Psychopharmacology What you should know to survive the LMCC and Internship

1. PsychopharmacologyWhat you should know to survive the LMCC and Internship Dr. Kate Huntington khuntington@toh.on.ca March 2012

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

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

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

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

7. How are the novel hypnotics 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

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

9. 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

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

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

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

17. SSRI’s: Indications • MDD • Premenstrual Dysphoric Disorder • GAD • Social phobia • PTSD • OCD • Panic Disorder

18. 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

19. 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)

20. 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 • SSRI discontinuation syndrome (slow taper) • Flu-like symptoms • Insomnia • Nausea • Imbalance • Sensory disturbances • Hyperarousal (agitation/anxiety)

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

22. 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)

23. 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

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

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

27. 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

28. 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

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

30. 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

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

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

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

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

35. 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

36. 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

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

38. 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 • Teratogenicity • Blood dyscrasias

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

40. For reference only

41. 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

42. 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

43. Choice of Initial Antidepressant in Adults • There is comparable efficacy between and within classes of medication, therefore, initial selection is based on: • Symptom profile • Side effect profile in relation to the individual patient • Patient preference • Cost • History of previous response of the patient or family members • Comorbid psychiatric or medical illnesses • Potential drug-drug interaction • The BEST antidepressant is the one that a patient will actually take acutely and for the long haul

44. Treatment choices in children • Concerns were raised about the safety of antidepressants (Paroxetine and Venlafaxine) in children and youth in 2004 • Further metaanalyses and epidemiologic studies now confirm that antidepressants in children and youth are safe with close (weekly) monitoring. • Problems with Venlafaxine and Paroxetine may have been related to poor adherence and discontinuation symptoms

45. Choice of Initial Treatment in children/youth • Mild to moderate depression: • Start with psychotherapy or non-medication interventions as first line • Second line is to add medication; best evidence is for Fluoxetine; other SSRI’s could be considered next • Moderate to severe depression: • First line is to consider medication but depending on patient/family preference, may also start with psychotherapy or monitoring • Note that the clinical presentation in children and youth can change quickly; they may appear severely depressed one week then by the next week be in a new relationship and everything is better…

46. 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

47. Goals of antidepressant therapy • REMISSION of symptoms and maintaining that level of improvement in order to prevent relapse and recurrence • Rate of relapse is significantly less for patients who achieve full remission of symptoms • Patients who have been ill longer tend to be more treatment resistant; there is also evidence of hippocampal atrophy with prolonged illness, leading to the concept of disease progression and the hope that this can be modified by treating all mood episodes to the point of remission

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

50. Stimulants: Mechanism of action (1) • Increases dopamine and NE actions by blocking their reuptake and facilitating their release • Improves the efficiency of information processing in the frontal subcortical circuits, relieving frontally mediated symptoms of inattention, hyperactivity and impulsivity.