Treatment-resistant depression: what happens when antidepressants do not work?

Priya (name changed), 32, from Kerala, had been struggling with recurring episodes of depression that affected her ability to carry out everyday activities. Despite taking medication for several weeks, she continued to experience symptoms. With her symptoms persisting, she sought further medical advice and is now undergoing repetitive transcranial magnetic stimulation (rTMS). This non-invasive procedure uses magnetic pulses to stimulate specific areas of the brain.Priya’s experience reveals a challenge in managing depression, say experts. While antidepressants help many people, some continue to experience symptoms despite treatment, requiring doctors to reassess the diagnosis and consider other interventions.Depression can involve persistent sadness, loss of interest in activities, disturbed sleep, fatigue, difficulty concentrating, changes in appetite and can affect one’s ability to work, maintain relationships and manage everyday activities.Assessing treatment resistanceTreatment-resistant depression is generally considered when a person has not responded adequately to at least two different antidepressants, taken at appropriate doses and for sufficient durations, usually six to eight weeks each.An estimated 30% of people with major depressive disorder who have tried antidepressants may experience treatment-resistant depression. The National Mental Health Survey of India estimated the lifetime prevalence of depressive disorders among adults at 5.25% and the current prevalence at 2.68%.However, it is for doctors to confirm whether the lack of improvement is due to treatment resistance or other factors. These could include missed doses, inadequate dosage or duration, side effects, drug interactions and coexisting medical conditions.“Before reaching a conclusion of treatment-resistant depression, all other factors need to be assessed,” says Venkatesh Madankumar, consultant psychiatrist, Prashanth Hospitals, Chennai. These also include alternative diagnoses, particularly bipolar disorder, which requires a different treatment approach.Vivian Kapil, consultant psychiatrist, SRM Prime Hospital, Chennai, says doctors must also assess for substance use, psychotic symptoms, post-traumatic stress disorder and other coexisting conditions. Physical health problems, including anaemia and thyroid disorders, may also contribute to symptoms or complicate treatment.Reviewing treatment optionsWhen an antidepressant does not provide adequate relief, doctors review the person’s response, medication adherence, dosage, duration of treatment and side effects before deciding on the next step.If there is some improvement and the medicine is well tolerated, increasing the dosage may be considered. If there is little or no improvement after an adequate trial, doctors may switch to another antidepressant. Combining medicines or adding psychotherapy, particularly cognitive behavioural therapy, are other options.In selected cases, additional medicines may be prescribed alongside an antidepressant. These decisions require specialist supervision and appropriate monitoring.Ketamine and esketamine may be considered in some cases of treatment-resistant depression, particularly when a faster response is needed. Some patients experience an improvement in symptoms within hours or days, but the response varies and may not be sustained. Potential adverse effects include dizziness, nausea, increased blood pressure and temporary changes in perception. These treatments require medical supervision.Electroconvulsive therapy (ECT) may be considered when depression is severe, other treatments have not helped, or urgent treatment is needed. This may be the case when a person is at high risk of suicide, has symptoms such as losing touch with reality, or is unable to eat or drink enough.ECT is done under anaesthesia. Some people may have headaches, feel confused for a short time or experience memory problems after the procedure. These effects can vary from person to person. A healthcare professional can help decide if ECT or another treatment is suitable, based on the person’s symptoms, medical history and past treatments.What is rTMS?Vasanth R., consultant psychiatrist, Apollo Speciality Hospitals, OMR, Chennai, says repetitive transcranial magnetic stimulation (rTMS), which uses repeated magnetic pulses to stimulate specific areas of the brain involved in mood regulation, is among the newer treatment options used in India. Its availability varies across centres, and the cost and need for multiple sessions may affect access.rTMS may be considered when antidepressants have not provided adequate relief. Its suitability and likely benefits vary between patients and depend on their medical history and clinical assessment. Some people may need further treatment if symptoms return after an initial response.Unlike ECT, rTMS does not require general anaesthesia. The person remains awake during the procedure, which usually involves repeated outpatient sessions over several weeks. Improvement may occur during treatment, but the time taken and the extent of improvement vary between individuals.Side effects can include scalp discomfort and headaches. Seizures are a rare but recognised risk. Before treatment, doctors assess the person’s medical history, including seizure risk and whether any implanted metal or electronic devices could interfere with the procedure.rTMS and ECT differ in their procedures, uses and evidence of effectiveness. Other options include vagus nerve stimulation (VNS), which uses electrical pulses to stimulate the vagus nerve.The choice of treatment, including whether to use these approaches, depends on each patient’s clinical condition, previous treatment response and individual needs.