Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression

Abstract

Background: There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine's safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP).

Methods: A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol.

Results: No antidepressants were associated with psychomimetic symptomatology except for citalopram (p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed.

Conclusions: Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.ClinicalTrials.gov identifier: NCT04226963.

Keywords: dissociation; ketamine; psychosis; safety; tolerability; treatment-resistant depression.

Conflict of interest statement

Conflict of interest statement: W has received research support from Actavis, Eli Lilly, Minerva Neurosciences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia. WJC has received research support from Actavis, Alkermes, Allergan, Auspex, Biogen, Bristol-Myers Squibb, Cephalon, Eli Lilly, Ferrier, Forest Laboratories, Gedeon Richter, GW Pharmaceuticals, Janssen, KCR, Lundbeck, Orion, Otsuka, Sanofi, and Servier; he has served on speakers bureaus for Adamed, Angelini, AstraZeneca, Bristol-Myers Squibb, Celon, GlaxoSmithKline, Janssen, Krka, Lekam, Lundbeck, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, and Zentiva; and he has served as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, and Roche. MG-W has received research support from Janssen, Servier, Alkermes, KCR, Lilly, Biogen, Celon; JS has received research support from Actavis, Eli Lilly, Minerva Neurosciences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia.

© The Author(s), 2021.

Figures

Figure 1.

Means and standard errors for the BPRS scores were measured after subsequent ketamine infusions in groups with and without lamotrigine coexisting treatment. *Significantly higher BPRS scores were observed between patients who were being treated with lamotrigine (n = 7) and those who were not (n = 42), with regards to BPRS score after the eighth infusion. A detailed analysis of the results showed that the BPRS score was higher after the fifth infusion compared with that after the seventh infusion. The differences between the remaining measurements were not significant (p > 0.05). BPRS, Brief Psychiatric Rating Scale.

Figure 2.

Means and standard errors for the BPRS scores were measured after subsequent ketamine infusions in groups with and without citalopram coexisting treatment. *Significantly higher scores in BPRS were observed, after the second infusion between patients who were taking citalopram (n = 4) and those who were not (n = 45). BPRS, Brief Psychiatric Rating Scale.

Figure 3.

Means and standard errors for the BPRS scores were measured after subsequent ketamine infusions in groups with and without coexisting lithium treatment. *Significantly higher BPRS scores were observed between patients being treated with lithium (n = 5) and those who were not (n = 44), after the sixth infusion, and after the eighth infusion. BPRS, Brief Psychiatric Rating Scale.

Figure 4.

Means and standard errors for the BPRS scores were measured after subsequent ketamine infusions in groups with and without valproate coexisting treatment. *Significantly higher BPRS scores were observed between patients being treated with valproate (n = 9) and those who were not (n = 40) following the sixth infusion, and after the eighth infusion. BPRS, Brief Psychiatric Rating Scale.