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

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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

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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.
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NEUROANATOMY AND MOOD
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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.
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THE LIMBIC SYSTEM

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

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Beatty, The Human Brain, 2001
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Kandel et al, Principles of Neural Science, 2000
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THE LIMBIC SYSTEM

• Functions Integration of internal and
  external inputs relevant to the
  coordination of the following neurobehavi
  oral processes
• Emotional
• Cognitive
• Vegetative
• Autonomic
• Motor

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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
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Mayberg, Br Med Bull 65193,2003
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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 structure not yet established.

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DSM-IV MAJOR DEPRESSION
A. At least 5 of the following for gt2 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/ othe
r functional impairment.
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A LIMBIC-CORTICAL MODEL OF DEPRESSION Pathogenesi
s
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
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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
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Mayberg, Br Med Bull 65193,2003
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NEUROCHEMISTRY AND MOOD
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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
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B Indirect gating (metabotropic receptors)
A Direct gating (ionotropic receptors)
Transmitter
1 G protein-coupled receptor
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
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Duman et al, J Nerv Ment Dis, 182692, 1994
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Nestler et al. Biol Psychiatry 52503, 2002
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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 primary actions.

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Kandel et al, Principles of Neural
Science, 2000
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Kandel et al, Principles of Neural
Science, 2000
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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
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Kandel et al, Principles of Neural
Science, 2000
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Kandel et al, Principles of Neural
Science, 2000
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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 a1 Linked to
phospholipase C, PI, PKC, DAG, Ca2 a2 Linked
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
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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

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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 levels Decreased tryptophan concentrations
Elevated norepinephrine in plasma and CSF Decreased 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 expression Decreased 5-HT transporter density in platelets
Blunted growth hormone response to clonidine Blunted prolactin response to fenfluramine, tryptophan, 5HT uptake inhibitors
ANTIDEPRESSANT EFFECTS ON THE NE SYSTEM ANTIDEPRESSANT EFFECTS ON THE 5-HT SYSTEM
Decreased norepinephrine turnover Increased serotonin turnover
Decreased ?-adrenergic receptor density in animal models Increased 5HT1A density/activity
Depressive relapse with catecholamine depletion Depressive relapse with tryptophan depletion
OVERALL INCREASE IN NE TRANSMISSION IN DEPRESSION OVERALL DECREASE IN 5HT TRANSMISSION IN DEPRESSION
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Dsa et al. Bipolar Dis, 4183, 2002
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OTHER NEUROTRANSMITTERS INVOLVED IN MOOD
DISORDERS

• Dopamine (DA)
• Acetylcholine (Ach)
• ? aminobutyric acid (GABA)
• Glutamate

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NEUROENDOCRINOLOGY AND MOOD
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Reiche, Lancet Oncol, 5617, 2004
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Martin and Reichlin, Clinical Neuroendocrinology,
1987
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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.

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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

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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

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NEUROIMMUNOLOGY AND MOOD
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Reiche,Lancet Oncol, 5617, 2004
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Turnbull et al, Physiol Rev 79(101, 1999
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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.

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Kronfol et al, Am J Psychiatry 157683, 2000
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GENETICS AND MOOD
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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

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Smoller et al, Am J Med Genetics Part C 123C48,
2003
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FIGURE 1. Estimates of the Heritability in
Liability to Major Depression in Studies of Male
and Female Twinsa
Sullivan et al, Am J Psychiatry 157(10)1552, 2000
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Tsuang et al, J Psychiatr Res 3813, 2004
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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 1591133, 2002
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EXPERIENTIAL FACTORS AND MOOD
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Engelmann et al, Front Neuroendocrinol 25132,
2004
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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 subjective
  experience of stress, but nonspecific stress
  reduction usually ineffective.

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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
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Influence of Life Stress on Depression
Moderation by a Polymorphism in the 5-HTT Gene
Caspi et al, Science 301386, 2003
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Social supports and serotonin gene moderate
depression in maltreated children
Kaufman et al, PNAS 101(49)17316, 2004
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INTEGRATIVE MODELS OF MOOD DISORDERS
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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 291765,
2004
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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 291765,
2004
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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 3413,2002
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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-3kinase and ERKMAP-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-3ß, 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.
Manji et al, Nature Med 7(5)541,2001
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BUTLER HOSPITAL MOOD DISORDERS RESEARCH PROGRAM

• Department of Psychiatry and Human Behavior
• Brown Medical School
• 345 Blackstone Blvd
• Providence, RI 02906
• TEL [phone]
• FAX [phone]