Taking Aim at Treatment Resistant Depression

Scientists are finding new therapeutic approaches to help overcome depression that does not respond to current treatments.

As many as half of individuals with major depressive disorder (MDD) have treatment resistant depression (TRD). TRD is characterized by a failure to achieve complete remission of depressive symptoms following at least six to eight weeks of treatment with at least one course of antidepressant medications. The plight of these individuals has spurred an ongoing search for more effective therapies for depression.

In one promising area of research, scientists are striving to develop new drugs that target the neurotransmitter glutamate as a possible alternative to the current widely used class of antidepressants that work on the serotonin and norepinephrine neurotransmitter systems. Glutamate amplifies signals flowing from brain cell to brain cell via communications points called synapses. In depressed individuals, the number and functioning of synapses is reduced in key regions of the brain. Drugs that affect the glutamate system are thought to stimulate brain cells to release brain growth factors that promote the creation of new synapses and the repair of synaptic connections damaged by stress and depression. A recent study found that this increased synaptic density was associated with reduced depression-related behavior in animals. According to a paper presented at the New York Academy of Sciences in April 2013, two new experimental drugs based on the glutamate system (mGluR2 and mGluR5) have demonstrated significant antidepressant effects in animals and are now in phase II trials in humans.


If your depression is resistant to treatment, these suggestions may help:

    • Look after your health with measures such as eating a nutritious diet, avoiding stress as much as possible, getting regular exercise, and getting enough sleep.
    • Take medications as instructed, and give them time to work—at least six weeks.
    • Ask your physician to reconfirm your diagnosis to rule out other possible causes of your symptoms.
    • Explore other possible treatment options with your physician.
    • Consume foods rich in omega-3 fatty acids, folate, and magnesium. Adequate levels of omega-3 fatty acids (found in cold-water fish and nuts) as well as folate and magnesium (found in whole grains, beans, leafy green vegetables, and nuts) are linked with lower risk of depression.

“It is hoped that research efforts such as these will lead to treatments that work rapidly and do not require patients to undergo multiple trials to find an effective medication,” says Maurizio Fava, MD, Executive Vice Chair of the MGH Department of Psychiatry. “TRD represents a challenge to patients and their medical care providers, and the need for therapies that can help people overcome it is great.

“However, with patience, perseverance, and professional guidance, chances are good that most individuals with depression will eventually find a treatment that relieves their symptoms, or at least greatly improves them.”

Trying Other Options

Long-term depression can have many negative consequences. It increases the risk of mortality from suicide, heart disease and stroke, interferes with appetite and sleep, and causes physical symptoms such as muscle tension, fatigue, headache and chronic pain. Depressed people are more likely to engage in risky behaviors such as alcohol or drug abuse, and to face problems with relationships at home and work. Chronic depression can cause problems with attention and speed cognitive decline as well.

The cause of TRD is often difficult to identify. Various studies have linked treatment resistance to magnesium deficiency, severe ongoing stress, especially severe depression that is difficult to resolve, medical illnesses, and comorbid psychiatric disorders such as obsessive compulsive disorder that can complicate treatment. In some instances a condition diagnosed as depression may actually be related to other factors, such as an endocrine imbalance. In some instances, blood levels of certain types of antidepressant medications may not reach the proper therapeutic range.

“More than 10 percent of patients with MDD will not respond even after multiple interventions that include various medications, psychotherapy, and treatments such as electroconvulsive therapy (ECT),” Dr. Fava says. “As many as 33 percent of patients may improve with treatment, but will continue to experience some symptoms despite multiple attempts to bring about complete remission.”

For patients who achieve partial response to an initial antidepressant, clinicians may opt to combine the first antidepressant with a second antidepressant, augment the first antidepressant with one or more other medications, or switch medications to a different class of antidepressant altogether. If these measures fail to improve symptoms of TRD, there are a number of other options that may work, including:

Psychotherapy and/or support groups: Regular counseling with a mental health professional can help patients understand the stresses and behaviors that are negatively affecting their mood and find ways to avoid events that can exacerbate depression. Support groups can reduce the sense of isolation and provide insights about depression.

Electroconvulsive therapy (ECT): ECT involves the carefully controlled use of electrical currents emitted by electrodes placed on the patient’s scalp to induce seizures in the brain. The procedure requires general anesthesia and may cause minor side effects such as headache and moderate memory loss, but it works faster and often has a higher success rate for TRD than medication and psychotherapy.

Repetitive transcranial magnetic stimulation (rTMS): Magnetic wire coils placed on the scalp produce electrical currents that stimulate cells in an area of the brain linked to mood regulation. The one-hour treatments are repeated from 20 to 30 times over four to six weeks, and research suggests they are only slightly less effective than ECT.

Vagus nerve stimulation (VNS): VNS involves implanting a permanent pacemaker in the vagus nerve on the left side of the neck. The nerve is stimulated via 30-second electrical impulses every five minutes. VNS has produced benefits for some patients, and its antidepressant effects appear to increase over time; however, more data are needed to support its use for TRD.

Deep brain stimulation (DBS): An electrode implanted in the brain. emits small electrical pulses to a region that plays a role in the brain’s reward system. The device is left permanently in place.

Bright light therapy: Exposure to sunlight or 10,000 Lux of light from a lamp or light box for 30 minutes daily can result in improvement in some patients.


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