Healthcare and Medical News for Atlanta Physicians

Treatment-Resistant Depression in Outpatient Setting

By John Tumeh, MD and Hatcher, PA-S and Stephen Davis, LMHC

Major Depressive Disorder (MDD) is the leading cause of disability worldwide.[1] According to the 2019 National Survey on Drug Use and Health (NSDUH), 7.8% of all U.S. adults above age 18 have experienced at least one major depressive episode.[2]

The prevalence of major depressive episodes was higher among adult females (9.6%) compared to males (6.0%), and the prevalence of adults with a major depressive episode was highest among individuals age 18-25 (15.2%). The majority of pharmacotherapy continues to occur in the primary care setting.

The following article therefore serves as a sequential treatment strategy for the treatment of MDD in the outpatient setting. The first step is to arrive at the diagnosis of a major depressive episode according to the diagnostic criteria outlined by the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5).[3]

Table 1 Adjunct Doses in Major DepressionThe diagnosis requires symptoms of loss of interest or pleasure (anhedonia) and/or depressed mood, plus four additional symptoms from the following list: insomnia, hypersomnia, fatigue, poor appetite or overeating, guilt, impaired concentration, psychomotor slowing or restlessness, or passive death wish/suicidal ideation. Symptoms must be present during a two-week period on a nearly daily basis. Medical causes of depression (e.g. hypothyroidism, glucocorticoid treatment, low testosterone) need to be ruled out, as they can potentially be quickly reversed.

Assessments to evaluate for symptom severity should be done at every visit. Examples include the Patient Health Questionnaire-9 (PHQ-9), Hamilton Depression Rating Scale (HAM-D), Quick Inventory of Depressive Symptomatology (QUIDS), and the Montgomery Asberg Depression Rating Scale (MADRS).

The goal of treatment is to achieve full remission, defined as the absence of significant signs or symptoms of depression for at least two months (Reference 3: DSM). A response is generally accepted to be a 50% or greater reduction in symptom score on a depression questionnaire. Initial treatment should consist of an antidepressant in combination with psychotherapy.[4] In most practices, the initial choice of an antidepressant will be a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Norepinephrine Reuptake Inhibitor (SNRI), bupropion (Wellbutrin) or mirtazapine (Remeron).

Only around one-third of patients are expected to achieve remission with the first antidepressant trial.[5] The American Psychiatric Association (APA) recommends an antidepressant trial length of 6-8 weeks. Prior to modifying treatment, the clinician should rule out treatment failure secondary to inadequate dose or duration of pharmacotherapy, nonadherence to treatment, inaccurate diagnosis (e.g. thyroid disease, nutritional deficiencies, sleep apnea, “latent” bipolarity) or psychiatric comorbidities (e.g. anxiety, personality, substance use disorders).

Inadequate response to a proper trial or intolerance to adverse effects should prompt consideration of either switching (e.g. changing from SSRI to SNRI, bupropion or mirtazapine) or augmentation, the addition of a non-antidepressant medication such as an atypical antipsychotic, mood stabilizer or thyroid replacement in conjunction with an antidepressant. The sequenced treatment alternatives to relieve depression trial (STAR*D) provided up to four treatment steps in treating an individual who was unresponsive to initial treatment with antidepressants.[6]

First-line augmentation includes atypical antipsychotics (more commonly utilized since the publication of the STAR*D trial in 2006), lithium and thyroid hormone. There are four atypical antipsychotics that are FDA-approved as augmentation strategies for treatment of MDD in patients with insufficient response to antidepressants: aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti) and olanzapine (Zyprexa).

Table 2

Berman et. al’s double-blind randomized trial of low-dose aripiprazole (2-20 mg) augmentation of antidepressants (SSRIs or SNRI) showed superiority to placebo in achieving remission (week 14, 36.8% vs 18.9%; P<.001)[7].

Lithium, although not currently FDA approved to treat depression, has been recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force as augmentation medication for treatment-resistant depression (TRD).[8] However, providers are cautious to begin lithium therapy due to an extensive side effect profile (e.g. nephrogenic diabetes insipidus, tremor, ataxia, hypothyroidism, etc.) and frequent monitoring.[9] Table 1 shows the recommended adjunct doses, and Table 2 displays the monitoring guidelines. [10],11

A patient can be treated for TRD after failing to respond to a trial of one antidepressant with the addition of at least one augmented therapy. Next steps would include one of the following: transcranial magnetic stimulation, intranasal esketamine, electroconvulsive therapy (ECT) or vagus nerve stimulation.

Directly targeting glutamatergic neurotransmission through utilization of intranasal esketamine may lead to faster treatment response and may improve response and remission rates. Esketamine is administered twice weekly for one month under the supervision of a healthcare provider, followed by a tapering across two additional months.

After administration, esketamine requires a 2-hour monitoring period for adverse side effects with routine blood pressure checks due to potential transient hypertensive state. Most commonly, patients will experience sedation and dissociation. Therefore, it is advised patients should not operate machinery 24 hours after administration.[11] Esketamine has recently shown potential for rapid antidepressant effects in patients with MDD, including TRD and suicidality.[12]

ECT remains the most effective treatment for TRD but requires anesthesia and can cause memory loss. In a study of 253 patients with MDD, 75% achieved remission by the end of ECT treatment and 54% showed response at the end of the first week of treatment.[13]

ECT is performed around 2-3 times per week for 3-4 weeks for a total of around 12 treatments. Mechanism of action includes induction of a brief seizure under anesthesia. ECT’s potential side effects include deficits in orientation, short-term memory function, attention, speech fluency and other executive functions.[14]

Transcranial magnetic stimulation (TMS), another neuromodulation therapy, has relatively few side effects, such as mild scalp irritation or headaches at the time of treatment, and is performed in the outpatient setting without need for anesthesia.[15] TMS uses focused magnetic field pulses to generate electrical currents in the dorsolateral prefrontal cortex (DLPFC), an area believed to be hypoactive in patients with MDD, resulting in increased blood flow and activation.[16]

TMS has been shown to decrease depressive symptoms by up to 58% and has achieved remission rates of 37.1%. It is administered in 20-30 sessions, once daily, five times per week. Each session lasts approximately 30 minutes.18 More recently, the speed of treatment has been accelerated by use of intermittent theta burst stimulation, allowing for faster and more numerous treatments per day. Cole et. al used neuronavigation to deliver accelerated theta burst TMS of 10 daily sessions across five days and reported remission rates of 79% within four weeks.[17] This is an exciting development in neuromodulatory therapy.

With this sequence of treatment, ideally more patients classified with major depressive disorder and treatment-resistant depression can achieve remission as they are treated with a personalized, evidence-based approach.

[1] Reddy M. Depression: The disorder and the burden. Indian Journal of Psychological Medicine [Internet]. 2010;32(1):1. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137804/

[2] 2019 National Survey of Drug Use and Health (NSDUH) Releases | CBHSQ Data [Internet]. www.samhsa.gov. 2019. Available from: https://www.samhsa.gov/data/release/2019-national-survey-drug-use-and-health-nsduh-releases

[3] American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596

Text citation: (American Psychiatric Association, 2013)

[4] Davidson JRT. Major Depressive Disorder Treatment Guidelines in America and Europe. The Journal of Clinical Psychiatry. 2010 Mar;71(suppl E1).

[5] Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials [Internet]. 2004 Feb 1 [cited 2020 Aug 5];25(1):119–42. Available from: https://pubmed.ncbi.nlm.nih.gov/15061154/

[6] Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials [Internet]. 2004 Feb 1 [cited 2020 Aug 5];25(1):119–42. Available from: https://pubmed.ncbi.nlm.nih.gov/15061154/

[7] Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr. 2009;14(4):197–206.

[8] Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H-J. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. The World Journal of Biological Psychiatry. 2013 Jul;14(5):334–85.

[9] Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. International Journal of Bipolar Disorders. 2016 Dec;4(1).

[10] Neuroscience Education Institute.

  1. Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Australian & New Zealand Journal of Psychiatry. 2012 Mar;46(3):192–211.

[11] SPRAVATO® (esketamine) | SPRAVATO® [Internet]. SPRAVATO® (esketamine). 2020 [cited 2022 Jan 7]. Available from: https://www.spravato.com/?&utm_source=google&utm_medium=cpc&utm_campaign=GO-USA-ENG-PS-Spravato-BC-PH-RN-DTC_Core_HV&utm_content=Spravato+-+HV&utm_term=spravato&gclid=CjwKCAiA5t-OBhByEiwAhR-hm4Bm9lBu5SFO8TJ6oe9atJGK3eHBRrOdviNU6iagsixxxk80f57TWhoC5XYQAvD_BwE&gclsrc=aw.ds

[12] Wang S-M, Kim N-Y, Na H-R, Lim HK, Woo YS, Pae C-U, et al. Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis. Clinical Psychopharmacology and Neuroscience [Internet]. 2021 May 31 [cited 2022 Jan 7];19(2):341–54. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077059/

[13] Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of Response and Remission in Major Depressive Disorder With Acute Electroconvulsive Therapy (ECT): A Consortium for Research in ECT (CORE) Report. wwwpsychiatristcom [Internet]. 2004 Apr 1;65. Available from: https://www.psychiatrist.com/jcp/depression/electroconvulsive-therapy/speed-response-remission-major-depressive-disorder/

[14] Getty SS, Faziola LR. Adverse effects of electroconvulsive therapy on cognitive performance. Mental Illness. 2017 Oct 19;9(2).

[15] Taylor R, Galvez V, Loo C. Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. Australasian Psychiatry. 2018 Jan 17;26(2):189–92.

[16] Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969. Epub 2012 Jun 11. PMID: 22689344.

[17] Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. American Journal of Psychiatry. 2021 Oct 29;

References

  1. Reddy M. Depression: The disorder and the burden. Indian Journal of Psychological Medicine [Internet]. 2010;32(1):1. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137804/
  2. 2019 National Survey of Drug Use and Health (NSDUH) Releases | CBHSQ Data [Internet]. www.samhsa.gov. 2019. Available from: https://www.samhsa.gov/data/release/2019-national-survey-drug-use-and-health-nsduh-releases
  3. Karrouri R, Hammani Z, Benjelloun R, Otheman Y. Major depressive disorder: Validated treatments and future challenges. World Journal of Clinical Cases [Internet]. 2021 Nov 6 [cited 2022 Jan 7];9(31):9350–67. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610877/
  4. Nemeroff CB. Special Report: Management of Major Depression—Yesterday, Today, and Tomorrow. Psychiatric News. 2021 Nov 1;56(11).
  5. Davidson JRT. Major Depressive Disorder Treatment Guidelines in America and Europe. The Journal of Clinical Psychiatry. 2010 Mar;71(suppl E1).
  6. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials [Internet]. 2004 Feb 1 [cited 2020 Aug 5];25(1):119–42. Available from: https://pubmed.ncbi.nlm.nih.gov/15061154/
  7. Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr. 2009;14(4):197–206.
  8. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H-J. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. The World Journal of Biological Psychiatry. 2013 Jul;14(5):334–85.
  9. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. International Journal of Bipolar Disorders. 2016 Dec;4(1).
  10. Neuroscience Education Institute.
  11. Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Australian & New Zealand Journal of Psychiatry. 2012 Mar;46(3):192–211.
  12. SPRAVATO® (esketamine) | SPRAVATO® [Internet]. SPRAVATO® (esketamine). 2020 [cited 2022 Jan 7]. Available from: https://www.spravato.com/?&utm_source=google&utm_medium=cpc&utm_campaign=GO-USA-ENG-PS-Spravato-BC-PH-RN-DTC_Core_HV&utm_content=Spravato+-+HV&utm_term=spravato&gclid=CjwKCAiA5t-OBhByEiwAhR-hm4Bm9lBu5SFO8TJ6oe9atJGK3eHBRrOdviNU6iagsixxxk80f57TWhoC5XYQAvD_BwE&gclsrc=aw.ds
  13. Wang S-M, Kim N-Y, Na H-R, Lim HK, Woo YS, Pae C-U, et al. Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis. Clinical Psychopharmacology and Neuroscience [Internet]. 2021 May 31 [cited 2022 Jan 7];19(2):341–54. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077059/
  14. Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of Response and Remission in Major Depressive Disorder With Acute Electroconvulsive Therapy (ECT): A Consortium for Research in ECT (CORE) Report. wwwpsychiatristcom [Internet]. 2004 Apr 1;65. Available from: https://www.psychiatrist.com/jcp/depression/electroconvulsive-therapy/speed-response-remission-major-depressive-disorder/
  15. Getty SS, Faziola LR. Adverse effects of electroconvulsive therapy on cognitive performance. Mental Illness. 2017 Oct 19;9(2).
  16. Taylor R, Galvez V, Loo C. Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. Australasian Psychiatry. 2018 Jan 17;26(2):189–92.
  17. Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969. Epub 2012 Jun 11. PMID: 22689344.
  18. Janicak P, Dokucu ME. Transcranial magnetic stimulation for the treatment of major depression. Neuropsychiatric Disease and Treatment. 2015 Jun;1549.
  19. Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. American Journal of Psychiatry. 2021 Oct 29;

Dr. John Tumeh headshotJohn Tumeh, MD

Dr. Tumeh is Chief of Psychiatry at Foundation Psychiatry, P.C. in Atlanta, GA. Heis a Diplomate of the American Board of Psychiatry and Neurology with board certification in Adult Psychiatry and a Fellow of the American psychiatric association. He earned his Doctor of Medicine (M.D.) from the University of Virginia School of Medicine and subsequently completed residency in General Adult Psychiatry at University of Pittsburgh’s Western Psychiatric Institute and Clinic.

Nancy Hatcher headshotNancy Hatcher, PA-S

Nancy Hatcher received her undergraduate degree from Auburn University. She is currently in her second year of PA school at the University of Lynchburg in Lynchburg, Virginia where she will graduate in 2022. Nancy has a passion for helping patients and is primarily interested in treatment-resistant depression and how she can better understand it for future care.

Stephen Davis headshotStephen Davis, LMHC

Stephen Davis is a graduate student at Richmont Graduate University in hopes to receive his master’s in Marriage and Family Therapy. Stephen also works for Dr. JohnTumeh and has been trained to administer Transcranial Magnetic Stimulation andEsketamine foundation Psychiatry, P.C.. He received his undergraduate degree in philosophy from the University of Alabama and plans to become a licensed professional counselor with a focus on family upon completion of his degree.

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