Ketamine: antidepressant or opioid mood-elevator?

The authors of this 39-site, Janssen-sponsored, double-blind, placebo-controlled study (Vanina Popova and colleagues, American Journal of Psychiatry 176:6:428-438, 2019) submitted its findings to FDA in support of its (now successful) application for approval of intranasal S-ketamine (Esketamine) for treatment-resistant depression.

A structural and pharmacodynamic analogue of phencyclidine (PCP), S-ketamine is withal documented to act across a broad spectrum of pharmacodynamic nanoactivity that includes moderately potent affinity to and agonistic activity at mu opioid receptors (to which are attributed clinically significant opioid-induced analgesia (early evidence of which emerged from discovery of an inverse relationship of S-ketamine dosage during surgical anesthesia and 24-hour post-surgical opioid requirement for mitigation of pain); moodelevation, also attributed to mu agonism, and pharmacologic tolerance with dependence, evinced by characteristic opioid withdrawal symptoms following drug discontinuation or excessive dosage reduction following sustained use (with severity proportional to dosage and duration of exposure). Also a nanoactive lever with potential for clinically significant subjective or behavioral activity is brain glutamatergic activity (ketamine is an N-methyl-D-aspartate receptor antagonist), robustly affecting neural growth and architecture, selectively reinforcing pathways laid down during learning; modulation of arousal during challenge and the faculties subsuming executive function; intensity of stimulation affecting cortical sensory processing, and mood regulation—processes that, in some instances, proceed pari passu with structural neuronal changes that reflect and facilitate neuronal activity during adaptation to environmental exposures and demands.

Despite its long residence in the U.S. pharmacopoeia (S-ketamine having been approved for use as a surgical anesthetic in 1970), little is known about behavioral manifestations of its effects in conscious brains, or the scaling of its behavioral and subjective effects during consciousness and while exposed to subanesthetic concentrations (as little was known about the veterinary anesthetic phencyclidine (PCP), a pharmacodynamic analogue, before its introduction to the street).

The authors’ study, intended to be one of three Phase III trials required by FDA to demonstrate efficacy and “qualify” for an approval of S-ketamine for treatment-resistant depression, (defined operationally by Popova and colleagues as absence of antidepressant response during two or more trials of antidepressants that have been prescribed for the same depressive episode in adequate dosage and for adequate duration), randomly assigned 227 male and non-pregnant female adult patients from a group nearly twice that size that had been winnowed down and refined by an olio of exclusion criteria (detected by diverse rating scales deemed proxies of sensitive and specific diagnostic assessment ) to yield a patient sample without psychotic symptoms, mania spectrum symptoms or history of bipolar disorder, recent suicidal or homicidal ideation or behavior, current substance use disorder or urine positivity for commonly abused drugs or drug classes, anxiety spectrum disorders, autism spectrum disorder, intellectual deficiency syndromes or other psychiatric, neuropsychiatric, or symptomatic or unstable somatic disorder or disease.

After a four-week baseline duration, for documentation of patients’ unresponsiveness to antidepressant monotherapy, the patients were randomized either to 28 days of treatment with coadministered S-ketamine (56 or 84 milligrams on each of two mornings per week) and one of four antidepressants in common usage in their outpatient settings (the SSRIs sertraline and escitalopram, and the SNRIs duloxetine and venlafaxine) at daily dosage associated with antidepressant response, or coadministration of a placebo nasal spray (flavored to taste like the Esketamine nasal spray) and one of the same four antidepressants taken by the patients of the alternate group. Adjunctive “benzodiazepines” were allowed in each group for indications unspecified and dosages not documented.

The patients were assessed for antidepressant response, using as primary outcome criterion the difference between groups in extent of reduction of Montgomery-Asberg Depression Scale ratings, which were done over the telephone by raters blind to patients’ treatment conditions. Secondary assessments were effectuated by other established symptomatic rating scales for depression, anxiety, and overall impairment, and adverse effects were monitored with systematic ratings informed by experience and drug-related expectation. A separate alertness scale allowed for quantitation of S-ketamine induced sedation.

The authors found that coadministration of S-ketamine with an antidepressant was associated with a larger reduction of Montgomery-Asberg Depression Rating Scale total score than was coadministration of placebo nasal spray and an antidepressant. The effect size was small (0.3), but met the threshold for statistical significance (unlike the primary outcome criteria of the first and third studies unaccountably responsible for Esketamine’s approval).

Patients receiving S-ketamine nasal spray twice weekly with an antidepressant showed a statistically significantly greater reduction in Montgomergy Asberg Depression Rating Scale scores for the totality of the duration extending from two hours after receiving their first S-ketamine doses through the twenty-eighth day of dosing.. The response and remission rates were higher in the S-ketamine group. By day 28 (end of study), the response and remission rates with S-ketamine nasal spray coadministered with an antidepressant were 69.3 percent and 52.5 percent. respectively; for the placebo nasal spray coadministered with an antidepressant, response and remission rates were 52 and 31 percent, respectively.

The number needed to treat (NNT, the number of patients that must be treated with S-ketamine nasal spray for one more patient to have responded than the number responding in the placebo nasal spray group) was six for “response” and five for “remission.”

What was not seen in the authors’ study was the superiority of an early onset (at the first primary outcome assessment): no difference (the statistically significant kind) was seen earlier in the S-ketamine than in the placebo nasal spray-cotreated patients. That is, S-ketamine-cotreated patients and placebo-cotreated patients showed no difference in antidepressant response until they were rated on day eight (and thereafter rated on days fifteen, twenty-two, and twenty-eight, relative to baseline).

Dissociative and sedative adverse effects were common in S-ketamine-treated patients. The latter was reported or observed in nearly half of the patients, but resolved within ninety minute after S-ketamine dosing. No patient is reported to have experienced serious or clinically significant adverse effects.

Without mentioning the results of the third Phase III trial required for S-ketamine’s approval, the authors conclude that adjunctively prescribed subanesthetic doses of S-ketamine may increase the magnitude of response of patients with treatment-resistant depression. They are uncertain about the failure of S-ketamine to accelerate response (as reported in prior studies). They believe that sedative and dissociative adverse effects of S-ketamine may prove clinically insignificant because of their brevity. (Obiter: No mention is made of the findings of the third Phase III clinical trial (the authors’ representing the second) required for S-ketamine approval for treatment resistant depression. No mention, that is, besides Alan Schatzberg’s “Commentary” in the same issue of the American Journal of Psychiatry wherein their study was published. In his essay entitled, in part, “…a Word to the Wise…” (informed by his own work (American Journal of Psychiatry 175(4):327-335, 2018)), Schatzberg chronicles the deaths of three S-ketamine-treated patients in the third Phase III clinical trial on behalf of S-ketamine’s approval (as an adjunct) for treatment-resistant depression. The three deaths, all suicides, occurred  four to twenty days after ketamine dosage had been reduced abruptly to 28 milligrams once weekly after 16 weeks at 84 mg twice weekly.  A preponderance of relapses in the entire group had occurred over the same span of 16 days (too soon for typical depressive relapse after discontinuation of an antidepressant regimen that has succeeded in a treatment-resistant patient).  Schatzberg’s evidence-based, closely reasoned essay raises suspicion that the three patients who completed acts of suicide and a preponderance of the (earlier-than-expected) depressive relapses of that study were related to a “protracted” opioid withdrawal syndrome. Our experience with S-ketamine comports with that of Schatzberg and raises similar concerns about insufficient study of clinical manifestations of S-ketamine’s opioid activity, especially the risk of opioid withdrawal syndromes in patients who are abruptly withdrawn from S-ketamine or whose dosages of S-ketamine are too rapidly tapered. Like Schatzberg, we are curious about why S-ketamine was approved for an indication in a vulnerable, pro-suicidal population after two of three Phase III efficacy studies yielded statistically insignificant efficacy findings.

Moreover, is ketamine an antidepressant or antidepressant augmentation? Can effects on sleep, energy, appetite, attention, and anhedonia be assessed after 24 hours? Or is ketamine a dissociative euphoriant that elevates mood by dint of acute opioid effects (representing a transient state-change with persistent effects, akin to that described after single doses of non-opioid, dissociative phenylethylamine-based drugs, such as methylenedioxy-methamphetamine (Ecstasy)) and withal, by dint of additional opioid activity, causes tolerance and dependence during twice- or thrice-daily dosing, enabling withdrawal symptoms following abrupt discontinuation after  longer exposures?) What would the results have been, were the drug administered not S-ketamine, but fentanyl or heroin? )

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