Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial

Abstract

IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

“…In agreement with this suggestion, our additional analysis comparing repeated ketamine to saline detected very few strainspecific differences. This is consistent with the results of the human placebo-controlled studies 55,58 and might similarly result from an inability of repeated ketamine to surpass placebo effects in this TRD model. Out of 18 assessed rodent models of depression, the genetic model used in the current study is one of the most robust and reliable 18 .…”

“…Collicular lesions reduce distractibility 54 , whereas hyper-responsive superior colliculus could enhance this condition 51 . Thus, in addition to the modulation of the visual perception 47,55 , repeated ketamine's effect on collicular topological properties might underlie attentional deficits.…”

“…Only five recent human studies included a control group 9,[55][56][57][58] , and, strikingly, they showed contradictory results. Ketamine either maintained antidepressant efficacy 9,56,57 or failed to outperform placebo 58 and was ineffective 55 , additionally causing side effects 55,58 . The study of Canuso et al 56 demonstrated that although the depressive symptoms diminish after ketamine at all time points, the suicidal ideation reduces only at 4 h, and displays no improvement at 24 h or at end-point day 25.…”

“…The study of Canuso et al 56 demonstrated that although the depressive symptoms diminish after ketamine at all time points, the suicidal ideation reduces only at 4 h, and displays no improvement at 24 h or at end-point day 25. The reasons for these mixed outcomes are unclear and might include higher treatment resistance levels 58 , chronic history of depression 58 , ineffective dosing, and possible tolerance-like phenomena 55,58,59 . For example, Sprague-Dawley rats develop tolerance to repeated administration of anesthetic doses of ketamine, possibly arising as a result of receptor desensitization, reduction of receptor density, or increased induction of metabolizing enzymes 60 .…”

Depression in primary care: part 2—management

“…Ketamine, a glutamatergic antagonist, for example, has received much attention and may produce dramatic effects in symptom reduction; however, it is administered by intravenous infusion and is associated with significant adverse effects including potential for abuse 187188. Attempts to deliver it intranasally have proved disappointing 189. However, since the acceptance of this review for publication the US Food and Drug Administration has approved the use of an intranasally delivered form of ketamine (esketamine) for treatment resistant depression.…”