation for 2 seconds, followed by an 8-second break, repeated in a 10-second cycle.
• Continuous TBS: A steady stream of stimulation without breaks.

Intermittent Theta-Burst Stimulation (TBS) is approved by the FDA as a treatment for treatment-resistant depression (TRD).

A newer approach called Accelerated TMS involves having multiple sessions of rTMS in a single day. This approach is particularly useful for people with TRD who need an urgent response to treatment. Accelerated schedules have been tested with both traditional rTMS and the newer TBS method.

Research shows that having multiple rTMS sessions in one day can increase brain plasticity (the brain’s ability to change) and improve the activity of brain cells. These treatments were generally well tolerated, with patients experiencing similar levels of comfort to those receiving sham (placebo) treatments.

Studies also found that high-frequency rTMS, low-frequency rTMS, bilateral rTMS (stimulation on both sides of the brain), and TBS were all more effective than sham treatments in improving symptoms.

Deep TMS in India

Deep TMS, being a non-invasive treatment option, has also gained attention as an alternative treatment in India. However, due to its cost and early stage of understanding and adoption, it is still not as common in hospitals. A few medical centres/hospitals offering deep TMS in India:

• Asha Neuro Modulation Clinic, Hyderabad
• Tulasi Healthcare, Mumbai
• Vivekanand Deep TMS Center & Psychiatric Services, Jaipur

Deep Brain Stimulation

Deep Brain Stimulation (DBS) is a treatment that involves placing a small, permanent device inside the brain through surgery. This device targets specific areas of the brain to either activate or silence their activity. The implant is connected to a pulse generator placed in the chest, which can be controlled externally to send repeated electrical signals to the target area.

Several brain regions have been explored as potential targets for DBS in people with treatment-resistant depression (TRD). These include:

• The nucleus accumbens
• The ventral capsule and striatum
• The subgenual cingulate cortex (SCC)

Small studies have shown promising results for each of these areas. One study focusing on the SCC reported that 92% of participants with TRD responded to the treatment two years after the device was implanted.

Deep Brain Stimulation in India

DBS is well-established in India as a treatment for Parkinson’s disease and tremors. However, it is still not widely used for depression or other psychological conditions. Since DBS for depression is still in its early stages in India, it is offered to clients who have exhausted their treatment options. The cost of DBS can range from ₹8 lakh to ₹20 lakh. A few medical centres/hospitals offering deep brain stimulation for select cases in India:

• All India Institute of Medical Sciences (AIIMS), Delhi
• NIMHANS, Bengaluru
• Manipal Hospital
• Apollo hospitals
• Max speciality hospital group

Vagus nerve stimulation

Vagus Nerve Stimulation (VNS) is a treatment designed to change brain activity by stimulating the vagus nerve, a key nerve that connects the brain to other parts of the body. This stimulation is thought to affect different brain networks, helping to treat certain psychiatric conditions.

The VNS system includes a small pulse generator implanted under the skin in the chest. This is connected to an electrode attached to the left vagus nerve in the neck. Together, they send gentle electrical pulses to the vagus nerve.

A separate device is used to adjust the settings of the pulse generator, and the system can be temporarily turned off by holding a magnet over the implant.

Vagus Nerve Stimulation in India

Like DBS, Vagus Nerve Stimulation (VNS) for depression is also in its experimental stage in India. The client goes through multiple stages of evaluation before the treatment. The cost of VNS in India can vary between ₹3 lahks to ₹6 lahks for the procedure, device and follow-up care.

Ketamine infusion

Ketamine is a medication being widely studied as a potential treatment for treatment-resistant depression (TRD). It works as an NMDA (N-methyl-D-aspartate) receptor blocker and is considered a rapid-acting antidepressant (RAAD).

The antidepressant effects of ketamine are not due to its intoxicating properties. Instead, the benefits are typically noticed about 3 hours after an intravenous (IV) infusion has been stopped, with the effects lasting for several days. Studies have shown that ketamine can quickly reduce symptoms of depression, including a significant reduction in suicidal thoughts in people with TRD. On average, its effects appear quickly and last about 5–7 days, with individuals who also have anxiety often responding particularly well.

More recently, an intranasal version of esketamine (a form of ketamine) has been developed. When used alongside oral antidepressants, it has shown promising results with ongoing treatment. Esketamine has now been approved by the FDA for restricted use in TRD.

Ketamine infusion in India

Ketamine infusion for depression and acute suicidal ideation is gaining traction in urban cities in India. Hospitals that offer Ketamine infusion in India are Fortis, Max Healthcare, and Aster CMI.

Psilocybin

Psilocybin is the active ingredient found in certain hallucinogenic mushrooms. When taken, the body converts it into psilocin, which affects serotonin receptors in the brain and may help treat depression.

Most research on psilocybin has been small-scale, focusing on patients with treatment-resistant depression (TRD). In one study involving 12 people with TRD, high doses of psilocybin showed promising results. After receiving two doses—first a low dose to ensure safety and then a high dose (25 mg) a week later—58% of participants experienced improvements in their symptoms that lasted for up to three months, even though the psychedelic effects only lasted around 6 hours.

Some side effects, such as anxiety and an increased heart rate, were reported during the treatment.

Psilocybin in India

Psilocybin is illegal and its therapeutic use is not yet recognised in the country. However, as more research is conducted into its benefits for mental health disorders, there could be opportunities for future exploration in India. 

“Although the world is full of suffering, it is also full of the overcoming of it.” – Helen Keller

Alternative therapy is a great option for those struggling with treatment-resistant depression or treatment-refractory depression, especially when traditional approaches that come under standard psychotherapy do not work. The above-mentioned therapies provide alternate solutions and can address underlying psychological, biological, and lifestyle factors in ways that conventional methods may not be able to address. 

Holistic care and tailoring approaches to individual needs that alternate therapies can offer can empower patients to regain hope and improve their overall quality of life. 

Also read Treatment Resistant Depression: Everything you need to know 

FAQs

1. What kind of lifestyle changes help with symptoms of depression?

Lifestyle changes like consistent physical activity/movement, especially when done outdoors, eating a well-balanced, nutritious diet while limiting sugary and processed foods, maintaining good sleep hygiene by avoiding screens an hour before bed, keeping the room dark, quiet and cool, help a lot. Other things you can do to deal better with the symptoms of depression are practising mindfulness, journalling, making time for activities you enjoy, limiting substances, creating a routine you can stick to, setting small, achievable goals, engaging in therapeutic modalities of CBT or gratitude practises, can greatly contribute in managing the symptoms of depression.

2. What is the best combination of treatment-resistant depression?

Combination pharmacotherapy which includes augmenting medication with mood stabilisers, advanced psychotherapy that includes cognitive behavioral therapy, dialectical behaviour therapy, psychodynamic therapy, interpersonal therapy, non-medication brain stimulation therapies like electroconvulsive therapy, vagus nerve stimulation, deep brain stimulation, and other lifestyle interventions like exercise, a good diet, mindfulness and meditation, can help with treatment-resistent depression.

3. What to do when ECT doesn’t work?

When ECT doesn’t work, it’s important to work with a therapist to reassess the broader picture, including lifestyle factors, social support and underlying health conditions that may be impacting recovery. Having a structured daily routine, a good sleep schedule, physical activity and a balanced diet, can help improve mood and energy levels. Having good interpersonal relationships and support systems can also help. Addressing holistic needs can create the potential for long-term healing.

4. What is the best stimulant for treatment-resistant depression?

Methylphenidate (ritalin) and amphetamines (adderall or vynanse) are commonly used stimulants for TRD, especially for symptoms like fatigue, low energy and poor focus. They work by increasing dopamine and norepinephrine levels, which can help boost motivation and concentration. The medicines need to be taken as part of a broader treatment plan under close medical supervision. 

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