On the Long Way Down: The Neurophenomenology of Ketamine

Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”?

For years, I've been utterly fascinated by these separate strands of research that rarely (if ever) intersect. Why is that? Because there's no such thing as “one receptor, one behavior.” And because like most scientific endeavors, neuro-pharmacology/psychiatry research is highly specialized, with experts in one microfield ignoring the literature produced by another (though there are some exceptions).¹

Ketamine is a dissociative anesthetic and PCP-derivative that can produce hallucinations and feelings of detachment in non-clinical populations. Phamacologically it's an NMDA receptor antagonist that also acts on other systems (e.g., opioid). Today I'll focus on a recent neuroimaging study that looked at the downsides of ketamine: anhedonia, cognitive disorganization, and perceptual distortions (Pollak et al., 2015).

Imaging Phenomenologically Distinct Effects of Ketamine

In this study, 23 healthy male participants underwent arterial spin labeling (ASL) fMRI scanning while they were infused with either a high dose (0.26 mg/kg bolus + slow infusion) or a low dose (0.13 mg/kg bolus + slow infusion) of ketamine ² (Pollak et al., 2015). For comparison, the typical dose used in depression studies is 0.5 mg/kg (Wan et al., 2015). Keep in mind that the number of participants in each condition was low, n=12 (after one was dropped) and n=10 respectively, so the results are quite preliminary.

ASL is a post-PET and BOLD-less technique for measuring cerebral blood flow (CBF) without the use of a radioactive tracer (Petcharunpaisan et al., 2010). Instead, water in arterial blood serves as a contrast agent, after being magnetically labeled by applying a 180 degree radiofrequency inversion pulse. Basically, it's a good method for monitoring CBF over a number of minutes.

ASL sequences were obtained before and 10 min after the start of ketamine infusion. Before and after the scan, participants rated their subjective symptoms of delusional thinking, perceptual distortion, cognitive disorganization, anhedonia, mania, and paranoia on the Psychotomimetic States Inventory (PSI). The study was completely open label, so it's not like they didn't know they were getting a mind-altering drug.

Behavioral ratings were quite variable (note the large error bars below), but generally the effects were larger in the high-dose group, as one might expect.

The changes in Perceptual Distortion and Cognitive Disorganization scores were significant for the low-dose group, with the addition of Delusional Thinking, Anhedonia, and Mania in the high-dose group. But again, it's important to remember there was no placebo condition, the significance levels were not all that impressive, and the n's were low.

The CBF results (below) show increases in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex, similar to previous studies using PET.

Fig 2a (Pollak et al., 2015). Changes in CBF with ketamine in the low- and high-dose groups overlaid on a high-resolution T1-weighted image.


Did I say the n's were low? The Fig. 2b maps (not shown here) illustrated significant correlations with the Anhedonia and Cognitive Disorganization subscales, but these were based on 10 and 12 data points, when outliers can drive phenomenally large effects. One might like to say...

For [the high-dose] group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups.

  ...but this clearly requires replication studies with placebo comparisons and larger subject groups.

Nonetheless, the fact remains that ketamine administration in healthy participants caused negative effects like anhedonia and cognitive disorganization at doses lower than those used in studies of treatment-resistant depression (many of which were also open label). Now you can say, “well, controls are not the same as patients with refractory depression” and you'd be right (see Footnote 1). “Glutamatergic signaling profiles” and symptom reports could show a variable relationship, with severe depression at the low end and schizophrenia at the high end (with controls somewhere in the middle).

A recent review of seven placebo-controlled, double-blind, randomized clinical trials of ketamine and other NMDA antagonists concluded (Newport et al., 2015):

The antidepressant efficacy of ketamine ... holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

The mysterious and paradoxical ways of ketamine continue...

So take it in don't hold your breath
The bottom's all I've found
We can't get higher than we get
On the Long Way Down

Lyrics by Robert DeLong, On the Long Way Down

Further Reading

Ketamine for Depression: Yay or Neigh?

Warning about Ketamine in the American Journal of Psychiatry

Chronic Ketamine for Depression: An Unethical Case Study?

still more on ketamine for depression

Update on Ketamine in Palliative Care Settings

Ketamine - Magic Antidepressant, or Expensive Illusion? - by Neuroskeptic

Fighting Depression with Special K - by Scicurious


Footnotes

¹ One exception is the present study, which discussed the divergent anhedonia results (compared to  previous findings of reduced anhedonia in depression). Another example is the work of Dr. John H. Krystal, which includes papers in both the schizophrenia and the treatment-resistant depression realms. However, most of the papers discuss only one and not the other. One notable exception (schizophrenia-related) said this:

...it is important to note that studies examining its effects on glutamateric pathways in the context of mood symptoms (178) may be highly informative for developing our understanding of its relevance to schizophrenia (111). Briefly, emerging models in this area postulate that ketamine may act as anti-depressant by promoting synaptic plasticity via intra-cellular signaling pathways, ultimately promoting brain-derived neurotrophic factor expression via synaptic potentiation (179) and in turns synaptic growth (178). In that sense, acute NMDAR antagonism may promote synaptic plasticity along specific pathways impacted in mood disorders, such as ventral medial PFC (180, 181, p. 916). Conversely, when administered to patients diagnosed with schizophrenia, NMDAR antagonists seem to worsen their symptom profile (182), perhaps by “pushing” an already aberrantly elevated glutamatergic signaling profile upward. Collectively such dissociable effects of ketamine may imply that along distinct circuits there may be an inverted-U relationship between ketamine’s effects and symptoms: depressed patients may be positioned on the low end of the inverted-U (178) and schizophrenia patents may be positioned on the higher end (183). Both task-based and resting-state functional connectivity techniques are well positioned to interrogate such system-level effects of NMDAR antagonists in humans.

² Low-dose ketamine: target plasma level of 50–75 ng/mL was specified (in practice this approximated a rapid bolus of an average of 0.12 mg/kg over 20 s followed by a slow infusion of 0.31 mg/kg/h).

High-dose ketamine: target plasma level of 150 ng/mL was specified (in practice this approximated a rapid bolus of 0.26 mg/kg over 20 s followed by a slow infusion of 0.42 mg/kg/h).


References

Petcharunpaisan S, Ramalho J, Castillo M. (2010). Arterial spin labeling inneuroimaging. World J Radiol. 2(10):384-98.

Pollak, T., De Simoni, S., Barimani, B., Zelaya, F., Stone, J., & Mehta, M. (2015). Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study Psychopharmacology DOI: 10.1007/s00213-015-4078-8

Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, Foulkes A, Mathew SJ, Charney DS, Murrough JW. (2015). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry 76(3):247-52.