Neuroactive steroids, compositions, and uses thereof

Abstract

Described herein are methods of treating tremor, e.g., essential tremor; depression, e.g., postpostum depression; and anxiety disorder, the method comprising administering to a human subject suffering from tremor, e.g., essential tremor; depression, e.g., postpostum depression, an anxiety disorder with a neuroactive steroid or a composition comprising a neuroactive steroid (e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone).

1 - 90 . (canceled) 
     
     
         91 . A method for treating a human subject suffering from depression or an anxiety disorder, the method comprising administering to the subject a therapeutically effective amount of a neuroactive steroid. 
     
     
         92 . The method of  claim 91 , wherein the depression is clinical depression, postnatal or postpartum depression, atypical depression, melancholic depression, Psychotic Major Depression (PMD), catatonic depression, Seasonal Affective Disorder (SAD), dysthymia, double depression, Depressive Personality Disorder (DPD), Recurrent Brief Depression (RBD), minor depressive disorder, bipolar disorder or manic depressive disorder, post-traumatic stress disorders, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. 
     
     
         93 . (canceled) 
     
     
         94 . The method of  claim 91 , wherein the depression is postpartum depression. 
     
     
         95 . The method of  claim 91 , wherein the method provides acute treatment of the depression. 
     
     
         96 . The method of  claim 91 , wherein the method provides maintenance treatment or preventative treatment. 
     
     
         97 . The method of  claim 91 , wherein the method provides acute treatment of the depression or anxiety disorder. 
     
     
         98 . The method of  claim 91 , wherein the method provides rapid onset of efficacy. 
     
     
         99 . The method of  claim 91 , wherein the therapeutic effect is sustained. 
     
     
         100 . The method of  claim 91 , wherein the efficacy is maintained after a single course of treatment of a compound described herein. 
     
     
         101 . The method of  claim 91 , wherein the therapeutic effect is does not cause an adverse event. 
     
     
         102 . The method of  claim 91 , wherein the method includes a course of treatment with multiple dosages or cycles of treatment. 
     
     
         103 . The method of  claim 102 , wherein the first and second dose or cycle of treatment include the same compound. 
     
     
         104 . The method of  claim 102 , wherein the first dose or cycle of treatment includes a first compound and the second dose or cycle of treatment includes a second compound that is different from the first compound. 
     
     
         105 . The method of  claim 91 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 96, 84, 48, 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         106 . The method of  claim 91 , wherein the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period. 
     
     
         107 . The method of  claim 91 , wherein the decrease from baseline in HAM-D score is from severe to symptom-free. 
     
     
         108 . The method of  claim 106 , wherein the baseline score is about 10 to 52. 
     
     
         109 . The method of  claim 106 , wherein the baseline score is at least 10, 15, or 20. 
     
     
         110 . The method of  claim 106 , wherein the HAM-D score at the end of the treatment period is about 0 to 10. 
     
     
         111 . The method of  claim 106 , wherein the HAM-D score at the end of the treatment period is less than 10, 7, 5, or 3. 
     
     
         112 . The method of  claim 106 , wherein the decrease in HAM-D score is from a baseline score of about 20 to 30 to a HAM-D score at the end of the treatment period is about 0 to 10. 
     
     
         113 . The method of  claim 106 , wherein the decrease in the baseline HAM-D score to HAM-D score at the end of the treatment period is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold. 
     
     
         114 . The method of  claim 106 , wherein the percentage decrease in the baseline HAM-D score to HAM-D score at the end of the treatment period is at least 50%. 
     
     
         115 . The method of  claim 91 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         116 . The method of  claim 91 , wherein the therapeutic effect is an improvement measured by the EPDS. 
     
     
         117 . The method of  claim 91 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         118 . The method of  claim 91 , wherein the therapeutic effect is a CGI score of 2 or less. 
     
     
         119 . The method of  claim 91 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         120 . The method of  claim 91 , whereby the subject is substantially relieved of at least one symptom within 3, 2, or 1 days; or 24, 20, 16, 12, 10, 8 hours or less of said administration. 
     
     
         121 . The method of  claim 91 , wherein the subject is substantially relieved of at least one symptom for 1, 2, 3, 4, 5, 6, or 7 days; 1, 2, 3, or 4 weeks; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. 
     
     
         122 . The method of  claim 121 , wherein the symptom is suicidity. 
     
     
         123 . The method of  claim 121 , wherein the symptom is impaired cognitive function. 
     
     
         124 . The solution of  claim 91 , wherein the neuroactive steroid is selected from pregnanolone, ganaxolone, alphadalone, alphaxalone, and allopregnanolone. 
     
     
         125 . The solution of  claim 91 , wherein the neuroactive steroid is allopregnanolone. 
     
     
         126 . The solution of  claim 91 , wherein the neuroactive steroid is deuterated allopregnanolone. 
     
     
         127 . The solution of  claim 91 , wherein the neuroactive steroid is an estrol. 
     
     
         128 . The method of  claim 91 , wherein the subject is a female. 
     
     
         129 . The method of  claim 128 , wherein the female is not breast feeding. 
     
     
         130 . The method of  claim 91 , wherein the subject is an adult. 
     
     
         131 . The method of  claim 91 , wherein the subject is from 18 to 45 years of age. 
     
     
         132 . The method of  claim 91 , wherein the subject is suffering from. 
     
     
         133 . The method of  claim 91 , wherein the subject has experienced a Major Depressive Episode in the postpartum period. 
     
     
         134 . The method of  claim 133 , wherein the period begins within the first 4 weeks following delivery of a baby. 
     
     
         135 . The method of  claim 91 , wherein the infusion occurs over at least 1, 2, 3, 4, 5, 6, or 7 days. 
     
     
         136 . The method of  claim 91 , wherein the infusion occurs over the course of 1, 2, 3, 4, 5, 6, or 7 days. 
     
     
         137 . The method of  claim 91 , wherein the infusion is bolus infusion. 
     
     
         138 . The method of  claim 91 , wherein the infusion is a plurality of bolus infusions. 
     
     
         139 . The method of  claim 91 , wherein the plurality of bolus infusions is administered in 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more. 
     
     
         140 . The method of  claim 91 , wherein the infusion is an intermittent infusion. 
     
     
         141 . The method of  claim 91 , wherein the infusion is a continuous infusion. 
     
     
         142 . The method of  claim 91 , the method comprises administering a plurality of infusions. 
     
     
         143 . The method of  claim 142 , comprising administering a first, second, and third infusion. 
     
     
         144 . The method of  claim 143 , wherein the administration of the second infusion begins no longer than 90, 60, 30, 10, or 5 minutes after the beginning or end of the administration of the first infusion. 
     
     
         145 . The method of  claim 143 , wherein the second infusion begins 0 to 90, 0 to 60, 0 to 30, 0 to 10, or 0 to 5 minutes after the beginning or end of the administration of the first infusion. 
     
     
         146 . The method of  claim 143 , wherein the second infusion begins no more than 60, 30, 20, 10, 5, 4, 3, 2, 1 minute(s) after the end of administration of the first infusion. 
     
     
         147 . The method of  claim 143 , wherein the second infusion begins at the end of administration of the first infusion. 
     
     
         148 . The method of  claim 143 , wherein the first infusion and the initiation of the second infusion are performed with the same delivery device. 
     
     
         149 . The method of  claim 143 , wherein the amount of neuroactive steroid delivered/unit time varies during the first infusion. 
     
     
         150 . The method of  claim 143 , wherein the first (step-up) infusion delivers a smaller amount of neuroactive steroid/unit time than the second (maintenance) infusion. 
     
     
         151 . The method of  claim 143 , wherein the first (step-up) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a larger amount of neuroactive steroid/unit time than the step dose that precedes it. 
     
     
         152 . The method of  claim 143 , wherein said third infusion is administered for a period of time that is between 5 and 20 hours, 8 and 16 hours, 10 and 15 hours, or 10 and 13 hours. 
     
     
         153 . The method of  claim 143 , wherein said first infusion is administered for 12+/−2 hours. 
     
     
         154 . The method of  claim 143 , wherein said first infusion is administered for 12 hours. 
     
     
         155 . The method of  claim 143 , wherein the amount of neuroactive steroid delivered/unit time varies during the first infusion. 
     
     
         156 . The method of  claim 151 , wherein administering said step-up dose comprises administering a continuously increasing amount of neuroactive steroid. 
     
     
         157 . The method of  claim 151 , wherein administering said step-up dose comprises administering a continuously increasing amount of neuroactive steroid/unit time. 
     
     
         158 . The method of  claim 151 , comprising a first, second, and third step dose. 
     
     
         159 . The method of  claim 158 , said first step dose is administered at an amount of neuroactive steroid/unit time of 5-50 μg/kg/hour. 
     
     
         160 . The method of  claim 158 , said first step dose is administered at an amount of neuroactive steroid/unit time of 5-50 μg/kg/hour, 10-40 μg/kg/hour, 20-30 μg/kg/hour, 20 μg/kg/hour, 21 μg/kg/hour, 22 μg/kg/hour, or 21.5 μg/kg/hour. 
     
     
         161 . The method of  claim 158 , said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 μg/kg/hour. 
     
     
         162 . The method of  claim 158 , said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 μg/kg/hour, 20-70 μg/kg/hour, 30-50 μg/kg/hour, 42 μg/kg/hour, 43 μg/kg/hour, or 44 μg/kg/hour. 
     
     
         163 . The method of  claim 158 , said third step dose is administered at an amount of neuroactive steroid/unit time of 25-150 μg/kg/hour, 
     
     
         164 . The method of  claim 158 , said third step dose is administered at an amount of neuroactive steroid/unit time of 25-150 μg/kg/hour, 40-100 μg/kg/hour, 60-70 μg/kg/hour, 63 μg/kg/hour, 64 μg/kg/hour, 65 μg/kg/hour, or 64.5 μg/kg/hour. 
     
     
         165 . The method of  claim 158 , wherein the third (step-down/downward taper) infusion delivers a smaller amount of neuroactive steroid/unit time than the second (maintenance) infusion. 
     
     
         166 . The method of  claim 158 , wherein the third (step-down/downward taper) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a lower amount of neuroactive steroid/unit time than the step dose that precedes it. 
     
     
         167 . The method of  claim 158 , wherein said third infusion is administered for a period of time that is between 5 and 20 hours, 8 and 16 hours, 10 and 15 hours, or 10 and 13 hours. 
     
     
         168 . The method of  claim 158 , wherein said third infusion is administered for 12+/−2 hours. 
     
     
         169 . The method of  claim 158 , wherein said third infusion is administered for 12 hours. 
     
     
         170 . The method of  claim 166 , wherein administering said downward taper dose comprises administering a continuously decreasing amount of neuroactive steroid. 
     
     
         171 . The method of  claim 166 , wherein administering said downward taper dose comprises administering a continuously decreasing amount of neuroactive steroid/unit time. 
     
     
         172 . The method of  claim 166 , comprising a first, second, and third step dose. 
     
     
         173 . The method of  claim 172 , said first step dose is administered at an amount of neuroactive steroid/unit time of 25-150 μg/kg/hour, 
     
     
         174 . The method of  claim 172 , said first step dose is administered at an amount of neuroactive steroid/unit time of 25-150 μg/kg/hour, 40-100 μg/kg/hour, 60-70 μg/kg/hour, 63 μg/kg/hour, 64 μg/kg/hour, 65 μg/kg/hour, or 64.5 μg/kg/hour. 
     
     
         175 . The method of  claim 172 , said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 μg/kg/hour. 
     
     
         176 . The method of  claim 172 , said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 μg/kg/hour, 20-70 μg/kg/hour, 30-50 μg/kg/hour, 42 μg/kg/hour, 43 μg/kg/hour, or 44 μg/kg/hour. 
     
     
         177 . The method of  claim 172 , said third step dose is administered at an amount of neuroactive steroid/unit time of 5-50 μg/kg/hour. 
     
     
         178 . The method of  claim 172 , said third step dose is administered at an amount of neuroactive steroid/unit time of 5-50 μg/kg/hour, 10-40 μg/kg/hour, 20-30 μg/kg/hour, 20 μg/kg/hour, 21 μg/kg/hour, 22 μg/kg/hour, or 21.5 μg/kg/hour. 
     
     
         179 . The method of  claim 143 , wherein the method comprises administering a second/maintenance infusion of 50-150 μg/kg/hour of the neuroactive steroid. 
     
     
         180 . The method of  claim 143 , wherein the second/maintenance infusion is 50-150 μg/kg/hour, 60-100 μg/kg/hour, 70-90 μg/kg/hour, 85 μg/kg/hour, 86 μg/kg/hour, or 87 μg/kg/hour. 
     
     
         181 . The method of  claim 143 , wherein said second/maintenance infusion is administered for a period of time that is between 5 and 80 hours, 10 and 70 hours, 20 and 50 hours, or 30 and 40 hours. 
     
     
         182 . The method of  claim 143 , wherein said second/maintenance infusion is administered for 36+/−5 hours. 
     
     
         183 . The method of  claim 143 , wherein said second/maintenance infusion is administered for 36 hours. 
     
     
         184 . The method of  claim 143 , wherein the plasma concentration of said second/maintenance infusion is measured at a preselected time. 
     
     
         185 . The method of  claim 143 , wherein said second/maintenance infusion results in a plasma concentration of 150 nM. 
     
     
         186 . The method of  claim 143 , wherein said second/maintenance infusion is administered at the same amount of neuroactive steroid/unit time over the entire second/maintenance infusion. 
     
     
         187 . The method of  claim 158 , wherein:
 said first step dose is 10 to 40% (e.g., 25%) of the second/maintenance infusion;   said second step dose is 30 to 70% of the second/maintenance infusion; and   said third step dose is 60 to 90% of the second/maintenance infusion.   
     
     
         188 . The method of  claim 137 , wherein:
 said first step dose is 60 to 90% of the second/maintenance infusion;   said second step dose is 30 to 70% of the second/maintenance infusion; and   said third step dose is 10 to 40% of the second/maintenance infusion.   
     
     
         189 . The method of  claim 158 , wherein:
 the amount of neuroactive steroid delivered/unit time in said first step dose is 10 to 40% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion;   the amount of neuroactive steroid delivered/unit time in said second step dose is 30 to 70% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; and   the amount of neuroactive steroid delivered/unit time in said third step dose is 60 to 90% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion.   
     
     
         190 . The method of  claim 172 , wherein:
 the amount of neuroactive steroid delivered/unit time in said first step dose is 60 to 90% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion;   the amount of neuroactive steroid delivered/unit time in said second step dose is 30 to 70% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; and   the amount of neuroactive steroid delivered/unit time in said third step dose is 10 to 40% of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion.   
     
     
         191 . A method for treating a human subject suffering from depression or an anxiety disorder, the method comprising:
 administering a first infusion of a neuroactive steroid, wherein said first/step-up infusion is administered for 8-16 hours;   administering a second/maintenance infusion of a neuroactive steroid, wherein said second/maintenance infusion is administered for 24-48 hours; and   administering a third infusion of a neuroactive steroid, wherein said third/downward taper infusion is administered for 8-16 hours;   said neuroactive steroid doses being sufficient to treat said subject.   
     
     
         192 . A method for treating a human subject suffering from depression or an anxiety disorder, the method comprising:
 administering a first infusion of a neuroactive steroid, said first/step-up infusion comprising administering a continuously increasing amount of neuroactive steroid at an amount of neuroactive steroid/unit time of 5-100 μg/kg/hour, 10-80 μg/kg/hour, or 15-70 μg/kg/hour;   administering a second/maintenance infusion of a neuroactive steroid, said second/maintenance infusion comprising administering an amount of neuroactive steroid/unit time of 50-100 μg/kg/hour, 70-100 μg/kg/hour, or 86 μg/kg/hour; and   administering a third infusion of a neuroactive steroid, said third/downward taper infusion comprising administering a continuously decreasing amount of neuroactive steroid at an amount of neuroactive steroid/unit time of 5-100 μg/kg/hour, 10-80 μg/kg/hour, or 15-70 μg/kg/hour;   said neuroactive steroid doses being sufficient to treat said subject.   
     
     
         193 . The method of  claim 191  or  192 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         194 . The method of  claim 193 , wherein the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period. 
     
     
         195 . The method of  claim 191  or  192 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         196 . The method of  claim 193 , wherein the therapeutic effect is an improvement measured by the EPDS. 
     
     
         197 . The method of  claim 191  or  192 , wherein the method provides therapeutic effect within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. 
     
     
         198 . The method of  claim 193 , wherein the therapeutic effect is a CGI score of 2 or less. 
     
     
         199 . The method of  claim 91 , wherein the neuroactive steroid is provided in a composition comprising a cyclodextrin. 
     
     
         200 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 0.1 to 10 mg/mL neuroactive steroid. 
     
     
         201 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid. 
     
     
         202 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 1.25 mg/mL neuroactive steroid. 
     
     
         203 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 2.5 mg/mL neuroactive steroid. 
     
     
         204 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 3.75 mg/mL neuroactive steroid. 
     
     
         205 . The method of  claim 91 , wherein the neuroactive steroid is provided at a concentration of 5 mg/mL neuroactive steroid. 
     
     
         206 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 1-30%, 2-18%, or 10-15% by weight of cyclodextrin per volume of composition. 
     
     
         207 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 1, 2.5, 5, 10, 12, 13, 15, or 30% by weight of cyclodextrin per volume of composition. 
     
     
         208 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition. 
     
     
         209 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 1-30%, 2-18%, or 10-15% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid. 
     
     
         210 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 1, 2.5, 5, 10, 12, 13, 15, or 30% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid. 
     
     
         211 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 5 mg/mL neuroactive steroid. 
     
     
         212 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 3.75 mg/mL neuroactive steroid. 
     
     
         213 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 2.5 mg/mL neuroactive steroid. 
     
     
         214 . The method of  claim 199 , wherein the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 1.25 mg/mL neuroactive steroid. 
     
     
         215 - 217 . (canceled) 
     
     
         218 . A method of treating a subject suffering from depression or an anxiety disorder comprising the steps of:
 a) receiving information related to the therapeutic effect of a neuroactive steroid in reducing the depression or anxiety disorder in a subject treated with the neuroactive steroid; and   b) administering to the subject a therapeutic compound if the information indicates that the depression or anxiety disorders reduced in the subject as compared to the subject before having received the neuroactive steroid (e.g., allopregnanolone),   thereby treating the subject.   
     
     
         219 - 220 . (canceled) 
     
     
         221 . The method of  claim 218 , wherein the information is received about 1, 2, or 3 months after administration of the neuroactive steroid. 
     
     
         222 . The method of  claim 218 , wherein the subject has been administered the neuroactive steroid less than about 3 months prior to receiving the information. 
     
     
         223 . The method of  claim 218 , wherein the subject has been administered the neuroactive steroid by intravenous infusion. 
     
     
         224 . The method of  claim 218 , wherein the therapeutic compound is administered by oral administration. 
     
     
         225 . The method of  claim 224 , wherein the therapeutic compound is administered as a solid composition. 
     
     
         226 - 235 . (canceled) 
     
     
         236 . The method of  claim 91 , wherein the depression is major depressive disorder.