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Educational Activity

Assessing Response to Treatment and Recognizing Residual Depressive Symptoms

Maurizio Fava, MD

Published: January 15, 2014

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston


After completing this educational activity, you should be able to:

  • Assess patients for residual depressive symptoms
  • Adjust treatment for patients with depression who respond to treatment but do not reach full symptom remission

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clintara, Covance, Covidien, Eli Lilly, ElMindaA, EnVivo, Euthymics Bioscience, Forest, Ganeden Biotech, GlaxoSmithKline, Harvard Clinical Research Institute, Icon Clinical Research, i3 Innovus/Ingenix, Janssen, Johnson & Johnson, Lichtwer, Lorex, MedAvante, NARSAD, NCCAM, NIDA, NIMH, Neuralstem, Novartis, Organon, Pamlab, Pfizer, Pharmaceutical Research Associates, Pharmavite, PharmoRx Therapeutics, Photothera, Roche, RCT Logic, Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; has been an advisor/consultant for Abbott, Affectis, Alkermes, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Bayer, Best Practice Project Management, BioMarin, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, CNS Response, Compellis, Cypress, DiagnoSearch Life Sciences, Dainippon Sumitomo, DOV, Edgemont, Eisai, Eli Lilly, EnVivo, ePharmaSolutions, EPIX, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenix, Janssen, Jazz, Johnson & Johnson, Knoll, Labopharm, Lorex, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuralstem, Neuronetics, NextWave, Novartis, NuPathe, Nutrition 21, Orexigen Therapeutics, Organon, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa, Puretech Ventures, PsychoGenics, Psylin Neurosciences, Rexahn, Ridge Diagnostics, Roche, Sanofi-Aventis, Sepracor, Servier, Schering-Plough, Solvay, Somaxon, Somerset, Sunovion, Supernus, Synthelabo, Takeda, Tal Medical, Tetragenex, Teva, TransForm, Transcept, and Vanda; has spoken for/been published by Adamed, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Imedex, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; has equity holdings in Compellis and PsyBrain; and has received income from a patent for Sequential Parallel Comparison Design (SPCD; licensed by MGH and RCT Logic), a patent application for a combination of azapirones and bupropion in MDD, and copyright royalties from Lippincott, Williams and Wilkins; Wolters Kluwer; World Scientific Publishing; and for the MGH Cognitive and Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs and Symptoms (DESS), and SAFER.

The Chair for this activity, Michael E. Thase, MD, has been an advisor/consultant for Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Dey, Forest, Gerson Lehman, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Ortho-McNeil, Otsuka, Pamlab, Pfizer, Roche, Shire, Sunovion, Takeda, and Transcept; has received grant/research support from AHRQ, Eli Lilly, Forest, NIMH, and Otsuka; has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, and Pfizer; has equity holdings in MedAvante; and has received royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company; and his spouse/partner is employed by Peloton Advantage.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Psychlopedia activity was published in September 2013 and is eligible for AMA PRA Category 1 Credit™ through September 30, 2016. The latest review of this material was August 2013.

Statement of Need and Purpose

The American Psychiatric Association’s (APA) Practice Guideline on treating major depressive disorder states that the goal of acute care treatment is remission and that the aim of maintenance care is the prevention of relapse. However, even after receiving recommended first-line treatments, only about a third of patients will achieve remission and only half of patients will respond (and not remit). Patients with depression who do respond to treatment but continue to have residual symptoms have a greater risk of relapse, relapse earlier, and typically have a more severe and chronic course of illness, more recurrent episodes, and greater impaired functioning than those without residual symptoms. To ensure that they are treated to remission, patients need to be assessed for a wide variety of mental and physical symptoms, such as cognitive problems, lack of energy, and sleeping difficulties, the 3 symptoms shown to dominate the course of depression. The APA recommends using measurement-based care to assess symptoms and measure treatment response. Unfortunately, many clinicians rely on subjective methods such as clinical intuition to guide treatment. To help patients achieve and maintain remission, several strategies are available, including switching or combining medications for nonresponders or augmenting medications for partial responders. When choosing strategies, clinicians should consider specific symptom presentations, onset and mechanism of action, and side effect and tolerability profiles. Treating depression to remission is difficult due to the heterogeneous nature of the disorder, and clinicians need education on how to recognize residual symptoms in depression, assess response to treatment, and adjust treatment regimens to tailor plans to individual patients and promote optimal outcomes. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on depression.

Disclosure of Off-Label Usage

Dr Fava 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.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.


This Psychlopedia activity is derived from the planning teleconference series “Depression: Addressing Partial Response After First-Line Antidepressant Treatment,” which was held in June 2013. This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding, visit The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Patients being treated for depression who do not fully respond to treatment are at risk for poor long-term outcomes. Despite experiencing considerable improvement in illness severity, patients may still have symptoms that persist, which are called residual symptoms. Effective assessment to detect residual symptoms and inadequate antidepressant response is a critical aspect of depression treatment.

Prevalence of Residual Symptoms

When evaluating patients being treated for depression, clinicians will most likely find that many patients are continuing to experience some symptoms. Remission is the goal of treatment, but the number of patients who become completely symptom-free with treatment is actually quite small. For example, a study1 found that after 8 weeks of fluoxetine treatment, half of the patients were considered to have fully responded to treatment, but less than one-fifth of these patients were completely symptom free and almost two-thirds were still experiencing 2 or more depressive symptoms.

The number of patients experiencing residual symptoms despite improving from treatment may actually be greater than studies indicate. Many of the studies that have been conducted on residual symptoms have focused on measuring DSM symptoms of MDD. However, the DSM-IV2 and DSM-53 focus on the psychological symptoms of depression, ignoring many of the behavioral and physical symptoms that patients frequently experience (AV 1).3,4 Therefore, clinicians need to look beyond DSM criteria and be alert for all of the symptoms their patients with depression may be experiencing, even when these patients are improving with treatment.

AV 1. Limitations of DSM-Specified Symptoms of Depression (00:42)

Based on American Psychiatric Association3 and Cassano and Fava4

Assessment of Response and Residual Symptoms

To accurately assess a patient’s response to treatment, clinicians may elect to take either a categorical or dimensional approach, although the best strategy is to use both approaches.

A categorical approach to assessment attempts to determine the overall degree of change that a patient experiences during treatment and uses terms such as responsepartial response, and nonresponse. The term remission may be used to describe a level of improvement in which the patient returns to a premorbid state of functioning and symptoms have largely abated. Remission (ie, “getting back to normal”), rather than response, has become the goal of treatment.

A dimensional approach uses measurement-based assessment tools such as the HDRSMADRSIDS, or QIDS to quantify a variety of aspects of the illness, including psychological, behavioral, and physical symptoms. Dimensional tools determine the degree of change that occurs in those symptoms during treatment.

However, clinicians must be aware that scales may have inadequate sensitivity to detect mild symptomatic changes, thus creating a statistical floor effect in which patients do not appear to be improving. Also, using a single scale may not capture all of the patient’s symptoms of depression. In a research setting, clinicians seek to overcome the floor effect by using large sample sizes or through population enrichment. For example, a study5 comparing SSRIs versus bupropion required a population of over 600 patients in each group to demonstrate that residual sleepiness and fatigue improved more in the patients taking bupropion. This is quite a large sample size, but the items measuring these 2 symptoms using the HDRS have limited sensitivity to detect changes. Clinicians can usually detect improvements in these symptoms relatively easily, but, for quantitative measurement, the CPFQ may be a better instrument to use than the HDRS. The CPFQ is a patient-rated scale to measure cognitive and physical functioning. In a study6 of 8 weeks of treatment with either escitalopram or escitalopram plus zolpidem, the mean HDRS scores between groups were equivalent, but the CPFQ showed significantly greater efficacy of the augmentation treatment for improving wakefulness, energy, memory, and mental acuity (AV 2).

AV 2. Mean Change in MGH-CPFQ Scores from Baseline to Week 8 for Patients With MDD and Insomnia (00:53)

Data from Fava et al6
Abbreviations are defined before the References

Although a clinician-rated tool may be very sensitive to change, clinicians may still inaccurately gauge change as a result of their own beliefs about the effectiveness of the treatment. Patient self-ratings avoid the issue of clinician bias but may not be always as sensitive to change. For these reasons, a combination of clinician- and patient-rated scales may be the best approach for effective assessment.

Timing is another important consideration when assessing response to treatment. Early assessment can detect initial changes, but continuing to assess changes at each visit is necessary because some symptoms will resolve more quickly than others. Those that do not resolve (ie, the residual symptoms) need to be identified and targeted with specific treatment.

Factors that Contribute to Residual Symptoms

When residual symptoms are detected during treatment, clinicians should appropriately classify each one and then consider possible contributing factors. True residual symptoms are those that are present at baseline and persist during treatment.

Comorbid psychiatric disorders. In patients with depression, the presence of comorbid disorders such as ADHD or an anxiety disorder can lead to symptoms such as anxiety, compulsive behavior, and cognitive difficulties that may be mistaken for residual symptoms of depression. For example, concentration problems may be a residual symptom of depression or related to a patient’s ADHD. In other cases, a comorbid psychiatric condition may contribute to residual symptoms. A study7 based on data from the National Comorbidity Survey found that generalized anxiety disorder was associated with more residual symptoms in respondents with MDD.

Comorbid medical disorders. Individuals who have depression as well as comorbid medical conditions may not be as responsive to antidepressant treatment, causing them to experience more residual symptoms. A study8 of patients with depression and medical comorbidity found that, as patients’ burden of medical illness increased, their likelihood of achieving response or remission from depression treatment decreased. For some patients to achieve complete symptom remission, medical conditions must be treated. Residual depressive symptoms combined with medical disorders also lead to worse outcomes for both conditions.9

Another important consideration is that medications being taken for medical conditions, such as hypertension, can have side effects like fatigue that may be mistaken for a residual symptom of depression.

Antidepressant side effects. Symptoms that are absent at baseline and emerge during treatment or that are present at baseline and worsen during treatment are most likely adverse events. Additionally, treatment-emergent side effects may exacerbate a symptom such as fatigue that was present at baseline, thus causing a symptom to persist that might otherwise have improved with treatment and making it difficult to classify these as residual symptoms or adverse events. Antidepressants have been found to have both physical side effects, such as sleep disturbances,10 and psychological side effects, including apathy and loss of memory and concentration.11 In many instances, persistent symptoms are most likely a combination of residual symptoms and antidepressant side effects.12

Delayed antidepressant effect. In some patients, certain symptoms may take longer to respond to antidepressant treatment. According to one study13 of patients receiving an SSRI for depression, anger and hostility improved in nearly half of patients after only 2 weeks of treatment; however, depression and anxiety did not improve until week 4 (AV 3). Thus, symptoms that initially appear to be residual may actually resolve after continued treatment. For this reason, clinicians should not consider any remaining symptoms to be nonresponsive to treatment.

AV 3. Time to Improvement of Different Symptoms During SSRI Treatment for Depression (0:39)

Data from Farabaugh et al13
Scores were assessed using the Symptom Questionnaire (SQ) subscales
Abbreviations are defined before the References

Treatment of Residual Symptoms

When a patient is experiencing residual symptoms, clinicians can follow strategies that have been tested in clinical trials. These approaches include continuing the same antidepressant treatment, switching to a same-class antidepressant, switching to a different-class antidepressant, or augmenting with a nonantidepressant (See “Strategies for Achieving Full Remission When First-Line Antidepressants Are Not Enough” by Andrew A. Nierenberg, MD).

Various mechanisms of action of drugs can affect symptoms in different ways. For example, Katz and colleagues14 demonstrated that desipramine (an SNRI) and paroxetine (an SSRI) had different effects on motor retardation and anxiety early in treatment, suggesting that a switch to or combination with an antidepressant of another class may be beneficial for resolving certain residual symptoms.

Another approach is augmentation with a nonantidepressant drug that targets a specific symptom. For example, in a study15 of residual fatigue and excessive sleepiness during SSRI treatment, patients who received adjunctive modafinil showed rapid improvement in both depressive symptoms and fatigue compared with placebo. Thus, augmenting antidepressants with agents targeting residual symptoms may be an effective way to help patients achieve asymptomatic remission.


Because patients being treated for depression will most likely experience residual symptoms, clinicians must assess for these symptoms at each visit. To provide effective assessment, clinicians should use both categorical and dimensional approaches and look for symptoms identified by the DSM as well as other psychological, behavioral, and physical symptoms frequently experienced by patients with depression. Using scales to measure symptoms can document their resolution over time, but no single scale is ideal for measuring every symptom. A combination of patient-rated and clinician-rated scales is best. Clinicians must consider factors such as comorbidities and treatment-emergent side effects that could contribute to the persistence, emergence, or worsening of symptoms. For patients experiencing true residual symptoms, clinicians must decide whether more time on the current treatment is needed or if the patient would benefit from switching or augmenting current treatment.

Clinical Points

  • Use patient- and clinician-rated assessment methods to detect residual symptoms
  • Watch for psychological, behavioral, and physical residual symptoms
  • Consider factors that may contribute to residual symptoms, including comorbidities or medication side effects
  • Consider if residual symptoms need more time to resolve with current treatment or if switching or augmenting medications is warranted

Drug Names

bupropion (Wellbutrin, Aplenzin, and others), desipramine (Norpramin and others), escitalopram (Lexapro and others), fluoxetine (Prozac and others), modafinil (Provigil and others), paroxetine (Paxil, Pexeva, and others), zolpidem (Ambien, Zolpimist, and others)


ADHD = attention deficit/hyperactivity disorder, CPFQ = Cognitive and Physical Functioning Questionnaire, DSM = Diagnostic and Statistical Manual of Mental Disorders, HDRS = Hamilton Depression Rating Scale, IDS = Inventory of Depressive Symptomatology, MDD = major depressive disorder, MADRS = Montgomery-Asberg Depression Rating Scale, QIDS = Quick Inventory of Depressive Symptomatology, SQ = Symptom Questionnaire, SNRI = selective noradrenergic reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor

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The Journal of Clinical Psychiatry
The Primary Care Companion for CNS Disorders

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