Feature|Articles|March 18, 2024
Navigating the Complexity of Major Depressive Disorder
Author(s)Roger S. McIntyre, MD, FRCPC
Key Takeaways
- MDD symptoms include depressed mood, loss of interest, and cognitive impairments, requiring personalized treatment approaches.
- The monoamine-deficiency theory links neurotransmitter depletion to MDD, supported by antidepressant mechanisms.
Paid content from Takeda Pharmaceuticals and Lundbeck
Major Depressive Disorder, or MDD, is a clinically heterogeneous condition, with a variety of symptoms spanning emotional, cognitive, and physical domains.1
MDD manifests as a complex combination of five or more symptoms, including the core symptoms, which are depressed mood and loss of interest (only one of these is required for an MDD diagnosis). Other symptoms include significant weight loss or weight gain or change in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, difficulty concentrating or indecisiveness, fatigue or low energy, feelings of worthlessness or excessive guilt, and recurrent thoughts of death or suicidal ideation. Everyone experiences MDD differently.1
While the etiology of MDD is complex, the monoamine-deficiency theory suggests a possible connection between levels of key neurotransmitters in the brain and MDD. This theory posits that the basis of MDD is a depletion of the neurotransmitters serotonin, norepinephrine, or dopamine in the central nervous system. Serotonin has been extensively studied for its role in depression. The hypothesized pathophysiology of MDD based on the monoamine-deficiency theory appears to be supported by the mechanism of action of antidepressants. These agents elevate the levels of neurotransmitters in the brain and have all been shown to be effective in the alleviation of depressive symptoms.2
The Case of Sarah: A 45-Year-Old Mother of Two
Meet "Sarah," a hypothetical patient with MDD. She is a 45-year-old mother of two active children and a professional, managing daily responsibilities across her personal and work life. Her MDD diagnosis was based on the full diagnostic criteria, including the five clinical symptoms shown in the image (i.e., loss of interest, difficulty concentrating, low energy, depressed mood, and excessive guilt), and she described her concerns to her psychiatrist as not enjoying the things she used to love, having trouble focusing, and not having the energy to do anything.
Loss of interest might manifest as a decreased enthusiasm for hobbies, like discontinuing bike rides or neglecting a collection of books she once enjoyed. Regarding difficulty concentrating, once-easy tasks may be more challenging. Colleagues at work have noticed she seems more distracted than usual. In her personal life, Sarah may complain about difficulty concentrating on daily tasks, such as packing her kids’ school bags. Sarah performs her daily activities and tasks, but they are a chore for her. She feels like she’s just going through the motions.
Sarah also experiences fatigue even without significant physical exertion. Getting out of bed or performing routine activities becomes challenging due to this low energy, a struggle she did not face previously. Examining Sarah's concerns and MDD symptoms beyond sadness illustrates how they may manifest in daily life. Recognizing these variations enables health care providers to develop tailored treatment plans for managing MDD, addressing symptoms that extend beyond sadness.
As a practicing psychiatrist, I’ve spent a lot of time delving into the complexities of treating MDD. Through my experience with patients, I’ve discussed different treatment options including
Please see additional Important Safety Information throughout and click for
Understanding the DSST and Speed of Processing
An important aspect of cognitive function that may be impaired in MDD is speed of processing, or SOP, which can be defined as the rate with which one can accurately process information.3,5
MDD patients can refer to issues with SOP as experiencing slowed thinking or taking longer to process what people are saying. I’ve heard patients say that someone will ask them a question and it may take longer than it should for them to respond.
The Digit Symbol Substitution Test, or DSST, is a neuropsychological test that most specifically measures processing speed, an aspect of cognitive function that may be impaired in MDD. On the DSST, patients are asked to match 9 symbols with their corresponding number, 1 to 9, according to a key. DSST scores are determined by quantifying the number of correct matches achieved within 90 seconds. As a reference, the mean score for healthy 45- to 54-year-old subjects is 50; the standard deviation is 15.5
TRINTELLIX’s SOP Data
Trintellix has been shown to improve performance on DSST. Additionally, Trintellix is the only antidepressant that has data on SOP in its US Prescribing Information.
Trintellix's SOP data draws from two 8-week studies, Study 7 and Study 8. Both studies were randomized, double-blind, placebo-controlled, and assessed the effect of Trintellix on DSST in patients aged 18-65 diagnosed with acute MDD (n = 602, each).5,6,7 Study 7 looked at fixed doses of both 10 mg/day and 20 mg/day, while Study 8 had a flexible dosing schedule (10 mg or 20 mg).6,7 Neither study included patients whose MDD was in remission, yet who continued to experience difficulty concentrating or slow thinking.6,7
Trintellix doses were statistically superior to placebo in improvement in number of correct responses on the DSST, with observed P values less than 0.001 and 0.05 for Study 7 and Study 8, respectively.5,6,7 The effects observed on DSST may reflect an improvement in depression.5 Comparative studies have not been conducted to demonstrate a therapeutic advantage for Trintellix over other antidepressants on DSST.
Common AEs (incidence greater than or equal to 5% for Trintellix) in Study 7 were nausea (16.4%, 20.8%, 4.1%) and headache (8.2%, 12.6%, 7.1%) for Trintellix 10 mg/day, Trintellix 20 mg/day, and placebo, respectively.6 SAEs were reported by 2 patients in the Trintellix 20-mg group and 2 patients in the placebo group.6 Withdrawals due to treatment-emergent adverse events (TEAEs) were 2.6% (Trintellix 10 mg), 4.3% (Trintellix 20 mg), and 4.1% (placebo).6
Common AEs (incidence greater than or equal to 5% for Trintellix) in Study 8 were nausea (20.4%, 4.2%), headache (10.2%, 8.4%), and diarrhea (5.6%, 2.6%) for Trintellix 10 mg/20 mg and placebo, respectively.7 Withdrawals due to TEAEs were 3.6% (Trintellix 10 mg/20 mg) and 3.7% (placebo).7 One patient in the Trintellix group attempted suicide, and one patient in the placebo group was hospitalized for worsening depression.7
Trintellix is contraindicated to patients with hypersensitivity to vortioxetine or any component of the Trintellix formulation. Additionally, do not use Monoamine Oxidase Inhibitors (MAOIs) intended to treat psychiatric disorders with Trintellix or within 21 days of stopping treatment with Trintellix, due to an increased risk of serotonin syndrome. Do not use Trintellix within 14 days of stopping an MAOI intended to treat psychiatric disorders, and do not start Trintellix in a patient being treated with MAOIs such as linezolid or intravenous methylene blue due to an increased risk of serotonin syndrome.
MDD Necessitates a Nuanced Approach to Diagnosis & Treatment
As illustrated by the hypothetical case of Sarah, the diverse manifestations of MDD symptoms underscore the importance of recognizing the unique needs of each patient to ensure comprehensive care that extends to the overall symptoms of MDD affecting patients' daily lives. In addition, the inclusion of measures like the DSST to assess speed of processing provides valuable insights into this aspect of cognitive function, an area that may be impacted in MDD. The availability of such data not only enhances our comprehension of the patient experience, but also offers another dimension when considering treatment.4,5
Dr. Roger McIntyre is a Professor of Psychiatry and Pharmacology at the University of Toronto, Canada, and Board Chair of the Depression and Bipolar Support Alliance (DBSA) in Chicago, Illinois, USA. Dr. McIntyre is a paid consultant for Takeda Pharmaceuticals and Lundbeck.
INDICATION
TRINTELLIX is indicated for the treatment of Major Depressive Disorder (MDD) in adults.
TRINTELLIX is available at 5 mg, 10 mg, and 20 mg tablets.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
- Hypersensitivity: Hypersensitivity to vortioxetine or any component of the TRINTELLIX formulation. Hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported in patients treated with TRINTELLIX.
- Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with TRINTELLIX or within 21 days of stopping treatment with TRINTELLIX, due to an increased risk of serotonin syndrome. Do not use TRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders.
- Linezolid and Methylene Blue: Do not start TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue, due to an increased risk of serotonin syndrome.
WARNINGS AND PRECAUTIONS
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults: Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing TRINTELLIX, in patients whose depression is persistently worse, or who are experiencing emergence of suicidal thoughts and behaviors. In pooled analyses of placebo-controlled trials of antidepressants, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients ages 24 and younger was greater than in placebo-treated patients.
- Serotonin Syndrome: Serotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
- Increased Risk of Bleeding: The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events, including but not limited to gastrointestinal. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.
- Activation of Mania/Hypomania: In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
- Discontinuation Syndrome: Adverse reactions have been reported upon abrupt discontinuation of treatment with TRINTELLIX at doses of 15 mg/day and 20 mg/day. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.
- Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including TRINTELLIX, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
- Hyponatremia: Hyponatremia has occurred as a result of treatment with serotonergic drugs, including TRINTELLIX, and in many cases appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinue TRINTELLIX in patients with symptomatic hyponatremia and institute appropriate medical intervention.
- Sexual Dysfunction: Use of serotonergic antidepressants, including TRINTELLIX, may cause symptoms of sexual dysfunction. In male patients, serotonergic antidepressant use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, use may result in decreased libido and delayed or absent orgasm.
ADVERSE REACTIONS
The most commonly observed adverse reactions for TRINTELLIX in 6- to 8-week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: nausea, constipation, and vomiting.
DRUG INTERACTIONS
Concomitant administration of TRINTELLIX and strong CYP2D6 inhibitors or strong CYP inducers may require a dose adjustment of TRINTELLIX.
PREGNANCY
Exposure to serotonergic antidepressants, including TRINTELLIX, in late pregnancy may increase the risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Monitor neonates who were exposed to TRINTELLIX in the third trimester for PPHN and drug discontinuation syndrome. Use of TRINTELLIX in the month before delivery may be associated with an increased risk of postpartum hemorrhage.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at
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1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
2 Delgado PL. Depression: the case for a monoamine deficiency. J Clin Psychiatry. 2000;61 Suppl 6:7-11.
3 Costa SL, Genova HM, DeLuca J, Chiaravalloti ND. Information processing speed in multiple sclerosis: past, present, and future. Mult Scler. 2017;23(6):772-789.
4 Jaeger J. Digit Symbol Substitution Test: the case for sensitivity over specificity in neuropsychological testing. J Clin Psychopharmacol. 2018;38(5):513-519.
5 TRINTELLIX (vortioxetine) prescribing information. Takeda Pharmaceuticals; 2021.
6 McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
7 Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RSE. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology. 2015;40(8):2025-2037.
TRINTELLIX is a trademark of H. Lundbeck A/S registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. TAKEDA and the TAKEDA logo are registered trademarks of Takeda Pharmaceutical Company Limited. ©2024 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. 1-877-TAKEDA-7 (1-877-825-3327). US-VOR-1417v1.0 03/24
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