Bupropion and dextromethorphan for reducing suicide risk in patients with depression

Abstract

This disclosure relates to a method of treating depression and / or reducing suicide risk, comprising administering a combination of about 90 mg to about 120 mg of bupropion chloride (or another molar equivalent of bupropion) and about 40 mg to about 50 mg of dextromethorphan hydrobromide (or another molar equivalent of dextromethorphan). This combination can be administered twice daily to individuals suffering from severe depression and scoring 3 or higher on the Suicide Proneness Item of the Montgomery-Aussberg Depression Rating Scale (MADRS-SI).

Description

[0001] This application is a divisional application of Chinese patent application No. 202180080875.5 (filed on December 1, 2021, invention title: Bupropion and Dextromethorphan for reducing the suicide risk of patients with depression).

[0002] Cross-references to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 120,160, filed December 1, 2020; U.S. Provisional Patent Application No. 63 / 120,672, filed December 2, 2020; and U.S. Provisional Patent Application No. 63 / 122,902, filed December 8, 2020; all of which are incorporated herein by reference in their entirety. Summary of the Invention

[0004] This disclosure relates to a method of treating depression and / or reducing suicide risk, comprising administering a combination of about 90 mg to about 120 mg of bupropion hydrochloride, or a molar equivalent of another form of bupropion, and about 40 mg to about 50 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan. This combination may be administered twice daily to individuals suffering from major depressive disorder and scoring 3 or higher on the Suiccidality Item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). Invention Details

[0005] The combination of dextromethorphan and bupropion can be used to treat depression (such as major depressive disorder) and / or reduce the risk of suicide. Patients receiving this combination therapy may have depression and may have a score of 2 or higher, or 3 or higher on the Suicide Proneness Item of the Montgomery-Osberg Depression Rating Scale (MADRS-SI).

[0006] Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals with extensive metabolizers. A person can be: 1) an extensive metabolizer of dextromethorphan—those who rapidly metabolize dextromethorphan; 2) an undesirable metabolizer of dextromethorphan—those who only undesirably metabolize dextromethorphan; or 3) an intermediate metabolizer of dextromethorphan—those whose metabolism of dextromethorphan falls between that of extensive and undesirable metabolizers. Extensive metabolizers can also be ultra-rapid metabolizers. Non-undesirable metabolizers of dextromethorphan include both extensive and intermediate metabolizers. Extensive metabolizers of dextromethorphan constitute a significant portion of the population. For example, dextromethorphan can be metabolized to dextrophene.

[0007] When the same dose of dextromethorphan is administered orally, plasma levels of dextromethorphan in poorly metabolized or intermediate metabolizers are significantly higher than those in widely metabolized dextromethorphan. Low plasma concentrations of dextromethorphan limit its clinical use as a single agent for both widely metabolized and potentially intermediate metabolized dextromethorphan. Bupropion inhibits the metabolism of dextromethorphan, increasing its plasma concentrations and thus its efficacy. Similarly, bupropion can reduce the frequency or dosage of dextromethorphan administration, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, without losing efficacy.

[0008] The MADRS is a scale assessed by clinicians. The MADRS is used to assess depressive symptoms over the past week. Participants rate 10 items to assess symptoms: 1) marked sadness, 2) reported sadness, 3) inner tension, 4) decreased sleep, 5) decreased appetite, 6) difficulty concentrating, 7) fatigue, 8) inability to feel, 9) pessimistic thoughts, and 10) suicidal thoughts. Each item is scored from 0 to 6.

[0009] The total score ranges from 0 to 60. A score of 0 indicates no symptoms, and a score of 60 indicates the most severe symptoms. A total score of 0 to 6 indicates that the patient is in the normal range (no depression), a score of 7 to 19 indicates "mild depression", a score of 20 to 34 indicates "moderate depression", and a score of 35 or above indicates "severe depression".

[0010] In some implementations, (e.g. for a type of depression) a person treated with the combination of dextromethorphan and bupropion has or is selected to have an MADRS score of at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 25-35, about 35-45, about 45-60, about 25-40, or about 40-60.

[0011] In some embodiments, combination treatment with dextromethorphan and bupropion results in a reduction in a person's MADRS score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-90%, or about 90-100% compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo. In some embodiments, the reduction is compared to pre-treatment baseline.

[0012] In some implementations, combination therapy with dextromethorphan and bupropion resulted in a MADRS score below 34, approximately 20-34, approximately 7-19, approximately 0-6, approximately 30 or less, approximately 26 or less, approximately 25 or less, approximately 20 or less, approximately 19 or less, approximately 17 or less, approximately 14 or less, approximately 12 or less, approximately 10 or less, approximately 8 or less, approximately 6 or less, approximately 5 or less, approximately 4 or less, approximately 3 or less, approximately 2 or less, approximately 1 or less, approximately 0, approximately 7 or less, approximately 0- 6, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11-12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 18-20, about 1-3, about 3-6, about 6-9, about 9-12, about 12-14, about 12-15, about 15-19, or about 15-20.

[0013] Treatment effectiveness can be assessed at any appropriate time, such as during weeks 1-2, 1-3, 1-4, 1-5, 1-6, 2-6, 4-6, 6-8, 8-12, 12-16, or longer, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or at any other time.

[0014] In some implementations, administration of the combination of dextromethorphan and bupropion results in at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100% of patients achieving a clinical response on the MADRS (defined as a reduction of at least 50% in the total MADRS score from baseline).

[0015] In some implementations, administration of the combination of dextromethorphan and bupropion will result in a clinical response on the MADRS (defined as a reduction of at least 50% in the total MADRS score from baseline) of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100%.

[0016] Treatment effectiveness can be assessed at any appropriate time, such as during weeks 1-2, 1-3, 1-4, 1-5, 1-6, 2-6, 4-6, 6-8, 8-12, 12-16, or longer, at the beginning or end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, or at any other time.

[0017] In some implementations, administration of the combination of dextromethorphan and bupropion results in a remission of depression (defined as a total MADRS score of 10 or lower) in at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100% of patients.

[0018] In some implementations, the combination of dextromethorphan and bupropion is likely to result in a person’s depression remission (defined as a total MADRS score of 10 or less) of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100%.

[0019] Treatment effectiveness can be assessed at any appropriate time, such as during weeks 1-2, 1-3, 1-4, 1-5, 1-6, 2-6, 4-6, 6-8, 8-12, 12-16, or longer, at the beginning or end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, or at any other time.

[0020] The Sheehan Disability Scale (SDS) is a self-assessment tool used to measure the impact of a patient's symptoms on three areas: work / school, social life, and family responsibilities. For each of these three areas, scores range from 0 to 10. Along this line, numbers best representing the extent of impairment in each area are marked from 0 (absolutely none) to 10 (extreme). Overall functional impairment can be assessed by summing the scores for each of the three areas, resulting in a total SDS score ranging from 0 (no impairment) to 30 (highly impaired).

[0021] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have the following Sheehan Disability Scale (SDS) scores: at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least 10 for each item on the SDS (0 to 10 scale); and at least about 5, at least 10, at least about 20, about 10–15, about 15–20, about 20–25, or about 25–30 for the total SDS score.

[0022] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a functional response on the SDS. A functional response on the SDS is defined as an SDS total score of 12 or lower. In some embodiments, the probability of a patient achieving a functional response on the SDS, or the number of patients achieving a functional response on the SDS, compared to baseline or placebo, is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or about 80%; and / or up to 100%. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0023] Treatment effectiveness can be assessed at any appropriate time, such as during weeks 1-2, 1-3, 1-4, 1-5, 1-6, 2-6, 4-6, 6-8, 8-12, 12-16, or longer, at the beginning or end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, or at any other time.

[0024] In some implementations, administration of the combination of dextromethorphan and bupropion resulted in at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100% of patients experiencing significant or moderate improvement in depressive symptoms after treatment (assessed by the Clinical Global Impression Improvement Scale).

[0025] In some implementations, the combination of dextromethorphan and bupropion is likely to result in a significant or moderate improvement in depressive symptoms (as assessed by the Clinical Global Impression Improvement Scale) in a person after treatment of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, and / or up to 100%.

[0026] Treatment effectiveness can be assessed at any appropriate time, such as during weeks 1-2, 1-3, 1-4, 1-5, 1-6, 2-6, 4-6, 6-8, 8-12, 12-16, or longer, at the beginning or end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, or at any other time.

[0027] Depression can manifest as depressive symptoms. These symptoms may include psychological changes such as mood swings, intense sadness, hopelessness, mental slowing, poor concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive problems, and / or circadian rhythm abnormalities.

[0028] Some patients may remain inadequately or unresponsive to treatment, even after treatment with medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-resistant depression, is a condition typically associated with patients who have failed treatment with at least two antidepressants. A partial diagnosis of TRD is made for patients who have not responded adequately to antidepressant therapy after appropriate doses and durations. TRD can be more difficult to treat due to comorbidities of other medical or mental illnesses (such as substance / alcohol abuse or eating disorders) or misdiagnosis of TRD. Some patients with TRD have not responded adequately to trials of one, two, three, or more antidepressants, or have been unresponsive or inadequately responsive to one, two, three, or more prior antidepressant treatments. In some implementations, patients undergoing treatment for treatment-resistant depression have failed with at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressant therapies. In addition to other patients with depression, the combination of bupropion and dextromethorphan can also be effective for patients with treatment-resistant depression who have suicidal ideation.

[0029] Patients who may benefit from the treatment described in this article include pediatric patients, such as those under approximately 18 years of age, approximately 0–5 years of age, approximately 5–10 years of age, approximately 10–12 years of age, or approximately 12–18 years of age; adult patients, such as those aged approximately 18–70 years of age, approximately 18–65 years of age, approximately 18–30 years of age, approximately 18–20 years of age, approximately 20–30 years of age, approximately 30–40 years of age, approximately 40–50 years of age, approximately 50–60 years of age, approximately 60–70 years of age, approximately 70–80 years of age, approximately 80–90 years of age, approximately 30–50 years of age, or approximately 50–65 years of age; and elderly patients, such as those aged 65 years and older, approximately 65–75 years of age, approximately 75–90 years of age, or 90 years of age and older; and patients approximately 41 years of age or older.

[0030] In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Asian, or selected as Asian. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Japanese, or selected as Japanese. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Korean, or selected as Korean. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Chinese, or selected as Chinese. Assignment of individuals to be Asian, Chinese, Japanese, or Korean may be based on self-reporting by that individual. Among these Asian individuals, the combination of dextromethorphan and bupropion may be effective for treating depression that cannot be treated with bupropion alone. This may be particularly important because Asian patients may suffer from more severe depression compared to people from other racial or cultural groups.

[0031] In some implementations, (e.g. for a type of depression) a person treated with the combination of dextromethorphan and bupropion has or is selected to have a major depressive episode lasting between about 8 weeks and about 24 months, about 1-6 months, about 6-12 months, about 1-2 years, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 7 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-4 years, about 4-6 years, about 6-10 years, about 10-20 years or longer.

[0032] In some implementations, (e.g., for a type of depression) a person treated with the combination of dextromethorphan and bupropion has had or is selected to have had approximately 1 to 100 or more lifetime depressive episodes, such as major depressive episodes, including at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 10, at least 15, at least 20, at least 30, etc. At least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 1-5, at least 5-10, at least 10-20, at least 20-30, at least 30-40, at least 40-50, at least 50-60, at least 60-70, at least 70-80, at least 80-90, at least 90-100, or at least 4-7 lifetime depressive episodes.

[0033] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a response to one or more prior antidepressant therapies (e.g., 1, 2, 3, 4, 5 or more prior antidepressant therapies), including prior antidepressant therapy in the current depressive episode (e.g., current major depressive episode).

[0034] In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is male, or is selected to be male. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is female, or is selected to be female.

[0035] The combination of bupropion and dextromethorphan is administered once or twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 3 months, at least 4 months, at least 5 months, or at least 6 months; and / or can be administered for up to 4 months, up to 6 months, up to 1 year, up to 2 years, or longer. In some embodiments, the combination of bupropion and dextromethorphan is administered twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 3 months, at least 4 months, at least 5 months, or at least 6 months; and / or can be administered for up to 4 months, up to 6 months, up to 1 year, up to 2 years, or longer. In some embodiments, the combination of bupropion and dextromethorphan is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, and thereafter twice daily.

[0036] In some embodiments, at least about 50 mg, at least about 70 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, or at least about 120 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion (e.g., another salt form or free base form) is administered once or twice daily. In some embodiments, bupropion is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0037] In some embodiments, up to about 70 mg, up to about 90 mg, up to about 100 mg, up to about 110 mg, up to about 120 mg, up to about 130 mg, or up to about 150 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion (e.g., another salt form or free base form) is administered once or twice daily. In some embodiments, bupropion is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0038] In some embodiments, about 0.8x mg to about 1.2x mg of bupropion hydrochloride or another molar equivalent of bupropion (e.g., another salt form or free base form) is administered once or twice daily, where x is about 50 mg (e.g., 40-60 mg), about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 140 mg. In some embodiments, bupropion is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily administration thereafter.

[0039] In some embodiments, about 50-150 mg, about 90-120 mg, about 100-110 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion (e.g., another salt form or free base form) is administered once or twice daily. In some embodiments, bupropion is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, and thereafter twice daily.

[0040] In some embodiments, at least about 30 mg, at least about 35 mg, at least about 40 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan (e.g., another salt form or free base form), is administered once or twice daily. In some embodiments, dextromethorphan is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0041] In some embodiments, up to about 50 mg, up to about 55 mg, up to about 60 mg, or up to about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan (e.g., another salt form or free radical form), is administered once or twice daily. In some embodiments, dextromethorphan is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0042] In some embodiments, about 0.8x mg to about 1.2x mg of dextromethorphan hydrobromide or another molar equivalent of dextromethorphan (e.g., another salt form or free base form) is administered once or twice daily, where x is about 30 mg (e.g., 24-36 mg), about 40 mg, about 50 mg, or about 60 mg. In some embodiments, dextromethorphan is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0043] In some embodiments, about 30-60 mg, about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan (e.g., another salt form or free base form), is administered once or twice daily. In some embodiments, dextromethorphan is administered once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice daily thereafter.

[0044] Administration of the combination of bupropion and dextromethorphan may result in the elimination of suicidal ideation. Elimination can be defined as a MADRS-SI score of 0 or 1 on a scale of 0 to 6. In some implementations, the number of patients achieving elimination of suicidal ideation or the probability of achieving suicidal ideation may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or up to about 100%, for example, when the combination is administered daily, such as twice daily, for 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks.

[0045] Taking a combination of bupropion and dextromethorphan can improve depressive symptoms, such as the Montgomery-Osberg Depression Rating Scale (MADRS) score. For example, after taking the combination daily (e.g., twice daily) for 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks, it can also reduce the suicidal tendency item (MADRS-SI) of the MADRS, for example, by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or up to about 100%.

[0046] In some embodiments, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, compared with administration of 60 mg dextromethorphan hydrobromide without bupropion, or with administration of a single dose of the combination of bupropion and dextromethorphan, the C6 levels of dextromethorphan in the human body were [data missing]. max Increased by approximately 15 to approximately 25 times.

[0047] In some embodiments, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, compared with administration of 60 mg dextromethorphan hydrobromide without bupropion, or with administration of a single dose of the bupropion and dextromethorphan combination, the C60 levels of dextromethorphan in the human body were significantly reduced. min Increased by approximately 35 to approximately 45 times.

[0048] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the AUC of dextromethorphan in the human body was compared with that of administration of 60 mg dextromethorphan hydrobromide without bupropion or with administration of a single dose of the combination of bupropion and dextromethorphan. 0-12 Increased by approximately 25 times to approximately 45 times.

[0049] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the C60 levels of dextromethorphan in the human body are reduced. max It is approximately 75-80 ng / mL.

[0050] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the C-value of dextromethorphan... minIt is approximately 42-50 ng / mL.

[0051] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the AUC of dextromethorphan in the human body is... 0-12 It is approximately 755 ng∙hr / mL.

[0052] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the C-level of bupropion in the human body is reduced. max It is approximately 85-90 ng / mL.

[0053] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the C60 of bupropion... min It is approximately 25-35 ng / mL.

[0054] In some implementations, after 8 days of receiving a combination of bupropion and dextromethorphan twice daily, the AUC of bupropion in the human body is... 0-12 It is approximately 660-670 ng∙hr / mL.

[0055] Example 1

[0056] An open-label phase III clinical trial was conducted using tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. These tablets were administered twice daily to patients with major depressive disorder. A total of 611 patients participated in the trial, and 597 patients received at least 6 months of treatment at the end of the trial. The mean baseline MADRS total score for the total number of patients before treatment was 32.7. Table 1 summarizes the results for the total number of patients.

[0057] Table 1. Changes in MADRS total score after treatment in all patients.

[0058]

[0059] In severe cases, major depressive disorder can lead to suicide. Among these patients, 37 had major depressive disorder with suicidal ideation, defined as a Montgomery-Osberg Depression Rating Scale (MADRS-SI) score ≥3 (suicidal ideation subgroup). For the suicidal ideation subgroup, at baseline, the mean total MADRS score was 36.8, the mean MADRS-SI score was 3.4, and the mean Sheehan Disability Rating Scale score was 21.2. The MADRS results for these patients are summarized in Table 2.

[0060] Table 2. Changes in MADRS total score after treatment in patients with suicidal ideation

[0061]

[0062] Furthermore, in the suicidal ideation subgroup, compared to baseline, the MADRS-SI score decreased by 67.1% at the end of week 1 of treatment, 73.5% at the end of week 2, and 82.4% at the end of week 4. Within the subgroup, 60.0% of patients achieved elimination of suicidal ideation at week 1, 68.8% at week 2, and 77.8% at week 4. Elimination was defined as a MADRS-SI score of 0 or 1 on a scale of 0 to 6. Post-treatment, 51.4% of patients in the subgroup achieved a functional response on the Sheehan's Disability Scale (defined as a total score ≤12) at week 1, 62.5% at week 2, and 76.9% at week 6. In the subgroup after treatment, 40.0% of patients achieved significant or moderate improvement in depressive symptoms at week 1 (assessed by the Clinical Global Impression Scale), 59.4% at week 2, and 69.2% at week 6. After treatment, 25.7% of patients in the subgroup achieved a clinical response to the MADRS at week 1 (defined as a ≥50% reduction in total MADRS score from baseline), 46.9% at week 2, and 69.2% at week 6. After treatment, 11.4% of patients in the subgroup achieved remission of depression at week 1 (defined as a total MADRS score ≤10), 28.1% at week 2, and 50.0% at week 6.

[0063] This disclosure relates to the following implementation plan:

[0064] 1. A method of treating depression or reducing the risk of suicide, comprising administering to a person a combination of about 90 mg to about 120 mg of bupropion chloride or a molar equivalent of another form of bupropion, and about 40 mg to about 50 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan; wherein the combination is administered twice daily to a person suffering from major depressive disorder and scoring 3 or higher on the Suicide Proneness Item of the Montgomery-Aussberg Depression Rating Scale (MADRS-SI).

[0065] 2. The method according to claim 1, wherein the combination comprises about 105 mg of bupropion chloride, or a molar equivalent of another form of bupropion, and about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan.

[0066] 3. The method according to item 1 or 2, wherein the combination is applied twice daily for at least one week.

[0067] 4. The method according to item 3, wherein the combination is applied twice daily for at least 2 weeks.

[0068] 5. The method according to item 4, wherein the combination is applied twice daily for at least 6 weeks.

[0069] 6. The method according to item 1, 2, 3, 4 or 5, wherein after administering the combination twice daily to a person for 1 week, the MADRS-SI of the person is reduced by at least 30%.

[0070] 7. The method according to item 1, 2, 3, 4, 5 or 6, wherein after administering the combination twice daily to a person for 2 weeks, the MADRS-SI of the person is reduced by at least 50%.

[0071] 8. The method according to item 1, 2, 3, 4, 5, 6 or 7, wherein after administering the combination twice daily to a person for 4 weeks, the MADRS-SI of the person is reduced by at least 60%.

[0072] 9. The method according to item 1, 2, 3, 4, 5, 6, 7 or 8, wherein after administering the combination twice daily for 8 days, the C-value of dextromethorphan in the human body is reduced compared to administering a single dose of the combination. max Increase by approximately 15 to approximately 25 times.

[0073] 10. The method according to item 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein after administering the combination twice daily for 8 days, compared with administering a single dose of the combination, the C-value of dextromethorphan in the human body is reduced. min Increased by approximately 35 to approximately 45 times.

[0074] 11. The method according to item 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein after administering the combination twice daily for 8 days, the AUC of dextromethorphan in the human body is compared with that of administering a single dose of the combination. 0-12 Increased by approximately 25 to approximately 45 times.

[0075] 12. The method according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein after administering the combination twice daily for 8 days, the C-value of dextromethorphan in the human body is [data missing]. max It is approximately 75 ng / mL to approximately 80 ng / mL.

[0076] 13. The method according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein after administering the combination twice daily for 8 days, the C of dextromethorphan min It ranges from approximately 42 ng / mL to approximately 50 ng / mL.

[0077] 14. The method according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein after administering the combination twice daily for 8 days, the AUC of dextromethorphan in the human body is... 0-12 It is approximately 755 ng∙hr / mL.

[0078] 15. The method according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein after administering the combination twice daily for 8 days, the C of bupropion in the human body... max It is approximately 85 ng / mL to approximately 90 ng / mL.

[0079] 16. The method according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein after administering the combination twice daily for 8 days, the C of bupropion... min It is approximately 25 ng / mL to approximately 35 ng / mL.

[0080] 17. The method according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein after administering the combination twice daily for 8 days, the AUC of bupropion in the human body 0-12 It is approximately 660 ng∙hr / mL to approximately 670 ng∙hr / mL.

Claims

1. Use of a drug combination in the manufacture of a medicine for treating depression or reducing the risk of suicide in a person in need, wherein the drug combination comprises about 90 mg to about 120 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion, and about 40 mg to about 50 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan, and wherein the person suffers from major depressive disorder and scores 3 or higher on the Suicide Proneness Item (MADRS-SI) of the Montgomery-Aussberg Depression Rating Scale.

2. The use according to claim 1, wherein the combination comprises about 105 mg of bupropion hydrochloride, or a molar equivalent of another form of bupropion, and about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another form of dextromethorphan.

3. The use according to claim 1 or 2, wherein the drug is administered twice daily.

4. The use according to claim 3, wherein the combination is applied twice daily for at least one week.

5. The use according to claim 4, wherein the combination is applied twice daily for at least 2 weeks.

6. The use according to claim 5, wherein the combination is applied twice daily for at least 6 weeks.

7. The use according to claim 1 or 2, wherein after administering the combination twice daily to a person for one week, the MADRS-SI of the person is reduced by at least 30%.

8. The use according to claim 1 or 2, wherein after administration of the combination twice daily to a human for 2 weeks, the MADRS-SI of the human is reduced by at least 50%.

9. The use according to claim 1 or 2, wherein after administration of the combination twice daily to a human for 4 weeks, the MADRS-SI of the human is reduced by at least 60%.

10. The use according to claim 1 or 2, wherein after administering the combination twice daily for 8 days, the C60 levels of dextromethorphan in the human body are reduced compared to administering a single dose of the combination. max Increase by approximately 15 to approximately 25 times.

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