Unearthing Unconventional Medications for Treatment Resistant Depression

Ann Wenzel, PharmD , Cash Wise Clinic Pharmacy/CentraCare

Background: According to the Journal of Clinical Psychiatry, approximately 8.9 million people nationally suffered from medication-treated major depressive disorder (MDD) in 2021. MDD is defined by the American Psychological Association (APA) as a depressed mood and/or loss of pleasure or interest for at least two weeks. Of those 8.9 million people, it is estimated that 30.9% suffer from treatment resistant depression (TRD), which can be classified as failure to respond or achieve remission after two or more trials of medication treatment of adequate dose and duration. TRD is associated with greater severity and duration of illness, disability, risk of suicide, and hospitalizations. Exploring new treatments for patients suffering from TRD can prove to be exhausting, which is why looking at new, unconventional therapies may not be so unrealistic.

Evidence: One unique treatment that has been studied more in depth recently is psilocybin. Psilocybin is a tryptamine alkaloid that can be found in different species of Psilocybe mushrooms. Classified as a schedule I drug by the Drug Enforcement Agency, it is known to produce psychedelic experiences, and more recently, has been found to have antidepressant effects. Goodwin et al. reports on a phase 2 double-blind trial using a single dose of psilocybin, paired with support from therapists, for treatment of resistant depression.  The results of the study showed a reduction in patient-reported depression severity, anxiety, affect, and an increase in functionality in those who received a one-time dose of psilocybin 25 mg. Another unique treatment explored is the use of ketamine. Ketamine is an ionotropic glutamatergic N-methyl-D-aspartate receptor antagonist, typically used for sedation and analgesia, but has been found to have rapid antidepressant effects. Ahmed et al. explored the use of ketamine in a randomized, double-blind, parallel-arm controlled study in those with TRD. The study showed a reduction in suicidal ideation and depression in patients who received one intravenous ketamine infusion per week for two consecutive weeks.

Discussion: Current guidelines from APA suggest that when a patient is a partial or nonresponder to a certain medication, they can either switch antidepressants or augment with another agent. It is estimated that 75% of patients with TRD go through a trial of 4 lines of medication before experiencing a satisfactory response, which can take months to years to reach an adequate response equivalent to a full trial. This puts into perspective the opportunities to explore other treatment options, but these options discussed are not always feasible for a patient. Though psilocybin and ketamine showed promising benefits from the studies mentioned above, some serious side effects can also be associated with the medications. Psilocybin can induce suicidal ideation, behavior, or self-injury, while ketamine can cause hemodynamic instability, severe dissociation, and if used long-term can lead to abuse, addiction, and neurotoxicity.

Clinical Impact: Neither ketamine or psilocybin has been deemed appropriate as first line use for TRD, rather they are to be used after other options are exhausted. Ketamine still has a place in therapy for TRD, but only after all other recommended non-electroconvulsive therapy treatments have been tried and failed. Psilocybin has yet to reach any official recommendation in therapy. Further research will be needed in order to determine the long term effects of these medications, but it is promising to see their initial impact on a patient’s mental health. Both medications have very specific patient parameters prior to starting, but could continue to be considered in patients who meet the qualifications and feel they are running out of options. The treatment of depression requires a personalized and patient-centric approach, and the availability of these medications can offer hope in the midst of a challenging journey.


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