Therapeutic Compatibility of Orally Administered Racemic Ketamine with Modafinil,a CYP3A4 Enzyme Inducer,in Treatment-Refractory Major Depressive Disorder

To the Editor,

Racemic ketamine, effective against treatment-refractory depression, is inexpensively and conveniently administered by the oral route even in office-based practice.^1,2 Ketamine is metabolized to norketamine by CYP2B6, CYP2C9, CYP2A6, and CYP3A4, among which CYP3A4 is the most important.^3,4 CYP3A4 is particularly important when ketamine is administered orally because it is present in the small intestine and, through intestinal first-pass metabolism, can lower the bioavailability of CYP3A4 substrates. ⁵

The oral bioavailability of ketamine is 20% to 30%. ¹ Modafinil, which is used on- and off-label to treat excessive daytime drowsiness, is a clinically significant inducer of gastrointestinal CYP3A4 in addition to hepatic CYP3A4. ⁶ Co- administration of ketamine with a CYP3A4 inducer such as modafinil could therefore be expected to further lower the oral bioavailability of the drug.

Although much is known about the pharmacokinetics and pharmacodynamics of ketamine, and although there has been a dramatic increase in the study of the efficacy of ketamine during the past decade, drug-drug interactions involving ketamine have been poorly studied and reported. ⁴ Knowledge about drug interactions can guide clinical practice. I therefore report, with the written consent of the patient, the absence of a clinically significant interaction between oral ketamine and modafinil in longstanding, antidepressant-refractory depression.

Case Report

AKS, a 40-year-old male, presented with a 15-year history of inability to experience joy, poor interest in everyday activities, fatigue, lethargy, excessive daytime drowsiness, lack of sustained focus, absence of goals in life, social anxiety, and generalized anxiety. Whereas he was able to perform everyday activities and hold a job, he experienced his symptoms as impairing and had substantially compromised quality of life.

He consulted general physicians, endocrinologists, neurologists, psychiatrists, and even practitioners of alternative medicine. He failed trials of various treatments (mostly in polypharmacy), including bupropion, fluoxetine, selegiline, and many other antidepressants, administered alone and with augmenting agents such as thyroxine and methylphenidate. Each treatment had been tried for at least 1 to 2 months or longer. He had even received donepezil, memantine, and levodopa in a desperate attempt to find something that worked for him. The only medications that provided symptomatic relief were clonazepam (1-2 mg/d) for anxiety and modafinil (200-400 mg/d) for daytime drowsiness.

Although he did not experience and complain of depression as a specific symptom, his constellation of symptoms associated with low mood suggested a diagnosis of major depressive disorder (MDD) that was both chronic and refractory to antidepressants.

Hematological, biochemical, and endocrinological tests, brain MRI, and other investigation results were all within normal limits. The irrational and unhelpful medications he was receiving (donepezil, memantine, levodopa, and others) were tapered and discontinued; only clonazepam (1 mg at night) and modafinil (200-400 mg in the morning, based on his workday needs) were continued because they were benefiting him. A sleep study identified obstructive sleep apnea (OSA). A continuous positive airway pressure device at night reduced his apnea/hypopnea index; there was no improvement in any symptom during waking hours. He was also evaluated for endocrinological disease and underwent a trial of testosterone; this did not help his depression, either.

As a side note, clonazepam was necessary because it was therapeutic for his work-related anxiety. It is possible that his daytime sleepiness/tiredness was due to the night-time clonazepam; but it is also possible that the daytime symptoms were due to his OSA. These were the reasons for the unusual combination of night-time clonazepam and daytime modafinil in the prescription.

Three months after first consultation, he accepted the offer for a trial of oral ketamine; simultaneously, dothiepin was started and uptitrated to 225 mg at night; aripiprazole 2 mg/d was later added. Dothiepin was chosen because he had not received it earlier; aripiprazole was added to augment response, if any, to dothiepin. This strategy proved successful because it was associated with a lengthened interval between maintenance ketamine doses (see below).

As another side note, in clinical practice, and especially during maintenance therapy, ketamine is used along with rather than instead of conventional antidepressants; in fact, the US Food and Drug Administration approval of intranasal esketamine is as an add-on treatment and not as monotherapy.

Oral ketamine (175 mg) was administered in liquid form, diluted in about 50 ml of water and sipped across 8 to 10 min initially, brought down to 3 to 4 minutes in later sessions. The justification for this dosing strategy has been provided elsewhere; it may be noted that fixed dosing rather than dosing by body weight characterizes treatment with oral and intranasal ketamine. ¹ The response to oral ketamine was excellent; he experienced complete remission of all symptoms in 1 to 2 days. An attempt was made, once, to administer a 150 mg dose, but the benefits wore off soon, so the patient was returned to the original dose.

Presently, he has been in almost continuous remission since the initiation of ketamine treatment and returns for booster sessions only when his original symptoms reappear, heralding relapse; this indicates that the maintenance treatment with dothiepin and aripiprazole may be prolonging the interval between ketamine sessions but, in themselves, are insufficient for maintenance of remission. During the past 13 months, he has received 16 sessions of oral ketamine, spaced 2-3 weeks apart initially, and about 4 weeks apart currently. Whereas he was clearly euphoric for about 30 minutes in the initial sessions, he was merely very happy during later sessions. No sessions were associated with any experience that was considered adverse.

Discussion

Modafinil induces CYP3A4 in the intestine and liver ⁶ and could substantially reduce the bioavailability of oral ketamine through first-pass metabolism. Modafinil also induces CYP2B6 but inhibits CYP2C9, both of which are involved in the minor metabolism of ketamine.^3,4 The net effect of these actions of modafinil on the conversion of ketamine to norketamine is unknown; however, a reasonable assumption is that, given the preeminence of CYP3A4 in the first-pass and subsequent metabolism of ketamine, modafinil is likely to reduce exposure to ketamine and increase norketamine relative to ketamine blood levels. In further support of this assumption, 80% of intestinal CYP enzyme is reported to be CYP3A4.^7,8

Norketamine crosses the blood-brain barrier but is less active than ketamine. ³ This is probably the first report on the safe and effective use of oral racemic ketamine in conjunction with a CYP3A4 inducer, and especially of the therapeutic compatibility of modafinil with orally administered ketamine in the context of treatment-refractory MDD. It is likely that norketamine, the active metabolite of ketamine, is also therapeutically potent in depression, and that modafinil does not reduce the antidepressant benefits of oral ketamine.

As a limitation to this report, the depression and remission therefrom are not supported by clinical ratings; it is not usual in everyday clinical practice to rate every patient using research instruments. When, at long-term follow up, it is apparent that a strategy worked, it is too late to go back in time and perform clinical ratings.

As final notes, despite the long history, depression as a personality trait was not considered because the symptoms remitted with ketamine; personality traits would be expected to be more enduring. And, suggestibility as an explanation for treatment response was also not considered because had the benefit been due to suggestibility, the patient would surely have responded to the various rational and irrational pharmacological interventions initiated earlier, or to the CPAP.