Mood Disorders

Rachel NoshenyNovember 25, 2002

Lecture Outline

I. Overview of disordersA. TypesB. SymptomsC. EpidemiologyD. Pharmacotherapy

II. Theories of the Pathophysiology of Mood Disorders

III. An example of current research: The effect of antidepressants on growth factor levels

Types of Mood Disorders

Major Depressive Disorder (MDD)

Bipolar Disorder

Types of Mood Disorders

Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke

Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized

Types of Mood Disorders

Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke

Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized

economic burden of tens of billions of dollars in the USA due to disability and premature death

Types of Mood Disorders

Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke

Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized

economic burden of tens of billions of dollars in the USA due to disability and premature death

Epidemiology of MDD

• Lifetime prevalence: 10%-25% in women

5%-12% in men

• most common age of onset: 25 to 44 years

• 1.5-3 times greater risk of developing the disorder if a first degree relative is affected

Diagnostic Criteria

•Depressed mood and/or loss of interest or pleasure (anhedonia)

• 4 other symptoms that impair functioning for at least a 2-week period, such as:

changes in sleep changes in interest level

changes in energy level changes in appetite

difficulty concentrating crying spells

suicidal ideation and/or plan feelings of worthlessness

feelings of hopelessness guilt or worry

psychomotor agitation or retardation

• symptoms are not a result of an underlying medical problem

Diagnostic Criteria

•Depressed mood and/or loss of interest or pleasure (anhedonia)

• 4 other symptoms that impair functioning for at least a 2-week period, such as:

changes in sleep changes in interest level

changes in energy level changes in appetite

difficulty concentrating crying spells

suicidal ideation and/or plan feelings of worthlessness

feelings of hopelessness guilt or worry

psychomotor agitation or retardation

• symptoms are not a result of an underlying medical problem

Dysfunction of the brain’s reward system?

Pharmacotherapy

SSRIs, Tricyclics(inhibit re-uptake)

MAOIs(inhibit breakdown)

Side effects:

Dry mouth

Constipation

Bladder problems

Sexual problems

Blurred vision

Dizziness

Drowsiness

Increased heart rate

Atypical Antidepressants

•Buproprion (wellbutrin or zyban)selective inhibitor of dopamine re-uptake

•Mianserin (tolmin)5-HT2 antagonistadrenergic autoreceptor antagonist

Types of Mood Disorders

Major Depressive Disorder (MDD)• around 16% of those effected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke

Bipolar Disorder• around 29% of those effected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized

Epidemiology of Bipolar Disorder

•Lifetime prevalence of 1.6%

•Onset typically in late adolescence to early adulthood

•Effects men and women equally

Symptoms of Mania

•A distinct period of persistently elevated, expansive, or irritable mood lasting at least 1 week

• 3 or more of the following symptoms during the mood disturbance:

inflated self-esteem decreased need for sleep

pressure to keep talking flight of ideas/racing thoughts

distractibility increase in goal-directed activity

excessive involvement in pleasurable and risky activities

• the mood disturbance disrupts normal functioning and/or has psychotic features

Subtypes of Bipolar Disorder

•Bipolar I: at least 1 lifetime manic episode

•Rapid cycling: occurrence of 4 or more mood episodes over the course of 1 year

• Mixed episode: co-occurrence of a depressive and manic episode

•Bipolar II: 1 or more episodes of depression and at least 1 mild manic (hypomanic) episode

Types of Mood Disorders

Do mania and depression

represent opposite ends of the

mood spectrum?

Symptoms of Mania

inflated self-esteem decreased need for sleep

pressure to keep talking flight of ideas/racing thoughts

distractibility increase in goal-directed activity

excessive involvement in pleasurable and risky activities

Irritable mood

changes in sleep changes in interest level

changes in energy level change in appetite

difficulty concentrating crying spells

suicidal ideation and/or plan feelings of worthlessness

feelings of hopelessness guilt or worry

psychomotor agitation or retardation

Symptoms of MDD

Lithium Chloride

Side Effects

drowsiness

weakness

nausea

fatigue

hand tremor

increased thirst and urination

weight gain

• limits excitability by modulating glutamate signaling

• inhibits cell death

•Of limited therapeutic value for treating those with:

mixed mania or rapid cycling

no relatives with bipolar disorder

many depressive episodes

co-morbid substance abuse

Glutamate Receptors

Leighton et al 2001

Mechanism of Excitotoxicity

Glutamate

Increased intracellular Calcium

•Protein Kinase C•Calcium calmodulin-dependent protein kinase II•Phospholipase•Proteases•Phosphatases•Nitric Oxide Synthase•Endonucleases

Mechanism of Excitotoxicity

•DNA damage•Decreased mitochondrial function•Increased free radicals

Lithium Chloride

Side Effects

drowsiness

weakness

nausea

fatigue

hand tremor

increased thirst and urination

weight gain

• limits excitability by modulating glutamate signaling

• inhibits cell death

•Of limited therapeutic value for treating those with:

mixed mania or rapid cycling

no relatives with bipolar disorder

many depressive episodes

co-morbid substance abuse

Anticonvulsants

CarbamazepineValproateLamotrigineGabapentinTopiramate

• epilepsy and bipolar disorder may both involve hyperexcitability

• Side effects include gastrointenstinal problems dizzinessheadache anxietydouble vision confusion

Anticonvulsants increase GABAergic activity

• inhibit enzymatic metabolism of GABA

• enhance Cl- influx through GABA receptor

• increase concentration of GABA

• increase rate of GABA synthesis

• upregulate GABA receptors

Anticonvulsants decrease hyperexcitability

• antagonize AMPA glutamate receptors

• inhibit sodium channel activity

• inhibit voltage-gated calcium channels

Other BD Pharmacotherapeutics

1. Antipsychotics

2. Calcium channel blockers

3. Cholinergic drugs*co-administration of lithium and choline*acetylcholinesterase inhibitors

What causes mood disorders?

• Monoaminergic dysfunction?

• Glutamate-mediated hyperexcitability?

• Excessive apoptosis?

• Insufficient neurotrophic support?

• Dysfunctional synaptic plasticity?

The Monoamine Hypothesis:

Depression is caused by insufficient activity at monoaminergic (serotonergic

and adrenergic) synapses

Evidence supporting the Monoamine Hypothesis:

• drugs that elevate mood increase levels of serotonin and/or norepinephrine in the synaptic cleft

• the monoaminergic systems are distributed throughout the limbic, striatal, and prefrontal circuits

• electroconvulsive shock elevates mood and changes expression of serotonergic receptors

• some depressed patients have abnormal monoaminergic tone

• drugs that deplete monoamines (like reserpine) can trigger depression

Limitations of the monoamine hypothesis

1. Cannot explain therapeutic lag time

2. Conflicting evidence regarding the overall effect of antidepressants on serotonergic and adrenergic tone

3. The number of neurotransmitters, neuromodulators, and hormones affected implicates intracellular signaling cascades

Manji et al 2001

What causes mood disorders?

•Monoaminergic dysfunction?

• Glutamate-mediated hyperexcitability?

• Excessive apoptosis?

• Insufficient neurotrophic support?

• Dysfunctional synaptic plasticity?

Intracellular signaling pathways important in mood disorders

Apoptotic proteins Neurotrophic factors2nd messenger cascades

*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription

Cell survival

Manji et al 2001

Brain imaging findings in MDD

Glucose metabolism/Blood flow Indicates change in activity

increases:• amygdala•Orbital cortex•Medial thalamus

decreases:• dorsolateral prefrontal cortex• cingulate cortex

Brain Structure Indicates cell atrophy/death

•enlarged 3rd ventricle

•reduced grey matter volume in prefrontal cortex, hippocampus, and striatum

• decreased volume of hippocampus

DepressedControl

Blue=less glucose metabolizedGreen=more glucose metabolized

Hypoactivity in frontal and prefrontal cortex and basal ganglia in depression

Brain imaging findings in MDD

Glucose metabolism/Blood flow Indicates change in activity

increases:• amygdala•Orbital cortex•Medial thalamus

decreases:• dorsolateral prefrontal cortex• cingulate cortex

Brain Structure Indicates cell atrophy/death

•enlarged 3rd ventricle

•reduced grey matter volume in prefrontal cortex, hippocampus, and striatum

• decreased volume of hippocampus

Chronic stress causes cell atrophy in the hippocampus

The hippocampus•sensitive to the neurotoxic effects of stress• important in LTP, learning, and memory

Intracellular signaling pathways important in mood disorders

Apoptotic proteins Neurotrophic factors2nd messenger cascades

*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription

Cell survival

Apoptosis

• a special kind of “controlled” cell death that minimizes damage to surrounding tissue

• essential for normal development of the nervous system

• occurs through tightly regulated signal transduction cascades inside the cell

• glutamate-mediated excitotoxicity is associated with excessive apoptosis

Lithium normalizes grey matter volume in BD patients

Lithium and Apoptosis

Bcl-2 inhibits apoptosis

• binds to proteins which destabilize the mitochondria •prevents release of ions/proteins from mitochondria

• inhibits activation of proteins which cause apoptosis

Lithium and valproate inhibit apoptosis

Du

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Increase in neurogenesis in hippocampus after chronic antidepressant treatment

Antidepressants may limit cell loss by increasing adult neurogenesis

Neurotrophic Factors

• essential for normal nervous system development

• important in the adult brain for maintenance of neurons and glia

• different neurotrophins are important for promoting survival of different cell types in different areas

Neurotrophic Factors

• essential for normal nervous system development

• important in the adult brain for maintenance of neurons and glia

• different neurotrophins are important for promoting survival of different cell types in different areas

Serotonergic neurons

Intracellular signaling cascades activated by neurotrophins

Effect of antidepressants on BDNF

• BDNF is a growth factor that is involved in serotonergic cell survival

• BDNF expression is increased in hippocampus by chronic antidepressant administration in rats

•Animals subjected to forced swim test show decreased BDNF levels in the hippocampus; antidepressants normalize these levels

•BDNF is protective against hippocampal atrophy associated with chronic stress

How do antidepressants upregulate BDNF?

•cAMP levels are up-regulated by chronic antidepressant treatment

•Levels of CREB mRNA in the hippocampus are increased by antidepressant treatment

• Drugs which inhibit cAMP breakdown may be antidepressant

Intracellular signaling pathways important in mood disorders

Apoptotic proteins Neurotrophic factors2nd messenger cascades

*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription

Cell survival

Intracellular signaling pathways important in mood disorders

Apoptotic proteins Neurotrophic factors2nd messenger cascades

*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription

Cell survivalPlasticity

Synaptic Plasticity

• change in the structure or biochemistry of a synapse that alters its effects on a post-synaptic neuron

• important for learning and memory

• can occur by

1. insertion of new AMPA receptors at synapse2. synaptogenesis3. neurogenesis4. axon and dendrite outgrowth5. Inhibition of cell death

Synaptic Plasticity

• change in the structure or biochemistry of a synapse that alters its effects on a post-synaptic neuron

• important for learning and memory

• can occur by

1. insertion of new AMPA receptors at synapse2. synaptogenesis3. neurogenesis4. axon and dendrite outgrowth5. Inhibition of cell death

antidepressants & mood stabilizers

Summary: Neuroplasticity and Mood Disorders

Via activation of serotonin and norepinephrine-mediated 2nd messenger cascades

Current Research: Effect of antidepressants on fibroblast growth factor

1. Explore the role of other growth factors in the mechanism of action of antidepressants

2. investigate whether growth factors are up-regulated in specific brain areas important in mood

Neurotrophic Factors

• essential for normal nervous system development

• important in the adult brain for maintenance of neurons and glia

• different neurotrophins are important for promoting survival of different cell types in different areas

Serotonergic neurons

•Supports survival of monaminergic and dopaminergic neurons• supports growth of glutamatergic synapses

Chronic desipramine causes up-regulation of FGF mRNA in frontal cortex

Mallei et al 2002

Chronic desipramine causes up-regulation of FGF in an anatomically-specific manner

control Desipramine-treatedM

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Chronic desipramine treatment alters composition of cortical glutamate receptors

Leighton et al 2001

Summary

1. How can we reconcile cell death and dysfunction in mood disorders with the lack of severe cognitive abnormalities?

2. Is there a distinct mood circuitry in the brain?

3. Can alteration of single molecules in a signal transduction cascade cause complex disorders such as mood disorders?

4. Can we design drugs based on our knowledge of dysfunctional intracellular signaling?

5. Is MDD (and is BD) one disease, or a group of different disorders?