Assessing Response to Treatment and Recognizing Residual Depressive Symptoms

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

Objective

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.

Acknowledgment

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 www.lillygrantoffice.com. 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.

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).

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.