Sanjay Mathew, MD

Expert Perspective

Insights Into Treatment-Resistant Depression: Current and Emerging Therapies

Practice Community
Houston, TX
Practice Niche
Hospital and Institute Affiliations
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Michael E. DeBakey Veterans Affairs Medical Center in Houston


Why are high rates of partial or inadequate responses to first-line antidepressant therapy seen in patients with major depressive disorder (MDD)?


There are many reasons why we see such high rates of partial or inadequate response to first-line antidepressant therapy. First, in many patients, the disease may not respond fully because the dose of antidepressant medication is not optimized. This might be because of side effects and poor tolerability even at the lowest starting doses. Thus, the patient is never able to receive the full benefit of the drug because it simply has not been dosed adequately. Doses may not be optimized because dose titration requires very close monitoring and follow-up, but in many care settings, patients are prescribed an antidepressant medication but have minimal follow-up, or a follow-up visit is scheduled too far down the road.

A second factor is that some patients might be poor or very rapid metabolizers of the antidepressant medication, which might contribute to either poor tolerability or inadequate therapeutic benefit.

A third reason pertains to the complex biology of depression; because there are numerous pathophysiologies underlying depression, it is possible that a standard selective serotonin reuptake inhibitor (SSRI) medication might not adequately address an individual’s core neurobiologic deficits.

Yet another factor pertains to inadequate medication adherence. Taking an antidepressant medication daily, even when tolerated, can be very difficult for a patient. Many patients will skip doses or use the drug in a subtherapeutic manner. This will generally jeopardize the ability to mount a full and satisfying resolution of the depressive symptoms.

Finally, there might be multiple social or psychological factors that impede the ability of standard therapies to work; these might include severe stressors at work or home, financial stressors, general health concerns, and social isolation and lack of support.


What are the risks associated with partial or inadequate MDD treatment?


The real risks are associated with the continued negative impact on quality of life and potential for increased morbidity, and for some, the risk for suicide. There are also economic consequences in terms of lost productivity on the job, absenteeism, and poor job performance.

There are also consequences for general medical health and impaired recovery from major health concerns such as cardiovascular disease.


What are the current challenges associated with treating patients with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)?


In many patients, depression does not respond fully, or if there is a response, the patient may experience relapse over the next year. Side effects can be troublesome, including weight gain, sexual side effects, dry mouth, and gastrointestinal side effects, among others. There is also the challenge that these medications often take several weeks or longer to work, and finding the right medication can be a long “trial-and-error” process, taking many months or even years.

We do not currently have any useful clinical or biologic markers that can effectively predict whether a specific drug will work for a specific patient. This makes clinical practice very challenging and often frustrating.


Can you discuss the potential therapeutic role of modulating pathways outside of the monoamine oxidase pathway in MDD? This might include opioidergic, ionotropic, and metabotropic glutamatergic receptor modulation.


There has been much interest over the past decade plus in developing non-monoaminergic drugs for depression. The glutamate system is one of the systems that has been studied extensively, with the goal of developing drugs that might work faster and address some of the core neurobiologic deficits found in MDD. This system has been implicated in multiple emotional and cognitive processes and has been an active area of pharmaceutical industry investigation.

Ketamine is an anesthetic agent that has recently been repurposed as an antidepressant. This drug acts as an ionotropic receptor antagonist at the N-methyl-D-aspartate (NMDA) receptor. Much of the work around ketamine has been in understanding why this approach is rapidly acting, and what are the downstream mechanisms following NMDA receptor blockade that result in rapid antidepressant benefit.


Can you briefly review your general treatment algorithms for patients with treatment-resistant depression?


We generally would start with a generic SSRI medication. If that has not been successful, we might consider another SSRI medication or an SNRI medication as monotherapy. For those with a partial response who have had some benefit, we would then consider augmentation strategies such as lithium, thyroid hormone, or an atypical antipsychotic.

For those whose depression does not respond to 2 trials of an SSRI or an SNRI, we might also consider a trial of mirtazapine or bupropion. Further down, we would consider a trial of a monoamine oxidase inhibitor if a patient’s depression is still unresponsive after 4 or more trials.

Earlier in the algorithm, and especially for patients with side effects and poor tolerability, we would consider a trial of repetitive transcranial magnetic stimulation. Of course, electroconvulsive therapy still remains the gold standard therapy for treatment-resistant MDD. We also consider the use of bright light therapy, which has shown good efficacy for patients with MDD even if they do not have seasonal depression.

Psychotherapy is also essential for many patients, and its focus can be individualized depending on the patient’s needs and presentation. Techniques might include behavioral activation, cognitive restructuring, lifestyle management, sleep hygiene, and mindfulness.

Disclosures: Dr Mathew served as a consultant for Alkermes, Allergan, and Fortress Biotech.