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Recent Advances In Neurobiology &Treatment Of Major Depression

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1 Recent Advances In Neurobiology &Treatment Of Major Depression
Background: While research continues to suggest the progressively pathological nature of major depression, new models propose that some pathophysiological effects of this disease may be slowed or altered; many clinicians support the theory of the disruption of the mind-body connection associated with depression1,2; as a result, symptomatic and functional improvement may be an increasingly recognized benchmark for establishing treatment goals; this thought-provoking presentation will review the latest clinical scientific advances and theories associated with the treatment and arresting major depressive disorder (MDD) References: Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70(8): Szelényi J, Vizi ES. The catecholamine cytokine balance: interaction between the brain and the immune system. Ann N Y Acad Sci. 2007;1113: Rakesh Jain, MD, MPH Associate Clinical Professor Department of Psychiatry & Beh. Sciences University of Texas Medical School Houston, Texas Assistant Clinical Professor Department of Psychiatry Texas Tech Medical School Midland, Texas Director, Psychiatric Drug Research Adult, Child and Adolescent R/D Clinical Research, Inc Lake Jackson, Texas .

2 A 20th Century Clinician’s View of Depression (“so yesterday… !”)
Major Depression Bio Psycho Social

3 For the 21st Century’s Clinician – A New Way to Look at Depression
Cellular Cell growth/survival/death Cell morphology: dendritic remodeling Molecular Susceptibility genes Protective genes Transcription factors mRNA Systems Critical neuronal circuitry Behavior Cognitive/Affective/Sensorymotor Environment Neurotransmission: Neurotransmitters and Neuropeptides Synaptic connectivity Environmental factors (including external environment: psychosocial stressors, sleep deprivation, internal environment gonadal/HPA steriods) PKC & MARCKS GSK-3 & substrates CREB & BDNF ERK MAP kinase Bcl-2 family of proteins) HPA = Hypothalamic-Pituitary-Adrenal; PKC = protein kinase C; MARCKS = myristoylated alanine-rich C kinase substrate; GSK = glycogen synthase kinase; CREB = cAMP responsive element binding; BDNF = brain-derived neurotrophic factor; ERK = extracellular signal regulated kinase; MAP = mitogen activated protein Schloesser RJ, Reviews 33:

4 Another Issue in Attempting Optimization of Outcomes – Appreciating the Cumulative Effect of Risk Factors on Depression 35 Controls (nonmaltreated) History of maltreatment 30 5-HTTLPR s/s BDNF val66met Low social support 25 Mood and Feeling Questionnaire (MFQ) Depression Scores 20 15 10 5 Risk Factors Study included 196 children (109 maltreated and 87 nonmaltreated controls) Adapted from: Kaufman J, et al. Biol Psychiatry. 2006;59(8): 4

5 Childhood Adversity Represents a Risk for Adulthood Disease
70 60 50 40 30 20 10 0 (n=502) 1 (n=253) Number of Adverse Childhood Experiences % of Study Members With the Condition Speaker Direction: This slide illustrates the role that adverse childhood psychosocial experiences (ie, stress) may have in the pathophysiological processes leading to age-related diseases Based on this research, the authors concluded that the effects of adverse childhood experiences on age-related disease risks in adulthood were nonredundant, cumulative, and independent of the influence of established developmental and concurrent risk factors This figure illustrates the distribution of mean prevalence of adult depression (panel 1), elevated inflammation (panel 2), and the clustering of metabolic risk markers (panel 3); each increased as a function of the number of adverse childhood experiences; furthermore, panel 4 shows that the risk of developing 1 or more of these 3 adult conditions was related to the number of adverse childhood experiences in a dose- response fashion Adverse psychosocial experiences in childhood are likely to be accompanied by other developmental risk factors for poor adult health, including family history of disease, low birth weight, and a history of being overweight in childhood Background: The purpose of this study was to evaluate the contribution of adverse psychosocial experiences in childhood to 3 adult conditions that are known to predict age-related diseases: depression, inflammation, and the clustering of metabolic risk markers; low socioeconomic status, maltreatment, and social isolation were identified as adverse psychosocial childhood experiences in this study Study members (N=1037) were born between April 1972 and March 1973 in Dunedin, New Zealand, and participated in the first follow-up assessment at age 3; assessments were carried out at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, and 32; the data shown were based on study members who completed the assessment at age 32 (n=972; 95.8% of the 1015 study members still alive in ) During the first decade of life, study members were assessed for exposure to 3 adverse psychosocial experiences (low socioeconomic status, maltreatment, and social isolation); psychiatric and physical examinations were conducted at age 32 for study members who provided blood samples (obtained by venipuncture); 26 pregnant women were excluded from the reported analyses Reference: Danese A, Moffitt TE, Harrington H, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. 2009;163(12): Panel 1: Major Depression Panel 2: hsCRP >3 mg/L Panel 3: Clustering of Metabolic Risk Markers Panel 4: ≥1 Disease Risk 32-year prospective study. Major depression (panel 1): z=4.94, P<.001. High-sensitivity C-reactive protein (hsCRP) level  3 mg/L (panel 2): z=3.24, P=.001. Clustering of metabolic risk markers (panel 3): z=4.58, P<.001. 1 age-related disease risks (panel 4): z=5.66, P<.001. Adapted from Danese A, et al. Arch Pediatr Adolesc Med. 2009;163(12):

6 Limbic Structures and Paralimbic Cortex
Cingulate gyrus Thalamus Anterior cingulate cortex (ACC) Hippocampus Speaker Direction: This slide serves as a reminder of the key portions of the brain that we believe are most involved in depression: the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC) The ACC and PFC are involved in planning, which may explain why some patients with depression have difficulty with even minor decisions1-4 The orbital frontal cortex (OFC) is involved in social interaction and maternal behavior5,6 The hippocampus, in addition to its role in memory, also provides feedback to the hypothalamic-pituitary-adrenal (HPA) axis1 The amygdala is also involved in memory, but particularly the emotional valence of an event or memory1 Background: The hippocampus is important for the forming and perhaps long-term storage of associative and episodic memories; included in the functions of hippocampal circuitry are control of learning and memory and regulation of the HPA axis, both of which are altered in depression; the hippocampus has connections with the amygdala and PFC, regions that are more directly involved in emotion and cognition, and thereby contribute to other major symptoms of depression1 The amygdala performs primary roles in the formation and storage of memories associated with emotional events; the amygdala is also involved in the modulation of memory consolidation1 The ACC can be divided anatomically based on attributed functions into executive (anterior), evaluative (posterior), cognitive (dorsal), and emotional (ventral) components; the ACC seems to be especially involved when effort is needed to carry out a task such as in early learning and problem solving; it may also be involved in functions such as error detection, anticipation of tasks, motivation, modulation of emotional responses, and for rendering new memories permanent1 The PFC is divided into the lateral, orbitofrontal, and medial prefrontal areas and is involved in "executive functions," such as working memory, decision making, planning, and judgment; it is thought that the reduced ability to recall the context of memories that occurs with advancing age is evidence that the PFC is also critical for context processing1; the ventromedial PFC receives integrated sensory information from the orbital PFC as well as fear- and reward-related input from the amygdala, medial temporal lobe, and nucleus accumbens; the ventromedial PFC projects to the hippocampus, diencephalon, and brainstem, where it regulates autonomic and neuroendocrine response and pain modulation2; the orbital PFC plays a role in correcting and inhibiting maladaptive, perseverative, and emotional responses3; hyperactivation of the orbital PFC is not seen in patients with mania4 The OFC has also come to be viewed as a critical site related to maternal behavior; mothers exhibited bilateral activation of the OFC while viewing pictures of their own vs unfamiliar infants; this also translated into the mothers rating their own moods more favorably while viewing pictures of their own infants5; Kringelbach et al used magnetoencephalography (MEG) in adults to show that brain activation in the medial OFC occurred within a seventh of a second in response to infant faces, but not to adult faces6 References: Charney DS, Nestler EJ, eds. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 2004. Öngür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3): Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49: MacDonald AW III, Cohen JD, Stenger VA, et al. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science. 2000;288(5472): Nitschke JB, Nelson EE, Rusch BD, et al. Orbitofrontal cortex tracks positive mood in mothers viewing pictures of their newborn infants. Neuroimage ;21(2): Kringelbach ML, Lehtonen A, Squire S, et al. A specific and rapid neural signature for parental instinct. PLoS ONE. 2008;3(2):e1664. Prefrontal cortex (PFC) Nucleus accumbens Amygdala Schloesser RJ, et al. Neuropsychopharmacology. 2008;33(1): Reprinted with permission from Macmillan Publishers Ltd.

7 Macro and Microscopic Structures Involved in Mood Disorders
` Schloesser RJ, Reviews 33:

8 Reduced dendritic arborization
Compromised neurotrophic support may alter synaptic structure in mood disorders Hippocampal Pyramidal Neurons SPEAKER DIRECTION This slide illustrates the conceptual shift toward the importance of neurogenesis in depression. In depression, we have decreased BDNF and a deficiency in neurotrophhic support, seen here in the hippocampus.1,2 Antidepressants may reverse this and here you can see the dendrites start to normalize with antidepressant treatment. Increased dendritic sprouting would be expected to help restore neuronal communication and neuronal circuits in depressed patients, which may then allow for symptom remission. A few important caveats should be noted:4,5 BDNF is more complex than what we have alluded to. It can be helpful in restoring normal physiology in depression in certain areas of the brain. However, BDNF in other areas of the brain can have depressogenic effects. In short, BDNF is not all good or all bad. It is also important to know that BDNF is one of many neurotrophic factors And finally, determining serum BDNF levels are not currently helpful in treating patients clinically. BACKGROUND Severe stress can cause several changes in these neurons, including a reduction in their dendritic branching, and a reduction in BDNF expression (which could be one of the factors mediating the dendritic effects).1 Antidepressants are thought to produce the opposite effects: they increase dendritic branching and BDNF expression of these hippocampal neurons. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus, and therefore may ameliorate certain symptoms of depression.1 Treatment of depression is attained by providing both trophic and neurochemical support; the trophic support restores normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. BDNF also facilitates the release of neurotransmitters that act on this restored, intact circuit. Administration of antidepressant treatments can prevent stress-induced decreases in BDNF levels.2 There is also evidence that antidepressants increase hippocampal BDNF levels in humans.3 Antidepressant induction of BDNF is at least partly mediated via the transcription factor CREB (cAMP response element binding protein). Antidepressant-induced up regulation of BDNF could help repair some stress-induced damage to hippocampal neurons and protect vulnerable neurons from further damage increased BDNF levels induced by antidepressants may promote hippocampal function. The findings could also explain why an antidepressant response is delayed: it would require sufficient time for levels of BDNF to gradually rise and exert their neurotrophic effects. Pittenger et al’s thorough review article on the topic of stress, depression, and neuroplasticity discusses the various neurotrophic factors, in particulary vascular endothelial growth factor (VEGF), that can be involved in depression. The article also discusses the “striking” differences between the role of neurotrophic factors on the amygdala as opposed to the hippocampus and prefrontal cortex (PFC).4 Martinowich et al note that BDNF may have “different and opposing” roles in the brain stress system and in the brain-reward system, including the nucleus accumbens.5 REFERENCES Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13-25. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15: Chen B, Dowlatshahi D, MacQueen GM, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50: Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33: Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nature Neuroscience. 2007;10(9): Normal dendritic arborization Depression Reduced dendritic arborization Micrograph1 Graphic representation2 1. Manji HK, et al. Biol Psychiatry. 2003;53: 2. Nestler EJ, et al. Neuron. 2002;34:13-25.

9 38 Female Outpatients With Recurrent Depression in Remission
Correlation Between Hippocampal Volume and Duration of Untreated Depression* 38 Female Outpatients With Recurrent Depression in Remission 6000 R2=.28 *P=.0006 n=38 5500 5000 Total Hippocampal Volume (mm3) 4500 4000 KEY POINTS In this study, letting depression go untreated was found to have deleterious effects on overall neuronal health. Untreated time depressed was significantly inversely related to hippocampal volume, with longer periods of untreated depression correlated with lower total hippocampal volume. BACKGROUND 38 outpatient female subjects with recurrent depression in remission were recruited for this study. Subjects were screened for medical problems and were specifically screened for incipient dementia. DSM-IV criteria were used to determine past episodes of major depression as well as for exclusion of other psychiatric diagnoses. Hippocampal volumes were measured using MRI scans. Total time treated was not found to be correlated with hippocampal volume. REFERENCE Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8): 3500 3000 1000 2000 3000 4000 Days of Untreated Depression *Significant inverse relationship between total hippocampal volume and the length of time depression went untreated. Sheline YI, et al. Am J Psychiatry. 2003;160(8): 9

10 Decreased Activity in Dorsolateral PFC and Dorsal ACC in Patients With MDD
Areas of increased activation in patients with MDD at rest red and decreased activation blue compared with controls Increased activity: lateral orbital PFC, ventromedial PFC, amygdala, thalamus, caudate Decreased activity: dorsolateral PFC, insula, pregenual and dorsal ACC, superior temporal gyrus Speaker Direction: These images demonstrate the areas of significant differences across 2 analyses (blue indicates decreased and red indicates increased activation) at rest compared with controls A total of 8 areas were identified as showing decreased activation in patients with MDD compared with controls, including: dorsolateral PFC and dorsal ACC, pregenual anterior and posterior cingulate, bilateral middle frontal gyri, insula, and left superior temporal gyrus Areas identified as “overactive” in patients with MDD included a series of deeper brain structures (eg, thalamus, caudate, and medial and inferior frontal gyri) as well as cortical structures, including the left superior frontal and right middle frontal gyri These data suggested to researchers that depression appeared to involve a considerable number of diverse cortical and subcortical brain regions and that there were significant differences in the way in which differing regions were abnormally active Background: The authors conducted multiple MEDLINE searches to initially identify all imaging studies (positron emission tomography [PET], functional magnetic resonance imaging [fMRI], single photon emission computerized tomography [SPECT]) including patients with depressive disorders published until early 2006; the search included the Medical Subheadings (MeSH) term of MDD as well as the keywords of ‘‘depressive disorder,’’ ‘‘depression,’’ ‘‘imaging,’’ ‘‘fMRI,’’ ‘‘PET,’’ and ‘‘SPECT”; in addition, they searched the reference list of identified articles and several reviews; studies were excluded if they were exclusively of patients with bipolar disorder; a total of 130 studies were initially identified by this process; a large number of studies were excluded due to the absence of coordinates; these images are from the resulting 38 studies included in the analysis Since 1998 a large number of functional imaging studies have been conducted in an attempt to help elucidate brain processes in MDD; however, because of the diversity of imaging techniques and the large number of studies, it has been difficult to gain a comprehensive understanding of the information the studies have provided; in recent years, a technique has been developed to aid in the understanding and integration of neuroimaging results gathered across studies; this technique is known as function-location meta-analysis; the most commonly applied is the activation likelihood estimation (ALE) technique The aim of this study was to quantitatively analyze the results of a large number of neuroimaging studies performed in the investigation of the pathophysiology of MDD; the findings suggest that despite the complexity and diversity of the imaging methods studied, there appears to be a pattern of distributed brain regions involved in the pathophysiology of this illness that may be identified and characterized with these techniques Reference: Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp. 2008;29(6): Fitzgerald PB, et al. Hum Brain Mapp. 2008;29(6): Reprinted with permission from John Wiley & Sons, Inc. 7

11 Comparison of 15 Subjects With MDD and 14 Healthy Controls
There Was a Correlation Between Gray Matter Volumetric Changes in MDD and Clinical Symptoms Comparison of 15 Subjects With MDD and 14 Healthy Controls Regions showing a negative correlation between gray matter concentration and depression severity p<0.05 Adjusted VBM Responses, Dorsolateral PFC (Brodmann Area 46) MADRS Score -0.1 -0.05 0.05 0.1 15 17 19 21 23 25 27 29 31 Adjusted VBM Responses, Medial Orbital PFC (Brodmann Area 11) MADRS Score -0.1 -0.05 0.05 0.1 15 17 19 21 23 25 27 29 31 r=-0.53 r=-0.57 Speaker Direction: These MRI images depict gray matter concentration reductions in patients with depression; in the lower panels, the adjusted gray matter concentration in the dorsolateral PFC and medial orbital PFC is plotted against the degree of depression severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) Significant correlations were found between MADRS scores and reduced gray matter concentration in the right dorsolateral PFC (r=-0.53) and the right medial orbital PFC (r=-0.57) Background: 15 right-handed subjects (6 females) meeting DSM-IV criteria for MDD (excluding subjects with concurrent Axis I disorders) and 14 right-handed healthy controls (6 females) matched for age, handedness, education, and fluid intelligence, were evaluated to investigate the relationship between affective symptoms, cognitive deficits, and structural abnormalities Reference: Vasic N, Walter H, Hose A, Wolf RC. Gray matter reduction associated with psychopathology and cognitive dysfunction in unipolar depression: a voxel-based morphometry study. J Affect Disord. 2008;109(1-2): MADRS=Montgomery-Asberg Depression Rating Scale. VBM=voxel-based morphometry. Vasic N, et al. J Affect Disord. 2008;109(1-2): Reprinted with permission from Elsevier Limited.

12 Neuroendocrine, Autonomic, and Immune Dysregulation in MDD
Speaker Direction: Mounting evidence suggests that inflammation may play a role in neuropsychiatric illnesses including major depression; this figure represents the inflammation-depression hypothesis and depicts the stress-induced activation of the inflammatory response involving both the sympathetic nervous system and HPA axis pathways The figure describes the following: Psychosocial stressors activate the CNS circuitry, including corticotropin-releasing hormone (CRH) and, ultimately, sympathetic nervous system outflow pathways via the locus coeruleus Acting through alpha and beta adrenergic receptors, catecholamines released from sympathetic nerve endings can increase inflammatory signaling molecule (eg, nuclear factor kappa B [NF-κB]) DNA binding in relevant immune cell types (including macrophages), resulting in the release of inflammatory mediators that promote inflammation; proinflammatory cytokines can access the brain, induce inflammatory signaling pathways, including NF-κB, and ultimately contribute to altered monoamine metabolism, increased excitotoxicity, and decreased production of relevant trophic factors Cytokine-induced activation of CRH and the HPA axis in turn leads to the release of cortisol, which, along with efferent parasympathetic nervous system pathways (eg, vagus nerve), serve to inhibit NF-κB activation and decrease the inflammatory response In the context of chronic stress and the influence of cytokines on glucocorticoid receptor function, activation of inflammatory pathways may become less sensitive to the inhibitory effects of cortisol, and the relative balance between the proinflammatory and anti-inflammatory actions of the sympathetic and parasympathetic nervous systems, respectively, may play an increasingly important role in the neural regulation of inflammation Interestingly, patients with depression with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses; preliminary data from patients with inflammatory disorders, as well as medically healthy patients with depression, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication Reference: Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9): CRH=corticotropin-releasing hormone. NF-κB=nuclear factor kappa B. ACTH=adrenocorticotropic hormone. Miller AH, et al. Biol Psychiatry. 2009;65(9): Reprinted with permission from Elsevier Limited.

13 Comparison of 5 Patients With MDD and 5 Matched Healthy Controls
Inflammatory Cytokine Levels Were Associated With Symptom Severity in Patients With MDD Comparison of 5 Patients With MDD and 5 Matched Healthy Controls A. Concentration B. Guilt C. Sadness 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.4058 P=.05 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.6711 P=.004* 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.5139 P=.02 Daily Mean VAS Score (mm) 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.735 P=.002* D. Self-Esteem 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.7785 P=.0007* E. Suicidal Thoughts 0.5 1.0 1.5 2.0 2.5 20 40 60 80 100 120 R2=0.566 P=.02 F. Tiredness Speaker Direction: These figures depict the correlations between daily ( h) mean log-transformed plasma IL-6 levels and Visual Analog Scale (VAS) scores for concentration (A), guilt (B), sadness (C), self-esteem (D), suicidal thoughts (E), and tiredness (F) in 5 patients with MDD and 5 matched controls; note that for each measure, a lower VAS score denoted a worse feeling IL-6 levels correlated significantly with most of the negative feelings commonly associated with MDD, including concentration, guilt, self-esteem, sadness, suicidal thoughts, and tiredness; asterisks next to the p-values indicated that correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction Background: IL-6 is a pleiotropic inflammatory cytokine that, in addition to its essential immune effects, exerts a plethora of neuroendocrine, hemostatic, and behavioral actions In this study, researchers compared plasma IL-6 levels measured hourly around the clock in patients with MDD (n=9; mean age=34.7) and healthy controls (n=9; mean age=34.3) matched by gender, age (5 years), body mass index (2 kg/m2), and menstrual cycle phase; diagnosis of MDD was confirmed by SCID Axis I diagnostic criteria; subjects’ perception of current mood state was assessed by a 10-item VAS-based questionnaire to allow self-report according to the DSM-IV criteria for MDD; the items of the questionnaire included: sadness, withdrawal, guilt, tiredness, appetite, craving for sweets/starches, concentration, self-esteem, suicidal thoughts, and physical discomfort Only 5 patients with MDD and matched controls completed the administered multiple- VAS questionnaire; because of the small number of subjects, correlations between daily mean IL-6 levels and VAS scores were tested in the pooled subject population Reference: Alesci S, Martinez PE, Kelkar S, et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab. 2005;90(5): Daily Mean VAS Score (mm) Daily Mean Log IL-6 (pg/mL) Daily Mean Log IL-6 (pg/mL) Daily Mean Log IL-6 (pg/mL) *Correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction. VAS=Visual Analog Scale. Adapted from Alesci S, et al. J Clin Endocrinol Metab. 2005;90(5):

14 Implications of Residual Symptoms

15 Depression Decreased Long-Term Survival After Myocardial Infarction (MI)
Long-Term Survival After MI in Relation to Beck Depression Inventory (BDI) Score During Hospitalization Cardiac Death-Free Survival (%) BDI <5 BDI 5 to 9 BDI 10 to 18 BDI ≥19 100 90 80 70 60 365 730 1095 1460 1825 N=896 Speaker Direction: The authors of this study conducted a 5-year follow-up of post-myocardial infarction (MI) patients assessed for depression during admission and 1 year later to evaluate a dose relationship between depression and long-term cardiac mortality1 As this figure indicates, there was a dose-response relationship between depression symptoms during an MI admission and long-term prognosis that began below the cutoff point of ≥10 suggested by Beck et al2 for defining at least mild symptoms1; patients with higher initial Beck Depression Inventory (BDI) scores had worse long-term prognosis regardless of symptom changes1 The authors commented that this suggested that depression symptoms within the normal range for a healthy population may constitute a risk in patients with coronary artery disease Background: The sample included 896 patients from a randomized trial with acute MI who completed the 21-item self-report BDI during hospitalization; consecutive patients admitted for an acute MI and meeting study eligibility criteria were recruited between January 1991 and October 1994; additional data were abstracted from hospital charts; home interviews were completed 1 year after discharge with 767 (89.9%) of the year survivors1 References: Lespérance F, Frasure-Smith N, Talajic M, Bourassa M. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002;105(9): Beck AT, Steer RA. Beck Depression Inventory: Manual. New York: Harcourt Brace Jovanovich; 1987. Days Postdischarge After MI Adapted from Lespérance F, et al. Circulation. 2002;105(9): 17

16 Depression and MI – Importance of Depression and its Optimum Treatment
data derived from MIND-IT study, participants had post-MI depression Event Rate: Non-responders = 25.6 % Untreated controls = 11.2 % Responders = % OBJECTIVE: Depression following myocardial infarction is associated with an increased risk of cardiac events, but attempts to alter cardiovascular prognosis by providing antidepressive treatment have not been successful. This may be because of the limited effects of antidepressive treatment on depression itself. The authors assessed whether nonresponse to treatment of post-myocardial infarction depression is associated with new cardiac events. METHOD: The authors made a subgroup analysis of a multicenter randomized, clinical trial on the effects of antidepressant treatment for post-myocardial infarction depression. Patients were enrolled in double-blind, placebo-controlled treatment with mirtazapine (30 mg/day) and, in the case of insufficient treatment response after 8 weeks, open treatment with citalopram. Patients were classified as responders to antidepressants (at least 50% reduction in Hamilton Depression Rating scale [HAM-D] score or HAM-D score <9 at 24 weeks) (N=43) or as nonresponders (N=27) and compared to untreated control subjects (N=98) on cardiac events (cardiac mortality or cardiac-related hospital admission) after 24 weeks post-random assignment and within 18 months after index infarction. RESULTS: The event rate was 25.6% among nonresponders, 11.2% among untreated control subjects, and 7.4% among responders. In relation to untreated comparison subjects, nonresponders had a hazard ratio of 2.66 for new cardiovascular events, which remained after the authors controlled for potential confounders (hazard ratio=2.92). CONCLUSIONS: This study provides further preliminary evidence that nonresponse to treatment of post-myocardial infarction depression may be associated with cardiac events. Efforts should be dedicated to developing more effective treatments for depressed patients with myocardial infarction Jonge P, Am J Psychiatry 2007;164: ; MI = myocardial infarction

17 Cellular and Molecular Changes in MDD

18 The Tripartite Synapse: The Role of Astroglia in Signaling
Speaker Direction: Astrocytes make contact with synapses in several regions of the brain in a structure that has been defined as the tripartite synapse, where the astrocytic process is associated with the presynaptic and postsynaptic elements of the synapse Panel (a) depicts an electron micrograph showing a presynaptic (Pre) and postsynaptic (Post) terminal enwrapped by the astrocytic process (green) forming the tripartite synapse Panel (b) demonstrates that the close association of the astrocytic process with the presynaptic and postsynaptic terminals exerts crucial roles in clearing K+ ions that accumulate following neuronal activity and in the uptake of the synaptic transmitter glutamate by the activity of plasma-membrane glutamate transporters Because many of the synapses in the CNS are tripartite in nature, disruption of astrocytic supportive functions and/or of gliotransmission has the potential to disrupt synaptic transmission, synaptic plasticity, and neuronal excitability—all of which may play a role in the development of neurological and psychiatric disorders Background: Recent research has shown astrocytes to have important roles in the regulation of synaptic transmission through detection of neuronal activity and the release of chemical transmitters; following injury to the nervous system or in conditions such as depression, the structure and protein expression of the astrocyte have been shown to be altered; what is still unknown is whether this structural change represents a reaction to injury in which the astrocyte is attempting to prevent further injury, or whether the astrocyte is providing detrimental signals that may contribute to the disorder Reference: Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007;13(2):54-63. Halassa MM, et al. Trends Mol Med. 2007;13(2):54-63. Reprinted with permission from Elsevier Limited.

19 Glia-Neuron Interaction May Influence Neurotrophic Factors
Speaker Direction: This theoretical model illustrates the effects of the CNS inflammatory cascade on neural plasticity; these effects include Diminished neurotrophic support Decreased neurogenesis Increased glutamatergic activation Oxidative stress Induction of apoptosis in relevant cell types such as astrocytes and oligodendrocytes Dysregulation of glial-neuronal interactions and cognitive function Excessive and/or prolonged activation of cytokine networks in the CNS, which can adversely affect neural plasticity, are thought to be relevant to the pathophysiology of depression Background: 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 CNS Cytokines, including IL-1, IL-6, and tumor necrosis factor (TNF)-, as well as interferon (IFN)- and IFN- (from T cells), induce the enzyme indoleamine 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 due to excessive exposure to cytokines, QUIN, and RNS/ROS, ultimately leading to downregulation of glutamate transporters, impaired glutamate reuptake, and increased glutamate release, as well as decreased production of neurotrophic factors Oligodendroglia are especially sensitive to the CNS inflammatory cascade and suffer damage due to overexposure to cytokines such as TNF-, which has a direct toxic effect on these cells, potentially contributing to apoptosis and demyelination The confluence of excessive astrocytic glutamate release, its inadequate reuptake by astrocytes and oligodendroglia, activation of NMDA receptors by QUIN, increased glutamate binding, and activation of extrasynaptic NMDA receptors (accessible to glutamate 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 Reference: Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry ;65(9): 5-HT=serotonin. BDNF=brain-derived neurotrophic factor. CNS=central nervous system. GLU=glutamate. IDO=indoleamine 2,3 dioxygenase. IFN=interferon. IL=interleukin. NMDA=N-methyl-D-aspartate. QUIN=quinolinic acid. RNS=reactive nitrogen species. ROS=reactive oxygen species. TNF=tumor necrosis factor. TRP=tryptophan. Miller AH, et al. Biol Psychiatry. 2009;65(9): Reprinted with permission from Elsevier Limited.

20 Dorsolateral PFC Brodmann Area 9 Caudal OFC Brodmann Area 474
Decreased Glial Density in Dorsolateral PFC and OFC in Patients With MDD Dorsolateral PFC Brodmann Area 9 Caudal OFC Brodmann Area 474 P=.006 Number of Glial Nuclei/mm3 x10-3 130 110 90 70 Control With Depression 140 120 100 80 60 Control With Depression Number of Glial Nuclei/mm3 x10-3 P=.005 Speaker Direction: Although imaging had already established structural changes in the brain associated with MDD, researchers in this study tested whether the pattern of specific cortical pathology (neuronal or glial cell pathology) could be identified in the OFC or dorsolateral PFC regions of the brain The plots shown on this slide demonstrate that the density of glial cells was significantly reduced in those subjects with MDD in Brodmann area 9 of the dorsolateral PFC and Brodmann area 474 of the caudal OFC; these marked reductions in glial densities may be related to the altered metabolism reported in these regions Background: Rajkowska and colleagues performed postmortem analysis of the left prefrontal regions of the brains of 12 subjects retrospectively diagnosed with MDD and 12 age- and sex- matched controls The PFC was chosen because this region is an important target of extensive monoamine projections originating in the brainstem nuclei, including the dorsal raphe, locus coeruleus, and ventral tegmental area; additionally, the majority of research in neuroimaging studies have implicated the PFC as a site of functional and structural abnormalities in mood disorders Computer-assisted 3-dimensional cell counting was used to identify abnormal cytoarchitecture in the brain regions of subjects with depression compared with psychiatrically normal controls Reference: Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9): OFC=orbitofrontal cortex. Adapted from Rajkowska G, et al. Biol Psychiatry. 1999;45(9): 27

21 Altered ACC Pyramidal Cell Dendritic Arborization in MDD
Postmortem study of layer VI ACC pyramidal neurons in 12 depressed suicide subjects vs 7 sudden-death controls Branch Order Number of Branches A Controls Depressed suicides 1 2 3 4 5 * Total Branch Length (µm) B Controls Depressed suicides 10 30 40 50 60 20 70 * Speaker Direction: In recent years, there has been a growing support of the view that neuronal connectivity and plasticity are altered in the brains of individuals with mood disorders This slide demonstrates the cellular changes in the brain that may occur in patients with mood disorders; the differences in dendritic branching shown on this slide suggest that the function of these principal ACC neurons may be affected in subjects with depression The top image is a representative example of reconstructed basilar dendritic arbors; the images of controls are on the left and images of subjects who were depressed and committed suicide are on the right; first-, second-, third-, fourth-, and fifth-order branches are represented in blue, yellow, white, pink, and green, respectively; note the fewer third-order branches in the reconstructed cell on the right When comparing numbers of basilar branches between groups, only third-order branches presented a significant difference, with patients who were depressed and committed suicide displaying 24% fewer branches than controls (bottom left chart) The fewer branches led to a significant reduction in third-order length—28% shorter in depressed suicides compared to controls (bottom right chart); this implied that fewer second-order branches grow into third-order branches; there was no difference between the number and length of fourth- and fifth-order branches indicating that more of these grow in depressed suicide subjects through a compensatory phenomenon Background: This study was conducted in 12 subjects who had depression and committed suicide, and sudden- death controls without mental illness (n=7); the depressed suicide group was comprised of 7 patients with MDD and 5 with bipolar disorder; all had committed suicide while depressed, 11/12 subjects were prescribed antidepressants in the last 3 months of life, and 4/12 were alcohol- dependent; for both case and control subjects, psychological autopsies were performed; a trained interviewer conducted the SCID-I with informants of the deceased The figures are from a Canadian study where postmortem ACC samples of the Brodmann area 24 from depressed suicide subjects and age-matched sudden-death controls were silver impregnated, and dendritic arborizations extended by layer VI pyramidal neurons were reconstructed and measured using the centrifugal method Reference: Hercher C, Canetti L, Turecki G, Mechawar N. Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides. J Psychiatr Res. [Epub ahead of print]. 1 2 3 4 5 Branch Order *Significant decrease in number of branches and total branch length at branch order 3 in depressed suicides. Adapted from Hercher C, et al. J Psychiatr Res. [Epub ahead of print]. Reprinted with permission from Elsevier Limited.

22 Reduced Neuronal Size in OFC of Patients With MDD
III II I IV V VI White Matter Layer Pia 200 500 Distance from Pia (µm) Control With Depression Rostral OFC [3H] 8-OH-DPAT Speaker Direction: Prefrontal cell pathology has been associated with major depression These images depict smaller neurons in tissue from the rostral OFC of patients with depression1 The right half of the picture displays an expanded view of cortical layers with neuronal cell bodies represented by open red circles (control subject) and blue closed circles (subject with depression); these circles correspond by their number, size, and location; in the subject with depression, sizes of neuronal cell bodies are smaller in layers II and III as compared with the control subject (both were Caucasian females, 73 and 71 years old, respectively); additionally, there were dramatic increases in the density of small neurons in layer II associated with significant reductions in the density of the largest neurons of this layer In the rostral OFC, the greatest reduction in mean neuronal cell body size was noted in layer II; in both the rostral OFC and dorsolateral PFC, densities of the largest neuronal sizes were significantly decreased, while the densities of small neurons were increased, suggesting that neuronal shrinkage or developmental deficiency may account for smaller neuronal sizes in these layers1 The left panel is a photomicrograph of the cell composition and delineation of the 6 cortical layers in the rostral OFC on the Nissl-stained, celloidin-embedded section; layer II, where neuronal diminution was especially pronounced in depression, can be distinguished from other cortical layers of normal human PFC by a particularly dense lamina of serotonergic receptors (Pazos et al,1987: Arango et al,1995) as it can be seen in the inserted color picture in the upper left; the yellow band represents the highest binding of the radiolabeled ligand [3H] 8-OH-DPAT to the serotonin 1A receptors Smaller neuronal size in subjects with depression has been confirmed by 4 independent studies2-5 Background: In this study, human postmortem brain tissues from the left prefrontal regions in the brains of 12 subjects with MDD and 12 controls were studied; 3 prefrontal brain regions were then analyzed to assess neuronal and glial cell densities, cell body size, and cortical thickness1 Morphometric analyses showed a 12% reduction (P<.01) in the thickness of the rostral OFC in the subjects with MDD compared to controls, which was accompanied by smaller neuronal cell bodies1 References: Rajkowska G. Histopathology of the prefrontal cortex in major depression: what does it tell us about dysfunctional monoaminergic circuits? Prog Brain Res. 2000;126: Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6(3): Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry ;45(9): Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58(6): Cotter D, Mackay D, Chana G, et al. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex. 2002;12(4): Adapted from Rajkowska G. Prog Brain Res. 2000;126: Reprinted with permission from Elsevier Limited.

23 Integrated Mind-Body Perspective of MDD—Treatment Implications

24 MDD Disease State (2009) A Clinician’s View Of Major Depression: 16 out of 9 symptoms! (And, all are important to the Clinician) Obsessive rumination Brooding Depressed mood Decreased interest or pleasure Significant appetite or weight change Fatigue Tearfulness Insomnia or hypersomnia Psychomotor disturbances Worthlessness/guilt Impaired concentration Thoughts of death/suicide Irritability Pain PURPOSE OF THE SLIDE To underscore that part of the complexity of MDD is the broad range of symptoms that may be present. SPEAKER DIRECTION Patients with major depressive disorder can present with a broad range of symptoms. A major depressive episode is a period of at least 2 weeks during which there is a predominantly depressed mood and/or the loss of interest or pleasure in nearly all activities, in addition to a constellation of other diagnostic symptoms. The mood is often described by the person as depressed, sad, hopeless, discouraged, or "down in the dumps." Some individuals emphasize somatic complaints rather than reporting feelings of sadness. Individuals may also report or exhibit increased irritability. Loss of interest or pleasure can also be present, as well as not feeling enjoyment in activities that were previously considered pleasurable. Appetite can increase or decrease. When appetite changes are severe, there may be significant loss or gain in weight. Patients with depression can report insomnia or over-sleeping in the form of prolonged sleep episodes at night or increased daytime sleep. Psychomotor changes may include agitation (eg, the inability to sit still, pacing, hand-wringing) or retardation (eg, slowed speech, thinking, and body movements). Decreased energy, tiredness, and fatigue may also be present. 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. Additionally, there may be thoughts of death, suicidal ideation, or suicide attempts. BACKGROUND The symptom groupings were based on the DSM-IV-TR diagnostic 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. Excessive worry over physical health Anxiety or phobias Associated symptoms DSM-IV diagnostic criteria APA. DSM-IV-TR. 2000:352,356.

25 Treatment May Improve Cerebral Activity in Patients With MDD
Speaker Direction: In the last several years, a large number of functional imaging studies have been conducted in an attempt to help elucidate brain processes in MDD The purpose of this study was to quantitatively analyze neuroimaging studies in MDD The researchers hypothesized, in part, that imaging results would confirm that, at rest, there would be a pattern of dorsal prefrontal underactivity and reciprocal increased activity in subcortical regions, and that changes in the direction of improved activity would be found in these regions in treatment studies The top panel of images (a) are of patients with depression at rest; as compared to controls, Areas identified as having increased activity (in red) included a series of deeper brain structures (eg, thalamus, caudate, medial and inferior frontal gyri) as well as cortical structures, including the left superior frontal and right middle frontal gyri There were eight areas of decreased activity (in blue), including pregenual anterior and posterior cingulate, bilateral middle frontal gyri, insula, and left superior temporal gyrus The lower panel of images (b) are of patients with MDD on treatment Increased activity (in red) was observed in the bilateral middle frontal gyri, dorsal and posterior cingulate cortex, and putamen, as well as several other cortical regions Decreased activity was noted in deeper structures (such as the insula, putamen, parahippocampal gyrus, hippocampus), as well as in the pre- and subgenual ACC, inferior medial PFC, and left superior frontal gyrus 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 Areas of increased activity at rest demonstrated decreased activity with treatment Areas of decreased activity in the cortical-limbic system at rest became increasingly active with treatment The treatment may improve abnormal activity in the dorsal prefrontal and subcortical regions in patients with depression Background: 3 separate quantitative meta-analytical studies were conducted; analysis was performed on 3 types of studies: 1) those conducted at rest comparing brain activation in patients with depression and controls—12 studies included; 2) those involving brain changes following antidepressant treatment—10 studies included; and 3) those comparing brain activation patterns induced by the induction of positive or negative emotion in patients with depression compared with controls—6 studies included Reference: Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp ;29(6): Fitzgerald PB, et al. Hum Brain Mapp. 2008;29(6): Reprinted with permission from John Wiley & Sons, Inc.

26 BDNF Change vs Depression Improvement BDNF Change vs Days of Treatment
Relationship Between Change in BDNF Levels, Duration of Treatment, and Treatment Response in Patients With MDD BDNF Change vs Depression Improvement BDNF Change vs Days of Treatment 2.0 1.5 1.0 0.5 0.0 -0.5 2 4 6 Cohen’s d for Depression Study analyzed (weighted by inverse variance) 2.0 1.5 1.0 0.5 0.0 -0.5 20 40 60 Period of Treatment (Days) 80 Study analyzed (weighted by inverse variance) r=0.65 P=.02 r=0.52 P=.01 Change in BDNF (Effect Size) Speaker Direction: BDNF is a neurotrophin related to neuronal survival, synaptic signaling, and synaptic consolidation; it may also be associated with neuroplastic changes that have been observed in patients with MDD; in several studies, important correlations between BDNF levels and MDD have been identified One of the objectives of this meta-analysis was to quantitatively analyze the association between BDNF blood levels and clinical changes in depression observed in patients while on antidepressant therapy Antidepressants prescribed to subjects in this analysis were SSRIs, SNRIs, and tricyclic antidepressants (TCAs) These scatter plots illustrate the association between BDNF change vs depression change (left graph) and vs days of antidepressant treatment (right graph) On the left, the figure illustrates that there was a significant correlation observed between BDNF levels vs change in depression symptoms (P=.02) The figure on the right shows there was also a significant correlation between BDNF changes and the period of treatment (P=.01) The authors concluded that BDNF levels increase in patients with MDD while on antidepressant therapy, which aligns with the neurotrophin hypothesis that increases in BDNF levels may increase neuronal survival and differentiation and, therefore, at least partially, reduce the synaptic plasticity associated with MDD Background: This was a systematic review and meta-analysis of the literature, searching MEDLINE, Cochrane CENTRAL, and SciELO databases and reference lists from retrieved articles for clinical studies comparing mean BDNF blood levels in patients with depression pre- and postantidepressant treatments or comparing patients with depression to healthy controls; 19 articles, including 1504 subjects, met the inclusion criteria Reference: Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008;11(8): Meta-regression based on 10 case control and 13 clinical trial studies assessing 1504 subjects Adapted from Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11(8):

27 12 Weeks of Cognitive Therapy
Impact of Cognitive Therapy on Amygdala and Prefrontal (Dorsolateral PFC) Activity in MDD a. Emotional b. Cognitive Is it you? UGLY Put the digits in numerical order BOLD Signal (% Change) 0.30 0.15 0.10 0.05 2 4 6 8 10 12 14 16 18 0.00 0.20 0.25 Pre Post Control Patients with depression (n=9) Controls (n=24) 0.15 0.10 0.05 0.00 -0.05 2 4 6 8 10 12 Time (Seconds) BOLD Signal (% Change) Speaker Direction: The fMRI images in the upper panels depict the sites where changes in BOLD signals (lower panels) were noted in the brain as 9 subjects with depression and 24 healthy controls completed tasks that involved rating the personal relevance of negative words (“Is it you?” UGLY) and arranging digits in numerical order before (pre) and after (post) 12 weeks of cognitive therapy (CT) CT was associated with a normalization of amygdala activity in response to emotional words (figures on left) as well as a shift towards normalization of dorsolateral PFC activity during a cognitive task that involved putting digits in numerical order in working memory (figures on right); amygdala activity in response to emotionally relevant information decreased and prefrontal activity on cognitive tasks increased to nearly the level observed in controls This study supports that CT should be considered as an option in the treatment of depression Background: It is theorized that CT as well as antidepressants affect the limbic and prefrontal circuitry, although their proximal mechanisms of action may differ; using fMRI, research has demonstrated increased amygdala activity in patients with depression (relative to controls) before CT in a task that required them to rate the personal relevance of emotional information, and decreased dorsolateral PFC activity (relative to controls) in a task that required them to arrange digits in numerical order; a primary goal of CT is to replace automatic emotional reactivity with more controlled processing; CT might thus increase inhibitory executive control, helping to interrupt or dampen automatic limbic reactions In this study, a small sample of subjects with depression were evaluated to determine if CT affected amygdala and dorsolateral PFC activity Reference: DeRubeis RJ, Siegle GJ, Hollon SD. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat Rev Neurosci. 2008;9(10): Time (Seconds) 12 Weeks of Cognitive Therapy Adapted from DeRubeis RJ, et al. Nat Rev Neurosci. 2008;9(10): Reprinted with permission from Macmillan Publishers Ltd.

28 Neurobiology of Exercise – A Complex Cascade
Structure CNS Function Disease External Input Visual Olfactory Acoustic Gustatory Somatosensory Repair Plasticity Protection Neurogenesis Transcription NA, 5-HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB Cognitive Controls Hippocampus, Cortex Learning & Memory Alzheimer’s Dementia Executive Controls Prefrontal & Cingulate Cortex Behavior Social Sexual Coping Addictive Escape Fight & Flight Stress Sleep Ingestive Schizophrenia Emotional Controls Amygdala, Prefrontal Cortex Depression Internal Feedback “Consequences of exercise” Motivational Controls Reward, Wanting, Selection Hypothalamus, Accumbens, VTA Sleep Disorders DA Parkinson’s Disease ROS Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Obesity Humoral Factors Neural Primary Afferents ANS & Endocrine Systems Energy Balance Diabetes Figure 1: A heuristic diagram for understanding the neurobiology of exercise and physical activity. ANS, autonomic nervous system; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; CREB, cyclic adenosine monophosphate response element-binding protein; CVD, cardiovascular disease; DA, dopamine; ERK, extracellular signal-regulated kinase; 5-HT, 5-hydroxytryptamine; GABA, gamma amino butyric acid; IBD, inflammatory bowel disease; NA, noradrenaline; NFB, nuclear factor of kappaB; ROS, reactive oxygen species; TrkB, tyrosine residue kinase receptor-type 2; VTA, ventral tegmental area; WAT, white adipose tissue. Muscle CVD Cardiovascular Consequences Immune Control Immune Disorder “Exercise” Metabolic Consequences Liver, WAT, Pancreas Gastrointestinal Control IBD, Constipation Colon Cancer Thermal Consequences Dishman RK et al. (2006), Obesity 14(3): ; VTA = ventral tegmental area; ROS = reactive oxygen species; WAT = white adipose tissue; NFKB = nuclear factor kappa B; ANS = autonomic nervous system ; CVD = cardiovascular disease 28

29 Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan
Scatterplots showing increase in fitness (VO2 peak) is related to increase in hippocampal volume cm3 Correlations significant for both left and right (even after including age, sex, years of education as covariates) Erikson Ki, Hippocampus (ahead of publication)

30 Track…Track…Track… Monitor…Monitor…Monitor

31 Anti-depressant Treatment and Effects on Pro- & Anti-inflammatory Cytokines
30 25 20 15 10 5 BT AT BT AT 40 35 30 25 20 15 10 5 IL-12 (pg/ml) HDRS Interleukin-12 (IL-12) levels The specific associations between antidepressant treatment and alterations in the levels of cytokines remain to be elucidated. In this study, we aimed to explore the role of IL-2, IL-4, IL-12, TNF-alpha, TGF-beta1, and MCP-1 in major depression and to investigate the effects of sertraline therapy. Cytokine and chemokine levels were measured at the time of admission and 8 weeks after sertraline treatment. Our results suggest that the proinflammatory cytokines (IL-2, IL-12, and TNF-alpha) and MCP-1 were significantly higher, whereas anti-inflammatory cytokines IL-4 and TGF-beta1 were significantly lower in patients with major depression than those of healthy controls. It seems likely that the sertraline therapy might have exerted immunomodulatory effects through a decrease in the proinflammatory cytokine IL-12 and an increase in the anti-inflammatory cytokines IL-4 and TGF-beta1. In conclusion, our results indicate that Th1-, Th2-, and Th3-type cytokines are altered in the depressed patients and some of them might have been corrected by sertraline treatment 9 8 7 6 5 4 3 2 1 BT AT Hamilton Depression Rating Scale – scores before and after treatment IL-4 (pg/ml) BT - before Treatment AT - after treatment Interleukin-4 (IL-4) levels Sutcigil L, Clinical and Developmental Immunology.2007.

32 Relationship between Depression, & Inflammatory Cytokines and Neurotrophic Factors
Positive co-relationship between depression and IL-6 Negative co-relationship between depression and BDNF R2 =.376 P=.0062 R2 = P=.0012 Yoshimura R, Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 722–726

33 Treatment Guidelines

34 Acute Phase Treatment of Major Depressive Disorder
Start of Trial: Medication and/or Psychotherapy Monitor: Degree of danger to self or others Symptomactic status Functional status Response to treatment Side effects Compliance Signs of switch to mania Other mental disorders, including alcohol and substance abuse General medical comorbidities If no response and clinical severity warrants, consider the following: Increase in dose of medication Increase in intensity of psychotherapy ECT 4-8 Weeks: Reassess Adequacy of Response No Response If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT If patient is currently receiving psychotherapy, consider: Adding or changing to medication No Response If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT If patient is currently receiving psychotherapy, consider: Adding or changing to medication Partial Response If patient is currently receiving medication, consider: Changing dose Augmenting antidepressant Changing antidepressant Adding or changing to psychotherapy ECT If patient is currently receiving psychotherapy, consider: Changing intensity of psychotherapy Changing type of psychotherapy Adding or changing to medication Full Response Go to Continuation Phase Treatment APA Practice Guidelines 34

35 First-Line Antidepressants: Guidelines
CANMAT APA SNRIs Desvenlafaxine, duloxetine, venlafaxine SSRIs Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline TCAs Amitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramine Serotonin modulators Nefadozone, trazodone Norepinephrine-serotonin modulator Mirtazapine MAOIs Moclobemide Isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine DNRI Bupropion Among the many antidepressant agents available, the CANMAT guidelines have recommended 12 second-generation agents as those which should be selected as initial treatment for a major depressive episode. These agents offer a variety of mechanisms of action, with most acting via serotonin and/or norepinephrine reuptake inhibition. A first-line treatment represents a balance of efficacy, tolerability and clinical support. Selection of a first-line agent depends on individual patient characteristics and therapeutic considerations. Second-line and third-line treatments are reserved for situations where first-line treatments are not indicated or cannot be used, or when first-line treatments have not worked. APA = American Psychiatric Association; TCA = tricyclic antidepressant; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitor American Psychiatric Association. Am J Psychiatry. 2010;[in press]. Lam RW, et al. J Affect Disord. 2009;117(Suppl 1):S26-S43. Key message: There are several first-line antidepressant agents available to choose, depending on an individual patient’s characteristics. 35

36 Discussion of Treatment Option
TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non-psychotic) 2008 version Patient Assessment & Discussion of Treatment Option Stage 0 Discuss EBPT as an option Stages 1-8 follow EBPT = Evidence Based Psychotherapy. EBPT is an option before starting pharmacotherapy, or in combination with pharmacotherapy at any stage in the algorithm (cont.) TMAP Guidelies, accessed Confidential: For Training Purposes Only 36 36

37 If Non-response, move to Stage 2
TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non- Psychotic) 2008 version SSRIs, BUP SR/XL MRT, SNRIs Response Stage 1 Continuation Augment with one of the following- SSRI, SNRI, BUP, MRT, BUS, or T3 (choose different MOA from Stage 1) Partial Response Stage 1 A If Non-response, move to Stage 2 TMAP Guidelies, accessed; BUP = bupropion; MRT = mirtazapine; BUS= buspirone; T3 = liothyronine; MOA = mechanism of action (cont.) Confidential: For Training Purposes Only 37 37

38 TMAP Advice on Critical Issues
Visit Frequency – at 2, 4, 6, 9 and 12 weeks (more if indicated.) Assessment Frequency – each visit – core symptoms, functional impairment, side-effect severity. A scale, such as QIDS-16 should be administered. Criteria for Medication Change - many factors. QIDS-16 response criteria are as follows – non-response 9 or greater, partial response 6-8, full response/remission 5 or less Medication Switching – cross taper is recommended Medication Doses – ranges provided Documentation – uniform documentation is an important component of the algorithm

39 ‘Enhanced’ Care: An Update for the 21st Century Clinician

40 Enhanced Care is Effective, Has long term benefits, and is Generalizeble Across Different Clinical Settings Results from IMPACT study Impact Intervention n= 906 Usual Care n= 895 Longer Term Benefits Works Across Settings Unutzer J, JAMA 2002;288: ; Hunkeler EM, BMJ 2006:332:

41 Algorithm-Based Care has better Outcomes as compared to Treatment as Usual
Clinical Ratings of Depressive Symptoms in Algorithm-Based vs. Usual Care Patient Self-Report of Depressive Symptoms in Algorithm-Based vs. Usual Care Trivedi MH, Arch Gen Psychiatry 2004;61:

42 Patient-Reported Reasons for Discontinuation of Antidepressant Therapy
Patients Discontinue Medication for Many Reasons – Some Stop Without Consulting You Patient-Reported Reasons for Discontinuation of Antidepressant Therapy Disliked side effects 62% Did not need medication 56% Feeling better 50% Felt medication was not working 32% MD told me to stop 12% Ran out of pills 11% Friend told me to stop 7% Weight gain 5% Forgot to take pills In a 1995 study examining factors that influence treatment adherence to antidepressant therapy, patients reported the above reasons for discontinuing therapy. In another study, 70% of patients who reported stopping their antidepressant medication did so without consulting their healthcare professional. In the 1995 study, adult patients were seen in one of two primary care clinics (n=247 eligible patients, of whom 164 agreed to participate in the telephone survey; 41 patients discontinued within one month). The majority of surveyed patients were prescribed TCAs. In the other study, in which 70% of patients who stopped taking their antidepressant medication did so without consulting their healthcare professional, the investigators collected survey data via written questionnaires to assess physician-patient communication about antidepressant therapy adherence (n=401). In another study, 70% of patients who reported stopping their antidepressant medication did so without consulting their healthcare professional. Bull SA, et al. JAMA. 2002;288: Lin EH, et al. Med Care. 1995;33:67-74. 42

43 Antidepressant Discontinuation Rates
Product Product disc. rate due to AE Placebo disc. rate Desvenlafaxine 50 mg (Pristiq) 4.1% 3.8% Escitalopram mg (Cipralex) 5.9% 2.2% Bupropion mg (Wellbutrin SR) 6% 3% Duloxetine mg (Cymbalta) 10% 4% Venlafaxine mg (Effexor XR) 12% Citalopram mg (Celexa) 15.9% 7.7% Mirtazapine mg (Remeron) 16% 7% Paroxetine mg (Paxil) 21% N/A As reflected in the product monographs, the rates of discontinuation due to AEs are captured in this chart of commonly prescribed antidepressants. Given these high discontinuation rates, it is important to optimize adherence to treatment when prescribing antidepressants. Patients should be made aware of the time lag to antidepressant effect, course of response, common and serious AEs, and the need to continue medications even when feeling better. AE = adverse event; SR = sustained release; N/A = not available Celexa Canadian Product Monograph. Cipralex Canadian Product Monograph. Cymbalta Canadian Product Monograph. Effexor XR Canadian Product Monograph. Paxil Canadian Product Monograph. Pristiq Canadian Product Monograph. Remeron Canadian Product Monograph. Wellbutrin SR Canadian Product Monograph. Key message: There is considerable variation in discontinuation rates reported in registration trials of antidepressant agents vs. placebo. 43

44 Why is Achieving Remission, even in the short run, so Important in Major Depression?
Time Allotted to Presentation = 25 minutes

45 The Kupfer Curve: The Life Story of Depression
Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.

46 What Is Remission? It Depends on Whom You Ask What is the
score on rating instrument? It Depends on Whom You Ask Are the symptoms gone? A Researcher’s Definition: Are the symptoms gone? Am I functioning well? Do I feel optimistic and self-confident? checked A Clinician’s Definition: A Patient’s Definition: Zimmerman M et al. Am J Psychiatry (1):

47 Remission’s Importance: Its Impact on Patient’s Lives
Impacts Physical Functioning1,2 Impacts Social Functioning1,2 Impacts Children’s Mental Well-being3 Impacts Occupational Functioning1,2 Impacts Marital Functioning4 Increased relapse risk; faster relapse5,6 1Sobocki P et al. Int J Clin Pract. 2006;60(7): ; 2Keller MB. JAMA. 2003;289(23): ; 3Weissman MM et al. JAMA. 2006;295(12): ; 4Bromberger JT et al. J Nerv Ment Dis. 1994;182(1):40-44; 5Thase M et al. Am J Psychiatry. 1992;149(8): ; 6Judd LL et al. J Affect Disord. 1998;50(2-3): 47

48 Does Treatment With Antidepressants, If It Leads to Remission, Have Any Impact on Brain Volume?
Subgenual PFC HAM-D >7 (n = 26) HAM-D <7 (n = 13) 586.8 mm3 712.7 mm3a 1 = BA25 – Subcallosal gyrus 2 = BA24 – Subgenual PFC 3 = BA32 – Paracingulate gyrus aP<0.05; PFC, prefrontal cortex Yucel K et al. Psychiatry Res. 2009;173(1):71-76.

49 ‘Dual’ Action vs. Single Action Anti-depressants

50 Interactions between serotonin and norepinephrine neurons
KEY POINTS There is “cross-talk” between 5-HT and NE. Pharmacologic selectivity may not translate into physiologic selectivity. 5-HT and NE modulate each other’s release at the point of origin and at the terminal end. REFERENCE Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press; 2000:254. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:254. Confidential: For Training Purposes Only.

51 Current Shortcomings in the Treatment of the Full Spectrum of Depressive Symptoms
a naturalistic, randomized trial of 573 primary care patients on SSRIs followed for 9 months Greco T, et al. J Gen Intern Med. 2004;19(8):

52 Danish University Studies: Comparison of Clomipramine (Dual-Action) vs SSRI
60% 50 46% 60 45 40 50 35 40 30 % remission 30% 25 30 19% 20 20 15 Refs: 1. Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90(1): 2. Danish University Antidepressant Group. J Affect Disord. 1990;18(4): 10 10 5 Clomipramine 150 mg/d (N = 50) Clomipramine 150 mg/d (N = 33) Citalopram 40 mg/d (N = 52) Paroxetine 30 mg/d (N = 27) Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90: Danish University Antidepressant Group. J Affect Disord. 1990;18:

53 Is the Combination of Serotonin and Norepinephrine superior to Either by Itself?
Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study % Response 16.7 35.7 7.7 5 10 15 20 25 30 35 40 45 50 55 Remission 0.0 7.1 53.8 DMI FLX DMI + FLX Nelson JC, Mazure CM, Jatlow PI, et al. Biol Psychiatry 2004;55:

54 Patient With Symptom Resolution (somatic-general item score = 0), %
Venlafaxine : Meta-analysis indicates the possibility of SNRI superior to SSRI in Remission Rates Week Patient With Symptom Resolution (somatic-general item score = 0), % 5 10 15 20 25 30 35 40 *† *‡ * 1 2 3 4 6 8 Thase ME et al. Br J Psychiatry;178: , 2001

55 All Randomized Patients
Duloxetine, SSRI, placebo: Focus on Remission Baseline HAM-D > 19 Remission Rate, % 5 10 15 20 25 30 35 40 45 50 All Randomized Patients *† * * P < 0.05 vs placebo † P vs SSRIs Thase ME et al. Poster presented at the 156th Annual meeting, APA, San Francisco, May 2003

56 Desvenlafaxine Remission Rate (Pooled Data: HAM-D17 Remission Rate, FOT)
50 Desvenlafaxine * Placebo 40 36 36 n=112 n=151 33 n=98 32 n=100 30 26 25 n=82 n=105 23 23 % patients n=73 n=73 20 10 50 mg 100 mg 200 mg 400 mg Data are from the intent-to-treat population. *p<0.05, †p<0.01, ‡p<0.001 for desvenlafaxine vs. placebo Thase ME, et al. Manuscript submitted. 56

57 Meta-analysis of TCAs vs SSRIs: 25 Studies
Ref: Anderson IM. SSRI vs. Tricyclic Antidepressants in depressed in-patients: a meta-analysis of efficacy and tolerability. Depression and Anxiety;vol 7,supp1:11-17, 1998 Hard copy send to all speakers Excellent article. 25 articles reviewed and included in this meta-analysis. Compared TCAs to SSRIs to Results. TCAs significantly more effective than SSRIs ( effect size -0.23, 95 % C to 0.05, P= 0.011TCAs.) Only dual action TCAs separated , not the mostly single action TCAs Anderson IM. Depress Anxiety. 1998;7(suppl 1):11-17.

58 Remission Rates with SSRIs vs. SNRIs Debate: What is the Latest?
A meta-analysis of head-to-head SSRIs vs. SNRIs trials Remission as the outcome measured Odds Ratio IV, Random, 95% CI 1 2 Favors SNRIs 0.2 0.5 5 Favors SSRIs 300 400 200 1.5 1 0.5 -0.5 -1 -1.5 100 500 Number of Patients in Each Trial (N) In (odds ratio) 600 SNRI remission rates were 5.7% higher Machado M et al. J Clin Pharm Ther. 2010;35(2):

59 Is Remission Enough of a “high” standard for Us to set ??

60 Mental Well-Being is Much More Than Absence of Symptoms
Valence Arousal PA NA −PA −NA Presence of fitness decrements Absence of fitness decrements Presence of fitness increments Absence of fitness increments NA, negative affect; PA, positive affect. Reprinted by permission from John Wiley & Sons, Inc: Panksepp J et al. Addiction. 2002;97(4): ; Burgdorf J, Panksepp J. Neurosci Biobehav Rev. 2006;30(2):

61 How Are You Feeling Right Now?
0 = very bad = very good 35 45 55 65 75 85 95 rest/sleep working h ome computer grooming, self care other watching television relaxing, nothing special shopping, errands preparing food eating walking, taking a walk playing exercising not mind wandering pleasant mind wandering unpleasant mind wandering neutral mind wandering making love talking, conversation listening to music praying/worshipping/meditating taking care of your children reading doing housework listening to radio, news commuting, traveling Killingsworth MA, Gilbert DT. Science. 2010;330(6006):932.

62 One Way to Measure That is via the Use of Scales Such as This…
The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) This scale asks zero questions about depression or negative mental health traits and focuses only on the mental well-being constructs Statements None of the Time Rarely Some of the Time Often All of the Time I’ve been feeling optimistic about the future 1 2 3 4 5 I’ve been feeling useful I’ve been feeling relaxed I’ve been feeling interested in other people I’ve had energy to spare I’ve been dealing with problems well I’ve been thinking clearly I’ve been feeling good about myself I’ve been feeling close to other people I’ve been feeling confident I’ve been able to make up my own mind about things I’ve been feeling loved I’ve been interested in new things I’ve been feeling cheerful © NHS Health Scotland, University of Warwick and University of Edinburgh, 2006, all rights reserved. Tennant R et al. Health Qual Life Outcomes. 2007:5:63. Accessed June 2, 2011.

63 And the Results Are… WEMWBS – Population Sample
Tennant R et al. Health Qual Life Outcomes. 2007:5:63.

64 Optimism Mitigates Biological Impact of Stress
Double-blind, placebo-controlled study showed that acute psychological stress increased serum levels of IL-6 and negative mood in 59 healthy men. Further analysis of this sample investigated the relationship between dispositional optimism and stress-induced changes in immunity and mood. Brydon L et al. Brain Behav Immun. 2009;23(6):

65 Complete and Several Types of Incomplete States of Mental Health
Incomplete mental illness Complete mental health Incomplete mental health Complete mental illness High subjective well-being symptoms Low subjective well-being symptoms Low mental illness symptoms High mental illness symptoms Struggling Flourishing Languishing Floundering Slade M. BMC Health Serv Res. 2010;10:26.

66 Clinical Practice and Wellness Measurement WHO-5
WHO (Five) Well-Being Index (1998 version) Over the Last Two Weeks All of the Time Most of the Time More than Half of the Time Less than Half of the Time Some of the Time At No Time I have felt cheerful and in good spirits □5 □4 □3 □2 □1 □0 I have felt calm and relaxed I have felt active and vigorous I woke up feeling fresh and rested My daily life has been filled with things that interest me Please indicate for each of the five statements which is closest to how you have been feeling over the last two weeks. Notice that higher numbers mean better well-being. Example: If you have felt cheerful and in good spirits more than half of the time during the last two weeks, put a tick in the box with the number 3 in the upper right corner. Accessed June 2, 2011.

67 Ideal outcome should be here
Defining Treatment Goals for Depression: An evolving concept? Ideal outcome should be here Outcomes are now here Outcomes were here Functional Recovery Changes in SDS scores? Pre-morbid functioning? Remission Not officially defined; varies between studies (e.g., HAM-D <7-10) DISCUSSION NOTES: Evidence for treatment response has traditionally been the foundation for the approval of new antidepressants. Clinical rating scales such as the Hamilton Depression Rating Scale for Depression have been the gold standard for measuring patient response and remission, however, these measures can leave patients with residual symptoms of depression that can impair patient functioning. Guidelines currently recommend that patients should be treated to symptomatic remission. With the recognition that patients in remission may still exhibit residual symptoms (which are associated with depressive relapse or recurrence), the bar is being raised once again, with the ultimate goal for the treatment of depression now moving towards functional recovery. Response % improvement in a validated depression rating scale from baseline (e.g., HAM-D) Adapted from: Nierenberg & DeCecco. J Clin Psychiatry 2001;62 (Suppl 16):5-9. Key message: Treatment objectives today focus on moving patients towards a more comprehensive goal: functional recovery. This is an important goal that goes beyond symptom remission and impacts on the global aspects of a patient’s quality of life.

68 Emergence of Functionality as Key to Anti-Depressant Effects – Focus on SDS and WHO-5
Guico-Pabia CJ, et al. Poster Presentation, American Academy of Nurse Practitioners, 2010

69 In Conclusion, Our View of Depression Is Evolving
Repetitive mood episodes may result in enduring functional and structural alterations in the sensitive brain areas Disruption in corticolimbic circuitry may create neuroendocrine, neuroimmune, and sympathetic dysregulation Inadequate monoamine and neurotrophic signaling combined with excessive glutaminergic and inflammatory cytokine transmission may precipitate a “breakdown” in vulnerable glia-neuron units An altered glia-neuron relationship may then further impede corticolimbic processing GABA Modulation Apoptotic oxidative NE DA + GRP/ NMB Neuroplasticity Growth Factors (eg, BDNF) JAK-STAT MAP kinase NFκB ACTH Depression Stressors Cytokine (eg, IL-1, TNF-) CORT CRH/ AVP 5-HT Speaker Direction: Review the main points of the presentation GRP=glucose-regulated protein. NMB=neuromedin B. AVP=arginine vasopressin. MAP=mitogen-activated protein. DA=dopamine. CORT=cortisol. JAK-STAT=janus kinase and signal transducer and activator of transcription. Adapted from Anisman H. J Psychiatry Neurosci. 2009;34(1):4-20.

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