Psychopharmacology What you need to know to survive the LMCC and Internship

1. PsychopharmacologyWhat you need to know to survive the LMCC and Internship Dr. Lisa McMurray Based on the 2013 lecture by Dr. Kate Huntington April 2014

2. Objectives To review: • indications for • mechanism of action • side effects (remember not everyone gets these) • monitoring parameters for the major classes of psychotropic medications To practice applying this knowledge

3. MCC Objectives for the Qualifying Examination(with my updates for DSM-5) • Initiate pharmacologic treatment of • ADHD • Agitation in Delirium • Dementia/Major Neurocognitive Disorder • Major Depressive Disorder • Manic Episode • Anxiety Disorders • Obsessive-Compulsive Disorder (formerly an anxiety disorder) • Substance withdrawal • Substance Use disorders (e.g. nicotine replacement)

4. MCC Objectives for the Qualifying Examination • Judicious use of pharmacotherapy in personality disorders • Attention to risk of abuse, overdose • Recognize Medication-Induced Movement disorders • e.g. dystonia due to antipsychotics

5. Which of the following is NOT a common side effect of SSRI’s? • a. Nausea • b. Headache • c. Rigidity • d. Anxiety • e. Sleep disruption

6. Which of the following is NOT a common side effect of SSRI’s? • a. Nausea • b. Headache • c. Rigidity • d. Anxiety • e. Sleep disruption

7. Which of the following receptors does Mirtazepine/Remeron NOT block? • a. Histamine • b. 5HT1 • c. 5HT2 • d. 5HT3 • e. Alpha 2

8. Which of the following receptors does Mirtazepine/Remeron not block? • a. Histamine • b. 5HT1 • c. 5HT2 • d. 5HT3 • e. Alpha 2

9. At which dose level does Venlafaxine/Effexor XR typically begin to have a noradrenergic effect? • a. 75mg • b. 150mg • c. 225mg • d. 300mg

10. At which dose level does Venlafaxine/Effexor XR typically begin to have a noradrenergic effect? • a. 75mg • b. 150mg • c. 225mg • d. 300mg

11. Which is not an indication for the use of Benzodiazepines? • a. Catatonia • b. Long term hypnotic • c. Mania • d. Alcohol withdrawal • e. Anxiety

12. Which is not an indication for the use of Benzodiazepines? • a. Catatonia • b. Long term hypnotic • c. Mania • d. Alcohol withdrawal • e. Anxiety

13. How are the novel hypnotics (e.g. Zopiclone, Zolpidem) different from Benzodiazepines? • a. Do not cause falls • b. Do not lead to tolerance • c. Used as long term hypnotics • d. More selective for the alpha one subtype of GABA-A receptor

14. How are the novel hypnotics (e.g. Zopiclone, Zolpidem) different from Benzodiazepines? • a. Do not cause falls • b. Do not lead to tolerance • c. Used as long term hypnotics • d. More selective for the alpha one subtype of GABA-A receptor

15. Which of these is the most prominent side effect of atypical antipsychotics? • a. Rigidity • b. Dystonia • c. Dyskinesia • d. Akathisia

16. Which of these is the most prominent side effect of atypical antipsychotics? • a. Rigidity • b. Dystonia • c. Dyskinesia • d. Akathisia

17. Which of the following is an example of a low potency typical antipsychotic? • a. Haloperidol (Haldol) • b. Pimozide (Orap) • c. Olanzapine (Zyprexa) • e. Clomipramine (Anafranil) • f. Chlorpromazine (Thorazine)

18. Which of the following is an example of a low potency typical antipsychotic? • a. Haloperidol (Haldol) • b. Pimozide (Orap) • c. Olanzapine (Zyprexa) • e. Clomipramine (Anafranil) • f. Chlorpromazine (Thorazine)

19. Which class of cognitive enhancers is indicated in mild to moderate Alzheimer’s Disease? • a. Cholinesterase inhibitor • b. NMDA receptor antagonist

20. Which class of cognitive enhancers is indicated in mild to moderate Alzheimer’s Disease? • a. Cholinesterase inhibitor • b. NMDA receptor antagonist

21. Which mood stabilizer can reduce the risk of suicide in Bipolar Disorder? • a. Valproic Acid/Epival • b. Lamotrigine/Lamictal • c. Lithium • d. Carbamazepine/Tegretol

22. Which mood stabilizer can reduce the risk of suicide in Bipolar Disorder? • a. Valproic Acid/Epival • b. Lamotrigine/Lamictal • c. Lithium • d. Carbamazepine/Tegretol

23. What is the most common excitatory neurotransmitter in the brain? • a. Serotonin • b. Glutamate • c. Norepinephrine • d. GABA • e. Dopamine

24. What is the most common excitatory neurotransmitter in the brain? • a. Serotonin • b. Glutamate • c. Norepinephrine • d. GABA • e. Dopamine

25. Antidepressants: Indications • MDD • Premenstrual Dysphoric Disorder • GAD • Social phobia • PTSD • OCD • Panic Disorder • Pain disorders (DSM-5 Somatic Symptom Disorder with predominant paiin) • (insomnia)

26. SSRI: Mechanism of Action • In depression, the serotonin neuron has a relative deficiency of serotonin and the autoreceptors and postsynaptic receptors are increased in number & sensitivity • When the reuptake pump is blocked, the level of serotonin increases in the somatodendritic area, sending a message to the nucleus to decrease production of autoreceptors • This leads to disinhibition of the serotonin neuron, releasing more serotonin at the axon terminal • Increased levels of serotonin in the synapse leads to changes in the post synaptic neuron gene products such as down regulation (decreased number and sensitivity) of postsynaptic receptors and increased production of BDNF

27. SSRI: Side Effect Profile • Headache • Anxiety and Agitation (mood and psychomotor circuits) • Nausea (weight/appetite circuit and GI receptors) • Diarrhea (peripheral GI 5HT3 & 5HT4 receptors) • Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (sleep circuit)

28. SSRI: Rare but Dangerous Side Effects • UGI bleeding (platelet dysfunction), esp. in combo with NSAID’s or other blood-thinning agents • SIADH • Osteoporosis and fractures in the elderly • Serotonin syndrome

29. SSRI discontinuation syndrome • Incidence: 20% after 6 weeks of use • Flu-like symptoms • Insomnia • Nausea • Imbalance • Sensory disturbances • Hyperarousal (agitation/anxiety) • Prevent with slow taper

30. Norepinephrine & Dopamine Reuptake Inhibitor:Mechanism of Action (Bupropion/Wellbutrin) • Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s

31. NDRI: Side Effect Profile • Seizures (not with extended release formulations & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) • Headache, Hypertension (SNS activation) • Agitation (mood and psychomotor circuits) and Anticholinergic* (relative decrease in parasympathetic tone) • Rash • Emesis, decreased appetite and weight loss (SNS activation) • Sleep disruption, Shaking and Sweating (sleep and psychomotor circuits and SNS activation) * (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare; bowel & bladder lose their tone & the heart goes off alone)

32. Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action(Venlafaxine/Effexor, Desvenlafaxine/Pristiq, Duloxetine/Cymbalta) • Blockade of serotonin reuptake at lower dose range • Blockade of serotonin and norepinephrine reuptake in mid dose range • Blockade of serotonin, norepinephrine and dopamine reuptake at very high dosages

33. SNRI: Side Effect Profile • As with SSRI’s in lower to mid dose range • As with NDRI in mid to high dose range

34. SNRI: Rare but Dangerous Side Effects • As with SSRI’s

36. NaSSA: Mechanism of Action • Blocks Alpha 2 autoreceptors on norepinephrine neurons & heteroreceptors on Serotonin neurons, causing more NE & 5HT to be released • NE neurons from the locus coeruleus innervate midbrain raphe 5HT neurons. Therefore, increased NE causes a further increase in 5HT release • Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep & sexual side effects • Blocks 5HT3, blocking GI side effects from peripheral receptors & from brainstem chemoreceptor trigger zone • Blocks H1 histamine receptors, causing sedation & weight gain

37. NaSSA: Side Effect Profile • Weight gain (H1 blockade) • Anticholinergic (relative decrease in parasympathetic tone) – very weak effect • Drowsiness (H1 blockade) • Equilibrium

38. NaSSA: Rare but Dangerous Side Effects • Neutropenia • Serotonin syndrome • Hepatotoxicity • SIADH • QT prolongation (Health Canada, 28 March 2014, post-marketing)

39. SARI: Mechanism of ActionSerotonin 2A antagonists/reuptake inhibitors (Trazodone/Desyrel) • Primarily blocks 5HT2A, reducing sexual dysfunction & sleep disruption & increasing effect of 5HT1A stimulation (5HT2A & 5HT1A oppose one another’s actions in several ways) • Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A (therapeutic effects) • H1 blockade causes sedation • Alpha One blockade leads to orthostatic hypotension

40. SARI: Side Effect Profile • Orthostatic hypotension • Sedation

41. SARI: Rare but Dangerous Side Effects • Serotonin syndrome • Priapism

42. TCA: Mechanism of ActionTricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2° amines (eg nortriptyline, desipramine) • Originally developed as treatment for schizophrenia (similar 3-ringed chemical structure); found ineffective for psychosis but helpful for depression. • Therapeutic effects and side effects from blocking Serotonin, Norepinephrine & Dopamine Reuptake • Some also have 5HT2 blocking ability (blocks sex & sleep side effects) • Side effects from blocking H1 histamine receptors, muscarinic receptors, alpha one adrenergic receptors • Overdose can lead to seizures and arrhythmias due to blockade of ion channels

43. Antihistamine – weight gain & sedation Anticholinergic – (remember toxidrome from NDRI) Anti-alpha adrenergic – dizziness, orthostatic hypotension TCA: Side Effect Profile

44. TCA: Rare but Dangerous Side Effects • Torsades de Pointes (due to blockade of fast sodium channels) • EKG – rule out bradycardia and prolonged QTc • Lytes – rule out electrolyte imbalance • Make sure not on type 1 or 3 antiarrythmic drugs • SIADH • Serotonin Syndrome

45. MAOI: Mechanism of ActionMonoamine oxidase inhibitors: “the classics” (phenylzine/nardil, tranylcypromine/parnate)Reversible inhibitor: (moclobemide/mannerix) HISTORY: • The first clinically effective antidepressants • Originally, an anti-tuberculosis drug, found to decrease comorbid depression • Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA

46. MAOI: Side Effect Profile • Side effects related to increase in serotonin norepinephrine & dopamine (see SSRI’s & NDRI’s) • Orthostatic hypotension

47. MAOI: Rare but Dangerous Side Effects • Hyperthermia i.e.Serotonin Syndrome • even more susceptible than with other serotonergic antidepressants; need to avoid anything that has serotonergic effects such as antidepressants and opioids) • When you see an MAOI, get a pharmacy consult, the patient should consult their pharmacist about any over - the – counter medications • Hypertensive crisis • Consult the dietician Re: MAOI diet • Patients need to avoid all foods with tyramine (aged foods such as aged cheeses and wines or tap beer) and any medications with noradrenergic effects (cold remedies, stimulants etc) • Hepatotoxicity • Blood dyscrasias

48. Serotonin Syndrome: HARMED • Hyperthermia • Agitation/Autonomic instability • Rigidity/Reflexes increased • MyoClonus/tremors • Encephalopathy • Diaphoresis

49. For reference only

50. Hypertensive Crisis • Norepinephrine (NE) is the amine most closely linked with control of blood pressure • MAO normally inactivates norepinephrine (NE) • Tyramine, an amine present in aged foods, causes release of norepinephrine (NE) • In the presence of MAOI, this increased NE cannot be broken down, resulting in a hypertensive crisis