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BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005

BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005. Lawrence H. Price, M.D. Professor of Psychiatry and Human Behavior Brown University School of Medicine Clinical Director and Director of Research Butler Hospital 345 Blackstone Blvd Providence, RI 02906.

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BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005

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  1. BIOMED 370: The Neurobiology of Mood DisordersMarch 3, 2005 Lawrence H. Price, M.D. Professor of Psychiatry and Human Behavior Brown University School of Medicine Clinical Director and Director of Research Butler Hospital 345 Blackstone Blvd Providence, RI 02906

  2. DEFINITIONS Emotion A complex feeling state, with psychological, somatic, and behavioral components, that is related to mood and affect. Mood The subjective experience of feeling or emotion as described by the individual; tends to be pervasive and sustained. Affect Feeling or emotion as expressed by the individual and observed by others; tends to be variable even over short time intervals.

  3. NEUROANATOMY AND MOOD

  4. THE NEUROBIOLOGY OF EUTHYMIA The maintenance of a normal mood state (euthymia) depends on the interactions of a widely distributed network of cortical-limbic and cortical-striatal pathways.

  5. THE LIMBIC SYSTEM • Structures • Cingulate cortex • Hippocampus • Amygdala • (Hypothalamus) • (Orbitofrontal cortex) • (N. accumbens, septal n.)

  6. Beatty, The Human Brain, 2001

  7. Kandel et al, Principles of Neural Science, 2000

  8. THE LIMBIC SYSTEM • Functions Integration of internal and external inputs relevant to the coordination of the following neurobehavioral processes: • Emotional • Cognitive • Vegetative • Autonomic • Motor

  9. A LIMBIC-CORTICAL MODEL OF MOOD REGULATION Cortical (Dorsal) Structures - Medial prefrontal, prefrontal, premotor, parietal, dorsal anterior cingulate, posterior cingulate Functions - Attention, cognition, motor, executive Subcortical Structures - Rostral anterior cingulate, striatum, thalamus, brainstem Functions - Gating, monitoring Limbic (Ventral) Structures - Medial orbitofrontal, subgenual cingulate, hypothalamus,hippocampus, anterior insula, amygdala, posterior cingulate Functions - Autonomic, vegetative, somatic

  10. Mayberg, Br Med Bull 65:193,2003

  11. NEUROANATOMY AND MOOD DISORDERS • Mood disorders • Structural changes have been associated with specific brain regions (e.g., hippocampus). • Functional changes have been associated with specific brain regions. • Unclear whether primary or secondary to pathogenesis. • Biological treatments for mood disorders • Effective treatments have been associated with functional changes in specific brain regions. • Effects on brain structurenot yet established.

  12. DSM-IV MAJOR DEPRESSION A. At least 5 of the following for >2 weeks, including (1) depressed mood or (2) loss of interest or pleasure. 1. depressed mood 2. decreased interest (apathy) or pleasure (anhedonia) 3. weight loss or decreased (anorexia)/increased appetite 4. insomnia or hypersomnia 5. psychomotor agitation or retardation 6. fatigue (anergia) 7. worthlessness or guilt 8. decreased concentration or indecisiveness 9. recurrent thoughts of death or suicidal ideation/plan/ attempt B. Clinically significant distress or social/occupational/ other functionalimpairment.

  13. A LIMBIC-CORTICAL MODEL OF DEPRESSION: Pathogenesis Cortical (Dorsal) Structures - Medial prefrontal, prefrontal, premotor, parietal, dorsal anterior cingulate, posterior cingulate Functions - Attention, cognition, motor, executive Limbic (Ventral) Structures - Medial orbitofrontal, subgenual cingulate, hypothalamus, hippocampus, anterior insula, amygdala, posterior cingulate Functions - Autonomic, vegetative, somatic Dorsal and ventral compartments have a reciprocal relationship

  14. A LIMBIC-CORTICAL MODEL OF DEPRESSION: Treatment Cortical (Dorsal) Structures - Medial prefrontal, prefrontal, premotor, parietal, dorsal anterior cingulate, posterior cingulate Functions - Attention, cognition, motor, executive Limbic (Ventral) Structures - Medial orbitofrontal, subgenual cingulate, hypothalamus, hippocampus, anterior insula, amygdala, posterior cingulate Functions - Autonomic, vegetative, somatic Disinhibition Inhibition Inhibition of ventral activity may disinhibit dorsal activity

  15. Mayberg, Br Med Bull 65:193,2003

  16. NEUROCHEMISTRY AND MOOD

  17. Figure 10.7 Synaptic transmission at chemical synapses involves several steps. An action potential arriving at the terminal of a presynaptic axon causes voltage-gated Ca2+ channels at the active zone to open. The influx of Ca2+ produces a high concentration of Ca2+ near the active zone, which in turn causes vesicles containing neurotransmitter to fuse with the presynaptic membrane and release their contents into the presynaptic cleft (a process termed exocytosis). The released neurotransmitter molecules then diffuse across the synaptic cleft and bind to specific receptors on the post-synaptic membrane. These receptors cause ion channels to open (or close), thereby changing the membrane conductance and membrane potential of the postsynaptic cell. The complex process of chemical synaptic transmission is responsible for the delay between action potentials in the pre- and post-synaptic cells compared with the virtually simultaneous transmission of signals at electrical synapses. The gray filaments represent the docking and release sites of the active zone. Kandel et al, Principles of Neural Science, 2000

  18. A Direct gating (ionotropic receptors) B Indirect gating (metabotropic receptors) 1 G protein-coupled receptor Transmitter Pore Channel Transmitter Extracellular side Gate Cytoplasmic side G protein Second-messenger cascade 2 Receptor tyrosine kinase Transmitter Second-messenger cascade Kandel et al, Principles of Neural Science, 2000

  19. Duman et al, J Nerv Ment Dis, 182:692, 1994

  20. Nestler et al. Biol Psychiatry 52:503, 2002

  21. NEUROTRANSMITTERS AND MOOD DISORDERS • Mood disorders • Hypothesized characteristic dysfunctional changes in specific neurotransmitter systems. • Good evidence for some such changes. • Hypothesized to be central to pathogenesis. • Biological treatments for mood disorders • Effective treatments known to cause characteristic changes in specific neurotransmitter systems. • These are their primaryactions.

  22. Kandel et al, Principles of Neural Science, 2000

  23. Kandel et al, Principles of Neural Science, 2000

  24. Serotonin Receptors RECEPTORS Receptors linked to second-messenger systems 5-HT1A linked to inhibition of adenylyl cyclase 5-HT1B linked to inhibition of adenylyl cyclase 5-HT1C linked to inhibition of adenylyl cyclase 5-HT1D linked to inhibition of adenylyl cyclase 5-HT1E linked to inhibition of adenylyl cyclase 5-HT2A linked to phospholipase and PI turnover 5-HT2B linked to phospholipase and PI turnover 5-HT2C linked to phospholipase and PI turnover 5-HT4 linked to stimulation of adenylyl cyclase 5-HT5 unknown linkage 5-HT6 linked to stimulation of adenylyl cyclase 5-HT7 linked to stimulation of adenylyl cyclase Receptors linked to an ion channel 5-HT3 GENE FAMILY Superfamily of receptors with seven trans-membrane regions coupled to G proteins Superfamily of ligand-gated channels 5-HT = 5-hydroxytryptamine (serotonin); PI = Phosphatidylinositide

  25. Kandel et al, Principles of Neural Science, 2000

  26. Kandel et al, Principles of Neural Science, 2000

  27. Noradrenergic Receptors Linked to Second-Messenger Systems TYPE SECOND-MESSENGER SYSTEM b1 Linked to stimulation of adenylyl cyclase b2 Linked to stimulation of adenylyl cyclase a1Linked to phospholipase C, PI, PKC, DAG, Ca2+ a2Linked to inhibition of adenylyl cyclase LOCATION Cerebral cortex, cerebellum Cerebral cortex, cerebellum Brain, blood vessels, spleen Presynaptic nerve terminals throughout the brain PI = Phosphatidylinositide PKC = Protein kinase C DAG = Diacyglycerol

  28. MONOAMINE THEORIES OF MOOD DISORDERS • Precursor deficit/excess • Abnormalities in post-translational processing • Transporter dysfunction • Receptor dysfunction • Abnormalities in signal transduction, effector activation, amplification • Abnormalities in transsynaptic modulation

  29. EVIDENCE IMPLICATING NE AND 5-HT IN MOOD DISORDERS

  30. D’sa et al. Bipolar Dis, 4:183, 2002

  31. OTHER NEUROTRANSMITTERS INVOLVED IN MOOD DISORDERS • Dopamine (DA) • Acetylcholine (Ach) •  aminobutyric acid (GABA) • Glutamate

  32. NEUROENDOCRINOLOGY AND MOOD

  33. Reiche, Lancet Oncol, 5:617, 2004

  34. Martin and Reichlin, Clinical Neuroendocrinology, 1987

  35. NEUROPEPTIDES AND MOOD DISORDERS • Mood disorders • Known characteristic dysfunctional changes in specific neuropeptide systems. • Unclear whether primary or secondary to pathogenesis. • Biological treatments for mood disorders • Effective treatments have been associated with changes in specific neuropeptide systems. • Most such changes believed secondary. • Efficacy of agents with primary neuroendocrine effects under investigation, but not yet established.

  36. Hypothalamic-Pituitary-Adrenal (HPA) Axis Hyperactivity in Depression • Increased basal cortisol levels in plasma, urine, and CSF • Increased frequency, duration, and magnitude of cortisol and ACTH secretory episodes • Resistance to suppression of cortisol and ACTH secretion by dexamethasone • Increased cortisol response to ACTH • Blunted ACTH response to CRH • Increased CSF levels of CRH • Adrenal and pituitary gland enlargement • Decreased glucocorticoid receptor binding on lymphocytes • Decreased postmortem CRH receptor binding in frontal cortex • Diminished glucocorticoid negative feedback

  37. HPA Axis Function and Antidepressants • HPA axis abnormalities in depression generally resolve with successful treatment • In rodents, chronic treatment with conventional antidepressants causes increased: • glucocorticoid binding • glucocorticoid receptor immunoreactivity • glucocorticoid receptor mRNA levels • glucocorticoid receptor gene promoter activity • Suppression of HPA activity by conventional antidepressants could result from enhanced HPA axis negative feedback • Antiglucocorticoids may have clinical antidepressant activity

  38. NEUROIMMUNOLOGY AND MOOD

  39. Reiche,Lancet Oncol, 5:617, 2004

  40. Turnbull et al, Physiol Rev 79(10:1, 1999

  41. CYTOKINES AND MOOD DISORDERS • Mood disorders • Hypothesized dysfunctional changes in specific cytokine systems. • Unclear whether primary or secondary to pathogenesis. • Biological treatments for mood disorders • Effective treatments have been associated with changes in specific cytokine systems. • Most such changes believed secondary.

  42. Kronfol et al, Am J Psychiatry 157:683, 2000

  43. GENETICS AND MOOD

  44. GENETICS AND MOOD DISORDERS • Mood disorders • Genetic factors known to increase risk, but inheritance is multifactorial. • Central to pathogenesis. • Biological treatments for mood disorders • Interaction of effective treatments with genetic risk factors (pharmacogenetics) under investigation, but not yet established. • Efficacy • Tolerability/adverse effects

  45. Smoller et al, Am J Med Genetics Part C 123C:48, 2003

  46. FIGURE 1. Estimates of the Heritability in Liability to Major Depression in Studies of Male and Female Twinsa Sullivan et al, AmJ Psychiatry 157(10):1552, 2000

  47. Tsuang et al, J Psychiatr Res 38:13, 2004

  48. FIGURE 2. Paths and Correlations Involving Genetic Risk for Major Depression in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins Kendler et al, Am J Psychiatry 159:1133, 2002

  49. EXPERIENTIAL FACTORS AND MOOD

  50. Engelmann et al, Front Neuroendocrinol 25:132, 2004

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