1. Mood Disorders Rachel Nosheny November 25, 2002

2. 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

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 planfeelings 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 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 planfeelings 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?

10. 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

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 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

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 changes in sleep changes in interest level changes in energy level change in appetite difficulty concentrating crying spells suicidal ideation and/or planfeelings of worthlessness feelings of hopelessness guilt or worry psychomotor agitation or retardation Symptoms of MDD

19. 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

20. Glutamate Receptors Leighton et al 2001

21. 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

22. 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

23. Anticonvulsants Carbamazepine Valproate Lamotrigine Gabapentin Topiramate epilepsy and bipolar disorder may both involve hyperexcitability Side effects include gastrointenstinal problemsdizziness headacheanxiety double visionconfusion

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 3.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 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

31. Manji et al 2001

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

33. Intracellular signaling pathways important in mood disorders Apoptotic proteinsNeurotrophic factors 2 nd messenger cascades *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription 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 3 rd ventricle reduced grey matter volume in prefrontal cortex, hippocampus, and striatum decreased volume of hippocampus

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

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 3 rd 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. Intracellular signaling pathways important in mood disorders Apoptotic proteinsNeurotrophic factors 2 nd messenger cascades *activated by neurotransmitter binding to metabotropic receptor *indirectly opens ion channels *alters gene transcription 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. Duman et al 2000 Increase in neurogenesis in hippocampus after chronic antidepressant treatment 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. 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

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

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

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

53. 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 synapse 2.synaptogenesis 3.neurogenesis 4.axon and dendrite outgrowth 5.Inhibition of cell death

54. 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 synapse 2.synaptogenesis 3.neurogenesis 4.axon and dendrite outgrowth 5.Inhibition of cell death antidepressants & mood stabilizers

55. Summary: Neuroplasticity and Mood Disorders Via activation of serotonin and norepinephrine- mediated 2 nd messenger cascades

56. 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

57. 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

58. Chronic desipramine causes up-regulation of FGF mRNA in frontal cortex Mallei et al 2002

59. Chronic desipramine causes up-regulation of FGF in an anatomically-specific manner control Desipramine-treated Mallei et al 2002

60. Chronic desipramine treatment alters composition of cortical glutamate receptors Leighton et al 2001

61. 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?