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Psychopharmacology: Part 1 Antidepressants and Anxiolytics

Psychopharmacology: Part 1 Antidepressants and Anxiolytics. Dr. Prashant Tibrewal. LITTLE BIT OF HISTORY. Serendipitous discovery in the 1950s led to the development of the first antidepressant agents: Iproniazid (for tuberculosis) Imipramine (for psychosis)

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Psychopharmacology: Part 1 Antidepressants and Anxiolytics

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  1. Psychopharmacology: Part 1Antidepressants and Anxiolytics Dr. Prashant Tibrewal

  2. LITTLE BIT OF HISTORY • Serendipitous discovery in the 1950s led to the development of the first antidepressant agents: Iproniazid (for tuberculosis) Imipramine (for psychosis) • Further investigations revealed their pharmacological activity on monoamine systems.

  3. A BIT MORE…… • In 1960s specific search for serotonin reuptake inhibitors started • Culminating in the derivation of first SSRI- Zimelidine (withdrawn) • Further search for specific SSRIs led to the development of landmark SSRI- Fluoxetine

  4. CLASSIFICATION Since then more than two dozen antidepressants, which work by seven distinct mechanisms, have been developed • TCA • SSRI • NDRI • NaSSA • SNRI • SARI • MAOI

  5. MECHANISM • Given the structural diversity of the members of each class, they may not resemble each other in terms of their pharmacokinetics, metabolism or toxicity. • However, most have an action on the metabolism and at the receptor for monoamine neurotransmitters: • Norepinephrine • Serotonin • Dopamine

  6. ADDITIONAL MECHANISMS • Augmentation of intracellular cyclic AMP • Augment levels of neurotrophic and transcription factors such as CREB and BDNF • Modulate excitatory transmission by decreasing binding at NMDA receptors or by inducing changes at AMPA receptors.

  7. MAO enzyme destroying neurotransmitter monoamine neurotransmitter NORMAL STATE -- no depression DEPRESSION -- caused by neurotransmitter deficiency MONOAMINE HYPOTHESIS Stahl S M, Essential Psychopharmacology (2000)

  8. MAO inhibitor blocks the enzyme from destroying monoamine neurotransmitter reuptake pump blocked by antidepressant Increase in neurotransmitters causes return to normal state Stahl S M, Essential Psychopharmacology (2000)

  9. Normal functioning Decrease in NT Receptors up-regulate due to lack of NT Monoamine Receptor Hypothesis of Depression Stahl S M, Essential Psychopharmacology (2000)

  10. CIRCUIT

  11. CIRCUIT

  12. CIRCUIT Ser Ne

  13. CIRCUIT Ser Ne

  14. CLASSICAL ANTIDEPRESSANTS • MAO inhibitors and • Tricyclics

  15. TYPES OF MAOI • Irreversible and non selective Phenelzine, Tranylcypromine, Isocarboxazid • RIMAs- Moclobemide • Selective for MAO B-- Deprenyl

  16. MAOI • Fell out of fame due to ‘cheese reaction’ – dietary tyramine metabolism inhibited by MAOI leading on to hypertensive crisis • Rigid dietary restrictions • RIMAs – Moclobemide fewer restrictions • Reserved for resistant or atypical cases

  17. MAOI • Risk of SSRI syndrome • Do not combine with TCAs or SSRIs • Never with an SSRI • RIMA can be better tolerated but less effective.

  18. TRICYCLICS First agents marketed in 1950’s • Amitryptiline • Doxepine • Imipramine • Clomipramine • Trimipramine • Desipramine • Nortriptyline

  19. TCAs

  20. Therapeutic action

  21. Therapeutic action Psychopharmacology of antidepressants: Stephen Stahl

  22. Side effects Psychopharmacology of antidepressants: Stephen Stahl

  23. Side effects Psychopharmacology of antidepressants: Stephen Stahl

  24. Side effects Psychopharmacology of antidepressants: Stephen Stahl

  25. Mechanism Block reuptake of Serotonin (5HT) and Norepinephrine (NE) Onset of antidepressant effect: 3-4 weeks

  26. SIDE EFFECTS Alpha-1 Blockade: Orthostasis, Sexual Dysfunction, Potential for cardiac conduction delays (QT prolongation) Histamine Blockade: Potential for weight gain, Sedation Acetylcholine Blockade: Cognitive Dulling Blurring of Vision Tachycardia Exacerbation of Asthma Sexual Dysfunction

  27. CONTRAINDICATIONS • Hypertensive patients • Cardiac conduction abnormalities (esp. prolonged QT) • Acute narrow angle glaucoma • GI dysmotility syndromes • Benign Prostatic Hypertrophy

  28. PROS AND CONS Strengths Effective, especially in severe depression. Low cost. Sedation perceived as a benefit. Can be used in pain, fibromyalgia and migraine Weaknesses Anticholinergic SEs. Cardiovascular toxicity in overdose. weight Gain. Multiple daily dosing. Titration. Overall SE Profile.

  29. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) • Fluoxetine • Fluvoxamine • Sertraline • Citalopram • Escitalopram • Paroxetine

  30. No or only weak effects at other monoamine transporter • That distinguishes them from the older TCAs, thus they are named selective.

  31. Widely used, first-line treatments for depression and anxiety • Multiple FDA indications • Safety in overdose • Tolerability- better side effect profiles than older drugs like TCAs and MAOIs

  32. Stahl S M, Essential Psychopharmacology (2000) 5--34 SEROTONIN IS PRODUCED tryptophan transporter AAADC 5HTP Tryptophan TRY-OH 5HT (Serotonin)

  33. Stahl S M, Essential Psychopharmacology (2000) 5--35 SEROTONIN IS DESTROYED serotonin transporter MAO

  34. SEROTONIN RECEPTORS Stahl S M, Essential Psychopharmacology (2000) 5--36 5HT1D autoreceptor alpha 2 hetero receptor serotonin transporter 5HT3 5HT4 5HT2C 5HTX 5HT2A 5HTY 5HTZ 5HT1A

  35. 5HT1A • Presynaptic and post synaptic • Antidepressant action • OCD • Panic • Social phobia • Bulimia

  36. 5HT1D • Anti- migraine actions

  37. 5HT2 • Agitation • Akathisia • Anxiety • Panic attacks • Insomnia • Sexual dysfunction

  38. 5HT3 • Nausea • GI distress • Diarrhoea • Headache

  39. Serotonin Pathways Raphe Nucleus Stahl S M, Essential Psychopharmacology (2000)

  40. PATHWAYS INVOLVED • Depression: disinhibition of pathway to prefrontal cortex • OCD: to basal ganglia • Panic Disorder: To limbic cortex and hippocampus • Bulimia: to hypothalamus

  41. Frontal Cortex Mood Stahl S M, Essential Psychopharmacology (2000)

  42. Akathisia/ Agitation Basal Ganglia OCD Stahl S M, Essential Psychopharmacology (2000)

  43. Limbic Anxiety Stahl S M, Essential Psychopharmacology (2000)

  44. Hypothalamus Appetite/bulimia Stahl S M, Essential Psychopharmacology (2000)

  45. Sleep Centers Insomnia Stahl S M, Essential Psychopharmacology (2000)

  46. Spinal Cord Sexual Dysfunction Stahl S M, Essential Psychopharmacology (2000)

  47. Brainstem Vomiting Center Nausea and vomiting Stahl S M, Essential Psychopharmacology (2000)

  48. Gut GI cramps/Diarrhea Stahl S M, Essential Psychopharmacology (2000)

  49. COMMON FEATURES • Similar mechanism of action • Efficacy equivalent to TCAs • Higher therapeutic index than TCAs • Safer and better tolerated - minimal cardiac effects - fewer anticholinergic effects • Better patient compliance

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