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Psychopharmacology: Part 1 Antidepressants and Anxiolytics

Learn about the history, classification, mechanisms, and types of antidepressants, including MAOIs, TCAs, and SSRIs. Understand how these drugs work, their side effects, contraindications, and pros and cons.

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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specific search for serotonin reuptake inhibitors started • Culminating in the derivation of first SSRI- Zimelidine (withdrawn) • Further search for specific SSRIs led to the development of landmark SSRI- Fluoxetine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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