Presentation on theme: "Recent Advances In Neurobiology &Treatment Of Major Depression"— Presentation transcript:
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, MPHAssociate Clinical ProfessorDepartment of Psychiatry & Beh. SciencesUniversity of Texas Medical SchoolHouston, TexasAssistant Clinical ProfessorDepartment of PsychiatryTexas Tech Medical SchoolMidland, TexasDirector, Psychiatric Drug ResearchAdult, Child and AdolescentR/D Clinical Research, IncLake Jackson, Texas.
2 A 20th Century Clinician’s View of Depression (“so yesterday… !”) MajorDepressionBioPsychoSocial
3 For the 21st Century’s Clinician – A New Way to Look at Depression CellularCell growth/survival/deathCell morphology:dendritic remodelingMolecularSusceptibility genesProtective genesTranscription factorsmRNASystemsCritical neuronal circuitryBehaviorCognitive/Affective/SensorymotorEnvironmentNeurotransmission:Neurotransmitters andNeuropeptidesSynaptic connectivityEnvironmental factors(including external environment:psychosocial stressors, sleep deprivation, internal environment gonadal/HPA steriods)PKC & MARCKSGSK-3 & substratesCREB & BDNFERK MAP kinaseBcl-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 proteinSchloesser RJ, et.al.2008.Neuropsychopharmacology Reviews 33:
4 Another Issue in Attempting Optimization of Outcomes – Appreciating the Cumulative Effect of Risk Factors on Depression35Controls (nonmaltreated)History of maltreatment305-HTTLPR s/sBDNF val66metLow social support25Mood and Feeling Questionnaire(MFQ) Depression Scores2015105Risk FactorsStudy 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 706050403020100 (n=502)1 (n=253)Number of Adverse Childhood Experiences% of Study Members With the ConditionSpeaker Direction:This slide illustrates the role that adverse childhood psychosocial experiences (ie, stress) may have in the pathophysiological processes leading to age-related diseasesBased 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 factorsThis 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 fashionAdverse 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 childhoodBackground: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 studyStudy 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 analysesReference: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 DepressionPanel 2:hsCRP >3 mg/LPanel 3:Clustering of Metabolic Risk MarkersPanel 4:≥1 Disease Risk32-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 gyrusThalamusAnterior cingulate cortex (ACC)HippocampusSpeaker 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 decisions1-4The orbital frontal cortex (OFC) is involved in social interaction and maternal behavior5,6The hippocampus, in addition to its role in memory, also provides feedback to the hypothalamic-pituitary-adrenal (HPA) axis1The amygdala is also involved in memory, but particularly the emotional valence of an event or memory1Background: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 depression1The 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 consolidation1The 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 permanent1The 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 mania4The 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 faces6References: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 accumbensAmygdalaSchloesser 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, et.al.2008.Neuropsychopharmacology Reviews 33:
8 Reduced dendritic arborization Compromised neurotrophic support may alter synaptic structure in mood disordersHippocampal Pyramidal NeuronsSPEAKER DIRECTIONThis 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.1,2Antidepressants 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:4,5BDNF 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 factorsAnd finally, determining serum BDNF levels are not currently helpful in treating patients clinically.BACKGROUNDSevere 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).1Antidepressants 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.1Treatment 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).4Martinowich 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.5REFERENCESNestler 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):Normaldendritic arborizationDepressionReduced dendritic arborizationMicrograph1Graphic representation21. 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 Remission6000R2=.28*P=.0006n=3855005000Total Hippocampal Volume (mm3)45004000KEY POINTSIn 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.BACKGROUND38 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.REFERENCESheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am JPsychiatry. 2003;160(8):350030001000200030004000Days 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 controlsIncreased activity: lateral orbital PFC, ventromedial PFC, amygdala, thalamus, caudateDecreased activity: dorsolateral PFC, insula, pregenual and dorsal ACC, superior temporal gyrusSpeaker Direction:These images demonstrate the areas of significant differences across 2 analyses (blue indicates decreased and red indicates increased activation) at rest compared with controlsA 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 gyrusAreas 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 gyriThese 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 activeBackground: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 analysisSince 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) techniqueThe 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 techniquesReference: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 SymptomsComparison of 15 Subjects With MDD and 14 Healthy ControlsRegions showing a negative correlation between gray matter concentration and depression severityp<0.05Adjusted VBM Responses, Dorsolateral PFC (Brodmann Area 46)MADRS Score-0.1-0.050.050.1151719212325272931Adjusted VBM Responses, Medial Orbital PFC (Brodmann Area 11)MADRS Score-0.1-0.050.050.1151719212325272931r=-0.53r=-0.57Speaker 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 abnormalitiesReference: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 pathwaysThe 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 coeruleusActing 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 factorsCytokine-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 responseIn 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 inflammationInterestingly, 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 medicationReference: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 MDDComparison of 5 Patients With MDD and 5 Matched Healthy ControlsA. ConcentrationB. GuiltC. Sadness0.51.01.52.02.520406080100120R2=0.4058P=.050.51.01.52.02.520406080100120R2=0.6711P=.004*0.51.01.52.02.520406080100120R2=0.5139P=.02Daily Mean VAS Score (mm)0.51.01.52.02.520406080100120R2=0.735P=.002*D. Self-Esteem0.51.01.52.02.520406080100120R2=0.7785P=.0007*E. Suicidal Thoughts0.51.01.52.02.520406080100120R2=0.566P=.02F. TirednessSpeaker 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 feelingIL-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 correctionBackground:IL-6 is a pleiotropic inflammatory cytokine that, in addition to its essential immune effects, exerts a plethora of neuroendocrine, hemostatic, and behavioral actionsIn 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 discomfortOnly 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 populationReference: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):
15 Depression Decreased Long-Term Survival After Myocardial Infarction (MI) Long-Term Survival After MI in Relation to Beck Depression Inventory (BDI) Score During HospitalizationCardiac Death-Free Survival (%)BDI <5BDI 5 to 9BDI 10 to 18BDI ≥1910090807060365730109514601825N=896Speaker 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 mortality1As 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 changes1The 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 diseaseBackground: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 survivors1References: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 MIAdapted 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 depressionEvent 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 infarctionJonge P, et.al. Am J Psychiatry 2007;164: ; MI = myocardial infarction
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 synapsePanel (a) depicts an electron micrograph showing a presynaptic (Pre) and postsynaptic (Post) terminal enwrapped by the astrocytic process (green) forming the tripartite synapsePanel (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 transportersBecause 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 disordersBackground: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 disorderReference: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 includeDiminished neurotrophic supportDecreased neurogenesisIncreased glutamatergic activationOxidative stressInduction of apoptosis in relevant cell types such as astrocytes and oligodendrocytesDysregulation of glial-neuronal interactions and cognitive functionExcessive 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 depressionBackground:Microglia are primary recipients of peripheral inflammatory signals that reach the brainActivated 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 CNSCytokines, 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) releaseMultiple 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 factorsOligodendroglia 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 demyelinationThe 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 apoptosisReference: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 MDDDorsolateral PFC Brodmann Area 9Caudal OFC Brodmann Area 474P=.006Number of Glial Nuclei/mm3 x10-31301109070ControlWith Depression1401201008060ControlWith DepressionNumber of Glial Nuclei/mm3 x10-3P=.005Speaker 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 brainThe 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 regionsBackground: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 controlsThe 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 disordersComputer-assisted 3-dimensional cell counting was used to identify abnormal cytoarchitecture in the brain regions of subjects with depression compared with psychiatrically normal controlsReference: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 controlsBranch OrderNumber of BranchesAControlsDepressed suicides12345*Total Branch Length (µm)BControlsDepressed suicides10304050602070*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 disordersThis 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 depressionThe 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 rightWhen 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 phenomenonBackground: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 deceasedThe 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 methodReference: 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].12345Branch 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 IIIIIIIVVVIWhite MatterLayerPia200500Distance from Pia (µm)ControlWith DepressionRostral OFC[3H] 8-OH-DPATSpeaker Direction:Prefrontal cell pathology has been associated with major depressionThese images depict smaller neurons in tissue from the rostral OFC of patients with depression1The 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 layerIn 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 layers1The 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 receptorsSmaller neuronal size in subjects with depression has been confirmed by 4 independent studies2-5Background: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 thickness1Morphometric 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 bodies1References: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 ruminationBroodingDepressed moodDecreased interest or pleasureSignificant appetite or weight changeFatigueTearfulnessInsomnia or hypersomniaPsychomotor disturbancesWorthlessness/guiltImpaired concentrationThoughts of death/suicideIrritabilityPainPURPOSE OF THE SLIDETo underscore that part of the complexity of MDD is the broad range of symptoms that may be present.SPEAKER DIRECTIONPatients 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.BACKGROUNDThe symptom groupings were based on the DSM-IV-TR diagnostic criteria and text description of associated symptoms.REFERENCEAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000;352,356.Excessive worry overphysical healthAnxiety or phobiasAssociated symptomsDSM-IV diagnostic criteriaAPA. 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 MDDThe purpose of this study was to quantitatively analyze neuroimaging studies in MDDThe 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 studiesThe 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 gyriThere were eight areas of decreased activity (in blue), including pregenual anterior and posterior cingulate, bilateral middle frontal gyri, insula, and left superior temporal gyrusThe lower panel of images (b) are of patients with MDD on treatmentIncreased activity (in red) was observed in the bilateral middle frontal gyri, dorsal and posterior cingulate cortex, and putamen, as well as several other cortical regionsDecreased 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 gyrusDepression 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 activeAreas of increased activity at rest demonstrated decreased activity with treatmentAreas of decreased activity in the cortical-limbic system at rest became increasingly active with treatmentThe treatment may improve abnormal activity in the dorsal prefrontal and subcortical regions in patients with depressionBackground: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 includedReference: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 MDDBDNF Change vs Depression ImprovementBDNF Change vs Days of Treatment2.01.51.00.50.0-0.5246Cohen’s d for DepressionStudy analyzed (weighted by inverse variance)2.01.51.00.50.0-0.5204060Period of Treatment (Days)80Study analyzed (weighted by inverse variance)r=0.65P=.02r=0.52P=.01Change 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 identifiedOne 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 therapyAntidepressants 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 MDDBackground: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 criteriaReference: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 subjectsAdapted 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 MDDa. Emotionalb. CognitiveIs it you?UGLYPut the digits in numerical orderBOLD Signal (% Change)0.300.150.100.05246810121416180.000.200.25PrePostControlPatients with depression (n=9)Controls (n=24)0.150.100.050.00-0.0524681012Time (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 controlsThis study supports that CT should be considered as an option in the treatment of depressionBackground: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 reactionsIn this study, a small sample of subjects with depression were evaluated to determine if CT affected amygdala and dorsolateral PFC activityReference: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 TherapyAdapted 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 StructureCNSFunctionDiseaseExternal InputVisualOlfactoryAcousticGustatorySomatosensoryRepairPlasticityProtectionNeurogenesisTranscriptionNA, 5-HT,GABA, Glutamate, GlycineBDNF/TrkBERK/CREBNFKBCognitive ControlsHippocampus, CortexLearning & MemoryAlzheimer’s DementiaExecutive ControlsPrefrontal & Cingulate CortexBehaviorSocialSexualCopingAddictiveEscapeFight & FlightStressSleepIngestiveSchizophreniaEmotional ControlsAmygdala, Prefrontal CortexDepressionInternal Feedback“Consequences of exercise”Motivational ControlsReward, Wanting, SelectionHypothalamus, Accumbens, VTASleep DisordersDA↓Parkinson’s Disease↑ROSMotor ControlsMotor CortexStriatum, Brainstem, Cerebellum, Spinal CordObesityHumoral FactorsNeuralPrimary AfferentsANS&Endocrine SystemsEnergy BalanceDiabetesFigure 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-bindingprotein; 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 oxygenspecies; TrkB, tyrosine residue kinase receptor-type 2; VTA, ventral tegmental area; WAT, white adipose tissue.MuscleCVDCardiovascularConsequencesImmune ControlImmune Disorder“Exercise”Metabolic ConsequencesLiver, WAT, PancreasGastrointestinal ControlIBD, Constipation Colon CancerThermal ConsequencesDishman 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 disease28
29 Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan Scatterplots showing increase in fitness (VO2 peak) is relatedto increase in hippocampal volume cm3Correlations significant for both left and right(even after including age, sex, years of education as covariates)Erikson Ki, et.al. Hippocampus (ahead of publication)
31 Anti-depressant Treatment and Effects on Pro- & Anti-inflammatory Cytokines 30252015105BT ATBT AT403530252015105IL-12 (pg/ml)HDRSInterleukin-12 (IL-12) levelsThe 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 treatment987654321BT ATHamilton Depression Rating Scale – scores before and after treatmentIL-4 (pg/ml)BT - before TreatmentAT - after treatmentInterleukin-4 (IL-4) levelsSutcigil L, et.al. Clinical and Developmental Immunology.2007.
32 Relationship between Depression, & Inflammatory Cytokines and Neurotrophic Factors Positive co-relationship between depression and IL-6Negative co-relationship between depression and BDNFR2 =.376P=.0062R2 =P=.0012Yoshimura R, et.al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 722–726
34 Acute Phase Treatment of Major Depressive Disorder Start of Trial:Medication and/or PsychotherapyMonitor:Degree of danger to self or othersSymptomactic statusFunctional statusResponse to treatmentSide effectsComplianceSigns of switch to maniaOther mental disorders, including alcohol and substance abuseGeneral medical comorbiditiesIf no response and clinical severity warrants, consider the following:Increase in dose of medicationIncrease in intensity of psychotherapyECT4-8 Weeks: Reassess Adequacy of ResponseNo ResponseIf patient is currently receiving medication, consider:Changing antidepressantAdding or changing to psychotherapyECTIf patient is currently receiving psychotherapy, consider:Adding or changing to medicationNo ResponseIf patient is currently receiving medication, consider:Changing antidepressantAdding or changing to psychotherapyECTIf patient is currently receiving psychotherapy, consider:Adding or changing to medicationPartial ResponseIf patient is currently receiving medication, consider:Changing doseAugmenting antidepressantChanging antidepressantAdding or changing to psychotherapyECTIf patient is currently receiving psychotherapy, consider:Changing intensity of psychotherapyChanging type of psychotherapyAdding or changing to medicationFull ResponseGo to Continuation Phase TreatmentAPA Practice Guidelines34
35 First-Line Antidepressants: Guidelines CANMATAPASNRIsDesvenlafaxine, duloxetine, venlafaxineSSRIsCitalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertralineTCAsAmitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramineSerotonin modulatorsNefadozone, trazodoneNorepinephrine-serotonin modulatorMirtazapineMAOIsMoclobemideIsocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromineDNRIBupropionAmong 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 inhibitorAmerican 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 versionPatient Assessment &Discussion of Treatment OptionStage 0Discuss EBPTas an optionStages 1-8 followEBPT = 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 https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdfConfidential: For Training Purposes Only3636
37 If Non-response, move to Stage 2 TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non- Psychotic) 2008 versionSSRIs, BUP SR/XLMRT, SNRIsResponseStage 1ContinuationAugment with one of the following- SSRI, SNRI, BUP, MRT, BUS, or T3 (choose different MOA from Stage 1)PartialResponseStage 1 AIf Non-response, move to Stage 2TMAP Guidelies, accessed https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf; BUP = bupropion; MRT = mirtazapine; BUS= buspirone; T3 = liothyronine; MOA = mechanism of action(cont.)Confidential: For Training Purposes Only3737
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 lessMedication Switching – cross taper is recommendedMedication Doses – ranges providedDocumentation – 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 SettingsResults from IMPACT studyImpact Intervention n= 906Usual Care n= 895Longer Term BenefitsWorks Across SettingsUnutzer J, et.al JAMA 2002;288: ; Hunkeler EM, et.al. 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 CarePatient Self-Report of DepressiveSymptoms in Algorithm-Based vs. Usual CareTrivedi MH, et.al. Arch Gen Psychiatry 2004;61:
42 Patient-Reported Reasons for Discontinuation of Antidepressant Therapy Patients Discontinue Medication for Many Reasons – Some Stop Without Consulting YouPatient-Reported Reasons for Discontinuation of Antidepressant TherapyDisliked side effects62%Did not need medication56%Feeling better50%Felt medication was not working32%MD told me to stop12%Ran out of pills11%Friend told me to stop7%Weight gain5%Forgot to take pillsIn 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 ProductProduct disc. rate due to AEPlacebo disc. rateDesvenlafaxine 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/AAs 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 availableCelexa 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 AskAre the symptoms gone?A Researcher’s Definition:Are the symptoms gone?Am I functioning well?Do I feel optimistic andself-confident?checkedA 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 Functioning1,2Impacts Social Functioning1,2Impacts Children’s Mental Well-being3Impacts Occupational Functioning1,2Impacts Marital Functioning4Increased relapse risk; faster relapse5,61Sobocki 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 PFCHAM-D >7 (n = 26)HAM-D <7 (n = 13)586.8 mm3712.7 mm3a1 = BA25 – Subcallosal gyrus2 = BA24 – Subgenual PFC3 = BA32 – Paracingulate gyrusaP<0.05; PFC, prefrontal cortexYucel 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 POINTSThere 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.REFERENCEStahl 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 monthsGreco T, et al. J Gen Intern Med. 2004;19(8):
52 Danish University Studies: Comparison of Clomipramine (Dual-Action) vs SSRI 60%5046%60454050354030% remission30%253019%202015Refs: 1. Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90(1):2. Danish University Antidepressant Group. J Affect Disord. 1990;18(4):10105Clomipramine150 mg/d(N = 50)Clomipramine150 mg/d(N = 33)Citalopram40 mg/d(N = 52)Paroxetine30 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%Response16.735.77.7510152025303540455055Remission0.07.153.8DMIFLXDMI + FLXNelson 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 RatesWeekPatient With Symptom Resolution (somatic-general item score = 0), %510152025303540*†*‡*123468Thase ME et al. Br J Psychiatry;178: , 2001
55 All Randomized Patients Duloxetine, SSRI, placebo: Focus on RemissionBaseline HAM-D > 19Remission Rate, %5101520253035404550All Randomized Patients*†** P < 0.05 vs placebo† P vs SSRIsThase 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) 50Desvenlafaxine*Placebo40‡3636n=112n=15133†n=9832†n=100302625n=82n=1052323% patientsn=73n=73201050 mg100 mg200 mg400 mgData are from the intent-to-treat population.*p<0.05, †p<0.01, ‡p<0.001 for desvenlafaxine vs. placeboThase 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, 1998Hard copy send to all speakersExcellent 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 TCAsAnderson 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 trialsRemission as the outcome measuredOdds RatioIV, Random, 95% CI12Favors SNRIs0.20.55Favors SSRIs3004002001.510.5-0.5-1-1.5100500Number of Patients in Each Trial (N)In (odds ratio)600SNRI remission rates were 5.7% higherMachado 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 ValenceArousalPANA−PA−NAPresence of fitness decrementsAbsence of fitness decrementsPresence of fitness incrementsAbsence of fitness incrementsNA, 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 good35455565758595rest/sleepworkinghome computergrooming, self careotherwatching televisionrelaxing, nothing specialshopping, errandspreparing foodeatingwalking, taking a walkplayingexercisingnot mind wanderingpleasant mind wanderingunpleasant mind wanderingneutral mind wanderingmakinglovetalking, conversationlistening to musicpraying/worshipping/meditatingtaking care of your childrenreadingdoing houseworklistening to radio, newscommuting, travelingKillingsworth MA, Gilbert DT. Science. 2010;330(6006):932.
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 illnessComplete mental healthIncomplete mental healthComplete mental illnessHigh subjective well-being symptomsLow subjective well-being symptomsLow mental illness symptomsHigh mental illness symptomsStrugglingFlourishingLanguishingFlounderingSlade 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 WeeksAll of the TimeMost of the TimeMore than Half of the TimeLess than Half of the TimeSome of the TimeAt No TimeI have felt cheerful and in good spirits□5□4□3□2□1□0I have felt calm and relaxedI have felt active and vigorousI woke up feeling fresh and restedMy daily life has been filled with things that interest mePlease 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 hereOutcomes are now hereOutcomes were hereFunctional Recovery Changes in SDS scores? Pre-morbid functioning?RemissionNot 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 areasDisruption in corticolimbic circuitry may create neuroendocrine, neuroimmune, and sympathetic dysregulationInadequate monoamine and neurotrophic signaling combined with excessive glutaminergic and inflammatory cytokine transmission may precipitate a “breakdown” in vulnerable glia-neuron unitsAn altered glia-neuron relationship may then further impede corticolimbic processingGABAModulationApoptotic oxidativeNEDA+−GRP/NMBNeuroplasticityGrowth Factors(eg, BDNF)JAK-STATMAP kinaseNFκBACTHDepressionStressorsCytokine(eg, IL-1, TNF-)CORTCRH/AVP5-HTSpeaker Direction:Review the main points of the presentationGRP=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.