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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.

Evidence-Based Approaches to Depression and Its Physical Symptoms: Part II

To provide psychiatrists with an update on the most current thinking regarding treatment of depression and its physical symptoms.

This activity is designed for psychiatrists. No prerequisites required.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, participants should be able to:

  • Identify the currently available medications used for depression and major depressive disorder.
  • Understand the relationship of pain-related complaints and the severity of depression.
  • Describe the advantages and limitations of the current generation of antidepressant agents being used in the treatment of major depression.
  • Evaluate existing data in the treatment of depression and its physical symptoms.

The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: January 15, 2004. Expiration date: January 15, 2006.

The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of the Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an unrestricted educational grant from Eli Lilly and Company.


Full Disclosure Policy Affecting CME Activities:
As a sponsor accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:


    Thomas W. Koenig, MD
    Assistant Professor
    Department of Psychiatry and Behavioral Sciences
    Johns Hopkins University School of Medicine
    Baltimore, Maryland
    Dr Koenig reports having no financial or advisory relationships with corporate organizations related to this activity.


    Charles B. Nemeroff, MD, PhD
    Reunette W. Harris Professor and Chair
    Department of Psychiatry and Behavioral Sciences
    Emory University School of Medicine
    Atlanta, Georgia
    Dr Nemeroff reports receiving grant and/or research support from Abbott Laboratories, American Foundation for Suicide Prevention, AstraZeneca LP, Bristol-Myers Squibb Company, Eli Lilly and Company, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co, Inc, National Alliance for Research on Schizophrenia and Depression, National Institutes for Mental Health, Pfizer, Inc, Stanley Foundation/National Alliance for the Mentally Ill, and Wyeth; serving as a consultant to Abbott Laboratories, Acadia Pharmaceuticals, AstraZeneca LP, Bristol-Myers Squibb Company, Corcept Therapeutics Inc, Cyberonics, Cypress Biosciences Inc, Eli Lilly and Company, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co, Inc, Neurocrine Biosciences, Novartis Corporation, Organon, Otsuka America Pharmaceutical, Inc, Sanofi-Synthelabo Inc, Scirex, Somerset Pharmaceuticals, and Wyeth; serving on the speakers’ bureau for Abbott Laboratories, AstraZeneca LP, Bristol-Myers Squibb Company, Eli Lilly and Company, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Organon, Otsuka America Pharmaceutical, Inc, Pfizer, Inc, and Wyeth; and serving on the Board of Directors for the American Foundation for Suicide Prevention, Cypress Biosciences Inc, the George West Mental Health Foundation, NovaDel Pharma Inc, and the Heinz C. Prechter Fund for Manic Depression. Dr Nemeroff also holds stock in Corcept Therapeutics Inc and Neurocrine Biosciences; and holds the patent for the method and devices for transdermal delivery of lithium (US 6 375 990 B1) and the  method to estimate serotonin and norepi-nephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April 2001).

    In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members have disclosed that their articles reference the following unlabeled/unapproved uses of drugs or devices:

    Drs Koenig and Nemeroff—duloxetine for treatment of depression.

    Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Evidence-Based Approaches to Depression and Its Physical Symptoms
Thomas W. Koenig, MD*

The link between depression and pain is gaining greater recognition and, therefore, greater understanding. Depression is often comorbid with chronic painful syndromes, and antidepressants have been used successfully to treat painful conditions, either alone or as adjunctive therapy. Today, we have deeper insight into the neurochemistry of pain. Involvement of the serotonergic and noradrenergic systems are common to both depression and pain. The descending inhibitory pathways from the limbic areas are modulated by serotonin and norepi-nepherine; thus, pain perception may be the result of dysregulation of these systems.1 These findings led to the first use of antidepres-sants, specifically tricyclic antidepressants (TCAs), to treat pain. TCAs modulate both the serotonergic and noradrenergic systems, supporting their use in painful syndromes. Selective serotonin reuptake inhibitors have shown modest success in pain treatment but not to the extent of the success seen with TCAs.2-8 However, the side-effect profile of TCAs is unacceptable to many patients.

General somatic complaints—painful and non-painful—are common with depressive illnesses. The high prevalence of these symptoms and their importance in determining successful treatment outcomes  are also gaining greater recognition. Ohayon and Schatzberg conducted a cross-sectional telephone survey of almost 19 000 older children and adults (aged >= 15 years).9  Their study results illuminated the much higher probability of somatic symptoms with depression. For example, subjects with major depression were more than 5 times as likely to report backaches, 2 times as likely to report gastrointestinal disease and joint/articular diseases, 4 times as likely to have headaches, and 3 times as likely to have limb pain compared with the remaining sample. A chronic painful condition was reported in 29% of the subjects with major depression, and co-occurrence of painful and non-painful physical conditions was reported in 14.5% of was not originally designed to examine the relationship between pain and depression, it confirms the results of the study by Simon et al, which reported that up to 69% of depressed patients report somatic complaints as the first presenting symptoms.10

Because physical symptoms are often the first signs of a depressive illness, many primary care physicians and their patients do not recognize or associate these symptoms with depression and, therefore, may not identify the symptoms. Alternatively, physicians and patients may spend a significant amount of time and healthcare resources pursuing a medical cause for the somatic complaint. Many patients who are initially treated in primary care are ill for an extended time before consulting a psychiatrist.

Resolution of somatic symptoms must be part of the definition of remission from depression. Somatic symptoms affect functionality and quality of life. Because of the recurring and chronic nature of depression, eliminating or minimizing associated somatic symptoms must be part of the treatment goal. Up to one half of all patients with depressive illness require some change in therapy to achieve remission, through switching antidepressants, adding a second antidepres-sant to the regimen, or augmenting current antidepressive therapy with a nonantidepres-sant. While patients are optimizing their treatment regimens, they are not in remission and are therefore more vulnerable to relapse and even suicide.

This issue of Advanced Studies in Medicine focuses on the presentation and treatment of the physical symptoms of depression, the most common of which is pain. We offer 2 interviews on this subject, with myself and Dr Charles B. Nemeroff. We each also present a case study discussing different challenges associated with managing the physical symptoms of depression. This issue also includes a reprint of a review article by Dr Nemeroff and colleagues on duloxetine and the clinical results of its 6 published studies in depressed patients.

My interview focuses on the presentation of somatic symptoms and the barriers to recognizing these symptoms earlier. I also discuss the concept of using dual-reuptake inhibitors in treating both pain and depression and the challenges of researchers in trying to tease out the relationships between these syndromes. My case study highlights some of the challenges in treating patients referred from a primary care physician who is unfamiliar with managing the somatic symptoms of depression.

Dr Nemeroff ’s interview focuses on the psy-chopharmacology behind dual-reuptake inhibitors and comments on the duloxetine studies, in particular the insights to be gained from the study results to date. His case study focuses on the challenge of treatment failure and the best way to determine follow-up strategies.

The reprint of the review article by Dr Nemeroff and colleagues discusses duloxetine and the clinical results of its 6 published studies in depressed patients. Duloxetine is a dual-reuptake inhibitor, affecting both the serotonergic and noradrenergic systems. However, it does not share the same tolerability limitations as TCAs. Duloxetine and other selective nor-epinephrine-serotonin reuptake inhibitors are currently being evaluated for the treatment of both depression and painful syndromes. Dr Nemeroff also participated in a roundtable meeting on partial response and nonresponse to antide-pressant therapy; the committee concluded that “simultaneous targeting of both the noradrenergic and serotonergic systems is the most effective strategy.”11 The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (an ongoing study funded by the National Institutes of Mental Health) is designed to assess different treatment strategies when patients fail initial treatment.12

As our understanding of the neural mechanisms of pain and depressive illnesses deepens, we cannot ignore the importance of treating somatic symptoms of depression—to increase remission, reduce changes of treatment regimens, reduce healthcare utilization during differential diagnosis, and to improve the lives of patients who suffer from this chronic and often debilitating mental illness.

1. Greden JF. Physical symptoms of depression: unmet needs. J Clin Psychiatry. 2003;64(suppl 7):5-11.
2. Ladabaum U, Glidden D. Effect of the selective serotonin reuptake inhibitor sertraline on gastric sensitivity and compliance in healthy humans. Neurogastroenterol Motil.
3. Creed F, Fernandes L, Guthrie E, et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology. 2003;124(2):303-317.
4. Bird H, Broggini M. Paroxetine versus amitriptyline for treatment of depression associated with rheumatoid arthritis: a randomized, double-blind, parallel-group study. J Rheumatol. 2000;27(12):2791-2797.
5. Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study. Eur J Pain. 2000;4(1):27-35.
6. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191-197.
7. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39(11):1852-1859.
8. Turkington D, Grant JB, Ferrier IN, Rao NS, Linsley KR, Young AH. A randomized controlled trial of fluvoxamine in prostatodynia, a male somatoform pain disorder. J Clin Psychiatry. 2002;63(9):778-781.
9. Ohayon MM, Schatzberg AF. Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry. 2003;60:39-47.
10. Simon GE, VonKorff M, Wagner EH, Barlow W. Patterns of antidepressant use in community practice. Gen Hosp Psychiatry. 1993;15(6):399-408.
11. Hirschfeld RM, Mongtomery SA, Aguglia E, et al. Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry.
12. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am.

*Assistant Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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