Managing Treatment-Resistant Depression with the "T-Rex" Combination.

Gryan Garcia, Ph.D., Psy.D., FNP-BC, PMHNP-BC | Clinical Advisor

Robert Spano, D.N.P., Ph.D., FNP-C, PMHNP-BC | Assistant Director of PMHNP Program

Western University of Health Sciences, Pomona, CA

Introduction

Treatment-resistant depression (TRD) poses a significant challenge in clinical practice, affecting approximately 30% of patients diagnosed with major depressive disorder [MDD] (Kolasa et al., 2023; McIntyre et al., 2023; Voineskos et al., 2020). Traditional monotherapies often fail to achieve remission, necessitating novel approaches. The combination of Trintellix (vortioxetine) and Rexulti (brexpiprazole), dubbed "T-Rex," has emerged as a promising strategy for managing TRD. This clinical review explores the anatomy and physiology relevant to TRD, the mechanisms of action of Trintellix and Rexulti, their application in practice, and the nursing implications for their use.

Anatomy and Physiology of Major Depressive Disorder

Depression is a complex, multifactorial disorder involving various brain regions, neurotransmitters, and neural circuits (Filatova et al., 2021; Fries et al., 2023). Key areas implicated in MDD include the prefrontal cortex, hippocampus, amygdala, and anterior cingulate cortex (Cui et al., 2024). These regions are associated with mood regulation, cognitive function, and emotional processing. Neurotransmitters such as serotonin, norepinephrine, and dopamine play crucial roles in mood and behavior. In MDD, dysregulation of these neurotransmitters leads to the characteristic symptoms of depression, including persistent sadness, anhedonia, fatigue, and cognitive impairments.

Serotonin. Produced in the raphe nuclei of the brainstem, serotonin is involved in mood regulation, anxiety, and sleep. In MDD, serotonin levels are often low, leading to depressive symptoms. Serotonin receptors are distributed throughout the brain, influencing various functions including mood, cognition, and perception (Berger et al. 2009; Jenkins et al., 2016; Kanova et al., 2021; Mitroshina et al., 2023).

Norepinephrine. Originating from the locus coeruleus, norepinephrine influences arousal, vigilance, and stress response. Dysregulation of norepinephrine pathways in MDD contributes to symptoms such as lack of energy, difficulty concentrating, and anhedonia (Atzori et al., 2016; Meng et al., 2023; Morris et al., 2020; Ross et al., 2021).

Dopamine. Primarily produced in the substantia nigra and ventral tegmental area, dopamine is crucial for reward processing and motivation. In MDD, impaired dopamine function leads to decreased motivation, pleasure, and an overall sense of well-being (Cardona-Acosta et al., 2023; Dresp-Langley, 2023; Juárez Olguín et al., 2016; Lewis et al., 2021).

In TRD, these neurotransmitter systems often exhibit abnormalities that render conventional monotherapies, such as selective serotonin reuptake inhibitors (SSRIs), less effective. This necessitates alternative pharmacological approaches that target multiple neurotransmitter systems and receptors to achieve therapeutic efficacy.

Mechanism of Action of Trintellix and Rexulti

Trintellix (Vortioxetine):

Trintellix is a multimodal antidepressant that exerts its effects through several mechanisms. It acts as a serotonin reuptake inhibitor, increasing serotonin availability in the synaptic cleft. Additionally, it modulates various serotonin receptors: it is an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. This unique profile not only enhances serotonergic transmission but also influences other neurotransmitter systems indirectly, improving mood, cognitive function, and anxiety symptoms (Christensen et al., 2023; Di Nicola et al., 2023; Li et al., 2023; Mattingly et al., 2023; McIntyre et al., 2024).

Rexulti (Brexpiprazole):

Rexulti is an atypical antipsychotic with a unique pharmacological profile. It acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at serotonin 5-HT2A and norepinephrine alpha-1B/2C receptors. This combination of actions helps modulate both serotonergic and dopaminergic activity, which is critical in managing TRD. By balancing these neurotransmitter systems, Rexulti can reduce depressive symptoms and improve overall mood stability (Lee et al., 2023; Lombardozzi et al., 2023; Siwek et al., 2023; Wee et al., 2023).

                                              Medication side effects

Both Rexulti and Trintellix can cause common side effects like drowsiness, dizziness, and nausea. However, there are some key differences in their potential side effects:

• Rexulti: Watch out for movement problems, high blood sugar, and allergic reactions.

• Trintellix: Be aware of risks for seizures, serotonin syndrome (causing agitation, confusion, and diarrhea), and suicidal thoughts.

Medication	Common Side Effects	Severe side effects	Labs to monitor
Rexulti	Drowsiness, dizziness, lightheadedness, shaking, increased appetite, weight gain, restlessness, trouble sleeping	High blood sugar, movement problems (tardive dyskinesia), neuroleptic malignant syndrome (NMS), low white blood cells, (Thrombocytopenia) severe allergic reactions	Blood sugar, A1C
Trintellix	Nausea, diarrhea, dry mouth, fatigue, sexual dysfunction, Insomnia.	Seizures, serotonin syndrome, suicidal thoughts, bleeding problems, liver problems	Liver function, AST, ALT, GGT, ALP, Bilirubin

Application to Practice

Case Study:

Patient Profile: A 45-year-old female with a 10-year history of MDD, presenting with persistent depressive symptoms despite trials of multiple SSRIs and SNRIs. She reports severe anhedonia, fatigue, and cognitive slowing, significantly impacting her daily functioning.

Intervention: After comprehensive evaluation and informed consent, the patient was initiated on the "T-Rex" combination. Trintellix was started at 10 mg daily, titrated to 20 mg over four weeks, while Rexulti was introduced at 1 mg daily, gradually increased to 2 mg.

Outcome: Within eight weeks, the patient demonstrated significant improvement in mood, energy levels, and cognitive function. She reported a marked reduction in anhedonia and fatigue, enabling her to resume work and social activities.

Nursing Implications

Assessment and Monitoring:

·      Baseline Assessment: Conduct thorough psychiatric evaluations, including history of previous treatments and response, current symptomatology, and any co-morbid conditions.

·      Regular Monitoring: Monitor for side effects, such as gastrointestinal disturbances with Trintellix and metabolic changes or akathisia with Rexulti. Regular follow-up appointments are essential to assess efficacy and adjust dosages.

·      Patient Education: Educate patients about the potential benefits and side effects of the "T-Rex" combination. Emphasize adherence to the medication regimen and the importance of reporting any adverse effects or concerns promptly.

Management of Side Effects:

·      Trintellix: Common side effects include nausea, diarrhea, and dizziness. These can be mitigated by taking the medication with food and gradually titrating the dose.

·      Rexulti: Monitor for weight gain, akathisia, and metabolic changes. Regular metabolic monitoring (e.g., glucose, lipid profile) and encouraging a healthy lifestyle can help manage these risks.

Collaboration and Communication:

-       Multidisciplinary Approach: Collaborate with psychiatrists, primary care providers, and other mental health professionals to ensure comprehensive care. Regular communication can help address any emerging issues promptly.

-       Patient Support: Provide ongoing emotional support and counseling to patients and their families. Address any concerns regarding medication adherence, lifestyle modifications, and coping strategies.

Frequently Asked Questions

Q1: What makes the "T-Rex" combination effective for TRD?

ü  A1: The "T-Rex" combination leverages the multimodal action of Trintellix and the dopaminergic modulation of Rexulti, targeting multiple neurotransmitter systems. This synergistic effect addresses the complex pathophysiology of TRD, offering improved symptom control and functional outcomes.

Q2: What are the primary side effects associated with this combination?

ü  A2: Common side effects include gastrointestinal disturbances (Trintellix) and metabolic changes or akathisia (Rexulti). Regular monitoring and patient education are crucial to manage these effects effectively.

Q3: How should dosages be adjusted in clinical practice?

ü  A3: Dosage adjustments should be based on clinical response and tolerability. Start with lower doses and titrate gradually. Regular follow-up is essential to monitor efficacy and side effects.

Q4: Can the "T-Rex" combination be used in patients with co-morbid conditions?

ü  A4: Yes, but it requires careful assessment and monitoring. Collaborate with other healthcare providers to ensure comprehensive management of co-morbid conditions and potential drug interactions.

Q5: How long does it take to see improvements with the "T-Rex" combination?

ü  A5: Clinical improvements are typically observed within 4 to 8 weeks of starting the combination therapy. However, individual responses may vary, and ongoing monitoring is essential to optimize treatment outcomes.

Q6: Are there any contraindications for using Trintellix and Rexulti together?

ü  A6: While there are no absolute contraindications, caution should be exercised in patients with a history of bipolar disorder, seizures, or severe cardiovascular conditions. A thorough evaluation of the patient's medical history and current medications is essential to avoid potential drug interactions and adverse effects.

Q7: How does the "T-Rex" combination compare to other treatment options for TRD?

ü  A7: The "T-Rex" combination offers a unique approach by targeting multiple neurotransmitter systems, which can be more effective for patients who have not responded to traditional monotherapies. While other options, such as augmentation with lithium or thyroid hormone, can be effective, the "T-Rex" combination may provide a better balance of efficacy and tolerability for some patients.

Additional Considerations

Pharmacoeconomic Impact:

TRD not only affects patients' quality of life but also imposes a significant economic burden due to increased healthcare utilization, lost productivity, and disability. The "T-Rex" combination, by improving treatment outcomes, has the potential to reduce these costs. Early and effective management of TRD can lead to decreased hospitalizations, fewer medical visits, and improved workplace productivity, translating into substantial cost savings for the healthcare system.

Future Directions:

Ongoing research is essential to further elucidate the mechanisms underlying TRD and to optimize treatment strategies. Future studies could explore the long-term efficacy and safety of the "T-Rex" combination, identify biomarkers for response prediction, and develop personalized treatment plans based on genetic and neurobiological profiles. Advances in neuroimaging and pharmacogenomics may also provide insights into the pathophysiology of TRD and guide the development of novel therapeutic targets.

Conclusion

The combination of Trintellix and Rexulti offers a promising approach for managing treatment-resistant depression, particularly in patients unresponsive to conventional monotherapies. By targeting multiple neurotransmitter systems, the "T-Rex" combination can improve depressive symptoms and overall functioning. Effective implementation in clinical practice requires thorough assessment, regular monitoring, and patient education to ensure optimal outcomes and minimal side effects. Nurses play a pivotal role in this multidisciplinary approach, providing critical support and ensuring adherence to treatment plans.

References

Atzori, M., Cuevas-Olguin, R., Esquivel-Rendon, E., Garcia-Oscos, F., Salgado-Delgado, R. C., Saderi, N., Miranda-Morales, M., Treviño, M., Pineda, J. C., & Salgado, H. (2016). Locus ceruleus norepinephrine release: A central regulator of cns spatio-temporal activation. Frontiers in Synaptic Neuroscience, 8, 25. https://doi.org/10.3389/fnsyn.2016.00025 

Berger, M., Gray, J. A., & Roth, B. L. (2009). The expanded biology of serotonin. Annual Review of Medicine, 60, 355–366. https://doi.org/10.1146/annurev.med.60.042307.110802 

Cardona-Acosta, A. M., & Bolaños-Guzmán, C. A. (2023). Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine. Neuropharmacology, 225, 109374. https://doi.org/10.1016/j.neuropharm.2022.109374 

Christensen, M. C., Schmidt, S. N., & Grande, I. (2023). Effectiveness of vortioxetine in patients with major depressive disorder and early-stage dementia: The MEMORY study. Journal of Affective Disorders, 338, 423–431. https://doi.org/10.1016/j.jad.2023.06.024 

Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024). Major depressive disorder: Hypothesis, mechanism, prevention and treatment. Signal Transduction and Targeted Therapy, 9(1), 30. https://doi.org/10.1038/s41392-024-01738-y 

Di Nicola, M., Pepe, M., Montanari, S., Spera, M. C., Panaccione, I., Simonetti, A., & Sani, G. (2023). Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes. European Neuropsychopharmacology: The Journal of The European College of Neuropsychopharmacology, 70, 21–28. https://doi.org/10.1016/j.euroneuro.2023.02.006 

Dresp-Langley B. (2023). From reward to anhedonia-dopamine function in the global mental health context. Biomedicines, 11(9), 2469. https://doi.org/10.3390/biomedicines11092469 

Filatova, E. V., Shadrina, M. I., & Slominsky, P. A. (2021). Major depression: One brain, one disease, one set of intertwined processes. Cells, 10(6), 1283. https://doi.org/10.3390/cells10061283 

Fries, G. R., Saldana, V. A., Finnstein, J., & Rein, T. (2023). Molecular pathways of major depressive disorder converge on the synapse. Molecular Psychiatry, 28(1), 284–297. https://doi.org/10.1038/s41380-022-01806-1 

Jenkins, T. A., Nguyen, J. C., Polglaze, K. E., & Bertrand, P. P. (2016). Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients, 8(1), 56. https://doi.org/10.3390/nu8010056 

Juárez Olguín, H., Calderón Guzmán, D., Hernández García, E., & Barragán Mejía, G. (2016). The role of dopamine and its dysfunction as a consequence of oxidative stress. Oxidative Medicine and Cellular Longevity, 2016, 9730467. https://doi.org/10.1155/2016/9730467 

Kanova, M., & Kohout, P. (2021). Serotonin-its synthesis and roles in the healthy and the critically ill. International Journal of Molecular Sciences, 22(9), 4837. https://doi.org/10.3390/ijms22094837 

Kolasa, M., & Faron-Górecka, A. (2023). Preclinical models of treatment-resistant depression: challenges and perspectives. Pharmacological Reports: PR, 75(6), 1326–1340. https://doi.org/10.1007/s43440-023-00542-9 

Lee, D., Slomkowski, M., Hefting, N., Chen, D., Larsen, K. G., Kohegyi, E., Hobart, M., Cummings, J. L., & Grossberg, G. T. (2023). Brexpiprazole for the treatment of agitation in alzheimer dementia: A randomized clinical trial. JAMA Neurology, 80(12), 1307–1316. https://doi.org/10.1001/jamaneurol.2023.3810 

Lewis, R. G., Florio, E., Punzo, D., & Borrelli, E. (2021). The brain's reward system in health and disease. Advances in Experimental Medicine and Biology, 1344, 57–69. https://doi.org/10.1007/978-3-030-81147-1_4 

Li, Z., Liu, S., Wu, Q., Li, J., Yang, Q., Wang, X., Peng, P., Wang, Q., Liu, Y., Li, M., Hao, Y., Xu, H., He, L., Wang, Y., Chen, S., & Liu, T. (2023). Effectiveness and safety of Vortioxetine for the treatment of major depressive disorder in the real world: A systematic review and meta-analysis. The International Journal of Neuropsychopharmacology, 26(6), 373–384. https://doi.org/10.1093/ijnp/pyad018 

Lombardozzi, G., Trovini, G., Amici, E., Kotzalidis, G. D., Perrini, F., Giovanetti, V., Di Giovanni, A., & De Filippis, S. (2023). Brexpiprazole in patients with schizophrenia with or without substance use disorder: An observational study. Frontiers in Psychiatry, 14, 1321233. https://doi.org/10.3389/fpsyt.2023.1321233 

Mattingly, G. W., Necking, O., Schmidt, S. N., Reines, E., & Ren, H. (2023). Long-term safety and efficacy, including anhedonia, of vortioxetine for major depressive disorder: Findings from two open-label studies. Current Medical Research and Opinion, 39(4), 613–619. https://doi.org/10.1080/03007995.2023.2178082 

McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., Ly-Uson, J., Mansur, R. B., McAllister-Williams, R. H., Murrough, J. W., Nemeroff, C. B., Nierenberg, A. A., Rosenblat, J. D., Sanacora, G., Schatzberg, A. F., Shelton, R., … Maj, M. (2023). Treatment-resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry: Official Journal of The World Psychiatric Association (WPA), 22(3), 394–412. https://doi.org/10.1002/wps.21120 

McIntyre, R. S., Phan, L., Kwan, A. T. H., Mansur, R. B., Rosenblat, J. D., Guo, Z., Le, G. H., Lui, L. M. W., Teopiz, K. M., Ceban, F., Lee, Y., Bailey, J., Ramachandra, R., Di Vincenzo, J., Badulescu, S., Gill, H., Drzadzewski, P., & Subramaniapillai, M. (2024). Vortioxetine for the treatment of post-COVID-19 condition: A randomized controlled trial. Brain: A Journal of Neurology, 147(3), 849–857. https://doi.org/10.1093/brain/awad377 

Meng, Q., Garcia-Garcia, A. L., Dranovsky, A., & Leonardo, E. D. (2023). Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood. Scientific Reports, 13(1), 3077. https://doi.org/10.1038/s41598-023-29175-x 

Mitroshina, E. V., Marasanova, E. A., & Vedunova, M. V. (2023). Functional dimerization of serotonin receptors: Role in health and depressive disorders. International Journal of Molecular Sciences, 24(22), 16416. https://doi.org/10.3390/ijms242216416 

Morris, L. S., McCall, J. G., Charney, D. S., & Murrough, J. W. (2020). The role of the locus coeruleus in the generation of pathological anxiety. Brain and Neuroscience Advances, 4, 2398212820930321. https://doi.org/10.1177/2398212820930321 

Ross, J. A., & Van Bockstaele, E. J. (2021). The locus coeruleus- norepinephrine system in stress and arousal: Unraveling historical, current, and future perspectives. Frontiers in Psychiatry, 11, 601519. https://doi.org/10.3389/fpsyt.2020.601519 

Siwek, M., Wojtasik-Bakalarz, K., Krupa, A. J., & Chrobak, A. A. (2023). Brexpiprazole-pharmacologic properties and use in schizophrenia and mood disorders. Brain Sciences, 13(3), 397. https://doi.org/10.3390/brainsci13030397 

Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020). Management of treatment-resistant depression: Challenges and strategies. Neuropsychiatric Disease and Treatment, 16, 221–234. https://doi.org/10.2147/NDT.S198774 

Wee, S. N., Liman, C., Waters, H. C., Houle, C. R., Renteria, M., Mukherjee, S. S., Surendran, S., Marcovici, J., Brubaker, M., Rasmussen Meehan, S., de Jong-Laird, A., Rush, A. J., & Sarkar, J. (2023). Life engagement improvement following initiation of brexpiprazole treatment in patients with MDD: A naturalistic, retrospective real-world study. Clinicoeconomics and Outcomes Research: CEOR, 15, 195–208. https://doi.org/10.2147/CEOR.S395255