Hanipsych, biology of depression

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  • Unipolar depression makes a large contribution to the burden of disease, being at third place worldwide and eighth place in low-income countries, but at first place in middle- and high-income countries.
    The disability-adjusted life years (DALYs) quantify the burden of diseases based on years of life lost due to premature mortality and years of life lived in less than full health.
    One DALY represents the loss of the equivalent of one year of full health. Using DALYs, the burden of diseases that cause early death but little disability (eg. drowning or measles) can be compared to that of diseases that do not cause death but do cause disability (e.g. cataract causing blindness).
  • Depressed patients have a 2 times greater overall mortality risk than the general population due to
    Direct causes (e.g. suicide)
    And indirect causes (e.g. medical illness)
  • The morbidity costs associated with depression in the workplace are derived from traditional research, including costs arising from workplace absenteeism of depressed employees, as well as reductions in workplace productivity during the employees’ episodes of depression1
    Up to 15% of patients with MDD severe enough to require hospitalization eventually die of suicide.2 This high mortality rate necessitates the accurate identification and immediate treatment of patients experiencing MDD
    Depression is associated with direct and indirect costs that place a significant burden on society1
    MDD, if left untreated, significantly worsens health and functioning, giving rise to physical complaints and increased use of health care resources3
    Sources:
    1.Greenberg PE, et al. J Clin Psychiatry. 1993;54:405-418.
    2.Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no. 93-0550. April 1993.
    3.Henk HJ, et al. Arch Gen Psychiatry. 1996;53:899-904.
  • Depression is a common complication of both acute and chronic medical illnesses
  • Once a pathologic mood state arises in the course of a primary medical disorder, it may in turn set off a variety of pathophysiologic events that can exacerbate the underlying medical condition. This, in turn, may lead to a reactive worsening of the patient’s mood, in what amounts to a ”vicious circle” or aversive cascade of synergistic events.
  • Key Points:
    MDD is currently defined as a chronic and recurrent condition; however, its progressive nature (the extent to which it is thought to worsen over time) is still disputed.1
    In addition to changing how a person behaves (functional consequences), MDD has been shown to cause physical changes (structural consequences) in the brain.2
    MDD, pain, and stress can lead to similar functional and structural changes in the brain2 This fact may help explain the progressive nature of the illness.
    As the course of MDD may worsen over time, the emphasis of treatment must be on remission and prevention of future episodes.3,4
    References:
    Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the "kindling" hypothesis. Am J Psychiatry 2000;157(8):1243-51.
    Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract 2007;61(12):2030-40.
    Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, Shea T. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992;49(10):809-16.
    APA. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000;157(4 suppl):1-45.
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  • Source: [Keller et al. Arch Gen Psychiatry 1992;49(10): Cumulative Probability of Recovery section, pag 811. Speaker notes: Keller et al. Arch Gen Psychiatry 1992;49(10): Cumulative Probability of Recovery section, pag 811, Varying Definitions of Recovery section, pag 815]
    Key Points:
    The likelihood of recovery from major depressive disorder (MDD) decreases as the length of an MDD episode increases.
    Treatments are most likely to be effective, and the probability of recovery is at its maximum, during the first 6 months of an MDD episode.
    The reduced probability of recovery over time highlights the urgency to treat depression early.
    The substantial reduction in recovery rates also suggests that depression is a chronic illness with a progressive course.
    Background:
    Four hundred thirty-one individuals with MDD who participated in the National Institute of Mental Health (NIMH) Collaborative Depression Study were prospectively observed for 5 years.
    These participants had no history of mania, hypomania, schizoaffective disorder, or underlying minor depression (lasting 2 or more years) and no chronic intermittent depressive disorder.
    Cumulative probabilities of recovery were calculated for intervals ranging from 1 week to 5 years.
    Recovery was defined as remission (Psychiatric Status Rating [PSR] score 1 or 2, the equivalent of minimal to absent symptoms, with no significant functional impairment) sustained for at least 8 weeks.
    Reference:
    Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, Shea T. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992;49(10):809-16.
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  • Speaker notes: [Kendler et al. Am J Psychiatry 2000;157(8):1243-51. Abst, Method section]
    Key Points:
    The kindling hypothesis states that previous episodes of depression change the brain, making patients more likely to experience subsequent episodes of depression.
    After 4 to 5 episodes, the best predictor of subsequent episodes of depression is the number of previous depressive episodes, not stress.
    Does this suggest that recurrent depression is a progressive disease?
    Background:
    Female twins from a population-based registry (N = 2395) were interviewed 4 times during a period of 9 years, forming a study group that contained 97,515 person-months and 1380 onsets of major depressive disorder (MDD).
    To assess the interaction between life-event exposure and the number of previous episodes of MDD in predicting future MDD episodes, discrete-time survival, a proportional hazards model, and piece-wise regression analyses were used.
    This pattern of results was unchanged by the addition of measures of event severity and genetic risk, as well as the restriction to “independent stressful life events”.
    The same pattern of results emerged when within-person changes in the number of episodes were examined.
    Reference:
    Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the "kindling" hypothesis. Am J Psychiatry 2000;157(8):1243-51.
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  • Key Points:
    There are three key brain areas involved in regulation of mood: the ventromedial prefrontal cortex (VMPFC – noted by light-red color), lateral orbital prefrontal cortex (LOPFC – noted by light green color), and dorsolateral prefrontal cortex (DLPFC – noted by light blue color).
    The VMPFC is hyperactive in depression3
    The LOPFC is hyperactive in depression3
    The DLPFC is hypoactive in depression4
    Connections between the VMPFC and DLPFC are through the cingulate and hippocampus.1
    A hyperactive VMPFC may result in injury to the hippocampus
    Background:
    VMPFC: receives integrated sensory information from the orbital prefrontal cortex, and fear- and reward-related input from the amygdala, medial temporal lobe, and ventral striatum (nucleus accumbens). It projects to the hippocampus, diencephalon, and brainstem, where it regulates autonomic and neuroendocrine response, pain modulation, aggression, and sexual and eating behaviors.1,2
    LOPFC (lateral and posterior): receives highly processed and integrated sensory information from the parietal cortex. It is also connected to the amygdala, ventral striatum, and lateral hypothalamus. Activity is increased in depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder. Orbital prefrontal cortex plays a role in correcting and inhibiting maladaptive, perseverative, and emotional responses (in part, generated by the amygdala).3
    DLPFC: has been implicated in cognitive control, solving complex tasks, maintenance, and manipulation of information in working memory. Decreased activity of the DLPFC in depression has been associated with psychomotor retardation and anhedonia.3,4
    References:
    Ongür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 2000;10:206-219.
    Swanson LW. In: Björklund A, Hökfelt T, eds. Handbook of Chemical Neuroanatomy;1987:1-124.
    Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 1998;49:341-61.
    MacDonald AW 3rd, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 2000;288:1835-8.
    Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002;53:545-74.
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  • Key Points:
    Two additional areas involved in mood regulation are the amygdala and the hippocampus.
    The amygdala is involved in emotional learning and memory.1
    Abnormal activation of the amygdala correlates with the severity of the depression2
    The amygdala may also be implicated in the tendency to ruminate1
    The hippocampus is involved in contextual learning and memory.3,4
    The hippocampus provides regulatory feedback to the hypothalamic-pituitary-adrenal (HPA) axis3,4
    Dysfunction in the hippocampus may be responsible for inappropriate emotional responses6
    The hippocampus is rich in corticosteroid receptors5
    Background:
    Amygdala: involved in recruiting and coordinating cortical arousal and neuroendocrine response to underdetermined (surprising and ambiguous) stimuli. It may also play a role in bipolar depression and anxiety.
    Hippocampus: plays a critical role in episodic and contextual learning and memory. It is rich in corticosteroid receptors and provides inhibitory feedback to the hypothalamic-pituitary-adrenal axis. Hippocampal dysfunction may be responsible for inappropriate context-dependent emotional responses.6
    References:
    Davidson RJ. Affective neuroscience and psychophysiology: toward a synthesis. Psychophysiology 2003;40(5):655-65.
    Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001;11(2):240-9.
    Squire LR, Knowlton BJ. In: Gazzaniga MS, ed. The New Cognitive Neurosciences;2000:765-79.
    Fanselow MS. Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res 2000;110(1-2):73-81.
    Reul JM, de Kloet ER. Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. J Steroid Biochem 1986;24(1):269-72.
    Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002;53:545-74.
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  • Source: [Hales RE, Yudofsky SC. Mood disorders. In: Textbook of Clinical Psychiatry. 4th ed. Arlington: American Psychiatric Publishing; 2003:slide 20.
    Key Points:
    Both serotonin (5-HT) and norepinephrine (NE) are neurotransmitters that have ascending tracts to the cerebral cortex and limbic area, as well as descending tracts to the spinal cord.2
    The cell bodies for these tracts originate in major nuclei of the midbrain. For the central nervous system, the 5-HT cell bodies are located in the raphe nuclei and the largest cluster of NE cells are located in the locus coeruleus.2
    Each of these midbrain nuclei has ascending tracts, which project to brain regions thought to be involved in depressive symptoms, as well as ascending and descending tracts involved in pain suppression.
    Decreased neurotransmission of 5-HT and NE is believed to be associated with depression.3
    5-HT- and NE-secreting neurons project upward from their respective nuclei in the brainstem, directly stimulating many areas of the brain.
    Brain areas stimulated include the prefrontal cortex, which is involved in executive functions, and the limbic system which include anatomical structures involved in behavior, motivation, and emotion, such as the hippocampus, anterior cingulate cortex, hypothalamus, and amygdala.
    References:
    Cooper JR, Bloom FE, Roth RH. In: The Biochemical Basis of Neuropharmacology 2003.
    Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci 1997;9(3):315-30.
    Hales RE, Yudofsky SC. Mood disorders. In: Textbook of Clinical Psychiatry. 4th ed. Arlington: American Psychiatric Publishing; 2003:479-86.
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  • Key Points:
    The hippocampus is at a “vulnerable intersection” of cognitive, emotional, and neuroendocrine regulation. It is rich in glucocorticoid receptors and is a recipient of significant input from excitatory glutaminergic neurons.
    The hippocampus, a region of the brain involved in emotional responses, may begin to atrophy in depression.
    Investigators have found that approximately half of persons with severe depression exhibit high levels of the stress hormone, cortisol, which is thought to be toxic to neurons. (Source: J. Douglas Bremner, MD, Yale University).
    This combined toxic impact may precipitate changes in growth and plasticity in the hippocampus.
    Background:
    The magnetic resonance imaging (MRI) scans above were obtained from a healthy control (left scan) and a person with severe depression (right scan).
    Indications of hippocampal atrophy are apparent in the diminished size of the area outlined in red in the enlargement of the scan obtained from the patient with depression.
    Reference:
    Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry 2000;157(1):115-8.
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  • Source: [Sheline et al. Am J Psychiatry 2003;160(8): Fig 1. Speaker notes: Sheline et al. Am J Psychiatry 2003;160(8): Fig legend].
    Key Points:
    In this study, failure to treat depression was found to have significant negative 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:
    Thirty-eight outpatient female participants with recurrent depression in remission were recruited for this study.
    Subjects were screened for medical problems and were specifically screened for incipient dementia.
    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria were used to determine past episodes of major depression as well as to exclude other psychiatric diagnoses.
    Hippocampal volumes were measured using magnetic resonance imaging (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):1516-8.
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  • Abbreviations: CRF: corticotropin releasing factor, ACTH: adrenocorticotropic hormone
    Key Points:
    During depressive episodes, normal mechanisms may malfunction and lead to hippocampal damage.
    Hippocampal dysfunction then leads to increase in glucocorticoids via the hypothalamic-pituitary-adrenal (HPA) axis.
    The increase in glucocorticoids continues to damage the hippocampus, resulting in a "runaway" system and even more neuronal damage.
    Reference:
    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34(1):13-25.
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  • Source: [Musselman et al. Arch Gen Psychiatry 1998;55(7): Abst, pag 580]
    Abbreviation: ACTH: adrenocorticotropic hormone
    Key Points:
    Major depressive disorder (MDD) may be more than just a psychiatric disease, as there is evidence of widespread systemic consequences.
    Neuroendocrine dysregulation and elevated sympathetic tone (activity in the sympathetic nervous system) may result in cardiovascular morbidity and increased risk of metabolic syndrome
    Immune response may be compromised in MDD
    Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD).
    This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction
    Treatment of depression in patients with CVD may improve dysphoria, and other signs and symptoms of depression, and improve quality of life.
    Background:
    Literature review of MEDLINE articles published from 1966 to 1997 using the search terms “major depression,” “psychiatry,” “cardiovascular disease,” and “pathophysiology” was used to develop the possible links between MDD and CVD
    Literature review includes studies investigating the role of depression in pathophysiological changes related to CVD and studies on the treatment of MDD in patients with CVD
    Reference:
    Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55(7):580-92.
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  • [Speaker notes: Sheline et al. Proc Natl Acad Sci USA 1996;93(9):3908-13. Table 1, pag 3910; Shimizu et al. Biol Psychiatry 2003;54(1):Abst, method section]
    Abbreviations: BDNF: brain-derived neurotrophic factor, 5-HT: serotonin, NE: norepinephrine
    Key Points:
    Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. One specific area where neurons continue to be born throughout life is in the dentate gyrus of the hippocampus.
    Neurogenesis is regulated by growth factors that can lead to the development of new cells, and other growth factors including BDNF keep the cells alive.
    BDNF is associated with production of new neurons and their growth and development.1
    The hippocampi appear to have important functions related to both mood and memory.
    Studies by Gould and others have shown that growth of new neurons in the hippocampus is a common phenomenon across mammalian species (eg, rats, monkeys, and humans).6
    Sheline compared hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity (n = 10) to matched normal controls (n = 10) by using volumetric magnetic resonance imaging.3
    BDNF has been shown to be associated with regulation of mood4, and in preclinical studies, to be influenced by stress and perception of pain.5
    In one study, patients with major depressive disorder (MDD) had significantly lower levels of BDNF compared to control subjects.4
    Antidepressant treatment was shown to raise BDNF levels back to normal levels
    Both 5-HT and NE are believed to play roles in the modulation of BDNF.1
    Background:
    Most neurons in the mammalian brain and spinal cord are generated during the pre- and perinatal periods of development. Nevertheless, neurons continue to be born throughout life in the olfactory bulb, which processes scents, and in the dentate gyrus of the hippocampus.
    Most existing neurons in the adult brain cannot divide. Some progenitor cells, however, remain, and they retain the capability for further division into new neurons. Apparently, in most parts of the adult brain, something inhibits progenitor cells from dividing, to produce new neurons. No one knows exactly why neurogenesis continues in some areas and not others.
    The hippocampi appears to have important functions related to both cognition and mood. Components of the hippocampus that may be involved in mood include the dentate gyrus (where adult neurogenesis occurs), and an area known as CA3.
    In a study of 33 patients with MDD, patients who had not received antidepressant treatment (n = 16) had significantly lower BDNF levels than treated patients (n = 17) as well as control subjects (n = 50).4
    In an animal study, both stress as well as acute and chronic pain states significantly lowered levels of BDNF mRNA in the rat hippocampus.5
    References:
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54(7):597-606.
    Gould E. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology. 1999;21(2 Suppl):46S-51S.
    Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996;93(9):3908-13.
    Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54(1):70-5.
    Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience 2005;133(4):999-1006.
    Gould E, Tanapat P, Rydel T, Hastings N. Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry 2000;48(8):715-20
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  • Abbreviations: BDNF: brain-derived neurotrophic factor, MDD: major depressive disorder
    Key Points:
    This slide demonstrates the role of BDNF in neuronal generation and growth through the metaphor of sunlight, which is necessary for plant growth.
    The BDNF target gene may be the site of flawed transduction in monoamine receptors.
    Under normal conditions, activation of the BDNF target gene allows BDNF to be produced, exerting a protective role on the development of brain neurons. However, when the BDNF gene is not activated under stressful conditions, BDNF is not produced, and neurons in the hippocampus may atrophy or die.
    This mechanism may be responsible for depression and is consistent with neuroimaging studies that have shown that hippocampal neurons in individuals with MDD are smaller and are functionally impaired.
    These findings suggest that early detection and diagnosis of depression are crucial to ensure optimal clinical and physiological outcomes for patients.
    Reference:
    Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press; 2000:187.
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  • Source: [Duric and McCarson. Neuroscience 2005;133(4):Fig 3a, Fig 3b, pag 1003. Speaker notes: Duric and McCarson. Neuroscience 2005;133(4): Experimental Procedures, Animal housing and handling section, pag 1000]
    Abbreviations: BDNF: brain-derived neurotrophic factor, CFA: complete Freund’s adjuvant
    Key Point:
    Acute and chronic stress (left graph), and acute and chronic pain (right graph) can contribute to decreased levels of BDNF mRNA levels in the rat hippocampus.
    BACKGROUND:
    In a preclinical study, 74 rats were subjected to either immobilization stress or injected with an inflammatory stimulus (formalin or complete Freund’s adjuvant, CFA). CFA is an antigen solution that promotes inflammatory response.
    Hippocampal BDNF mRNA levels were quantified using ribonuclease protection assays.
    Results showed that exposure to both acute and chronic stress and pain can result in decreased BDNF expression.
    Reference:
    Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience 2005;133(4):999-1006.
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  • Abbreviations: BDNF: brain-derived neurotrophic factor, MDD: major depressive disorder
    Key Points:
    Chronic MDD may cause structural alterations in the brain.2
    Volume loss in the hippocampus may be associated with stress-induced reduction in neurotrophic factors1
    Compromised neuroendocrine regulation in MDD can lead to systemic consequences, such as cardiovascular disease.2,3
    Functional brain imaging during various phases of MDD and treatment show that MDD may be associated with diminished neurotrophic support, resulting in impaired neuroplasticity, neurogenesis, and cellular resilience.2
    Cerebral areas affected by MDD have significant noradrenergic and serotonergic innervation.2
    Antidepressants may restore neuroplasticity, neurogenesis, and neural resilience by modulating BDNF through serotonin and/ or norepinephrine transmission in relevant areas.2,4,5
    References:
    Sheline YI. 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity. Biol Psychiatry 2000;48(8):791-800.
    Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001;7(5):541-7.
    Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991;14:219-45.
    Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000;20(24):9104-10.
    Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54(1):70-5.
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  • Key Point:
    Let’s take a look at how the neurotransmitters 5-HT and NE can affect and possibly reverse structural changes associated with MDD.
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  • Speaker notes: [Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001;7(5):para 1, pag 541.]
    Abbreviations: NE: norepinephrine, 5-HT: serotonin, CREB: cAMP response element binding protein, BDNF: brain-derived neurotrophic factor, cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, NMDA: N-methyl D-aspartate receptor
    Key Points:
    Elevation of glucocorticoid and excitatory neurotransmitter activity caused by chronic mood disorders may impair neuroplasticity and cellular resilience.1
    Use of antidepressants with 5-HT and/or NE can regulate the expression of BDNF by activating intracellular cascades that eventually lead to synthesis of BDNF.3-5
    BDNF interacts with the TrkB receptor to enhance neuroplasticity and neurogenesis5
    BDNF helps improve cellular resilience by facilitating synthesis of a neuroprotective factor-Bcl-25
    References:
    Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003;53(8):707-42.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression andantidepressant action. Nat Neurosci 2006;9(4):519-25.
    Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000;20(24):9104-10.
    Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54(1):70-5.
    Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001;7(5):541-7.
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  • Source: [Shimizu et al. Biol Psychiatry 2003;54(1): Abst, Methods section, pag 70, Results section, para 1 pag 72. Speaker notes: Shimizu et al. Biol Psychiatry 2003;54(1): Abst pag 70, pag Fig 1, pag 72]
    Abbreviations: BDNF: brain-derived neurotrophic factor, HAMD: Hamilton Rating Scale for Depression, MDD: major depressive disorder
    Key Points:
    Measurements of plasma BDNF in patients with MDD reveal that treatment with antidepressants can raise BDNF levels to those of control individuals without MDD.
    Plasma BDNF levels were significantly lower in patients with MDD who did not receive antidepressant therapy when compared to healthy individuals and treated patients with MDD.
    Increases in BDNF correlated with improvement in depressive symptoms.
    Background:
    Two groups of patients with MDD were recruited for this study.
    One group was antidepressant naïve (n = 16)
    One group was being treated with antidepressants (n = 17)
    All patients fulfilled the DSM-IV criteria for MDD, and other Axis I disorders were ruled out
    The severity of depression was determined by the HAMD17.
    A control group (n = 50) was recruited that was age-matched and did not have any medical or psychiatric diagnoses based on a clinical interview.
    Plasma BDNF levels were collected from patients each morning and were measured using an immunoassay system.
    Reference:
    Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54(1):70-5.
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  • Abbreviations: BDNF: brain-derived neurotrophic factor, CREB: cAMP response element binding protein, MDD: major depressive disorder, 5-HT: serotonin, NE: norepinephrine
    Key Points:
    So, what exactly is BDNF doing? Does it just promote neuronal growth?
    As it turns out, the story may be a bit more complicated, as BDNF is involved not only in growth, but also in reorganization and eventual "pruning" (selecting only active, important networks), hypothetically leading to normalization of neuronal connections and proper function.
    Under normal conditions:
    There is a balance between excitatory input, glucocorticoids, and monoaminergic regulation.
    BDNF is synthesized in appropriate amounts to maintain neuroplasticity, neurogenesis, and cellular resilience.
    In MDD:
    There appears to be inadequate monoaminergic activity, combined with excessive corticosteroid activity and excitatory input.
    BDNF synthesis is compromised, resulting in disruption in neuroplasticity (relevant information is no longer processed properly), cellular resilience (neurons undergo atrophy and apoptosis), and neurogenesis. (In animal models, the absence of neurogenesis negated the behavioral effects of antidepressants).
    Hypothetically, treatment with monoamine- (5-HT and/or NE) elevating antidepressants elevates BDNF levels, helping to restore dynamic homeostasis.
    Reference:
    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34(1):13-25.
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  • Speaker notes: Duman et al. Arch Gen Psychiatry 1997;54(7): Fig 4 pag 601.
    Abbreviations: BDNF: brain-derived neurotrophic factor, MDD: major depressive disorder, 5-HT: serotonin, NE: norepinephrine
    Key Points:
    BDNF is downregulated in MDD, but antidepressant treatment (including 5-HT and/or NE) can increase BDNF synthesis.1
    BDNF hypothetically may normalize neuronal connections, thus influencing regulation of mood2 and perception of pain3 (shown in clinical and animal studies, respectively).
    Increased BDNF promotes neuroplasticity, neurogenesis, and neuroprotection (the 3 “Ns”).1
    Background:
    In preclinical studies, long-term (≥ 2 weeks), but not short-term, administration of antidepressants can result in increased BDNF synthesis.1
    Direct injection of BDNF into brain parenchyma can result in sustained antidepressant and analgesic effects in rat studies.4,5
    References:
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54(7):597-606.
    Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54(1):70-5.
    Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neutrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience 2005;133(4):999-1006.
    Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997;56(1):131-7.
    Siuciak JA, Clark MS, Rind HB, Whittemore SR, Russo AF. BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J Neurosci Res 1998;52:149-58.
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  • Key Points:
    In patients with major depressive disorder (MDD), chance of recovery diminishes with increasing length of depression.1 Therefore, remission, not just response to treatment, is the goal.
    Let’s review more information that supports the treatment goal of remission in patients with MDD.
    Reference:
    Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, Shea T. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992;49(10):809-16.
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  • Source: [Drevets et al. J Neurosci 1992;12(9): Page 3634]
    This figure was created by Primo Scientific Corporation for the use in GMSB slide sets.
    Abbreviations: PFC: prefrontal cortex, PET: positron emission tomography
    Key Point:
    Blood flow was found to be increased in the amygdala and left medial and lateral orbital cortex, extending to ventrolateral PFC; these findings may implicate that these areas in the cortical circuitry play a role in the pathophysiology of depressive symptoms.
    Background:
    In an attempt to map the functional neuroanatomy of unipolar major depression, differences in regional cerebral blood flow were measured in patients with depression with positive family history (n = 13) and healthy controls (n = 33) using PET.
    Data were obtained from the subtraction of composite images from depressed and control subjects, and cortical regions thus defined were statistically tested on a second set of subjects.
    Reference:
    Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci 1992;12(9):3628-41.
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  • Source: [Frodl et al. J Clin Psychiatry 2004;65(4):Fig 2 pag 496. Speaker notes: Frodl et al. J Clin Psychiatry 2004;65(4): Abst Results section pag 492, Table 1 pag 493]
    Abbreviations: MDD: major depressive disorder, DSM-IV: Diagnosis and Statistical Manual of Disorders, HAMD: Hamilton Rating Scale for Depression
    Key Point:
    A retrospective analysis showed that remitted patients at 1-year follow up had significantly greater hippocampal volume at baseline (and at 1 year) compared to nonremitted patients. This suggests that hippocampal volume in patients with MDD may be directly related to the ability to achieve remission.
    Background:
    Thirty patients with MDD (on the basis of DSM-IV criteria) and 30 matched controls were examined at hospital admission and 1 year later.
    Medical histories were taken and magnetic resonance images (MRIs) were performed to determine the presence of MDD and to measure any changes in hippocampal volume.
    The HAMD was used to measure MDD symptoms, and remission was defined as a HAMD17 score of 7 or less.
    The overall HAMD score at admission for the group with depression was 23.7, with the remitted (n = 18) and nonremitted (n = 12) subgroups scoring 24.7 and 22.2, respectively.
    Reference:
    Frodl T, Meisenzahl EM, Zetzsche T, Höhne T, Banac S, Schorr C, Jäger M, Leinsinger G, Bottlender R, Reiser M, Möller HJ. Hippocampal and amygdala changes in Patients with major depressive disorder and healthy controls during a 1-year follow-up. J Clin Psychiatry 2004;65(4):492-9.
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  • Abbreviations: 5-HT: serotonin, NE: norepinephrine, VMPFC: ventromedial prefrontal cortex, DLPFC: dorsolateral prefrontal cortex, MDD: major depressive disorder
    Key Points:
    Summary of reviewed data:
    Specific parts of the brain are involved in the pathophysiology of MDD, with imbalances in metabolism and activity observed in various areas throughout the prefrontal cortex and limbic system.
    Antidepressants have been shown to increase levels of neurotrophins, which may lead to increased neuroplasticity, neurogenesis, and neuroprotection.
    Antidepressant use has also been shown to “correct” dysfunction in areas of the brain that are negatively affected by depression. This correction may be associated with improvement in depressive symptoms.
    Taken together, the evidence reviewed suggests that antidepressants may act as neurochemical modulators, allowing the systems that are out of balance to return to homeostasis.
    References:
    Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000;48(8):830-43.
    Brody AL, Saxena S, Mandelkern MA, Fairbanks LA, Ho ML, Baxter LR. Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Biol Psychiatry. 2001;50(3):171-8.
    Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 2004;5(1):11-25.
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  • Source: [Pintor et al. J Affect Disord 2003;73(3): Abst pag 237, Table 1 and Resuls section pag 239; page 240. Speaker notes: Pintor et al. J Affect Disord 2003;73(3): Methods section pag 239, Results section, pag 239 and 240, Table 5 pag 243]
    Abbreviations: MDD: major depressive disorder, HAMD: Hamilton Rating Scale for Depression
    Key Points:
    Patients with MDD who were not treated to remission were at a significantly greater risk of relapse (p<.0001).
    Remitted patients were 4.5 times less likely to relapse over a 2-year period than nonremitted patients.
    Background:
    One hundred eighty-three patients with MDD were followed for up to 2 years after partial (n = 71) or complete (n = 112) remission was achieved.
    Patients were followed up monthly until 2 years or relapse
    Patients were maintained on treatment, and patients not in remission were switched to different treatments if no response was obtained after 6 weeks of treatment.
    In this group, a minimum of 3 therapeutic strategies were tested. Medications or dosages were also changed if tolerance issues arose.
    Remission was defined as a HAMD17 score ≤7.
    Reference:
    Pintor L, Gasto C, Navarro V, Torres X, Fananas L. Relapse of major depression after complete and partial remission during a 2-year follow-up. J Affect Disord 2003;73(3):237-44.
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  • Source: [Miller et al. J Clin Psychiatry 1998;59(11):Table 1 pag 610. Speaker notes: Miller et al. J Clin Psychiatry 1998;59(11): Psychosocial variables section pag 607, Table 5 pag 614]
    Abbreviations: SR: self reported, SD: standard deviation, MDD: major depressive disorder, CGI-I: Clinical Global Impression-improvement, HAMD: Hamilton Rating Scale for Depression
    Key Points:
    Only individuals who attained complete symptom resolution (or fully remitted) functioned normally in interpersonal domains, such as the work composite scale as shown.
    Those who responded but did not achieve remission functioned similarly to patients with MDD, and dissimilarly from normal controls.
    Additionally, those with chronic MDD had a high level of social dysfunction overall.
    Background:
    This long-term study of patients with chronic MDD assessed response to treatment in a pool of patients who had been treated with either sertraline or imipramine in a 12-week acute-treatment trial.
    The Social Adjustment Scale-Self Reported (SAS-SR) scores of patients treated with sertraline or imipramine were compared to other, previously reported community samples from a general population.
    Scales used in the study: Longitudinal Follow-up Evaluation (LIFE), Medical Outcomes Study Short Form (SF-36), Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ), and the SAS-SR.
    The work composite scale that was used to measure social adjustment used 3 work-related items from the SAS-SR, concerning, employment status, working up to educational level, etc.
    High scores indicated worse status
    Community scores indicated the ability to work to an education level, be employed, and hold a full-time job
    The baseline and endpoint score was 1.4 for the community sample, and the endpoint score was 1.45 for patients with MDD who attained remission
    Remission was defined as having both a CGI-I score of 1 or 2 and a HAMD17 score 7.2
    Response was defined as a CGI-I score of 1 or 2, a HAMD24 score ≤15, an improvement of at least 50% from baseline on the HAMD24, and a CGI-S score ≤3.2
    Criteria for response and remission had to be met at 2 consecutive ratings at least 2 weeks apart.2
    References:
    Miller IW, Keitner GI, Schatzberg AF, Klein DN, Thase ME, Rush AJ, Markowitz JC, Schlager DS, Kornstein SG, Davis SM, Harrison WM, Keller MB. The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry 1998;59(11):608-19.
    Rush AJ, Koran LM, Keller MB, Markowitz JC, Harrison WM, Miceli RJ, Fawcett JA, Gelenberg AJ, Hirschfeld RM, Klein DN, Kocsis JH, McCullough JP, Schatzberg AF, Thase ME. The treatment of chronic depression, part 1: study design and rationale for evaluating the comparative efficacy of sertraline and imipramine as acute, crossover, continuation, and maintenance phase therapies. J Clin Psychiatry 1998;59(11):589-97.
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  • Abbreviations: NE: norepinephrine, HT: serotonin, BDNF: brain-derived neuronal factor
    Key Points:
    In depression, painful symptoms are common and relevant to diagnosis and treatment.
    Inadequately treated depression may have a progressive course and result in structural changes in the brain.
    Activation of NE and/or 5-HT pathways may lead to an increase in BDNF, resulting in neuroprotective benefits and restoration of neuroplasticity and neurogenesis .
    It is important to choose an effective treatment first because failure to achieve remission may lead to more frequent relapses and future failures in treatment response.1
    By addressing emotional and physical symptoms of depression, antidepressants that enhance 5-HT and/or NE may increase the chance of remission and optimal functional outcome.
    Reference:
    Oswald P, Souery D, Kasper S. Predictive factors of resistance to antidepressant treatments: results from a European multicentre study. Eur Neuropsychopharmacol 15(suppl 3) S326-7.
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  • Hanipsych, biology of depression

    1. 1. Neurobiology of Depression: An Integrated View Dr. Hani Hamed Dessoki, M.D.Psychiatry Prof. Psychiatry Chairman of Psychiatry Department Beni Suef University Supervisor of Psychiatry Department El-Fayoum University APA member This information is provided in response to your request and is intended for your scientific and/or educational purpose and is not intended for promotional use. This material is copyrighted by Lilly USA, LLC with all rights reserved.
    2. 2. Agenda ♦ Introduction ♦ Somatic depression ♦ Neurobiology of depression ♦ Different management ♦ Take home Message ♦ Future direction
    3. 3. Depression … the 21st Century illness
    4. 4. ‫♦‬ ‫♦‬ ‫♦‬ ‫♦‬ ‫♦‬ ‫المرض النفسي والعصبي الذي أصبح يصيب054 مليون إنسان فوق‬ ‫سطح الرض.‬ ‫وان الكتئاب وحده وصل الي041مليون انسان,‬ ‫أما حالت القلق والخوف فقد وصلت في العالم الي002 مليون‬ ‫انسان خائف وقلق..‬ ‫ووصل الدمان في العالم أيضا الي031 مليون إنسان مدمن..‬ ‫أما الرقام في مصر فإنها تؤكد وجود مليون و002 ألف إنسان مصري‬ ‫يعاني عذاب الكتئاب.‬ ‫جريدة الهرام، الخميس 22 من ذى القعدة 2341 هـ   02 اكتوبر 1102 السنة 631 العدد 80654‬
    5. 5. Depression Samedi 9 novembre 2013
    6. 6. World Bank Reports Year 2000 Anxiety Depression is 4th greatest health problem Year 2020 Will be 2nd greatest health problem causing disability 7
    7. 7. Challenges By the year 2020, depression is projected to reach 2nd place of the ranking of DALYs(WHO) One DALY (disability-adjusted life years) represents the loss of the equivalent of one year of full health By the year 2030, depression is projected to reach 1st place of the ranking of DALYs 10 Leading causes of burden of disease (DALYs), world 2004 and 2030
    8. 8. Challenges Depressed patients a 2 times greater overall mortality risk than the general population Direct causes Indirect causes (e.g. suicide) (e.g. medical illness)
    9. 9. Economics of Depression — U.S.A. Data - Total Annual Cost ~$44 Billion Lost productivity— 55% Suicide—17% Outpatient care— 6% Pharmaceuticals— 3% Inpatient care— 19% Greenberg PE, et al. J Clin Psychiatry. 1993;54:405-418. U.S. data.
    10. 10. Recognition of general practice patients Up to 50% of general practice patients may have some depressive symptoms. Approximately 5% of these will have major depression defined by DSM-III-R criteria. Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)
    11. 11. Prevalence of depression 5.8% of men 9.5% of women 10-15% of elderly ≥ 65 years WHO - Fact Sheet N° 265, December  2001
    12. 12. Depressed Patients Usually Present with Physical Symptoms 69% Presented ONLY With Physical Symptoms Other N = 1146 patients with major depression 1. Simon GE, et al. N. Engl J Med. 1999;341(18):1329-1335.
    13. 13. Prevalence of Depression in Chronic Disease Alzheimer's disease HIV CAD Stroke MI Diabetes 11% 12% 17% 23% 25% 27% Cancer Parkinson's disease NHDS, NAMCS, NHAMCS Sutor B, et al. Mayo Clin Proc. 1998;73(4):329-337; Jiang et al, CNS Drugs, 2002 42% 51%
    14. 14. Mechanisms of depression and medical comorbidity Primary medical illness/condition Neuroendocrine, immune dysfunction, inflammatory change Premorbid coping skills, cognitive set, and personality traits Social supports Pathologic mood state e.g., depression Ellison et al. Mood Disorders in Later Life. Informa 2009
    15. 15. General practice patients and recognised major depression How do patients with major depression usually present in primary care?  Patients with major depression often present with predominantly physical (somatic) symptoms such as: • significant weight loss, or gain • insomnia or hypersomnia • agitation or retardation • fatigue or loss of energy  The presence of physical symptoms reduces the likelihood of diagnosis by the GP.  Many patients with major depression also have a physical illness. Blacker and Clare (1987); Bridges et al (1991); Freeling et al (1985)
    16. 16. The association between depression and medical illness Depression is associated with disability caused by a variety of diseases. Pulmonary CN S Stroke Alzheimer’s disease Parkinson’s disease Chronic obstructive pulmonary disease Cardiac Myocardial infarction Rheumatic Arthritis Gurland et al (1988)
    17. 17. Cause or Effect? Functional ability Morbidity Negative attitude Depression Medical illness Neglect health Biochemical changes
    18. 18. RECIPROCAL RELATIONSHIP Pain Depression
    19. 19. Chronic pain & depression  Many factors can interfere with the successful treatment of chronic pain including undiagnosed diseases, mental disorders, emotional distress, personality traits, and personal beliefs.  Depression is not simply a comorbid condition but interacts with chronic pain to increase morbidity and mortality.
    20. 20. Major Depressive Disorder (MDD) ♦ MDD can be a chronic, recurrent, and progressive condition1 ♦ MDD is associated with alterations in functional and structural changes in the brain2 ♦ MDD, stress, and pain are all associated with similar suppression of neurotrophic factors and compromised neuroplasticity2 ♦ Remission, not response, is the ultimate goal of treatment3,4 1. 2. Kendler et al. Am J Psychiatry 2000;157(8):1243-51. Maletic et al. Int J Clin Pract 2007;61(12):2030-40. 3. 4. Keller et al. Arch Gen Psychiatry 1992;49(10):809-16. APA. Am J Psychiatry 2000;157(4 suppl):1-45.
    21. 21. Depression ♦ Rate of recurrence after 1st episode is 50%. ♦ Rate of recurrence after 2nd episode is 70%. ♦ Rate of recurrence after 3rd episode is 80%.
    22. 22. Rates of Recovery Diminish with Duration of Major Depressive Episode 100 % Recovery Rate 60 N = 431 54 40 20 16 11 6 1 0 6 Months 1 Year 2 Years Recovery = 8 weeks of Psychiatric Status Rating (PSR) 1 or 2 Recovery = sustained remission Keller et al. Arch Gen Psychiatry 1992;49(10):809-16. 4 Years 5 Years
    23. 23. Progression of Depression: Adverse Effects of Each Successive Episode 10 Likelihood of recent life stress precipitating depression Risk (Odds Ratio) of depression onset per month Risk (Odds Ratio) 8 6 4 2 0 Female subjects only N = 2395 0 1 2 3 4 5 6 7-8 Number of Previous Depressive Episodes Kendler et al. Am J Psychiatry 2000;157(8):1243-51. 9-11
    24. 24. Key Brain Areas Involved in Regulation of Mood ♦ (A) Ventromedial prefrontal cortex (VMPFC)1 • Modulates pain and aggression, and sexual and eating behaviors2 • Regulates autonomic and neuroendocrine response B5 A5 ♦ (B) Lateral orbital prefrontal cortex (LOPFC)3 • Activity is increased in depression, obsessivecompulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder • Corrects and inhibits maladaptive, perseverative, and emotional responses ♦ (C) Dorsolateral prefrontal cortex (DLPFC)4 C5 • Cognitive control, solving complex tasks, and manipulation of information in working memory • Hypoactivity of DLPFC in depression has been associated with neuropsychological manifestation of depression Reprinted with permissions, from the Annual Review of Psychology, Volume 53, © 2002 by Annual Reviews www.annualreviews.org 1. Ongür and Price. Cereb Cortex 2000;10(3):206-19. 2. Swanson. In: Handbook of Chemical Neuroanatomy;1987:1-124. 3. Drevets. Annu Rev Med 1998;49:341-61. 4. MacDonald et al. Science 2000;288(5472):1835-8. 5. Davidson et al. Annu Rev Psychol 2002;53:545-74.
    25. 25. Key Brain Areas Involved in Regulation of Mood (Cont.) ♦ (A) Amygdala: regulates cortical arousal and neuroendocrine response to surprising and ambiguous stimuli1 • Role in emotional learning and memory • Activation of amygdala correlates with degree of depression2 • Implicated in tendency to ruminate on negative memories2 A6 ♦ (B) Hippocampus: has a role in episodic, contextual learning and memory3,4 • Rich in corticosteroid receptors5 • Regulatory feedback to hypothalamic-pituitaryadrenal axis • Hippocampal dysfunction may be responsible for inappropriate emotional responses 1. Davidson. Psychophysiology 2003;40(5):655-65. 2. Drevets. Curr Opin Neurobiol 2001;11(2):240-9. 3. Squire et al. In: The New Cognitive Neurosciences;2000:765-79. B6 Reprinted with permissions, from the Annual Review of Psychology, Volume 53, © 2002 by Annual Reviews www.annualreviews.org 4. Fanselow. Behav Brain Res 2000;110(1-2):73-81. 5. Reul and De Kloet. J Steroid Biochem 1986;24(1):269-72. 6. Davidson et al. Annu Rev Psychol 2002;53:545-74.
    26. 26. Serotonin (5-HT) and Norepinephrine (NE) Pathways in the Human Brain1 Limbic System Prefrontal Cortex Amygdala Raphe Nuclei (5-HT source) Hippocampus Locus Coeruleus (NE source) Descending 5-HT pathways Descending NE pathways By permission of Oxford University Press, Inc. Page 209, figure 8.11 from “Biochemical Basis of Neuropharmacology” by Cooper Jack (2002) 1.Cooper et al. In: The Biochemical Basis of Neuropharmacology 2003.
    27. 27. Brain Atrophy in Depression? Atrophy of the Hippocampus in Depression Normal Depression Reprinted with permission from Bremner et al. Am J Psychiatry 2000 Bremner et al. Am J Psychiatry 2000;157(1):115-8.
    28. 28. Correlation Between Hippocampal Volume and Duration of Untreated Depression* Female Outpatients With Recurrent Depression in Remission Total Hippocampal Volume (mm3) 6000 R2 = .28 N = 38 5500 5000 4500 4000 3500 3000 0 1000 2000 3000 4000 Days of Untreated Depression *p = .0006 *Significant inverse relationship between total hippocampal volume and the length of time depression went untreated Sheline et al. Am J Psychiatry 2003;160(8):1516-8.
    29. 29. Hippocampal Dysfunction Contributes to Neuroendocrine Dysregulation Reprinted from Neuron, 34(1), Nestler EJ, et al., “Neurobiology of Depression”, pp 13-25, (2002), with permission from Elsevier. Nestler et al. Neuron 2002;34(1):13-25.
    30. 30. Major Depressive Disorder May Have Systemic Consequences Musselman DL, et al. Archives of General Psychiatry. 1998;55(7):580-592. Copyright © (1998), American Medical Association. Musselman et al. Arch Gen Psychiatry 1998;55(7):580-92.
    31. 31. Brain-derived Neurotrophic Factor (BDNF), Stress, and Neurogenesis in the Adult Brain ♦ Neurogenesis (the birth of new neurons) continues postnatally and into adulthood • BDNF is associated with production of new neurons and their growth and development1 ♦ The hippocampi appear to have important functions related to both mood and memory • Data suggest that neurogenesis occurs in the hippocampus 2 • Data from depressed patients have shown reduced hippocampal volume3 ♦ BDNF influences regulation of mood4 and perception of pain5 ♦ BDNF is downregulated in MDD and increased with successful antidepressant treatment4 ♦ Both 5-HT and NE are believed to play roles in the modulation of BDNF1 1. Duman et al. Arch Gen Psychiatry 1997;54(7):597-606. 2. Gould E. Neuropsychopharmacology 1999;21(2 suppl):46S-51S. 3. Sheline et al. Proc Natl Acad Sci USA 1996;93(9):3908-13. 4. Shimizu et al. Biol Psychiatry 2003;54(1):70-5. 5. Duric and McCarson. Neuroscience 2005;133(4):999-1006.
    32. 32. The Monoamine Hypothesis of Gene Action: The Impact of Stress on BDNF Preprinted with permissions from Cambridge University Press. Stahl. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.
    33. 33. Pain and Stress Lower BDNF Gene Expression in Animal Models Changes in Hippocampal BDNF Synthesis 8 8 6 6 4 4 * 2 0 Acute and Chronic Pain Pg BDNF mRNA/ng β-actin mRNA Pg BDNF mRNA/ng β-actin mRNA Acute and Chronic Stress Control * Acute Stress Chronic Stress 2 0 * * * 6h 24h 10-Day CFA * Control 2:45h Formalin *p<.05 compared to control Duric and McCarson. Neuroscience 2005;133(4):999-1006.
    34. 34. Major Depressive Disorder: The Consequences ♦ Structural changes in the hippocampus and prefrontal cortex often accompany MDD1 ♦ MDD may be associated with diminished neurotrophic support, resulting in impaired neuroplasticity, neurogenesis, and cellular resilience2 ♦ Cerebral areas affected by MDD have significant noradrenergic and serotonergic innervation 2 1. 2. Sheline. Biol Psychiatry 2000;48(8):791-800. Manji et al. Nat Med 2001;7(5):541-7.
    35. 35. Antidepressants: The Importance of Serotonin and Norepinephrine in the Treatment of Depression
    36. 36. Beyond Synapse: 5-HT and NE Aid BDNF Synthesis (Preclinical Evidence) ┴ = inhibitory 1. 2. Manji et al. Biol Psychiatry 2003;53(8):707-42. Tsankova et al. Nat Neurosci 2006;9(4):519-25.
    37. 37. Successful Antidepressant Treatment can be Associated with BDNF Increase 35 Plasma BDNF (ng/mL) 30 25 20 * 15 10 5 (n = 50) (n = 16) (n = 17) Control Depressedtreatment-naïve Depressed-treated 0 *p<.01 vs. control or treated Mixed group of antidepressants used for treatment HAMD17 = 27.8±10.2 and 18.8±11.4 for untreated and treated groups respectively Shimizu et al. Biol Psychiatry 2003;54(1):70-5.
    38. 38. Network Hypothesis of Depression Reprinted from Neuron, 34(1), Nestler EJ, et al., “Neurobiology of Depression”, pp 13-25, (2002), with permission from Elsevier. Nestler et al. Neuron 2002;34(1):13-25.
    39. 39. Summary: BDNF, Depression, and Antidepressants ♦ BDNF is downregulated in MDD and increased with antidepressant treatment1,2 ♦ BDNF has a hypothetical neurotrophic effect that influences regulation of mood2 and perception of pain3 in clinical and animal studies ♦ 5-HT and/or NE are believed to play roles in the modulation of BDNF1 ♦ Increase in BDNF promotes the 3 Ns • Neuroplasticity, neurogenesis, and neuroprotection (cellular resilience)1 1. 2. 3. Duman et al. Arch Gen Psychiatry 1997;54(7):597-606. Shimizu et al. Biol Psychiatry 2003;54(1):70-5. Duric and McCarson. Neuroscience 2005;133(4):999-1006.
    40. 40. Remission, Not Response, is the Goal of Treatment of Depression
    41. 41. Regional Blood Flow Abnormalities in Patients with Depression Ventrolateral PFC Amygdala Medial Orbital 0 2.0 t-value 4.5 0 2.0 t-value 4.0 Patients with depression had increased blood flow in amygdala and left medial and lateral orbital cortex, extending to ventrolateral PFC Drevets et al. J Neurosci 1992;12(9):3628-41.
    42. 42. Hippocampal Volume (mm3) Structural Difference in the Hippocampus of Remitted vs. Nonremitted Patients Remitted, left hippocampus Remitted, right hippocampus 4.5 Nonremitted, left hippocampus Nonremitted, right hippocampus 4.0 3.5 3.0 Remitted (N = 18) Nonremitted (N = 12) Left Hemisphere Frodl et al. J Clin Psychiatry 2004;65(4):492-9. Remitted Nonremitted (N = 18) (N = 12) Right Hemisphere
    43. 43. Summary: Restoring Homeostasis and Harmony ♦ Continuous antidepressant use may be associated with increased 5-HT and/or NE in the prefrontal cortex and limbic system1 ♦ Effective antidepressant treatment may be associated with decreased activity in the VMPFC, hippocampus and amygdala, and increased activity in the DLPFC1,2 ♦ Changes in activity may correlate with symptomatic improvement in MDD: decrease in sadness, anxiety, psychomotor retardation, and fatigue as well as improvement in cognitive functioning1,2 ♦ Activation of 5-HT and/or NE may help restore adaptive homeostasis by modulating balance between excitatory and inhibitory inputs in key brain areas, and by optimizing neuroplasticity, neurogenesis, and neuroprotection2,3 1. 2. 3. Mayberg et al. Biol Psychiatry 2000;48(8):830-43. Brody et al. Biol Psychiatry 2001;50(3):171-8. Duman. Neuromolecular Med 2004;5(1):11-25.
    44. 44. What Happens if Remission is Not Achieved? % of Patients Who Relapsed (2-Year Follow-up Study) 100 % of Patients 90 80 * 67.6% 70 60 50 40 30 15.2% 20 10 (n = 71) 0 Patients Not in Remission *p<.0001 Pintor et al. J Affect Disord 2003;73(3):237-44. (n = 112) Patients in Remission
    45. 45. Functional Benefits of Remission Work Composite Scale of the Social Adjustment Scale-SR (Mean ± SD) 4 3 * ** 2 1 * (n = 482) (n = 202) (n = 122) (n = 299) Normal Remission Response Nonresponse *p≤.05 vs. nonresponse **p≤.05 vs. response Only remitters function at levels comparable to healthy people Miller et al. J Clin Psychiatry 1998;59(11):608-19.
    46. 46. Take Home Message ♦ Inadequately treated depression may have a progressive course and result in structural changes in the brain ♦ Activation of NE and/or 5-HT pathways may lead to an increase in BDNF, resulting in neuroprotective benefits and restoration of neuroplasticity and neurogenesis ♦ It is important to choose an effective treatment first because failure to achieve remission may lead to more frequent relapses and future failures in treatment response1 1. Oswald et al. Eur Neuropsychopharmacol 2005;15(suppl 3):S326-7.
    47. 47. Future Directions
    48. 48. TODAY…. diagnosis trials and errors effective treatment TOMORROW…. tailor made
    49. 49. Future of Behavioral Health has Arrived ♦ Patients with depression and anxiety are frustrated with drug treatments because of poor response (up to 5 trials). ♦ Also, some of these medications increase anxiety, resistance to treatment, insomnia, and sexual dysfunction. ♦ Sometimes they may quit medications. ♦ It is better to choose psychotropic medications based on the individual genetic characteristics, metabolizing pathways leading to better medication tolerance. ♦ This give the patient the confidence to continue treatment. ♦ Test can done by a simple cheek swab (Assure Rx- GeneSightRx).
    50. 50. Cells Show Signs of Faster Aging After Depression Study found structures called telomeres were shorter in people with the condition By Brenda Goodman HealthDay Reporter TUESDAY, Nov. 12 (HealthDay News) -- The cells of people who have had depression may age more quickly, a new study suggests. Dutch researchers compared cell structures called telomeres in more than 2,400 people with and without depression. Like the plastic tips at the ends of shoelaces, telomeres cap the ends of chromosomes to protect the cell's DNA from damage. Telomeres get a bit shorter each time a cell divides, so they are useful markers for aging. The researchers found that the telomeres of people who had ever been depressed were significantly shorter -- about 83 to 84 base pairs of DNA shorter, on average -- than those of people who had never suffered from depression. The results remained even after researchers accounted for a host of lifestyle factors that can also damage DNA, such as heavy drinking and cigarette smoking. Since people naturally lose about 14 to 20 base pairs of DNA in the telomeres each year, the researchers said the difference represents about four to six years of advanced aging.
    51. 51. Telomeres
    52. 52. A telomere ♦ A telomere is a region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) 'end' and merοs (μέρος, root: μερ-) 'part.' Telomere regions deter the degradation of genes near the ends of chromosomes by allowing chromosome ends to shorten, which necessarily occurs during chromosome replication. ♦ Without telomeres, the genomes would progressively lose information and be truncated after cell division because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand. ♦ Over time, due to each cell division, the telomere ends become shorter.

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