This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Improving the Care and Management of Patients With Inadequate Response to Depression Treatment

Assessing the Risk Factors for Difficult-to-Treat Depression and Treatment-Resistant Depression

Bradley Gaynes, MD, MPH

Published: January 27, 2016

Assessing the Risk Factors for Difficult-to-Treat Depression and Treatment-Resistant Depression

Depression is the leading cause of disability among people across the globe, according to the World Health Organization. Among those who have been diagnosed, many fail to achieve remission after following recommended antidepressant medication and psychosocial therapies. In particular, difficult-to-treat and treatment-resistant depression may cause severe impairments for patients, including diminished cognitive functioning, increased medical bills, and decreased workplace performance, as well as an increased risk of developing comorbid illnesses. However, many tools are available to clinicians for identifying treatment-resistant depression, including rating scales such as the 9-question Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS-SR16), as well as clinical evidence related to risk factors for difficult-to-treat or treatment-resistant depression. Accurately identifying treatment-resistant depression is the first step toward changing treatment regimens to help patients achieve remission.

(J Clin Psychiatry 2016;77[suppl 1]:4-8)

From the Department of Psychiatry, University of North Carolina, Chapel Hill.

This article is derived from the planning teleconference series "Improving the Care and Management of Patients With Inadequate Response to Depression Treatment," which was held in March 2015 and supported by an educational grant from Otsuka Pharmaceutical Development & Commercialization, Inc.

Dr Gaynes has no personal affiliations or financial relationships with any commercial interest to disclose relative to this article.

Corresponding author: Bradley Gaynes, MD, MPH, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7160 (

© Copyright 2016 Physicians Postgraduate Press, Inc.

Depression is a serious medical illness that affects approximately 350 million people worldwide.1 In 2012, approximately 16 million US adults (about 7% of the population) reported at least one major depressive episode in the previous year.2 The primary treatment objective for clinicians who diagnose patients with major depressive disorder (MDD) is to help them to achieve remission.3

In treatment guidelines,3 remission is defined as a patient who has demonstrated at least 3 weeks without the 2 core symptoms (ie, sad mood and diminished interest) and no more than 2 of the other symptoms in the MDD criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM).4 In addition, patients in remission should be functioning at their premorbid psychosocial levels.3

Unfortunately, many patients have only partial or no response at all to treatments. About one-third of patients achieve remission following initial antidepressant therapy, and approximately two-thirds of all patients reach remission after up to 4 acute treatment trials.5 If patients do not achieve remission, their MDD may be considered treatment-resistant, but exactly when to apply this term is vague. This article addresses the definition of treatment-resistant depression (TRD), the consequences of not achieving remission from MDD, and the risk factors for TRD. Also discussed are residual symptoms that can remain after remission. It is critical for clinicians to identify features of depression that can be difficult-to-treat as early as possible so that they can closely monitor patients and then decide whether a more aggressive treatment plan is needed.

What Is Treatment-Resistant Depression?

No universally accepted definition of difficult-to-treat or TRD exists.6 However, an overview of the phases of MDD treatment can put the concept of resistance into context and lead to a clearer understanding.

Treatment Phases

The American Psychiatric Association (APA) recognizes 3 main phases of treatment for patients who have been diagnosed with MDD—the acute phase, the continuation phase, and the maintenance phase.3 Once remission of the depressive episode occurs, the acute phase of treatment is considered to be over and the continuation phase begins (Figure 1).7

Figure 1

Click figure to enlarge

Acute phase. Following a thorough examination of the patient and a careful review of all symptoms, clinicians should focus primarily on helping their patients achieve remission from a major depressive episode, and then on returning them to a normal level of functioning at work/school and in interpersonal relationships.3 Treatment in this phase can include a number of approaches including pharmacotherapy, depression-focused psychotherapy, and somatic therapy.3 Clinicians should recommend that their patients take antidepressants for 4 to 6 weeks to ensure that they have had a sufficient duration of time to respond.3 Psychotherapy may require more time, up to a few months, for meaningful improvement.

Several scales are available for clinicians to use to measure depressive severity in their patients, and treatment guidelines3 recommend using them not only in the diagnostic process but also in the ongoing assessment of therapeutic benefits. On the self-administered 9-item Patient Health Questionnaire8 (PHQ-9), a score of less than 10 indicates partial response while a score under 5 signals remission. A score of 5 or less on the 16-item self-report Quick Inventory of Depressive Symptomatology9 (QIDS-SR16) would also be considered remission. These 2 questionnaires are easy to use in clinical practice because they address all of the DSM criteria for MDD, are short and simple enough for patients to complete on their own, and do not require specialized training to calculate scoring like the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale.8,9

clinical points

  • Clinicians should closely evaluate patients for signs of potential treatment resistance before beginning any treatment.
  • Residual symptoms can remain in patients who have achieved remission and can signify difficult-to-treat depression.
  • Clinicians should ensure that patients receive adequate dosages and durations of antidepressant therapies or psychotherapies before considering augmentation or switching strategies.
  • Some patients who appear to have TRD may actually have treatment adherence problems, which should be addressed.

If a patient is not responding, treatment strategies may need to be reassessed.3 However, before changing treatment strategies, clinicians should recognize that patients who are thought to have TRD could have been misdiagnosed or are being inadequately treated.3 A reexamination of potential primary and comorbid causes of depression is recommended. Clinicians need to consider whether the patient has psychotic depression, bipolar disorder, or comorbid psychiatric disorders that may be preventing adequate response. Once the diagnosis of MDD is confirmed, clinicians should assess the patient’s level of adherence to the prescribed treatment regimen. If adherence is problematic, reasons why should be examined. If adherence is not an issue, the solution may be to optimize the dose of medication or increase the frequency of psychotherapy. If the patient has reached remission, clinicians should then proceed to the continuation phase.

Continuation phase. During the continuation phase, clinicians should monitor patients for 4 to 9 months to ensure that no recurring depressive symptoms are present.3 If symptoms return during this time, patients would then be classified as having a relapse of the same depressive episode. However, if during this period patients show no relapse of depressive symptoms, they are in recovery. If patients develop depressive symptoms at a later time, their diagnosis is a recurrent episode or the presentation of a new, separate depressive episode. The American Psychiatric Association (APA) suggests depression-focused psychotherapy (specifically cognitive-behavioral therapy) as the preferred choice of treatment since data suggest that it provides the most consistently efficacious results for preventing relapse in patients diagnosed with difficult-to-treat depression or TRD.3

Maintenance phase. The maintenance phase primarily serves those patients who have had 3 or more depressive episodes in their lifetime or have been diagnosed with chronic MDD. However, those with risk factors for recurrence (eg, residual symptoms, early age at onset, ongoing stressors) or with comorbid illnesses should also be considered as candidates for maintenance treatment.3 During this phase, clinicians should strive to maintain recovery and prevent relapse by continuing any medication or adjunctive therapies that have proven effective. Patients should also continue any successful psychotherapy, but at a reduced frequency from the acute phase.

Treatment Resistance

A useful definition of TRD would require consensus on the criteria for an adequate treatment trial (ie, minimum dose and duration of therapy, with a particular adherence level) as well as on the specific number of unsuccessful treatment trials that are required before the episode is deemed resistant. In studies of therapies for patients with "treatment-resistant" MDD over the years, researchers have used a variety of definitions. For example, some investigators have defined treatment-resistance as a failure to decrease depressive severity by at least 50%, or below a specific cutoff point on a rating scale, and have differed on whether resistance begins after only 1 adequate treatment trial or whether more unsuccessful trials are required.10 Although the APA treatment guidelines not only define remission but also describe therapeutic options for TRD, they acknowledge that the definition of treatment resistance needs to be clarified.3

In general, resistance is often considered to be the failure of 2 adequate treatment trials to bring about remission.11 Studies suggest that after 2 failed treatment trials, the odds of achieving remission significantly decrease.5 Researchers have proposed multiple staging models of treatment resistance based on the number and complexity of failed treatment trials.6 By focusing on the different levels of treatment-resistance that patients may experience, these models may aid clinicians in better understanding the full complexity of TRD.

The Thase and Rush staging model6 presents clinicians with 5 separate stages of treatment resistance with each level increasing in severity. This model may be a helpful tool for some clinicians; however, it relies primarily upon monitoring patients for failed antidepressant trials and makes no concession for psychotherapy. Also, by separating classes of antidepressants into different stages, this model suggests that a hierarchy of effectiveness exists regarding antidepressants, which the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has shown to be inaccurate and may cause clinicians to prescribe a medication that may not be the best fit for their patient.

The Massachusetts General Hospital staging method (MGH-S)6 also monitors treatment-resistance based on the number of previously failed antidepressant trials. Unlike the Thase and Rush method, the MGH-S assigns a point value for each unsuccessful trial, inquires specifically about the adequacy of dosage and duration of each trial, and accounts for augmented and combined treatment strategies.

The Maudsley Staging Method (MSM)6 is the most recent staging model to be adapted and focuses on using a multidimensional staging method, unlike its predecessors. While it focuses only on monitoring the number of unsuccessful antidepressant trials, the MSM does not differentiate between classes of medications.

Why Is Understanding Treatment Resistance Important?


Treatment-resistance is common among patients who have been diagnosed with depression. Studies have found that approximately 10%-30% of patients diagnosed with MDD develop chronic major depression—meaning that symptoms exist for 2 years or longer—despite having been adequately treated.12 The STAR*D trial (which included a broad range of adults diagnosed with MDD) found that, among individuals who received antidepressant medication as initial acute treatment, only 37% achieved remission, according to QIDS-SR16 scores (Figure 2).5 Among those who received the second level of acute treatment, 31% reached remission, or 19% of the original sample, meaning that 56% of those who began acute treatment remitted after 1 or 2 treatment trials.5 If treatment resistance is defined as the failure of 2 or more treatment trials to achieve remission, then the study suggests that 44% of those treated for nonpsychotic MDD have TRD.5 The STAR*D study findings also suggested that switching between different classes of antidepressants does not appear to make any significant difference in achieving remission compared with switching to another agent in the same class.11

Figure 2

Click figure to enlarge

Consequences of Treatment Resistance and Difficult-to-Treat Depression

Disease course. For patients who have been diagnosed with MDD, not achieving remission can have severe consequences, including an increased risk of suicide.13 A review14 of studies found that 17% of patients with TRD had made a suicide attempt. Quality of life is also lower among those with TRD than those who achieve remission.14

Individuals with difficult-to-treat depression, who achieve remission but have residual symptoms or who remain functionally impaired despite resolution of symptoms, have faster relapse into major and minor depressive episodes, have more recurrences, have shorter periods of wellness, and have fewer symptom-free weeks than patients in remission without residual symptoms.15 For physicians seeking to predict who is likely to have a recurrence of a depressive episode, patients with residual symptoms following remission were found to relapse to their next major depressive episode 3 times faster compared with those who fully recovered.16

Patients who have residual symptoms of depression after remission are at greater risk of developing a more severe or chronic course of depression in the future than those without residual symptoms.15 After analyzing the results of the STAR*D study, Rush et al5 suggested that if patients who develop chronic MDD had been treated earlier with more aggressive treatments, they may have had a higher chance for remission.

Financial repercussions. In addition to affecting the course of the depressive illness itself, not achieving remission has financial consequences. In 2000, approximately $26 billion was spent on medical care, including inpatient and outpatient care and medications, for US patients diagnosed with depression.17 That amount includes both patients who remitted and those with TRD. By 2010, medical care costs had increased to nearly $99 billion.18 Individuals with TRD are more likely to be hospitalized and were found to incur 81.5% higher costs annually than patients whose depression is not treatment-resistant.19

Problems in social arenas and the workplace. Patients with TRD experience impaired social adjustment and lack of involvement in activities as well as diminished sexual enjoyment.20 They also are less productive at work. A 2006 study by Kessler et al21 suggested that patients diagnosed with mood disorders such as bipolar disorder and MDD have a decreased ability to maintain functionality and focus in the workplace. Their study assessed absenteeism (missed days of work) and presenteeism (low performance while at work) using the World Health Organization’s Health and Work Performance Questionnaire (HPQ). The same study21 also discovered that, while patients who have been diagnosed with depression report an average of 8.7 days absent from work annually, they report 18.2 days of decreased performance while at their workplace. These data add up to an average of 225 million workdays and $36.6 billion lost in workplace productivity each year in the United States.21 A 2015 report18 found 7.7 days of absenteeism and 31.9 days of presenteeism per worker with MDD annually.

What are the Risk Factors for Treatment Resistance?

The acute phase of treatment should not be considered complete if patients have not reached remission or if, despite meeting remission criteria, they have residual symptoms.3 By being aware of risk factors associated with TRD, clinicians may be able to identify certain red flags that will help them determine which patients may be potentially nonresponsive and require more aggressive management. In essence, for these individuals, clinicians should have a lower threshold for considering more aggressive treatment regimens, such as maximizing doses sooner or considering augmentation earlier.


Psychiatric comorbidity. The presence of psychiatric comorbidity is an important factor to consider when treating patients with possible TRD.3 Patients who have comorbid substance abuse or anxiety disorders have an increased likelihood of developing difficult-to-treat depression or TRD.22 In addition, the presence of comorbid personality disorders may be associated with an increased rate of TRD.23 A history of physical, sexual, or emotional abuse can also be associated with a co-occurring posttraumatic stress disorder that can increase the likelihood of suboptimal response to treatment.24

Medical comorbidity. In addition to psychiatric comorbidity, medical comorbidity can substantially increase the likelihood of treatment resistance. Patients who are chronically ill have a higher rate of developing depressive disorders than individuals in the general population.25 In fact, depressive symptoms may also exacerbate medical issues in patients, suggesting that the relationship may be bidirectional.25 For example, many patients who have been diagnosed with depression also report higher levels of obesity than those patients who are not depressed.26

Organic factors such as thyroid disorders,3 vitamin B12 or folate deficiencies,3 and anemia27 can be associated with depressive symptoms, as can side effects from medications for medical illnesses.3 Patients diagnosed with depression also may have impaired cognitive or neurologic functioning.3 Chronic depressive symptoms have been associated with cortical atrophy,28 and even patients who achieve remission may present with cognitive dysfunction.29 The presence of comorbid medical illnesses and the medications used to treat them are key factors to consider when assessing an individual for TRD and may guide clinicians toward more accurate and efficient methods of treatment for their patients.

Genetic Variations in Drug Responses

Eventually, genetic variations may be able to predict response to an antidepressant medication. Unfortunately, genotyping research has not yet produced applicable clinical data about which individuals will have a greater likelihood of response to a particular antidepressant therapy based on their genetics.30 Independent of whether clinicians can genetically predict response rate, close monitoring of side effects in patients is key to helping increase the likelihood of adherence and response. More information is being discovered regarding genetic variations in drug responses that may help identify those who are at risk for TRD.

What Should be Done Next?

If an individual is not responding to an adequate trial of an antidepressant, the first thing the clinician should consider is whether the diagnosis is correct. For example, if psychotic symptoms are present, the patient will most likely not improve with antidepressant monotherapy and might worsen if the symptoms are not fully addressed. Similarly, if the underlying illness is bipolar disorder rather than MDD, adequate treatment would follow a different treatment track. If an individual is experiencing depressive symptoms not from MDD but rather from a substance use disorder, the depression treatment may not be successful. A key point for any clinician to consider when an individual is not responding to initial treatment is whether the diagnosis itself is correct.

Another important decision that psychiatrists must make is whether the treatment trial itself has been adequate. Many individuals may not complete an adequate trial—from either a dosing, duration, or adherence perspective—which consists of at least a moderately dosed antidepressant for a minimum of 4 to 6 weeks. Patient nonadherence also plays a substantial role in TRD. If patients do not follow their clinician’s instructions on when to take their medication, they may experience sleep problems which may negatively impact their chances for remission. Patients may also take their medications only when they believe that they need them or may disrupt or stop treatment once they feel better because they believe that they are in recovery. Clinicians must carefully monitor their patients and ensure that they fully understand what classifies as adherence to medication therapy so that if TRD is a possible diagnosis, it is not made in error.

Physicians should also be aware of any environmental or social stressors that may exacerbate or contribute to their patients’ symptoms. These stressors can interfere with the effectiveness of treatment. If by 6 weeks the patient has no quantifiable response to a moderate dose of medication therapy, clinicians should consider a switch or augmentation strategy.3 Data from the STAR*D study5 suggests that those who have a partial response may benefit more from augmentation, whereas patients with no response may benefit more from switching to a different treatment option.


Difficult-to-treat depression or TRD affects many people worldwide every year. Clinicians should closely monitor their patients for treatment adherence, response, and adverse effects and adjust treatment quickly to increase the chances for remission. Patients who experience TRD have been found to have an overall lower quality of life than those patients who achieve remission. By using rating scales such as the QIDS-SR16 and PHQ-9 and monitoring for comorbid illnesses, side effects of treatment, and nonadherence, clinicians are more likely to be able to accurately diagnose their patients with difficult-to-treat depression. Clinicians should also be fully aware of their patients’ medical history as some psychiatric and medical conditions can increase the likelihood of developing TRD. For patients who are at risk of developing TRD, clinicians should evaluate whether they have had an adequate trial of antidepressants for both dosage and duration, potentially augment the treatment with psychotherapy, or switch the patient to an antidepressant in a different class.

Disclosure of off-label usage: Dr Gaynes has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration-approved labeling has been presented in this activity.


1. World Health Organization. Depression: Fact Sheet No. 369. October 2012. Accessed July 10, 2015.

2. National Institute of Mental Health. Major depression with severe impairment among adults. Accessed June 19, 2015.

3. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. Arlington, VA: American Psychiatric Association; 2010.

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

5. 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. PubMed doi:10.1176/appi.ajp.163.11.1905

6. Trevino K, McClintock SM, McDonald Fischer N, et al. Defining treatment-resistant depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014;26(3):222-232. PubMed

7. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry. 1991;52(suppl):28-34. PubMed

8. Kroenke K, Spitzer RL. The PHQ-9: a new depression diagnostic and severity measure. Psychiatr Ann. 2002;32(9):509-515. doi:10.3928/0048-5713-20020901-06

9. Carmody TJ, Rush AJ, Bernstein IH, et al. Making clinicians lives easier: guidance on use of the QIDS self-report in place of the MADRS. J Affect Disord. 2006;95(1-3):115-118. PubMed doi:10.1016/j.jad.2006.03.024

10. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):26-31. PubMed

11. Gaynes BN. Identifying difficult-to-treat depression: differential diagnosis, subtypes, and comorbidities. J Clin Psychiatry. 2009;70(suppl 6):10-15. PubMed doi:10.4088/JCP.8133su1c.02

12. Blanco C, Okuda M, Markowitz JC, et al. The epidemiology of chronic major depressive disorder and dysthymic disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2010;71(12):1645-1656. PubMed doi:10.4088/JCP.09m05663gry

13. Fawcett J. Antidepressants: partial response in chronic depression. Br J Psychiatry Suppl. 1994;26(26):37-41. PubMed

14. Mrazek DA, Hornberger JC, Altar CA, et al. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv. 2014;65(8):977-987. PubMed doi:10.1176/

15. Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry. 2000;157(9):1501-1504. PubMed doi:10.1176/appi.ajp.157.9.1501

16. Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998;50(2-3):97-108. PubMed doi:10.1016/S0165-0327(98)00138-4

17. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-1475. PubMed doi:10.4088/JCP.v64n1211

18. Greenberg PE, Fournier AA, Sisitsky T, et al. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015;76(2):155-162. PubMed doi:10.4088/JCP.14m09298

19. Lepine BA, Moreno RA, Campos RN, et al. Treatment-resistant depression increases health costs and resource utilization. Rev Bras Psiquiatr. 2012;34(4):379-388. PubMed doi:10.1016/j.rbp.2012.05.009

20. Petersen T, Papakostas GI, Mahal Y, et al. Psychosocial functioning in patients with treatment resistant depression. Eur Psychiatry. 2004;19(4):196-201. PubMed doi:10.1016/j.eurpsy.2003.11.006

21. Kessler RC, Akiskal HS, Ames M, et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. Am J Psychiatry. 2006;163(9):1561-1568. PubMed doi:10.1176/appi.ajp.163.9.1561

22. Bennabi D, Aouizerate B, El-Hage W, et al. Risk factors for treatment resistance in unipolar depression: a systematic review. J Affect Disord. 2015;171:137-141. PubMed doi:10.1016/j.jad.2014.09.020

23. Souery D, Oswald P, Massat I, et al, for the Group for the Study of Resistant Depression. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007;68(7):1062-1070. PubMed doi:10.4088/JCP.v68n0713

24. Kaplan MJ, Klinetob NA. Childhood emotional trauma and chronic posttraumatic stress disorder in adult outpatients with treatment-resistant depression. J Nerv Ment Dis. 2000;188(9):596-601. PubMed doi:10.1097/00005053-200009000-00006

25. Benton T, Staab J, Evans DL. Medical co-morbidity in depressive disorders. Ann Clin Psychiatry. 2007;19(4):289-303. PubMed doi:10.1080/10401230701653542

26. Carey M, Small H, Yoong SL, et al. Prevalence of comorbid depression and obesity in general practice: a cross-sectional survey. Br J Gen Pract. 2014;64(620):e122-e127. PubMed doi:10.3399/bjgp14X677482

27. Chen MH, Su TP, Chen YS, et al. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry. 2013;13(1):161. PubMed doi:10.1186/1471-244X-13-161

28. Harvey PD. Cognitive impairments in major depression and bipolar disorders. Psychiatry (Edgmont). 2007;4(1):12-14. PubMed

29. Papazacharias A, Nardini M. The relationship between depression and cognitive deficits. Psychiatr Danub. 2012;24(suppl 1):S179-S182. PubMed

30. Fabbri C, Porcelli S, Serretti A. From pharmacogenetics to pharmacogenomics: the way toward the personalization of antidepressant treatment. Can J Psychiatry. 2014;59(2):62-75. PubMed

Volume: 77

Quick Links: Depression (MDD)