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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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Biomed 370 the neurobiology of mood disorders march 3 2005

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


Biomed 370 the neurobiology of mood disorders march 3 2005

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.

AffectFeeling or emotion as expressed by the individual and observed by others; tends to be variable even over short time intervals.


Biomed 370 the neurobiology of mood disorders march 3 2005

NEUROANATOMY AND MOOD


Biomed 370 the neurobiology of mood disorders march 3 2005

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.


Biomed 370 the neurobiology of mood disorders march 3 2005

THE LIMBIC SYSTEM

  • Structures

    • Cingulate cortex

    • Hippocampus

    • Amygdala

    • (Hypothalamus)

    • (Orbitofrontal cortex)

    • (N. accumbens, septal n.)


Biomed 370 the neurobiology of mood disorders march 3 2005

Beatty, The Human Brain, 2001


Biomed 370 the neurobiology of mood disorders march 3 2005

Kandel et al, Principles of

Neural Science, 2000


Biomed 370 the neurobiology of mood disorders march 3 2005

THE LIMBIC SYSTEM

  • FunctionsIntegration of internal and external inputs relevant to the coordination of the followingneurobehavioral processes:

    • Emotional

    • Cognitive

    • Vegetative

    • Autonomic

    • Motor


Biomed 370 the neurobiology of mood disorders march 3 2005

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


Biomed 370 the neurobiology of mood disorders march 3 2005

Mayberg, Br Med Bull 65:193,2003


Biomed 370 the neurobiology of mood disorders march 3 2005

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.


  • Biomed 370 the neurobiology of mood disorders march 3 2005

    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.


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Mayberg, Br Med Bull 65:193,2003


    Biomed 370 the neurobiology of mood disorders march 3 2005

    NEUROCHEMISTRY AND MOOD


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Nestler et al. Biol Psychiatry 52:503, 2002


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.


  • Biomed 370 the neurobiology of mood disorders march 3 2005

    Kandel et al, Principles of Neural Science, 2000


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Kandel et al, Principles of Neural Science, 2000


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Kandel et al, Principles of Neural Science, 2000


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Kandel et al, Principles of Neural Science, 2000


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Noradrenergic Receptors Linked to

    Second-Messenger Systems

    TYPESECOND-MESSENGER SYSTEM

    b1Linked to stimulation of adenylyl cyclase

    b2Linked 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


    Monoamine theories of mood disorders

    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


    Evidence implicating ne and 5 ht in mood disorders

    EVIDENCE IMPLICATING NE AND 5-HT IN MOOD DISORDERS


    Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Other neurotransmitters involved in mood disorders

    OTHER NEUROTRANSMITTERS INVOLVED IN MOOD DISORDERS

    • Dopamine (DA)

    • Acetylcholine (Ach)

    •  aminobutyric acid (GABA)

    • Glutamate


    Biomed 370 the neurobiology of mood disorders march 3 2005

    NEUROENDOCRINOLOGY AND MOOD


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Reiche,

    Lancet Oncol,

    5:617, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Martin and Reichlin,

    Clinical Neuroendocrinology,

    1987


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.


  • Hypothalamic pituitary adrenal hpa axis hyperactivity in depression

    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


    Hpa axis function and antidepressants

    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


  • Biomed 370 the neurobiology of mood disorders march 3 2005

    NEUROIMMUNOLOGY AND MOOD


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Reiche,Lancet Oncol, 5:617, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.


  • Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    GENETICS AND MOOD


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


  • Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    EXPERIENTIAL FACTORS AND MOOD


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Engelmann et al, Front Neuroendocrinol 25:132, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

    STRESS AND MOOD DISORDERS

    • Mood disorders

      • Stressors known to increase risk.

      • 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 decrease the subjectiveexperience of stress, but nonspecific stress reduction usually ineffective.


  • Mood disorders and psychosocial stress

    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


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Influence of Life Stress on Depression: Moderation by a

    Polymorphism in the 5-HTT Gene

    Caspi et al, Science 301:386, 2003


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Social supports and serotonin gene moderate depression in maltreated children

    Kaufman et al, PNAS 101(49):17316, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

    INTEGRATIVE MODELS OF MOOD DISORDERS


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.

    Hasler et al, Neuropsychopharmacology 29:1765, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.

    Hasler et al, Neuropsychopharmacology 29:1765, 2004


    Biomed 370 the neurobiology of mood disorders march 3 2005

    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.

    Nestler et al, Neuron 34:13,2002


    Biomed 370 the neurobiology of mood disorders march 3 2005

    Fig. 2 Neuroplasticity and cellular resilience in mood disorders.

    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.

    Manji et al, Nature Med 7(5):541,2001


    Butler hospital mood disorders research program

    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


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