Intranasal administration of ketamine to treat depression
Inventors
Charney, Dennis S. • Mathew, Sanjay J. • Manji, Husseini K. • Zarate, Jr., Carlos A. • Krystal, John H.
Assignees
Yale University • Icahn School of Medicine at Mount Sinai • US Department of Veterans Affairs • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-8785500-B2
Publication Date
2014-07-22
Expiration Date
2027-03-20
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Abstract
Methods and compositions for the treatment of treatment-resistant depression are described. More specifically, the invention demonstrates that intranasal administration of ketamine is effective to ameliorate the symptoms of depression in a patient who has not responded to an adequate trial of one antidepressant in the current episode and has recurrent or chronic depressive symptoms (>2 years).
Core Innovation
The invention relates to methods and compositions for the treatment of treatment-resistant depression, with a particular focus on intranasal administration of ketamine. It has been demonstrated that intranasal administration of ketamine is effective to ameliorate symptoms of depression in patients who have not responded to an adequate trial of at least one antidepressant during their current episode and who have recurrent or chronic depressive symptoms lasting more than 2 years. The ketamine can be administered in a pharmaceutically acceptable carrier at doses ranging between about 0.1 mg/kg per day to about 3.0 mg/kg per day.
The problem addressed by the invention is the inadequacy of current antidepressant medications which take weeks to months to achieve full therapeutic effects, resulting in continued suffering and increased risk of self-harm in depressed patients. Treatment-resistant depression remains a considerable clinical challenge with substantial morbidity. There is a need for pharmacological strategies that produce rapid onset of antidepressant effects, ideally within hours, and that provide sustained relief. Existing therapies also often require clinical settings due to intravenous administration or have side effects that limit usability and patient acceptance.
The invention further contemplates alternative administration routes including intravenous and transdermal administration of ketamine to treat treatment-resistant depression. Furthermore, administration may be a single dose or multiple doses, and ketamine can be combined with other antidepressant agents, such as lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines. The invention also provides for devices enabling patient self-administration of metered doses of ketamine via nasal spray inhalers or transdermal patches, facilitating outpatient treatment and improving patient acceptability.
Claims Coverage
The patent contains one independent claim directed to a method of treating depression. The claim covers intranasal administration of ketamine for treatment of depression resistant to at least two adequate antidepressant treatments. The inventive features focus on the patient population, administration route, dosage, and combination with other antidepressants.
Method of treating treatment-resistant depression by intranasal ketamine
Intranasal administering ketamine to a patient who suffers from depression and has not responded to at least two adequate antidepressant treatments, at a dosage sufficient to alleviate depression symptoms.
Specific ketamine dosage range
Administering ketamine in a pharmaceutically acceptable carrier at a dose between about 0.1 mg/kg per day to about 3.0 mg/kg per day.
Rapid symptom alleviation
Symptoms of depression are alleviated within 2 hours of intranasal administration of ketamine.
Single or multiple dose regimens
Method may comprise intranasal administration of a single dose or multiple doses of ketamine, wherein a single dose can provide symptom relief for about 7 days.
Combination therapy with a second antidepressant agent
The method may further comprise administering a pharmaceutically effective dose of a second antidepressant agent, which can be lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, or benzodiazepines.
Definition of adequate antidepressant treatments and patient selection
Adequate antidepressant treatments are selected from a list including atypical antipsychotics, benzodiazepines, bupropion, electroconvulsive therapy, lamotrigine, lithium, monoamine oxidase inhibitors, selective norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, valproic acid, nefazodone, trazodone, and pramipexole; patients have failed at least two adequate treatments, optionally from different classes.
The claims collectively cover methods of treating treatment-resistant depression using intranasal administration of ketamine at defined doses, providing rapid and sustained antidepressant effects. They include combinations with other antidepressant agents and specify patient populations characterized by failure of at least two adequate antidepressant treatments using recognized classes. The claims emphasize single or multiple dose regimens and rapid symptom relief within hours.
Stated Advantages
Rapid onset of antidepressant effects within hours of administration.
Sustained relief from depressive symptoms lasting up to about 7 days after a single dose.
Ability for patient self-administration, allowing outpatient treatment and eliminating the need for intravenous administration in a clinical setting.
Reduced need for higher doses of second antidepressant agents when used in combination.
Ketamine is inexpensive and readily available with minor adverse side effects.
Nasal administration is non-invasive and socially acceptable.
Documented Applications
Treatment of treatment-resistant depression in patients who have not responded to at least two adequate antidepressant treatments.
Management of chronic major depression including major depressive disorder, seasonal affective disorder, bipolar depression, mood disorders related to medical conditions, and other depressive disorders resistant to treatment.
Outpatient treatment through self-administration of intranasal ketamine.
Repeated administration of intravenous ketamine for rapid mood stabilization in hospital settings.
Use of transdermal ketamine patches for treatment-resistant depression.
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