Content Sponsored by Otsuka America Pharmaceutical Inc. and Lundbeck for which Gerald A. Maguire, M.D. is a paid consultant.

Major Depressive Disorder (MDD) – also known as depression – is a chronic debilitating disease characterized by symptoms that last at least two weeks causing significant functional impairment. While symptoms of depression differ for each individual patient, some common symptoms may include a depressed mood that affects how a person thinks, feels and behaves or a loss of interest in activities a patient once enjoyed. Patients may also experience physical symptoms such as fatigue, sleep disturbance, body aches and changes in appetite[i]. Unfortunately, it can be difficult to diagnose new patients with depression. As healthcare providers we know it can also be challenging to evaluate the progress of patients already diagnosed with this condition[ii].

Typically, providers may diagnose a patient based on a comprehensive psychiatric evaluation. Additionally, a physical exam, imaging studies and lab tests may provide supportive information or help with differential diagnosis. We clinicians often rely on a combination of these diagnostic methods. Once a diagnosis is reached, it is important that providers work with patients to create a comprehensive treatment plan that is best for them, which may include medication, psychotherapy or some combination of the two[iii],[iv].

While a variety of medications are available, antidepressants are the most common treatment for depression. In fact, approximately 87% of patients diagnosed with MDD receive antidepressants as treatment[v]. Despite taking an antidepressant, many people may still experience symptoms of depression, or partial response, making it imperative that providers conduct routine check-ins with patients to evaluate their progress on their current medication regimen[vi].

Conversations earn trust

When connecting with patients living with depression who are already taking an antidepressant, it may be tempting for providers to fall back on re-evaluation by checklist alone. In my experience, however, this can lead to feeling a lack of connection with the patient. Instead, when teaching my own students and residents, I guide clinicians to encourage discussion and to ask open-ended questions that prompt the medical examination in a conversational form. That dialogue is critical to building a therapeutic alliance, which is foundational to developing an efficacious treatment plan for each individual patient[vii].

Additionally, establishing this communication style early on in a patient’s journey helps lay the groundwork for clinicians as they continuously assess the progress a patient may or may not be making on their current medication. While a patient may not walk into their provider’s office and say, “I’m depressed,” or “I’m not experiencing adequate relief for my depression,” most of the time, they will often share what negative feelings they are experiencing. It is imperative that providers open the floor for effective conversation and listen with a critical ear to get to the root of the problem.

In my practice, for example, I encourage my patients to consistently check in when starting a new medication (via phone or secured electronic communication) and then less frequently as time goes on and they may experience fewer depressive symptoms. At that point, we can revaluate and decrease the regularity of our communication to an appropriate level. For me, ensuring my patients play an active role in their treatment is an important factor in providing quality care[viii]

It’s never a good thing if a patient becomes frustrated when they feel a medication is not working, or they are only experiencing a partial response. Medications may take some time to take full effect – but after that point, it may be time for providers to reexamine their patient’s treatment plan[ix].

If a patient is not responsive to their initial treatment after 4-8 weeks, or if they and their doctor are not seeing the progress they had hoped for, it may be time to switch medication classes, make adjustments to the current dosage, or consider adjunctive treatment options[x],[xi]. With my patients, if a patient has a partial response but is still experiencing lingering symptoms of depression on their current antidepressant after two months, I’ll start a discussion with them on options that may help provide them with adequate symptom control.

Just like diagnosing and reevaluating a patient, it’s vital to look at them holistically when considering add-on therapies, including asking them about family, personal, social and medical histories[xii]. These are crucial factors in treatment and may be indicative of a patient’s response to starting new medications. Additionally, providers should encourage their patients to take an all-inclusive approach to treating their depression and overall mental health.

For example, it’s important that health care providers ensure their patients maintain strong social connections with family and friends. Additionally, staying active through appropriate exercise, avoiding drugs and alcohol, maintaining a regular sleep schedule and surrounding themselves with things that bring them joy (e.g., pets, family, hobbies, etc.) may benefit patients living with depression. These lifestyle changes coupled with continued therapy are best practices for helping patients with their depression, in addition to pharmacological interventions[xiii].

Addressing partial response with adjunctive treatment

Brexpiprazole, marketed under the brand name REXULTI®, is a prescription medicine indicated for use as an adjunctive therapy to antidepressants in adults with MDD who experience partial response.

Please see IMPORTANT SAFETY INFORMATION below, including the BOXED WARNING regarding Increased Mortality in Elderly Patients with Dementia-Related Psychosis and Suicidal Thoughts and Behaviors.

When the patient’s healthcare provider determines that their current antidepressant is not enough to treat the patient’s depression, they may prescribe brexipirazole to be taken with an antidepressant. In fact, data from two six week, double-blind, placebo-controlled, fixed-dose pivotal trials of adult patients aged 18-65 showed that adding brexpiprazole to the antidepressant showed a greater reduction in depression symptoms compared to the antidepressant plus placebo. The most common adverse reactions that occurred in greater than or equal to 5% or patients and at least twice the rate of placebo were akathisia and weight increase[xiv].

Encouraging continued conversations

As providers, it is vital that we have conversations around partial response and recurrence with patients as part of our continued, comprehensive communication practices. Providers should always maintain an open line of communication with patients, specifically around stopping any medication treatments and new or worsening depressive symptoms or side effects from their depression medications. 

It is important that mental health providers encourage patients to feel empowered to speak with their doctor about any concerns they have with their symptoms or treatment plan. If patients are not seeing the progress they’d hoped for after a couple of months on their current antidepressant, it is important that they know there are options, such as psychotherapy, or adjusting, changing or adding medications that may help them achieve adequate symptom relief for their depression[xv].

INDICATION and IMPORTANT SAFETY INFORMATION for
REXULTI® (brexpiprazole)

INDICATION

REXULTI is indicated for:

  • Use as an adjunctive therapy to antidepressants in adults with major depressive disorder

IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Contraindication: In patients with known hypersensitivity reaction to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke.  REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.
  • Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
  • Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular diseases.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI has the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials, the most common adverse reactions were:

  • (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs. placebo): akathisia and weight increase

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at
1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

Learn more at www.rexultihcp.com.


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[ii] Nierenberg, A. (2001). Current perspectives on the diagnosis and treatment of major depressive disorder. The American Journal of Managed Care, 7(11 Suppl), S353–S366.
[iii] Gelenberg, A. (2010). Using assessment tools to screen for, diagnose, and treat major depressive disorder in clinical practice. The Journal of Clinical Psychiatry, 71, e01–. https://doi.org/10.4088/JCP.8125cc5c
[iv] Halverson, J. L. (2020, September 07). Depression. Retrieved March 31, 2021, from https://emedicine.medscape.com/article/286759-overview
[v] Olfson M, Blanco C, Marcus SC. Treatment of Adult Depression in the United States. JAMA Intern Med. 2016;176(10):1482–1491. doi:10.1001/jamainternmed.2016.5057
[vi] Fava, M. (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology, 20(3_suppl), 29–34. https://doi.org/10.1177/1359786806064325
[vii] Krupnick, J., Sotsky, S., Simmens, S., Moyer, J., Elkin, I., Watkins, J., & Pilkonis, P. (1996). The Role of the Therapeutic Alliance in Psychotherapy Pharmacotherapy Outcome: Findings in the National Institute Of Mental Health Treatment of Depression Collaborative Research Program. Journal of Consulting and Clinical Psychology, 64(3), 532–539. https://doi.org/10.1037/0022-006X.64.3.532
[viii] Krupnick, J., Sotsky, S., Simmens, S., Moyer, J., Elkin, I., Watkins, J., & Pilkonis, P. (1996). The Role of the Therapeutic Alliance in Psychotherapy Pharmacotherapy Outcome: Findings in the National Institute Of Mental Health Treatment of Depression Collaborative Research Program. Journal of Consulting and Clinical Psychology, 64(3), 532–539. https://doi.org/10.1037/0022-006X.64.3.532
[ix] Fava, M. (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology, 20(3_suppl), 29–34. https://doi.org/10.1177/1359786806064325
[x] American psychiatric Association practice guidelines for the treatment of patients with major depressive disorder. (2010). American Psychiatric Association. doi:10.1176/appi.books.9780890423387.654001
[xi] Fava, M. (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology, 20(3_suppl), 29–34. https://doi.org/10.1177/1359786806064325
[xii] Jesulola, E., Micalos, P., & Baguley, I. (2018). Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model – are we there yet? Behavioural Brain Research, 341, 79–90. https://doi.org/10.1016/j.bbr.2017.12.025
[xiii] Goracci, A., Rucci, P., Forgione, R., Campinoti, G., Valdagno, M., Casolaro, I., Carretta, E., Bolognesi, S., & Fagiolini, A. (2016). Development, acceptability and efficacy of a standardized healthy lifestyle intervention in recurrent depression. Journal of Affective Disorders, 196, 20–31. https://doi.org/10.1016/j.jad.2016.02.034
[xiv] Thase, M., Youakim, J., Skuban, A., Hobart, M., Augustine, C., Zhang, P., McQuade, R., Carson, W., Nyilas, M., Sanchez, R., & Eriksson, H. (2015). Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. The Journal of Clinical Psychiatry, 76(9), 1224–1231. https://doi.org/10.4088/JCP.14m09688
[xv] Fava, M. (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology, 20(3_suppl), 29–34. https://doi.org/10.1177/1359786806064325