Neurobiologie de la Dépression Le corps et l’esprit

Présentation au sujet: "Neurobiologie de la Dépression Le corps et l’esprit"— Transcription de la présentation:

1 Neurobiologie de la Dépression Le corps et l’esprit

2 Objectifs Major depressive disorder (MDD)
Une maladie complexe avec des symptômes affectifs et physiques1 Une maladie chronique, persistante et progressive1 Associée à des modifications fonctionelles et structurales du cortex2,3 Les Neurotrophines jouent un rôle dans la médiation de ces changements4 Les traitements antidepresseurs peuvent restorer les bases physiologiques5 La Remission est le but premier du traitement6,7 PURPOSE OF THE SLIDE To present the learning objectives and overview of the presentation. KEY POINTS1–7 Upon completion of this program, one should be able to: Understand that depression is a complex disorder that involves a variety of core and associated symptoms beyond emotional symptoms, such as painful physical symptoms. Be familiar that brain areas involved in depression may also play a part in pain. Be knowledgeable that the progressive nature of major depressive disorder (MDD) may be mediated by functional and structural changes in the brain. Discuss the potential role that antidepressants play in modulating both depression and pain. Be aware of research that supports the necessity of trying to achieve remission for MDD. REFERENCES American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356. Maletic V. Pathophysiology of pain and depression: the role of dual-acting antidepressants. Prim Psychiatry. 2005;12(suppl 10):7–9. Apkarian AV, et al. chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24:10410–10415. Castrén E, et al. Role of neurotrophic factors in depression. Curr Opin Pharmacol. 2006;6:1–4. Himmerich H, et al. Successful antidepressant therapy restores the disturbed interplay between TNF-α system and HPA axis. Biol Psychiatry. 2006;60:882–888. Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66 (suppl 8):5–12. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(suppl 4):1–45. 1. American Psychiatric Association (APA). DSM-IV-TR; 2000:352, Maletic V. Prim Psychiatry. 2005;12(suppl 10): 7–9. 3. Apkarian AV, et al. J Neurosci. 2004;24:10410– Castrén E, et al. Curr Opin Pharmacol. 2006;6:1– Himmerich H, et al. Biol Psychiatry. 2006;60:882– Keller MB. J Clin Psychiatry. 2005;66(suppl 8):5– American Psychiatric Association. Am J Psychiatry. 2000;157(suppl 4):1–45.

3 La complexité du trouble dépression majeure (MDD)
PURPOSE OF THE SLIDE To transition to the first section of the presentation, which will be to discuss the complexity of major depressive disorder (MDD) and conceptualizing it beyond the core mood symptoms.

4 Origines multiples et symptômes associés
Symptomes émotionels Culpabilité Suicide Perte d’intérêts Tristesse Symptomes associés Regression Ruminations obsessionelles Irritabilité Préoccupations somatiques excessives Douleurs Les pleurs Anxiété et phobies Symptomes physiques Manque d’énergie Diminution de la concentration Troubles alimentaire Troubles du sommeil Troubles psychomoteurs PURPOSE OF THE SLIDE Establish that depression is a complex disorder that can be manifested through a variety of emotional, physical, and other associated symptoms (e.g., anxiety, worry, and pain). Note that the complexity of the symptom presentation can lead to depression being a difficult condition to diagnose. The variety of symptoms of depression suggests that many areas of the brain and neural networks may be involved in depression. KEY POINTS There is a broad range of major depressive disorder (MDD) symptoms. The mood in major depression is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities. The mood is often described by the person as depressed, sad, hopeless, discouraged, or “down in the dumps”. Some individuals emphasize somatic complaints (e.g., body aches and pains) rather than reporting feelings of sadness. Many individuals report or exhibit increased irritability. Loss of interest or pleasure is nearly always present, at least to some degree, and not feeling enjoyment in activities that were previously considered pleasurable. Appetite is usually reduced, yet other individuals have increased appetite. When appetite changes are severe, there may be significant loss or gain in weight. The most common sleep disturbance associated with depression is insomnia. Less frequently, individuals present with over-sleeping in the form of prolonged sleep episodes at night or increased daytime sleep. Psychomotor changes include agitation (e.g., the inability to sit still, pacing, hand-wringing) or retardation (e.g., slowed speech, thinking, and body movements). Decreased energy, tiredness, and fatigue are common. The sense of worthlessness or guilt associated with depression may include unrealistic negative evaluation of one's worth or guilty preoccupations or ruminations over minor past failings. Many individuals report impaired ability to think, concentrate, or make decisions. They may appear easily distracted or complain of memory difficulties. Frequently, there may be thoughts of death, suicidal ideation, or suicide attempts. BACKGROUND The symptom groupings were based on the DSM-IV-TR core criteria and text description of associated symptoms. REFERENCE American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000;352,356. American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356.

5 Quel est la prévalence des symptômes douloureux chez le patient déprimé?
Patients déprimés Etudes comprenant à la fois la dépression et des symptômes douloureux: Maux de têtes Dorsalgies Nuqualgies Extremités/douleurs articulaires Précordialgies Douleurs périnéennes Douleurs abdominales Douleurs générales MDD sans Symptômes douloureux 35% MDD avec Symptômes douloureux 65% Moyenne des prevalences, données de14 études sur les symptômes douloureux chez des patients déprimés PURPOSE OF THE SLIDE Focus on the high prevalence of associated pain in patients with depression. KEY POINTS In a major meta-analysis, two-thirds of patients with depression experienced pain symptoms as well. Symptoms included headaches, and back, neck, extremity/joint, chest, pelvic, abdominal, and general pain. The prevalence rates of associated painful symptoms in patients with depression did not differ in psychiatric versus primary care settings. BACKGROUND Bair et al searched the MEDLINE database from 1966 through July 30, 2002, using the combined search terms depression or depressive disorders and pain. Articles were identified by a manual search of bibliographies from all retrieved articles. Studies were limited to human studies reported in English. Studies were eligible for inclusion if they addressed both depression and pain symptoms, loosely defined. The definition of pain condition, location of pain, and duration of pain complaint varied considerably among studies. Several different scales were used to assess depression. REFERENCE Bair MJ, et al. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433–2445. MDD=major depressive disorder. Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445.

6 L’évolution des effets
‘Network’: Dérègulation des circuits neuronaux1 Changements Fonctionnels et structuraux Symptômes neuropsychiatriques Emotional5 Cognitive5 Behavioral7 Physical6 Manifestations systémiques Stress1 Dérègulation des systèmes Neuroendocrine et Immunitaires2 Vulnérabilité genétique3,4 Blessures6 Impact au niveaux Cellulaire et subcellulaire 4 Intracellular signaling Gene transcription Neurotrophic support PURPOSE OF THE SLIDE To introduce the concept that the complex manifestation of depression as an illness reflects a multitude of underlying changes that occurs at several levels. KEY POINTS The exact etiology of depression is not known, but a number of factors are associated with the precipitation of the illness, including stressful life events1, genetic vulnerabilities2–3, and injury.4 In the context of these stresses, the occurrence of major depressive disorder (MDD) is associated with a number of alterations throughout the neurobiology of the brain. The macro levels include not only symptoms that are experienced by the patient,4,5–6 but recent evidence suggest that changes in the functional connectivity as well as structural areas within the brain are altered. The micro levels indicate that these neurobiological changes are mediated through neurotransmitter, neuroendocrine,7 and subcellular mechanisms.3 The next section of the presentation will review these neurobiological changes at both the macro and micro levels, especially as MDD becomes more progressive over time. REFERENCES Sheline YI, et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50(9):651–658. Gatt JM, et al. A genotype-endophenotype-phenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci. 2007;6(1):75–104. Carlson PJ, et al. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx. 2006;3(1):22–41. Blackburn-Munro G, et al. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol. 2001;13(12):1009–1023. Gatt JM, et al. A genotype-endophenotype-phenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci. 2007;6(1):75–104. Drevets WC. Curr Opin Neurobiol. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders 2001;11(2):240–249. American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356. Raison CL, et al. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24–31. 1. Sheline YI, et al. Biol Psychiatry. 2001;50:651– Raison CL, et al. Trends Immunol. 2006;27:24– Gatt JM, et al. J Integr Neurosci. 2007;6:75– Carlson PJ, et al. NeuroRx. 2006;3:22– Drevets WC. Curr Opin Neurobiol ;11:240– Blackburn-Munro G, et al. J Neuroendocrinol. 2001;13: American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356.

7 Evolution Progressive et Chronique de la Dépression majeures (MDD)
PURPOSE OF THE SLIDE To transition to the next section of the presentation regarding the course of major depressive disorder (MDD). KEY POINTS MDD is believed to be an episodic illness, but for most patients with MDD, it is experienced recurrently. Research findings suggest that recurrent and chronic MDD may be associated with underlying neurobiological alterations.

8 Progression de la Dépression -“Kindling”- Effets de chaque épisode Successif
10 2 4 6 8 Likelihood of recent life stress precipitating depression Risk (odds ratio) of depression onset per month Female participants only N=2,395 Risk (odds ratio) PURPOSE OF THE SLIDE To discuss that the progressive nature of major depressive disorder (MDD) is shown by the relationship between onset, life events, and the previous number of depressive episodes. KEY POINTS Members of female–female twin pairs from a population-based registry (N=2,395), who were interviewed four times over a period of 9 years, formed a study group that contained 97,515 person–months and 1,380 onsets of major depression. Discrete-time survival, proportional hazards model, and piece-wise regression analyses were used to examine the interaction between life event exposure and number of previous depressive episodes in the prediction of episodes of major depression. For those with zero to nine previous depressive episodes, the depressogenic effect of stressful life events declined substantially with increasing episode number. However, the association between stressful life events and major depression was not substantially influenced by additional episodes. This pattern of results was robust to the addition of indices of event severity, measures of genetic risk, and restriction to independent stressful life events. The same pattern was also seen upon examining within-person changes in number of episodes. Thus, these results are consistent with the kindling hypothesis but suggest a threshold at which the mind/brain is no longer additionally sensitized to the depressive state. Chief predictor of future recurrence after nine episodes is the episode count, not presence of stress. REFERENCE Kendler KS, et al. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the "kindling" hypothesis. Am J Psychiatry. 2000;157(8):1243–1251. 1 2 3 4 5 6 7–8 9–11 Nombre d’épisode dépressifs antérieurs Kendler KS, et al. Am J Psychiatry. 2000;157:1243–1251.

9 Les Symptômes physiques ne répondent pas de façon équivalente aux traitements antidépresseurs
1.4 Emotional symptoms N=573 Non-somatic depressive symptoms 1.2 Positive well-being 1.0 Physical symptoms 0.8 Improvement Non-pain somatic symptoms Treatment effect size 0.6 Pain somatic symptoms 0.4 0.2 PURPOSE OF THE SLIDE To point out that painful physical symptoms are often residual symptoms, even with treatment, and thus patients can continue to be at risk for recurrence. KEY POINTS A naturalistic, randomized trial of 573 primary care patients taking selective serotonin reuptake inhibitors (SSRIs) showed that, over time, emotional and physical symptoms of major depressive disorder (MDD) respond differently to treatment. Adult patients considered clinically depressed by their primary care physician were randomized to SSRI treatment from 37 practice sites. Depression outcome was assessed by the 9-item Patient Health Questionnaire (PHQ-9) depression scale and The Hopkins Symptoms Checklist subscale (HSCL-20). Physical symptoms were assessed by 14 of the 15 items on the PHQ-15 (sexual dysfunction was excluded). Social, work and well being parameters were determined using the 36-item Short-form Health Survey (SF-36), the Work Limitations Questionnaire, and the Medical Outcomes Study. Following treatment with an antidepressant, mood symptoms of MDD improved; however, physical symptoms, and, in particular, painful physical symptoms, were more likely to persist. BACKGROUND Treatment-effect size: this analysis provides a way to make comparisons that adjust for the variability in outcomes. It is calculated by dividing the difference (mean change) by the standard deviation. REFERENCE Greco T, et al. The outcome of physical symptoms with treatment of depression. J Gen Intern Med. 2004;19:813–818. Baseline 1 month 3 months 6 months 9 months ARTIST=A Randomized Trial Investigating SSRI Treatment; SSRI=selective serotonin reuptake inhibitor. Adapted from: Greco T, et al. J Gen Intern Med. 2004;19:813–818.

10 Les Symptômes douloureux résiduels diminuent la rémission dans la Dépression
Étude longitudinale de 3 ans, adultes agés 55–85 10 20 30 40 50 60 70 80 MDD only MDD and painful symptoms % Patients (depressed at baseline) achieving endpoint recovery N=102 N=119 9% 47% ( PURPOSE OF THE SLIDE To reinforce the impact of painful physical symptoms on the course and recovery from depression. KEY POINTS The study was part of the Longitudinal Aging Study Amsterdam (LASA), which drew a random sampling of 3,107 adults aged 55–85. Data were collected at 5-month intervals over 3 years. Two consecutive measurements of pain or depression were necessary to contribute to the analyses. The Center for Epidemiologic Studies Depression scale (CES-D), used commonly in the EU, is a 20-item self-reported scale measuring depressive symptoms. Items are scored on how often subjects experience each symptom in the previous week: 0 (rarely or none of the time) to 3 (most or all of the time). A score of ≥16 (out of 60) is a general measure of clinically relevant depressive symptoms. Depressed = CES-D ≥16; Recovery from depression = CES-D <16. Pain was determined by a subscale of the Nottingham Health Profile (NHP). Patients answered yes or no to the following: I am in pain when I am standing; I find it painful to change position; I am in pain when I am sitting; I am in pain when I walk; I am in constant pain. Total scores ranged from 0 (low) to 5 (high). Subjects with “pain” were those with a Nottingham score ≥1. Recovery from pain = 0 (low or no pain) on the NHP. When painful symptoms and depression coexist, chances of recovery from depression are greatly diminished. In this study, nearly half of those patients diagnosed with depression recovered by endpoint. This compares with a recovery rate of just 9% for those who experienced both depression and pain at baseline. REFERENCE Geerlings SW, et al. Longitudinal relationship between pain and depression in older adults: sex, age and physical disability. Soc Psychiatry Psychiatr Epidemiol. 2002;37:23–30. La relation étroite entre symptômes douloureux and dépression démontre la nécessité de stratégies de traitements progressives MDD=major depressive disorder. Geerlings SW, et al. Soc Psychiatry Psychiatr Epidemiol. 2002;37:23–30.

11 Modifications Fonctionnelles et Structurales de cerveau dans la MDD et la Douleur
PURPOSE OF THE SLIDE To transition to the next section of the presentation. KEY POINTS At this point, we have discussed the complexity of the presentation of major depressive disorder (MDD), that it often has a recurrent and chronic course, and that it may be progressive over time with greater risk for recurrence related to residual symptoms, such as painful physical symptoms, and recurrent episodes. In the following section we focus on some of the underlying neurobiologic changes associated with the occurrence of MDD.

12 Aires du Cerveau impliquées dans la MDD
Cortex Prefrontal2 Cortex insulaire1 cortex cingulaire ant.3 Hippocampe5 Nucleus accumbens4 Amygdale2 PURPOSE OF THE SLIDE Introduce some of the brain regions that are involved in major depressive disorder (MDD). KEY POINTS Some of the areas that may be involved in MDD are: prefrontal cortex (PFC), anterior cingulate cortex (ACC), primary and secondary somatosensory cortex, mid-insular cortex, posterior cerebellum, amygdala, hippocampus, thalamus, and nucleus accumbens. BACKGROUND Kennedy et al. observed changes in the opioid system in 14 female patients with MDD and 14 controls via positron emission tomography examining the binding potential of the mu-opioid receptor. Researchers found significant reductions in binding potential in patients with MDD in the following regions: anterior insular cortex, anterior and posterior thalamus, ventral basal ganglia, amygdala, periamygdala cortex, and inferior temporal cortex.1 Gaughran et al. found higher levels of fibroblast growth factor (FGF) in the post-mortem hippocampal tissue of depressed subjects compared with healthy controls.2 Drevets reviewed the literature to examine the role of the PFC in MDD. The authors found reduced glucose metabolism (decreased activity) within this region in patients who had unipolar depression compared to healthy controls.3 Blood flow in the amygdala also differed in MDD patients compared to healthy controls.1 Whittle et al. stated that the ventral portion of the ACC is thought to be involved in the processing of negative, fear-related emotions. Activation of the right ventral ACC has been shown to positively correlate with depression severity in MDD patients.4 Schlaepfer et al. found a significant improvement in treatment-resistant depression, specifically the anhedonic component of depression (N=3), following the implantation of deep-brain stimulating electrodes in the nucleus accumbens.5 REFERENCES Kennedy SE, et al. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63:1199–1208. Gaughran F, et al. Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res Bull. 2006;70:221–227. Drevets WC. Neuroimaging and neuropathologic studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11:240–249. Whittle S, et al. The neurobiological basis of temperament: towards a better understanding of psychopathology. Neurosci Biobehav Rev. 2006;30:511–524. Schlaepfer TE, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharm. 2007;April 11 [Epub ahead of print]. 1. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:1199– Drevets WC. Curr Opin Neurobiol. 2001;11:240– Whittle S, et al. Neurosci Biobehav Rev. 2006;30:511– Schlaepfer TE, et al. Neuropsychopharmacology ;33:368– Gaughran F, et al. Brain Res Bull. 2006;70:221–227.

13 Diminution de l’Activité dans le DLPFC chez les patients avec un MDD
Aires avec une augmentation de l’activité chez le patient avec MDD au repos (rouge) et diminution de l’activité (bleu) comparés aux contrôles. PURPOSE OF THE SLIDE To introduce some of the regional cortical activity differences observed with patients with major depressive disorder (MDD). KEY POINTS Images are from a meta-analysis of nine studies comparing patients with MDD and control subjects at rest. Total of eight areas were identified as decreased activation in patients with MDD compared with controls, including: pregenual anterior and posterior cingulate, bilateral middle frontal gyri, insula and left superior temporal gyrus. Areas identified as “overactive’’ in patients included a series of deeper brain structures (e.g., thalamus, caudate, medial and inferior frontal gyri) as well as cortical structures (including the left superior frontal and right middle frontal gyri). Depression appears to involve a considerable number of diverse cortical and subcortical brain regions and there are significant differences in the way in which differing regions are abnormally active in the disorder. REFERENCE Fitzgerald PB, et al. A meta-analytic study of changes in brain activation in depression. Human Brain Map. 2008;29:683–695. Activité augmentée: lateral orbital prefrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus, caudate Activité diminuée: dorsolateral prefrontal cortex, insula, pregenual and dorsal anterior cingulate cortex, superior temporal gyrus Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695. dorsolateral prefrontal cortex = DLPCF

14 Orbitofrontal cortical (gyrus rectus)
Les Patients avec MDD présentent un cortex Orbitofrontal médian plus petit que les Contrôles *P=.02 Orbitofrontal cortical (gyrus rectus) volume (mm3) MOFC * PURPOSE OF THE SLIDE To look at some of the potential structural changes observed in patients with depression. Reduced cortical volumes have been found in subregions of the frontal cortex, including the subgenual anterior cingulate and medial orbitofrontal cortex. KEY POINTS Neuroimaging studies have begun to show how functional differences in the brain between depressed and healthy patients can be associated with structural differences—though we still don’t know how this happens. The medial orbitofrontal cortex (MOFC; shaded in red on the image at left) has a role in the regulation of emotion and mood. In patients with depression (N=15), the MOFC was 32% smaller in volume than controls (N=20), as is indicated in the chart on the right. This finding was significant after statistically controlling for brain size. The authors hypothesize that decreases in volume of the MOFC in patients may be a risk factor for the development of depression. BACKGROUND The study consisted of 15 patients with a history of DSM-IV depression and currently treated with antidepressant medication (paroxetine, fluoxetine, or desipramine). Patients with a history of post-traumatic stress disorder (PTSD) or current medication use other than antidepressants were excluded. Comparison subjects (N=20) were healthy subjects selected to be similar to the patients for gender, age, years of education, and handedness. Depressed patients, on average, were in remission for 30 weeks and had an average of two prior depressive episodes. REFERENCE Bremner JD, et al. Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry. 2002;51:273–279. Patients avec MDD ont une réduction de 32% MOFC (VMPFC) que les patients contrôles MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex. Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.

15 Découvertes de l’imagerie Cérébrale
Les études montrent des modifications dans les aires amygdaliennes, dans l’hypocampe, le cortex préfrontal et cingulaires antérieure aisnsi que dans le cortex orbitofrontal1–3 Plusieurs études ont démontrés une hypoactivité préfrontale corticale et un retour à la norme après traitement4 Plusieurs études ont démontrés une hyperactivité limbique (spécialment cingulaire) et un retour à la norme après traitement4 Des études plus récentes ont mis l’accent sur le network neuronal (limbique, préfrontal) et ses modifications dans le temps2,4–6 Il existe une hétérogenité importante entre les patients, ce qui fait que l’imagerie ne peut pas prédire un diagnostic individuel PURPOSE OF THE SLIDE To summarize neuroimaging and depression studies that have been replicated. KEY POINTS Most of the replicated findings have found decreased activity in the prefrontal cortex (PFC), and increased activity in the cingulate and amygdala.1–4 More recently, researchers have been looking less at increases or decreases in specific brain areas, and looking more at the networks and how the areas of the brain function relative to each other, specifically how the PFC and limbic system communicate in good health and in the depressed state.2,4–6 Finally, while imaging has been a very useful research tool, it is not currently a clinical tool that can or should be used to make a diagnosis of depression. Sheline reviewed three-dimensional magnetic resonance imaging (MRI) studies of neuroanatomic changes in unipolar major depression. Brain changes associated with early-onset major depression have been reported in the hippocampus, amygdala, caudate nucleus, putamen, and frontal cortex. Many of these reported changes occur in structures that comprise a neuroanatomic circuit called the limbic–cortical–striatal–pallidal–thalamic tract (LCSPT).1 The LCSPT circuit has two proposed arms. The first proposed arm is the limbic–thalamic–cortical branch composed of the amygdala and hippocampus, mediodorsal nucleus of the thalamus, and medial and ventrolateral prefrontal cortex. The second proposed arm is the limbic–striatal–pallidal–thalamic branch.2 Nestler et al. reviewed some proposed neurobiologic concepts of depression, including genetic and environmental factors, neural circuitry, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, impairment of neurotrophic mechanisms, and impairment in brain reward pathways (including the nucleus accumbens, hypothalamus, and amygdala).3 Mayberg reviewed functional neuroimaging studies in the context of a limbic–cortical network model and discussed the importance of modulating dysfunctional limbic–cortical pathways in depression.4 Fales and colleagues used emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control and emotion-processing circuitry. Functional MRI (fMRI) results of 27 MDD patients and 24 controls showed an enhanced amygdala response to fear-related stimuli; controls showed increased activity in the right dorsolateral PFC when ignoring fear stimuli, which the depressed patients did not show.5 Siegle and colleagues tested 27 MDD patients and 25 controls on completing tasks requiring executive control (digit sorting) and emotional information processing. fMRI assessment showed that, relative to controls, depressed patients displayed sustained amygdala reactivity on emotional tasks and decreased dorsolateral PFC activity on digit sorting.6 REFERENCES Sheline YI. 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity. Biol Psychiatry. 2000:48(8):791–800. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry. 2003;54(3):338–352. Nestler EJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13–25. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193–207. Fales CL, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–384. Siegle GJ, et al. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198–209. 1. Sheline YI. Biol Psychiatry. 2000;48:791– Sheline YI. Biol Psychiatry. 2003;54:338– Nestler EJ, et al. Neuron ;34:13– Mayberg HS. Br Med Bull. 2003;65:193– Fales CL, et al. Biol Psychiatry. 2008;63: 377– Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209.

16 La douleur chronique peut entraîner une atrophie de la matière grise cérébrale
Les zones en rouge Indiquent les régions où la densité de matière grise est réduite chez les patients (CBP) par rapport aux contrôles Une tranche du thalamus antérieur droit à la pointe de la diminution de la matière grise thalamique PURPOSE OF THE SLIDE Transition to structural changes that may be observed in gray matter in patients with chronic pain conditions. KEY POINTS This is the first study showing brain structural changes in patients with chronic pain. 26 patients fulfilling the International Association for the Study of Pain (IASP) criteria for chronic back pain (CBP) with pain duration of at least 1 year were compared with 26 matched volunteers. The source of CBP was not distinguished, although the main source of pain was lumbosacral. Voxel-based morphometry (VBM) has been validated against other standard measures. Images were first normalized into a standard space and then segmented. Voxel values reflect absolute amounts (volume in arbitrary units) of gray matter. In the VBM image on the left, gray matter density is bilaterally reduced in the dorsolateral prefrontal cortex (PFC). These observed changes likely constitute the cognitive and behavioral properties (pain perception) of chronic pain. The image on the right shows a significant decrease in gray matter density was observed in the right anterior thalamus. The left thalamus also showed a decrease in gray matter density; however, this decrease did not pass the significant threshold. The thalamus has an importance in mediating nociceptive inputs to the cortex. All told, patients with CBP had 5–11% less neocortical gray matter volume, similar to the effects of 10 to 20 years of normal aging compared with controls. The decrease in volume was related to pain duration, indicating a 1.3 cm3 loss of gray matter for every year of chronic pain. These are meaningful differences, though association cannot explain causality. The authors hypothesize that as atrophy of elements of the circuitry progresses, the pain condition becomes more irreversible and less responsive to therapy. REFERENCE Apkarian AV, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24(46):10410–10415. Les patients atteints de CBP ont 5-11% de matière grise en moins que la population normale, ce qui équivaut à ans de vieillissement normal. Images copyright 2006 by the Society for Neuroscience Apkarian AV, et al. J Neurosci. 2004;24:10410–10415.

17 La Dépression et la Douleur interfèrent avec les voies de communications intracérébrale
MDD Cognitive/executive cortex Dorsolateral PFC Dorsal ACC Douleur? Limbic formations Hippocampus Amygdala Nucleus accumbens Integrative cortex Lateral orbital PFC Rostral PFC Medial PFC Emotional/visceral cortex Ventral ACC Ventral medial PFC Hypothalamus PURPOSE OF THE SLIDE To summarize in general how depression impacts cortico–limbic circuitry. KEY POINTS Here we see a simplified graphical representation of the cortico–limbic feedback loop. If there is activation in the limbic part, this activation will lead to increased activity in the paralimbic prefrontal cortex that will then go towards integrative cortex to the executive function cortex, so it is emotion, behavior, cognition, and then shutting down the limbic system. In people who have depression, the loop never seems to close in an adaptive way. Emotions have lost their adaptive value. There is increased activity in limbic formation that persists and that drives hypothalamus and causes increased sympathetic activity that causes increase in the hypothalamic pituitary adrenal (HPA) axis. Something that has started in the mind has now propagated to the rest of the body. Pain, too, may inhibit cortico–limbic feedback, but to what degree and how is the subject of debate.1 It is these three circles on the bottom right that we have focused most of our attention on. BACKGROUND At least one study suggests that the processing of pain in limbic formations such as the hippocampus and entorhinal cortex affects connectivity with the dorsolateral prefrontal cortex (PFC) and therefore impacts the perception of chronic pain.1 Patients with functional illnesses such as depression may have altered pain processing. The mechanisms underlying altered pain processing in depression are unknown, but may include changes in the HPA axis. More subtle changes in neurotransmitter systems and other forms of neural plasticity may also contribute.2 REFERENCES Casey KL, Tran ATD. Cortical mechanisms mediating acute and chronic pain in humans. In: Handbook of Clinical Neurology. 3rd series. Boston, MA: Elsevier;2006:159–77. Borsook D, et al. Reward-aversion circuitry in analgesia and pain: Implications for psychiatric disorders. Eur J Pain. 2007;11:7–20. Illustration based on: Mayberg HS. Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin N Am. 2003;13:805–815. Drevets WC. Neuroimaging and neuropathologic studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11:240–249. Phillips ML, et al. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry. 2003;54:515–528. Ongur D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex. 2000;10:206–219. Phan KL, et al. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002;16:331–348. Siegle CJ, et al. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198–209. Tracey I. Nociceptive processing in the human brain. Curr Opin Neurobiol. 2005;15:478–487. Hariri AR, et al. Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biol Psychiatry. 2006,59:888–897. Brody AL, et al. Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Biol Psychiatry. 2001;50:171–178. ACC=anterior cingulate cortex; MDD=major depressive disorder; PFC=prefrontal cortex. Maletic V, et al. Int J Clin Pract. 2007;61:2030–2040.

18 Les changements Neuroendocriniens, Neuroimmune et les changements cellulaires dans la MDD et la douleur PURPOSE OF THE SLIDE To transition from the macro level of cortical activity and structural changes associated with mood and pain to the more micro levels of neuroendocrine, neuroimmune, and cellular changes associated with major depressive disorder (MDD).

19 Similitudes des troubles entre l’axe Hypothalamo-cortico-surrénalien et les Cytokines
Stress and Depression1,2 Pain3 PURPOSE OF THE SLIDE To introduce neuroendocrine and neuroimmune changes associated with depression, pain, and stress. KEY POINTS Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. These studies demonstrate that stress and antidepressant treatment exert opposing actions on the expression of specific neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition.1,2 Stress and depression: A mechanism by which the brain reacts to stress and depression is activation of the hypothalamus–pituitary–adrenal (HPA) axis. The activity of the HPA axis is controlled by several brain pathways, including the hippocampus (which exerts an inhibitory influence on hypothalamic corticotropin-releasing factor (CRF) containing neurons) and the amygdala (which exerts a direct excitatory influence on hypothalamic CRF containing neurons). Levels of glucocorticoids that are seen under normal physiological circumstances seem to enhance hippocampal inhibition of HPA activity and may enhance hippocampal function and therefore promote cognitive abilities. However, under sustained elevations of glucocorticoids, seen under conditions of prolonged, severe stress and possibly in patients with depression, hippocampal neurons may be damaged and reduction of neurogenesis may occur. Abnormal, excessive activation of the HPA axis has been observed in approximately half of individuals with depression.3 Patients with major depression who are otherwise medically healthy have also been observed to have activated inflammatory pathways. Activation of macrophages due to inflammatory challenges (infection, tissue damage, or destruction) may cause release of proinflammatory cytokines. These cytokines enter several areas of the afferent sensory systems and can lead to increased activity. Once in the brain, cytokines can cause altered metabolism of serotonin (5-HT) and dopamine (DA), activation of corticotrophin-releasing hormone (CRH) leading to increased serum glucocorticoid levels, and disruption of synaptic plasticity through changes in growth factors such as brain-derived neurotrophic factor (BDNF).4 Pain:5 Similarly, chronic stress evoked by chronic pain can lead to loss of negative glucocorticoid feedback on the HPA axis, driving this axis to generate more glucocorticoids by downregulation of the glucocorticoid receptor within the brain and periphery. Inflammation and nerve injury stimulate neurons in the dorsal horn of the spinal cord, which then relay pain signals to the thalamus. Monoamines in the brainstem normally descend to the spinal cord to act as a “brake” on nociceptive transmission. Increased glucocorticoid activity during chronic pain can lead to monoamine depletion in descending inhibitory systems. Loss of glucocorticoid inhibition of proinflammatory cytokines leads to increased peripheral inflammation, contributing to pain sensitization. Although acute stress is analgesic, chronic stress from chronic pain can lead to downregulation of inhibitory circuits between the limbic system and somatosensory cortex, leading to enhanced pain perception. Chronic pain-induced downregulation of inhibitory limbic-somatosensory circuits may also lead to depressed mood. REFERENCES Duman R. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56:140–145. Duman R. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 2004;5:11–25. Nestler EJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13–25. Raison CL, et al. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunol. 2006;27:24–31. Blackburn-Munro G, et al. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol. 2001;13:1009–1023. red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axis Adapted from: 1. Raison, et al. Trends in Immunol. 2006;27:24– Nestler EJ, et al. Neuron. 2002;34:13– Blackburn-Munro G, et al. J Neuroendocrinol. 2001;13:1009–1023.

20 Les Cytokines Les cytokines ont une action soit autocrine, c'est-à-dire qu'elles agissent sur la cellule sécrétrice elle-même, soit paracrine, c'est-à-dire qu'elles agissent sur les cellules voisines de celles qui les ont sécrétées, soit endocrine, c'est-à-dire qu'elles agissent à distance après avoir été véhiculées par le sang. Leur action autocrine et paracrine prédomine sur leur effet endocrine qui s'observe surtout en cas d'hypersécrétion. modes d'action : * l'activation de récepteurs membranaires * l'intervention sur plusieurs messagers intracellulaires, * une action nucléaire au niveau du génome, modifiant soit la replication du DNA (cycle cellulaire), soit sa transcription en RNA et en protéines correspondantes, responsables des effets. Chaque cytokine peut être produite par différents types de cellules et agir sur différents types de cellules. L'action d'une cytokine est généralement dépendante de celle d'une ou de plusieurs autres. Leurs effets sont interdépendants, pleiotropiques et en cascade.

21 Phagocytic immune cell
Les Cytokine inflammatoires qui Potentialisent la douleur sont modulée par les cellules gliales IL-6 TNF Dorsal IL-1 IL-1 TNF Sciatic Nerve IL-6 Glia Pathogen Dorsal horn Dorsal horn Phagocytic immune cell Gray matter Ventral horn Ventral horn Hyperalgesia White matter PURPOSE OF THE SLIDE To further illustrate the changes in neuroimmune function related to inflammatory cytokines and the neuron–glia relationship. KEY POINTS Glial activation in the spinal cord dorsal horn leads to enhancement of pain, called hyperalgesia. Activation of phagocytic immune cells (e.g., macrophages) around an otherwise healthy peripheral nerve (e.g., sciatic nerve) leads to the release of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin (IL)-1, and IL-6), as well as other proinflammatory substances that act directly on the sciatic nerve. The sensory nerves of the sciatic terminate in the spinal cord dorsal horn and, as such, inflamed nerves lead to activation of glia in this region. Glial activation results in hyperalgesia. Glia that become activated in response to these neurally derived signals, in turn, release neuroexcitatory substances, including proinflammatory cytokines (PICs), nitric oxide (NO), prostaglandins (PG), and others. REFERENCE Wieseler-Frank J, et al. Immune-to-brain communication dynamically modulates pain: Physiological and pathological consequences. Brain Behav Immun. 2005;19:104–111. Ventral IL=interleukin; TNF=tumor necrosis factor. Wieseler-Frank J, et al. Brain Behav Immun. 2005;19:104–111.

22 Symptômes Psychiatriques, associés aux Cytokines inflammatoires1–3
Fatigue Maux et douleurs Dépression et anhédonie Difficulté de concentration Anxiété et irritabilité Troubles du sommeil, de l’appetit et de la libido PURPOSE OF THE SLIDE To discuss how symptoms that have been shown to be associated with inflammatory cytokines also mirror depressive psychiatric symptoms. KEY POINTS Symptoms associated with illness and elevated cytokines are similar to the ones that are observed in major depressive disorder (MDD).1–2 Studies support elevations in cytokines and neuroinflammation in patients with MDD. Kim et al examined 48 patients with MDD who were hospitalized with 63 control subjects:3 At baseline, interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1 production, and interferon (IFN)-γ/IL-4 ratio were significantly higher, whereas IFN- γ, IL-2, and IL-4 were significantly lower in MDD patients. After treatment, IL-6 and TGF-ß1 production were significantly lower than before treatment. Activation of monocytic proinflammatory cytokines, and inhibition of both Th1 and Th2 cytokines may be associated with immunological dysregulation in MDD. REFERENCES Raison CL, et al. Neuropsychiatric adverse effects of interferon  recognition and management. CNS Drugs. 2207;19(2):105–123. Dantzer R, et al. From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Rev. 2007; doi: /nrn2297 [Epub ahead of print] Kim, Y-K, et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuro-Psychopharm Biol Psych. 2007;31:1044–1055. Raison CL, et al. CNS Drugs. 2005;19:105– Dantzer R, et al. Nat Rev Neurosci. 2008;9;46– Kim YK, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–1053.

23 Les cytokines inflammatoires peuvent interférer avec le BDNF
1.0 1.2 BDNF Relative levels 0.4 0.6 0.2 0.8 IL-1 (20 ng/mL) * IL-1 (5 ng/mL) *P=.05 Model animal PURPOSE OF SLIDE To introduce one mechanism by which cytokines may influence neuroplasticity. KEY POINTS Study with rat embryonic cortical cells showed that:1 Exposure to exposure to BDNF (10 ng/mL, 10 minutes) increased the amount of phosphorylated Akt (P-Akt). Interleukin (IL)-1ra blocks the suppression by IL-1 of brain-derived neurotrophic factor (BDNF)-induced activation of Akt. IL-1 places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. REFERENCE Tong L, et al. Interleukin-1 impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging. 2008;29:1380–1393. BDNF=brain-derived neurotrophic factor; IL=interleukin. Tong L. Neurobiol Aging. 2008;29:1380–1393.

24 Les rôles du facteur neurotrophique cérébral (BDNF)
Les BDNF et d'autres facteurs neurotrophiques sont impliqués dans la santé ou la croissance des cellules ainsi que dans l'apoptose des cellules cérébrales. Le BDNF est nécessaire pour la croissance et les fonctions du système nerveux, pour l'apprentissage et pour la mémoire. BDNF est exprimé dans le cerveau via les neurones et la glia3 Monoamine neurones tels que la sérotonine (5-HT), la norépinéphrine (NE), et la dopamine (DA), ainsi que l'acide γ-aminobutyrique (GABA) et le glutamate de neurones les Monoamines sont impliquées dans la régulation de la synthèse et de la libération de BDNF Une Downregulation des neurotrophines se produit dans la dépression, dans l’anxiété ,1-2, 4 et la douleur5 Traitement de la MDD rétabli les fonctions du BDNF PURPOSE OF THE SLIDE To introduce the role of brain-derived neurotrophic factor (BDNF) and neurotrophic factors in mediating the transition from functional to structural change in depression. KEY POINTS BDNF and neurotrophic factors may play a key role in the structural changes in depression. It is expressed through neurons—such as monoamine, γ-aminobutyric acid (GABA), and glutamate neurons—and through glia.1 BDNF may also be critical for nervous system function, and for learning and memory.2 Because depression, anxiety, and pain can all impact BDNF synthesis,3–5 treatment may restore the function of BDNF.6 Antidepressants can be an important part of that treatment.7 BACKGROUND Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. These studies demonstrate that stress and antidepressant treatment exert opposing actions on the expression of specific neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition.3 There is a growing body of evidence demonstrating that stress decreases the expression of BDNF in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures (including the hippocampus as well as the prefrontal cortex) that has been observed in depressed subjects.3 The review by Castren et al. of animal and human data states that neurotrophic factors such as BDNF do not control mood, but act as “necessary tools” in the modulation of networks and in how plastic change influences mood. Antidepressant treatment can promote neuronal plasticity by activating neurotrophic factors.2 Gervasoni et al. studied 26 DSM-IV MDD patients and 26 healthy controls. An analysis of variance found that treatment had an effect on the normalization of serum BDNF levels.6 Ivy et al. looked at the impact of both antidepressants and physical exercise on BDNF transcription in rats. Both serotonin (5-HT) and norepinephrine (NE) appeared to be important in antidepressant-induced BDNF regulation. While 5-HT activation played some role in exercise-induced BDNF regulation, NE may be the more important monoamine in exercise-induced BDNF regulation.7 REFERENCES Charney DS, et al. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Science STKE. 2004;225:re5:1–10. Castren E, et al. Role of neurotrophic factors in depression. Curr Opin Pharmacol. 2006;6:1–4. Duman RS, et al. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–1127. Chen B, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Science. 2006;314:140–143. Duric V, et al. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005;133:999–1006. Gervasoni N, et al. Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode. Neuropsychobiology. 2005:51:234–238. Ivy AS, et al. Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav. 2003;75:81–88. 1. Castren E, et al. Curr Opin Pharmacol. 2006;6:1–4. 2. Duman RS, et al. Biol Psychiatry. 2006;59:1116– Charney DS, et al. Sci STKE. 2004;225:1– Chen B, et al. Science. 2006;314:140– Duric V, et al. Neuroscience. 2005;133:999– Ivy AS, et al. Pharmacol Biochem Behav. 2003;75:81– Gervasoni N, et al. Neuropsychobiology. 2005;51:234–238.

25 La dépression récurrente et les tentatives de suicide sont corrélés avec un taux de BDNF faible
Patients avec MDD premier episode ou recurrent Patients avec MDD avec ou sans TS 2000 2000 *P<.001 *P<.001 1800 * 1800 * 1600 1600 1400 1400 1200 1200 * BDNF (pg/mL) 1000 BDNF (pg/mL) 1000 800 800 600 600 400 400 200 200 100 100 PURPOSE OF THE SLIDE To illustrate how brain-derived neurotrophic factor (BDNF) may have clinical implications for patients with major depressive disorder (MDD). KEY POINTS Plasma BDNF levels were assessed in 77 patients with MDD and 95 comparison subjects. Plasma BDNF levels were significantly lower for patients who were experiencing a recurrent episode compared with patients who were in their first episode or were control subjects (P<.001). Depressive patients with and without suicide attempts also had significantly lower plasma BDNF levels than normal controls. Plasma BDNF in suicidal depressive patients was significantly lower than in non-suicidal patients. The central box represents the values from the lower to upper quartile (25 to 75 percentile). The middle line represents the median. The line represents connects the means. REFERENCE Lee B-H, et al. Decreased BDNF levels in depressed patients. J Affect Disord. 2007;101:239–244. Normal control First episode Recurrent episode Normal control Without SA With SA BDNF plasmatique mesuré chez 77 patients avec MDD et 95 contrôles normaux BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder; TS=suicide attempt. Lee BH. J Affect Disord. 2007;101:239–244.

26 Une altération de la communication entre le neurone et la glie contribue à la MDD
PURPOSE OF THE SLIDE To illustrate implications of interaction between immune system and neural elements (glia and neurons) for patients with MDD. KEY POINTS Microglia are primary recipients of peripheral inflammatory signals that reach the brain. Activated microglia in turn initiate an inflammatory cascade whereby release of relevant cytokines, chemokines, inflammatory mediators and reactive nitrogen and oxygen species (RNS and ROS, respectively) induces mutual activation of astroglia, thereby amplifying inflammatory signals within the central nervous system (CNS). Cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α as well as interferon (IFN)-α and IFN-γ (from T cells) induce the enzyme, indolamine 2,3 dioxygenase (IDO), which breaks down tryptophan (TRP), the primary precursor of serotonin (5-HT) into quinolinic acid (QUIN), a potent N-methyl-d-aspartate (NMDA) agonist and stimulator of glutamate (GLU) release. Multiple astrocytic functions are compromised owing to excessive exposure to cytokines, QUIN and RNS/ROS, ultimately leading to downregulation of GLU transporters, impaired GLU reuptake and increased GLU release, as well as decreased production of neurotrophic factors. Of note, oligodendroglia are especially sensitive to the CNS inflammatory cascade and suffer damage due to overexposure to cytokines such as TNF-α, which has a direct toxic effect on these cells, potentially contributing to apoptosis and demyelination. The confluence of excessive astrocytic glutamate release, it’s inadequate reuptake by astrocytes and oligodendroglia, activation of NMDA receptors by QUIN, increased glutamate binding to extrasynaptic NMDA receptors (accessible to GLU released from glial elements and associated with inhibition of BDNF expression), decline in neurotrophic support, and oxidative stress, ultimately disrupt neural plasticity through excitotoxicity and apoptosis. Maletic V, Raison C. 2008, Frontiers in Bioscience, in press. Image used with permission from V. Maletic.

27 Modification de la glie dans le cortex préfrontal du patient déprimé
Immunoréactivité gliale dans le cortex préfrontal1 Contrôle (27 ans) MDD (32 ans) La réduction de la densité et du nombre de cellules gliales est l’altération majeure de la pathologie cellulaire dans la dépression1–4 PURPOSE OF THE SLIDE To highlight the glial changes associated with depression. KEY POINTS1 This slide shows glial immunoreactivity in the prefrontal cortex of a pair of subjects. On the left is a 27-year-old healthy control; on the right is a 32-year-old patient with depression. Note that in spite of similar age, astroglia in depressed subjects are less numerous, have smaller cell bodies, and tend to be less “bushy”. Overall, this study reported a 75% glia reduction in depressed patients aged 30–45 compared to age-matched controls. BACKGROUND Rajkowska and Miguel-Hidalgo reviewed glial and neuronal pathology in depression. Several postmortem studies have reported changes in astroglia packing density in mood disorders. Examination of glial fibrillary acidic protein (GFAP) immunoreactivity in the prefrontal cortex revealed a 75% reduction in young subjects compared to age-matched controls.1 As noted earlier, several reports suggest that reductions in glial cell density and number are the most prominent cell pathology noted in depression.1–4 REFERENCES Rajkowska G, et al. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6(3):219–233. Rajkowska G, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9):1085–1098. Ongür D, et al. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95(22):13290–13295. Si X, et al. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacol. 2004;29:2088–2096. Images courtesy of Bentham Science Publishers. 1. Rajkowska G, et al. CNS Neurol Disord Drug Targets. 2007;6:219– Rajkowska G, et al. Biol Psychiatry. 1999;45:1085– Ongür D, et al. Proc Natl Acad Sci USA. 1998;95:13290– Si X, et al. Neuropsychopharmacol. 2004;29:2088–2096.

28 Rôle du traitement antidépresseur dans la restoration neurobiologique
PURPOSE OF THE SLIDE At this point, the underlying structural, functional, neuroendocrine, neuroimmune, and cellular alterations have been reviewed. What is the evidence that antidepressant treatment can restore these systems?

29 Voie nociceptive ascendante
5HT et Norepinephrine modulateurs de la perception de l’humeur et de la douleur1–3 Locus coeruleus (source de NE) Raphe nuclei (source de 5-HT) Amygdala Hippocampe Voie NE descendante Voie 5HT descendante Voie nociceptive ascendante Système limbique Cortex prefrontal KEY POINTS One of the guiding principles in the development of pharmacotherapeutics for depression has been the monoamine hypothesis.1 While some findings have not been universally confirmed, there is considerable support for dysfunctional serotonergic or noradrenergic neurotransmission in patients with depression.1 Serotonin (5-HT) and norepinephrine (NE) are part of the body's endogenous analgesic system, which inhibits transmission of ascending pain signals from the periphery.2 Because 5-HT and NE are key neurotransmitters in both mood regulation and in the modulation of pain perception, it is hypothesized that increasing the activity of both 5-HT and NE may help in the treatment of mood disorders as well as in pain disorders. BACKGROUND 5-HT and NE are also involved in directly modulating pain at the level of the dorsal horn in the spinal cord. 5-HT both inhibits and facilitates the perception of pain. 5-HT inhibits pain via the descending inhibitory arm of the descending modulatory pathway, and it facilitates the perception of pain via the descending facilitatory arm of the descending modulatory pathway.2,3 NE inhibits the perception of pain via the descending inhibitory arm of the descending modulatory pathway. NE does not seem to be involved in the facilitatory aspect of pain perception in the descending modulatory pathway.2 REFERENCES Bymaster FP, et al. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11(12):1475–1493. Fields HL, et al. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 1991;14:219–245. Fields H. State-dependent opioid control of pain. Nat Rev Neurosci. 2004;5(7):565–575. 5-HT=serotonin; NE=norepinephrine. Adapted from: 1. Bymaster FP, et al. Curr Pharm Des. 2005;11:1475– Fields H. Nat Rev Neurosci. 2004;5:565– Fields HL, et al. Annu Rev Neurosci. 1991;14:219–245.

30 L’activité de l’amygdale est augmentée dans la MDD
IRM fonctionelle chez des patients avec MDD (N=11) et contrôles sains (N=11) Déprimés Contrôles 0.4 * *P<.05 compared to control 0.3 0.2 0.1 % Signal -0.1 PURPOSE OF THE SLIDE Illustrate how antidepressant treatment may normalize amygdala activity. KEY POINTS In this study, amygdala activity was measured by functional magnetic resonance imaging following presentation of emotional (fearful, neutral, happy) faces. Depressed patients had significantly greaterleft amygdala activation to face presentation than control subjects, but did not differ significantly in right amygdala activation. Following 8-week antidepressant treatment, subjects had significant reduction in both right and left amygdala activation in response to all face presentations. Meanwhile, Hamilton Depression Rating Scale (HAMD)-17 scores were reduced from 23.3 to 9.7. BACKGROUND 11 DSM-IV depressed, right-handed adult patients were matched with 11 controls. In addition, depressed subjects had HAM-D17 scores >17, while controls had scores <8. Subjects were presented with masked fearful (F), masked neutral (N), and masked happy (H) faces for 40 msec followed by a 160-msec neutral face presentation. Depressed subjects were treated with the selective serotonin reuptake inhibitor sertraline at doses titrated according to clinical response. REFERENCE Sheline YI, et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50:651–658. -0.2 -0.3 Amygdale gauche Amygdale droite Sheline YI, et al. Biol Psychiatry. 2001;50:651–658.

31 L’action de l’antidépresseur au niveau intacellulaire neuronal
5-HT NE neuro- plasticity PKA CaMK synapto- genesis cell survival BDNF neuro- genesis PURPOSE OF THE SLIDE To illustrate how monamines affects cellular signaling and therefore can increase brain-derived neurotrophic factor (BDNF). KEY POINTS Here you see a serotonin (5-HT) receptor and norepinephrine (NE) receptor on the cell membrane. 5-HT and NE bind to these receptors, which are linked to G-proteins and an array of second messenger signal transduction systems, which ultimately change gene transcription at the level of DNA. The ultimate, targeted increase in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) may lead to increased cell survival through synaptogenesis, neuroplasticity, and neurogenesis. This is just the opposite of what happens in depression. 5-HT and NE may be gateways to neurogenesis in areas of the brain known to be involved in depression. REFERENCE Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge UP: New York, NY; 2008. CREB 5-HT=serotonin; BDNF=brain-derived neurotrophic factor; CaMK=calcium-calmodulin-dependent kinase; CREB=cAMP response element binding protein; NE=norepinephrine; PKA=protein kinase A. Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge UP: New York, NY; Copyright permission granted by Neuroscience Education Institute

32 Réponse des astrocytes aux neurotransmeteurs†
Les monoamines régulent la synthèse du BDNF dans une culture astrocytaire Réponse des astrocytes aux neurotransmeteurs† DA 150μM 5-HT 1μM NE 1μM Baseline 1mM 1mM PURPOSE OF THE SLIDE Further support to show that monoamines regulate brain-derived neurotrophic factor (BDNF) synthesis. KEY POINTS In animal (rat) studies, Juric et al. looked at how the monoamines norepinephrine (NE), serotonin (5-HT), and dopamine (DA) affected BDNF levels in cortical and cerebellar astrocytes, two areas where BDNF is produced.1 While the introduction of all three monoamines over the course of 4 hours translated into elevated BDNF levels, NE did so at four times that of baseline. 5-HT and DA did so at roughly twice the degree of baseline levels. By increasing BDNF levels, all three monoamines may provide trophic support against neurodegenerative and mood disorders. BACKGROUND In the authors’ previous study, it was demonstrated that neonatal rat cortical and cerebellar astrocytes in primary culture contain significant amounts of BDNF protein, therefore confirming the ability of non-neuronal cells (astrocytes), like neurons, to synthesize BDNF.2 This study illustrated above looked at NE, 5-HT, and DA in rat cortical and cerebellar astrocytes. Cells were incubated for 4 hours in serum-free medium containing H20 control cells or each monoamine.1 A single application of the neurotransmitters evoked upregulation of BDNF cellular content in the astrocytes. BDNF returned to basal levels when incubation was extended beyond 12 hours (for 5-HT) and 24 hours (for NE and DA). REFERENCES Juric DM, et al. Monoaminergic neuronal activity up-regulates BDNF synthesis in cultured neonatal rat astrocytes. Brain Research. 2006;1108:54–62. Miklic S, et al. Differences in the regulation of BDNF and NGF synthesis in cultured neonatal rat astrocytes. Int J Dev Neurosci. 2004;22:119–130. NE augmente le BDNF de 4 fois ou plus dans les astrocytes corticaux et cérebelleux; la 5-HT et la DA provoquent une augmentation de 2 x. †Cultured astrocytes incubated for 4 hours with monoamine neurotransmitters; 5-HT=serotonin; BDNF=brain-derived neurotrophic factor; DA=dopamine; NE=norepinephrine. Juric DM, et al. Brain Research. 2006;1108:54-62.

33 La remission est le but du traitement
PURPOSE OF THE SLIDE To return to the clinical relevance of restoration of the underlying neurobiology – why remission needs to be the goal.

34 L’obtention de la rémission est difficile
Influence sur la capacité de travail Condition physique1,2 Fonctionnement social1,2 Répercussion sur le bien-être des enfants3 La vie matrimoniale4 Risque de futurs épisodes1,2 Risque de suicide5 Rémission (ou non) Peut avoir un effet sur… PURPOSE OF THE SLIDE Draw attention to the many potential consequences of depression. KEY POINTS It’s important to note some of the potential consequences of untreated depression. For the individual, both physical and occupational function can be compromised, as can one’s social life.1,2 Relationships with spouses can be put at risk.3 And, as Weissman’s research has shown, the mental health of children of depressed parents can be greatly impacted.4 Without complete remission, future episodes become more likely.1,2 And, of most concern, suicidality (suicidal ideation and suicidal attempts) can increase in those patients who do not achieve remission.5 BACKGROUND The naturalistic longitudinal observational study by Sobocki et al. of 447 depressed patients found depressive symptoms to be associated with substantially decreased physical, mental, and social functioning. A longer time to, or lack of, remission was associated with negative consequences such as a greater likelihood of future episodes.1 Keller conducted an expansive review of past, present, and future directions in depression treatment, reiterating the importance of achieving remission in treatment and outlining key physical and psychosocial factors involved in patients’ lives.2 Bromberger et al found non-remitted women to have higher dissatisfaction toward their husbands.3 151 children (aged 7–17) whose depressed mothers were being treated with medication as part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were assessed to determine whether effective treatment of their mothers was associated with reduction of symptoms and diagnoses in the children.4 Judd et al looked at the impact of subsyndromal symptoms of depression (SSD) and found that persistent SSD were associated with increased lifetime suicidal ideation and suicide attempts.5 REFERENCES Sobocki P, et al. The mission is remission: health economic consequences of achieving full remission with antidepressant treatment for depression. Int J Clin Pract. 2006;60:791–798. Keller MB. Past, present and future directions for defining optimal treatment outcome in depression. JAMA. 2003;289:3152–3160. Bromberger JT, et al. Marital support and remission of treated depression: a prospective pilot study of mothers of infants and toddlers. J Nerv Ment Dis. 1994;182:40–44. Weissman MM, et al. Remissions in maternal depression and child psychopathology: a STAR*D-child report. JAMA. 2006;295:1389–1398. Judd LL, et al. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord. 1997;45:5–18. 1. Sobocki P, et al. Int J Clin Pract. 2006;60:791– Keller MB. JAMA. 2003;289:3152– Weissman MM, et al. JAMA. 2006;295:1389– Bromberger JT, et al. J Nerv Ment Dis. 1994;182:40– Judd LL, et al. J Affect Disord. 1997;45:5–17.

35 Diminution de la matière grise chez des patients non-rémission comparés à des patients ayant atteint la rémission 3 année d'étude prospective comparant 38 patients avec 30 contrôles sains Baisse significativement plus importante de la densité de matière grise a été noté dans la non-rémission comparé à la rémission des patients MDD dans: Hippocampe Cortex cingulaire anterieur Cortex dorsomédial préfrontal Cortex dorsolatéral préfrontal Significativité à P<0.01 PURPOSE OF THE SLIDE To illustrate the relevance of remission to the underlying neurobiology. KEY POINTS A revisit of the study previously showing prospectively that depression was associated with a decline in gray matter density and to point out that there were differences based on the remission status of the patients. Patients who achieved remission during the prospective study had significantly less gray matter density decline than patients who were not able to achieve remission. REFERENCE Frodl TS, et al. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry. 2008;65(10):1156–1165. Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165.

36 *P=.029 compared with control
Un taux de cortisol plasmatique élevé peut prédire une rechute chez les patients MDD (Dex/CRH Neuroendocrine Test) 38 patients en rémission d’une MDD, suivi 12 mois 250 Rémission prolongée (N=20) Rechute dépressive (N=12) 200 Contrôles (N=24) 150 Cortisol (nmol/L) * 100 50 *P=.029 compared with control PURPOSE OF THE SLIDE To illustrate that remission of underlying neurobiological changes are also important for reducing risk of relapse. KEY POINTS Thirty-eight depressed outpatients (23 women, 15 men) in remission (Montgomery–Asberg Depression Rating Scale [MADRS] score <8) underwent the dexamethasone/corticotropin-releasing hormone (dex/CRH) test and were followed up for 12 months regarding the occurrence of a new depressive episode and were compared with 24 controls (13 men, 11 women). Figure shows the mean cortisol plasmatic levels and standard error of the mean (SEM) before 1-year follow-up for the depressive relapse group, prolonged remission group and control group. High delta and area under the curve (AUC) values in the DEX/CRH test compared with controls subjects can be associated with a higher risk of relapse. REFERENCE Aubry J-M, et al. The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressive outpatients. J Psych Res. 2007;41:290–294. 2:45 3:00 3:30 3:45 4:00 4:15 4:30 Time (PM) Dex/CRH=dexamethasone/corticotropin-releasing hormone; MDD=major depressive disorder. Aubry JM, et al. J Psychiatr Res. 2007;41:290–294.

37 Facteurs obstacles à la rémission et qui peuvent prédire la récurrence
Stresseurs aigüs et chroniques1,2 Sévérité et durée de l’épisode dépressif1,2 Echecs des traitements antérieurs2 Anxiété1 Symptômes somatiques douloureux3 Troubles de la personnalité2 Abus de substances4 Maladies somatiques4 Récurrence Sévérité, nombres et durées des épisodes précédants5 Mauvais contrôle des symptômes (subsyndromal symptoms)5 Comorbité anxieuse et abus de substances5 Symtômes somatiques douloureux6 Evènements stressants7 Stratégies d’adaptations insuffisantes ou inadéquates7 PURPOSE OF THE SLIDE To discuss a number of factors that may be associated with inability to achieve remission. KEY POINTS Parker et al examined 182 patients with major depressive disorder (MDD) and prospectively followed them for 12 months. Non-recovery was predicted most consistently by higher baseline levels of anxiety and depression; high trait anxiety and a lifetime anxiety disorder; disordered personality function; and having reported exposure to acute and enduring stressors at baseline assessment.1 Task force summary of recommendations for defining remission, relapse, and recovery. Discussed factors associated with remission: the type, dose, and duration of treatment; baseline symptom severity; the degree of treatment resistance; the presence of concurrent Axis I, II, or III conditions; environmental supports and stressors; the prior course of illness (e.g., chronic versus acute illness); and individual genetic vulnerability.2 Fava discusses that treating physical as well as psychological symptoms of depression may result in higher percentages of patients achieving remission.3 Other factors identified as associated with remission or lack of remission from clinical perspective, epidemiologic data, and a prospective study.4–7 REFERENCES Parker G, et al. Predictors of 1-year outcome in depression. Aust N Z J Psychiatry. 2000;34(1):65–70. Rush AJ, et al. ACNP Task Force. Report by ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31(9):1841–1853. Fava M. Depression with physical symptoms: Treating to remission. J Clin Psych. 2003;64(suppl 7):24–28. Keller MB. Issues in treatment-resistance depression. J Clin Psych. 2005;66(suppl 8):5–12. Keller MB. The long-term treatment of depression. J Clin Psych. 1999;60(suppl 17):41–45; discussion 46–48. Ohayon MM. Specific characteristics of the pain/depression association in the general population. 2004;65(suppl 12):5–9 Bockting CL, et al. Depression Evaluation Longitudinal Therapy Assessment Study Group. Prediction of recurrence in recurrent depression and the influence of consecutive episodes on vulnerability for depression: a 2-year prospective study. J Clin Psychiatry. 2006;67(5):747–-755. 1. Parker G, et al. Aust N Z J Psychiatry. 2000;34:56– Rush AJ, et al. Neuropsychopharmacology. 2006;31:1841– Fava M. J Clin Psychiatry. 2003;64(suppl 7):24– Keller MB. J Clin Psychiatry. 2005;66(suppl 8):5– Keller MB. J Clin Psychiatry. 1999;60(suppl 17):41– Ohayon MM. J Clin Psychiatry. 2004;65(suppl 12):5–9. 7. Bockting CL, et al. J Clin Psychiatry. 2006;67:747–755.

38 L’amélioration des symptômes douloureux dans la MDD augmente les chances de rémission
100 *P<.001 2 pooled studies * 36% Patients en rémission (études de 9-semaines) (%) 18% N=77 N=49 50% Amélioration des symptômes Physiques douloureux 50% Amélioration des symptômes physiques douloureux PURPOSE OF THE SLIDE Not only is pain common among patients with depression, but improvement of pain symptoms associated with depression may improve chances for remission. Successful treatment of pain symptoms may be an important consideration for optimizing depression treatment outcomes. KEY POINTS Pain symptoms associated with depression may have an important impact on depression outcomes. In the two 9-week studies by Fava, successful treatment of pain was associated with a significantly greater chance of achieving remission. Note: The two groups (of ≥50% or <50% improvement in painful physical symptoms) were not divided based on treatment given, so both groups could contain patients randomized to either active treatment or placebo. These findings underscore the urgency to address painful symptoms along with other prominent symptoms of depression. BACKGROUND In the Fava study, pooled data from two different studies where patients were randomized to receive active treatment (N=244) or placebo (N=251) revealed a similar relationship in the remission rate. The remission rate for pain responders (50% improvement in Visual Analog Scale [VAS] overall pain) was twice that observed for pain nonresponders (36.2% versus 17.8%, P<.001). Of 495 patients with depression: Remission was defined as a Hamilton Depression Rating Scale (HAMD)-17 total score 7. Painful physical symptom improvement was measured by VAS for overall pain from baseline to last observation of 50% or greater. Patients showing a pain response within the first two weeks of starting therapy had an estimated 35.4% probability of achieving depressive symptom remission versus 20.9% for patients not showing early pain response. REFERENCE Fava M, et al. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry. 2004;65(4):521–530. Rémission=HAMD-17 total score 7 Fava M, et al. J Clin Psychiatry. 2004;65:521–530.

39 Conclusions Il est important de choisir le traitement le plus efficace, le risque d’échouer d’obtenir la rémission, conduit à des rechutes plus fréquentes Le succès du traitement limite les changements fonctionnels, empêchant ainsi les modifications de structure durables La rémission permet la normalisation des fonctions immunitaires et neuroendocriniennes Une thérapie efficace optimise les supports neurotrophiques et favorise les effets neuroprotecteurs, la plasticité synaptique et la neurogenèse La rémission de tous les symptômes dépressifs, y compris des douleurs et les conséquences systémiques, est le but ultime du traitement PURPOSE OF THE SLIDE To summarize the key take home messages from the presentation. KEY POINTS Evidence has been presented that depression is a complex disorder. For many patients, depression is a recurrent illness and with recurrence, the illness itself becomes progressively chronic and associated with long-term changes in the underlying neurobiology. The underlying neurobiology of depression has shown disruptions in connectivity and communication within brain regions and resulting structural changes. Many of the deregulation associated with depression also play a role in the processing and perception of pain, resulting in depressed patients being vulnerable to painful physical symptoms. Lack of remission continues to have significant risks associated for the patient; therefore, treatment interventions need to target both the emotional and painful physical symptoms of depression.