Psychopharmacology What you should know to survive the LMCC and Internship

1. PsychopharmacologyWhat you should know to survive the LMCC and Internship Kate Huntington, MD April 2008

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

7. SSRI’s: Indications • MDD • GAD • Social phobia • PTSD • OCD • Augmentation in BD • Premenstrual Dysphoric Disorder • Panic Disorder

13. 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, causing autoreceptors (the brakes) to decrease in number & sensitivity • This turns off the brake on the serotonin neuron and electrical impulses flow down the axon, releasing more serotonin at the axon terminal • Increased levels of serotonin in the synapse leads to down regulation (decreased number and sensitivity) of postsynaptic receptors & other downstream changes

14. SSRI: Side Effect Profile • Headache • Anxiety (limbic projections) and Agitation (basal ganglia projections) • Nausea (chemoreceptor trigger zone) • Diarrhea (peripheral GI 5HT3 & 5HT4 receptors) • Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (Brainstem sleep centre)

15. SSRI: Rare but Dangerous Side Effects • UGI bleeding (platelet dysfunction) • SIADH • SSRI discontinuation syndrome (slow taper) • Serotonin syndrome

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

17. NDRI: Side Effect Profile • Seizures (not with SR formulation & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) • Headache • Agitation (limbic cortex) • Rash • Emesis • Sleep disruption (limbic cortex) and Shaking (cerebellum)

18. Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action(Venlafaxine/Effexor) • Blockade of serotonin reuptake up to about 150 mg • Blockade of serotonin and norepinephrine reuptake from about 150-225mg • Blockade of serotonin, norepinephrine and dopamine reuptake above 225 mg

19. SNRI: Side Effect Profile • Same as SSRI up to 150 mg • >150 mg, may also see sustained increase in diastolic BP & other noradrenergic-type side effects (see NDRI)

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

22. NaSSA: Mechanism of Action • Blocks Alpha 2 autoreceptors on norepinephrine neurons & heteroreceptors on Serotonin neurons, causing more NE & 5HT to be released (puts the brakes on the brakes) • 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

23. NaSSA: Side Effect Profile • Weight gain (H1 blockade) • Anticholinergic: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (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) • Drowsiness (H1 blockade) • Equilibrium

24. NaSSA: Rare but Dangerous Side Effects • Neutropenia • Serotonin syndrome • Hepatotoxicity • Possibly SIADH

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

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

27. SARI: Rare but Dangerous Side Effects • Serotonin syndrome

28. TCA: Mechanism of ActionTricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2° amines (eg nortriptyline, desipramine) • 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 & sodium channels in the heart & brain

29. Antihistamine – weight gain & sedation Anticholinergic – (remember toxidrome from NaSSA) Anti-alpha adrenergic – dizziness, orthostatic hypotension Blockade of fast sodium channels – prolongation of QTc (risk of Torsades) TCA: Side Effect Profile

30. TCA: Rare but Dangerous Side Effects • Torsades de Pointes • 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

31. MAOI: Mechanism of ActionMonoamine oxidase inhibitors: “the classics” (phenylzine/nardil, tranylcypromine/parnate)Reversible inhibitor: (moclobemide/mannerix) • Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA

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

33. MAOI: Rare but Dangerous Side Effects • Blood dyscrasias • Hepatotoxicity • Teratogenicity • Serotonin Syndrome - (even more susceptable than with other serotenergic antidepressants) • 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 cheese and wine)

34. Serotonin Syndrome Co-incidence with the addition or increase of a serotenergic agent Development of at least 4 major or 3 major plus 2 minor criteria

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

36. Starting Antidepressants: General Guidelines • Start with a reuptake inhibitor or mirtazepine (not a TCA or MAOI) • Start at lowest possible dose (half of this with anxiety and in the elderly and medically frail) • Increase by this increment about every five half lives (or about once a week) until one of the following endpoints: • Intolerable side effects • Full response • Maximum dose • Continue to monitor for therapeutic effects, side effects and safety

37. Course of Recovery From Depression Response 2-3 weeks: Improved sleep, appetite, vegetative shifts 3-4 weeks: objective improvement energy suicidal ideation may  6-8 weeks: subjective improvement

39. Stimulants: Indications • ADHD • Narcolepsy • (treatment resistant depression)

40. Stimulants: Mechanism of action • Increases dopamine and NE actions by blocking their reuptake and facilitating their release • Action in DL prefrontal cortex improves attention, concentration, executive function and wakefulness • Action in Basal Ganglia may improve hyperactivity • Action in medial prefrontal cortex may improve depression, fatigue and sleepiness

41. Stimulants: Common Side Effects • Headaches and Heart concerns(palpitations, tachycardia and hypertension) • Insomnia, Irritibility and Increased stimulation • Dizziness • Exacerbation of tics, tremor • Stomach: anorexia, nausea, abdo pain, weight loss, possibly slowing of normal growth in children

42. Stimulants: Rare Side Effects • Psychosis

43. Stimulants:Ongoing Monitoring • Blood pressure at baseline and with dose increases • In children, ongoing monitoring of height and weight

45. Common MDE Mania Mixed state Catatonia Schizophenia with prominent affective symptoms Schizoaffective disorder Uncommon Delirium NMS Parkinson’s Disease ECT: Indications

46. ECT: Indications (cont.) • Indications for First Line Use: • Need for rapid improvement (suicide, malnutritian, catatonia, severe psychosis or agitation) • When other treatments are more risky (elderly, pregnant) • Patient preference • Psychotic depression (gold standard – 95% response)

47. ECT: Relative Contraindications(weigh pros & cons) • Space occupying cerebral lesions • Increased ICP • Recent MI • Recent CVA • Aneurysm • Retinal detachment • Pheochomocytoma

48. ECT: Mechanism of Action • Neurotransmitter theory • Enhances DA, 5HT & NE neurotransmissiom • Neuroendocrine theory • Increased release of neurohormones including prolactin, TSH, ACTH & endorphins • Anticonvulsant theory • Increase in seizure threshold during course of ECT; CSF of animals receiving ECS is anticonvulsant when given IV to recipient animals

49. ECT: Side Effect Profile • Common • Headache • Muscle ache • Nausea • Memory impairment • Delirium • Amnesia (anterograde & retrograde) • No longterm deficits

50. ECT: Side Effect Profile • Rare: • Mortality 1/10,000-0.2 / 100 000 • Cardiovascular • 2° initial vagal stimulation • Bradycardia / asystole / ectopic activity • 2° sympathetic stimulation • Increased HR & increased BP • Prolonged apnea • Pseudocholinesterase deficiency • Prolonged seizure • Treat with IV benzo