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Tools for Depression: Evaluating Comorbidities and Side Effects

  • Authors: Larry Culpepper, MD, MPH
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Target Audience and Goal Statement

This activity is intended for psychiatrists, primary care physicians, and other healthcare providers who manage adult patients with major depressive disorder (MDD).

The goal of this activity is to educate physicians about the use of rating scales to measure side effects and comorbid disorders in depression and about appropriate screening for and treatment of depression in patients with comorbid psychiatric disorders.

Upon completion of this activity, participants will be able to:

  1. Propose methods to evaluate diagnostic possibilities and comorbidities, treatment adherence and treatment side effects for adults with MDD
  2. Compare strategies for the treatment of MDD, taking in to account individual patient characteristics and the presence of comorbid disorders
  3. Describe how to discuss side effects with patients so as to improve adherence to treatment
  4. Delineate the prevalence of psychiatric disorders comorbid with MDD


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  • Larry Culpepper, MD, MPH

    Professor and Chair of Family Medicine, Boston University School of Medicine; Chief of Family Medicine, Boston Medical Center, Boston, Massachusetts


    Disclosure: Larry Culpepper, MD, MPH, has disclosed the following relevant financial relationships:
    Served as an advisor to: AstraZeneca Pharmaceuticals LP; Forest Laboratories, Inc.; Labopharm Inc.; Pfizer Inc.; Trovis Pharmaceuticals, LLC
    Served as a speaker or a member of a speakers bureau for: Merck & Co., Inc.
    Owns stock, stock options or bonds from: Labopharm Inc.

    Dr. Culpepper does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr. Culpepper does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Margaret McLaughlin, PhD

    Scientific Director, Medscape, LLC


    Disclosure: Margaret McLaughlin, PhD has disclosed no relevant financial relationships.

CME Reviewer

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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    Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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Tools for Depression: Evaluating Comorbidities and Side Effects

Authors: Larry Culpepper, MD, MPHFaculty and Disclosures


Measurement-Based Care

Depression in the developed world is the leading cause of disability. In contrast to many chronic medical illnesses that develop later in life, depression, an episodic-recurrent condition for most affected adults, has its onset in early to middle adulthood in many, and it will require monitoring and treatment long-term in most. In the first special report in this series, we defined instruments that can be of value in the screening and diagnosis of major depression and in monitoring treatment response. This article will consider tools that can assist in the evaluation of potential comorbidities and monitoring of treatment of major depression, including treatment adherence and side effects.

In contrast to physical conditions, major depression is an intangible construct not assessable through laboratory or imaging techniques. Consequently, diagnosis and monitoring require valid (addressing the essence of the condition) and reliable (consistent and replicable) measures of constructs based on criteria recognized through diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders 4th edition text revision (DSM-IV-TR).[1] While the psychological measurement tools available may not be as powerful as laboratory tools used for physical conditions, this does not mean the approach to depression management should be any less scientific or evidence-based. It does mean that the measures available might be more prone to error. However, this is an issue of precision rather than one suggesting that care should be less science or evidence based. Clinically, this imprecision is managed through confirmation of tool-based measurements by an efficient clinical interview guided by the patient's measured responses.

In recent years numerous studies have demonstrated that the qualitative judgment of clinicians regarding diagnosis and change in illness severity is poor (high error) compared with their use of objective psychological measures followed by confirmatory clinical interview. Given their time constraints, this is particularly a concern for primary care physicians. Consequently an approach termed "measurement-based care" has evolved, which produces significantly better patient outcomes in terms of symptom reduction and improvement in functioning.

Measurement-based care includes measuring phenomena important to clinical decision-making, adherence to a guideline or treatment algorithm regarding the threshold, timing, and alternatives related to these management decisions.[2] The STAR-D study, the TMAP, and the MacArthur Depression toolkit all provide depression guidelines. In STAR-D, measures and potential treatment adjustment occurred at 2, 4, 6, 9, and 12 weeks. Contact at these times was made by visit, phone, or online. The measurement tools included ones that:

  • Evaluate other diagnostic possibilities and comorbidities;
  • Evaluate treatment adherence;
  • Monitor symptoms and evaluate treatment response (symptom severity, functioning, suicidality); and,
  • Evaluate side effects generally and, in selected patients, key potential side effects including weight, sleep, and sexual dysfunction.

The routine use of such tools can save the physician time, improve treatment decisions, reduce clinical errors, and guide inclusion of other professionals using collaborative care strategies.

Tools to Evaluate Other Diagnostic Possibilities and Comorbidities

Such tools assist in clarifying the initial diagnosis of major depression and also are useful in reevaluating diagnosis in patients who later prove to be "treatment resistant." These tools efficiently measure whether the physician should consider other psychiatric diagnoses including anxiety disorders, bipolar disorder, and substance abuse. Tools commonly used include the Generalized Anxiety Disorder 2-item (GAD-2) scale and GAD-7 for anxiety,[3-5] the Mood Disorder Questionnaire (MDQ) for manic or hypomanic symptoms suggestive of bipolar disorder,[6] and the Alcohol Use Disorders Identification Test (AUDIT), CAGE, or other substance abuse instruments. Additional tools include brief instruments to measure sleepiness suggestive of depression-related insomnia or a sleep disorder (the Epworth Sleepiness Scale [ESS]), and post-traumatic stress disorder (PTSD). In selected patients, cognitive impairment can be assessed using tools such as the Mini Mental Status Exam or the Mini-Cog.[7,8] An alternative approach to using psychiatric disease-specific tools is to use an integrated tool such as My Mood Monitor (M3), which evaluates anxiety, bipolar, PTSD symptoms, and substance use using 27 items.[9]


GAD-7 is a valid, brief instrument similar to the Patient Health Questionnaire (PHQ)-9.[3] Two questions from the GAD-7 can be used as a first-step screener (GAD-2) and have been combined with the PHQ-2 questions to form the PHQ-4.[4,5] When used alone, the GAD-2 has an overall sensitivity of 65% (about one third of patients with an anxiety disorder are not detected) and specificity of 88%.[3] The M3anxiety module has a sensitivity of 82% and a specificity of 78%. M3 questions specifically explore generalized anxiety disorder (2 questions), panic disorder (2 questions), social anxiety disorder (1 question), PTSD (4 questions; the only anxiety disorder separately scored, sensitivity of 88% and a specificity of 76%), and obsessive compulsive disorder (3 questions).[9]

In settings where PTSD is prevalent, a brief screen such as the Primary Care PTSD Screen may be useful.[10] A 4-item screen designed for use in primary care, it is considered positive if any 3 items are answered positively.

Bipolar Disorder

Because antidepressants used as monotherapy can precipitate a switch to mania or a mixed bipolar episode, bipolar disorder must be considered before the diagnosis of major depression is established. The MDQmay be useful in detecting bipolar symptoms.[6] However, sensitivity and specificity of the MDQ have not been determined in primary care use.[11] Given its many false-positive results, a clinical interview is required to determine a final diagnosis. Of note, interviewing a family member or close friend (with the patient's permission), including having them complete the MDQ, may provide key information. The bipolar module of the M3 has a sensitivity of 88% and a specificity of 70% in primary care practice.[9]

Substance Use Disorders

Alcohol and other substance use and abuse should be investigated during the evaluation of depressive symptoms both to determine the correct diagnosis and plan appropriate treatment. Alcohol or substance abuse may be the cause of the symptoms that suggest a diagnosis of major depression. Abuse also may be comorbid.

A number of tools may be used to screen for alcohol and substance abuse. The CAGE-AID, is the familiar 4-question CAGE modified to ask about "drinking or drugs" rather than simply drinking. The CAGE-AID focuses on lifetime use and while individuals who are drug dependent screen positive, individuals who are at risk may not.[12] AUDIT was developed by the World Health Organization to identify persons whose alcohol consumption has become hazardous or harmful to their health.[13] It is a 10-item screening questionnaire with 3 questions on the amount and frequency of drinking, 3 questions on alcohol dependence, and 4 on problems caused by alcohol; a 3-question version is also available that performs adequately in primary care settings (AUDIT-C). Questions are scored using a 5-point Likert scale and take under 2 minutes to administer. The Drug Abuse Screening Test detects drug abuse or dependence disorders and is most useful in settings in which seeking treatment for drug use problems is not the patient's stated goal. It is available in both 20-item and 10-item formats and an adolescent version.[14] Depending on the scoring criteria, these tests generally have sensitivities in the 80%-97% range and widely varying specificities (30%-98%).

There are numerous additional tools available for substance abuse screening in the primary care setting. A useful source is the Alcohol and Drug Abuse Institute database at the University of Washington.

Tools to Evaluate Treatment Adherence

About 25% of all prescribed doses are not taken. Given the nature of the disease and potential side-effect burden of available treatments, nonadherence may be significantly higher than 25% with antidepressants. Nonadherence may be due to never getting the prescription filled or starting to take the medication, discontinuing medication prematurely, not adjusting dose as directed, or sporadically omitting doses. Patients often are reluctant to inform a physician that they have not taken medication as prescribed and may be more comfortably and accurately divulge this using a self-report tool. Unfortunately physician estimates of nonadherence are no better than chance alone, and office-based pill counts, while better, seriously overestimate adherence.[15]

There are few relevant tools available that are practical for use in the primary care setting. In the STAR-D study, which was based in small group psychiatric and primary care practices, the Brief Medication Questionnaire was used successfully.[2,15] This instrument includes 3 screens. The 5-item Regime Screenasks the patient how they took each medication in the past week. The 2-item Belief Screen asks about drug effects and bothersome features. The 2-item Recall Screen asks about difficulties in remembering to take medication. Using as a gold standard the Medication Events Monitoring System (based on pill container caps with embedded microprocessors), the Regime and Belief Screens were 80%-100% sensitive to ongoing nonadherence and the Recall Screen was 90% sensitive for episodic nonadherence.

If a patient reports missing 3 or more of the most recent 14 days of medication, the physician can assume significant nonadherence as the likely cause for lack of significant clinical improvement (eg, little change on the PHQ-9 or Quick Inventory of Depressive Symptomatology [QIDS]). If nonadherence is due to side effects, clinical decisions should address their management. If due to other concerns (eg, stigma, lack of understanding or worries, cost concerns), these can be addressed through education and joint problem solving with the patient.[3]

Tools to Evaluate Side Effects


The Frequency, Intensity, and Burden of Side Effects-Rating (FIBSER) questionnaire uses 3 questions with a 6-point Likert measurement scale.[16] While it does not measure specific side effects, it does measure 3 side-effect domains of impact: frequency, intensity, and burden. The FIBSER questionnaire is brief, reliable, and has both face and construct validity. Its brevity makes it a useful tool for routine clinical practice.

A score of 0-2 on question 3 (burden of side effects) represents an acceptable low side-effect burden usually requiring no treatment adjustment. A score of 3 or 4 indicates moderate side-effect burden that should be evaluated further (eg, timing related to dose change, patient concerns, etc), and an adjustment such as a dose decrease considered. A score of 5 or 6 indicates a high burden warranting a change such as dose decrease, switching, or direct treatment of the side effect(s).[2]

Specific Side Effects

In STAR-D, more than 90% of remitters had at least 1 residual depressive symptom (median = 3). The most common residual symptom domains were sleep disturbance (71.7%) and appetite or weight disturbance (35.9%).[17] Those with a greater number of residual symptom domains were more likely to relapse. Consequently, in addition to monitoring weight, in selected patients tools to identify and monitor specific symptoms including sleepiness and sexual dysfunction may be of use.

Sexual dysfunction. The Arizona Sexual Experience Scaleuses 5 items with 6-point Likert scales to evaluate sexual dysfunction and changes in sexual function in patients taking psychotropic drugs.[18,19] Each question measures a separate domain: drive, arousal, penile erection or vaginal lubrication, ability to reach orgasm, and satisfaction with orgasm. It has excellent reliability and validity.

Particularly in patients reporting sexual concerns during past episodes of depression or at diagnosis of a current episode, documentation of the nature and severity of dysfunction prior to starting antidepressants can provide insight into pre-existing sexual function problems and any changing pattern of dysfunction following treatment.

Sleepiness. Sleepiness in depressed patients may represent a symptom of the depression or a separate sleep disorder. The ESS[20,21] is a widely used tool for measuring persistent daytime sleepiness in adults. It asks patients to rate their chance of sleeping in 8 typical scenarios and produces quantifiable results that can efficiently guide a subsequent clinical interview. Scores on the ESS of 10 points or higher indicate daytime sleepiness and scores of 16 points or higher indicate high levels of daytime sleepiness.[22,23]


Brief questionnaires can provide the physician with tools to improve their assessment of patients with major depression and provide guidance to the management of its treatment. The tools above can guide identification of comorbidities or other diagnostic possibilities, help determine the degree of adherence to prescribed medications, and identify any side effects that emerge. The results can save the physician clinical time and guide confirmatory interviews and treatment decisions. Patient outcomes using such measurement-based care are improved over that resulting from usual practice.

Supported by an independent educational grant from Bristol-Myers Squibb.

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