SAN DIEGO — Alternatives with new mechanisms of action are needed after 50 years of drug development focusing on monoamines for treating major depressive disorder, according to a session presented at Psych Congress.
“Some people think that since the 1950s, almost everything we’ve ever studied has targeted one of two basic monoamine systems, and that the main reason we have 25% of people we can’t get better is because of the fact that there are depressions that have very little to do with monoamine neurotransmission,” Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania Perelman School of Medicine, said during his presentation. “Now it’s time to look beyond that.”
Thase said that contemporary antidepressant therapy follows an implicit algorithm that starts simple, like beginning a patient on a first-line antidepressant, then grows more complex, like switching a patient to another antidepressant or combining treatments or using an adjunct.
The STAR*D (the Sequenced Treatment Alternatives to Relieve Depression) study highlighted the limited efficacy of antidepressants in real-world settings. After this pivotal study, use of antidepressants plus second-generation antipsychotics has increased amid concerns about longer-term safety and currently, investigation is underway for a new generation of adjunctive therapies that target novel mechanisms.
Thase created a list of the top 10 drug combinations that have been used to treat MDD over the past 50 years and upcoming treatments that hold promise to help educate psychiatrists, but noted that the list holds no scientific validity. He began with treatments that are rarely used today that were very common in the past then moved on to the newest treatments.
#10 – Perphenazine and amitriptyline — the preferred treatment for psychotic/delusional MDD in early practice guidelines;
#9 – Combining a tricyclic antidepressant and a monoamine oxidase inhibitor — Thase noted that probably about less than 1% of psychiatrists still use this strategy;
#8 – Adjunctive benzodiazepines and other anxiolytics — Thase said that he uses this mainly as a palliative treatment;
#7 – Adjunctive psychostimulants — Thase said this may be good for comorbid patients with ADHD, binge eating disorder and sleep apnea;
#6 – Adjunctive low-dose trazodone — though common, Thase noted that it does not always show great antidepressant effect;
#5 – Adjunctive thyroid hormone;
#4 – Adjunctive lithium — the first ‘proven’ adjunct’;
#3 – Combining newer generation antidepressants — Thase said that bupropion and mirtazapine are preferred for use in antidepressant combinations);
#2 – Adjunctive second-generation antipsychotics — quetiapine, aripiprazole, Rexulti (brexpiprazole; Otsuka, Lundbeck), and olanzapine + fluoxetine are approved for treatment-resistant depression, and there is positive evidence for risperidone and Vraylar (cariprazine, Allergan);
#1 – Adjunctive ketamine and intranasal esketamine.
However, there’s still more work to be done, Thase concluded.
“I ranked ketamine number one because I root for the home team and we have not had a kick-ass therapy in a long time. It works differently and it works within a day or two,” Thase said. “Now esketamine is the first of what will hopefully be a large number of novel treatments that seem to be coming forward. At the end of the day, it’s your care that matters most — having a logical, sequential approach, not giving up on your patient and when you’re stuck, asking someone for help.” – by Savannah Demko
Thase, ME. Top 10 drug combinations in MDD: Past, current and future. Presented at: Psych Congress; Oct. 3-6, 2019; San Diego.
Disclosure: Thase reports multiple ties to industry.