Mood Disorders Rachel Nosheny November 25, 2002

1. Mood Disorders Rachel Nosheny November 25, 2002

2. Lecture Outline • Overview of disorders • A. Types • B. Symptoms • C. Epidemiology • D. Pharmacotherapy • Theories of the Pathophysiology of Mood Disorders • III. An example of current research: The effect of antidepressants on growth factor levels

3. Types of Mood Disorders Major Depressive Disorder (MDD) Bipolar Disorder

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. MAOIs (inhibit breakdown) Pharmacotherapy Side effects: Dry mouth Constipation Bladder problems Sexual problems Blurred vision Dizziness Drowsiness Increased heart rate SSRIs, Tricyclics (inhibit re-uptake)

11. Atypical Antidepressants • Buproprion (wellbutrin or zyban) • selective inhibitor of dopamine re-uptake • Mianserin (tolmin) • 5-HT2 antagonist • adrenergic autoreceptor antagonist

12. 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

13. Epidemiology of Bipolar Disorder • Lifetime prevalence of 1.6% • Onset typically in late adolescence to early adulthood • Effects men and women equally

14. 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

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

16. Types of Mood Disorders

17. Do mania and depression represent opposite ends of the mood spectrum?

18. 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

19. 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

20. Glutamate Receptors Leighton et al 2001

21. Mechanism of Excitotoxicity Mechanism of Excitotoxicity Glutamate Increased intracellular Calcium • Protein Kinase C • Calcium calmodulin-dependent protein kinase II • Phospholipase • Proteases • Phosphatases • Nitric Oxide Synthase • Endonucleases • DNA damage • Decreased mitochondrial • function • Increased free radicals

22. 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

23. Carbamazepine Valproate Lamotrigine Gabapentin Topiramate Anticonvulsants • epilepsy and bipolar disorder may both involve hyperexcitability • Side effects include • gastrointenstinal problems dizziness • headache anxiety • double vision confusion

24. 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

25. Anticonvulsants decrease hyperexcitability • antagonize AMPA glutamate receptors • inhibit sodium channel activity • inhibit voltage-gated calcium channels

26. Other BD Pharmacotherapeutics 1. Antipsychotics 2. Calcium channel blockers • Cholinergic drugs • *co-administration of lithium and choline • *acetylcholinesterase inhibitors

27. What causes mood disorders? • Monoaminergic dysfunction? • Glutamate-mediated hyperexcitability? • Excessive apoptosis? • Insufficient neurotrophic support? • Dysfunctional synaptic plasticity?

28. The Monoamine Hypothesis: Depression is caused by insufficient activity at monoaminergic (serotonergic and adrenergic) synapses

29. 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

30. Limitations of the monoamine hypothesis • Cannot explain therapeutic lag time • Conflicting evidence regarding the overall effect of antidepressants on serotonergic and adrenergic tone • The number of neurotransmitters, neuromodulators, and hormones affected implicates intracellular signaling cascades

31. Manji et al 2001

32. What causes mood disorders? • Monoaminergic dysfunction? • Glutamate-mediated hyperexcitability? • Excessive apoptosis? • Insufficient neurotrophic support? • Dysfunctional synaptic plasticity?

33. *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Intracellular signaling pathways important in mood disorders 2nd messenger cascades Apoptotic proteins Neurotrophic factors Cell survival

34. Manji et al 2001

35. 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

36. Hypoactivity in frontal and prefrontal cortex and basal ganglia in depression Control Depressed Blue=less glucose metabolized Green=more glucose metabolized

37. 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

38. Chronic stress causes cell atrophy in the hippocampus • The hippocampus • sensitive to the neurotoxic effects of stress • important in LTP, learning, and memory

39. *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription Intracellular signaling pathways important in mood disorders 2nd messenger cascades Apoptotic proteins Neurotrophic factors Cell survival

40. 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

41. Lithium normalizes grey matter volume in BD patients

42. Lithium and Apoptosis

43. 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

44. Lithium and valproate inhibit apoptosis

45. Increase in neurogenesis in hippocampus after chronic antidepressant treatment Duman et al 2000 Antidepressants may limit cell loss by increasing adult neurogenesis

46. 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

47. 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

48. Intracellular signaling cascades activated by neurotrophins

49. 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

50. 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