Efficacy of Lu AA21004 on Cognitive Dysfunction in Major Depressive Disorder

• ClinicalTrials.gov Identifier: NCT01564862
• Recruitment Status: Completed
• First Posted: March 28, 2012
• Results First Posted: February 5, 2015
• Last Update Posted: February 5, 2015
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

The purpose of this study is to evaluate the effects of Lu AA21004, once daily (QD), on cognitive dysfunction in patients with major depressive disorder.

Condition or disease	Intervention/treatment	Phase
Depressive Disorder, Major	Drug: vortioxetine (Lu AA21004); Drug: Duloxetine; Drug: Placebo	Phase 2

Detailed Description:

Lu AA21004 is under codevelopment by Takeda Global Research & Development Center, Inc. and H. Lundbeck A/S for the treatment of MDD.

This study will consist of a screening period within 10 days of the Baseline Visit followed by an 8-week double-blind treatment period and a one-week taper down period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 602 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Flexible Dose Study on the Efficacy of Lu AA21004 on Cognitive Dysfunction in Adult Subjects With Major Depressive Disorder (MDD)
• Study Start Date: April 2012
• Actual Primary Completion Date: February 2014
• Actual Study Completion Date: February 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vortioxetine (Lu AA21004) QD; Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Drug: vortioxetine (Lu AA21004); Lu AA21004 capsules
Active Comparator: Duloxetine QD; Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Drug: Duloxetine; Duloxetine capsules; Other Name: Cymbalta
Placebo Comparator: Placebo QD; Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).	Drug: Placebo; Placebo matching capsules

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST) [ Time Frame: Baseline and Week 8 ]
   The DSST assesses relative contributions of speed, memory, executive function and visual scanning. Participants are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time for a total possible score of 0 to 133. Higher scores-correct number of symbols reflects greater objective cognitive functioning. An increase in score represents an improvement in an integrated measure of cognitive function. An Analysis of Covariance (ANCOVA) model was used with treatment and center as fixed factors and the Baseline value as a covariate.

Secondary Outcome Measures :

1. Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore [ Time Frame: Baseline and Week 8 ]
   PDQ is a patient-rated scale designed to subjectively assess cognitive dysfunction, comprising four 5-item subscales: Attention/Concentration, Retrospective Memory, Prospective Memory, and Planning/Organization for a total possible score of 0 to 40. The subscale Attention/Concentration is the sum of items 1, 5, 9, 13, and 17 with a range of 0-20; while the subscale Planning/Organization is the sum of items 4, 8, 12, 16, and 20 with the score range of 0 to 20. The scores of the subscales Attention/Concentration and Planning/Organization were summed. Higher scores reflect greater participant-perceived cognitive dysfunction in the domains identified. A decrease in score represents an improvement in subjective cognitive function in the domains identified. A Mixed Model Repeated Measures (MMRM) model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
2. Clinical Global Impressions-Improvement (CGI-I) Score at Week 8 [ Time Frame: Baseline, Week 8 ]
   The CGI-I assesses the clinician's impression of the subject's state of mental illness improvement and consists of one question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a seven-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). Higher scores indicate greater worsening of illness. Values closest to 1 for this outcome measure indicate the greatest improvement of symptoms. A MMRM model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
3. Change From Baseline to Week 8 in the Trail Making Test (TMT-A) [ Time Frame: Baseline and Week 8 ]
   The TMT is a two-part cognitive test. TMT-A assesses cognitive processing speed and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower scores represent better speed of processing. A decrease in score over the study represents an improvement in speed in processing. An ANCOVA model was used with treatment and center as fixed factors and the baseline value as a covariate.
4. Change From Baseline to Week 8 in the Trail Making Test B (TMT-B) [ Time Frame: Baseline and Week 8 ]
   The TMT is a two-part cognitive test. TMT-B assesses executive functioning and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower score for TMT-B represents better executive function. A decrease in score over the study represents an improvement in executive function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
5. Change in Time From Baseline to Week 8 in the Stroop Test [ Time Frame: Baseline and Week 8 ]
   The STROOP test assesses the ability to inhibit a prepotent response to reading words while performing a task that requires attention control. It comprises of 2 sheets with 50 words each, up to 50 correct responses for each of the congruent and incongruent Stroop tests. Participants have 4 minutes to name the ink color of each word. Lower time to complete the test indicates better performance. Higher number of correct responses indicates better responses. A decrease in the time to complete the tests and an increase in the number of correct responses both indicate improvement over the course of the study. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
6. Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT) [ Time Frame: Baseline and Week 8 ]

   The GMLT measures executive functioning and spatial problem solving. Participants learn a hidden pathway through a maze of 10 x 10 grid of tiles on a computer touch screen using step-by-step guess, with trial and error feedback after each step. Once the pathway is learned, participants repeat the same pathway four more times. It usually takes 5-6 minutes to administer this test. Lower score equals better performance. A decrease in score over the course of the study indicates improved executive function.

   An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

7. Change From Baseline to Week 8 in the Detection Task (DT) [ Time Frame: Baseline and Week 8 ]
   The DT is a computerized test that measures simple reaction time and psychomotor speed. The task requires participants to respond by pressing a "yes" button as soon as an onscreen playing card is turned over and is red, and by pressing a "no" button if the card is not red. It takes 2 minutes to be administered. There is no minimum or maximum scores since it is a time-based assessment. Lower score equals better performance. A decrease in score over the course of the study indicates improved speed of processing and psychomotor function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
8. Change From Baseline to Week 8 in the Identification Task (IT) [ Time Frame: Baseline and Week 8 ]
   The IT measured choice reaction time: the participant pressed a "yes" button whenever an onscreen playing card turned face up and was red, or a "no" button if the card was not red. The IT took on average 2 minutes to complete. Lower scores equal better performance. A decrease in score over the course of the study indicates improved visual attention/vigilance. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
9. Change From Baseline to Week 8 in the One-Back Task [ Time Frame: Baseline and Week 8 ]
   The One-Back test measures the cognitive domain of attention and working memory through yes or no responses to 30 trials. The task requires participants to report when a stimulus item presented serially is the same as an item one step back from the item at hand for a total correct responses 0 to 100. It usually takes 2-3 minutes to be administered. Higher scores equal better performance. An increase in score over the course of the study indicates improved attention/working memory. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
10. Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression [ Time Frame: Baseline and Week 8 ]
    Improvement of Cognitive Dysfunction is determined using the change from Baseline to Week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score and the Digital Symbol Substitution Test (DSST) total number of correct symbols. The MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression). The DSST assesses relative contributions of speed, memory, executive function and visual scanning. The proportion of direct effect from treatment = DSST difference / (DSST difference + coefficient*MADRS difference).
11. Change From Baseline to Week 8 in the MADRS Total Score [ Time Frame: Baseline, Week 1, Week 4 and Week 8 ]
    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates improvement.
12. Percentage of Participants With MADRS Response at Week 8 [ Time Frame: Baseline and Week 8 ]
    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Response was defined as a ≥50% decrease in MADRS Total Score from Baseline.
13. Percentage of Participants in MADRS Remission at Week 8 [ Time Frame: Week 8 ]
    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Remission was defined as a MADRS total score ≤10.
14. Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score [ Time Frame: Baseline, Week 1, Week 4 and Week 8 ]
    The CGI-S assesses the clinician's impression of the subject's current state of mental illness and consists of one question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill). A MMRM model with baseline*week, center, week, treatment and week*treatment as factors was used for analyses.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The participant has recurrent MDD as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.3x). The current MDE should be confirmed using the Mini International Neuropsychiatric Interview (MINI) V6.0.0.
4. The participant has received prescribed treatment for a previous episode of depression.
5. The participant has a MADRS total score ≥26 at both the screening and baseline visits.
6. Participant reports subjective cognitive dysfunction (such as difficulty concentrating, slow thinking, and difficulty in learning new things or remembering things).
7. The reported duration of the current major depressive episode (MDE) is at least 3 months
8. The participant is a man or woman between 18 and 65 years old, inclusive.
9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of the study and for 30 days after completion of the study.

Exclusion Criteria:

1. The participant has previously participated in this study.
2. The participant has a history of severe drug allergy or hypersensitivity, or known hypersensitivity to any of the excipients of the investigational medicinal product (IMP).
3. The participant has known hypersensitivity to duloxetine.
4. The participant has hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency.
5. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
6. The participant has a score ≥70 on the DSST (numbers correct) at the Baseline Visit.
7. The participant is, in the opinion of the investigator, not able to complete the neuropsychological tests validly at the Baseline Visit.
8. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.

9. The participant has 1 or more of the following:

   1. Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR (as assessed by the MINI Version 6.0.0).
   2. Current or history of attention deficit hyperactivity disorder (ADHD), pervasive developmental disorder, manic or hypomanic episode, schizophrenia, or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
   3. Current diagnosis of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in sustained full remission for at least 2 years prior to Screening. (Participant must also have negative urine drug screen prior to Baseline).
   4. Presence or history of a clinically significant neurological disorder (including epilepsy).
   5. Neurodegenerative disorder (Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, etc).
   6. Any DSM-IV Axis II disorder that might compromise the study.
10. The participant has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with study treatment or impair treatment compliance.
11. The participant has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests.
12. The participant is diagnosed with reading disability (dyslexia).
13. The participant has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.
14. The participant, in the opinion of the investigator, poses a risk of harm to others.
15. The participant has initiated formal cognitive or behavioral therapy, systemic psychotherapy within less than 6 months of study screening, or has plans to initiate such therapy during the study.
16. The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.
17. The current depressive symptoms are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each at the recommended dose.
18. The participant has a history of moderate or severe head trauma (for example, loss of consciousness for more than 1 hour) or other neurological disorders or systemic medical diseases that are, in the opinion of the investigator, likely to affect central nervous system functioning.
19. The participant has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of investigational drug. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin.

20. The participant has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

    Note: For the purposes of this protocol, the following conditions are considered unstable due to the potential impact on assessment of MDD response and/or cognitive status: pain disorders, chronic fatigue syndrome, fibromyalgia, obstructive sleep apnea, and known cases of HIV, HBV, and HCV

21. The participant has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma.
22. The participant is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study evaluation period as specified in the Excluded Medications Section.
23. The participant has received any investigational compound <30 days before Screening or 5 half-lives prior to Screening.
24. The participant has clinically significant abnormal vital signs as determined by the investigator.

25. The subject has thyroid stimulating hormone (TSH) outside the normal range at the Screening Visit.

    Note: If TSH value is outside the normal range, a free T4 will be obtained. Subjects who have elevated TSH but normal T4 (i.e. subclinical hypothyroidism) will be excluded. For subjects who are on thyroid hormone replacement therapy, a lower TSH with normal T4, are eligible to participate in the study only if there are no clinical symptoms of hypothyroidism .

26. The participant has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the Screening Visit:

    1. A serum creatinine value >1.5 times the upper limits of normal (×ULN).
    2. A total serum total bilirubin value >1.5×ULN.
    3. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2×ULN.
27. The participant has an abnormal electrocardiogram (ECG) as determined by the central reader and confirmed as clinically significant by the investigator.
28. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.
29. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.
30. The participant has been previously exposed to LuAA21004 compound.
31. The participant has a history of lack of response to previous adequate treatment with duloxetine.

Contacts and Locations

Locations

United States, Arizona

Tucson, Arizona, United States

United States, Arkansas

Little Rock, Arkansas, United States

United States, California

Bellflower, California, United States

Carson, California, United States

Cerritos, California, United States

Glendale, California, United States

Imperial, California, United States

Los Angeles, California, United States

Norwalk, California, United States

Oakland, California, United States

Paramount, California, United States

San Bernardino, California, United States

Santa Ana, California, United States

Wildomar, California, United States

United States, Colorado

Colorado Springs, Colorado, United States

Denver, Colorado, United States

United States, Connecticut

Norwalk, Connecticut, United States

United States, Florida

Lauderhill, Florida, United States

Miami, Florida, United States

Orlando, Florida, United States

Sanford, Florida, United States

St. Petersburg, Florida, United States

Tampa, Florida, United States

West Palm Beach, Florida, United States

United States, Illinois

Chicago, Illinois, United States

Hoffman Estates, Illinois, United States

Naperville, Illinois, United States

Oak Brook, Illinois, United States

Skokie, Illinois, United States

United States, Indiana

Indianapolis, Indiana, United States

United States, Kansas

Prairie Village, Kansas, United States

United States, Louisiana

Shreveport, Louisiana, United States

United States, Maryland

Baltimore, Maryland, United States

United States, Massachusetts

Haverhill, Massachusetts, United States

United States, Missouri

St. Louis, Missouri, United States

United States, Nebraska

North Platte, Nebraska, United States

United States, Nevada

Las Vegas, Nevada, United States

United States, New York

Buffalo, New York, United States

New York, New York, United States

Staten Island, New York, United States

United States, Ohio

Avon lake, Ohio, United States

Beachwood, Ohio, United States

Garfield Heights, Ohio, United States

Toledo, Ohio, United States

United States, Oklahoma

Oklahoma City, Oklahoma, United States

United States, Oregon

Portland, Oregon, United States

United States, Pennsylvania

Allentown, Pennsylvania, United States

Norristown, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

United States, South Carolina

Columbia, South Carolina, United States

United States, Tennessee

Franklin, Tennessee, United States

Memphis, Tennessee, United States

United States, Texas

Dallas, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

The Woodlands, Texas, United States

United States, Utah

Orem, Utah, United States

Salt Lake City, Utah, United States

United States, Washington

Kirkland, Washington, United States

Seattle, Washington, United States

United States, Wisconsin

Brown Deer, Wisconsin, United States

Milwaukee, Wisconsin, United States

Bulgaria

Kazanlak, Bulgaria

Novi Iskar, Bulgaria

Pleven, Bulgaria

Plovdiv, Bulgaria

Sofia, Bulgaria

Tzerova Koria, Bulgaria

Finland

Helsinki, Finland

Kuopio, Finland

Turku, Finland

Germany

Berlin, Germany

Bochum, Germany

Chemnitz, Germany

Hannover, Germany

Munchen, Germany

Schwerin, Germany

Westerstede, Germany

Wiesbaden, Germany

Poland

Bialystok, Poland

Leszno, Poland

Lodz, Poland

Torun, Poland

Russian Federation

Ekaterinburg, Russian Federation

Nizhny Novgorod, Russian Federation

Saint-Petersburg, Russian Federation

Smolensk, Russian Federation

Stavropol, Russian Federation

Ukraine

Kharkiv, Ukraine

Kyiv, Ukraine

Luhansk, Ukraine

Ternopil, Ukraine

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Senior Medical Director Clinical Science; Takeda

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jacobson W, Zhong W, Nomikos GG, Christensen MC, Kurre Olsen C, Harvey PD. Effects of vortioxetine on functional capacity across different levels of functional impairment in patients with major depressive disorder: a University of California, San Diego Performance-based Skills Assessment (UPSA) analysis. Curr Med Res Opin. 2020 Jan;36(1):117-124. doi: 10.1080/03007995.2019.1657692. Epub 2019 Aug 29.

Christensen MC, Sluth LB, McIntyre RS. Validation of the University of California San Diego Performance-based Skills Assessment (UPSA) in major depressive disorder: Replication and extension of initial findings. J Affect Disord. 2019 Feb 15;245:508-516. doi: 10.1016/j.jad.2018.11.034. Epub 2018 Nov 5.

Christensen MC, Loft H, McIntyre RS. Vortioxetine improves symptomatic and functional outcomes in major depressive disorder: A novel dual outcome measure in depressive disorders. J Affect Disord. 2018 Feb;227:787-794. doi: 10.1016/j.jad.2017.11.081. Epub 2017 Nov 16.

Keefe RSE, Nomikos G, Zhong W, Christensen MC, Jacobson W. A Subgroup Analysis of the Impact of Vortioxetine on Functional Capacity, as Measured by UPSA, in Patients with Major Depressive Disorder and Subjective Cognitive Dysfunction. Int J Neuropsychopharmacol. 2018 May 1;21(5):442-447. doi: 10.1093/ijnp/pyy020.

Christensen MC, Munro V. Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome. Curr Med Res Opin. 2018 Apr;34(4):593-600. doi: 10.1080/03007995.2017.1416952. Epub 2018 Jan 16.

Harvey PD, Jacobson W, Zhong W, Nomikos GG, Cronquist Christensen M, Kurre Olsen C, Merikle E. Determination of a clinically important difference and definition of a responder threshold for the UCSD performance-based skills assessment (UPSA) in patients with major depressive disorder. J Affect Disord. 2017 Apr 15;213:105-111. doi: 10.1016/j.jad.2017.02.014. Epub 2017 Feb 14.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01564862
• Other Study ID Numbers: LuAA21004_202; 2011-005298-22 ( EudraCT Number ); U1111-1126-0091 ( Registry Identifier: WHO )
• First Posted: March 28, 2012
• Results First Posted: February 5, 2015
• Last Update Posted: February 5, 2015
• Last Verified: February 2015

Keywords provided by Takeda:

Drug Therapy

Additional relevant MeSH terms:

Depressive Disorder; Depression; Depressive Disorder, Major; Cognitive Dysfunction; Mood Disorders; Mental Disorders; Behavioral Symptoms; Cognition Disorders; Neurocognitive Disorders; Duloxetine Hydrochloride; Vortioxetine; Serotonin and Noradrenaline Reuptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Antidepressive Agents; Psychotropic Drugs; Dopamine Agents; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Serotonin Uptake Inhibitors; Serotonin Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists