Emerging Therapeutic Options for Treatment-Resistant Depression

One-third of patients with depression do not achieve an adequate clinical response to available treatment and are considered to have treatment-resistant disease. During a presentation given by Roger S. McIntyre, MD, FRCPC, a professor in the Departments of Psychiatry and Pharmacology at the University of Toronto, and Andrew J. Cutler, MD, a clinical professor in the Department of Psychiatry at SUNY Upstate Medical, at the Neuroscience Education Institute Max! Virtual Meeting, they discussed new research and therapeutic options for treatment-resistant depression.

The treatment algorithm for depression starts with an antidepressant; if it is ineffective or intolerable, the recommendation is to switch, combine with other antidepressants, or augment the medication. “The problem is, we don’t have really great data to tell us which one to do. It’s also controversial how long you might wait until you do one of those things,” said Dr. Cutler. If patients are not seeing a 20% to 25% improvement in the first two weeks, physicians should do something, he advised.

“Our currently available antidepressants don’t get as many people well as we would like,” said Dr. Cutler. “If we use the criterion of full remission, we really don’t do such as a great job.”

Consider switching to another antidepressant when it is the first antidepressant trial, there are poorly tolerated side effects to the initial antidepressant, there is no response (defined as <25% improvement) to the initial antidepressant, there is more time to wait for a response, and the patient prefers to make a switch.

Consider an adjunctive medication when there have been two or more antidepressant trials, the initial antidepressant is well tolerated, there is a partial response (defined as >25% improvement) to the initial antidepressant, there are specific residual symptoms or side effects to the initial antidepressant that can be targeted, there is less time to wait for a response, and the patient prefers to add a medication.

Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory. Numerous studies have shown regional changes in glutamate receptors, as well as elevated levels of glutamate in the brains of patients with major depressive disorder (MDD). Glutamatergic targets like ketamine, esketamine, and rapastinel have shown promise in treating MDD.

In March 2019, the FDA approved intranasal esketamine in conjunction with an oral antidepressant for treatment-resistant depression. This agent is self-administered by the patient, but it must be administered in the clinic, so it requires patients to go into the clinic twice a week for the first four weeks of treatment (induction phase). Patients must also be monitored for two hours after administration. “This is a significant time commitment,” said Dr. Cutler.

The 5HT2A receptor is known to play a key role in regulating mood, anxiety, schizophrenia, and consciousness. Hallucinogens that target the 5HT2A receptor agonism have shown promise for both MDD and treatment-resistant depression. Psilocybin has received breakthrough therapy designation for treatment-resistant depression and MDD. A study of psilocybin observed a clear reduction in depression symptoms starting at week one and continuing through three months. “It’s an old approach that seems to be reawakened,” said Dr. McIntyre.

Opioid agents like buprenorphine and ALKS 5461 have shown efficacy in treatment of MDD. “Opioid systems are relevant to reward, which is a key disturbance in depression,” said Dr. McIntyre. “Some people would also … refer to the pain of depression as similar an experience as physical pain.”

Anhedonia is a common symptom of MDD reported in nearly 75% of patients. Anhedonia and impaired reward circuit pathways are associated with a poorer prognosis and suboptimal treatment response. A study showed that as anhedonia improves, there is a direct improvement of quality of life and function, Dr. McIntyre explained.

A study found that low-dose buprenorphine reduced suicidal ideation. ALKS 5461 (buprenorphine plus samidorphan) improved core and overall symptoms of depression, and there was no evidence of abuse potential.

“I think the next five to seven years [will be] truly exciting for patients,” said Dr. McIntyre. “It’s about [treatment] alternatives that work better, work faster, and are better for patient-reported outcomes.”

Presentation: Out of the Pipeline: What Next? Optimizing Outcomes for Treatment-Resistant Depression. Presented at the Neuroscience Education Institute Max! Virtual Meeting, Nov. 5-8, 2020.