Assessing Response to Treatment and Recognizing Residual Depressive Symptoms

Maurizio Fava, MD

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

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 response, partial 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 HDRS, MADRS, IDS, 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.

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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.

Conclusion

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)

Abbreviations

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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References

  1. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60(4):221–225. Full Text
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
  4. Cassano P, Fava M. Depression and public health: an overview. J Psychosom Res. 2002;53(4):849–857. PubMed
  5. Papakostas GI, Nutt DJ, Hallett LA, et al. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry. 2006;60(12):1350–1355. PubMed
  6. Fava M, Asnis GM, Shrivastava RK, et al. Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized controlled trial. J Clin Psychiatry. 2011;72(7):914–928. Full Text
  7. Mojtabai R. Residual symptoms and impairment in major depression in the community. Am J Psychiatry. 2001;158(10):1645–1651. PubMed
  8. Iosifescu DV, Nierenberg AA, Alpert JE, et al. The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry. 2003;160(12):2122–2127. PubMed
  9. Kennedy N, Foy K. The impact of residual symptoms on outcome of major depression. Curr Psychiatry Res. 2005;7(6):441–446. PubMed
  10. Zajecka J, Amsterdam J, Quitkin F, et al. Changes in adverse events reported by patients during 6 months of fluoxetine therapy. J Clin Psychiatry. 1999;60(6):389–394. Full Text
  11. Bolling MY, Kohlenberg RJ. Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patient satisfaction. Psychother Psychosom. 2004;73(6):380–385. PubMed
  12. Fava M, Graves LM, Benazzi F, et al. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry. 2006;67(11):1754–1758. Full Text
  13. Farabaugh A, Sonawalla S, Johnson DP, et al. Early improvements in anxiety, depression, and anger/hostility symptoms and response to antidepressant treatment. Ann Clin Psychiatry. 2010;22(3):166–171. PubMed
  14. Katz MM, Tekell JL, Bowden CL, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology. 2004;29(3):566–579. PubMed
  15. Fava M, Thase ME, DeBattista C, et al. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153–159. PubMed
Assessing Response to Treatment and Recognizing Residual Depressive Symptoms
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