Skip to main content
NCBI home page
Primary Care Companion to The Journal of Clinical Psychiatry logoLink to Primary Care Companion to The Journal of Clinical Psychiatry
. 2007;9(4):295–302.

Translating Evidence on Depression and Physical Symptoms Into Effective Clinical Practice

PMCID: PMC2018842  PMID: 17934554

Physical symptoms that seem to have no physical cause may obscure a mood disorder. In a series of presentations chaired by David A. Fishbain, M.D., experts reviewed evidence and offered opinions regarding diagnosis and treatment for overlapping pain and depression in primary care patients.

Pain and Depression in Primary Care

Although a patient may be more concerned with physical symptoms than emotional ones, Bill H. McCarberg, M.D., stated that clinicians must remember that painful physical symptoms often have an emotional aspect.

Presentation and Diagnosis

In primary care, patients often have physical symptoms that health care providers are unable to explain. Kroenke and Mangelsdorff1 reviewed 1000 patient records from an internal medicine clinic and found an organic etiology for patients' symptoms in only 16% of cases despite diagnostic testing in more than two thirds of the cases (Table 1). Ten percent of the symptoms were considered to have a psychological cause related to depression, stress, anxiety, or grief. A review2 of European studies showed an association between depression and painful physical symptoms in 46 of the 70 studies reviewed, whether in the general population, in patients presenting to a primary care physician, or in patients presenting to pain clinics or psychiatric clinics.

Table 1.

Three-Year Incidence and Probable Etiology of 14 Common Symptoms in 1000 Internal Medicine Outpatientsa

graphic file with name i1523-5998-9-4-295-t01.jpg

Open in a new tab

Kroenke and Price3 found that in patients with any of 14 physical symptoms common in primary care, the lifetime risk of common psychiatric disorders was at least twice as high as in those without the symptom. Further, Dr. McCarberg advised that the greater the number of unexplained physical symptoms a patient has, the less likely it is that the primary problem is an anatomical abnormality. Katon et al.4 found that when the number of medically unexplained somatic symptoms rose above 5 in women or 3 in men, the rates of lifetime major depressive disorder (MDD) or panic disorder increased significantly.

Physical symptoms are often the chief complaint of patients with depression, particularly in a primary care setting. Simon et al.5 showed that 69% of patients with depression reported only somatic symptoms. Dr. McCarberg commented that when patients focus on physical symptoms, psychiatric disorders are more difficult for physicians to recognize than when patients report psychological symptoms. One study showed a drop in physician recognition of depression from 77% when psychosocial symptoms were described by patients to 22% when only physical symptoms were mentioned.6

Relationship Between Pain and Depression

Neurochemical pathways provide a link between depressive symptoms and physical symptoms. Many of the ascending serotonin and norepinephrine pathways in the brain mediate mood, suicidal ideation, changes in appetite, sleep, and pleasure; descending serotonergic and noradrenergic pathways modulate pain, such as headache and vague joint, back, or abdominal pain.7,8 If norepinephrine-serotonin pathways malfunction, many emotional areas of the brain as well as physical areas of the body may be affected, and patients may experience physical complaints as well as depression.8 Significant associations have been found between pain conditions and mood and anxiety disorders. McWilliams et al.9 found that people with arthritis, migraine, and low back pain were at greater risk (odds ratio [OR] = 1.48 to 3.86) of having MDD, panic disorder, and generalized anxiety disorder, than people without a pain condition. Dr. McCarberg remarked that conversely, people with emotional symptoms are at increased risk for physical health problems. For example, at a 13-year follow-up10 of people free of heart trouble at baseline, those with a history of a major depressive episode were at a 4 times greater risk for myocardial infarction than those who did not experience a depressive episode (the risk was independent of major coronary risk factors).

Conclusion

Dr. McCarberg concluded that depression not only affects the brain but also has an effect on the body; therefore, treating the whole patient, not just the pain and not just the emotional symptoms, is important for achieving a successful outcome.

The Effect of Painful Physical Symptoms on Depression Remission

Response and Remission

Response and remission are not interchangeable terms, explained David A. Fishbain, M.D. Response refers to the level of change in symptoms since baseline, nonresponse is a less than 25% decrease in baseline rating scale scores, partial response is a 25% to 50% decrease in baseline scores, and response is a greater than 50% decrease in baseline scores.11 Remission is the complete resolution of depressive symptoms and is defined as a score of less than 8 on the 17-item Hamilton Rating Scale for Depression (HAM-D) or a score of less than 11 on the Montgomery-Asberg Depression Rating Scale. Remission is the optimal outcome of treatment but is difficult to achieve. For example, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,12 only 28% of patients achieved remission by 12 to 14 weeks.

Dr. Fishbain stated that patients who achieve remission have a better prognosis for their depression, function better, have a lower risk of relapse, and use fewer medical services compared with patients who merely respond to antidepressant treatment.13 For patients who have demonstrated nonresponse, partial response, or response, treatment options for achieving remission include switching to an antidepressant in the same or another class as the first agent, augmenting with an antidepressant from a different class, or augmenting with an agent other than an antidepressant (Table 2).14

Table 2.

Treatment Options Adapted From STAR*D to Bring Patients With Depression Into Remissiona

graphic file with name i1523-5998-9-4-295-t02.jpg

Open in a new tab

Prevalence and Consequences of Physical Symptoms and Depression

Pain is common in depression. Dr. Fishbain cited a large community survey15 in Europe that found painful physical symptoms in 50% of respondents with depression. Further, another study16 reported that primary care out-patients with 1 physical symptom had a 2% prevalence of mood disorders, whereas among outpatients with 9 or more physical symptoms, mood disorder prevalence was 60%.

Patients with physical symptoms associated with depression were more likely than depressed patients who did not have physical symptoms to3,15–18:

  • be severely depressed

  • have nonremitting depression

  • be at risk for depression relapse

  • have complex symptoms

  • be difficult to treat

  • have other psychiatric comorbidities

  • have poor treatment outcomes

  • lose work productivity

  • require polypharmacy

Pain in patients with MDD is associated with increased health care costs19 and increased severity of fatigue, insomnia, psychomotor retardation, weight gain, and impaired concentration.20

Dr. Fishbain further suggested that a bilateral relationship may exist between pain and depression. For example, among neurology outpatients, the odds of having pain increased in patients with depression, and the odds of having depression increased in patients with pain.21 A community survey22 in Canada found that only 5.9% of respondents without back pain had major depression but in comparison, 19.8% of respondents with chronic back pain had major depression. As pain severity increased, the rate of major depression increased in a linear fashion. Greater severity of painful physical symptoms has also been associated with increased severity of depression.23

Response to antidepressants and remission of depression are affected by physical symptoms. One study24 showed that a greater number of somatic symptoms present at baseline predicted delayed response to fluoxetine, and another study25 found that more severe body pain at baseline predicted nonresponse to paroxetine among patients with late-life depression. Denninger et al.18 reported that the degree of improvement in physical symptoms correlated with achievement of remission. Karp et al.26 found that time to remission with imipramine was significantly longer in subjects with more pain at baseline.

Further, risk of relapse is greater in patients who have residual symptoms, including somatic symptoms, after depression treatment. Paykel et al.17 reported that 76% of subjects with residual symptoms relapsed, whereas 25% of those without residual symptoms relapsed. Dr. Fishbain emphasized the importance of treating physical symptoms as well as psychological ones to prevent relapse after depression treatment.

Efficacy of Antidepressants for Pain and Achieving Remission

Managing somatic symptoms and pain are important considerations when selecting medications to treat comorbid depression. A meta-analysis by Fishbain and colleagues27 of studies of patients diagnosed with psychogenic pain or somatoform pain disorder showed that antidepressants significantly decreased pain intensity (z = 5.71, p < .0001) compared with placebo.

Further, dualaction antidepressants that block both serotonergic and noradrenergic reuptake have been found to be more effective than other antidepressants for the treatment of pain. In a review of animal and human studies by Fishbain et al.,28 pain relief was demonstrated in 100% of trials of serotonergicnoradrenergic antidepressants, compared with 89% of studies using noradrenergic antidepressants, and 14% of studies using serotonergic antidepressants. Similarly, a meta-analysis by O'Malley et al.29 found that tricyclic antidepressants (TCAs), which are all dualaction antidepressants but are serotonergic and noradrenergic in varying proportions, appeared to have a greater likelihood of analgesic effect than selective serotonin reuptake inhibitors (SSRIs) for headache, fibromyalgia, functional gastrointestinal syndromes, and idiopathic pain. Lynch30 found that 80% of TCA studies showed a beneficial effect for pain compared with only about 36% of SSRI studies. Additionally, a calculation31 of the number of patients needed to treat showed SSRIs to be less effective for various types of neuropathic pain than TCAs.

In reference to depression remission, dual action antidepressants appear to also offer an advantage over the SSRIs. Clomipramine, a dualaction antidepressant, demonstrated greater remission rates than the SSRI citalopram.32 The SSRI fluoxetine combined with the noradrenergic antidepressant desipramine showed a superior rate of remission after 4 weeks compared with desipramine alone (71% vs. 14%).33 Patients treated with the serotoninnorepinephrine reuptake inhibitor (SNRI) venlafaxine also had a significantly higher remission rate (45%) than those treated with the SSRIs fluoxetine, paroxetine, or fluvoxamine (35%).34 Finally, the SNRI duloxetine produced a greater remission rate (43%) than the SSRIs paroxetine, sertraline, or fluoxetine (38%).35

Interestingly, the SSRIs also appear to be less effective for the somatic symptoms of depression than for the emotional symptoms of depression. Greco et al.36 studied depressed primary care patients during 9 months of SSRI treatment and found that, while depressive symptoms continued to gradually improve, somatic symptoms decreased most during the first month and then ceased to resolve. In the same population,37 69% of patients reported pain at baseline and 58% still reported pain after 3 months, and the odds ratio for poor treatment response was positively correlated with severity of pain.

One study38 showed that venlafaxine, an SNRI, is effective for neuropathic pain, although it is not approved by the U.S. Food and Drug Administration (FDA) for this use. Patients with diabetic peripheral neuropathic pain treated with higher doses (> 150 mg/day) of extended-release venlafaxine had significantly greater mean Visual Analog Pain Relief scores than placebo by week 6 of the study, as well as significantly reduced mean Visual Analog Pain Intensity scores (p < .001).38 Dr. Fishbain noted that when venlafaxine is used at lower doses, it acts like an SSRI, but at higher doses, it has more dualaction activity.

Duloxetine, an SNRI balanced in noradrenergic and serotonergic activity, is FDA-approved for the treatment of diabetic peripheral neuropathic pain as well as MDD (Figure 1).39 Duloxetine has been shown to separate from placebo at week 1 for its analgesic effect and this may be secondary to its balanced activity.39 Duloxetine has also been shown to be effective for backache, shoulder pain, time in pain while awake, and interference with daily activities secondary to pain in patients with MDD.40 Fava et al.41 found that patients whose pain responded to duloxetine had better rates of depression remission than those whose pain did not respond (39% vs. 25%).

Figure 1.

Figure 1.

Open in a new tab

Mean Change From Baseline in 24-Hour Average Pain Severity Score for Different Doses of Duloxetine for Diabetic Peripheral Neuropathic Paina

Conclusion

Dr. Fishbain concluded that alleviating painful physical symptoms in depression can speed remission and improve overall remission rates. Further, dualaction antidepressants are more effective at achieving remission because they are more effective in treating the painful physical symptoms of depression than SSRIs. A treatment plan for depression associated with pain and other somatic symptoms should include 3 aspects: aggressive pain treatment, the targeting of individual somatic symptoms, and the use of antidepressants that have demonstrated analgesic properties (Table 3).

Table 3.

Treatment Plan for Depression Associated With Pain and Other Somatic Symptoms

graphic file with name i1523-5998-9-4-295-t03.jpg

Open in a new tab

Managing Treatment-Resistant Depression With Painful Physical Symptoms in Primary Care

In primary care, patients may seek treatment for depression, or for pain, or for a combination of both pain and depression, but many may not respond to initial treatment approaches, according to Ronald M. Glick, M.D.

Treatment-Resistant Depression With Comorbid Pain

Treatment resistance is a major problem in depression treatment. About 40% of patients with depression do not respond fully to adequate treatment.42 The STAR*D study14 resulted in a protocol for patients with depression who do not respond to the first medication prescribed (see Table 2). At each step of the protocol, a few more patients responded until eventually most patients responded to and tolerated their medication.43 No evidence-based protocol like the STAR*D exists for treatment-resistant depression with comorbid pain.

Comorbid pain may contribute to treatment resistance and may warrant specific treatment or consultation. It is uncertain whether the data on treatment-resistant depression can be generalized to patients with comorbid pain; however, the use of dualaction medications appears to be the best strategy. Dr. Glick emphasized the importance of asking patients with treatment-resistant depression whether they have pain. Because depression is the primary concern, many patients will not mention that they suffer from pain unless asked.

Pain With Comorbid Depression

Dr. Glick noted that some patients seeking traditional treatment for chronic pain may be reluctant to acknowledge psychological symptoms, but patients seeking more integrative approaches may recognize an association between their painful symptoms and depression.

Patients with chronic pain, particularly when they have comorbid depression, tend to become increasingly passive because activity increases their pain. Dr. Glick encourages patients to take a more active role in their pain management through exercise, diet, and stress management. Almost all patients with pain and/or depression could benefit from increased activity. Thirty minutes of aerobic exercise per day, whether it is walking at a brisk pace or something more rigorous, has analgesic and antidepressant effects.44–46 Physical therapy or a pain rehabilitation program can be helpful for patients with a chronic pain syndrome47 or with a specific musculoskeletal cause for their pain.48 Being overweight can contribute to pain. Counseling encourages patients to reduce portion size, increase intake of fruits and vegetables, shift away from red meat and saturated fats, and shift toward foods with more omega-3 fatty acids such as coldwater fish and plant sources of fat.

Treatments that alleviate stress also seem to reduce pain. Sometimes patients are resistant to the idea that their pain may have a psychological component because they think that the physician does not believe their pain is real, so the idea of stress management is more palatable to these patients. Dr. Glick suggested that activities such as yoga, meditation, and other mind-body approaches may have a role in pain management. However, a patient whose life has been taken over by pain may benefit most from working individually with a psychologist who is knowledgeable about treatment of pain.

Given the prevalence of chronic pain, primary care physicians are experienced in addressing a wide array of general health and musculoskeletal conditions that result in pain. However, it is important to recognize when to refer patients with pain and comorbid depression or with treatment-resistant depression with pain to a psychiatrist, a psychologist, or to a pain management program. Warning signs that a referral is appropriate include suicidality, bipolar features (especially if there is a strong family history of bipolar disorder or prominent mood lability), irritability, substance use issues, prominent interpersonal or Axis II personality disorder features, full chronic pain syndrome in which the pain takes over and functioning continually declines, and cases in which standard methods of care have not helped.

Medication Choices

In patients primarily concerned with depression, addressing pain may help manage treatment-resistant depression. Dr. Glick supported the use of agents that boost both serotonin and norepinephrine such as venlafaxine and duloxetine.49 Higher doses of duloxetine (120 mg/day) may produce a better analgesic effect than lower doses.39,50,51 In Dr. Glick's clinical experience, at least 150 mg/day of venla-faxine are needed to achieve an analgesic effect. Dr. Glick recommended the TCA nortriptyline for pain and depression, dosed in an antidepressant range of 50 to 75 mg/day, but also cautioned that the dose should be reduced in older patients because of the risks of sedation, falls, and heart arrhythmia.52

Duloxetine carries a specific indication for use in neuropathic pain conditions such as diabetic neuropathy, but can be helpful for patients with fibromyalgia and other chronic pain states.39,50,51 Dr. Glick stated that specifically for fibromyalgia or neuropathic pain, a higher dose (120 mg/day or 60 mg p.o. b.i.d.) may provide a greater benefit than the reduced dose of 60 mg/day most commonly used for depression. Similarly, the anticonvulsant pregabalin produces a better analgesic effect at a dose of 600 mg/day t.i.d.53 Pregabalin does not have a specific antidepressant effect but can be used in patients primarily presenting with pain,54 either alone or in concert with an antidepressant.

As with the primary management of depression, when treating depression with comorbid pain the choice of medication can be influenced by the desire for an energizing effect or for a sedating effect. Some patients with pain and depression have prominent lethargy, but others have prominent insomnia. Dr. Glick explained that in his clinical experience, venlafaxine has had energizing effects at higher doses, similar to bupropion; whereas trazodone, nortriptyline, mirtazapine, and amitriptyline have had sedating effects. Mirtazapine and amitriptyline are also associated with weight gain and sluggishness. Because of the risk of metabolic syndrome, atypical antipsychotics should be avoided unless the patient has comorbid bipolar disorder or psychotic illness.55 However, physicians should note that atypicals may have analgesic properties.56

To combat insomnia, Dr. Glick recommended that patients avoid caffeine after the middle of the day, avoid exercise late in the day, and practice stress management approaches. Patients may also take 3 to 9 mg of melatonin at bedtime to promote sleepiness. For patients with sleep difficulties associated with myofascial pain or fibromyalgia, Dr. Glick recommended 2 to 4 mg of the muscle relaxant tizanidine at bedtime, although liver function should be monitored. If insomnia does not improve with behavioral approaches and monotherapy, particularly in the presence of obesity, Dr. Glick suggested screening for sleep apnea. Often, once sleep is improved, patients report both better mood and less pain.

Dr. Glick advised caution with combined serotonergic agents, such as the SSRI escitalopram and the pain medication tramadol, because of potential serotonin syndrome. Serotonin syndrome can cause hyperarousal symptoms such as tachycardia, irritability, anxiety, tremor or shakiness, and seizures.57 Medication should be stopped if even mild symptoms of serotonin syndrome occur.

Conclusion

Dr. Glick summarized steps for treating patients with primary pain and comorbid depression (Table 4). First, identify specific syndromes to treat, e.g., prophylactic agents for recurrent migraine. Next, help the patient shift to an active self-management strategy. Prescribe medications that treat both pain and depression, and select appropriately energizing or sedating medications. Polypharmacy will probably be necessary for adequate control of pain combined with depression. Then, if needed, use whatever consultation is available in the community.

Table 4.

Steps for Managing Primary Pain With Comorbid Depression

graphic file with name i1523-5998-9-4-295-t04.jpg

Open in a new tab

Successfully Managing Depressed Patients With Pain

Louis Kuritzky, M.D., remarked that most clinicians can readily anticipate that patients with chronic pain disorders often subsequently develop comorbid depression; however, it may come as a surprise that patients with depression can have painful symptoms that result from the depression itself. The impact of pain on treatment outcomes of depression deserves more attention, according to Dr. Kuritzky. Pain as a symptom of depression has been overlooked in diagnostic criteria58 but is now being recognized as an important component with serious implications.59 When patients have multiple unexplained physical symptoms, depression should be high on the list of possible diagnoses.1,60,61

“Depressalgia” and Treatment Outcomes

Dr. Kuritzky referred to the pain of depression as “depressalgia” because it does not necessarily fit into any specific pain category (e.g., migraine or osteoarthritis) but rather appears to be part of depression itself. One study6 showed that 76% of patients who received a diagnosis of depression had initially reported somatic symptoms. Dr. Kuritzky noted that unexplained musculoskeletal pain and back pain in particular should alert clinicians to suspect depression. In a study62 of primary care patients with depression, 43% had nonspecific musculoskeletal complaints and 39% had back pain.

Depression is likely to persist if pain is present and vice versa. Patients who were referred to a neurology outpatient clinic were more likely to still have depression at 3 months and at 12 months if pain symptoms were persistent than were patients without persistent pain symptoms, and similarly, patients were more likely to have continued pain if depression was present than they were if depression was not present.63

The presence of unresolved pain in patients with depression has 3 predictable consequences: (1) delay in time to depression remission,26 (2) decreased likelihood of depression remission, and (3) increased likelihood of relapse.41 The consequences of failing to achieve full remission in depression are decreased quality of life, social disability, increased use of medical resources, greater risk of suicide, and increased risk of relapse.64–66

Treating Depression With Pain

Dr. Kuritzky stressed the importance of recognizing that not all agents that are effective for depression have an impact on pain in depression. A meaningful connection between serotonin and norepinephrine has been recognized in modulation of pain.67 Dr. Kuritzky explained that combined serotonin and norepinephrine modulation may be the endogenous pain-damping system from the central nervous system: serotonin modulation alone is typically not enough to treat depression and pain.

In a study36 of primary care patients taking SSRIs, the treatment effect sizes on depression symptom clusters were measured; painful physical symptoms had the lowest effect size, while non-somatic depressive symptoms had the greatest effect size. As Dr. Kuritzky elaborated, the SSRIs were effective for affective symptoms, but much less so for pain. In another study,68 severity of pain at baseline predicted treatment response to SSRI therapy for depression; patients with the least pain had the best remission rate, supporting the concept that SSRIs are most efficacious in patients without comorbid pain.

Agents that modulate both nor-epinephrine and serotonin have been shown to have a favorable impact on pain in patients with or without depression. The TCAs amitriptyline and desipramine and the SSRI fluoxetine were tested in patients with painful diabetic neuropathy. Moderate or greater relief of pain was found in 74%, 61%, and 48% of the treatment groups, respectively. The TCAs were found to be as effective in patients with depression as without, but the SSRI was effective only in patients with depression, suggesting an affective component to the measured pain reduction, rather than a direct pain relief effect independent of depression.69 The SNRI venlafaxine, which modulates both norepinephrine and serotonin, was also shown to produce a statistically significant reduction in painful diabetic neuropathy versus placebo.38

Nemeroff et al.41,70 reviewed 6 double-blind, controlled trials of the SNRI duloxetine for MDD and found that in 4 studies, duloxetine was significantly superior to placebo in reducing mean HAM-D total scores. As part of these trials,41,70 pain scores were obtained, and duloxetine was also significantly superior to placebo on pain measures; in accordance with the commentary above, these duloxetine trials41 demonstrated that patients who had a greater than 50% decrease in painful symptoms had a rate of remission from depression twice that observed for pain nonresponders.

Conclusion

Dr. Kuritzky concluded that unexplained physical symptoms, particularly pain, are commonplace in depressed patients and may delay an appropriate diagnosis and adequate treatment. The goal for treatment of depression is remission, which is correlated with a reduction in painful symptoms. When pain fails to remit, resolution of depressive symptoms, likelihood of attaining complete remission, time to remission, and likelihood of relapse are all altered unfavorably. Because of the interrelatedness of depression and pain, clinicians would do well to recognize which agents among the therapeutic choices for depression may also favorably impact pain.

Drug names: bupropion (Wellbutrin and others), citalopram (Celexa and others), clomipramine (Anafranil and others), desipramine (Norpramin and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), imipramine (Tofranil, Surmontil, and others), lithium (Eskalith, Lithobid, and others), mirtazapine (Remeron and others), nortriptyline (Pamelor and others), paroxetine (Paxil, Pexeva, and others), pregabalin (Lyrica), sertraline (Zoloft and others), tizanidine (Zanaflex and others), tramadol (Ultram and others), venlafaxine (Effexor and others).

Disclosure of off-label usage: The chair has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside U.S. Food and Drug Administration–approved labeling has been presented in this article.

Pretest and Objectives

graphic file with name i1523-5998-9-4-pre.jpg

Posttest

graphic file with name i1523-5998-9-4-post.jpg

Registration Form

graphic file with name i1523-5998-9-4-reg.jpg

Footnotes

This Academic highlights section of The Primary Care Companion to The Journal of Clinical Psychiatry presents the highlights of the planning teleconference “Translating Evidence on Depression and Physical Symptoms Into Effective Clinical Practice,” which was held November 27, 2006. This report was prepared by the CME Institute of Physicians Postgraduate Press, Inc., and was supported by an educational grant from Eli Lilly and Company.

The planning teleconference was chaired by David A. Fishbain, M.D., from the Departments of Psychiatry and Behavioral Sciences, Neurological Surgery, and Anesthesiology, University of Miami School of Medicine, Miami, Fla. The faculty were Ronald M. Glick, M.D., Departments of Psychiatry, Physical Medicine and Rehabilitation, and Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.; Louis Kuritzky, M.D., Department of Community Health and Family Medicine, University of Florida, Gainesville; and Bill H. McCarberg, M.D., Founder, Chronic Pain Management Program, Kaiser Permanente, San Diego, Calif.

In the spirit of full disclosure and in compliance with all ACCME Essential Areas and Policies, the faculty for this CME article were asked to complete a statement regarding all relevant financial relationships between themselves or their spouse/partner and any commercial interest (i.e., a proprietary entity producing health care goods or services consumed by, or used on, patients) occurring at least 12 months prior to joining this activity. The CME Institute has resolved any conflicts of interest that were identified. The disclosures are as follows: Dr. Fishbain is a consultant for, has received honoraria from, and is a member of the speakers/ advisory board for Eli Lilly. Dr. Kuritzky is a member of the speakers/advisory boards for GlaxoSmithKline, Bayer, Pfizer, Eli Lilly, and IMS Global Insights. Dr. McCarberg is a member of the speakers/advisory boards for Purdue, Pfizer, Mylan, Merck, Eli Lilly, Ligand, PriCara, Forest, Endo, Abbott, Alpharma, and Cephalon. Dr. Glick has no personal affiliations or financial relationships with any proprietary entity producing health care goods or services consumed by, or used on, patients to disclose relative to the presentation.

The opinions expressed herein are those of the faculty and do not necessarily reflect the views of the CME provider and publisher or the commercial supporter.

REFERENCES CITED

  1. Kroenke K, Mangelsdorff AD.. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med. 1989;86:262–266. doi: 10.1016/0002-9343(89)90293-3. [DOI] [PubMed] [Google Scholar]
  2. Garcia-Cebrian A, Gandhi P, and Demyttenaere K. et al. The association of depression and painful physical symptoms: a review of the European literature. Eur Psychiatry. 2006 21:379–388. [DOI] [PubMed] [Google Scholar]
  3. Kroenke K, Price R.. Symptoms in the community: prevalence, classification, and psychiatric comorbidity. Arch Intern Med. 1993;153:2474–2480. [PubMed] [Google Scholar]
  4. Katon W, Lin E, and Von Korff M. et al. Somatization: a spectrum of severity. Am J Psychiatry. 1991 148:34–40. [DOI] [PubMed] [Google Scholar]
  5. Simon GE, VonKorff M, and Piccinelli M. et al. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999 341:1329–1335. [DOI] [PubMed] [Google Scholar]
  6. Kirmayer LJ, Robbins JM, Dworkind M.. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry. 1993;150:734–741. doi: 10.1176/ajp.150.5.734. [DOI] [PubMed] [Google Scholar]
  7. Fields HL, Heinricher MM, Mason P.. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 1991;14:219–245. doi: 10.1146/annurev.ne.14.030191.001251. [DOI] [PubMed] [Google Scholar]
  8. Stahl SM.. The psychopharmacology of painful physical symptoms in depression [BRAINSTORMS] J Clin Psychiatry. 2002;63:382–383. doi: 10.4088/jcp.v63n0501. [DOI] [PubMed] [Google Scholar]
  9. McWilliams LA, Goodwin RD, Cox BJ.. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004;111:77–83. doi: 10.1016/j.pain.2004.06.002. [DOI] [PubMed] [Google Scholar]
  10. Pratt LA, Ford DE, and Crum RM. et al. Depression, psychotropic medication, and risk of myocardial infarction. Circulation. 1996 94:3123–3129. [DOI] [PubMed] [Google Scholar]
  11. Nierenberg AA, Dececco LM. Definition of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001 62suppl 16. 5–9. [PubMed] [Google Scholar]
  12. Trivedi MH, Rush AJ, and Wisniewski SR. et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006 163:28–40. [DOI] [PubMed] [Google Scholar]
  13. Miller IW, Keitner GI, and Schatzberg AF. et al. The treatment of chronic depression, pt 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry. 1998 59:608–619. [DOI] [PubMed] [Google Scholar]
  14. Rush AJ, Fava M, and Wisniewski SR. et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004 25:119–142. [DOI] [PubMed] [Google Scholar]
  15. Demyttenaere K, Bonnewyn A, and Bruffaerts R. et al. Comorbid painful physical symptoms and depression: prevalence, work loss, and help seeking. J Affect Disord. 2006 92:185–193. [DOI] [PubMed] [Google Scholar]
  16. Kroenke K, Spitzer RL, and Williams JB. et al. Physical symptoms in primary care: predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994 3:774–779. [DOI] [PubMed] [Google Scholar]
  17. Paykel ES, Ramana R, and Cooper Z. et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995 25:1171–1180. [DOI] [PubMed] [Google Scholar]
  18. Denninger JW, Mahal Y, and Merens W. et al. The relationship between somatic symptoms and depression. In: New Research Abstracts of the 155th Annual Meeting of the American Psychiatric Association; May 21, 2002; Philadelphia, Pa. Abstract NR251:68–69. [Google Scholar]
  19. Gameroff MJ, Olfson M.. Major depressive disorder, somatic pain, and health care costs in an urban primary care practice. J Clin Psychiatry. 2006;67:1232–1239. doi: 10.4088/jcp.v67n0809. [DOI] [PubMed] [Google Scholar]
  20. Ohayon MM. Specific characteristics of the pain/depression association in the general population. J Clin Psychiatry. 2004 65suppl 12. 5–9. [PubMed] [Google Scholar]
  21. Williams LS, Jones WJ, and Shen J. et al. Prevalence and impact of depression and pain in neurology outpatients. J Neurosurg Psychiatry. 2003 74:1587–1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Currie WR, Wang J.. Chronic back pain and major depression in the general Canadian population. Pain. 2004;107:54–60. doi: 10.1016/j.pain.2003.09.015. [DOI] [PubMed] [Google Scholar]
  23. Munoz RA, McBride ME, and Brnabic AJ. et al. Major depressive disorder in Latin America: the relationship between depression severity, painful somatic symptoms, and quality of life. J Affect Disord. 2005 86:93–98. [DOI] [PubMed] [Google Scholar]
  24. Papakostas GI, Petersen TJ, and Iosifescu DV. et al. Somatic symptoms as predictors of time to onset of response to fluoxetine in major depressive disorder. J Clin Psychiatry. 2004 65:543–546. [DOI] [PubMed] [Google Scholar]
  25. Karp JF, Weiner D, and Seligman K. et al. Body pain and treatment response in late-life depression. Am J Geriatr Psychiatry. 2005 13:188–194. [DOI] [PubMed] [Google Scholar]
  26. Karp JF, Scott J, and Houck P. et al. Pain predicts longer time to remission during treatment of recurrent depression. J Clin Psychiatry. 2005 66:591–597. [DOI] [PubMed] [Google Scholar]
  27. Fishbain DA, Cutler RB, and Rosomoff HL. et al. Do antidepressants have an analgesic effect in psychogenic pain and somatoform disorder? a meta-analysis. Psychosom Med. 1998 60:503–509. [DOI] [PubMed] [Google Scholar]
  28. Fishbain DA, Cutler RB, and Rosomoff HL. et al. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: a structured review. Pain Med. 2000 1:310–316. [DOI] [PubMed] [Google Scholar]
  29. O'Malley PG, Jackson JL, and Santoro J. et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999 48:980–990. [PubMed] [Google Scholar]
  30. Lynch M.. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26:30–36. [PMC free article] [PubMed] [Google Scholar]
  31. Sindrup SH, Jensen TS.. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;88:389–400. doi: 10.1016/S0304-3959(99)00154-2. [DOI] [PubMed] [Google Scholar]
  32. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine: a controlled multicenter study. Psychopharmacology (Berl) 1986;90:131–138. doi: 10.1007/BF00172884. [DOI] [PubMed] [Google Scholar]
  33. Nelson JC, Mazure CM, and Bowers MB Jr. et al. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991 48:303–307. [DOI] [PubMed] [Google Scholar]
  34. Thase ME, Entsuah AR, Rudolph RL.. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234–241. doi: 10.1192/bjp.178.3.234. [DOI] [PubMed] [Google Scholar]
  35. Thase M, Lu Y, and Joliat M. et al. Remission in placebo-controlled trials of duloxetine with an SSRI comparator. In: New Research Abstracts of the 156th Annual Meeting of the American Psychiatric Association; May 22, 2003; San Francisco, Calif. Abstract NR840:313–314. [Google Scholar]
  36. Greco T, Eckert G, Kroenke K.. The outcome of physical symptoms with treatment of depression. J Gen Intern Med. 2004;19:813–818. doi: 10.1111/j.1525-1497.2004.30531.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Bair MJ, Robinson RL, and Eckert GJ. et al. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004 66:17–22. [DOI] [PubMed] [Google Scholar]
  38. Rowbotham MC, Goli V, and Kunz NR. et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004 110:697–706.Correction 2005; 113:248. [DOI] [PubMed] [Google Scholar]
  39. Goldstein DJ, Lu Y, and Detke MJ. et al. Duloxetine vs placebo in patients with painful diabetic neuropathy. Pain. 2005 116:109–118. [DOI] [PubMed] [Google Scholar]
  40. Detke MJ, Lu Y, and Goldstein DJ. et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002 63:308–315. [DOI] [PubMed] [Google Scholar]
  41. Fava M, Mallinckrodt C, and Detke M. et al. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher rates of remission? J Clin Psychiatry. 2004 65:521–530. [DOI] [PubMed] [Google Scholar]
  42. Fava M, Davidson KG.. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179–200. doi: 10.1016/s0193-953x(05)70283-5. [DOI] [PubMed] [Google Scholar]
  43. Rush AJ, Trivedi JH, and Wisniewski SR. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 163:1905–1917. [DOI] [PubMed] [Google Scholar]
  44. Hoffman MD, Hoffman DR.. Does aerobic exercise improve pain perception and mood? a review of the evidence related to healthy and chronic pain subjects. Curr Pain Headache Rep. 2007;11:93–97. doi: 10.1007/s11916-007-0004-z. [DOI] [PubMed] [Google Scholar]
  45. De Moor MH, Beem AL, and Stubbe JH. et al. Regular exercise, anxiety, depression and personality: a population-based study. Prev Med. 2006 42:273–279. [DOI] [PubMed] [Google Scholar]
  46. Mannerkorpi K.. Exercise in fibromyalgia. Curr Opin Rheumatol. 2005;17:190–194. doi: 10.1097/01.bor.0000154202.56962.85. [DOI] [PubMed] [Google Scholar]
  47. Assis MR, Silva LE, Alves AM.. A randomized controlled trial of deep water running: clinical effectiveness of aquatic exercise to treat fibromyalgia. Arthritis Rheum. 2006;55:57–65. doi: 10.1002/art.21693. [DOI] [PubMed] [Google Scholar]
  48. Domaille M, Mascarenhas R, and Dayal N. et al. Evaluation of the Bristol Royal Infirmary physiotherapy programme for the management of patients with osteoarthritis of the knee. Musculoskeletal Care. 2006 4:78–87. [DOI] [PubMed] [Google Scholar]
  49. Barkin RL, Barkin S.. The role of venlafax-ine and duloxetine in the treatment of depression with decremental changes in somatic symptoms of pain, chronic pain, and pharmacokinetics and clinical considerations of duloxetine pharmacotherapy. Am J Ther. 2005;12:431–438. doi: 10.1097/01.mjt.0000162011.58990.94. [DOI] [PubMed] [Google Scholar]
  50. Arnold LM, Rosen A, and Pritchett YL. et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005 119:5–15. [DOI] [PubMed] [Google Scholar]
  51. Arnold LM, Lu Y, and Crofford LJ. et al. for the Duloxetine Fibromyalgia Trial Group. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004 50:2974–2984. [DOI] [PubMed] [Google Scholar]
  52. Brambilla P, Cipriani A, and Hoptopf M. et al. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry. 2005 38:69–77. [DOI] [PubMed] [Google Scholar]
  53. Sabatowski R, Galvez R, and Cherry DA. et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004 109:26–35. [DOI] [PubMed] [Google Scholar]
  54. Lawson K.. Emerging pharmacological therapies for fibromyalgia. Curr Opin Investig Drugs. 2006;7:631–636. [PubMed] [Google Scholar]
  55. Ramaswamy K, Masand PS, Nasrallah HA.. Do certain atypical antipsychotics increase the risk of diabetes? a critical review of 17 pharmacoepidemiologic studies. Ann Clin Psychiatry. 2006;18:183–194. doi: 10.1080/10401230600801234. [DOI] [PubMed] [Google Scholar]
  56. Fishbain DA, Cutler RB, and Lewis J. et al. Do the second-generation “atypical neuroleptics” have analgesic properties? a structured evidence-based review. Pain Med. 2004 5:359–365. [DOI] [PubMed] [Google Scholar]
  57. Boyer EW, Shannon M.. The serotonin syndrome. N Engl J Med. 2005;352:1112–1120. doi: 10.1056/NEJMra041867. [DOI] [PubMed] [Google Scholar]
  58. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association. 2000 [Google Scholar]
  59. Ohayon MM, Schatzberg AF.. Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry. 2003;60:39–47. doi: 10.1001/archpsyc.60.1.39. [DOI] [PubMed] [Google Scholar]
  60. Tylee A, Gandhi P.. The importance of somatic symptoms in depression in primary care. Prim Care Companion J Clin Psychiatry. 2005;7:167–177. doi: 10.4088/pcc.v07n0405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Bair MJ, Robinson RL, and Katon W. et al. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003 163:2433–2445. [DOI] [PubMed] [Google Scholar]
  62. Gerber PD, Barrett JA, and Oxman TE. et al. The relationship of presenting physical complaints to depressive symptoms in primary care patients. J Gen Intern Med. 1992 7:170–173. [DOI] [PubMed] [Google Scholar]
  63. Williams LS, Jones WJ, and Shen J. et al. Outcomes of newly referred neurology outpa-tients with depression and pain. Neurology. 2004 63:674–677. [DOI] [PubMed] [Google Scholar]
  64. Judd LL, Akiskal HS, Paulus MP.. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord. 1997;45:5–18. doi: 10.1016/s0165-0327(97)00055-4. [DOI] [PubMed] [Google Scholar]
  65. Judd LL, Akiskal HS, and Maser JD. et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998 50:97–108. [DOI] [PubMed] [Google Scholar]
  66. Maier W, Gansicke M, Weiffenbach O.. The relationship between major and sub-threshold variants of unipolar depression. J Affect Disord. 1997;45:41–51. doi: 10.1016/s0165-0327(97)00058-x. [DOI] [PubMed] [Google Scholar]
  67. Stahl SM.. Does depression hurt? [BRAINSTORMS] J Clin Psychiatry. 2002;63:273–274. doi: 10.4088/jcp.v63n0401. [DOI] [PubMed] [Google Scholar]
  68. Bair MJ, Eckert GJ, and Robinson RL. et al. Impact of pain on depression: treatment efficacy. J Gen Intern Med. 2002 17:183. [Google Scholar]
  69. Max MB, Lynch SA, and Muir J. et al. Effects of desipramine, amitriptyline, and fluoxe-tine on pain in diabetic neuropathy. N Engl J Med. 1992 326:1250–1256. [DOI] [PubMed] [Google Scholar]
  70. Nemeroff CB, Schatzberg AF, and Goldstein DJ. et al. Duloxetine for the treatment of major depressive disorder. Psychopharmacol Bull. 2002 36:106–132. [PubMed] [Google Scholar]

Articles from Primary Care Companion to The Journal of Clinical Psychiatry are provided here courtesy of Physicians Postgraduate Press, Inc.

RESOURCES