[Frontiers in Bioscience 14, 5031-5051, June 1, 2009]

Depression and pain

Michael J. Robinson1, Sara E. Edwards1, Smriti Iyengar1, Frank Bymaster2, Michael Clark3, Wayne Katon4

1Lilly USA, LLC, Indianapolis, IN, 2Department of Psychiatry, Indiana University Medical School, Indianapolis, IN, 3Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 4Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA


1. Abstract
2. Introduction
3. Mechanisms of the mood and pain link
3.1. Brain structures involved in mood and pain
3.1.1. Insular cortex
3.1.2. Prefrontal cortex
3.1.3. Anterior cingulate cortex
3.1.4. Amygdala
3.1.5. Hippocampus
3.2. Shared neurocircuitries and neurochemicals between mood and pain
3.2.1. Hypothalamic-pituitary-adrenal axis
3.2.2. Cytokines
3.2.3. Limbic and paralimbic structures
3.2.4. Ascending and descending pain tracks
3.2.5. Monoamines
3.2.6. Neurotrophic factors
3.2.7. Psychological overlaps Catastrophizing in pain and depression Learned helplessness End-organ sensitization
4. Multidimensional treatment of depression and pain
4.1. Theory of allostasis
4.2. Optimization of treatment
4.2.1. Treating depression and pain Psychotherapy Exercise Pharmacotherapy options
5. Perspectives
6. Acknowledgements
7. References


Depression and pain disorders are often diagnosed in the same patients. Here we summarize the shared pathophysiology between both disorders and the importance of addressing all symptoms in patients with comorbid pain and depression. We describe anatomical structures that are activated and/or altered in response to both depression and pain - examples include the insular cortex, the prefrontal cortex, the anterior cingulate cortex, the amygdala, and the hippocampus. Both disorders activate common neurocircuitries (e.g. the hypothalamic-pituitary-adrenal axis, limbic and paralimbic structures, ascending and descending pain tracks), common neurochemicals (e.g. monoamines, cytokines, and neurotrophic factors), and are associated with common psychological alterations. One explanation for the interaction and potentiation of the disease burden experienced by patients affected by both pain and depression is provided by the concept of allostasis. In this model, patients accumulate allostatic load through internal and external stressors, which makes them more susceptible to disease. To break this cycle, it is important to treat all symptoms of a patient. Therapeutic approaches that address symptoms of both depression and pain include psychotherapy, exercise, and pharmacotherapy.


Depression and pain disorders are common comorbidities. Epidemiological studies report a mean prevalence rate of major depressive disorder (MDD) in patients with chronic pain assessed in pain clinics of 52%, and a mean prevalence of pain in depressed patients of 65% (1). In a primary care setting, 69.1% of patients with MDD reported at least moderate pain symptoms, while only 38.6% of patients without MDD reported moderate pain symptoms (2).

Comorbidity of pain and depression has a negative impact on several outcome measures: health care related costs are significantly higher (2), productivity is decreased with more days absent from work (3), and most importantly, the likelihood of remission of depressive symptoms is decreased (4). Achieving remission is critical in the treatment of depression. Patients with residual symptoms are more likely to experience a relapse of depressive episodes (5,6), and to do so earlier than patients without residual symptoms (7). Also, patients with MDD who do not reach remission experience substantial impairment in their physical, occupational, and social functioning (5,6). Residual depressive symptoms are associated with a higher rate of suicide attempts (8) and negatively impact marital interactions (9) and the mental health of children of depressed patients (10). One effect of the presence of major depression in chronic pain conditions is increased absenteeism in those patients resulting in economic implications (11).

Here we summarize the current knowledge in the literature with regard to the biological and psychological processes shared by depression and chronic pain disorders. We present how multiple overlapping anatomical structures, physiological pathways, and neurocircuitries are altered by both diseases. Beyond this evidence based science, we introduce the theoretical concept of allostasis to further demonstrate the complex interactions between depression and pain.

Allostasis is defined as the ability of the organism to maintain stability by reacting to external and internal stress with change. While this adaptation is beneficial for coping with stress and allows the individual to continue to function, high levels of activity in this system due to excessive stress induce the accumulation of allostatic load, which in turn makes the individual more susceptible to disease (12). The extent to which allostatic load is accumulated, and subsequently the susceptibility to disease, is highly variable between individuals and is influenced by many internal and external factors. Vulnerability factors that increase the risk of depression include genetic and environmental predispositions. Caspi and colleagues demonstrated in a longitudinal birth-cohort study that a functional polymorphism in the promoter region of the serotonin transporter alters the response to stressful life events and the incidence of depression following such events (13). Another prominent environmental vulnerability factor is childhood trauma, which is reported by a high percentage of adults affected by depression (14).

Another source for increased allostatic load, and therefore a higher risk to develop a depressive disorder, is current stressors - either environmental, e.g. stressful life events, or internal, e.g. pain due to a medical illness. An example of an external stressor with a strong association to triggering a depressive episode is divorce (15). Chronic pain in longitudinal studies of community respondents has also been shown to be associated with a high risk for the development of depression (16). Therefore, the importance of allostasis for depression and pain is twofold: both depression and pain can increase allostatic load, and increased allostatic load can in turn trigger the manifestation of depression and pain.

The purpose of this review is to raise awareness in both mood and pain clinicians for the close interactions and commonalities in the pathophysiologies of pain and depression. Comorbidity with pain and depression potentiates the disease burden, which is reflected in longer symptom duration, more severe symptoms, and worse outcomes. To achieve optimal therapeutic success, it is essential to treat both pain and depression when they coexist.


3.1. Brain structures involved in mood and pain

Several brain regions have been implicated in both major depressive disorder (MDD) and pain (Table 1 and Figure 1). The most extensive research has been done on the insular cortex, prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala and hippocampus.

3.1.1. Insular cortex

The insular cortex is frequently activated in response to pain (17,18). Tonic pain is an example of a pain sensation that is encoded by this brain structure (19). Imaging studies using functional magnetic resonance imaging (fMRI) confirmed the central role of the insular cortex in pain processing (20,21), and showed its importance during integration of sensory and cognitive components of pain perception (22).

On the other hand, pathophysiological changes in the insular cortex might contribute to depression as this brain area is responsible for processing information from sensory experiences to create an emotionally relevant context. Imaging studies revealed focal changes of the serotonin 5HT2 receptor status in the insular cortex of depressed patients (23).

3.1.2. Prefrontal cortex

The most prominent feature of the PFC is its role in executive functions like working memory, planning, and judgment; impairments of all of these functions are observed in patients with MDD (24,25). Positron emission tomography (PET) revealed increased blood flow in patients with MDD from the left ventrolateral PFC to the medial PFC (26), and decreased activity in the PFC ventral region to the genu of the corpus callosum combined with a gray matter volume reduction of 48% in this area (27). Patients with MDD show altered activation of the PFC during the processing of emotions (28). fMRI imaging revealed an imbalance between right and left PFC in patients with MDD linked to negative emotional judgment compared to healthy controls (29). Consistent with altered brain structure in depression, human postmortem studies revealed reduced size and density of neurons and glial cells in the prefrontal cortex of patients with MDD (30-32). In a rodent model for depression, the PFC showed the greatest reduction in synaptic plasticity proteins in response to adolescent separation (33).

In patients with chronic back pain, reduced gray matter density has been described for the bilateral dorsolateral PFC (34). Activation of the PFC has been observed in clinical pain conditions and is associated with a role in attending to or ignoring painful stimulation (18). A critical role for the PFC on individual differences in pain perception (35), perceived control over pain (36), and spatial discrimination of pain was shown in fMRI studies (37).

3.1.3. Anterior cingulate cortex

The ACC plays an important role in conflict detection and emotional evaluation of error. In addition, it is connected to brain structures that influence the emotional valence of thought, autonomic and visceral responses, and mood regulation. All of these functions are disturbed during depression (38).

Electroencephalographic examinations showed differences in the activity of the rostral ACC between responders and non-responders to antidepressant therapy (39). Magnetic resonance imaging (MRI) of medication-naïve female depressed patients showed a reduction in volume of the ventral ACC and the amygdala in comparison to healthy controls (40). Analysis of glucose metabolism demonstrated a significant negative correlation with age in patients with MDD, but not in healthy controls (41). Higher metabolic rates of the ACC in conjunction with higher loudness dependence of the auditory evoked potential (LDAEP) values are predictive for better treatment response in depressed patients (42). In rodent models, the modulation of depression by the rostral ACC has been shown by lesion studies (43).

The activation of the ACC in response to thermal and mechanical pain was shown in human fMRI studies with healthy volunteers (44). Migraine patients have significant decreases of gray matter in the cingulate cortex compared to healthy controls when examined by MRI (45). Single photon emission computed tomography (SPECT) demonstrated reduced blood flow in the ACC in patients with chronic pain conditions (46). Additional neuroimaging studies revealed that both felt pain in an individual and seen pain in another person activates the ACC, but not necessarily identical neurons (47).

3.1.4. Amygdala

The amygdala performs a primary role in the formation and storage of memories associated with emotional events (24), processes which are disturbed in patients with MDD. PET shows increased blood flow in the amygdala of patients with MDD (26). Conflicting results are reported in the literature regarding the amygdala volume in depressed patients. While some studies did not find differences between healthy control subjects and patients affected by MDD (48), others report a decrease (40,49) or an increase (50) of the amygdala volume in depressed patients. Within a group of depressed patients, suicidal patients with MDD have a larger amygdala volume than non-suicidal patients with MDD (51). Activity levels of the amygdala are increased during stress and in patients with anxiety and mood disorders (52).

The amygdala plays a key role in attaching emotional significance to pain (18). Imaging studies show an activation of the amygdala in response to different painful stimuli (53,54). Intervention studies in rodents confirmed the central role of the amygdala in pain perception (55-58).

3.1.5. Hippocampus

The hippocampus provides an important feedback inhibition of the hypothalamic-pituitary-adrenal gland (HPA) axis (59). A direct link exists between the hippocampus and the PFC, and it has been shown in rodent experiments that the hippocampus exerts a direct excitatory influence on PFC interneurons (60). The hippocampus is important in the control of mood (61) and for the formation of associative and episodic memories (62). Reduced hippocampal volume compared to controls has been reported in adult patients with MDD (50,63-68), with a statistically significant inverse relationship between duration of untreated depression and degree of hippocampal volume loss (69). However, it is not clear if depressed patients have reduced hippocampal volume in the premorbid state, or if the reduction is caused by the disorder. A study in depressed children and adolescents did not detect any hippocampal volume reduction in comparison to a control group (49).

Activation of the hippocampus has been demonstrated in healthy volunteers in response to a pain stimulus (70). Patients with fibromyalgia show decreased presynaptic dopaminergic activity in several brain regions, including the hippocampus, compared to healthy controls (71). Changes in the hippocampal morphology and gene expression were observed in rodents in response to chronic pain (72-74). Similarly, chronic stress models of depression in rodents induce changes in synapse morphology in hippocampal subregions (75).

3.2. Shared neurocircuitries and neurochemicals between mood and pain

Shared neurocircuitries and neurochemicals play an important role connecting the pathophysiologies of depression and pain disorders. Those shared pathways enable cross talk between both disorders on several levels - within and between brain regions, intercellular and through neurochemical signaling. Therefore, alterations in the activity of neurocircuitries and the levels of neurochemicals due to either disorder can affect the other disorder.

3.2.1. Hypothalamic-pituitary-adrenal axis

Both patients with MDD and those with chronic pain experience dysregulation of the HPA axis (76) (Figures 2A, 2B). The brain reacts to stress and depression with activation of the HPA axis. The hippocampus and the amygdala are two of several brain structures that control the activity of the HPA axis. The hippocampus exerts an inhibitory influence on hypothalamic neurons that contain corticotropin-releasing-factor (CRF), while the amygdala has a direct excitatory influence on these hypothalamic neurons. Glucocorticoid levels under physiological conditions seem to enhance hippocampal inhibition of HPA axis activity (via feedback loops coupled to glucocorticoid receptors) (76). Increased glucocorticoid levels, as seen in response to stressors like pain and potentially depression, may not only damage hippocampal neurons, but reduce neurogenesis (77). Additionally, the negative feedback mechanism between increased glucocorticoid levels and the HPA axis can be disrupted as a result of prolonged stress, which causes maladaptive responses of the HPA axis (76). Many psychiatric patients, including those with MDD, show abnormal, excessive activation of the HPA axis (78). It has been shown that the HPA axis normalizes in response to treatment with antidepressants (79). Rodent data show that increased glucocorticoid levels induce a loss of synapses within the hippocampus. In these animals, examination of the cellular volume in the hippocampal CA3 area revealed that increased glucocorticoid levels have no effect on the neuropil and glial volume in the proximal subfield of the CA3, but induce changes in the middle subfield of the CA3. These changes include the occurrence of more astrocytic processes and a decrease of tissue volume made up of non-glial cells (80).

Chronic pain is a persistent stressor, which in turn interrupts the negative glucocorticoid feedback on the HPA axis. This induces the generation of higher glucocorticoid levels by the HPA axis by down-regulation of the glucocorticoid receptors within the brain and the periphery (76). Dysfunction of the HPA axis has been shown to be predictive as to which individuals among psychologically at risk patients will develop chronic widespread pain (81). In a rodent model, a central role of the CRF-1 receptor in the amygdala for pain sensitization (82) and for the development of pain-related anxiety has been demonstrated (58).

3.2.2. Cytokines

Both patients with depressive symptoms and patients with pain disorders often display enhanced cytokine levels including interleukin-6 (IL-6), C-reactive protein (CRP), interleukin-1-beta (IL-1-beta), and tumor necrosis factor alpha (TNF-alpha) (83,84). Cytokines are small proteins released by cells and play an important role in intercellular communication. Examples include lymphokines, interleukins and other cell signaling molecules (Figures 2A, 2B). Activation of inflammatory pathways has been observed in otherwise medically healthy patients with MDD (85). Cytokines that are released in response to an activation of inflammatory pathways can enter the brain. There they may cause alterations of the metabolism of serotonin and dopamine (84). Additionally, cytokines activate CRF, which in turn leads to an increase of serum glucocorticoid levels (84). Under physiological conditions, increased serum glucocorticoid levels induce an inhibition of the HPA axis. After prolonged stress, this negative feedback mechanism is disrupted as detailed above. In patients with MDD, a positive correlation between inflammatory responses and long-term hyperactivity of the HPA axis has been observed (86), while during remission of depressive symptoms a normalization of both cytokine levels and HPA axis activity has been described (87). Additionally, in patients with MDD, correlations between cytokine levels and response to antidepressant treatment have been observed (88). Interestingly, patients whose HPA axis activity does not normalize during remission are more likely to experience an earlier relapse of their depressive symptoms (89). Support for the importance of cytokines in the pathophysiology of depression comes from observations in cancer patients who develop depressive symptoms after treatment with cytokines like interferon (76). Additionally, cytokine levels seem to differ between suicidal and non-suicidal patients with MDD (90).

Cytokines play a central role in the generation and transmission of pain (83,91,92). Patients with complex regional pain syndromes present with a pro-inflammatory cytokine profile with increased mRNA and protein levels of TNF-alpha and interleukin-2, and decreased levels of interleukin-4 and interleukin-10, compared to a control group (93). In patients with peripheral neuropathy, a similar pro-inflammatory cytokine profile is associated with pain (94).

3.2.3. Limbic and paralimbic structures

As described above, several brain structures have been implicated in both depression and pain. Beyond anatomical co-localizations, evidence in the literature points to the common activation of neurocircuitry during pain and clinical signs of depression in those regions.

Eisenberger and colleagues demonstrated with an fMRI study that, during experiments that induce feelings of social exclusion, the same brain regions (ACC and right ventral PFC) are activated as in response to physical pain (95). Activation of the ACC is associated with the affective dimension of pain, and the degree of neuronal activation is correlated to levels of symptoms of depression (96). Compared to healthy controls, patients with MDD show a relative hyperactivation of the PFC in response to a thermal pain stimulus, which might explain their reduced thermal pain perception on the skin (97). Interestingly, patients with MDD and pain symptoms experience improvement of their pain symptoms in response to treatment with transcranial magnetic stimulation delivered to the left dorsolateral PFC (98).

The amygdala is essential for the interaction between pain and depression (99), and its central role in both pain and anxiety, a hallmark of depression, was recently illustrated in a rodent study. In this study, the investigators selectively blocked the CRF receptors in the amygdala, which inhibited anxiety-like behavior and nocifensive pain responses in animals that had received intraarticular injections with kaolin/carrageenan in 1 knee to induce arthritis (58). Additionally, anxiogenic effects of chronic pain have been demonstrated in rodents, and it was hypothesized that this phenomenon might be associated with changes in the opiodergic function of the amygdala (100). Neugebauer and colleagues proposed a hypothetical model in which the amygdala's role in facilitating pain perception is modulated by negative and positive emotions and so is directly influenced by the depressive state of a patient. In this model, negative emotions increase activity in the amygdala, while positive emotions deactivate the amygdala. The amygdala itself is linked to both facilitating and inhibitory pathways modulating pain; thus, an activation of the amygdala could both decrease and increase pain perception, dependent on which pathways within the amygdala are activated. The model differentiates between negative emotions that are associated with pain reduction, like fear and stress, which activate pain inhibitory pathways within the amygdala, and negative emotions that correlate with increased pain, like depression and anxiety disorders, which activate pain facilitating pathways within the amygdala. Positive emotions inhibit the pain facilitating pathway within the amygdala (99).

In a rodent study it was shown that chronic pain induces similar damage to the hippocampus as seen after stress, including changes in morphology and decreased brain-derived neurotrophic factor (BDNF) levels and neurogenesis, which might explain the development of depressive-like symptoms that are often observed in chronic pain patients (72), in cancer patients (101), and in patients with cardiovascular diseases (102). On a molecular level, similar decreased expression of BDNF and neurokinin 1 has been observed in the rodent hippocampus in models for pain and depression (103).

3.2.4. Ascending and descending pain tracks

Howard Fields and colleagues describe a pain modulating circuit including the amygdala, the periaqueductal gray, the dorsolateral pontine tegmentum (DLPT), and the rostral ventromedial medulla (RVM) (104). This circuit controls pain transmission through the dorsal horn of the spinal cord and the trigeminus through descending projections. The circuit is under bidirectional control by on- and off-cells. These cells are located in the RVM and extend their axons into the spinal cord where they induce or inhibit dorsal horn pain signals from nociceptive neurons. It is hypothesized that this circuit could also generate or enhance perceived pain intensity, which in turn might be a physiological mechanism through which mood can modulate pain perception (104-106).

3.2.5. Monoamines

Descending serotonin and noradrenaline pathways have been suggested as modulators of pain perception, i.e. they are associated with activating the "on" and "off" cells. The serotonergic neurons implemented in these descending pain tracks are in the raphe nuclei located in the RVM, while the noradrenergic neurons originate in the locus coeruleus part of the DLPT (106,107). Both tracts project over descending pathways into the spinal dorsal horn where they exhibit inhibitory influences. While under normal conditions these inhibitory influences are modest, in times of acute stress they can completely inhibit the perception of painful stimuli. In addition to these descending pathways, serotonergic and noradrenergic neurons project into various brain regions and are involved in the control of mood, movement, emotions, cognition, and several other processes. Dysfunction of these ascending projections may contribute to the classical symptoms of depression, and antidepressants facilitate these pathways. Therefore, the serotonergic and noradrenergic neurons of the raphe nuclei and the locus coeruleus, respectively, directly link pain and symptoms of depression, such that their dysregulation might provoke or enhance either or both (108).

3.2.6. Neurotrophic factors

The down-regulated expression of several neurotrophic factors has been implicated in the pathophysiology of depression and pain. The most prominent and widespread representative of this group is BDNF, a polypeptide that acts through the tyrosine kinase coupled receptor TrkB. BDNF plays a role in the brain, especially within the hippocampus, in neuronal differentiation (109) and survival (110), neurogenesis (111,112), synaptic plasticity (113-115), connectivity (116), maintenance of morphology (117), and learning and memory (118). In adults, it is important for maintenance of neuroplasticity that allows the brain to alter its structure in response to stimuli (119). Rodents that are subjected to stress exhibit depressive-like activity and have decreased levels of BDNF (120). Intrahippocampal administration of BDNF decreases the stress-induced depressive-like activity (121), and antidepressants reverse the stress-induced decrease in BDNF levels (120,122). Human postmortem studies revealed that BDNF expression is suppressed in the hippocampus and the ventral PFC of depressed untreated suicide patients (123,124). Compared with untreated subjects, patients receiving antidepressant treatment at the time of death show increased expression of BDNF in the hippocampus (125). While BDNF serum levels are reduced in depressed patients (126-128), treatment with antidepressants can normalize them (129-131). In patients with panic disorder, BDNF serum levels are significantly higher in responders to cognitive behavioral therapy (CBT) than in non-responders (132). Humans heterozygous for a BDNF mutation present smaller hippocampal volumes (133-135) and seem to be impaired when performing hippocampal-dependent memory functions (136,137). No consensus has been reached as to if this mutation predisposes for anxiety and depressive disorders in humans (138). Homozygous mice with an equivalent BDNF mutation show increased anxiety-related behaviors that cannot be normalized with an antidepressant (138).

Similar to observations in depressed patients, hippocampal BDNF expression is reduced in rodents exposed to stress and pain (73,103). Contrasting to the hippocampal down-regulation, BDNF expression appears to be up-regulated in the spinal dorsal horn in response to pain stimuli (73,139) and seems to drive spinal noradrenergic sprouting following nerve injury (140). Continuous BDNF release after nerve damage stimulates faster peripheral nerve regeneration and potentially reduces neuropathy in rats (141). Evidence from neuronal cell culture models points to a possible role of BDNF in "central sensitization", an experimental paradigm paralleling human neuropathic pain (142). Interestingly, pretreatment of rodents with the antidepressant imipramine before pain challenge prevents alterations of BDNF gene expression in both the hippocampus and the spinal dorsal horn, without providing significant behavioral analgesia. Pretreatment of the same animals with the analgesic indomethacine reverses BDNF up-regulation only in the spinal cord, not in the hippocampus, and reduces peripheral hyperalgesia. The authors concluded that neither analgesic nor antidepressant treatment alone can completely protect against the behavioral and molecular effects of persistent pain (143).

Other examples of neurotrophic factors with implications in the pathophysiology of both pain and depression include nerve growth factor (NGF) (144-149), neurotrophin-3 (NT-3) (121,150-152) and neurokinin-1 (NK-1) (73,153,154).

3.2.7. Psychological overlaps Catastrophizing in pain and depression

Catastrophizing (expecting the worst possible outcome) is a common phenomenon in both patients with depression and pain, and has negative implications for treatment outcomes. Patients that exhibit catastrophizing describe their situation as horrible and unbearable. Imaging studies in patients with fibromyalgia that exhibit catastrophizing of their pain symptoms revealed activation of brain areas involved in anticipation of pain (medial frontal cortex and cerebellum), attention to pain (dorsal ACC and dorsolateral PFC), emotional aspects of pain (claustrum) and motor control. These results support a role of catastrophizing in the perception of pain (155). In patients with lower back pain, catastrophizing is a predictor for higher long-term disability levels (156). Similarly, patients that catastrophize their pain expectations before knee replacement surgery experience greater postoperative pain (157). Generally, catastrophizing appears to be positively related to the severity of pain (158).

In elderly patients, a strong correlation between magnitude of depressive symptoms and catastrophizing has been found (159). In children that experienced physical traumas, the child's catastrophic appraisal of persistent vulnerability after the trauma strongly correlates with the experienced stress reaction (160). Similarly, children with recurrent abdominal pain develop more depressive symptoms the more they catastrophize the pain (161). Chronic pain patients' increased catastrophizing is linked to increased depression (162). Further support for the strong interactions between depression and pain was also found in patients with chronic pain, in whom catastrophizing of pain symptoms and levels of depressive symptoms are predictors for suicidal behavior (163). Greater pain catastrophizing has been associated with future depressive symptoms in pain patients (164), as well as in spouses of chronic pain patients (165). Learned helplessness

Learned helplessness is defined as a state in which the individual has learned that a condition is out of the individual's control and therefore no attempts are undertaken to change a given situation. Chronic pain patients and depressed patients often display signs of learned helplessness. In fibromyalgia patients, it has been demonstrated that learned helplessness mediates between pain and depressive symptoms (166). In chronic pain patients, the degree of helplessness is a predictor for the level of pain experienced (167).

Close association between the level of helplessness and depressive symptoms has been described in patients with scleroderma (168) or multiple sclerosis (169), but also in healthy volunteers (170). In a rodent model it was demonstrated that learned helplessness is associated with decreased neurogenesis in the hippocampus, an effect that is reversed by treatment with an antidepressant (171). End-organ sensitization

Irritable bowel syndrome (IBS) is an example for an end-organ sensitization observed in patients with depression in which the degree of pain experienced is influenced by catastrophizing (172). IBS is one of several central hypersensitivity pain disorders that are associated with depression (173,174); other examples are fibromyalgia (175), headache (176), and pelvic pain (177). A role for serotonin mechanisms in the pathophysiology of these conditions has been suggested, and successful treatment with antidepressants is described in the literature (178).


4.1. Theory of allostasis

Allostasis has been defined as "the ability to achieve stability through change" (12,179). Allostasis protects the body in response to internal and external stress through activation of the HPA axis, the autonomic nervous system, and the cardiovascular, metabolic and immune systems (12). An allostatic load accumulates when this system is chronically challenged (180). McEwen differentiates 4 mechanisms that lead to the accumulation of allostatic load: frequent stress, lack of adaptation to repeated stressful stimuli, inability to terminate an allostatic response after the stressful stimulus ceased, and inadequate response by some allostatic system that triggers compensatory increases in others (12). This model illustrates the importance of addressing all symptoms of a patient. Pain and depression are examples of comorbidities frequently diagnosed in the same patients. Besides common pathways in their pathogenesis, both disorders can lead to an accumulation of allostatic load, which in turn can trigger the manifestation of depression or pain syndromes. Successful treatment acknowledges the interdependence of both conditions and addresses the whole patient instead of isolated disease manifestations.

4.2. Optimization of treatment

4.2.1. Treating depression and pain

In the case of pain and depression comorbidity, it is common for patients to attribute their disease burden to either one or the other condition, and then seek help from respective specialists. As such, it is imperative that physicians carefully evaluate patients presenting with either pain or depression for symptoms of both disorders and tailor their treatment accordingly. Failure to address each comorbidity adversely impacts outcome. For example, the presence of pain predicts a longer time to remission in patients with MDD (181). Similarly, improvement of associated painful symptoms in patients with MDD significantly (p-value less than .001) increased the chances of remission of depression (182). Multiple treatment approaches are available. Psychotherapy

Several psychotherapeutic approaches are being explored to treat patients with comorbid depression and pain. To date randomized controlled trials have supported the efficacy of CBT in treating both MDD (183,184) and pain disorders (185,186). CBT for pain or CBT for depression may be part of a comprehensive treatment plan for the patient with comorbid symptoms or disorders.

For the treatment of MDD, the combination of pharmacotherapy with CBT is optimal in some patient populations, such as chronic depression (187-189) and adolescents (190).

Similarly, current treatment recommendations emphasize the value of CBT in the treatment of chronic pain conditions in combination with other treatment strategies (186,191). Several studies also provide evidence for the efficacy of CBT monotherapy for patients with chronic pain (192,193) and CBT has been recommended for the treatment of comorbid psychiatric symptoms in headache patients (194). A meta-analysis of psychotherapeutic approaches for chronic lower back pain showed improvements of pain and depression in response to CBT and self-regulatory treatment (192). Similarly, a study in highly disabled chronic pain patients confirmed efficacy of CBT for improvement of their depression and pain symptoms (195). Interdisciplinary CBT has been proven to be beneficial for adolescent pain patients and their families (196). Exercise

Beneficial effects of physical exercise have been described for patients with both depression and pain disorders. In women with fibromyalgia, group exercise improves both pain and depressive symptoms (197). Within this patient group, muscle strengthening and aerobic exercise programs seem to be equally beneficial (198); aquatic exercise improves pain symptoms to a comparable extent as aerobic exercise, but produces superior results with regard to depressive symptoms (199). Similarly, aerobic exercise improves depression and pain symptoms in patients with rheumatoid arthritis (200) and ankylosing spondylitis (201). Pharmacotherapy options

As described above, serotonin and noradrenalin are involved in the pathophysiologies of both pain and depression. Tricyclic antidepressants (TCA) and the newer serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine (202) and milnacipran (203) have shown efficacy in the treatment of both conditions, an effect that might be due partially to their facilitating influence on both serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) seem to be less efficient in the combined treatment of pain (particularly neuropathic pain) and depression (202).

Significant empirical evidence is available for the efficacy of SNRIs in the treatment of pain disorders, pain symptoms and depression (204,205). Data from placebo-controlled trials suggest that SNRIs have direct analgesic effects independent of their antidepressant effects (206). Improvement of depression (207-212) and pain symptoms (182,208,209,213,214,215,216) in response to SNRIs has been observed in patients with MDD overall, and in subgroups including postmenopausal women (217), elderly patients (218,219), elderly patients with arthritis (220), and patients with melancholic depression (221). Patients with pain disorders that showed clinical improvement in response to treatment with SNRIs include women with fibromyalgia (222,223,203,224), patients with MDD and multisomatoform disorder (225), and patients with trigeminal neuralgia (226). In patients with atypical facial pain, SNRIs seem to be only modestly effective for pain relief (227). Limited information is available regarding the efficacy and safety of SNRIs in pediatric patients. Case reports of depressed children and adolescents with pain describe improvement of both pain and depressive symptoms in these patients in response to SNRIs (228,229).

Mixed results regarding their efficacy for the treatment of pain and depression are available for SSRIs. A study in patients with IBS found no improvement over placebo for pain and depressive symptoms in response to SSRIs (230). On the other hand, some studies showed efficacy of SSRIs in improving pain symptoms in depressive patients. Examples are a study in adult patients with IBS (231) and a trial in children and adolescents with abdominal pain (232).

Extensive data in the literature support the efficacy of TCAs for the alleviation of pain symptoms in chronic pain patients; examples include patients with postherpetic neuralgia (233), neuropathic pain after spinal cord injury (234), fibromyalgia (235), diabetic peripheral neuropathic pain (236), somatoform pain disorder in the orofacial region (237), chronic headaches (238), especially tension-type headaches (239), and central post-stroke pain (240). Limiting the use of TCAs in the treatment of pain syndromes is the relatively high frequency of treatment emergent adverse events (compared to other antidepressants) (241,242), and potential lethality after intentional and accidental overdoses with TCAs (243,244).

Only 1 open-label observational study examined the efficacy of a tetracyclic antidepressant in treating depression and pain comorbidity; it showed improvement of depression and pain symptoms in response to treatment with a tetracyclic antidepressant (245).


In summary, the pathophysiologies of depression and pain overlap in many aspects. Empirical evidence illustrates the importance of shared brain structures and common neurocircuitries and neurochemicals in the development of both disorders. The presence of both pain and depressive symptoms worsens the overall outcome of affected patients with longer treatment durations, more severe symptoms, and lesser likelihood of remission. One explanation for the observed interactions of pain and depression is based on the concept of allostasis, in which the accumulation of allostatic load is hypothesized to be responsible for greater vulnerability caused by external and internal stressors - which can include pain and depression. Therefore, it is essential for treatment success to recognize the comorbidity with pain and depression in affected patients and to treat both disorders. Examples of therapeutic options that target both disorders include cognitive behavioral therapy, exercise, and pharmacotherapy. Future research is needed to further clarify the multiple interactions of pain and depressive disorders, including effects on neurotrophins, which will aid in the development of more effective treatment strategies addressing all symptoms with which a patient might present.


This work was sponsored by Lilly USA, LLC. Drs. Robinson, Edwards and Iyengar are full-time employees of Lilly USA, LLC. Lilly USA, LLC, contracted the technical writing of this manuscript with i3 Statprobe, a division of Ingenix, which is a subsidiary of UnitedHealth Group. The authors thank Dr. Alexandra Heinloth for assistance with the preparation of the manuscript.


1. Matthew Bair, Rebecca Robinson, Wayne Katon, Kurt Kroenke: Depression and pain comorbidity: a literature review. Arch Intern Med 163, 2433-45 (2003)

2. Marc Gameroff, Mark Olfson: Major depressive disorder, somatic pain, and health care costs in an urban primary care practice. J Clin Psychiatry 67, 1232-9 (2006)

3. Koen Demyttenaere, Anke Bonnewyn, Ronny Bruffaerts, Terry Brugha, Ron De Graaf, and Jordi Alonso: Comorbid painful physical symptoms and depression: prevalence, work loss, and help seeking. J Affect Disord 92, 185-93 (2006)

4. Sandra Geerlings, Jos Twisk, Aartjan Beekman, Dorly Deeg, and Willem van Tilburg: Longitudinal relationship between pain and depression in older adults: sex, age and physical disability. Soc Psychiatry Psychiatr Epidemiol 37, 23-30 (2002)

5. Martin Keller: Past, present, and future directions for defining optimal treatment outcome in depression: remission and beyond. JAMA 289, 3152-60 (2003)

6. Patrik Sobocki, Mattias Ekman, Hans Agren, Bo Runeson, and Bengt Jonsson: The mission is remission: health economic consequences of achieving full remission with antidepressant treatment for depression. Int J Clin Pract 60, 791-8 (2006)

7. Lewis Judd, Hagop Akiskal, Jack Maser, Pamela Zeller, Jean Endicott, William Coryell, Martin Paulus, Jelena Kunovac, Andrew Leon, Timothy Mueller, John Rice, and Martin Keller: Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord 50, 97-108 (1998)

8. Noel Kennedy and Kevin Foy: The impact of residual symptoms on outcome of major depression. Curr Psychiatry Rep 7, 441-6 (2005)

9. Joyce Bromberger, Katherine Wisner, and Barbara Hanusa: Marital support and remission of treated depression. A prospective pilot study of mothers of infants and toddlers. J Nerv Ment Dis 182, 40-4 (1994)

10. Myrna Weissman, Daniel Pilowsky, Priya Wickramaratne, Ardesheer Talati, Stephen Wisniewski, Maurizio Fava, Carroll Hughes, Judy Garber, Erin Malloy, Cheryl King, Gabrielle Cerda, Bella Sood, Jonathan Alpert, Madhukar Trivedi, and John Rush: Remissions in maternal depression and child psychopathology: a STAR*D-child report. JAMA 295, 1389-98 (2006)

11. Sarah Munce, Stephen Stansfeld, Emma Blackmore, and Donna Stewart: The Role of Depression and Chronic Pain Conditions in Absenteeism: Results From a National Epidemiologic Survey. J Occup Environ Med 49, 1206-11 (2007)

12. Bruce McEwen: Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 840, 33-44 (1998)

13. Avshalom Caspi, Karen Sugden, Terrie Moffitt, Alan Taylor, Ian Craig, HonaLee Harrington, Joseph McClay, Jonathan Mill, Judy Martin, Aantony Braithwaite, and Richie Poulton: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386-9 (2003)

14. Valentina Moskvina, Anne Farmer, Victoria Swainson, Joanna O'Leary, Cerise Gunasinghe, Mike Owen, Nick Craddock, Peter McGuffin, and Ania Korszun: Interrelationship of childhood trauma, neuroticism, and depressive phenotype. Depress Anxiety 24, 163-8 (2007)

15. Michelle Rotermann: Marital breakdown and subsequent depression. Health Rep 18, 33-44 (2007)

16. John McBeth, Gary Macfarlane, and Alan Silman: Does chronic pain predict future psychological distress? Pain 96, 239-45 (2002)

17. Maud Frot and Francois Mauguiere: Dual representation of pain in the operculo-insular cortex in humans. Brain 126, 438-50 (2003)

18. Casey Kenneth and Tran Tri: Cortical mechanisms mediating acute and chronic pain in humans. In: Handbook of Clin Neurology. Eds: Cervero F., Jensen T. S., Elsevier, Boston, Massachusetts. (2006)

19. Mathias Schreckenberger, Thomas Siessmeier, Anne-Odette Viertmann, Christian Landvogt, Hans Buchholz, Roman Rolke, Rolf-Detlef Treede, Peter Bartenstein, and Frank Birklein: The unpleasantness of tonic pain is encoded by the insular cortex. Neurology 64, 1175-83 (2005)

20. Marwan Baliki, Dante Chialvo, Paul Geha, Robert Levy, Norman Harden, Todd Parrish, and Vania Apkarian: Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci 26, 12165-73 (2006)

21. Frank Seifert and Christian Maihofner: Representation of cold allodynia in the human brain--a functional MRI study. Neuroimage 35, 1168-80 (2007)

22. Marie-Claire Albanese, Emma Duerden, Pierre Rainville, and Gary Duncan: Memory traces of pain in human cortex. J Neurosci 27, 4612-20 (2007)

23. Francoise Biver, David Wikler, Francoise Lotstra, Philippe Damhaut, Serge Goldman, and Julian Mendlewicz: Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 171, 444-8 (1997)

24. Nemeroff Charles: Part IV: Mood Disorders. In: Neurobiology of Mental Illness, 2nd edition. Eds: Charney D. S., Nestler E. J., Oxford University Press, New York (2004)

25. Saptarshi Mondal, Vijay Sharma, Sanjay Das, Udita Goswami, and Ankur Gandhi: Neuro-cognitive functions in patients of major depression. Indian J Physiol Pharmacol 51, 69-75 (2007)

26. Wayne Drevets, Tom Videen, Joseph Price, Sheldon Preskorn, Thomas Carmichael, and Marcus Raichle: A functional anatomical study of unipolar depression. J Neurosci 12, 3628-41 (1992)

27. Wayne Drevets, Joseph Price, Joseph Simpson Jr., Richard Todd, Theodore Reich, Michael Vannier, and Marcus Raichle: Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824-7 (1997)

28. Thomas Frodl, Johanna Scheuerecker, Jessica Albrecht, Anna Kleemann, Steffanie Muller-Schunk, Nikolaos Koutsouleris, Hans-Juergen Moller, Hartmut Bruckmann, Martin Wiesmann, and Eva Meisenzahl: Neuronal correlates of emotional processing in patients with major depression. World J Biol Psychiatry, 1-7 (2007)

29. Simone Grimm, Johannes Beck, Daniel Schuepbach, Daniel Hell, Peter Boesiger, Felix Bermpohl, Ludwig Niehaus, Heinz Boeker, and Georg Northoff: Imbalance between Left and Right Dorsolateral Prefrontal Cortex in Major Depression Is Linked to Negative Emotional Judgment: An fMRI Study in Severe Major Depressive Disorder. Biol Psychiatry 63, 369-76 (2008)

30. Dost Oenguer, Wayne Drevets, and Joseph Price: Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95, 13290-5 (1998)

31. Grazyna Rajkowska, Jose Miguel-Hidalgo, Jinrong Wei, Ginny Dilley, Stephen Pittman, Herbert Meltzer, James Overholser, Bryan Roth, and Craig Stockmeier: Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45, 1085-98 (1999)

32. Victor Vostrikov, Natalya Uranova, and Diana Orlovskaya: Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. Schizophr Res 94, 273-80 (2007)

33. Melanie Leussis and Susan Andersen: Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model. Synapse 62, 22-30 (2008)

34. Vania Apkarian, Yamaya Sosa, Sreepadma Sonty, Robert Levy, Norman Harden, Todd Parrish, and Darren Gitelman: Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 24, 10410-5 (2004)

35. Tim Salomons, Tom Johnstone, Misha-Miroslav Backonja, Alexander Shackman, and Richard Davidson: Individual differences in the effects of perceived controllability on pain perception: critical role of the prefrontal cortex. J Cogn Neurosci 19, 993-1003 (2007)

36. Katja Wiech, Raffael Kalisch, Nikolaus Weiskopf, Burkhard Pleger, Klaas Stephan, and Raymond Dolan: Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J Neurosci 26, 11501-9 (2006)

37. Yoshitetsu Oshiro, Alexandre Quevedo, John McHaffie, Robert Kraft, and Robert Coghill: Brain mechanisms supporting spatial discrimination of pain. J Neurosci 27, 3388-94 (2007)

38. George Alexopoulos, Faith Gunning-Dixon, Vassilios Latoussakis, Dora Kanellopoulos, and Christopher Murphy: Anterior cingulate dysfunction in geriatric depression. Int J Geriatr Psychiatry 23, 347-55 (2008)

39. Chistoph Mulert, Georg Juckel, Michael Brunnmeier, Gregor Leicht, Roland Mergl, Hans-Juergen Moeller, Ulrich Hegerl, and Oliver Pogarell: Rostral anterior cingulate cortex activity in the theta band predicts response to antidepressive medication. Clin EEG Neurosci 38, 78-81 (2007)

40. Yanqing Tang, Fei Wang, Guangrong Xie, Jun Liu, Lehua Li, Linyan Su, Ying Liu, Xian Hu, Zhong He, and Hilary Blumberg: Reduced ventral anterior cingulate and amygdala volumes in medication-naive females with major depressive disorder: A voxel-based morphometric magnetic resonance imaging study. Psychiatry Res 156, 83-6 (2007)

41. Jakub Konarski, Sidney Kennedy, Roger McIntyre, Shahryar Rafi-Tari, Joanna Soczynska, and Helen Mayberg: Relationship between regional brain metabolism, illness severity and age in depressed subjects. Psychiatry Res 155, 203-10 (2007)

42. Christoph Mulert, Georg Juckel, Michael Brunnmeier, Susanne Karch, Gregor Leicht, Roland Mergl, Hans-Juergen Moller, Ulrich Hegerl, and Oliver Pogarell: Prediction of treatment response in major depression: integration of concepts. J Affect Disord 98, 215-25 (2007)

43. Stephanie Bissiere, Kevin McAllister, Hans-Rudolf Olpe, and John Cryan: The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat. Behav Brain Res 175, 195-9 (2006)

44. Frank Seifert, Isabella Jungfer, Martin Schmelz, and Christian Maihofner: Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: A functional MRI study. Hum Brain Mapp (2007)

45. Tobias Schmidt-Wilcke, Susanne Ganssbauer, Irene Neuner, Ulrich Bogdahn, and Arne May: Subtle grey matter changes between migraine patients and healthy controls. Cephalalgia 28, 1-4 (2007)

46. Tetsumi Honda, Toshihiko Maruta, and Kumiko Takahashi: Brain perfusion abnormality in patients with chronic pain. Keio J Med 56, 48-52 (2007)

47. India Morrison and Paul Downing: Organization of felt and seen pain responses in anterior cingulate cortex. Neuroimage 37, 642-51 (2007)

48. Melissa Munn, Jim Alexopoulos, Tomoyuki Nishino, Casey Babb, Lisa Flake, Tisha Singer, Tilak Ratnanather, Hongyan Huang, Richard Todd, Michael Miller, and Kelly Botteron: Amygdala volume analysis in female twins with major depression. Biol Psychiatry 62, 415-22 (2007)

49. Isabelle Rosso, Christina Cintron, Ronald Steingard, Perry Renshaw, Ashley Young, and Deborah Yurgelun-Todd: Amygdala and hippocampus volumes in pediatric major depression. Biol Psychiatry 57, 21-6 (2005)

50. Claudia Lange and Eva Irle: Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med 34, 1059-64 (2004)

51. Serap Monkul, John Hatch, Mark Nicoletti, Stan Spence, Paolo Brambilla, Acioly Lacerda, Roberto Sassi, Alan Mallinger, Matcheri Keshavan, and Jair Soares: Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol Psychiatry 12, 360-6 (2007)

52. David Diamond, Adam Campbell, Collin Park, and Rose-Marie Vouimba: Preclinical research on stress, memory, and the brain in the development of pharmacotherapy for depression. Eur Neuropsychopharmacol 14 Suppl 5, S491-S495 (2004)

53. Paul Geha, Marwan Baliki, Dante Chialvo, Norman Harden, Judith Paice, and Vania Apkarian: Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 128, 88-100 (2007)
PMid:17067740    PMCid:1850186

54. Bhavna Kulkarni, Deborah Bentley, Rebecca Elliott, Peter Julyan, Erich Boger, Anthony Watson, Yvonne Boyle, Wael El-Deredy, and Anthony Jones: Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum 56, 1345-54 (2007)

55. Yarimar Carrasquillo and Robert Gereau: Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception. J Neurosci 27, 1543-51 (2007)

56. Olivier Yu, Nathalie Parizel, Laure Pain, Blandine Guignard, Bernard Eclancher, Yves Mauss, and Daniel Grucker: Texture analysis of brain MRI evidences the amygdala activation by nociceptive stimuli under deep anesthesia in the propofol-formalin rat model. Magn Reson Imaging 25, 144-6 (2007)

57. Gerusa Dalmolin, Channa Silva, Nadia Belle, Maribel Rubin, Carlos Mello, Joao Calixto, and Juliano Ferreira: Bradykinin into amygdala induces thermal hyperalgesia in rats. Neuropeptides 41, 263-70 (2007)

58. Guangchen Ji, Yu Fu, Katherine Ruppert, and Volker Neugebauer: Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. Mol Pain 3, 13 (2007)
PMid:17550594    PMCid:1891279

59. Lauren Jacobson and Robert Sapolsky: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12, 118-34 (1991)

60. Patrick Tierney, Eric Degenetais, Anee-Marie Thierry, Jacques Glowinski, and Yves Gioanni: Influence of the hippocampus on interneurons of the rat prefrontal cortex. Eur J Neurosci 20, 514-24 (2004)

61. Andrew Morse and Carrolee Barlow: Unraveling the complexities of neurogenesis to guide development of CNS therapeutics. Drug Discovery Today: Therapeutic Strategies 3, 495-501 (2006)

62. Davis Kenneth: Dementia. In: Neurobiology of Mental Illness, 2nd edition. Eds: Charney D. S., Nestler E. J., Oxford University Press, New York (2004)

63. Stephanie Campbell, Michael Marriott, Claude Nahmias, and Glenda MacQueen: Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161, 598-607 (2004)

64. Jun Xia, Jun Chen, Yicheng Zhou, Jingfeng Zhang, Bo Yang, Liming Xia, and Chengyuan Wang: Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technolog Med Sci 24, 500-2, 506 (2004)

65. Frank Macmaster, Yousha Mirza, Philip Szeszko, Lauren Kmiecik, Philip Easter, Preeya Taormina, Michelle Lynch, Michelle Rose, Gregory Moore, and David Rosenberg: Amygdala and Hippocampal Volumes in Familial Early Onset Major Depressive Disorder. Biol Psychiatry (2007)

66. Douglas Bremner, Meena Narayan, Eric Anderson, Lawrence Staib, Helen Miller, and Dennis Charney: Hippocampal volume reduction in major depression. Am J Psychiatry 157, 115-8 (2000)

67. Yvette Sheline, Po Wang, Mokhtar Gado, Jjohn Csernansky, and Michael Vannier: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93, 3908-13 (1996)

68. Yvette Sheline, Milan Sanghavi, Mark Mintun, and Mokhtar Gado: Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19, 5034-43 (1999)

69. Yvette Sheline, Mokhtar Gado, and Helena Kraemer: Untreated depression and hippocampal volume loss. Am J Psychiatry 160, 1516-8 (2003)

70. Ulrike Bingel, Markus Quante, Rene Knab, Burkhart Bromm, Cornelius Weiller, and Christian Buchel: Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 99, 313-21 (2002)

71. Petra Schweinhardt, Michael Lee, and Irene Tracey: Imaging pain in patients: is it meaningful? Curr Opin Neurol 19, 392-400 (2006)

72. Vanja Duric and Kenneth McCarson: Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain 7, 544-55 (2006)

73. Vanja Duric and Kenneth McCarson: Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain. Mol Pain 3, 32 (2007)
PMid:17974009    PMCid:2174921

74. She-Wei Guo, Ming-Gang Liu, Ya-Li Long, Li-Ying Ren, Zhuo-Min Lu, Hou-You Yu, Jun-Feng Hou, Hua Li, Cui-Ying Gao, Xiu-Yu Cui, Yang-Yuan An, Junfa Li, Lan-Feng Zhao, and Jun Chen: Region- or state-related differences in expression and activation of extracellular signal-regulated kinases (ERKs) in naive and pain-experiencing rats. BMC Neurosci 8, 53 (2007)
PMid:17650295    PMCid:1949833

75. H. S. Donohue, Paul Gabbott, Heather Davies, Jose Rodriguez, M. Isabel Cordero, Carmen Sandi, Nikolay Medvedev, Victor Popov, F. M. Colyer, Chris Peddie, and Michael Stewart: Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 140, 597-606 (2006

76. Gordon Blackburn-Munro and Ruth Blackburn-Munro: Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 13, 1009-23 (2001)

77. Eric Nestler, Michel Barrot, Ralph DiLeone, Amelia Eisch, Stephen Gold, and Lisa Monteggia: Neurobiology of depression. Neuron 34, 13-25 (2002)

78. Innis Robert: Part II: Methods of Clinical Neurobiological Research. In: Neurobiology of Mental Illness. Eds: Charney D. S., Nestler E. J., Oxford University Press, New York (2007)

79. Hubertus Himmerich, Petra Zimmermann, Marcus Ising, Stefan Kloiber, Susanne Lucae, Heike Kunzel, Elisabeth Binder, Florian Holsboer, and Manfred Uhr: Changes in the hypothalamic-pituitary-adrenal axis and leptin levels during antidepressant treatment. Neuropsychobiology 55, 28-35 (2007)

80. Despina Tata, Veronica Marciano, and Brenda Anderson: Synapse loss from chronically elevated glucocorticoids: relationship to neuropil volume and cell number in hippocampal area CA3. J Comp Neurol 498, 363-74 (2006)

81. John McBeth, Alan Silman, A Gupta, Yee Chiu, David Ray, Richard Morriss, Chris Dickens, Yvonne King, and Gary Macfarlane: Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study. Arthritis Rheum 56, 360-71 (2007)
Can't connect to PubMed

82. Guangchen Ji and Volker Neugebauer: Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. J Neurophysiol 97, 3893-904 (2007)
Can't connect to PubMed

83. Sota Omoigui: The biochemical origin of pain: The origin of all pain is inflammation and the inflammatory response. Part 2 of 3 - Inflammatory profile of pain syndromes. Med Hypotheses 69, 1169-78 (2007)
Can't connect to PubMed

84. Charles Raison, Lucile Capuron, and Andrew Miller: Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27, 24-31 (2006)
Can't connect to PubMed

85. Naomi Simon, Kate McNamara, Candice Chow, Richard Maser, George Papakostas, Mark Pollack, Andrew Nierenberg, Maurizio Fava, and Kwok-Kin Wong: A detailed examination of cytokine abnormalities in Major Depressive Disorder. Eur Neuropsychopharmacol (2008)

86. Derek Humphreys, Liana Schlesinger, Marcelo Lopez, and Veronica Araya: Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders. Endocrine 30, 371-6 (2006)
Can't connect to PubMed

87. Hubertus Himmerich, Elisabeth Binder, Heike Kunzel, Andreas Schuld, Susanne Lucae, Manfred Uhr, Thomas Pollmacher, Florian Holsboer, and Marcus Ising: Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis. Biol Psychiatry 60, 882-8 (2006)
Can't connect to PubMed

88. Triin Eller, Veiko Vasar, Jakov Shlik, and Eduard Maron: Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 32, 445-50 (2008)
Can't connect to PubMed

89. Jean-Michel Aubry, Nicola Gervasoni, Christian Osiek, Guillaume Perret, Michel Rossier, Gilles Bertschy, and Guido Bondolfi: The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients. J Psychiatr Res 41, 290-4 (2007)
Can't connect to PubMed

90. Yongki Kim, Sangyoup Lee, S. H. Kim, Sang Hee Shim, Sang Won Han, Sang Ho Choi, and Benjamin Lee: Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuropsychopharmacol Biol Psychiatry 32, 356-61 (2008)
Can't connect to PubMed

91. Gretchen Summer, Edgar Romero-Sandoval, Oliver Bogen, Olayinka Dina, Sachia Khasar, and Jon Levine: Proinflammatory cytokines mediating burn-injury pain. Pain 135, 98-107 (2008)
Can't connect to PubMed

92. Wei Guo, Hu Wang, Mineo Watanabe, Kohei Shimizu, Shiping Zou, Stacey LaGraize, Feng Wei, Ronald Dubner, and Ke Ren: Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27, 6006-18 (2007)
Can't connect to PubMed

93. Nurcan Uceyler, Tatiana Eberle, Roman Rolke, Frank Birklein, and Claudia Sommer: Differential expression patterns of cytokines in complex regional pain syndrome. Pain 132, 195-205 (2007)
Can't connect to PubMed

94. Nurcan Uceyler, Jan Rogausch, Klaus Toyka, and Claudia Sommer: Differential expression of cytokines in painful and painless neuropathies. Neurology 69, 42-9 (2007)
Can't connect to PubMed

95. Naomi Eisenberger, Matthew Lieberman, and Kipling Williams: Does rejection hurt? An FMRI study of social exclusion. Science 302, 290-2 (2003)
Can't connect to PubMed

96. Thorsten Giesecke, Richard Gracely, David Williams, Michael Geisser, Frank Petzke, and Daniel Clauw: The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. Arthritis Rheum 52, 1577-84 (2005)
Can't connect to PubMed

97. Karl-Juergen Baer, Gerd Wagner, Mandy Koschke, Silke Boettger, Michael Boettger, Ralf Schlosser, and Heinrich Sauer: Increased Prefrontal Activation During Pain Perception in Major Depression. Biol Psychiatry 62, 1281-7 (2007)
Can't connect to PubMed

98. David Avery, Paul Holtzheimer III, Walid Fawaz, Joan Russo, John Neumaier, David Dunner, David Haynor, Keith Claypoole, Chandra Wajdik, and Peter Roy-Byrne: Transcranial magnetic stimulation reduces pain in patients with major depression: a sham-controlled study. J Nerv Ment Dis 195, 378-81 (2007)

99. Volker Neugebauer, Weidong Li, Gary Bird, and Jeong Han: The amygdala and persistent pain. Neuroscientist 10, 221-34 (2004)
Can't connect to PubMed

100. Minoru Narita, Chihiro Kaneko, Kan Miyoshi, Yasuyuki Nagumo, Naoko Kuzumaki, Mayumi Nakajima, Kana Nanjo, Kiyomi Matsuzawa, Mitsuaki Yamazaki, and Tsutomu Suzuki: Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology 31, 739-50 (2006)
Can't connect to PubMed

101. Ulrich Wedding, Anja Koch, Bernd Rohrig, Ludger Pientka, Heinrich Sauer, Klaus Hoffken, and Iris Maurer: Depression and functional impairment independently contribute to decreased quality of life in cancer patients prior to chemotherapy. Acta Oncol 47, 56-62 (2008)
Can't connect to PubMed

102. Viola Vaccarino, Delia Johnson, David Sheps, Steven Reis, Sheryl Kelsey, Vera Bittner, Thomas Rutledge, Leslee Shaw, George Sopko, and Noel Bairey Merz: Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol 50, 2044-50 (2007)
Can't connect to PubMed

103. Vanja Duric and Kenneth McCarson: Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience 133, 999-1006 (2005)
Can't connect to PubMed

104. Howard Fields: Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 122, 245-53 (2000)
Can't connect to PubMed

105. Howard Fields: State-dependent opioid control of pain. Nat Rev Neurosci 5, 565-75 (2004)
Can't connect to PubMed

106. Howard Fields, Mary Heinricher, and Peggy Mason: Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14, 219-45 (1991)
Can't connect to PubMed

107. Frank Bymaster, Thomas Lee, Mary Knadler, Michael Detke, and Smriti Iyengar: The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des 11, 1475-93 (2005)
Can't connect to PubMed

108. Stephen Stahl and Mike Briley: Understanding pain in depression. Hum Psychopharmacol 19 Suppl 1, S9-S13 (2004)
Can't connect to PubMed

109. Fernando Aguado, Maria Carmona, Esther Pozas, Agustin Aguilo, Francisco Martinez-Guijarro, Soledad Alcantara, Victor Borrell, Rrafael Yuste, Carlos Ibanez, and Eduardo Soriano: BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Development 130, 1267-80 (2003)
Can't connect to PubMed

110. Nadine Johnson-Farley, Khushboo Patel, Deborah Kim, and Daniel Cowen: Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures. Brain Res 1154, 40-9 (2007)
Can't connect to PubMed

111. Jaewon Lee, Wenzhen Duan, and Mark Mattson: Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82, 1367-75 (2002)
Can't connect to PubMed

112. Mikko Sairanen, Gguilherme Lucas, Patrik Ernfors, Maija Castren, and Eero Castren: Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25, 1089-94 (2005)
Can't connect to PubMed

113. Steve Danzer, Kristy Crooks, Donald Lo, and James McNamara: Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22, 9754-63 (2002)

114. Alexander Figurov, Lucas Pozzo-Miller, Petur Olafsson, Ti Wang, and Bai Lu: Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706-9 (1996)
Can't connect to PubMed

115. Lucas Pozzo-Miller, Wolfram Gottschalk, Li Zhang, Kathryn McDermott, Jing Du, Raj Gopalakrishnan, Chikara Oho, Zu-Hang Sheng, and Bai Lu: Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19, 4972-83 (1999)

116. Igor Branchi, Nadia Francia, and Enrico Alleva: Epigenetic control of neurobehavioural plasticity: the role of neurotrophins. Behav Pharmacol 15, 353-62 (2004)
Can't connect to PubMed

117. Jessica Gorski, Steven Zeiler, Susan Tamowski, and Kevin Jones: Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 23, 6856-65 (2003)

118. Hong Kim, Sang-Hak Lee, Sung-Soo Kim, Jae-Hyun Yoo, and Chang-Ju Kim: The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups. Int J Dev Neurosci 25, 243-9 (2007)
Can't connect to PubMed

119. Kimberley McAllister, Lawrence Katz, and Donald Lo: Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22, 295-318 (1999)
Can't connect to PubMed

120. Ronald Duman and Lisa Monteggia: A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59, 1116-27 (2006)
Can't connect to PubMed

121. Yukihiko Shirayama, Andrew Chen, Shin Nakagawa, David Russell, and Ronald Duman: Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22, 3251-61 (2002)

122. Masashi Nibuya, Shigeru Morinobu, and Ronald Duman: Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15, 7539-47 (1995)

123. Yogesh Dwivedi, Hooriyah Rizavi, Robert Conley, Rosalinda Roberts, Carol Tamminga, and Ghanshyam Pandey: Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60, 804-15 (2003)
Can't connect to PubMed

124. Felicien Karege, Genevieve Vaudan, Michele Schwald, Nader Perroud, and Romano La Harpe: Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136, 29-37 (2005)
Can't connect to PubMed

125. Biao Chen, Dar Dowlatshahi, Glenda MacQueen, Jun-Feng Wang, and Trevor Young: Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50, 260-5 (2001)
Can't connect to PubMed

126. Felicien Karege, Guillaume Perret, Guido Bondolfi, Michele Schwald, Gilles Bertschy, and Jean-Michel Aubry: Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109, 143-8 (2002)
Can't connect to PubMed

127. Felicien Karege, Guido Bondolfi, Nicola Gervasoni, Michele Schwald, Jean-Michele Aubry, and Gilles Bertschy: Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 57, 1068-72 (2005)
Can't connect to PubMed

128. Eiji Shimizu, Kenji Hashimoto, Naoe Okamura, Kaori Koike, Naoya Komatsu, Chikara Kumakiri, Michiko Nakazato, Hiroyuki Watanabe, Naoyuki Shinoda, Sin-ichi Okada, and Masaomi Iyo: Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54, 70-5 (2003)
Can't connect to PubMed

129. Cigdem Aydemir, Esra Yalcin, Sabahat Aksaray, Cebrail Kisa, Sema Yildirim, Tayfun Uzbay, and Erol Goka: Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 30, 1256-60 (2006)
Can't connect to PubMed

130. Nicola Gervasoni, Jean-Michel Aubry, Guido Bondolfi, Christian Osiek, Michele Schwald, Gilles Bertschy, and Felicien Karege: Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode. Neuropsychobiology 51, 234-8 (2005)
Can't connect to PubMed

131. Ali Gonul, Fisun Akdeniz, Fatma Taneli, Ozlem Donat, Cagdas Eker, and Simavi Vahip: Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 255, 381-6 (2005)
Can't connect to PubMed

132. Keisuke Kobayashi, Eiji Shimizu, Kenji Hashimoto, Mitsumori Mitsumori, Kaori Koike, Naoe Okamura, Hiroki Koizumi, Shintaro Ohgake, Daisuke Matsuzawa, Lin Zhang, Michiko Nakazato, and Masaomi Iyo: Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: as a biological predictor of response to group cognitive behavioral therapy. Prog Neuropsychopharmacol Biol Psychiatry 29, 658-63 (2005)
Can't connect to PubMed

133. Joshua Bueller, Macksood Aftab, Srijan Sen, Diana Gomez-Hassan, Margit Burmeister, and Jon-Kar Zubieta: BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59, 812-5 (2006)
Can't connect to PubMed

134. Lukas Pezawas, Beth Verchinski, Venkata Mattay, Joseph Callicott, Bhaskar Kolachana, Richard Straub, Michael Egan, Andreas Meyer-Lindenberg, and Daniel Weinberger: The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24, 10099-102 (2004)
Can't connect to PubMed

135. Philip Szeszko, Robert Lipsky, Claudia Mentschel, Delbert Robinson, Handan Gunduz-Bruce, Serge Sevy, Manzar Ashtari, Barbara Napolitano, Robert Bilder, John Kane, David Goldman, and Anil Malhotra: Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 10, 631-6 (2005)
Can't connect to PubMed

136. Michael Egan, Masami Kojima, Joseph Callicott, Terry Goldberg, Bhaskar Kolachana, Alessandro Bertolino, Eeugene Zaitsev, Bert Gold, David Goldman, Michael Dean, Bai Lu, and Daniel Weinberger: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257-69 (2003)
Can't connect to PubMed

137. Ahmad Hariri, Terry Goldberg, Venkata Mattay, Bhaskar Kolachana, Joseph Callicott, Michael Egan, and Daniel Weinberger: Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23, 6690-4 (2003)

138. Zhe-Yu Chen, Deqiang Jing, Kevin Bath, Aalessandra Ieraci, Tanvir Khan, Chia-Jen Siao, Daniel Herrera, Miklos Toth, Chingwen Yang, Bruce McEwen, Barbara Hempstead, and Francis Lee: Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140-3 (2006)
Can't connect to PubMed

139. Li Li, Cory Xian, Jin-Hua Zhong, and Xin-Fu Zhou: Upregulation of brain-derived neurotrophic factor in the sensory pathway by selective motor nerve injury in adult rats. Neurotox Res 9, 269-83 (2006)

140. Ken-ichiro Hayashida, Bridgette Clayton, James Johnson, and James Eisenach: Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats. Pain 136, 348-55 (2008)
Can't connect to PubMed

141. EstherVogelin, John Baker, J. Gates, Vivek Dixit, Mihai Constantinescu, and Neil Jones: Effects of local continuous release of brain derived neurotrophic factor (BDNF) on peripheral nerve regeneration in a rat model. Exp Neurol 199, 348-53 (2006)
Can't connect to PubMed

142. Van Lu, Klaus Ballanyi, William Colmers, and Peter Smith: Neuron type-specific effects of brain-derived neurotrophic factor in rat superficial dorsal horn and their relevance to 'central sensitization'. J Physiol 584, 543-63 (2007)
Can't connect to PubMed

143. Vanja Duric and Kenneth McCarson: Effects of analgesic or antidepressant drugs on pain- or stress-evoked hippocampal and spinal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression in the rat. J Pharmacol Exp Ther 319, 1235-43 (2006)
Can't connect to PubMed

144. Sophie Pezet and Stephen McMahon: Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29, 507-38 (2006)
Can't connect to PubMed

145. Kenneth Wild, Di Bian, Dawn Zhu, James Davis, Anthony Bannon, Tie Zhang, and Jean-Claude Louis: Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Ther 322, 282-7 (2007)
Can't connect to PubMed

146. Shaaban Mousa, Bopaiah Cheppudira, Mohammed Shaqura, Oliver Fischer, Julia Hofmann, Rainer Hellweg, and Michael Schafer: Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain. Brain 130, 502-13 (2007)
Can't connect to PubMed

147. Duncan Atherton, Omeed Taherzadeh, Paul Facer, David Elliot, and Praveen Anand: The potential role of nerve growth factor (NGF) in painful neuromas and the mechanism of pain relief by their relocation to muscle. J Hand Surg (Br) 31, 652-6 (2006)
Can't connect to PubMed

148. Olaf Schulte-Herbruggen, Sabine Chourbaji, Heidrun Muller, Heidi Danker-Hopfe, Christiane Brandwein, Peter Gass, and Rainer Hellweg: Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness. Exp Neurol 202, 404-9 (2006)
Can't connect to PubMed

149. Francesco Angelucci, Aleksander Mathe, and Luigi Aloe: Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. Prog Brain Res 146, 151-65 (2004)
Can't connect to PubMed

150. Christoph Hock, Klaus Heese, Franz Muller-Spahn, Peter Huber, Walter Riesen, Roger Nitsch, and Uwe Otten: Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression. Mol Psychiatry 5, 510-3 (2000)
Can't connect to PubMed

151. Tracy Wilson-Gerwing and Valerie Verge: Neurotrophin-3 attenuates galanin expression in the chronic constriction injury model of neuropathic pain. Neuroscience 141, 2075-85 (2006)
Can't connect to PubMed

152. E. K. Chung, Xuejun Zhang, Hongxi Xu, Joseph Sung, and Zhaoxiang Bian: Visceral hyperalgesia induced by neonatal maternal separation is associated with nerve growth factor-mediated central neuronal plasticity in rat spinal cord. Neuroscience 149, 685-95 (2007)
Can't connect to PubMed

153. Yohji Fukazawa, Takehiko Maeda, Norikazu Kiguchi, Kkazuo Tohya, Michio Kimura, and Shiroh Kishioka: Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats. J Pharmacol Sci 104, 159-66 (2007)
Can't connect to PubMed

154. Samuel McLean: Do substance P and the NK1 receptor have a role in depression and anxiety? Curr Pharm Des 11, 1529-47 (2005)
Can't connect to PubMed

155. Richard Gracely, Michael Geisser, Thorsten Giesecke, Masilo Grant, Frank Petzke, David Williams, and Daniel Clauw: Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 127, 835-43 (2004)
Can't connect to PubMed

156. Jeanine Verbunt, Judith Sieben, Johan Vlaeyen, Piet Portegijs, and Andre Knottnerus: A new episode of low back pain: Who relies on bed rest? Eur J Pain 12, 508-16 (2008)
Can't connect to PubMed

157. Maya Roth, Dean Tripp, Mark Harrison, Michael Sullivan, and Patricia Carson: Demographic and psychosocial predictors of acute perioperative pain for total knee arthroplasty. Pain Res Manag 12, 185-94 (2007)

158. Robert Edwards, Clifton Bingham III, Jennifer Bathon, and Jennifer Haythornthwaite: Catastrophizing and pain in arthritis, fibromyalgia, and other rheumatic diseases. Arthritis Rheum 55, 325-32 (2006)
Can't connect to PubMed

159. Vivian Kraaij, E. Pruymboom, and Nadia Garnefski: Cognitive coping and depressive symptoms in the elderly: a longitudinal study. Aging Ment Health 6, 275-81 (2002)
Can't connect to PubMed

160. Karen Salmon, Emma Sinclair, and Richard Bryant: The role of maladaptive appraisals in child acute stress reactions. Br J Clin Psychol 46, 203-10 (2007)
Can't connect to PubMed

161. Laura Kaminsky, Marli Robertson, and Deborah Dewey: Psychological correlates of depression in children with recurrent abdominal pain. J Pediatr Psychol 31, 956-66 (2006)

162. Mark Jensen, Judith Turner, and Joan Romano: Changes after multidisciplinary pain treatment in patient pain beliefs and coping are associated with concurrent changes in patient functioning. Pain 131, 38-47 (2007)
PMid:17250963    PMCid:1986708

163. Robert Edwards, Michael Smith, Ian Kudel, and Jennifer Haythornthwaite: Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain 126, 272-9 (2006)

164. Xin Li, Monique Gignac, and Aslam Anis: Workplace, psychosocial factors, and depressive symptoms among working people with arthritis: a longitudinal study. J Rheumatol 33, 1849-55 (2006)

165. Michelle Leonard and Annmarie Cano: Pain affects spouses too: personal experience with pain and catastrophizing as correlates of spouse distress. Pain 126, 139-46 (2006)
PMid:16860476    PMCid:1894886

166. Rand Palomino, Perry Nicassio, Melanie Greenberg, and Ernesto Medina Jr.: Helplessness and loss as mediators between pain and depressive symptoms in fibromyalgia. Pain 129, 185-94 (2007)

167. Han Samwel, Andrea Evers, Ben Crul, and Floris Kraaimaat: The role of helplessness, fear of pain, and passive pain-coping in chronic pain patients. Clin J Pain 22, 245-51 (2006)

168. Emi Matsuura, Akihide Ohta, Futoshi Kanegae, Yoshiro Haruda, Osamu Ushiyama, Shuichi Koarada, Riko Togashi, Yoshifumi Tada, Noriaki Suzuki, and Kohei Nagasawa: Frequency and analysis of factors closely associated with the development of depressive symptoms in patients with scleroderma. J Rheumatol 30, 1782-7 (2003)

169. Sieberen van der Werf, Andrea Evers, Peter Jongen, and Gijs Bleijenberg: The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis. Mult Scler 9, 89-94 (2003)

170. John Ozment and David Lester: Helplessness and depression. Psychol Rep 82, 434 (1998)

171. Jessica Malberg and Ronald Duman: Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28, 1562-71 (2003)

172. Jeffrey Lackner, Brian Quigley, and Edward Blanchard: Depression and abdominal pain in IBS patients: the mediating role of catastrophizing. Psychosom Med 66, 435-41 (2004)

173. Roger Jones, Radoslav Latinovic, Judith Charlton, and Martin Gulliford: Physical and psychological co-morbidity in irritable bowel syndrome: a matched cohort study using the General Practice Research Database. Aliment Pharmacol Ther 24, 879-86 (2006)

174. Alexander Cole, Kenneth Rothman, Howard Cabral, Yuqing Zhang, and Francis Farraye: Migraine, fibromyalgia, and depression among people with IBS: a prevalence study. BMC Gastroenterol 6, 26 (2006)
PMid:17007634    PMCid:1592499

175. Dan Buskila and Hagit Cohen: Comorbidity of fibromyalgia and psychiatric disorders. Curr Pain Headache Rep 11, 333-8 (2007)

176. Adrienne Means-Christensen, Peter Roy-Byrne, Cathy Sherbourne, Michelle Craske, and Murray Stein: Relationships among pain, anxiety, and depression in primary care. Depress Anxiety 25, 593-600 (2008)

177. Carolina Lorencatto, Carlos Petta, Maria Navarro, Luis Bahamondes, and Alessandra Matos: Depression in women with endometriosis with and without chronic pelvic pain. Acta Obstet Gynecol Scand 85, 88-92 (2006)

178. Lee Smith: Serotonin mechanisms in pain and functional syndromes: management implications in comorbid fibromyalgia, headache, and irritable bowl syndrome - case study and discussion. J Pain Palliat Care Pharmacother 18, 31-45 (2004)

179. Sterling Peter and Eyer Joseph: Allostasis: a new paradigm to explain arousal pathology. In: Handbook of life stress, cognition and health. Eds: Fisher S., Reason J., John Wiley, New York (1988)

180. Bruce McEwen and Eliot Stellar: Stress and the individual. Mechanisms leading to disease. Arch Intern Med 153, 2093-101 (1993)

181. Jordan Karp, John Scott, Patricia Houck, Charles Reynolds III, David Kupfer, and Ellen Frank: Pain predicts longer time to remission during treatment of recurrent depression. J Clin Psychiatry 66, 591-7 (2005)

182. Maurizio Fava, Craig Mallinckrodt, Michael Detke, John Watkin, and Madelaine Wohlreich: The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry 65, 521-30 (2004)

183. Giovanni Fava, Gianna Savron, Silvana Grandi, and Chiara Rafanelli: Cognitive-behavioral management of drug-resistant major depressive disorder. J Clin Psychiatry 58, 278-82 (1997)

184. Jeffrey Vittengl, Lee Clark, Todd Dunn, and Robin Jarrett: Reducing relapse and recurrence in unipolar depression: a comparative meta-analysis of cognitive-behavioral therapy's effects. J Consult Clin Psychol 75, 475-88 (2007)

185. Roger Chou and Laurie Huffman: Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 147, 492-504 (2007)

186. Roger Chou and Laurie Huffman: Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 147, 505-14 (2007)

187. Martin Keller, James McCullough, Daniel Klein, Bruce Arnow, David Dunner, Alan Gelenberg, John Markowitz, Charles Nemeroff, James Russell, Michael Thase, Madhukar Trivedi, and John Zajecka: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 342, 1462-70 (2000)

188. Erin Michalak and Raymond Lam: Breaking the myths: new treatment approaches for chronic depression. Can J Psychiatry 47, 635-43 (2002)

189. Noreen Bannan: Multimodal therapy of treatment resistant depression: a study and analysis. Int J Psychiatry Med 35, 27-39 (2005)

190. Sanjeev Pathak, Christopher Kratochvil, Gregory Rogers, Susan Silva, Benedetto Vitiello, Elizabeth Weller, and John March: Comparative efficacy of cognitive behavioral therapy, fluoxetine, and their combination in depressed adolescents: initial lessons from the treatment for adolescents with depression study. Curr Psychiatry Rep 7, 429-34 (2005)

191. Ivan Molton, Christina Graham, Brenda Stoelb, and Mark Jensen: Current psychological approaches to the management of chronic pain. Curr Opin Anaesthesiol 20, 485-9 (2007)

192. Benson Hoffman, Rebecca Papas, David Chatkoff, and Robert Kerns: Meta-analysis of psychological interventions for chronic low back pain. Health Psychol 26, 1-9 (2007)

193. Marcella Ottonello: Cognitive-behavioral interventions in rheumatic diseases. G Ital Med Lav Ergon 29, A19-A23 (2007)

194. Gay Lipchik, Todd Smitherman, Donald Penzien, and Kenneth Holroyd: Basic principles and techniques of cognitive-behavioral therapies for comorbid psychiatric symptoms among headache patients. Headache 46 Suppl 3, S119-S132 (2006)

195. Lance McCracken, Fiona Mackichan, and Christopher Eccleston: Contextual cognitive-behavioral therapy for severely disabled chronic pain sufferers: effectiveness and clinically significant change. Eur J Pain 11, 314-22 (2007)

196. Christopher Eccleston, Peter Malleson, Jacqui Clinch, Hannah Connell, and Catherine Sourbut: Chronic pain in adolescents: evaluation of a programme of interdisciplinary cognitive behaviour therapy. Arch Dis Child 88, 881-5 (2003)
PMid:14500306    PMCid:1719328

197. Daniel Rooks, Shiva Gautam, Matthew Romeling, Martha Cross, Diana Stratigakis, Brittany Evans, Don Goldenberg, Maura Iversen, and Jeffrey Katz: Group Exercise, Education, and Combination Self-management in Women With Fibromyalgia: A Randomized Trial. Arch Intern Med 167, 2192-200 (2007)

198. Cigdem Bircan, Seide Karasel, Berrin Akgun, Oezlem El, and Serap Alper: Effects of muscle strengthening versus aerobic exercise program in fibromyalgia. Rheumatol Int 28, 527-32 (2008)

199. Marcos Assis, Luciana Silva, Adriana Alves, Ana Pessanha, Valeria Valim, Daniel Feldman, Turibio Neto, and Jamil Natour: A randomized controlled trial of deep water running: clinical effectiveness of aquatic exercise to treat fibromyalgia. Arthritis Rheum 55, 57-65 (2006)

200. Geri Neuberger, Lauren Aaronson, Byron Gajewski, Susan Embretson, Perri Cagle, Janice Loudon, and Peggy Miller: Predictors of exercise and effects of exercise on symptoms, function, aerobic fitness, and disease outcomes of rheumatoid arthritis. Arthritis Rheum 57, 943-52 (2007)

201. Hyuan-Ja Lim, Young-Im Moon, and Myeong Lee: Effects of home-based daily exercise therapy on joint mobility, daily activity, pain, and depression in patients with ankylosing spondylitis. Rheumatol Int 25, 225-9 (2005)

202. Michael Jann and Julian Slade: Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 27, 1571-87 (2007)

203. Olivier Vitton, Michael Gendreau, Judy Gendreau, Jay Kranzler, and Srinivas Rao: A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Hum Psychopharmacol 19 Suppl 1, S27-S35 (2004)

204. Sanjay Gupta, Nikhil Nihalani, and Prakash Masand: Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Ann Clin Psychiatry 19, 125-32 (2007)

205. Karl Thor, Michael Kirby, and Lars Viktrup: Serotonin and noradrenaline involvement in urinary incontinence, depression and pain: scientific basis for overlapping clinical efficacy from a single drug, duloxetine. Int J Clin Pract 61, 1349-55 (2007)

206. David Perahia, Yili Pritchett, Durisala Desaiah, and Joel Raskin: Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol 21, 311-7 (2006)

207. David Perahia, Fen Wang, Craig Mallinckrodt, D. J. Walker, and Michael Detke: Duloxetine in the treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Psychiatry 21, 367-78 (2006)

208. Michael Detke, Yili Lu, David Goldstein, Robert McNamara, and Mark Demitrack: Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res 36, 383-90 (2002)

209. Michael Detke, Yili Lu, David Goldstein, John Hayes, and Mark Demitrack: Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 63, 308-15 (2002)

210. Michael Detke, Curtis Wiltse, Craig Mallinckrodt, Robert McNamara, Mark Demitrack, and Istvan Bitter: Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol 14, 457-70 (2004)

211. David Goldstein, Craig Mallinckrodt, Yili Lu, and Mark Demitrack: Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry 63, 225-31 (2002)

212. David Goldstein, Yili Lu, Michael Detke, Curtis Wiltse, Craig Mallinckrodt, and Mark Demitrack: Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 24, 389-99 (2004)

213. David Goldstein, Yili Lu, Michael Detke, James Hudson, Smriti Iyengar, and Mark Demitrack: Effects of duloxetine on painful physical symptoms associated with depression. Psychosomatics 45, 17-28 (2004)

214. Stephen Brannan, Craig Mallinckrodt, Eileen Brown, Madelaine Wohlreich, John Watkin, and Alan Schatzberg: Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res 39, 43-53 (2005)

215. Nicholas DeMartinis, Paul Yeung, Richard Entsuah, and Amy Manley: A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry 68, 677-88 (2007)

216. Phil Lee, Liang Shu, Xiufeng Xu, Chuan Wang, Min Lee, Chia-Yih Liu, Jin Hong, Sandra Ruschel, Joel Raskin, Samual Colman, and Gavan Harrison: Once-daily duloxetine 60 mg in the treatment of major depressive disorder: multicenter, double-blind, randomized, paroxetine-controlled, non-inferiority trial in China, Korea, Taiwan and Brazil. Psychiatry Clin Neurosci 61, 295-307 (2007)

217. Hadine Joffe, Claudio Soares, Laura Petrillo, Adele Viguera, Brittny Somley, Jennifer Koch, and Lee Cohen: Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine. J Clin Psychiatry 68, 943-50 (2007)

218. Craig Nelson, Madelaine Wohlreich, Craig Mallinckrodt, Michael Detke, John Watkin, and John Kennedy: Duloxetine for the treatment of major depressive disorder in older patients. Am J Geriatr Psychiatry 13, 227-35 (2005)

219. Joel Raskin, Curtis Wiltse, Alan Siegal, Javaid Sheikh, Jimmy Xu, James Dinkel, Benjamin Rotz, and Richard Mohs: Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 164, 900-9 (2007)

220. Madelaine Wohlreich, Michael Sullivan, Craig Mallinckrodt, Amy Chappell, Tina Oakes, John Watkin, and Joel Raskin: Duloxetine for the Treatment of Recurrent Major Depressive Disorder in Elderly Patients: Treatment Outcomes in Patients With Comorbid Arthritis. Psychosomatics in press (2007)

221. Craig Mallinckrodt, John Watkin, Chaofeng Liu, Madelaine Wohlreich, and Joel Raskin: Duloxetine in the treatment of Major Depressive Disorder: a comparison of efficacy in patients with and without melancholic features. BMC Psychiatry 5, 1 (2005)
PMid:15631624    PMCid:546184

222. Lesley Arnold, Yili Lu, Leslie Crofford, Madelaine Wohlreich, Michael Detke, Smriti Iyengar, and David Goldstein: A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 50, 2974-84 (2004)

223. Lesley Arnold, Amy Rosen, Yili Pritchett, Deborah D'Souza, David Goldstein, Smriti Iyengar, and Joachim Wernicke: A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119, 5-15 (2005)

224. Michael Gendreau, Michael Thorn, Judy Gendreau, Jay Kranzler, Saulo Ribeiro, Richard Gracely, David Williams, Philip Mease, Samuel McLean, and Daniel Clauw: Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol 32, 1975-85 (2005)

225. Kurt Kroenke, Nicholas Messina III, Isma Benattia, Jay Graepel, and Jeff Musgnung: Venlafaxine extended release in the short-term treatment of depressed and anxious primary care patients with multisomatoform disorder. J Clin Psychiatry 67, 72-80 (2006)

226. Mikiko Ito, Keizo Yoshida, Hiroyuki Kimura, Norio Ozaki, and Kenichi Kurita: Successful treatment of trigeminal neuralgia with milnacipran. Clin Neuropharmacol 30, 183-5 (2007)

227. Heli Forssell, Tiina Tasmuth, Olli Tenovuo, Goeran Hampf, and Eija Kalso: Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. J Orofac Pain 18, 131-7 (2004)

228. Pushpal Desarkar, Anindya Das, and Vinod Sinha: Duloxetine for childhood depression with pain and dissociative symptoms. Eur Child Adolesc Psychiatry 15, 496-9 (2006)

229. Karen Meighen: Duloxetine treatment of pediatric chronic pain and co-morbid major depressive disorder. J Child Adolesc Psychopharmacol 17, 121-7 (2007)

230. Nicholas Talley, John Kellow, Philip Boyce, Christopher Tennant, Sandy Huskic, and Michael Jones: Antidepressant Therapy (Imipramine and Citalopram) for Irritable Bowel Syndrome: A Double-Blind, Randomized, Placebo-Controlled Trial. Dig Dis Sci 53, 108-15 (2008)

231. Jan Tack, Dorine Broekaert, Benjamin Fischler, Lukas Oudenhove, Annemie Gevers, and Jozef Janssens: A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 55, 1095-103 (2006)

232. John Campo, James Perel, Amanda Lucas, Jeff Bridge, Mary Ehmann, Catherine Kalas, Kelly Monk, David Axelson, Boris Birmaher, Neal Ryan, Di Lorenzo Carlo, and David Brent: Citalopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders: an exploratory study. J Am Acad Child Adolesc Psychiatry 43, 1234-42 (2004)

233. Stephen Tyring: Management of herpes zoster and postherpetic neuralgia. J Am Acad Dermatol 57, S136-S142 (2007)

234. Diana Rintala, Sally Holmes, Daisy Courtade, Richard Fiess, Luz Tastard, and Paul Loubser: Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil 88, 1547-60 (2007)

235. Don Goldenberg: Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 21, 499-511 (2007)

236. Troels Jensen, Misha-Miroslav Backonja, Sergio Hernandez, Solomon Tesfaye, Paul Valensi, and Dan Ziegler: New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 3, 108-19 (2006)

237. Masako Ikawa, Kazuo Yamada, and Shinobu Ikeuchi: Efficacy of amitriptyline for treatment of somatoform pain disorder in the orofacial region: A case series. J Orofac Pain 20, 234-40 (2006)

238. Glen Tomkins, Jeffrey Jackson, Patrick O'Malley, Erin Balden, and James Santoro: Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med 111, 54-63 (2001)

239. Diego Bettucci, Lucia Testa, Silvia Calzoni, Paola Mantegazza, Michele Viana, and Francesco Monaco: Combination of tizanidine and amitriptyline in the prophylaxis of chronic tension-type headache: evaluation of efficacy and impact on quality of life. J Headache Pain 7, 34-6 (2006)

240. Achim Frese, Ingo Husstedt, Bernd Ringelstein, and Stefan Evers: Pharmacologic treatment of central post-stroke pain. Clin J Pain 22, 252-60 (2006)

241. Vinu Jose, Anil Bhansali, Debasish Hota, and Promila Pandhi: Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. Diabet Med 24, 377-83 (2007)

242. Claus Rosenberg, Lise Lauritzen, Jorgen Brix, Jorgen Jorgensen, Palle Kofod, and Liselotte Bayer: Citalopram versus amitriptyline in elderly depressed patients with or without mild cognitive dysfunction: a danish multicentre trial in general practice. Psychopharmacol Bull 40, 63-73 (2007)

243. Hueseyin Caksen, Sinan Akbayram, Dursun Odabas, Hanefi Ozbek, Mehmet Erol, Cihangir Akgun, Oguz Tuncer, and Cahide Yilmaz: Acute amitriptyline intoxication: an analysis of 44 children. Hum Exp Toxicol 25, 107-10 (2006)

244. Mary McKenzie and Bentson McFarland: Trends in antidepressant overdoses. Pharmacoepidemiol Drug Saf 16, 513-23 (2007)

245. Rainer Freynhagen, Uta Muth-Selbach, Peter Lipfert, Markus F. Stevens, Kai Zacharowski, Thomas Tolle, and Hans von Giesen: The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin 22, 257-64 (2006)

246. Vladimir Maletic, Michael Robinson, Tina Oakes, Smriti Iyengar, Susan Ball, and James Russell: Neurobiology of depression: an integrated view of key findings. Int J Clin Pract 61, 2030-40 (2007)
PMid:17944926    PMCid:2228409

247. S. A. Shah, P. Murali Doraiswamy, Mustafa Husain, Patricio Escalona, Chongzheng Na, Gary Figiel, L. J. Patterson, Everett Ellinwood, Jr., William McDonald, Orest Boyko, Charles Nemeroff, K. Ranga Rama Krishnan: Posterior fossa abnormalities in major depression: a controlled magnetic resonance imaging study. Acta Psychiatr Scand 85, 474-9 (1992)

248. Paul Fitzgerald, Angela Laird, Jerome Maller, and Zafiris Daskalakis: A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp 29, 683-95 (2008)

249. Alexander Ploghaus, Charvy Narain, Christian Beckmann, Stuart Clare, Susanna Bantick, Richard Wise, Paul Matthews, Nicholas Rawlins, and Irene Tracey: Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 21, 9896-903 (2001)

250. David Scott, Mary Heitzeg, Robert Koeppe, Christian Stohler, and Jon-Kar Zubieta: Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J Neurosci 26, 10789-95 (2006)

251. Penelope Kostopoulos, Marie-Claire Albanese, and Michael Petrides: Ventrolateral prefrontal cortex and tactile memory disambiguation in the human brain. Proc Natl Acad Sci U S A 104, 10223-8 (2007)

252. Renee Dupont, Terry Jernigan, William Heindel, Nelson Butters, Kimberly Shafer, Thomine Wilson, John Hesselink, and Christian Gillin: Magnetic resonance imaging and mood disorders. Localization of white matter and other subcortical abnormalities. Arch Gen Psychiatry 52, 747-55 (1995)

Abbreviations: ACC: anterior cingulate cortex; BDNF: brain-derived neurotrophic factor; CBT: cognitive behavioral therapy; CRF: corticotropin-releasing-factor; CRP: C-reactive protein; DLPT: dorsolateral pontine tegmentum, fMRI: functional magnetic resonance imaging; HPA: hypothalamic-pituitary-adrenal gland; IBS: Irritable bowel syndrome; IL-1-beta: interleukin-1-beta; IL-6: interleukin-6; LDAEP: loudness dependence of the auditory evoked potential; MDD: major depressive disorder; MRI: Magnetic resonance imaging; NGF: nerve growth factor; NK1: neurokinin-1; NT-3: neurotrophin-3; PET: Positron emission tomography; PFC: prefrontal cortex; RVM: rostral ventromedial medulla; SNRI: serotonin and norepinephrine reuptake inhibitor; SPECT: Single photon emission computed tomography; SSRI: selective serotonin reuptake inhibitors; TCA: Tricyclic antidepressants; TNF-alpha: tumor necrosis factor alpha

Key Words: Neurobiology, treatment, mood disorder, duloxetine, pain

Send correspondence to: Michael Robinson, Lilly USA, LLC, Lilly Corporate Center, Drop Code 4103, Indianapolis, IN 46285, Tel: 317-651-1138, Fax: 317-651-7386, E-mail:Robinson_Michael_J@Lilly.com