Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish

Abstract

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Keywords: Antidepressant; area 25; glutamate; prefrontal cortex; rTMS.

Figure 1. Potential actions of intranasal ketamine on cortical areas BA24, BA25, and the insular cortex, and their relationship to the pathways mediating the emotional aspects of pain

A midsagittal MRI of the human head showing the relationship between intranasal delivery of drug and its proximity to structures of the vmPFC. Some of the pathways mediating the emotional aspects of pain are represented in red, with projections from medial thalamus to insular cortex and anterior cingulate cortex (BA24), both of which project to subgenual BA25. BA25 in turn projects back down to brainstem, as well as to amygdala, hypothalamus and the nucleus accumbens. Brain structures not located near the midline are indicated with dashed lines.

Figure 2. Glutamate NMDA receptor circuits in dorsolateral prefrontal cortex play a key role in mental representations of visual space

A. Monkeys perform a visuospatial working memory task in which they have to remember an ever-changing spatial position over a brief delay period. The monkey fixates on a central spot as a cue is briefly flashed at one of eight locations (e.g. 180°). The monkey then remembers that position for several seconds during the Delay period. When the fixation spot extinguishes, the monkey responds by moving its eyes to the remembered location, and if correct receives a juice reward. The position of the cue changes randomly over hundreds of trials, thus requiring the constant updating of the contents of working memory. B. An example of a neuron in the dlPFC that represents spatial position over the Delay period. These neurons often fire to the Cue, and then continue to generate persistent firing across the Delay period, but only for their preferred spatial position, not for other locations. C. Goldman-Rakic^[57] uncovered the layer III dlPFC microcircuits that generate these neural representations. Pyramidal cells receive highly processed visuospatial information from the parietal association cortex, with clusters of cells receiving similar locations. Pyramidal cells with a similar “preferred direction” excite each other to generate the persistent firing needed to maintain information in the absence of sensory stimulation. The spatial specificity is enhanced through lateral inhibition from GABAergic interneurons; e.g. when the Cue is at 0°, the 0° pyramidal cells inhibit the 180° pyramidal cells by engaging GABAergic projections. D. Blockade of NMDAR-NR2B in the dlPFC markedly weakens the ability of dlPFC circuits to generate neural representations of visual space. Similar effects were found with systemic administration of ketamine. E. NMDAR-NR2B in the dlPFC are found exclusively within the post-synaptic density on pyramidal cell spines, and not at extra-synaptic sites. Based on data from^[56].

Figure 3. Potential circuit interactions between dorsolateral prefrontal cortex and BA24 and BA25

Tract-tracing studies in monkeys indicate that the dorsolateral PFC areas 9 and 46 can influence medial PFC circuits through direct projections to BA24, and indirect projections to BA25 via areas 10m and 32. They can also influence the insular cortex via 10m projections through orbital PFC (note: insular cortex is not evident on these Brodmann human brain maps, and thus is not shown for the sake of clarity). Studies of rTMS in patients with depression suggest that activation of the left dlPFC serves to inhibit BA25, while deactivation of the right dlPFC is helpful.