Method of treating major depressive disorder

Abstract

The invention provides methods of treating depressive disorders, in particular major depression but other depressive orders also, with prodrug stimulants or analogs including amphetamine prodrugs, methylphenidate prodrugs, and methylphenidate analogs, Such methods of treatment may utilize the prodrug stimulant or analog as monotherapy or, more commonly, as an adjunct to antidepressant medication treatment to augment their effect. The invention includes combination methods of treatment in which an amphetamine prodrug, methylphenidate prodrug, or methylphenidate analog is administered to an individual in need with one or more other active agents, either in separate forms or as a single pharmaceutical formulation. Packaged pharmaceutical compositions containing an amphetamine or methylphenidate prodrug, instructions for using the prodrug to treat certain disorders, and optionally one or more other active agents are provided by the invention.

1 . (canceled) 
     
     
         2 . A method of treating major depressive disorder comprising (i) diagnosing a patient as having major depressive disorder and as failing to achieve remission in response to antidepressant therapy and (ii) administering to the patient an effective amount lisdexamfetamine dimesylate together with an additional active agent, wherein the additional active agent is an antidepressant, and the effective amount is an amount effective in a clinical trial of efficac of lisdexamfetamine dimes late for treating major depressive disorder, in which data is submitted to the FDA. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The method of  claim 2  wherein from 2.5 to 200 mg lisdexamfetamine dimesylate is administered daily. 
     
     
         7 . The method of  claim 2 , wherein 15 to 100 mg lisdexamfetamine dimesylate is administered once per day. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 2 , wherein the effective amount is additionally an amount effective to decrease major depressive disorder symptoms. 
     
     
         10 . The method of  claim 9 , wherein the decrease in major depressive disorder symptoms is a 50% or greater reduction of symptoms identified on a depression symptom rating scale or achieving a score less than or equal to 7 on the HRSD 17 ; or less than or equal to 5 on the QIDS-SR 16 ; or less than or equal to 10 on the MADRS. 
     
     
         11 . The method of  claim 2 , wherein the additional active agent is an antidepressant selected from a selective serotonin reuptake inhibitor, a serotonin 5HT receptor partial agonist or antagonist, a norepinephrine dopamine reuptake inhibitor, a serotonin norepinephrine dopamine reuptake inhibitor, a selective serotonin norepinephrine reuptake inhibitor, a serotonin 5-HT1a partial agonist, a serotonin 5-HT1b agonist, a serotonin 5-HT2 antagonist, a serotonin 5-HT6 antagonist, a serotonin-2 antagonist reuptake inhibitor, a serotonin-1 agonist reuptake inhibitor, a mixed serotonin antagonist reuptake inhibitor/partial agonist/dopamine agonist, an alpha-2 antagonist/serotonin 5HT2-3 receptor antagonist, a serotonin modulator or stimulator, a mixed serotonin antagonist/melatonin agonist, a mixed serotonin dopamine antagonist, a tricyclic antidepressant, a tetracyclic antidepressant, a bis-aryl-sulphanyl modulator, a beta-3 adrenoreceptor stimulator or agonist, a beta-3 adrenoreceptor antagonist, a nicotinic acetylcholine receptor agonist or antagonist, an enkephalinergic modulator, an aprepitant, a neurokinin (NK) antagonist, a NK1, 2, or 3 antagonist, a neuropeptide (NP) Y antagonist, a NPY1, 2, or 3, or 5 antagonist, a substance P antagonist, a corticotrophin-releasing hormone (CRH or CRF) antagonist, a CRH (or CRF)-1 antagonist, a glucocorticoid receptor agonist or partial agonist, a glucocorticoid receptor antagonist, a glucocorticoid receptor type II antagonist, an anti-convulsant, a glutamate modulator, an mGluR receptor modulator, agonist or antagonist, an mGluR2/3 agonist, an mGluR5 antagonist, an estrogen receptor agonist or antagonist, a melatonin receptor agonist or antagonist, a glycine transporter inhibitor, an alpha-1 receptor agonist, an alpha-1 receptor antagonist, an alpha-2 receptor agonist, an alpha-2 receptor antagonist, a vasopressin-1B (V1B) agonist or antagonist, an NMDA modulator (i.e., a partial agonist, agonist, or antagonist), a mood modulating (i.e., stabilizing) agent, a monoamine oxidase inhibitor, or a combination of the foregoing. 
     
     
         12 . The method of  claim 11 , wherein the additional active agent is clovoxamine, femoxetine, flesinoxan, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, desvenlafaxine, mirtazapine, venlafaxine, atomoxetine, reboxetine, thionisoxetine, bupropion, mianserin, nefazodone, trazodone, doxepin, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine, tranylcypromine, isocarboxazid, phenelzine, selegiline, moclobemide, buspirone, tryptophan, pindolol, agomelatine, amibegron, casopitant, delucemine, elzasonan, gepirone, mecamylamine, milnacipran, miraxion, nemifitide, pexacerfont, saredutant, tofisopam, vestipitant, vilazodone, aripiprazole, clozapine, loxapine, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, asenapine, iloperidonepimavanserin, lithium, valproic acid, carbamazepine, eslicarbazepine, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, riluzole, varenicline, L or pharmaceutically active salts or prodrugs thereof, or a combination of the foregoing. 
     
     
         13 . (canceled) 
     
     
         14 . The methods of claim  52 , wherein the additional active agent an antidepressant chosen from mirtazapine, escitalopram, fluoxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, and the pharmaceutically acceptable salts and hydrates of any of the foregoing. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . A method of using lisdexamfetamine dimesylate comprising informing a user that the lisdexamfetamine dismesylate may be used to treat major depressive disorder. 
     
     
         18 . The method of  claim 17  additionally comprising providing the user with an amount of lisdexamfetamine dimesylate effective in a clinical trial of efficacy of lisdexamfetamine dimesylated for treating major depressive disorder, in which data is submitted to the FDA. 
     
     
         19 . The method of  claim 18 , additionally comprising providing lisdexamfetamine dimesylate in a container and the informing is by reference to a package insert associated with the container. 
     
     
         20 . The method of  claim 17 , wherein the informing is by reference to information material; by reference to a package active agent insert, a flyer or an advertisement; by presentation of information at a seminar, conference, or other educational presentation; or by a conversation between a pharmaceutical sales representative and a medical care worker. 
     
     
         21 - 26 . (canceled) 
     
     
         27 . A method of using lisdexamfetamine dimesylate comprising (i) conducting a clinical trial of the efficacy lisdexamfetamine dimesylate for treating major depressive disorder and (ii) informing a purchaser of the lisdexamfetamine dismesylate that the lisdexamfetamine dismesylate is efficacious for treating major depressive disorder. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 27 , wherein the clinical trial generates data that is submitted to the FDA. 
     
     
         30 . The method of  claim 2 , wherein the amphetamine prodrug, methylphenidate prodrug, or methylphenidate analog is lisdexamfetamine and 15 to 75 mg lisdexamfetamine are administered daily.