Residual Symptoms and the Risk of Relapse in Major Depression

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvani​a School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Major depressive disorder is one of the world’s leading causes of disability.1 To effectively treat patients with MDD who do not obtain the desired results with first-line antidepressants, psychiatrists sometimes use adjunctive therapies to try to optimize response.

In general, within 6 to 12 weeks of treatment, patients should begin to experience a resolution of symptoms. Response to an antidepressant is usually defined as at least a 50% improvement in depressive symptoms as measured by a validated assessment tool. As patients continue with treatment, they should enter remission (defined as having no or minimal symptoms) and return to their premorbid level of functioning.2 Unfortunately, many patients do not reach full remission with initial antidepressant treatment and may continue to have mild depressive symptoms despite showing some improvement. Such minor symptoms, in turn, convey an increased risk of subsequent relapse. Therefore, clinicians must not only help patients achieve remission but also eliminate any residual symptoms.

First-Line Treatment Options

To help patients move from a state of illness to a state of wellness, should psychiatrists treat depression with pharmacotherapy, psychotherapy, or both? Focused psychotherapy and antidepressants have been proven to be effective treatments and have comparable effects in outpatient studies lasting 12 to 16 weeks.3,4 Both modalities have advantages. For pharmacology, it is the speed of action; for psychotherapy, it is the continuation of benefit after patients have reached remission and discontinued medication. Antidepressants have a faster onset of action but are more likely than psychotherapy to be associated with relapse when a patient discontinues them.2,5 Antidepressants also have characteristic side effects that are linked to their mechanism(s) of action. Deciding which approach to take should be strongly influenced by the patient’s preference. Starting both treatments together is recommended for patients with more severe, chronic, and complex forms of depression.2

Several different classes of antidepressants are now considered to be first-line options for therapy, including SSRIs, SNRIs, and bupropion.2 When choosing an antidepressant, one of the most important factors to consider is the patient’s past response to a given medication; if he or she has had a good experience with a particular agent, then using it again is preferable to choosing another agent. Because the efficacy of available antidepressants is similar, their side effect profile is what distinguishes them. Therefore, another important selection consideration is the patient’s anticipated tolerance of the side effects.2 Other issues to consider are half-life or drug interactions, as well as medication cost. For cost effectiveness, virtually all of the most widely prescribed antidepressants are generally now available in more affordable generic forms.

While generally effective, current treatments for depression do have limitations. The STAR*D study6 of more than 2,800 patients who took the SSRI citalopram showed that only one-third of the patients improved enough during the acute phase of treatment to meet remission criteria. More than half of the patients showed little to no improvement and were classified as nonresponders.6 Among the patients who reached remission in STAR*D, more than 90% had one or more residual symptom; frequent residual symptoms included cognitive, sleep, and appetite problems.7

Partial Responders and Relapse

AV 1. Work Production Loss in Employed Partial Remitters Versus Complete Remitters (00:33)

Data from Romera et al8

When patients do not enter complete remission, they are at risk for relapse. Partial remission is associated with symptoms including depressed mood, somatic symptoms, sexual dysfunction, and anxiety, without meeting criteria for MDD.8 Of patients in STAR*D whose depression met remission criteria but who had residual symptoms, the rate of relapse increased as the number of residual symptom domains increased.7 Additionally, remitters with residual symptoms also have more depressive episodes, a shorter time between episodes,9,10 continued impairment at work and in relationships,8 and a greater risk of suicide compared with those who are asymptomatic.11,12 Patients with residual subthreshold depressive symptoms relapsed to their next major depressive episode more than 3 times faster than asymptomatic recovery patients.10 Functional impairments also affect work productivity and incur indirect costs as employed partial remitters were absent 3 times more days from work than employed complete remitters, and more than half had been on sick leave compared with less than one-third of complete remitters (AV 1).8 Because of this impaired functioning and the risks of relapse and suicide, patients with residual symptoms need to be treated until they reach asymptomatic remission, if possible.

Assessing Patients’ Response

One of the best approaches to ensuring that a patient does reach asymptomatic remission is to consistently measure outcomes with a standardized scale at frequent follow-up visits. This process can help build the therapeutic alliance and engage the patient. Clinicians can also efficiently ascertain whether a patient who has not responded to initial treatment with antidepressant monotherapy might need dosage optimization; a medication switch, augmentation, or combination; or psychotherapy.

To quantify patients’ symptom presentations and response to treatment, scales that are useful in clinical practice include the PHQ-9, QIDS, and BDI; the HDRS and MADRS are generally more relevant in research settings.2 Although the PHQ-9 and QIDS were developed using DSM-IV criteria for depression, the DSM-5 criteria are not so different that these scales are obsolete. The BDI is longer than the PHQ-9 and QIDS but collects a greater amount of information about the patient, including cognitive symptoms, which is a common residual symptom. For more information on assessment scales, see “Assessing Response to Treatment and Recognizing Residual Depressive Symptoms.”


AV 2. Possible Reasons for Nonresponse in Major Depressive Disorder (00:37)

Based on the APA2

When a patient has not fully responded to treatment, clinicians should consider several possible reasons.2 The APA practice guidelines state that nonresponse could be due to an inaccurate diagnosis or co-occurring medical and/or psychiatric disorders, inadequate medication dosage or frequency of psychotherapy, poorly managed side effects, nonadherence to treatment, or several other factors (AV 2).2

Adjusting Treatment by Switching or Augmenting Medications

After the first stage of treatment, clinicians should examine patients’ level of improvement. If their condition is substantially improved within 4 to 8 weeks, treatment would then progress to the continuation phase of therapy. However, if after dose optimization and 16 weeks of treatment without an improvement of at least 50%, the clinician should decide whether to switch medications or to augment the current regimen (AV 3).2

AV 3. Acute Phase Treatment of MDD (0:43)

Based on the APA2
Abbreviations are defined before the References

Both switching and augmentation strategies have benefits and risks. If the patient is experiencing intolerable side effects with the current medication at the optimized dose, switching to another first-line agent is warranted.2 Ideally, clinicians should keep the patient on as few medications as possible to reduce cost, drug interactions, and side effects and to encourage medication adherence.

In patients who have responded to the first course of antidepressant medication but have not remitted, augmenting can enhance the effects of their medication. Common augmentation strategies include second-generation antipsychotics, lithium and other mood stabilizers, modafinil and the conventional psychostimulants, buspirone and benzodiazepines, and thyroid hormone.2 Second-generation antipsychotics are effective as adjuncts, but they can cause weight gain and associated metabolic side effects.2 The utility of adjunctive lithium therapy has not been well-established with newer generation antidepressants, and stimulants and benzodiazepines are controlled drugs that may be associated with abuse.2,13 For more information about adjusting treatment, see “Strategies for Achieving Full Remission When First-Line Antidepressants Are not Enough.”


Despite clinicians’ efforts, a considerable proportion of patients will not achieve asymptomatic remission after initial MDD treatment. They may experience residual symptoms, which increases the risk of relapse. For patients who do not achieve an adequate level of improvement with the initial therapy, clinicians should address any barriers, such as inadequate dosage or patient nonadherence, and decide whether augmentation therapy or switching medications is warranted. New, effective, safe, and cost-effective options for adjunctive treatments to antidepressants are needed.

Clinical Points

  • Acknowledge that limitations exist with first-line treatments for MDD
  • Assess patients for residual depressive symptoms, which increase the risk of relapse
  • Assess the potential reasons for partial response
  • Adjust treatment strategies for patients with depression who respond to treatment but do not reach full, asymptomatic remission

Drug Names

bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), lithium (Lithobid and others), modafinil (Provigil)


APA = American Psychiatric Association, BDI = Beck Depression Inventory, ECT = electroconvulsive therapy, HDRS = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale, MDD = major depressive disorder, QIDS = Quick Inventory of Depressive Symptomatology, PHQ-9 = 9-item Patient Health Questionnaire, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor

Take the online posttest.


  1. World Health Organization. The Global Burden of Disease: 2004 Update. Geneva, Switzerland: WHO Press; 2008. Accessed August 5, 2013.
  2. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. Washington, DC: American Psychiatric Association; 2010. Accessed August 5, 2013.
  3. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project Results: a comprehensive review of the findings. Curr Psychiatry Rep. 2007;9(6):449–459. PubMed
  4. Cuijpers P, van Straten A, Andersson G, et al. Psychotherapy for depression in adults: a meta-analysis of comparative outcome studies. J Consult Clin Psychol. 2008;76(6):909–922. PubMed
  5. Hollon SD, DeRubeis RJ, Shelton RC, et al. Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Arch Gen Psychiatry. 2005;62(4):417–422. PubMed
  6. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40. PubMed
  7. 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. PubMed
  8. Romera I, Perez V, Menchón JM, et al. Social and occupational functioning impairment in patients in partial versus complete remission of a major depressive disorder episode: a six-month prospective epidemiological study. Eur Psychiatry. 2010;25(1):58–65. PubMed
  9. 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
  10. 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
  11. Murphy JM, Monson RR, Olivier DC, et al. Affective disorders and mortality: a general population study. Arch Gen Psychiatry. 1987;44(5):473–480. PubMed
  12. Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord. 1997;45(1–2):5–18. PubMed
  13. Zusky PM, Biederman J, Rosenbaum JF, et al. Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study. J Clin Psychopharmacol. 1988;8(2):120–124. PubMed