Antidepressant Drugs

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 Sertraline Paroxetine 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. Biogenic Theory of Depression • 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?.

6. Amine neurotransmitters are either degraded (metab) or reuptaken MAO Mito COMT

7. The purpose of antidepressants is the increase the [neurotransmitters] in the synapse

8. 1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS

9. 2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS

10. 3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;

11. Selective Serotonin Reuptake Inhibitor

12. OUT Cl- Na+ Glu GABA Cl- Na+ GABAA receptor Glutamate/AMPA receptor Inhibition Excitation IN

13. Cerebral cortex Cerebral cortex Information integration cognition, thought, mood, emotion Motor output Sensory input Information integration cognition, thought, mood, emotion Motor output Sensory input norepinephrine acetylcholine histamine dopamine serotonin

14. Arousal: • Processing signals relate to plain & pleasure. Regulating • body homeostasis • Emotion and feeling • Attention • 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 !

18. 7 transmembrane domain receptor Out NH2 In 2nd messengers G COOH

19. Ionotropic Metabotropic

20. The monoamines Dopamine Epinephrine (adrenergic) Norepinephrine (noradrenergic) Serotonin

21. Neurotransmitter receptors Neurotransmitter receptors Ion pumps Second messengers Protein kinases Transcription Factors Cell nucleus Ion channels

23. 7-transmembrane-domain receptors

24. Excitatory input Glutamate Neuromodulatory inputs Neuromodulatory inputs ACh GluR NE M1 b1 Ca2+ 5-HT DA IP3 + DG D1 Ca2+-dependent Kinases/phosphatases cAMP PKC 5-HT2C Hist Hist PKA Down-stream substrates H2 H1 Gene expression Short-term synaptic modification Long-term synaptic modification

25. 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.

26. Catecholamines Norephinephrine

27. 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.  and  receptors.

28. A synapse that uses norepinephrine (NE)

29. MAO Inhibitors Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles Antidepressant Selective inhibitor, reboxetine Stimulant Cocaine blocks the NET Reuptake of NE

30. NE potentiation of responses to GABA Purkinje cells

31. Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Out GABA GABA PO4 In

32. GABA + cAMP GABA + NE GABA GABA response time Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cAMP as intracellular intermediary.

33. PKA reg PKA cat NE GABAA receptor b-adrenergic receptor b1 AC PO4 Gs cAMP ATP

34. Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Out GABA GABA PO4 In POSTSYNAPTIC MODULATION

35. Why does a small amount of stress help you learn better? But, too much chronic, severe stress  DEPRESSION

36. Before LTP Presynaptic Postsynaptic After LTP More glutamate receptors = bigger response b-adrenergics and memory

37. LTP decays Presynaptic Postsynaptic After LTP More glutamate receptors = bigger response After several hours…….

38. Unless b-adrenergic activation of postsynaptic cell takes place… Active during memory formation NE Glu Stabilization of LTP cAMP PKA Inhibition of protein phosphatase I

39. b-adrenergic receptor activation helps memories • better memories when you are paying attention • because of higher emotional stimulation

40. INDOLEAMINE SEROTONIN (5-HT)

41. 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.

43. PRESYNAPTIC MODULATION

44. Noradrenergic Control of Serotonergic Release Receptors NE 2-AR 5-HT 1-AR 5-HT1 5-HT2 5-HT3 NE 1 2 3 Mianserin

45. Humans 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 The purpose of antidepressants is to increase the levels of circulating neurotransmitters in the synapse.

46. The 5-HT neurons in the brain

47. A synapse that uses serotonin/5-HT

48. Fluoxetine/Prozac blocks the SERT Treatment of depression. anxiety disorders, obsessive-compulsive disorders Re-uptake of 5-HT/serotonin

49. Genetic variation in the gene promoter region of the serotonin transporter. risk factor for anxiety, alcoholism, mood disorders slight differences in level of expression

50. Catecholamines Dopamine