Methods for treating bipolar disorder

Abstract

The invention is directed to a method of treating bipolar disorder in a subject, comprising administering a therapeutically effective amount of a carbamate compound, or pharmaceutically acceptable salt or amide thereof.

Claims

1. A method of diminishing manic symptoms in a mammal suffering from bipolar disorder, wherein the mammal is exhibiting manic symptoms of bipolar disorder, comprising the administration of a therapeutically effective amount of a compound having structural Formula (1) or a pharmaceutically acceptable salt thereof, to a mammal in need thereof: ##STR00007## wherein, R is hydrogen; x is 1; and R.sub.1 and R.sub.2 are hydrogen, to thereby diminish the manic symptoms in the mammal suffering from bipolar disorder.

2. The method of claim 1, wherein the compound having structural Formula (1) is an enantiomer substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer of the compound having structural Formula (1) predominates.

3. The method of claim 2, wherein one enantiomer predominates to the extent of about 90% or greater.

4. The method of claim 3, wherein one enantiomer predominates to the extent of about 98% or greater.

5. The method of claim 2, wherein the enantiomer is (S) or (L) enantiomer as represented by Structural Formula (1a): ##STR00008##

6. The method of claim 5, wherein one enantiomer predominates to the extent of about 90% or greater.

7. The method of claim 6, wherein one enantiomer predominates to the extent of about 98% or greater.

8. The method of claim 2, wherein the enantiomer is (R) or (D) enantiomer, as represented by Structural Formula (1b): ##STR00009##

9. The method of claim 8, wherein one enantiomer predominates to the extent of about 90% or greater.

10. The method of claim 9, wherein one enantiomer predominates to the extent of about 98% or greater.

11. The method of claim 8, wherein the enantiomer is (R)-(beta-amino -benzenepropyl)carbamate.

12. The method of claim 11, wherein the enantiomer of (R)-(beta-amino -benzenepropyl)carbamate predominates to the extent of about 90% or greater.

13. The method of claim 12, wherein the enantiomer of (R)-(beta-amino -benzenepropyl)carbamate predominates to the extent of about 98% or greater.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows the influence of the tested compound on spontaneous activity (distance traveled) in mice.

EXAMPLE 1

(2) O-carbamoyl-(D)-phenylalaninol (hereinafter, referred to test compound) was tested for the effects on the forced swimming test, an animal model of depression, in both mice and rats. After single doses of the test compound the mean duration of immobility was reduced with an ED.sub.50 (median effective dose) of 16.6 mg/kg PO (per os) in mice and 18.5 mg/kg PO in rats. The test compound was even more potent after multiple dosing in mice with an ED.sub.50 of 5.5 mg/kg PO. These data suggest that the test compound shows antidepressant properties.

(3) (Methods)

(4) Male CD-1 mice (16-24 g) and male Wistar rats (90-125 g) were utilized in these experiments. The test compound (10, 15 and 30 mg/kg) was dissolved in physiological saline (0.9%) and administered orally in a volume of 1 mL/100 g body weight.

(5) Mice and rats were placed in glass cylinders of 1000 ml beakers (height 14 cm, diameter 11.5 cm) and 4000 ml beakers (height 24.5 cm, diameter 18.0 cm), respectively, containing water (25 degrees Celsius) up to a height of 9.0 cm for mice and 19.0 cm for rats. Each mouse or rat was placed in the glass cylinder and allowed to swim for 2 minutes, following which, they were observed for a period of 4 minutes for signs of immobility. Immobility was defined as lack of movement, such as floating in the water with little or no movement of hind legs. Duration of immobility was timed with a stopwatch and recorded. In some experiments, mice or rats were allowed to swim for 6 or 10 minutes, respectively, one day prior to the forced swimming experiment.

(6) In the single dose test, mice or rats were given test compound or 0.9% NaCl and placed in glass cylinders 1 hour or 4 hours post-treatment, respectively. In the multiple dose experiments, mice were dosed twice a day for 3 days and given an additional dose on Day 4. In addition, the mice were placed in the glass cylinders containing water at 25 degrees Celsius and allowed to swim for six minutes on Day 3. Statistical evaluation was performed using a computer program (The Pharmacological Calculation System of Tallarida and Murray (#425475-04-7-1992)) based on probit analysis. Statistical significance was determined using Student's t-test at a P value of <0.05.

(7) (Results)

(8) The test compound, administered in a single dose, to mice reduced mean duration of immobility in a dose-dependent manner for doses of 10, 15 and 30 mg/kg PO. 10 mg/kg of the test compound reduced the mean duration of immobility to 101 sec compared to 131 sec for control (with 0.9% NaCL only). Doses of 15 and 30 mg/kg produced significant reductions of mean immobility time from 154 sec (control) to 80 sec and from 132 sec (control) to 30 sec, respectively. The ED.sub.50 value (50% reduction in mean immobility time) for the test compound was 16.6 mg/kg.

(9) The test compound, after multiple dosing, to mice reduced mean duration of immobility in a dose-dependent manner for doses of 3, 5 and 8 mg/kg PO. At 3 mg/kg of test compound, mean duration of immobility was reduced to 63 sec from 85 sec for control. Doses of 5 and 8 mg/kg produced significant reductions of mean immobility time from 136 sec (control) to 73 sec and from 114 sec (control) to 39 sec, respectively. The ED.sub.50 value for the test compound was 5.5 mg/kg PO.

(10) In rats, the test compound administered at 30 mg/kg significantly reduced mean duration of immobility from 38 sec (control) to 9 sec at 4 hours post-treatment. Doses of test compound at 10 and 15 mg/kg also reduced duration of immobility from 74 sec (control) to 62 sec and 65 sec (control) to 39 sec, respectively, but these differences were not statistically significant. The ED.sub.50 was 18.5 mg/kg PO which is similar to the ED.sub.50 value in mice above.

(11) Mice administered antidepressant compounds show reduction of the mean duration of immobility compared to control as measured in the forced swim test. Thus, compounds that are active in the mouse forced swim test may show antidepressant propertied and could alleviate the depressive symptoms of bipolar disorder.

EXAMPLE 2

(12) The test compound was tested for binding to the dopamine, norepinephrine and serotonin transporters and for the effects on dopamine, norepinephrine and serotonin reuptake. The test compound showed weak binding to the dopamine and norepinephrine transporter and weak effects on dopamine and norepinephrine reuptake compared to cocaine.

(13) (Methods)

(14) The test compound was weighed and dissolved in DMSO (dimethyl sulfoxide) to make a 10 or 100 mM stock solution. An initial dilution to 50 or 500 M in assay buffer for binding, or to 1 or 10 mM in assay buffer for uptake, was made. Subsequent dilutions were made with assay buffer supplemented with DMSO, maintaining a final concentration of 0.1% DMSO. Pipetting was conducted using a Biomek 2000 robotic workstation. The concentrations of the test compounds are shown in following Table 1.

(15) TABLE-US-00001 TABLE 1 Concentrations of Test Compound tested Concentration Assay Range Binding hDAT (human dopamine transporter) 21.6 nM-100 M hSERT (human serotonin transporter) 21.6 nM-100 M hNET (human norepinephrine transporter) 21.6 nM-10 M Uptake hDAT (human dopamine transporter) 31.6 nM-10 M hSERT (human serotonin transporter) 31.6 nM-100 M hNET (human norepinephrine transporter) 31.6 nM-100 M

(16) Inhibition of Radioligand Binding of [.sup.125I]RTI-55 to hDAT, hSERT or hNET in Clonal Cells:

(17) Cell preparation: HEK293 cells (American Type Culture Collection, ATCC) expressing hDAT, hSERT or hNET inserts are grown to 80% confluence on 150 mm diameter tissue culture dishes in a humidified 10% CO.sub.2 environment at 37 C. and served as the tissue source. HEK-hDAT and HEK-hSERT cells were incubated in Dulbecco's modified Eagle's medium supplemented with 5% fetal bovine serum, 5% calf bovine serum, 0.05 U penicillin/streptomycin and puromycin (2 g/mL). HEK-hNET cells were incubated in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 0.05 U penicillin/streptomycin and geneticin (300 g/mL). Cell membranes are prepared as follows. Medium is poured off the plate, and the plate is washed with 10 ml of calcium- and magnesium-free phosphate-buffered saline. Lysis buffer (10 ml; 2 mM HEPES with 1 mM EDTA) is added. After 10 min, cells are scraped from plates, poured into centrifuge tubes, and centrifuged 30,000g for 20 min. The supernatant fluid is removed, and the pellet is resuspended in 12-32 ml of 0.32 M sucrose using a Polytron at setting 7 for 10 sec. The resuspension volume depends on the density of binding sites within a cell line and is chosen to reflect binding of 10% or less of the total radioactivity.

(18) Assay conditions: Each assay tube contains 50 l of membrane preparation (about 10-15 g of protein) prepared as above, 25 l of test compound, compound used to define non-specific binding (mazindol or imipramine), or buffer (Krebs-HEPES, pH 7.4; 122 mM NaCl, 2.5 mM CaCI2, 1.2 mM MgS04, 10 M pargyline, 100 M tropolone, 0.2% glucose and 0.02% ascorbic acid, buffered with 25 mM HEPES), 25 l of [.sup.125I]RTI-55 (()-2-Carbomethoxy-3-(4-iodophenyl)tropane, iometopane, 40-80 pM final concentration) and additional buffer (Krebs-HEPES) sufficient to bring up the final volume to 250 l. Membranes are preincubated with the test compound for 10 min at 25 C. prior to the addition of the [.sup.125I]RTI-55. The assay tubes are incubated at 25 C. for 90 min. Binding is terminated by filtration over GF/C filters using a Tomtec 96-well cell harvester. Filters are washed for six seconds with ice-cold saline. Scintillation fluid is added to each square and radioactivity remaining on the filter is determined using a Wallac - or beta-plate reader. Specific binding is defined as the difference in binding observed in the presence and absence of 5 M mazindol (HEK-hDAT and HEK-hNET) or 5 M imipramine (HEK-hSERT). Two or three independent competition experiments are conducted with duplicate determinations. GraphPAD Prism is used to analyze the ensuing data, with IC.sub.50 values converted to K.sub.i values using the Cheng-Prusoff equation (K.sub.i=IC.sub.50/(1+([RTI-55]/K.sub.d RTI-55))).

(19) Filtration Assay for Inhibition of [.sup.3H]Neurotransmitter Uptake in HEK293 Cells Expressing Recombinant Biogenic Amine Transporters:

(20) Cell preparation: Cells are grown to confluence as described above. The medium is removed, and cells are washed twice with phosphate buffered saline (PBS) at room temperature. Following the addition of 3 ml Krebs-HEPES buffer, the plates are warmed in a 25 C. water bath for 5 min. The cells are gently scraped and then triturated with a pipette. Cells from multiple plates are combined. One plate provides enough cells for 48 wells, which is required to generate data on two complete curves for the test compound.

(21) Uptake inhibition assay conditions: The assay is conducted in 96 1-ml vials. Krebs-HEPES (350 l) and test compound, compounds used to define non-specific uptake, or buffer (50 l) are added to vials and placed in a 25 C. water bath. Specific uptake is defined as the difference in uptake observed in the presence and absence of 5 M mazindol (HEK-hDAT and HEK-hNET) or 5 M imipramine (HEK-hSERT). Cells (50 l) are added and preincubated with the test compound for 10 min. The assay is initiated by the addition of [.sup.3H]dopamine, [.sup.3H]serotonin, or [.sup.3H]norepinephrine (50 l, 20 nM final concentration). Filtration through Whatman GF/C filters presoaked in 0.05% polyethylenimine is used to terminate uptake after 10 min. The IC.sub.50s are calculated applying the GraphPAD Prism program to triplicate curves made up of 6 drug concentrations each. Two or three independent determinations of each curve are made.

(22) (Results)

(23) The test compound was tested for its effects on radioligand ([.sup.125I]RTI-55) binding to and [.sup.3H]dopamine uptake by HEK cells expressing eDNA for the human dopamine transporter (HEK-hDAT cells), its effects on radioligand ([.sup.125I]RTI-55) binding and [.sup.3H]serotonin uptake by HEK cells expressing eDNA for the human serotonin transporter (HEK-hSERT cells), and its effects on radioligand ([.sup.125I]RTI-55) binding and [.sup.3H]norepinephrine uptake by HEK cells expressing eDNA for the human norepinephrine transporter (HEK-hNET cells).

(24) In HEK-hDAT cells, the affinity of the compound for the binding site was lower than the affinity of cocaine, the standard compound, for the same site(s). The K.sub.i value for the displacement of [.sup.125I]RTI-55 by the test compound was 14,200 nM, and the K.sub.i value for cocaine displacement of [.sup.125I]RTI-55 binding was 236 nM. In the uptake assays test compound was less potent at blocking the uptake of [.sup.3H]dopamine, with an IC.sub.50 value of 2900 nM, as compared to the potency of cocaine (IC.sub.50=385 nM). A Hill coefficient other than one suggests complex interactions with binding or uptake sites.

(25) In HEK-hSERT cells, the affinity of the compound for the binding site was lower than the affinity of cocaine, the standard compound, for the same site(s). The K.sub.i value for the displacement of [.sup.125I]RTI-55 by test compound was 81,500 nM, and the K.sub.i value for cocaine displacement of [.sup.125I]RTI-55 binding was 361 nM. In the uptake assays 31,827 was less potent at blocking the uptake of [3H]serotonin, with an IC.sub.50 value greater than 100 M, as compared to the potency of cocaine (IC50=355 nM).

(26) In HEK-hNET cells, the affinity of the test compound for the binding site was lower than the affinity of cocaine, the standard compound, for the same site(s). The K.sub.i value for the displacement of [.sup.125I]RTI-55 test compound was 3700 nM, and the K.sub.i value for cocaine displacement of [.sup.125I]RTI-55 binding was 505 nM. In the uptake assays test compound was less potent at blocking the uptake of [.sup.3H]norepinephrine, with an IC.sub.50 value of 4400 nM, as compared to the potency of cocaine (IC.sub.50=194 nM). The obtained results are shown in following Table 2:

(27) TABLE-US-00002 TABLE 2 Effects of test compound on HEK-hDAT, HEK-hSERT and HEK-hNET cells Test Compound Cocaine HEK-hDAT cells [.sup.125I]RTI-55 Binding K.sub.i (nM) 14,200 3,500 236 58 Hill coefficient 0.77 0.12 0.83 0.04 [.sup.3H]Dopamine Uptake IC.sub.50 (nM) 2900 920 385 54 HEK-hSERT cells [.sup.125I]RTI-55 Binding K.sub.i (nM) 81,500 2,900 361 65 Hill coefficient 2.28 0.05 0.77 0.04 [.sup.3H]Serotonin Uptake IC.sub.50 (nM) >100 M 355 39 HEK-hNET cells [.sup.125I]RTI-55 Binding K.sub.i (nM) 3700 1000 505 67 Hill coefficient 1.45 0.34 0.67 0.07 [.sup.3H]NE Uptake IC.sub.50 (nM) 4400 1100 194 29

(28) Numbers represent the meansSEM from at least three independent experiments, each conducted with duplicate (for binding assays) or triplicate (for uptake assays) determinations. When the K.sub.i or the IC.sub.50 for the test compound is greater than 10 M, only two experiments are conducted and no standard error is reported.

EXAMPLE 3

(29) The test compound administered at 10, 30 and 100 mg/kg subcutaneously (SC) was assessed to determine the influence on spontaneous activity of wild-type and homozygous mutant dopamine transporter knockout (KO) mice. The test compound selectively reduced activity of the KO mice in a dose-dependent manner suggesting that the test compound was highly efficacious in depressing hyper motor activity in dopamine transporter KO mice.

(30) (Methods)

(31) Male and female wild-type and homozygous mutant dopamine transporter KO mice (n10 mice/genotype/agent; produced by in vivo homologous recombination and bred at Duke University Medical Center, Durham, N.C.) were tested for spontaneous activity in the open field following a single injection of the vehicle or compound. Mice were placed into the open field for 30 min and administered SC the vehicle (sterile water), 2 mg/kg amphetamine, or three concentrations of the test compound (10, 30, 100 mg/kg). All drugs were given in a volume of 5 mL/kg. Animals were returned to the open field for an additional 90 min. Spontaneous activity was evaluated in an automated Omnitech Digiscan apparatus (Accuscan Instruments, Columbus, Ohio). Activity was summated at 5 min intervals over the 2 h period of testing. Horizontal activity or locomotion was measured in terms of the total distance covered in cm, vertical activity or rearing was expressed in terms of the total numbers of vertical beam breaks, and stereotypy was quantified in terms of repetitive breaks of a given beam or beams with intervals of less than 1 sec. For the analyses, 10 WT and 10 KO mice were run in each of the treatment groups with approximately equal numbers of males and females assigned to each group. Data were analyzed by the Statistical Package for Social Sciences programs (version 11.0 for Windows; SPSS Science, Chicago, Ill.). The results for each dependent variable were analyzed by repeated analyses of variance (RMANOVA) for within subjects effects (group differences over time) and between-subjects effects (tests of main effects and interactions). Bonferroni corrected pair-wise comparisons were used as the post-hoc tests. A p <0.05 was considered significant.

(32) (Results)

(33) Baseline: KO mice showed higher levels of locomotor, rearing and stereotypical activities compared to WT mice.

(34) Drug Treatment: Amphetamine at 2 mg/kg SC increased locomotor, rearing and stereotypical activities in WT mice and decreased them in KO animals relative to the respective vehicle controls. The test compound reduced activities in a dose-dependent fashion and the 100 mg/kg dose suppressed activities more efficiently than amphetamine. Please see representative Figure below for the locomotor activity (distance traveled in cm) collapsed over the 90 min post-injection period for Amphetamine (AMPH) and test compound. Rearing and stereotyped behavior showed similar results.

(35) The obtained results are shown in FIG. 1.

EXAMPLE 4

(36) The effects of the test compound (15-30 mg/kg, IP) on the ability to antagonize aggressive behavior in isolated mice were examined. The test compound showed an ED.sub.50 slightly more potent compared to imipramine in reducing isolation-induced aggression.

(37) (Methods)

(38) Male CD-1 mice (15-20 g) were utilized in this experiment. The test compound (15, 22 and 30 mg/kg) was dissolved in physiological saline (0.9%) and administered orally (PO) in a volume of 1 mL/100 g body weight.

(39) Mice were isolated for up to 8 weeks in individual solid walled wire cages (242017 cm). The animals were not disturbed except to replenish food. Aggression was tested by placing an intruder mouse into the home cage of the resident animal. Aggression was characterized by an attack on the intruder during a three minute period. For Experimentation, following the demonstration of fighting behavior, each resident mouse was given test compound. Only those resident mice displaying fighting behavior were selected. Sixty minutes later the intruder was reintroduced into the home cage and the pairs were observed for the presence or absence of fighting behavior. ED.sub.50 values were calculated from the percent inhibition of fighting in computer program based on probit analysis.

(40) (Results)

(41) The table below shows the effects of the test compound at doses of 15, 22 and 30 mg/kg on fighting behavior. There was dose-related inhibition of isolation-induced fighting behavior with an ED.sub.50 of 25.9 mg/kg. In comparison, imipramine (30 mg/kg PO inhibited fighting behavior by 50%.

(42) The obtained results are shown in following Table 3.

(43) TABLE-US-00003 TABLE 3 Isolation-induced fighting in mice Dose Inhibition of ED.sub.50 (mg/kg, PO) Treatment (mg/kg PO) n Fighting (%) (confidence limits) Test Compound 15 18 28 22 18 44 25.9 30 18 56 (17.7-37.9) Imipramine 15 10 20 ~30 30 10 50

EXAMPLE 5

(44) The primary objective of this study was to determine the efficacy of 2 target doses of test compound (200 and 400 mg/day) in comparison with placebo during 6 weeks of treatment in adult human subjects with moderate or severe major depression without psychotic features. An active comparator (paroxetine) was included to assist in distinguishing a negative study from a failed study. In addition, an exit interview was intended to gather information on unexpected benefits of the test compound in order to refine the clinical development program. One or both doses of the test compound demonstrated statistically significantly greater efficacy than placebo on a broad array of secondary efficacy variables of mood and well-being, suggesting antidepressant activity for the compound. In addition, positive effects of the test compound on ratings of physical energy/fitness, reduction in sadness or depression and mental energy or motivation.

(45) (Methods)

(46) This was a randomized, double-blind, parallel-group, active, and placebo-controlled, multicenter study conducted in the U.S. (23 centers) and Canada (4 centers). There were 2 phases: a pretreatment phase (screening/washout and a baseline visit) and a 6-week, double-blind treatment phase. Paroxetine, a positive control, was included to evaluate assay sensitivity. After washout (if needed) of prohibited substances, subjects were randomly assigned (1:1:1:1) to receive the test compound titrated to a target dose of 200 mg/day or 400 mg/day, matching placebo, or a fixed dose (20 mg/day) of paroxetine. Study drug was given twice daily for 6 weeks. Efficacy and safety were assessed weekly during the double-blind phase. Subjects completing the study underwent an Exit Interview (Your Health and Well-Being) and completed an Assessment of Benefits of Clinical-trial Drug-treatment (ABCD) questionnaire (U.S. sites only).

(47) (Results)

(48) The table below summarizes the results for the primary efficacy endpoint and many of the principal secondary endpoints for the ITT (LOCF) and per-protocol (LOCF) analysis sets. Neither the 200-mg nor the 400-mg dose of the test compound was statistically significantly superior to placebo on the primary endpoint, change from baseline at Week 6 in the MADRS total score (ITT [LOCF] analysis set), although paroxetine did achieve statistically significant superiority to placebo, confirming assay sensitivity. However, 1 or both doses of test compound were statistically significantly superior to placebo on several key secondary efficacy variables at Week 6: CGI-I (200 and 400 mg), CGI-S (400 mg), MADRS response (>50% improvement in MADRS total score) (400 mg), and the sum of the apparent and reported sadness items (Items 1 and 2) of the MADRS (200 and 400 mg), suggesting antidepressant activity for the compound. Statistical significance was achieved more often in secondary analyses (across the ITT [LOCF], per-protocol [LOCF], and ITT [observed case] analysis sets) with test compound 400 mg, but both test compound doses achieved statistically significant superiority to placebo in many analyses. In a few analyses the 200-mg dose achieved statistical significance when the 400-mg dose did not (1 item of the MADRS, 3 items of the CDS-R, 1 CDS-R cluster [ITT (LOCF) analysis set]). Thus, there was no strong evidence for a dose response relationship for test compound. Paroxetine was superior to placebo, based on the ITT (LOCF), per-protocol (LOCF), and the ITT (observed case) analysis sets, for nearly all secondary efficacy variables. On the self-rated CDS-R, only paroxetine was statistically significantly more effective than placebo (for all analysis sets). Results for test compound on the primary endpoint varied by sex: men achieved nominally statistically significant superiority to placebo at 200 mg, whereas women achieved statistically significant superiority to placebo at 400 mg. From the subject's perspective, based on the Exit Interview and the questionnaire (ABCD) on the benefits of treatment in the study (U.S. sites only), improvements in mood and well-being were frequently experienced in all 4 treatment groups.

(49) Paroxetine was the medication subjects preferred to take again, followed closely by test compound 200 mg. Although there were statistically significant differences between each of the active treatments and placebo on from 8 to 14 of the 51 ABCD items, there were no statistically significant differences between paroxetine and test compound (combined), or between test compound 400 mg and test compound 200 mg, for any of the items on the ABCD questionnaire. The obtained results are shown in following Table 4.

(50) TABLE-US-00004 TABLE 4 Selected Efficacy Results (Intent-to-Treat [LOCF] and Per-Protocol [LOCF] Analysis Sets) Mean Result p-Values Versus Placebo Placebo TC 200 mg TC 400 mg Paroxetine TC 200 TC 400 Endpoint.sub.a (N = 117) (N = 115) (N = 120) (N = 117) mg mg Paroxetine ITT Primary: (LOCF) MADRS total 10.3 12.1 12.4 14.1 0.118.sub.b 0.112.sub.b 0.001 score Secondary: CGI-S Score 1.0 1.2 1.3 1.5 0.061 0.035 0.002 CGI-I score.sub.c .sub.c .sub.c .sub.c .sub.c 0.035 0.030 <0.001 MADRS 27% 36% 41% 48% 0.107 0.020 0.001 response rate MADRS 11% 15% 19% 26% 0.358 0.066 0.001 remission.sub.d rate MADRS 2.6 3.2 3.4 3.9 0.026 0.012 <0.001 sadness (Items 1 + 2) MADRS core 6.7 8.6 8.7 9.7 0.024 0.022 0.001 mood subscale 3 Atypical 0.2 0.4 0.8 0.6 0.834 0.078 0.762 items of HAM-D 31 Per- MADRS total 10.7 14.8 15.0 17.1 0.006.sub.b 0.010.sub.b <0.001 Protocol score (LOCF) CGI-S score 1.1 1.5 1.6 1.9 0.016 0.022 <0.001 CGI-I score.sub.c .sub.c .sub.c .sub.c .sub.c 0.004 0.025 <0.001 MADRS 29% 40% 50% 60% 0.055 0.011 <0.001 response rate MADRS 14% 20% 29% 35% 0.206 0.037 0.003 remission.sub.d rate CGI-I = Clinical Global Impressions - Improvement; CGI-S = Clinical Global Impressions - Severity; HAM-D 31 = 31-Item Hamilton Depression Scale; LOCF = last observation carried forward; MADRS = Montgomery-Asberg Depression Rating Scale. .sub.aChange from baseline at Week 6. .sub.bThese p-values for test compound versus placebo are adjusted for multiple comparisons using Dunnett's procedure. .sub.cWeek 6 assessment; categorical analysis. .sub.dRemission was defined as a MADRS total score less than 9.

(51) Results from the U.S. sites of the Exit Interview and the self-rated and blinded ABCD questionnaire on the benefits of treatment in the study provided a context for interpreting the results of TC-MDD-201 from the subject's perspective. The exit interview data indicated that positive experiences most frequently included improvements in mood and well-being in all 4 treatment groups. This was supported by data from the ABCD questionnaire, in which the most improved aspect of health during the trial was reduction in sadness and depression. Mood, generally speaking, was the first symptom to improve, with improvement noticed mostly within the first three weeks of receiving study medication (Exit Interview data).

(52) In general, there were few differences between the 4 treatment groups within the 51 items on the ABCD questionnaire. Those that were apparent were generally most robust between placebo and the active medications (i.e., physical energy/fitness, reduction in sadness or depression and mental energy or motivation) rather than between the active medications themselves. In post hoc analyses, statistically significant superiority to placebo was observed for test compound 200 mg, test compound 400 mg, and paroxetine on 14, 8, and 14 items, respectively, of the questionnaire. However, there were no statistically significant differences between test compound 400 mg and test compound 200mg, or between paroxetine and test compound (combined scores for both doses) for any of the 51 items on the ABCD questionnaire.

(53) References Cited

(54) All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

(55) The discussion of references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.

(56) The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatus within the scope of the invention, in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.