Larry Culpepper, MD, MPH, discusses achieving treatment goals for patients with MDD.

WHAT ARE THE CHALLENGES IN ACHIEVING REMISSION?

Larry Culpepper, MD, MPH, discusses achieving treatment goals for patients with MDD.

CHALLENGES OF PATIENT MANAGEMENT

Achieving remission for patients with MDD can be an uphill battle

More than half of patients with MDD fail to achieve symptom resolution with first-line therapies.1 Of those patients who achieve remission, over 90% have at least 1 residual symptom.2

The challenge of taking patients beyond partial response is further complicated by the fact that remission rates decrease with each subsequent line of therapy.1,3

Remission rates decreased while discontinuation due to side effects increased with each additional change in therapy1
chart showing % rate on left axis, with numbers from 0 to 100, and across bottom copy reads, Step 1, Step 2, Step 3, Step 4, with bar charts above each step - left bar in blue is response, right bar in green is remission. Results - Step 1 shows 48.6 and 36.8; Step 2 shows 28.5 and 30.6, Step 3 shows 16.8 and 13.7, and Step 4 shows 16.3 and 13.0.

In the STAR*D trial, a large study of 3671 patients with MDD, each additional line of antidepressant therapy was associated with decreased rates of remission and increased rates of discontinuation.1

Remission rates decreased while discontinuation due to side effects increased with each additional change in therapy1
chart showing % rate on left axis, with numbers from 0 to 100, and across bottom copy reads, Step 1, Step 2, Step 3, Step 4, with bar charts above each step - left bar in blue is response, right bar in green is remission. Results - Step 1 shows 48.6 and 36.8; Step 2 shows 28.5 and 30.6, Step 3 shows 16.8 and 13.7, and Step 4 shows 16.3 and 13.0.

In the STAR*D trial, a large study of 3671 patients with MDD, each additional line of antidepressant therapy resulted in decreased rates of remission and increased rates of discontinuation.1

Residual symptoms increase risks in MDD

Patients with residual symptoms are at an increased risk for relapse and other serious consequences, including3–5

  • Greater likelihood of experiencing recurrent episodes of MDD
  • Significant psychosocial disability rate
  • Faster relapse rate
  • More chronic future course of disease
  • Work impairment

Common residual symptoms seen in patients with MDD are depressed mood or diminished interest (anhedonia), cognitive problems, insomnia, and fatigue.2,6–8

  • In one study following patients with MDD in remission, 76% of patients with residual symptoms relapsed over the 15-month follow-up period vs 25% of those without residual symptoms9

Not all patients with MDD are the same

Major depressive disorder presents a complex challenge—symptoms, progression, and response vary greatly from patient to patient.10 For a diagnosis of MDD according to the DSM-5, five or more symptoms must be present during the same 2-week period and represent a change from previous functioning. At least 1 of the 5 symptoms must be either depressed mood or loss of interest/pleasure.11

  • There are 227 different ways to meet the criteria for MDD per the DSM-5; this means it is possible for 2 patients with MDD to have no symptoms in common12
  • The neurologic basis for depression or the rationale for such symptomatic heterogeneity in MDD suggests it is not fully understood, reinforcing the need to understand other potential biologic causes10

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

Not all patients with MDD are the same

Major depressive disorder presents a complex challenge—symptoms, progression, and response vary greatly from patient to patient.10 For a diagnosis of MDD according to the DSM-5, 5 or more symptoms must be present during the same 2-week period and represent a change from previous functioning. At least 1 of the 5 symptoms must be either depressed mood or loss of interest/pleasure.11

  • There are 227 different ways to meet the criteria for MDD per the DSM-5; this means it is possible for 2 patients with MDD to have no symptoms in common12
  • The neurologic basis for depression or the rationale for such symptomatic heterogeneity in MDD suggests it is not fully understood, reinforcing the need to understand other potential biologic causes10

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

It is time to look beyond the monoaminergic system

With the heterogeneous nature of MDD, it is not surprising that numerous pathways and biologic processes have been implicated in the pathophysiology of depression. However, FDA-approved antidepressants primarily target monoamine pathways (serotonin, norepinephrine, and/or dopamine).13

Primary targets of FDA-approved antidepressants are monoaminergic
Chart showing how FDA-approved antidepressants target monoamine pathways. On left of chart is listing, from top to bottom TCAs, MAOIs, SSRIs, NDRI, SNRIs, Atypical antipsychotics.  Across top is Monoamines as header, with Serotonin column on left, Norepinephrine column in center, and Dopamine column on right. Across from each name on listing are checkmarks that apply to different pathways: TCAs has serotonin and norepinephrine checked, MAOIs has all 3 checked, SSRIs only has serotonin checked, NDRI has norepinephrine and dopamine checked, SNRIs has serotonin and norepinephrine checked, and Atypical antipsychotics has all 3 checked

MAOIs, monoamine oxidase inhibitors; NDRIs, norepinephrine-dopamine reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

For patients unresponsive or partially responsive to antidepressant therapies, understanding neurobiologic systems beyond the monoaminergic pathways may be important.
Learn about the potential role of the endogenous opioid system in MDD. WATCH THE VIDEO

References: 1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 2. Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010;40(1):41-50. 3. Practice guideline for the treatment of patients with major depressive disorder, third edition. American Psychiatric Association website. https://psychiatryonline.org/pb/assets/raw/sitewide/
practice_guidelines/guidelines/mdd.pdf. Published October 2010. Accessed July 14, 2017. 4. Judd LL, Schettler PJ, Rush AJ, Coryell WH, Fiedorowicz JG, Solomon DA. A new empirical definition of major depressive episode recovery and its positive impact on future course of illness. J Clin Psychiatry. 2016;77(8):1065-1073. 5. Miller IW, Keitner GI, Schatzberg AF, et al. The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry. 1998;59(11):608-619. 6. Conradi HJ, Ormel J, de Jonge P. Symptom profiles of DSM-IV-defined remission, recovery, relapse, and recurrence of depression: the role of the core symptoms. Depress Anxiety. 2012;29(7):638-645. 7. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):5-9. 8. Shelton RC, Tomarken AJ. Can recovery from depression be achieved? Psychiatr Serv. 2001;52(11):1469-1478. 9. Paykel ES, Ramana R, Cooper Z, et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25(6):1171-1180. 10. Nelson JC, Pikalov A, Berman RM. Augmentation treatment in major depressive disorder: focus on aripiprazole. Neuropsychiatr Dis Treat. 2008;4(5):937‐948. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. 12. Zimmerman M, Ellison W, Young D, Chelminski I, Dalrymple K. How many different ways do patients meet the diagnostic criteria for major depressive disorder? Compr Psychiatry. 2015;56:29-34. 13. Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81-97. 14. Amitriptyline [prescribing information]. Princeton, NJ: Sandoz Inc; 2014. 15. Norpramin [prescribing information]. Bridgewater, NJ: sanofi-aventis US LLC; 2014. 16. Imipramine [prescribing information]. Fairfield, NJ: Excellium Pharmaceutical Inc; 2012. 17. Emsam [prescribing information]. Morgantown, WV: Somerset Pharmaceuticals Inc; 2015. 18. Zoloft [prescribing information]. New York, NY: Pfizer Inc; 2017. 19. Wellbutrin XL [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2014. 20. Cymbalta [prescribing information]. Indianapolis, IN: Lilly USA LLC; 2016. 21. Viibryd [prescribing information]. Allergan USA Inc; 2011. 22. Seroquel [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.

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