Approximately 20–30% of patients with major depressive disorder do not respond adequately to several cycles of antidepressant treatment. While definitions in the literature may vary in detail, this type of depression is commonly referred to as ‘treatment-resistant depression’ (TRD) or ‘difficult-to-treat depression’ (DTD, Conway et al., 2017). Importantly, this subset of depressed patients is characterized by increased mortality and poorer health-related quality of life compared to non-TRD (Fekadu et al., 2009). Even if remission can be achieved, the risk of relapse in these patients is increased within the first year after remission (Kennedy et al., 2004).

To date, there are only a limited number of treatment options available for TRD (Johnston et al., 2019). In particular, ketamine has emerged as a new and effective treatment in this patient population. The rapid antidepressant effects of ketamine were first described by Berman and colleagues (Berman et al., 2000) and have been replicated in numerous studies (Fond et al., 2014; Corriger and Pickering 2019). Racemic ketamine is usually administered as intravenous infusion either as monotherapy or in combination with pre-existing psychiatric medication (Lee et al., 2015, Marcantoni et al., 2020, Marchetti et al., 2015). Clinical trial data demonstrated a higher therapeutic efficacy of higher infused ketamine doses (0.5–1.0 mg/kg) than lower dosing (0.1–0.2 mg/kg). Although repeated infusions are required due to a short-term efficacy of racemic ketamine, the most optimal dosing frequency in TRD remains to be established (McIntyre et al., 2021). Furthermore, the S-enantiomer of ketamine (i.e., esketamine) has been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency, and Swissmedic as a nasal spray which is indicated, in conjunction with an oral antidepressant, in adults with TRD (Popova et al., 2019; Krystal et al., 2020). Therapeutic benefit of intranasal esketamine was shown for 56 mg and 84 mg doses, administered twice a week for 4 weeks, then once weekly for another 4 weeks, and subsequently once every 1–2 weeks (McIntyre et al., 2021).

The nasal and intravenous routes of administration both have their advantages and disadvantages. From a safety perspective, it is important to note that both routes lead to rapid increases in circulating ketamine concentrations with associated effects and side effects. The latter may include, among other things, rapid increases in blood pressure, sedation, and profound perceptual changes. Unsurprisingly, the FDA has mandated that esketamine nasal spray may be administered only under the supervision of a healthcare provider (FDA, 2019). Similarly, ketamine infusions must be closely monitored in a clinical setting (Sanacora et al., 2017; Zorumski and Conway 2017). Another consideration is patient preference, and, in many contexts, oral dosing will be more practical, less expensive and more convenient for the patient.

Oral immediate release ketamine has been investigated as an analgesic in a number of studies (Lauretti et al., 1999; Marchetti et al., 2015; Schoevers et al., 2016) and as a rapid acting antidepressant in a few other studies (Berman et al., 2000; Zarate et al., 2006; DiazGranados et al., 2010). Side effects observed in these studies comprised dizziness, hallucinations, nausea, vomiting, drowsiness, confusion, light-headedness, headache, somnolence, and anxiety (Schoevers et al., 2016). The benefits of oral ketamine application appear to include an overall good safety when used for longer periods of time, including at home, convenient use, as well as a higher accessibility and affordability compared to other routes of administration (Andrade, 2019).

Here, we evaluated the efficacy and safety of a novel formulation of prolonged-release oral racemic ketamine (KET01) administered twice daily for 14 days in TRD patients as a phase 2 proof-of-concept study. KET01 (produced by Develco Pharma Schweiz AG) is a multi-particulate drug delivery system with retard polymer coated active pellets as internal phase in a tablet. The active substance in KET01 is the racemic mixture of the hydrochloride salt of ketamine. Since TRD patients may have had some improvement to the antidepressant treatment, the trial investigated KET01 as add-on therapy to the ongoing antidepressant therapy and without washout period for the existing treatment. Another reason for using KET01 as an adjunct treatment is a lower bioavailability of orally administered ketamine compared to IV or intranasal administration. Furthermore, since the onset of response to the oral administration is delayed compared to IV or intravenous delivery, rapid significant clinical effects were not expected, even with daily administration. For these reasons, we decided to administer KET01 as an add-on treatment in the severely affected depressive patients.