The Pain-Depression Conundrum: Bridging the Body and Mind

Pain and depression seem to go hand in hand. What person with intractable pain would not, understandably, be depressed? Yet the relationship of these conditions is complex and unpredictable. Indeed, people in pain are not invariably depressed, although approximately one third of patients with pain do experience comorbid depression. By contrast, three fourths of those with depression will present with physical symptoms, including pain.

The Pain-Depression Conundrum: Bridging the Body and Mind

Author: Rollin M. Gallagher, MD, MPH
Medical Writer: Sophia Cariati, MA

 October 2, 2002;
 Medscape clinical upate based on session presented at the 21st Annual Scientific Meeting of the American Pain Society.

Certainly, individuals with pain-related disorders are at risk for depression. In fact, some research suggests that pain can be the best indicator of depression, especially among the elderly. A number of studies also suggest that depression can augment the impairment associated with pain. In a 24-month study of 228 elderly patients with depression or pain living in retirement communities, Mossey and colleagues evaluated the severity of depression and pain and their impact on functional activity. Initially, almost 50% of the patients who did not suffer depression reported limitations associated with their pain. Over the course of 2 years, however, people who began experiencing depressive symptoms also began reporting more impairment associated with the pain. In addition, high levels of depression were consistently associated with high levels of pain-associated impairment, and in the presence of pain, even low levels of depression were associated with increased healthcare utilization.

The relationship between pain and depression clearly is complex and still emerging. Recent research shows that serotonin and norepinephrine may modulate pain as well as mood. Understanding the shared pathophysiology of these phenomena will help clinicians to manage both conditions and ultimately help their patients to achieve remission. This Clinical Update will detail the epidemiologic, neurobiologic, and pharmacologic correlates of pain and depression.

Pain and Depression in Primary Care

Painful or uncomfortable physical symptoms are among the most common reasons individuals seek medical care. In a recent study, 107 HMO participants were asked to record all symptoms they experienced during a given 3-week period. The results revealed that each person experienced at least 1 symptom, including backache, headache, or stomach pain, every 3-4 days. Yet patients reported less than 6% of these problems to a physician.

When and why, then, do people bring their aches and pains to the doctor? Evidence suggests that people seek out medical care when symptoms become worrisome, interfere with their daily lives, or are disabling. In addition, studies show that when depression, anxiety, panic, or other psychiatric conditions are present, symptoms are more likely to reach this threshold. In fact, persons who seek healthcare for fatigue, migraine headaches, and gastrointestinal complaints experience more stressful life events, more distress, and are more likely to have an anxiety or depressive disorder than are those who do not seek care.

Several studies of irritable bowel syndrome (IBS) poignantly demonstrate the role of psychiatric disorders in healthcare-seeking behavior for corporeal aches and pains. Drossman and colleagues studied 72 patients with IBS who sought medical care, 82 persons with IBS who had not sought medical care, and 84 healthy subjects. They found that patients with IBS who seek care and those with IBS who do not seek care experience the same symptoms. However, IBS patients who seek help from a physician are significantly more likely to have psychiatric disorders, abnormal personality patterns, and more life stress.

In fact, evidence suggests that half of all high medical care users are psychologically distressed. What specific psychiatric disorders are most common among this group? According to a study by Katon and colleagues, 40% have depressive disorders, 22% have generalized anxiety disorder, 20% have somatization disorders, 12% have panic disorder, and 5% are alcohol abusers.

Statistics on the relationship between specific common physical symptoms and psychiatric disorders in primary care patients illustrate the pervasiveness of this comorbidity. Kroenke and colleagues found that the presence of any physical symptom increased the likelihood of a diagnosis of a mood or anxiety disorder by as much as 3-fold. Furthermore, 34% of patients with joint or limb pain, 38% of patients with back pain, 40% of patients with headache, 46% of patients with chest pain, and 43% of patients with abdominal pain also had a mood disorder.

While psychological problems may be prevalent among high healthcare users, what specific symptoms prompt most patients to seek out medical care? Physical symptoms account for half of all primary care physician visits. And while physical symptoms restrict the activities of Americans an average of 9.7 days annually, most of these physical manifestations are never explained by a disease or injury (Figures 1, 2).

Figure 1. Medical symptoms associated with current major depression.


Figure 2. Medical symptoms associated with lifetime major depression.

Kroenke, a leading researcher of symptoms in patient samples, reviewed the records of 1000 patients over 3 years to examine the incidence, evaluations performed, and outcome of symptoms commonly reported in primary care. At some point during the study period, approximately 9% of patients had presented with chronic pain, 8% with fatigue, and 5% with dizziness, headache, edema, low back pain, dysphoria, insomnia, and abdominal pain. Despite the high incidence of symptoms, only 16% of new physical symptoms reported were ever linked to physical injury or disease-related pathology.
The Links Between Physical and Psychological Complaints

Whether explained or unexplained, the number and severity of symptoms have been shown to rise with number and severity of psychological complaints. Patients with anxiety or depressive disorders are more apt to complain of multiple symptoms. Likewise, as the number of physical symptoms increases so does the risk of experiencing anxiety and depression. Evidence further suggests that stressful life events, psychological distress, and depressive and anxiety disorders are associated with a range of medical symptoms with no identified pathology.

In a study of 500 primary care adult patients, Kroenke found a number of independent predictors of mental disorders. These included recent stress, 6 or more physical symptoms, higher reported severity of symptoms, lower self-rating of overall health, age younger than 50 years, and physician perception of the encounter as difficult. In addition, patients with depressive or anxiety disorders were more likely to experience unmet expectations after the visit (20% vs 8%, P < .001) and to report persistent psychiatric symptoms 3 months after the initial visit, compared with those without such disorders. Thus, this subgroup of patients may warrant closer psychiatric evaluation.
Barriers to Recognizing Depression in Primary Care

Despite its pervasiveness in the primary care setting, depression goes undetected in the majority of cases. Studies have found that 50% of patients who experience major depression are not diagnosed by their primary care physicians. Several factors are thought to contribute to this phenomenon, including time and cost restrictions. In addition, 50% to 80% of patients with depression initially present with a physical symptom. These individuals are significantly less likely to receive an accurate psychiatric diagnosis than are those who tell their physician they’re feeling “down.” Medical school curricula that teach students to rule out physical disease before considering mental disorders may also contribute to these missed diagnoses. Because of the frequency of depression and anxiety in medically ill populations, relative to the rare conditions students are taught to look for, this is akin to the proverbial problem of teaching the students “to look for zebras (medical disorders) in a herd of horses.” Thus, high rates of unnecessary tests are ordered, driving up the cost of care, increasing the chance of a spurious positive finding and the risk of prolonging the illness, with secondary consequences for the patient.

Since most Americans receive their only mental health care in the primary care setting, improving recognition rates of depression in primary care has important public health implications. In fact, citing the ability to reduce clinical morbidity, the United States Preventive Services Task Force recently recommended depression screening for all adults in primary care settings.

International studies confirm that the relationship between somatic symptoms and depression is not a uniquely Western phenomenon. Simon and colleagues analyzed World Health Organization data to examine this phenomenon in more than 5400 patients at 15 primary care centers in 14 countries. As is the case in the United States, approximately 10% of these patients were diagnosed with major depression. Forty-five percent to 95% of depressed patients reported only somatic symptoms. Half reported multiple unexplained symptoms and 11% denied psychological symptoms of depression when questioned. Purely somatic presentation was more common in patients who lacked an ongoing relationship with their doctor, perhaps because of the issues of trust and stigmatization of depression.

Chronic Pain and Depression

Does chronic pain cause the depression or does depression cause the pain? Current evidence supports both relationships. Research shows that patients with persistent or chronic pain are at risk for developing an anxiety or depressive disorder. A recent analysis of data from the World Health Organization, found that 22% of primary care patients complained of persistent pain, which was defined as experiencing at least 6 months of pain plus disability because of the pain and/or receipt of medical care for the pain. Those with persistent pain were 4 times more likely to have an anxiety or depressive disorder than were pain-free individuals.

A host of other psychological and social factors may also be involved in the development of chronic pain. Gureje and colleagues analyzed data from the World Health Organization to examine persistent pain in more than 3000 primary care patients around the world. Researchers found that 49% of patients who experienced persistent pain at baseline continued to have persistent pain 12 months later. The best independent predictor of persistent pain was the number of pain sites. Psychiatric disorder, poor self-rated overall health, and occupational related disability were also found to be independently associated with chronic pain. Furthermore, persistent pain at baseline predicted the onset of a psychological disorder with the same strength that a baseline psychological disorder predicted the onset of persistent pain.

In their review of the epidemiology of pain and depression in primary care, Von Korff and Simon made 4 broad generalizations. They are as follows:

* Pain is as strongly associated with anxiety as with depressive disorders;
* The number of pain sites (diffuseness of pain) and the extent to which pain interferes in daily life are the characteristics that most strongly predict depression;
* Certain psychological symptoms of depression, including low energy, sleep disturbances, and worry, are common among pain patients whereas guilt and loneliness are not; and
* Psychological distress and disability often surface and resolve early during the course of a pain disorder that evolves into a chronic condition.

Based upon their findings, these researchers hypothesized that pain and psychological illness have reciprocal psychological and behavioral effects. They proposed 2 theories about the mechanisms underlying the pain-depression comorbidity: (1) some individuals are genetically susceptible to both physical and psychological symptoms and a state in which psychological distress amplifies unpleasant physical sensations; (2) the physical and psychological stress of pain may induce or aggravate psychological distress.

Other, more recent models of the relationship between pain and mood blend the evidence from studies of neurobiological and biobehavioral concepts such as sensitization, conditioning, and kindling to explain the comorbidity of pain and depression.

The Neurochemical Connection Between Pain and Depression

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1. Gallagher RM, Verma S, Mossey J. Chronic pain. Sources of late-life pain and risk factors for disability. Geriatrics. 2000;55:40-44, 47.
2. Magni G, Marchetti M, Moreschi C, et al. Chronic musculoskeletal pain and depressive symptoms in the national health and nutrition examination. I. Epidemiologic follow-up study. Pain. 1993;53:163-168.
3. Roy R. A psychosocial perspective on chronic pain and depression in the elderly. Soc Work Health Care. 1986;12:27-36.
4. Dworkin SF, Von Korff M, LeResche L. Multiple pains and psychiatric disturbance: an epidemiologic investigation. Arch Gen Psychiatry. 1990;47:239-244.
5. Parmelee PA, Katz IR, Lawton MP. The relation of pain to depression among institutionalized aged. J Gerontol. 1991;46:15-21.
6. Wesley AL, Gatchel RJ, Polatin PB, et al. Differentiation between somatic and cognitive/affective components in commonly used measurements of depression in patients with chronic low-back pain. Let’s not mix apples and oranges. Spine. 1991;16(6 suppl):S213-S215.
7. Stewart RB, Blashfield R, Hale WE, et al. Correlates of Beck Depression Inventory scores in an ambulatory elderly population: symptoms, disease, laboratory values, and medications. J Fam Pract. 1991;32:497-502.
8. Mossey J, Gallagher RM, Tirumalasetti F. The effects of pain and depression on physical functioning in elderly residents of a continuing care retirement community. Pain Medicine. 2000;1:340-350.
9. Mossey JM, Gallagher RM. Longitudinal evaluation of the effects of pain and depression on the physical functioning of continuing care retirement community residents: Implications for the treatment of pain in older individuals. Pain Medicine. 2:246-247.
10. Gallagher RM, Mossey J. Inadequate pain care for elders: The need for a primary care-pain medicine community collaboration. Pain Medicine. 2002;3:180.
11. Demers RY, Altamore R, Mustin H. An exploration of the dimensions of illness behavior. J Fam Pract. 1980;11:1085-1092.
12. Katon W, Von Korff M, Lin E, et al. Distressed high utilizers of medical care. DSM-III-R diagnoses and treatment needs. Gen Hosp Psychiatry. 1990;12:355-362.
13. Katon W, Von Korff M, Lin E, et al. A randomized trial of psychiatric consultation with distressed high utilizers. Gen Hosp Psychiatry. 1992;14:86-98.
14. Drossman DA. Do psychosocial factors define symptom severity and patient status in irritable bowel syndrome? Am J Med. 1999;107:41S-50S
15. Drossman DA, Whitehead WE, Toner BB, et al. What determines severity among patients with painful functional bowel disorders? Am J Gastroenterol. 2000;95:974-980.
16. Sandler RS, Drossman DA, Nathan HP, McKee DC. Symptom complaints and health care seeking behavior in subjects with bowel dysfunction. Gastroenterology. 1984;87:314-318.
17. Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care. Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3:774-779.
18. Walker EA, Katon WJ, Jemelka RP. Psychiatric disorders and medical care utilization among people in the general population who report fatigue. J Gen Intern Med. 1993;8:436-440.
19. Drossman DA, McKee DC, Sandler RS, et al. Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology. 1988;95:701-708.
20. Kroenke K. Studying symptoms: sampling and measurement issues. Ann Intern Med. 2001;134(9 Pt 2):844-853.
21. Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med. 1989;86:262-266.
22. Kroenke K, Jackson JL, Chamberlin J. Depressive and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103:339-347.
23. Kroenke K, Spitzer RL, deGruy FV III, Swindle R. A symptom checklist to screen for somatoform disorders in primary care. Psychosomatics. 1998;39:263-272.
24. Watson D, Pennebaker JW. Health complaints, stress, and distress: exploring the central role of negative affectivity. Psychol Rev. 1989;96:234-254.
25. Katon W, Sullivan M, Walker E. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med. 2001;134(9 Pt 2):917-925.
26. Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. Rockville, Md: U.S. Department of Health and Human Services; 1993. AHCPR Publication No. 93-0550.
27. Simon GE, VonKorff M. Recognition, management, and outcomes of depression in primary care. Arch Fam Med. 1995;4:99-105.
28. Kirmayer LJ, Robbins JM, Dworkind M, Yaffe MJ. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry. 1993;150:734-741.
29. Regier DA, Goldberg ID, Taube CA. The de facto US mental health services system: a public health perspective. Arch Gen Psychiatry. 1978;35:685-693.
30. Pignone MP, Gaynes BN, Rushton JL, et al. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:765-776.
31. Screening for depression: recommendations and rationale. Ann Intern Med. 2002;136:760-764.
32. Screening for Depression. Recommendations and Rationale. May 2002. Agency for Healthcare Research and Quality, Rockville, Md. Available at: http://www.ahrq.gov/ clinic/3rduspstf/depression/ depressrr.htm. Accessed September 11, 2002.
33. Simon GE, VonKorff M, Piccinelli M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341:1329-1335.
34. Gureje O, Simon GE, Von Korff M. A cross-national study of the course of persistent pain in primary care. Pain. 2001;92:195-200.
35. Hendler N. Depression caused by chronic pain. J Clin Psychiatry. 1984;45(3 Pt 2):30-38.
36. Magni G, Moreschi C, Rigatti-Luchini S, Merskey H. Prospective study on the relationship between depressive symptoms and chronic musculoskeletal pain. Pain. 1994;56:289-297.
37. Turk DC, Okifuji A, Scharff L. Chronic pain and depression: role of perceived impact and perceived control in different age cohorts. Pain. 1995;61:93-101.
38. Kuch K. Psychological factors and the development of chronic pain. Clin J Pain. 2001;17(4 suppl):S33-S38.
39. Blackburn-Munro G, Blackburn-Munro RE. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol. 2001;13:1009-1023.
40. Dohrenwend BP, Raphael KG, Marbach JJ, Gallagher RM. Why is depression comorbid with chronic myofascial face pain? A family study test of alternative hypotheses. Pain. 1999;83:183-192.
41. Schwartz L, Slater MA, Birchler GR, Atkinson JH. Depression in spouses of chronic pain patients: the role of patient pain and anger, and marital satisfaction. Pain. 1991;44:61-67.
42. Banks S, Kerns RD: Explaining high rates of depression in chronic pain: A diathesis-stress framework. Psychol Bull. 1996;119:95-110.
43. Von Korff M, Simon G. The relationship between pain and depression. Br J Psychiatry Suppl. 1996;101-108.
44. Rome HP Jr, Rome JD. Limbically augmented pain syndrome (LAPS): Kindling, corticolimbic sensitization, and the convergence of affective and sensory symptoms in chronic pain disorders. Pain Medicine. 2000; 1: 7-23.
45. Stahl SM. Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry. 1998;59(suppl 4):5-14.
46. Vetulani J, Sulser F. Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature. 1975;257:495-496.
47. Peroutka SJ, Snyder SH. Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science. 1980;210:88-90.
48. Humble M. Noradrenaline and serotonin reuptake inhibition as clinical principles: a review of antidepressant efficacy. Acta Psychiatr Scand Suppl. 2000;402:28-36.
49. Montgomery SA. Predicting response: noradrenaline reuptake inhibition. Int Clin Psychopharmacol. 1999;14(suppl 1):S21-S26.
50. Montgomery SA. Reboxetine: additional benefits to the depressed patient. J Psychopharmacol. 1997;11(4 suppl):S9-S15.
51. Venditti LN, Arcelus A, Birnbaum H, et al. The impact of antidepressant use on social functioning: reboxetine versus fluoxetine. Int Clin Psychopharmacol. 2000;15:279-289.
52. Levitt AJ, Joffe RT, Kamil R, McIntyre R. Do depressed subjects who have failed both fluoxetine and a tricyclic antidepressant respond to the combination? J Clin Psychiatry. 1999;60:613-616.
53. Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry. 1990;47:411-418.
54. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 1999;46:212-220.
55. Moreno FA, Gelenberg AJ, Heninger GR, et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry. 1999;46:498-505.
56. Ishigooka J. Serotonin-noradrenaline reuptake inhibitors(SNRIs) Nippon Rinsho. 2001;59:1523-1529.
57. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871-880.
58. Turcotte JE, Debonnel G, de Montigny C, et al. Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001;24:511-521.
59. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci. 2001;26:37-43.
60. Fields HL. Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res. 2000;122:245-253.
61. Fields HL, Basbaum AI. Brainstem control of spinal pain-transmission neurons. Annu. Rev. Physiol. 1978;40:217-248.
62. Fields HL, Bry J, Hentall I, Zorman G. The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J Neurosci. 1983;3:2545-2552.
63. Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 1991;14:219-245.
64. Fields HL, Malick A, Burstein R. Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla. J Neurophysiol. 1995;74:1742-1759.
65. Fields HL, Vanegas H, Hentall ID, Zorman G. Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. Nature. 1983;306:684-686.
66. Mason P. Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. Annu Rev Neurosci. 2001;24:737-777.
67. Mason P, Gao K. Raphe magnus serotonergic neurons tonically modulate nociceptive transmission. Pain Forum. 1998;7:143-150.
68. Mico JA, Gibert-Rahola J, Casas J, et al. Implication of beta 1- and beta 2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants. Eur Neuropsychopharmacol. 1997;7:139-145.
69. Gray AM, Pache DM, Sewell RD. Do alpha2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds? Eur J Pharmacol. 1999;378:161-168.
70. Schreiber S, Backer MM, Pick CG. The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms. Neurosci Lett. 1999;273:85-88.
71. Eschalier A, Montastruc JL, Devoize JL, et al. Influence of naloxone and methysergide on the analgesic effect of clomipramine in rats. Eur J Pharmacol. 1981;74:1-7.
72. Sierralta F, Pinardi G, Miranda HF. Effect of p-chlorophenylalanine and alpha-methyltyrosine on the antinociceptive effect of antidepressant drugs. Pharmacol Toxicol. 1995;77:276-280.
73. Tura B, Tura SM. The analgesic effect of tricyclic antidepressants. Brain Res. 1990;518:19-22.
74. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol. 1978;4:451-462.
75. Ardid D, Jourdan D, Mestre C, et al. Involvement of bulbospinal pathways in the antinociceptive effect of clomipramine in the rat. Brain Res. 1995;695:253-256.
76. Sawynok J. Cowan A, eds. Novel Aspects of Pain Management: Opioids and Beyond. New York: Wiley; 1999:179-228.
77. Sawynok J, Reid A. Interactions of descending serotonergic systems with other neurotransmitters in the modulation of nociception. Behav Brain Res. 1996;73:63-68.
78. Rainville P, Bushnell MC, Duncan GH. Representation of acute and persistent pain in the human CNS: potential implications for chemical intolerance. Ann N Y Acad Sci. 2001;933:130-141.
79. Ren K, Dubner R. Central nervous system plasticity and persistent pain. J Orofac Pain. 1999;13:155-163; discussion 164-171.
80. Sawynok J, Esser MJ, Reid AR. Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain. 1999;82:149-158.
81. Sawynok J, Reid AR, Esser MJ. Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain. 1999;80:45-55.
82. Coderre TJ, Fundytus ME, McKenna JE, Dalal S, Melzack R. The formalin test: a validation of the weighted-scores method of behavioural pain rating. Pain. 1993;54:43-50.
83. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993;52:259-285.
84. O’Malley PG, Jackson JL, Santoro J, et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999;48:980-990.
85. O’Malley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15:659-666.
86. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. Clin Psychiatry. 2002;63:308-315.
87. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol 1994;35:S50-S53.
88. Fishbain DA, Cutler R, Rosomoff HL, et al. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review. Pain Medicine. 2000;1:310-316.
89. Olfson M, Marcus SC, Druss B, Elinson L, Tanielian T, Pincus HA. National trends in the outpatient treatment of depression. JAMA. 2002;287:203-209.
90. Turk DC. Combining somatic and psychosocial treatment for chronic pain patients: perhaps 1 + 1 does = 3. Clin J Pain. 2001;17:281-283.
91. Gallagher RM, Verma S. Managing pain and comorbid depression: A public health challenge. Semin Clin Neuropsychiatry. 1999;4:203-220.
92. Gallagher RM. Treatment planning in pain medicine. Integrating medical, physical, and behavioral therapies. Med Clin North Am. 1999;83:823-849, viii.
93. Fishbain DA. Current research on chronic pain and suicide. Am J Public Health. 1996;86:1320-1321.
94. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry. 1991;52(suppl):28-34.
95. AHCPR. Rockville, Md: US Departments of Health and Human Services; 1992. Publication 93-0551.
96. Von Korff M, Goldberg D. Improving outcomes in depression. BMJ. 2001;323:948-949.
97. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200.
98. Fawcett J, Barkin RL. Efficacy issues with antidepressants.J Clin Psychiatry. 1997;58(suppl 6):32-39.
99. Nierenberg AA, Wright EC. Evolution of remission as the new standard in the treatment of depression. J Clin Psychiatry. 1999;60(suppl 22):7-11.
100. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry. 1999;60:142-156.
101. Dawson R, Lavori PW, Coryell WH, Endicott J, Keller MB. Maintenance strategies for unipolar depression: an observational study of levels of treatment and recurrence. J Affect Disord. 1998;49:31-44.
102. Dunner DL. Acute and maintenance treatment of chronic depression. J Clin Psychiatry. 2001;62(suppl 6):S10-S16.
103. Preskom SH. Outpatient Management of Depression: A Guide for the Primary Care Practitioner. Caddo, Okla: Professional Communications, Inc.; 1999.
104. Anderson IM, Cowen PJ. Clomipramine enhances prolactin and growth hormone responses to L-tryptophan.Psychopharmacology (Berl). 1986;89:131-133.
105. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors.Br J Psychiatry. 2001;178:234-241.
106. Moclobemide: a reversible MAO-A-inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. J Affect Disord. 1993;28:105-116.
107. Max MB. Antidepressants as analgesics. In: Fields HL, Liebeskind JC, eds. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical Issues (Progress in Pain Research and Management series). Seattle, Wash: IASP Press; 1994:229-246.
108. Fishbain D. Evidence-based data on pain relief with antidepressants. Ann Med. 2000;32:305-316.
109. Fishbain DA. Re: The meeting of pain and depression: comorbidity in women. Can J Psychiatry. 2000;45:88.
110. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250-1256.
111. Magni G. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs. 1991;42:730-748.
112. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26:30-36.
113. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371-1377.
114. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42:135-144.
115. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250-1256.
116. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23:255-259.
117. Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54:1009-1015.
118. Weissman MM, Klerman GL, Prusoff BA, Sholomskas D, Padian N. Depressed outpatients. Results one year after treatment with drugs and/or interpersonal psychotherapy. Arch Gen Psychiatry. 1981;38:51-55.
119. Sonawalla SB, Fava M. Severe depression: is there a best approach? CNS Drugs. 2001;15:765-776.
120. Murphy GE, Simons AD, Wetzel RD, Lustman PJ. Cognitive therapy and pharmacotherapy: singly and together in the treatment of depression. Arch Gen Psychiatry. 1984;41:33-41.
121. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(suppl 13):23-29.
122. Scott J, Teasdale JD, Paykel ES, et al. Effects of cognitive therapy on psychological symptoms and social functioning in residual depression. Br J Psychiatry. 2000;177:440-446.
123. Fava GA, Rafanelli C, Grandi S, et al. Six-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1998;155:1443-1445.


Rollin M. Gallagher, MD, MPH
Professor of Psychiatry, Anesthesiology, and Public Health and Director of Pain Medicine, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania; Director, Pain Medicine and Comprehensive Rehabilitation Center, Graduate Hospital, Philadelphia, Pennsylvania


Rollin M. Gallagher, MD, MPH, has disclosed that he has served as advisor or consultant to Lilly, Janssen, Purdue, and Endo Pharmaceuticals.


Sophia Cariati, MA
Freelance Health & Science Writer, New York, NY.

Disclosure: Sophia Cariati has no significant financial interests to disclose.


Priscilla Scherer, RN
Editor, Medscape Neurology & Neurosurgery

Reviewed by Lindsay 8-10-2010

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