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Antidepressant drugs

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  • Drugs used in affective disorders (antidepressants)
  • Transcript

    • 1. Antidepressant Drugs
    • 2. What are Antidepressants? • Drugs that are used to relieve or prevent psychic depression. • Work by altering the way in which specific chemicals, called neurotransmitters, work in our brains (i.e. in the case of depression, some of the neurotransmitter systems don’t seem to be working properly). • They increase the activity of these chemicals in our brains
    • 3. Available Antidepressants • 1) Tricyclics and Tetracyclics (TCA) Imipramine Doxepin Desipramine Amoxepine Trimipramine Maprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline • 2) Monoamine Oxidase Inhibitors (MAOIs) Tranylcypramine Phenelzine Moclobemide • 3) Serotonin Selective Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine SertralineParoxetine Citalopram • 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine Duloxetine • 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs) Nefazodone Trazodone • 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion • 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs) Mirtazapine • 8) Noradrenalin Specific Reuptake Inhibitor (NRI) Reboxetine • 9) Serotonin Reuptake Enhancer Tianeptine
    • 4. Amine Hypothesis • 1950: Reserpine  Induce depression • Study: Reserpine depletes storage or amine neurotransmitters such as serotonin and norepinephrine • Break-through: MAOI and TCA • Then: Depression  Amine-dependent synaptic transmission (Antidepressants  Amine by means of reuptake and metabolism) • Conclusion: Major model for the subsequent antidepressants, except Buproprion.
    • 5. • The precise cause of affective disorders remains elusive. • Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT). ↓ Activity of NE and 5 -HT systems?. Biogenic Theory of Depression
    • 6. MAO COMT Amine neurotransmitters are either degraded (metab) or reuptaken Mito
    • 7. The purpose of antidepressants is the increase the [neurotransmitters] in the synapse
    • 8.       Block of Amine Pump for: Drug Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine (Prozac) + + +++ 0, + 0, + Fluvoxamine (Luvox) 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 +++ 0 0 0 0 Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine (Seroxat) + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline (Zoloft) + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +  1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS
    • 9.       Block of Amine Pump for: Drug Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine + + +++ 0, + 0, + Fluvoxamine 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 +++ 0 0 0 0 Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine 0 0 +++ ++ 0, +  2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS
    • 10.       Block of Amine Pump for: Drug Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine + + +++ 0, + 0, + Fluvoxamine 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 +++ 0 0 0 0 Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +  3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;
    • 11.       Block of Amine Pump for: Drug Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine (Prozac) + + +++ 0, + 0, + Fluvoxamine (Luvox) 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 +++ 0 0 0 0 Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine (Seroxat) + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline (Zoloft) + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +  Selective Serotonin Reuptake Inhibitor
    • 12. OUT IN Cl- Cl- Na+ Na+ GABAA receptor Glutamate/AMPA receptor G A B A G l u Inhibition Excitation
    • 13. Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output acetylcholine norepinephrine serotonin dopamine histamine Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output
    • 14. Arousal: 1. Processing signals relate to plain & pleasure. Regulating body homeostasis 2. Emotion and feeling 3. Attention 4. Wakefulness & sleep 5. learning The construction of consciousness.
    • 15. Fast: GABA, glutamate, acetylcholine Slow: biogenic amines Dopamine Serotonin/5-HT NE Acetylcholine Peptides
    • 16. Ionotropic and metabotropic receptors Fast Ion flow in/out milliseconds Slow Second messenger cascades seconds 1/1000 of a second !
    • 17. Out In G 7 transmembrane domain receptor 2nd messengers NH2 COOH
    • 18. Ionotropic Metabotropic
    • 19. The monoamines Dopamine Epinephrine (adrenergic) Norepinephrine (noradrenergic) Serotonin
    • 20. Second messengers Protein kinases Transcription Factors Cell nucleus Ion pumps Ion channels Neurotransmitter receptors Neurotransmitter receptors
    • 21. 7-transmembrane-domain receptors
    • 22. Glutamate Ca2+ Ca2+ -dependent Kinases/phosphatases Down-stream substrates Gene expression Short-term synaptic modification Long-term synaptic modification cAMP PKA Hist DA NE ACh 5-HT Hist PKC IP3 + DG GluR β1 D1 H2 M1 5-HT2C H1 Excitatory input Neuromodulatory inputs Neuromodulatory inputs
    • 23. Particular modulator transmitters should not be regarded as purely excitatory or inhibitory. Their exact action depends on context. On the same cell, they can be either excitatory or inhibitory depending on the state of the cell.
    • 24. Catecholamines Norephinephrine
    • 25. NE System Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus). • Mood: -- higher functions performed by the cortex. • Cognitive function: -- function of cortex. • Drive and motivation: -- function of brainstem • Memory and emotion: -- function of the hippocampus and amygdala. • Endocrine response: -- function of hypothalamus. α and β receptors.
    • 26. A synapse that uses norepinephrine (NE)
    • 27. Reuptake of NE Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles Selective inhibitor, reboxetine Cocaine blocks the NET Antidepressant MAO Inhibitors Stimulant
    • 28. NE potentiation of responses to GABA Purkinje cells
    • 29. PO4 Cl- Cl- GABA Cl- Cl- Cl- Cl- Cl- Cl- GABA Out In
    • 30. time GABA response GABA GABA + NE GABA + cAMP Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cAMP as intracellular intermediary.
    • 31. β1NE Gs AC ATP cAMP PKA reg PKA cat PO4 GABAA receptorβ-adrenergic receptor
    • 32. PO4 Cl- Cl- GABA Cl- Cl- Cl- Cl- Cl- Cl- GABA Out In POSTSYNAPTIC MODULATION
    • 33. Why does a small amount of stress help you learn better?Why does a small amount of stress help you learn better? But, too much chronic, severe stress  DEPRESSION
    • 34. β-adrenergics and memory Presynaptic Postsynaptic Before LTP After LTP More glutamate receptors = bigger response
    • 35. After LTP More glutamate receptors = bigger response After several hours……. Presynaptic Postsynaptic LTP decays
    • 36. Unless β-adrenergic activation of postsynaptic cell takes place… NE Glu cAMP PKA Inhibition of protein phosphatase I Active during memory formation Stabilization of LTP
    • 37. β-adrenergic receptor activation helps memories -better memories when you are paying attention because of higher emotional stimulation
    • 38. INDOLEAMINE SEROTONIN (5-HT)
    • 39. Serotonin System As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. --same areas implicated in depression. This system is also involve in: • Anxiety. • Sleep. • Sexual behavior. • Rhythms (Suprachiasmatic nucleus). • Temperature regulation. • CSF production.
    • 40. PRESYNAPTIC MODULATION
    • 41. Noradrenergic Control of Serotonergic Release NE 5-HT NE α2-AR α1-AR 1 2 3 Mianserin 5-HT1 5-HT2 5-HT3 Receptors
    • 42. Serotonin - a chemical manifestation of personality High level of serotonin: compulsives obsessive-compulsive disorders e.g. compulsive hand-washing Low levels of serotonin: depression, suicide. Listening to Prozac, P.D. Kramer, 1993 Humans The purpose of antidepressants is to increase the levels of circulating neurotransmitters in the synapse.
    • 43. The 5-HT neurons in the brain
    • 44. A synapse that uses serotonin/5-HT
    • 45. Re-uptake of 5-HT/serotonin Fluoxetine/Prozac blocks the SERT Treatment of depression. anxiety disorders, obsessive-compulsive disorders
    • 46. Genetic variation in the gene promoter region of the serotonin transporter. risk factor for anxiety, alcoholism, mood disorders slight differences in level of expression
    • 47. Catecholamines Dopamine
    • 48. Dopamine pathways in the brain
    • 49. Dopamine pathways do many things: Control flow of blood through the brain Motor control (nigrostriatal) system Behavioural control Dopamine is the brain’s motivational chemical. It works on glutamate synapses to modulate their excitability. A shortage of brain dopamine causes an indecisive personality, unable to initiate even the body’s own movement. Parkinson’s disease. Time stops. L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs) Excess dopamine, more arousal. Attention defecit disorder. May cause schizophrenia. Dopamine’s action is essential for drug addiction.
    • 50. DARP-32 Dopamine and cAMP-regulated phosphoprotein Molecular weight, 32 kDa DARP-32 is a molecular integrator
    • 51. Other neuromodulators (NE, serotonin) probably work in a similar way to dopamine They assist with the selection/maintenance of different neural ensembles.
    • 52. Molecular actions of dopamine
    • 53. Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission Effects on personality? Dopamine D4 receptor - novelty seeking Promoter of serotonin transporter gene - harm avoidance/anxiety Genetics
    • 54. D4 dopamine receptor 16 amino acid repeat sequence present in two to 11 copies - minisatellite phrase
    • 55. D4 dopamine receptor The larger the number of repeats, the more ineffective is the dopamine D4 receptor in signalling
    • 56. The larger the number of loop 3 repeats, the more ineffective the dopamine D4 receptor in signalling “Long” D4DR genes imply low responsiveness to dopamine “short” D4DR gene imply high responsiveness The idea People with “long” D4DR genes have low responsiveness to dopamine, so they need to take a more adventurous approach to life to get the same dopamine “buzz” that short-gened people get from simple things. Obviously, this is just one possible factor of many. Don’t oversimplify! Genetics
    • 57. Why do antidepressants take so long to work? The current prevailing hypothesis…
    • 58. Neurotrophin Hypothesis
    • 59. Chronic, severe
    • 60. Mechanism for the Delay in Onset of the therapeutic Effect of Antidepressant Medications.

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