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Mood Disorders Rachel Nosheny November 25, 2002 Lecture Outline I. Overview of disorders A. Types B. Symptoms C. Epidemiology D. 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 Dysfunction of the brain’s reward system? •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 Pharmacotherapy MAOIs (inhibit breakdown) Side effects: Dry mouth Constipation Bladder problems Sexual problems Blurred vision Dizziness Drowsiness Increased heart rate SSRIs, Tricyclics (inhibit re-uptake) Atypical Antidepressants •Buproprion (wellbutrin or zyban) selective inhibitor of dopamine re-uptake •Mianserin (tolmin) 5-HT2 antagonist adrenergic 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 •Bipolar II: 1 or more episodes of depression and at least 1 mild manic (hypomanic) 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 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 Symptoms of MDD 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 Lithium Chloride • 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 Side Effects drowsiness weakness nausea fatigue hand tremor increased thirst and urination weight gain Glutamate Receptors Leighton et al 2001 Mechanism of Excitotoxicity Mechanism of Excitotoxicity Glutamate Increased intracellular Calcium •DNA damage •Decreased mitochondrial function •Increased free radicals •Protein Kinase C •Calcium calmodulin-dependent protein kinase II •Phospholipase •Proteases •Phosphatases •Nitric Oxide Synthase •Endonucleases Lithium Chloride • 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 Side Effects drowsiness weakness nausea fatigue hand tremor increased thirst and urination weight gain Anticonvulsants Carbamazepine Valproate Lamotrigine Gabapentin Topiramate • epilepsy and bipolar disorder may both involve hyperexcitability • Side effects include gastrointenstinal problems headache double vision dizziness anxiety 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 2nd messenger cascades Apoptotic proteins *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Neurotrophic factors Cell survival Manji et al 2001 Brain imaging findings in MDD Glucose metabolism/Blood flow Indicates change in activity Brain Structure Indicates cell atrophy/death increases: • amygdala •Orbital cortex •Medial thalamus •enlarged 3rd ventricle decreases: • dorsolateral prefrontal cortex • cingulate cortex •reduced grey matter volume in prefrontal cortex, hippocampus, and striatum • decreased volume of hippocampus Hypoactivity in frontal and prefrontal cortex and basal ganglia in depression Control Blue=less glucose metabolized Green=more glucose metabolized Depressed Brain imaging findings in MDD Glucose metabolism/Blood flow Indicates change in activity Brain Structure Indicates cell atrophy/death increases: • amygdala •Orbital cortex •Medial thalamus •enlarged 3rd ventricle decreases: • dorsolateral prefrontal cortex • cingulate cortex •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 2nd messenger cascades Apoptotic proteins *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Neurotrophic factors 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 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 Serotonergic neurons 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 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 upregulated 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 2nd messenger cascades Apoptotic proteins *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Neurotrophic factors Cell survival Intracellular signaling pathways important in mood disorders 2nd messenger cascades Apoptotic proteins *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Neurotrophic factors Cell survival Plasticity 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. 2. 3. 4. 5. insertion of new AMPA receptors at synapse synaptogenesis neurogenesis axon and dendrite outgrowth 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. 2. 3. 4. 5. insertion of new AMPA receptors at synapse synaptogenesis neurogenesis axon and dendrite outgrowth Inhibition of cell death antidepressants & mood stabilizers Summary: Neuroplasticity and Mood Disorders Via activation of serotonin and norepinephrinemediated 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 Serotonergic neurons Neurotrophic Factors •Supports survival of monaminergic and dopaminergic neurons • supports growth of glutamatergic synapses • 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 Chronic desipramine causes up-regulation of FGF mRNA in frontal cortex Mallei et al 2002 Mallei et al 2002 Chronic desipramine causes up-regulation of FGF in an anatomically-specific manner control Desipramine-treated 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?