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Mood Disorders

Mood Disorders. Neurobiological Causes and Pharmacological Intervention. Key issues and questions. Target of antidepressant or mood-stabilizing drugs: People with Mood Disorders! What constitutes a “Mood Disorder”? What is the neurochemical basis of clinically significant mood change?

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Mood Disorders

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  1. Mood Disorders Neurobiological Causes and Pharmacological Intervention

  2. Key issues and questions • Target of antidepressant or mood-stabilizing drugs: • People with Mood Disorders! • What constitutes a “Mood Disorder”? • What is the neurochemical basis of clinically significant mood change? • What is the neurochemical basis of changes produced by drugs that treat mood disorders? • How well do the drugs work?

  3. Mood Disorders The structure of mood disorders Normal affective responses on a continuum-brief in duration vs. dominant and sustained • Unipolar Mood Disorder • A state of depression (or mania) • Mostly depression • Bipolar Mood Disorder • Alternation between depression and mania • Subtypes • Bipolar I (full manic episodes) • Bipolar II (hypomanic episodes) • Cyclothymia (“moodiness” – up and down) • Anxiety Disorders

  4. Nature of Unipolar Mood Disorders • Depressive Disorders • Melancholic depression (40-60%)-symptoms • Atypical depression (~15%)-symptoms • Dysthymia-symptoms • If there are different levels of depression, and different types, is the underlying neurochemical problem different in nature or degree? • Therefore, are pharmacological therapies different for each subtype?

  5. Facts & Statistics • 7-8% lifetime prevalence • Usually recurrent • Major Depression or Dysthymia: Females > Males • Mean age of onset: 25 yrs • ~50% concordance for monozygotic twins • Length of episode varies • Remission is common • Risk of suicide • Bipolar Disorders: Females = Males • Similar in children and adults, ~80% concordance in monozygotic twins

  6. Genetic influence on depression Risk of developing unipolar depression increases with multiple family members with depression

  7. Behaviors addressed by antidepressant drug use DSM IV Criteria 1-4 for major depressive episode (5/9): • Persistence of depressed mood nearly every day (> 2 weeks) • Diminished interest or pleasure, eg., loss of libido (anhedonia and vegetative) • Weight fluctuations and loss of appetite (vegetative) • Insomnia or hypersomnia (vegetative)

  8. Specific behavioral changes that need to be targeted by antidepressant drugs DSM IV Criteria 5-9 for Depression • Psychomotor agitation or retardation (feelings of restlessness or being slowed down) • Fatigue or loss of energy • Worthlessness; guilt • Inability to think, concentrate or act decisively • Preoccupation with thoughts of death or suicidal ideation

  9. Anxiety Disorders • Panic Attack • period of intense fear or discomfort in which the following occurs: sweating, trembling, choking, chest pain, nausea, dizziness, fear of losing control, derealization or depersonalization, chills or hot flashes • Agoraphobia • Panic Disorder w/o agoraphobia (GAD) • Social Anxiety Disorder • fear in social situations • exposure to social situations provokes anxiety • social situations avoided • distress interferes with normal routine • Obsessive Compulsive Disorder

  10. Melancholic anxious, loss of pleasure in all activities dread future insomnia, early morning awakening loss of appetite symptoms worst in the morning excessive inappropriate guilt Atypical lethargic, fatigued increase in appetite symptoms best in morning extreme sensitivity to environmental stimuli (perceived or actual/positive or negative) Depression Subtypes • Dysthymia • symptoms of depression chronic but less severe

  11. Neurochemical changes reduced or elevated norepinephrine levels differences in the number of serotonin receptors - may be regulated by dysfunction in serotonin activity “biogenic amine hypothesis” Dysfunction in cortisol secretion Physiological Correlates what is the basis of this elevation in cortisol?

  12. Stress Response • CRF-corticotropin releasing factor • orchestrates behavioral/endocrine/immune response to stress-interaction with NE • interactions with brain areas responsible for fear reaction, transforming experiences into feeling and memory system • CRF administered to laboratory rats results in symptoms of “depression” • excessive levels may explain behavioral symptoms of sleep disturbances, appetite changes, psychomotor symptoms • CRF has two receptor subtypes-novel targets of antidepressant therapy?

  13. Hypothalamic-Pituitary-Adrenal Axis - - Hypothalamus PFC Hippocampus (glucocorticoid receptors) CRH - Pituitary ACTH NE Adrenal cortex Cortisol

  14. Hypothalamic-Pituitary-Adrenal Axis - - Hypothalamus PFC Hippocampus (glucocorticoid receptors) CRH - Pituitary ACTH 5HT Adrenal cortex Cortisol

  15. Dexamethasone – synthetic glucocorticoid Reduces ACTH production “normal” patients show reduction (suppression) in cortisol levels in blood depressed patients do not abnormal negative feedback loop-most prominent in melancholic depression Dexamethasone Suppression Test-not a diagnostic tool

  16. Some, but not all, depressed individuals show lack of dexamethasone suppression of cortisone Marginal differences between “suppressors” and “nonsuppressors” in response to pharmacotherapy Some depressed patients, despite elevated cortisol, show no problems with adrenal or pituitary glands Dexamethasone Suppression Test-continued

  17. Melancholic vs. Atypical Depression • Melancholic: hypercortisolism may explain symptoms of depression • impaired feedback loop • hyperactive, anxiety, insomnia, loss of appetite • Atypical: CRF does not stimulate cortisol response • impaired feedback loop • lethargic, fatigued, hyperphagic, hypersomnic,

  18. Animal Models of Depression Diathesis-Stress concept Antidepressant drugs screened on the following preclinical paradigms: • Behavioral Despair/Learned Helplessness • HPA transgenic • Olfactory Bulbectomy

  19. Evidence for: altered serotonin and norepinephrine levels in depressed and suicide victims (blood and CSF) drugs which reduce NE/5-HT result in depression/suicidal tendencies (reserpine) drugs which elevate serotonin and NE (MAOi, amphetamine) also alleviate symptoms Evidence against: response to SSRI’s is slow effect on serotonin reuptake is similar, but between-patient variability melancholic depressed patients show high NE - may be driving by high CRF levels answer: not a simple relationship Biogenic Amine Hypothesis

  20. Action of Antidepressant Drugs on CNS • Effects on the following Monoamine neurotransmitters • Norepinephrine (noradrenaline): NE • Dopamine: DA • Serotonin (5-hydroxytryptamine): 5-HT

  21. Treatment of Depression • Pharmacotherapy • Tricyclic antidepressants (TCA) • Heterocyclic or 2nd and 3rd generation • Monoamine oxidase inhibitors (MAOI) • Selective serotonin reuptake inhibitors (SSRI) • Non-Pharmacologic • Electroconvulsive therapy (ECT)

  22. Action of Antidepressant Drugs on CNS • Increase synaptic neurotransmitter levels • Impair natural mechanisms for reducing monamine actions • Reuptake pumps • Enzymatic inactivation (MAO) • Autoreceptors • Alter receptor levels (after repeated use)

  23. Synaptic Effects

  24. drug inactivates monoamine oxidases

  25. Synaptic Transmission: the Synapse normal reuptake of NT substance from synaptic cleft to presynaptic neuron inhibition of reuptake pumps: more NT in synapse

  26. Serotonin/Permissive Hypothesis: • Serotonin as “inhibitory” neurotransmitter • Inhibit rage – self rage (suicide?) • Mood disorders: release of inhibitory damper serotonin norepinephrine = mania • Balance of 5HT and NE regulates mood

  27. MAO metabolizes serotonin in the presynaptic neuron

  28. Serotonergic Distribution in the Brain

  29. Synthesis of Norephinephrine:

  30. Locus coeruleus Noradrenergic distribution in the brain

  31. Receptor Subtypes (transmembrane proteins) • 5-HT • nine know receptor subtypes • grouped into class 1, 2 and 3 • 5-HT1a is both presynaptic (autofeedback loop) and postsynaptic • NE • acute use vs. chronic use • altered sensitivity/number receptors • which types?

  32. Classes of Antidepressant Therapy: • MAOi • TCA • Also used for anxiety disorders and pain • Panic and phobia (MAO) • Obsessive-Compulsive Disorder (TCA) • Pain (TCA) • SSRI (selective serotonin reuptake inhibitors) • anxiety • OCD – clomipramine, fluvoxamine, paroxetine, sertraline

  33. High level or mood neurotransmitter RECEPTOR Clinical effect Low level or mood Introduction of drug therapy The receptor hypothesis of antidepressant action Alterations in receptor expression

  34. Receptor Subtypes in Depressed Patients • Not all studies find an association • Increased number if 5HT1a neurons • increased inhibition of 5HT transmission • Altered number of 5HT2 receptors • Presynaptic and postsynaptic • Changes match chronic stress animal model

  35. Therapeutic Lag • Theory: improved mood following SSRI treatment corresponds to augmented serotonergic transmission • this enhanced 5-HT activity is partially due to autoreceptor blockade • New therapy: combine SSRI with 5HT1a antagonist • Problems: antidepressant efficacy correlated with postsynaptic 5HT1a receptor affinity

  36. The altered gene (s) hypothesis of antidepressant action • Excess neurotransmitter leads to alterations in: • Genes that code for receptors • receptor expression • sensitivity of receptors • differences in expression in pre- and post-synaptic receptors • upregulate or sensitize 5HT1a in hippocampus • desensitize 5HT2 receptors elsewhere in the brain • Genes that serve to protect and/or facilitate neuronal function (eg., brain derived neurotrophic factor) • BDNF does not appear to be associated with disease

  37. Relationship of SSRI’s to BDNF levels and neuronal function

  38. Interaction of stress, corticosteriods and depression:

  39. Side effects • MAO inhibitors • dietary restrictions – • serotonin syndrome- • Tricyclic Antidepressants • cardiac arrhythmias, respiratory depression • serotonin syndrome • severe sedation

  40. Side effects • Blockade of NE uptake • tachycardia • tremors • Blockade of 5-HT uptake • GI disturbances • interactions with l-tryptophan • increase/decrease in anxiety (dose dependent) • sexual dysfunction • Blockade of histamine receptors • potentiation of depressant drugs • sedation • weight gain • hypotension • Blockade of Ach receptors • blurred vision, • drymouth • constipation

  41. Efficacy of Antidepressant Therapy • Use of a placebo or active control (randomized, controlled clinical trial) or any control • Consistency of study populations • Efficacy of one group over another? • Treatment guidelines • dose, duration, compliance • starting dose-enduring response • patient compliance-adverse events

  42. MAOi atypical and refractory (fail to respond to other types of medications) TCA melancholic depression not effective in reactive depression Efficacy subtypes • SSRI • mild to moderate depression • better tolerated than TCAs • do not take with MAOi • Heterocyclics • use when severe insomnia is present • useful in elderly

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