Treatments for depression and other diseases with a low dose agent

Abstract

The present invention relates to improved compositions and methods for the treatment or prevention of various diseases, including forms of depression, including, for example, breakthrough depression and treatment-refractory depression, and other mood disorders, as well as Parkinson's disease, bipolar disorder, bipolar disorder, attention deficit disorder (ADHD), Restless Leg Syndrome (RLS), and obesity. In some embodiments, the compositions and methods comprise low dose naltrexone or related opioid antagonists.

What is claimed is: 
     
         1 . A method of treating or preventing breakthrough depression, comprising administering a therapeutically effective low dose amount of naltrexone to a patient in need thereof. 
     
     
         2 . The method of  claim 1 , wherein the therapeutically effective low dose amount of naltrexone is administered in conjunction with a patient's pre-existent anti-depression treatment,
 wherein the pre-existent anti-depression treatment comprises one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI).   
     
     
         3 . The method of  claim 1  or  2 , wherein breakthrough depression comprises depressive relapse and/or recurrence. 
     
     
         4 . The method of  claims 1 - 3 , wherein the therapeutically effective low dose amount of naltrexone is administered at doses that reverse or prevent desensitization of a dopamine receptor. 
     
     
         5 . The method of  claim 4 , wherein the dopamine receptor is one or more of the D 2  and D 3  receptors. 
     
     
         6 . The method of  claims 1 - 5 , wherein the therapeutically effective low dose amount of naltrexone is administered at doses that are substantially below levels that induce significant opioid blockade. 
     
     
         7 . The method of  claim 4  or  6 , wherein the amount of naltrexone administered is less than 10 mg. 
     
     
         8 . The method of  claim 4  or  6 , wherein the amount of naltrexone administered is about 1-4 mg. 
     
     
         9 . The method of  claim 4  or  6 , wherein the amount of naltrexone administered is about 1 mg. 
     
     
         10 . The method of  claims 2 - 9 , wherein the dopamine active anti-depressant agent is one or more of bupropion, aripiprazole, and sertraline. 
     
     
         11 . The method of  claim 2 - 9 , wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone, and milnacipran. 
     
     
         12 . The method of  claim 2 - 9 , wherein the dopamine active augmenting agent is one or more of an amphetamine salt, pramipexole, and ropinirole. 
     
     
         13 . The method of  claim 2 - 9 , wherein the SSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, and zimelidine. 
     
     
         14 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises reduction in length of a depressive episode. 
     
     
         15 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises recovery of an anti-depressive effect of the patient's pre-existent anti-depression treatment regimen. 
     
     
         16 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises a reduction in the rate of relapse after major depressive episodes. 
     
     
         17 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises prevention or reversal of loss of efficacy of the patient's pre-existent anti-depression treatment. 
     
     
         18 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises reduction in an effective dosage of the patient's pre-existent anti-depression treatment. 
     
     
         19 . The method of  claim 18 , wherein the reduction in an effective dosage of the patient's pre-existent anti-depression treatment causes one or more of a reduction in side effects and increase in patient adherence. 
     
     
         20 . The method of any of the above claims, wherein the therapeutically effective low dose amount of naltrexone is administered orally or subcutaneously. 
     
     
         21 . A method of preventing or treating treatment-refractory depression, comprising administering a therapeutically effective low dose amount of naltrexone to a patient in need thereof. 
     
     
         22 . The method of  claim 21 , wherein the therapeutically effective low dose amount of naltrexone is administered in conjunction with a patient's pre-existent anti-depression treatment, wherein the pre-existent anti-depression treatment comprises one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI). 
     
     
         23 . The method of  claim 21  or  22 , wherein treatment-refractory depression comprises depressive relapse and/or recurrence. 
     
     
         24 . The method of  claims 21 - 23 , wherein the therapeutically effective low dose amount of naltrexone is administered at doses that reverse or prevent desensitization of a dopamine receptor. 
     
     
         25 . The method of  claim 24 , wherein the dopamine receptor is one or more of the D 2  and D 3  receptors. 
     
     
         26 . The method of  claims 21 - 25 , wherein the therapeutically effective low dose amount of naltrexone is administered at doses that are substantially below levels that induce significant opioid blockade. 
     
     
         27 . The method of  claim 24  or  26 , wherein the amount of naltrexone administered is less than 10 mg. 
     
     
         28 . The method of  claim 24  or  26 , wherein the amount of naltrexone administered is about 1-4 mg. 
     
     
         29 . The method of  claim 24  or  26 , wherein the amount of naltrexone administered is about 1 mg. 
     
     
         30 . The method of  claim 22 - 29 , wherein the dopamine active anti-depressant agent is one or more of bupropion, aripiprazole, and sertraline. 
     
     
         31 . The method of  claim 22 - 29 , wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone, and milnacipran. 
     
     
         32 . The method of  claim 22 - 29 , wherein the dopamine active augmenting agent is one or more of an amphetamine salt, pramipexole, and ropinirole. 
     
     
         33 . The method of  claim 22 - 29 , wherein the SSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, and zimelidine. 
     
     
         34 . The method of any of the above claims, wherein the preventing or treating treatment-refractory depression comprises reduction in length of a depressive episode. 
     
     
         35 . The method of any of the above claims, wherein the preventing or treating treatment-refractory depression comprises recovery of an anti-depressive effect of the patient's pre-existent anti-depression treatment regimen. 
     
     
         36 . The method of any of the above claims, wherein the preventing or treating treatment-refractory depression comprises a reduction in the rate of relapse after major depressive episodes. 
     
     
         37 . The method of any of the above claims, wherein the preventing or treating treatment-refractory depression comprises prevention or reversal of loss of efficacy of the patient's pre-existent anti-depression treatment. 
     
     
         38 . The method of any of the above claims, wherein the wherein the preventing or treating treatment-refractory depression comprises reduction in an effective dosage of the patient's pre-existent anti-depression treatment. 
     
     
         39 . The method of  claim 38 , wherein the reduction in an effective dosage of the patient's pre-existent anti-depression treatment causes one or more of a reduction in side effects and increase in patient adherence. 
     
     
         40 . The method of any of the above claims, wherein the effective amount of low dose naltrexone is administered orally or subcutaneously. 
     
     
         41 . A method of preventing or treating breakthrough depression, comprising administering a combination of a therapeutically effective low dose amount of naltrexone and a therapeutically effective amount of one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI) to a patient in need thereof. 
     
     
         42 . The method of  claim 41 , wherein the combination is administered in conjunction with a patient's pre-existent anti-depression treatment, wherein the pre-existent anti-depression treatment comprises one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitors (SSRI). 
     
     
         43 . The method of  claim 41  or  42 , wherein breakthrough depression comprises depressive relapse and/or recurrence. 
     
     
         44 . The method of  claims 41 - 43 , wherein the low dose naltrexone is administered at doses that reverse or prevent desensitization of a dopamine receptor. 
     
     
         45 . The method of  claim 44 , wherein the dopamine receptor is one or more of the D 2  and D 3  receptors. 
     
     
         46 . The method of  claims 41 - 45 , wherein the therapeutically effective low dose amount of naltrexone is administered is administered at doses that are substantially below levels that induce significant opioid blockade. 
     
     
         47 . The method of  claim 44  or  46 , wherein the amount of naltrexone administered is less than 10 mg. 
     
     
         48 . The method of  claim 44  or  46 , wherein the amount of naltrexone administered is about 1-4 mg. 
     
     
         49 . The method of  claim 44  or  46 , wherein the amount of naltrexone administered is about 1 mg. 
     
     
         50 . The method of  claims 41 - 49 , wherein the dopamine active anti-depressant agent is one or more of bupropion, aripiprazole, and sertraline. 
     
     
         51 . The method of  claim 41 - 49 , wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone, and milnacipran. 
     
     
         52 . The method of  claims 41 - 49 , wherein the dopamine active augmenting agent is one or more of an amphetamine salt, pramipexole, and ropinirole. 
     
     
         53 . The method of  claims 41 - 49 , wherein the SSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, and zimelidine. 
     
     
         54 . The method of  claims 41 - 49 , wherein the preventing or treating breakthrough depression comprises reduction in length of a depressive episode. 
     
     
         55 . The method of  claims 41 - 49 , wherein the preventing or treating breakthrough depression comprises recovery of the anti-depressive effect of the patient's pre-existent anti-depression treatment regimen. 
     
     
         56 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises a reduction in the rate of relapse after major depressive episodes. 
     
     
         57 . The method of any of the above claims, wherein the preventing or treating breakthrough depression comprises prevention or reversal of loss of efficacy of the patient's pre-existent anti-depression treatment. 
     
     
         58 . The method of any of the above claims, wherein the wherein the preventing or treating breakthrough depression comprises reduction in an effective dosage of the patient's pre-existent anti-depression treatment. 
     
     
         59 . The method of  claim 58 , wherein the reduction in an effective dosage of the patient's pre-existent anti-depression treatment causes one or more of a reduction in side effects and increase in patient adherence. 
     
     
         60 . The method of any of the above claims wherein the effective amount of low dose naltrexone is administered orally or subcutaneously. 
     
     
         61 . The method of  claims 41 - 60 , wherein the naltrexone and one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitors (SSRI) are co-formulated in a single dosage form. 
     
     
         62 . The method of  claim 41 , wherein the dosage form is an oral dosage form. 
     
     
         63 . The method of  claim 41 , wherein the dosage form is a subcutaneous dosage form. 
     
     
         64 . A method of preventing or treating treatment-refractory depression, comprising administering a combination of a therapeutically effective low dose amount of naltrexone and a therapeutically effective amount of one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI) to a patient in need thereof. 
     
     
         65 . The method of  claim 64 , wherein the combination is administered in conjunction with a patient's pre-existent anti-depression treatment, wherein the pre-existent anti-depression treatment comprises one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitors (SSRI). 
     
     
         66 . The method of  claim 64  or  65 , wherein treatment-refractory depression comprises depressive relapse and/or recurrence. 
     
     
         67 . The method of  claims 64 - 66 , wherein the low dose naltrexone is administered at doses that reverse or prevent desensitization of a dopamine receptor. 
     
     
         68 . The method of  claim 67 , wherein the dopamine receptor is one or more of the D 2  and D 3  receptors. 
     
     
         69 . The method of  claims 64 - 68 , wherein the low dose naltrexone is administered at doses that are substantially below levels that induce significant opioid blockade. 
     
     
         70 . The method of  claim 67  or  69 , wherein the amount of naltrexone administered is less than 10 mg. 
     
     
         71 . The method of  claim 67  or  69 , wherein the amount of naltrexone administered is about 1-4 mg. 
     
     
         72 . The method of  claim 67  or  69 , wherein the amount of naltrexone administered is about 1 mg. 
     
     
         73 . The method of  claims 64 - 72 , wherein the dopamine active anti-depressant agent is one or more of bupropion, aripiprazole, and sertraline. 
     
     
         74 . The method of  claim 64 - 73 , wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone, and milnacipran. 
     
     
         75 . The method of  claims 64 - 73 , wherein the dopamine active augmenting agent is one or more of an amphetamine salt, pramipexole, and ropinirole. 
     
     
         76 . The method of  claims 64 - 73 , wherein the SSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, and zimelidine. 
     
     
         77 . The method of  claims 64 - 73 , wherein the preventing or treating treatment-refractory depression comprises reduction in length of a depressive episode. 
     
     
         78 . The method of  claims 64 - 73 , wherein the preventing or treating treatment-refractory depression comprises recovery of the anti-depressive effect of the patient's pre-existent anti-depression treatment regimen. 
     
     
         79 . The method of  claims 64 - 73 , wherein the preventing or treating treatment-refractory depression comprises a reduction in the rate of relapse after major depressive episodes. 
     
     
         80 . The method of  claims 64 - 73 , wherein the preventing or treating treatment-refractory depression comprises prevention or reversal of loss of efficacy of the patient's pre-existent anti-depression treatment. 
     
     
         81 . The method of  claims 64 - 73 , wherein the wherein the preventing or treating treatment-refractory depression comprises reduction in an effective dosage of the patient's pre-existent anti-depression treatment. 
     
     
         82 . The method of  claim 81 , wherein the reduction in an effective dosage of the patient's pre-existent anti-depression treatment causes one or more of a reduction in side effects and increase in patient adherence. 
     
     
         83 . The method of  claim 64  or  65 , wherein the effective amount of low dose naltrexone is administered orally. 
     
     
         84 . The method of  claim 64  or  65 , wherein the naltrexone and one or more of a dopamine active anti-depressant agent, a dopamine active augmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitors (SSRI) are co-formulated in a single dosage form. 
     
     
         85 . The method of  claim 64 , wherein the dosage form is an oral dosage form. 
     
     
         86 . The method of  claim 64 , wherein the dosage form is a subcutaneous dosage form. 
     
     
         87 . The methods of  claim 64  or  65 , where the outcome is rapid antidepressant response compared to the usual latency for response to traditional antidepressant pharmacotherapy. 
     
     
         88 . The method of  claim 87 , wherein the rapid antidepressant response is less than about 10 days. 
     
     
         89 . The method of  claim 87 , wherein the usual latency for response to traditional antidepressant pharmacotherapy is about 3-6 weeks. 
     
     
         90 . A method of treating breakthrough depression, comprising administering a therapeutically effective low dose amount of naltrexone to a patient in need thereof, wherein:
 the patient is on an antidepressant regimen comprising a pro-dopaminergic agent and   the therapeutically effective low dose amount of naltrexone is about 1 mg bid.