Use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain
The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain synthetic pain disorder (CRPD) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.
1. A method of treating bipolar depression or major depressive disorder, comprising administering a pharmaceutical composition containing an effective amount of a compound or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier to a patient in need of such treatment, wherein the compound is (2S, 6S)-hydroxynorketamine, (2R, 6R)-hydroxynorketamine, (2S,6R)-hydroxynorketamine, (2R,6S)-hydroxynorketamine, (S)-dehydronorketamine, (R)-dehydronorketamine, or any combination of the foregoing.
2. The method of claim 1 , wherein the compound is (2R,6R)-hydroxynorketamine.
3. The method of any one of claim 2 , wherein the compound is administered together with an additional active agent.
4. The method of claim 2 where an effective amount of the compound is an amount effective to decrease depressive symptoms, wherein a decrease in depressive symptoms is the achievement of
a 50% or greater reduction of symptoms identified on a depression symptom rating scale, or
a score less than or equal to 7 on the HRSD 17 , or
less than or equal to 5 on the QID-SR 16 , or
less than or equal to 10 on the MADRS.
5. A method of treating a patient for bipolar depression, major depressive disorder, comprising
(1) determining that the patient is a ketamine non-responder; and
(2) administering an effective amount of isolated (2S,6S)-hydroxynorketamine, isolated (2R,6R)-hydroxynorketamine, isolated (2S,6R)-hydroxynorketamine, isolated (2R,6S)-hydroxynorketamine, isolated (R)-dehydroxynorketamine, or isolated (S)-dehydronorketamine to the patient.
6. The method of claim 5 , wherein the isolated (2S,6S)-hydroxynorketamine, isolated (2R,6R)-hydroxynorketamine, isolated (2S,6R)-hydroxynorketamine, isolated (2R,6S)-hydroxynorketamine, isolated (R)-dehydroxynorketamine, or isolated (S)-dehydronorketamine is administered together with an additional active agent.
7. The method of claim 2 , wherein the compound is in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier and the composition is formulated for oral administration, intravenous administration, or intramuscular injection.
8. The method of claim 2 , wherein the composition is a solution and contains from about 0.05 mg/ml to about 0.5 mg/ml of the compound.
9. The method of claim 2 , wherein the composition is formulated as an oral dosage form containing about 0.2 mg to about 500 mg of the compound.
10. The method of claim 2 , of treating bipolar depression.
11. The method of claim 2 , of treating major depressive disorder.