Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Guías para evaluación y tratamiento de depresión perimenopausica parte 2 / Guidelines for evaluation and treatment of perimenopausal depression: part2

Resumen Hay una nueva apreciación de la perimenopausia, definida como las etapas de transición temprana y tardía de la menopausia, también como la posmenopausia temprana, como una ventana de vulnerabilidad para el desarrollo de síntomas depresivos y episodios depresivos mayores. Sin embargo, las recomendaciones clínicas sobre cómo identificar, caracterizar y tratar la depresión clínica están faltando. Para abordar esta brecha, se convocó un panel de expertos para revisar sistemáticamente la literatura publicada y desarrollar lineamientos sobre la evaluación y manejo de la depresión perimenopáusica. Las áreas abordadas incluyeron: 1) epidemiología; 2) presentación clínica; 3) efectos terapéuticos de los antidepresivos; 4) efectos de la terapia hormonal; y 5) la eficacia de otras terapias (por ejemplo, psicoterapia, ejercicio y productos naturales para la salud). En general, la evidencia sugiere que la mayoría de las mujeres de mediana edad que experimentan un episodio depresivo mayor durante la perimenopausia han tenido un episodio previo de depresión. La depresión de la mediana edad se presenta con síntomas depresivos clásicos comúnmente en combinación con síntomas de la menopausia (es decir, síntomas vasomotores, trastornos del sueño) y problemas psicosociales. Los síntomas de la menopausia se complican, coexisten y se superponen con la presentación de la depresión. El diagnóstico implica la identificación de la etapa menopáusica, la evaluación de los síntomas psiquiátricos y de la menopausia (los cuales son concurrentes), apreciación de los factores psicosociales comunes en la mediana edad, diagnósticos diferenciales y el uso de pruebas de detección con instrumentos validadas. Las opciones terapéuticas probadas para la depresión (es decir, antidepresivos, psicoterapia) son la primera línea de tratamientos para la depresión perimenopáusica. Aunque la terapia con estrógenos no está aprobada para tratar la perimenopausia, existe evidencia de que tiene efectos antidepresivos en mujeres perimenopáusicas, particularmente en aquellas con síntomas vasomotores concomitantes. Los datos sobre estrógeno más progestina son escasos y no concluyentes.

Abstract There is a new appreciation of the perimenopause ­ defined as the early and late menopause transition stages as well as the early postmenopause - as a windowof vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: 1) epidemiology; 2) clinical presentation; 3) therapeutic effects of antidepressants; 4) effects ofhormonetherapy;and5)efficacyofothertherapies(eg,psychotherapy,exercise,andnatural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (ie, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (ie, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.

Consenso. Parte I Guías para evaluación y tratamiento de depresión perimenopausica: recomendaciones / Consensus. Part I Guidelines for evaluation and treatment of perimenopausal depression: recommendations

Hay una nueva apreciación de la perimenopausia, definida como las etapas de transición temprana y tardía de la menopausia, también como la posmenopausia temprana, como una ventana de vulnerabilidad para el desarrollo de síntomas depresivos y episodios depresivos mayores. Sin embargo, las recomendaciones clínicas sobre cómo identificar, caracterizar y tratar la depresión clínica están faltando. Para abordar esta brecha, se convocó un panel de expertos para revisar sistemáticamente la literatura publicada y desarrollar lineamientos sobre la evaluación y manejo de la depresión perimenopáusica. Las áreas abordadas incluyeron: 1) epidemiología; 2) presentación clínica; 3) efectos terapéuticos de los antidepresivos; 4) efectos de la terapia hormonal; y 5) la eficacia de otras terapias (por ejemplo, psicoterapia, ejercicio y productos naturales para la salud). En general, la evidencia sugiere que la mayoría de las mujeres de mediana edad que experimentan un episodio depresivo mayor durante la perimenopausia han tenido un episodio previo de depresión. La depresión de la mediana edad se presenta con síntomas depresivos clásicos comúnmente en combinación con síntomas de la menopausia (es decir, síntomas vasomotores, trastornos del sueño) y problemas psicosociales. Los síntomas de la menopausia se complican, coexisten y se superponen con la presentación de la depresión. El diagnóstico implica la identificación de la etapa menopáusica, la evaluación de los síntomas psiquiátricos y de la menopausia (los cuales son concurrentes), apreciación de los factores psicosociales comunes en la mediana edad, diagnósticos diferenciales y el uso de pruebas de detección con instrumentos validadas. Las opciones terapéuticas probadas para la depresión (es decir, antidepresivos, psicoterapia) son la primera línea de tratamientos para la depresión perimenopáusica. Aunque la terapia con estrógenos no está aprobada para tratar la perimenopausia, existe evidencia de que tiene efectos antidepresivos en mujeres perimenopáusicas, particularmente en aquellas con síntomas vasomotores concomitantes. Los datos sobre estrógeno más progestina son escasos y no concluyentes.

There is a new appreciation of the perimenopause ­ defined as the early and late menopause transition stages as well as the early postmenopause - as a windowof vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: 1) epidemiology; 2) clinical presentation; 3) therapeutic effects of antidepressants; 4) effects of hormone therapy; and 5) efficacy of other therapies (eg, psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (ie, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (ie, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.