Pharmacology of Antidepressants

1. Pharmacology of Antidepressants Dr Andrew P Mallon

4. Classes of AntidepressantsTricyclic-tertiary amines • amitriptyline (Elavil) • imipramine (Tofranil) • doxepin (Sinequan) • clomipramine (Anafranil) • trimipramine (Surmontil)

5. Classes of AntidepressantsTricyclic-secondary amines • desipramine (Norpramin) • nortriptyline (Pamelor) • protriptyline (Vivactyl) • amoxapine (Ascendin)

6. Classes of AntidepressantsAtypical (non-tricyclic) • maprotiline (Ludiomil) • trazodone (Desyrel) • bupropion (Wellbutrin) • venlafaxine (Effexor) • nefazodone (Serzone) • mirtazapine (Remeron)

7. Classes of AntidepressantsSpecific serotonin reuptake inhibitors (SSRIs) • fluoxetine (Prozac) • sertraline (Zoloft) • paroxetine (Paxil) • fluvoxamine (Luvox) • citalopram (Celexa)

8. Classes of AntidepressantsMonoamine oxidase inhibitors (MAOIs) • phenelzine (Nardil) • isocarboxazid (Marplan) • tranylcypromine (Parnate) • selegiline (Deprenyl)

9. Classes of AntidepressantsPsychostimulants • methylphenidate (Ritalin) • dextro-amphetamine (Dexedrine) • magnesium pemoline (Cylert) • dex + amphetamine (Adderall) • methamphetamine (Desoxyn) • modafinil (Provigil)

10. Evaluation of the depressed patientGoals of the evaluation • Establish a diagnosis • Identify specific target symptoms • Consider comorbidity • Quantify depression and/or specific symptoms

11. Evaluation of the depressed patient • Obtain psychiatric history and perform mental status exam • Identify and r/o underlying medical problems • Physical exam in the past year

12. Evaluation of the depressed patient • Optional exams: • Laboratory • Neurological exam • Dexamethasone suppression test • TRH test

13. Is an antidepressant indicated? • The decision to treat a patient with antidepressants should be based on the following: • Severity of symptoms and ability to identify target symptoms • Impairment of functioning • Patient’s view of medication • Not necessarily the specific diagnosis

14. Predictors of antidepressant response. • Acute onset • Severe depressive symptoms • Positive previous response to medication • Patient’s willingness to accept medication as an aid to successful treatment

15. How to start antidepressants? • Start low to assess tolerance of side effects • Increase dosage rapidly as tolerated • Maintain typical dose for at least 4 to 8 weeks

16. Most common reasons antidepressants fail • Dosage too low • Duration of trial to short • Poor compliance • Intolerable side effects

17. What is an adequate trial? • Adequate dose: • 5 mg/kg/d • Nortriptyline 100 to 150/d (therapeutic window) • Fluoxetine 20 mg/d • Adequate duration: • 4 – 8 weeks

19. Indications for serum levels • Unequivocally useful for: • Patients who are not responding to usual doses • Patients who are at increased risk for toxicity, e.g. cardiac patients • May be useful for: • Patients where prompt response is critical • Determining compliance and metabolic availability

20. Therapeutic Blood Levelsfor antidepressants • Known: • imipramine • desipramine • nortriptyline • Possibly known: • amitriptyline • Under assessment: • All other antidepressants

21. How Antidepressants Work • Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”. • There are two important observations that contribute to this rationale.

22. How Antidepressants Work • Many drugs require long term administration to be effective. • Drugs of abuse require repeated administration to produce tolerance and physical dependence.

23. How Antidepressants Work • Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse. • That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity).

24. “Synaptic Pharmacology”of antidepressants • Acute: • Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor. • Chronic: • Down regulation of the post-synaptic receptors • Alteration of second messenger systems • Alteration of protein synthesis.

25. After Dosing Antidepressants(days) Synaptic effects: hours to days Side effects: hours to days Therapeutic effect: 1 to 6 weeks Series 1

26. Pharmacokinetics of Antidepressants • Absorption is rapid • Metabolism: extensive 1st pass • Oxidation, hydroxylation, demethylation • 5% = “slow acetylators” • Protein bound: 90 – 95%

28. Antidepressant half-lives (hrs)

29. Cardiac Side-effectsof tricyclic antidepressants • Cardiac conduction delay • Anti-arrhythmic at therapeutic doses • Arrhythmigenic at toxic doses • Minimal effects on cardiac output

30. Cardiac Side-effectsof tricyclic antidepressants • Monitoring EKG parameters: • QTc = 450 msec • PR = 210 msec • QRS - >30% above baseline

32. How to choose an antidepressant • Rationale should be based on side effects, not efficacy • The SSRIs, secondary amines, and atypical antidepressants, are generally better choices. • Why?

33. Norepinephrine uptake blockadePossible clinical consequences • Tremors • Tachycardia

34. Norepinephrine uptake blockade (potency)

35. Serotonin reuptake blockadePossible clinical consequences • Gastrointestinal disturbances • Anxiety (dose – dependent) • Sexual dysfunction

36. Serotonin uptake blockade(potency)

37. Blocking selectivity5-HT vs. NE

39. Dopaminergic uptake blockadePossible clinical consequences • Psychomotor activation • Antiparkinsonian effects • Psychoses • Increased attention/concentration

40. Dopamine uptake blockade(potency)

41. Histamine H1 blockadePossible clinical consequences • Sedation, drowsiness • Weight gain • hypotension

42. Histamine H1 receptor blockade(affinity)

43. Muscarinic receptor blockadepossible clinical consequences • Blurred vision • Dry mouth • Sinus tachycardia • Constipation • Urinary retention • Memory dysfunction

44. Muscarinic receptor blockade(affinity)

45. alpha – 1 receptor blockadepossible clinical consequences • Postural hypotension • Reflex tachycardia • Dizziness

46. alpha-1 receptor blockade (affinity)

48. imipramine (Tofranil)receptor affinities

49. fluoxetine (Prozac)receptor affinities