biomed 370 the neurobiology of mood disorders march 3 2005 n.
Download
Skip this Video
Download Presentation
BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005

Loading in 2 Seconds...

play fullscreen
1 / 61

BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005 - PowerPoint PPT Presentation


  • 101 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'BIOMED 370: The Neurobiology of Mood Disorders March 3, 2005' - lark


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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

slide2

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.

slide4

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.

slide5

THE LIMBIC SYSTEM

  • Structures
          • Cingulate cortex
          • Hippocampus
          • Amygdala
          • (Hypothalamus)
          • (Orbitofrontal cortex)
          • (N. accumbens, septal n.)
slide7

Kandel et al, Principles of

Neural Science, 2000

slide8

THE LIMBIC SYSTEM

  • Functions Integration of internal and external inputs relevant to the coordination of the following neurobehavioral processes:
          • Emotional
          • Cognitive
          • Vegetative
          • Autonomic
          • Motor
slide9

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

slide11

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.
slide12

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.

slide13

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

slide14

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

slide17

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

slide18

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

slide21

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.
slide24

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

slide27

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

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
other neurotransmitters involved in mood disorders
OTHER NEUROTRANSMITTERS INVOLVED IN MOOD DISORDERS
  • Dopamine (DA)
  • Acetylcholine (Ach)
  •  aminobutyric acid (GABA)
  • Glutamate
slide33

Reiche,

Lancet Oncol,

5:617, 2004

slide34

Martin and Reichlin,

Clinical Neuroendocrinology,

1987

slide35

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
slide41

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.
slide44

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
slide46

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

slide48

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

slide51

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

slide53

Influence of Life Stress on Depression: Moderation by a

Polymorphism in the 5-HTT Gene

Caspi et al, Science 301:386, 2003

slide54

Social supports and serotonin gene moderate depression in maltreated children

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

slide56

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

slide57

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

slide58

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

slide59

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