2. 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

3. 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. DEFINITIONS

4. NEUROANATOMY AND MOOD

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

6. Structures Cingulate cortexCingulate cortex HippocampusHippocampus AmygdalaAmygdala (Hypothalamus)(Hypothalamus) (Orbitofrontal cortex)(Orbitofrontal cortex) (N. accumbens, septal n.)(N. accumbens, septal n.) THE LIMBIC SYSTEM

7. Beatty, The Human Brain, 2001

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

9. Functions Integration of internal and external inputs relevant to the coordination of the following neurobehavioral processes: EmotionalEmotional CognitiveCognitive VegetativeVegetative AutonomicAutonomic MotorMotor THE LIMBIC SYSTEM

10. 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 A LIMBIC-CORTICAL MODEL OF MOOD REGULATION

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

12. Mood disorders Structural changes have been associated with specific brain regions (e.g., hippocampus).Structural changes have been associated with specific brain regions (e.g., hippocampus). Functional changes have been associated with specific brain regions.Functional changes have been associated with specific brain regions. Unclear whether primary or secondary to pathogenesis.Unclear whether primary or secondary to pathogenesis. Biological treatments for mood disorders Effective treatments have been associated with functional changes in specific brain regions.Effective treatments have been associated with functional changes in specific brain regions. Effects on brain structure not yet established.Effects on brain structure not yet established. NEUROANATOMY AND MOOD DISORDERS

13. 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 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 7. worthlessness or guilt 8. decreased concentration or indecisiveness 8. decreased concentration or indecisiveness 9. recurrent thoughts of death or suicidal ideation/plan/ 9. recurrent thoughts of death or suicidal ideation/plan/attempt B. Clinically significant distress or social/occupational/ other functional impairment. DSM-IV MAJOR DEPRESSION DSM-IV MAJOR DEPRESSION

14. 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 A LIMBIC-CORTICAL MODEL OF DEPRESSION: Pathogenesis Dorsal and ventral compartments have a reciprocal relationship

15. 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 A LIMBIC-CORTICAL MODEL OF DEPRESSION: Treatment Disinhibition Inhibition Inhibition of ventral activity may disinhibit dorsal activity

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

17. NEUROCHEMISTRY AND MOOD

18. 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 Ca 2+ channels at the active zone to open. The influx of Ca 2+ produces a high concentration of Ca 2+ 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

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

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

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

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

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

25. RECEPTORS Receptors linked to second-messenger systems 5-HT 1A linked to inhibition of adenylyl cyclase 5-HT 1B linked to inhibition of adenylyl cyclase 5-HT 1C linked to inhibition of adenylyl cyclase 5-HT 1D linked to inhibition of adenylyl cyclase 5-HT 1E linked to inhibition of adenylyl cyclase 5-HT 2A linked to phospholipase and PI turnover 5-HT 2B linked to phospholipase and PI turnover 5-HT 2C linked to phospholipase and PI turnover 5-HT 4 linked to stimulation of adenylyl cyclase 5-HT 5 unknown linkage 5-HT 6 linked to stimulation of adenylyl cyclase 5-HT 7 linked to stimulation of adenylyl cyclase Receptors linked to an ion channel 5-HT 3 GENE FAMILY Superfamily of receptors with seven trans-membrane regions coupled to G proteins Superfamily of ligand-gated channels Serotonin Receptors 5-HT = 5-hydroxytryptamine (serotonin); PI = Phosphatidylinositide

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

28. TYPESECOND-MESSENGER SYSTEM  1 Linked to stimulation of adenylyl cyclase  2 Linked to stimulation of adenylyl cyclase  1 Linked to phospholipase C, PI, PKC, DAG, Ca 2+  2 Linked to inhibition of adenylyl cyclase LOCATION Cerebral cortex, cerebellum Cerebral cortex, cerebellum Brain, blood vessels, spleen Presynaptic nerve terminals throughout the brain Noradrenergic Receptors Linked to Second-Messenger Systems PI = Phosphatidylinositide PKC = Protein kinase C DAG = Diacyglycerol

29. 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

30. EVIDENCE IMPLICATING NE AND 5-HT IN MOOD DISORDERS ALTERATIONS IN THE NE SYSTEM IN DEPRESSION ALTERATIONS IN THE 5-HT SYSTEM IN DEPRESSION Abnormalities in MHPG levelsDecreased tryptophan concentrations Elevated norepinephrine in plasma and CSFDecreased 5-HIAA in the CSF Increased  -adrenergic receptors in post-mortem brain Increased 5HT2 & 5HT1A binding in post- mortem cortex Increased  2 receptors in post-mortem brain Decreased 5HT1A binding in post-mortem limbic areas Altered LC neuron density and TH expressionDecreased 5-HT transporter density in platelets Blunted growth hormone response to clonidineBlunted prolactin response to fenfluramine, tryptophan, 5HT uptake inhibitors ANTIDEPRESSANT EFFECTS ON THE NE SYSTEM ANTIDEPRESSANT EFFECTS ON THE 5-HT SYSTEM Decreased norepinephrine turnoverIncreased serotonin turnover Decreased  -adrenergic receptor density in animal models Increased 5HT1A density/activity Depressive relapse with catecholamine depletionDepressive relapse with tryptophan depletion OVERALL INCREASE IN NE TRANSMISSION IN DEPRESSION OVERALL DECREASE IN 5HT TRANSMISSION IN DEPRESSION

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

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

33. NEUROENDOCRINOLOGY AND MOOD

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

35. Martin and Reichlin, Clinical Neuroendocrinology, 1987

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

37. 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

38. 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

39. NEUROIMMUNOLOGY AND MOOD

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

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

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

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

44. GENETICS AND MOOD

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

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

47. Sullivan et al, Am J Psychiatry 157(10):1552, 2000 FIGURE 1. Estimates of the Heritability in Liability to Major Depression in Studies of Male and Female Twins a

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

49. Kendler et al, Am J Psychiatry 159:1133, 2002 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

50. EXPERIENTIAL FACTORS AND MOOD

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

52. Mood disorders Stressors known to increase risk.Stressors known to increase risk. Sometimes primary to pathogenesis, but often secondary.Sometimes primary to pathogenesis, but often secondary. Psychosocial treatments for mood disorders Effective treatments target specific aspects of the mood disorder (e.g., CBT, IPT).Effective treatments target specific aspects of the mood disorder (e.g., CBT, IPT). Effective treatments decrease the subjective experience of stress, but nonspecific stress reduction usually ineffective.Effective treatments decrease the subjective experience of stress, but nonspecific stress reduction usually ineffective. STRESS AND MOOD DISORDERS

53. Mood Disorders and Psychosocial Stress  EARLY LIFE STRESS  Neglect  Abuse  ADULT STRESS  Object loss (feelings of abandonment isolation loneliness despair)  Failure (feelings of failure self-esteem worthlessness guilt) Inadequate nurturance

54. Caspi et al, Science 301:386, 2003 Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

55. Kaufman et al, PNAS 101(49):17316, 2004 Social supports and serotonin gene moderate depression in maltreated children

56. INTEGRATIVE MODELS OF MOOD DISORDERS

57. Hasler et al, Neuropsychopharmacology 29:1765, 2004 Figure 1. Example of how neuroanatomical abnormalities may relate to candidate genes and to key components of major depression. Some of the key components have a greater potential to serve as endophenotypes than others. Not all functional directions are indicated for the purpose of clarity of the figure.

58. Hasler et al, Neuropsychopharmacology 29:1765, 2004 Figure 2. Example of how neurochemical abnormalities may relate to candidate genes and to key components of major depression. Some of the key components have a greater potential to serve as endophenotypes than Others. Not all functional directions are indicated for the purpose of clarity of the figure.

59. Nestler et al, Neuron 34:13,2002 Figure 3. Neurotrophic Mechanisms in Depression The panel on the left shows a normal hippocampal pyramidal neuron and its innervation by glutamatergic, monoaminergic, and other neurons. Its regulation by BDNF (derived from hippocampus or other brain areas) is also shown. Severe stress causes several changes in these neurons, including a reduction in their dendritic arborizations, and a reduction in BDNF expression (which could be one of the factors mediating the dendritic effects). The reduction in BDNF is mediated partly by excessive glucocorticoids, which could interfere with the normal transcriptional mechanisms (e.g., CREB) that control BDNF expression. Antidepressants produce the opposite effects: they increase dendritic arborizations and BDNF expression of these hippocampal neurons. The latter effect appears to be mediated by activation of CREB. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus, and ameliorate certain symptoms of depression.

60. Manji et al, Nature Med 7(5):541,2001 Genetic and neurodevelopmental factors, repeated affective episodes and illness progression might contribute to impaired cellular resilience, volumetric reductions and cell death/atrophy. Stress and depression likely contribute to impaired cellular resilience by reducing BDNF, increasing glutamatergic function via NMDA and non-NMDA receptors, and reducing cell energy capacity. Neurotrophic factors like BDNF enhance cell survival by activating 2 signaling pathways: PI-3–kinase and ERK–MAP- kinase. BDNF promotes cell survival by increasing expression of cytoprotective protein, Bcl-2. Bcl-2 attenuates cell death by impairing release of Ca ++ and cytochrome c, sequestering proforms of death-inducing caspase enzymes, and enhancing mitochondrial Ca ++ uptake. Chronic antidepressant increases BDNF and its receptor TrkB. Li and VPA upregulate cytoprotective protein Bcl-2. Li and VPA also inhibit GSK-3β, resulting in neuroprotective effects. VPA activates the ERK-MAP-kinase pathway, which may have neurotrophic and neurite outgrowth effects. BDNF, brain derived neurotrophic receptor; trkB, tyrosine kinase receptor for BDNF; NGF, nerve growth factor; Bcl-2 and Bcl-x – anti- apoptotic members of Bcl-2 family; BAD and Bax, pro-apoptotic members of Bcl-2 family; Ras, Raf, MEK, ERK, components of ERK MAP kinase pathway; CREB, cyclic AMP responsive element binding protein; Rsk-2. Ribosomal S-6 kinase; ROS, reactive oxygen species; GR, glucocorticoid receptor, GSK-3, glucogen synthase kinase. Fig. 2 Neuroplasticity and cellular resilience in mood disorders.

62. BUTLER HOSPITAL MOOD DISORDERS RESEARCH PROGRAM Department of Psychiatry and Human Behavior Brown Medical School 345 Blackstone Blvd Providence, RI 02906 TEL 401- 455-6537 FAX 401- 455-6534