A 28-year-old Caucasian female with bipolar I disorder diagnosed 4 years before, was hospitalized in an inpatient psychiatry clinic due to treatment-resistant depressive episode with extensive suicidal thoughts. Mental status has been deteriorating for 4 months before admission. During her illness, the patient was hospitalized five times due to depressive episodes and had two manic episodes without hospitalization. The patient had been treated with ketamine twice, first during previous hospitalization (IV) and second time during described stay (oral).
One year before she was hospitalized in the same facility due to severe treatment resistant depressive episode and despite treatment modifications she did not achieve remission, thus she was offered ketamine treatment. A dosage of 0.5mg/kg ketamine hydrochloride intravenous infusion over a period of 40 min was given two times per week for a period of 4 weeks (eight times in total) as add-on treatment to standard of care. After the ketamine administration period, an intermittent mood improvement lasting 1 week has been observed (six points reduction in MADRS score):no manic symptoms appeared. Further pharmacological modifications were made:after 6-month hospitalization patient achieved partial remission and was discharged on lamotrigine 400 mg/day, lithium carbonate 750 mg/day, clozapine 100 mg/day, and topiramate 400 mg/day.
On admission the patient presented decreased mood, decreased energy, suicidal thoughts, feeling of constant inner tension, difficulties concentrating, withdrawal from social interactions, sleeping difficulties. Somatic causes were excluded after physical examination, neurological examination, and laboratory tests (blood morphology, electrolytes, kidney and liver profile, TSH, FT4, CRP, B12, folate levels, urine test, toxicology) which turned out normal.
During the time since her previous hospitalization, the treatment has been modified in the outpatient care:clozapine has been discontinued, the dose of topiramate has been reduced to 100 mg/day, bupropion 300 mg/day, and chlorprothixene 60 mg/day have been added. Lithium serum level was 0,87 mmol/L on dose of 1,000 mg/day. In the EEG record slow basic activity and slow waves in the front-temporo-parietal region on the left side were described; the MRI scan did not reveal any pathological changes. The pharmacological changes listed above did not cause any improvement; for this reason the patient was qualified for readministration of ketamine, this time in oral form.
The dose of ketamine administered orally was 2.5 mg/kg. During the first 10 min half of the dosage was administered and in the next 30 min the remaining part was sipped. Ketamine was administered twice weekly during 4 weeks. After 2nd week of ketamine administration the daily dose of lithium was reduced due to its increased serum level (1.42 mmol/L) to 750mg/day which resulted in 0.74 mmol/L serum concentration. During the third week of oral ketamine administration period, manic symptoms were observed. The patient presented increased sex drive, elevated psychomotor activity, racing thoughts, irritability, problems falling asleep and total sleep reduction. She spent a significant amount of money on online shopping, cleaned her locker several times, and became talkative. The symptoms were present for 2 days; after that time depressive symptoms returned with additional appetite increase. Thus decision for continuation of ketamine treatment was made. One day after the last dose of ketamine, the patient presented manic symptoms again. She had intermittent periods of elevated mood, her energy was constantly increased, she presented maladaptive affect regulation, decreased need for sleep, increased sex drive, she became talkative, dressed inappropriately, had increased appetite. The patient demonstrated psychomotor agitation with accompanying suicidal thoughts, lasting for 1 week. Depressive symptoms were still present, but manic symptoms clearly dominated. No psychotic symptoms were present. Drug screen was negative. One week after finishing ketamine administration lithium dose was increased again up to 1,000 mg/day reaching serum level 1.11 mmol/L.
The symptoms resolved after a period of 16 days. During first three doses of ketamine administration patient presented sedation, dizziness, and some dissociative symptoms. The symptoms were of moderate intense and resolved during next 40 min after the last sip of oral ketamine. No other significant adverse events were observed. Treatment timeline is presented in Figure 1.
Both protocols, intravenous and oral, included recording of basic life parameters such as heart rate, arterial pressure, oxygen saturation level, respiratory rate and body temperature measured every 15 min. In both protocols psychometric assessment included: Montgomery Asberg Depression Rating Scale structured interview (MADRS-Sigma) and Young Mania Rating Scale (YMRS) completed before IV and oral administrations and after 3rd, 5th, and 7th dose as well as 1 week after finishing the treatment.
The oral route of administration is probably the least costly and most acceptable way to administer ketamine in patients with depression. The existing literature on oral ketamine suggests that oral doses should range from 2-3 mg/kg. It is approximately the dose of 0.5 mg/kg IV multiplied by the oral bioavailability correction factor which is 4-5. This factor is a result of high first-pass metabolism. It is also the dose most commonly used in the oral ketamine study by Hartberg. Nevertheless it is worth noticing that off-label use of oral ketamine is based on very limited research and no dose-ranging study has been published so far. Additionally antidepressive effect and possible adverse effects of norketamine:the main metabolite of ketamine administered orally are presently unknown although no serious adverse events have been reported so far.
The case report is a part of the naturalistic ketamine trial, approved by the bioethical regulatory of the institution, NKBBN/172/2017; 172-674/2019, NCT04226963. The patient was informed about potential risks and limitations as well as reasonable expectations of ketamine treatment for depression and consent for treatment and gave an informed consent for the participation in the trial. The previously mentioned cases are presented according to guidelines for disguising case material.
The MADRS and YMRS scores and concomitant medications are summarized in Table 1.