The year 2019 saw two novel antidepressants receive FDA approval amid a series of disappointing phase III trials.

A lengthy four years after receiving breakthrough designation, esketamine (Spravato) was finally approved as an adjunct to an oral antidepressant for the treatment of treatment-resistant depression (TRD). It is currently in review by Health Canada. The S-enantiomer of ketamine is a non-competitive glutamate N-methyl-D-Aspartate (NMDA) receptor antagonist and is administered intranasally. Medical supervision is required during dosing due to the risks of sedation and dissociation. The efficacy of esketamine appears to be somewhat modest – it met its primary endpoint in only one of three trials – but addresses a need for more options in managing TRD. At present, the only FDA-approved therapies for TRD are a combination of fluoxetine and olanzapine, ECT, transcranial magnetic stimulation and vagus nerve stimulator implantation.

Also approved this year was brexanolone (Zulresso, formerly SAGE-547), a GABA-A receptor modulator for the treatment of postpartum depression (PPD). The active agent is allopregnanolone, a neuroactive metabolite of progesterone, and is administered as an infusion over 60 hours. Brexanolone is the first drug specifically indicated for PPD. In two phase III trials, it significantly reduced HAM-D scores at 60 hours. However, the benefits were modest: a least-squares mean reduction from baseline in total HAM-D score of 19.5 points (vs. a 14.0 point reduction with placebo) in study 1; and a 14.6 point reduction (vs. a 12.1 point reduction with placebo) in study 2 (Meltzer-Brody et al. Lancet 2018;392:1058-1070). The FDA rejected the manufacturer’s suggestion of in-home administration and required supervision by a healthcare provider for the duration of the infusion due to the risks of excessive sedation and sudden loss of consciousness. Continuous pulse oximetry is required to monitor for hypoxia, and assessments for excessive sedation are needed every two hours. The infusion will require at least five infusion bags since the product once mixed can only be used for 12 hours at room temperature.

Novel antidepressants are few and far between. There was a 30-year gap between the approvals of imipramine and fluoxetine; and a 20-year gap between venlafaxine and vortioxetine. So the approval of two agents in 2019 was a signal achievement.

Other studies, often of combination therapies in difficult-to-treat populations, did not fare as well. A trial in treated patients with suicidal ideation found that ketamine augmentation was no more effective than placebo in reducing suicidal thinking (Ionescu et al. J Affect Disord 2019;243:516-524). A pilot study of the dopamine agonist ropinirole showed no benefit as an augmentation agent in depression (Gershon et al. J Clin Psychopharmacol 2019;39:78-81). The PANDA trial of sertraline in primary care found no antidepressant benefit at six weeks and only limited benefit at 12 weeks, although there was some improvement in anxiety (Lewis et al. Lancet Psychiatry 2019;6:903-914). A separate study of sertraline found no benefit on HAM-D-17 scores when drug was added to interpersonal psychotherapy in women with postpartum depression (O’Hara et al. J Affect Disord 2019;245:524-532). The Youth Depression Alleviation-Combined Treatment (YoDA-C) trial reported that adding fluoxetine to cognitive behavioural therapy provided no further benefit compared to CBT alone in young patients with moderate-to-severe depression (Davey et al. Lancet Psychiatry 2019;6:735-744). Finally, an eight-week trial reported that placebo was more effective in improving symptoms of depression than a blend of nutraceuticals with putative antidepressant properties (folinic acid; omega-3; 5-HTP, zinc picolinate) (Sarris et al. J Affect Disord 2019;245:1007-1015).