1. ANTI-PSYCHOTIC DRUGS (since 1950’s) Mainly 15-45 age range, but increasing in kids! Stop PANIC, HOSTILITY, FEAR Before 1950’s in the WEST: Dr. Freeman (US) popularized lobotomies for curing many mental illnesses >18,000 lobs US (1939-1950) Rosemary Kennedy had one Lived to 86 but suffered as a result

2. East: Extract of the Indian Snakeroot plant (used as antidote to snake bites) RAUWOLFIA was used Depletes serotonin and catecholamines but many side effects: nausea, nightmares

3. THE TRICYCLIC ANTIDEPRESSANTS R = CH 2 CH 2 CH 2 NMe 2 X = Cl CHLORPROMAZINE [aka: Thorazine, Promactil, Prozil, Sanopron,...] Chloropromazine was a cheap, failed anti-histamine, which was unbelievably effective: withdrawn patients became active violent patients became calmed 95% of those institutionalized could go home (75-200 mg daily)

4. Chlorpromazine is a so-called ‘dirty drug’: antagonist for many different postsynaptic receptors: dopamine receptors (subtypes D1, D2, D3 and D4): account for antipsychotic properties serotonin receptors (5-HT1 and 5-HT2): antiaggressive properties but also leading to weight gain, fall in blood pressure, sedation histamine receptors (H1 receptors): accounts for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain M1 and M2 muscarinic acetylcholine receptors: symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, loss of memory dopamine reuptake inhibitor: (mild) antidepressive

5. Dopamine present in greater amounts in brains of schizophrenics, so all tricyclic antidepressants antagonize the D 2 site ~ 20 second-generation drugs are in use and they are more specific for the desired D 2 receptor (as well as 5- HT 2, see next slide) eg. Fluphenazine (dose 2-10 mg): Current Canadian Tricyclic Anti-Depressants: maprotiline, amitryptyline,clomipramine desipramine, doxepin, imipramine, nortryptyline, trimipramine, chlorpromazine, methotrimeprazine, fluphenazine, perphenazine, prochlorperazine, thioproperazine, trifluoperazine, mesoridazine, pericyazine,pipotiazine, thioridazine,flupenthixol, thiothixene, zuclopenthixol, mirtazapine

6. Additional binding to the 5-HT 2 (serotonin) sites helps to control POSITIVE (voices) and NEGATIVE (withdrawal) symptoms egs. HALDOL (Haloperidol) and CLOZARIL (Clozapine) 2-6 mg 25 mg initially There are many variants of each, and all have reduced side effects, but Clozapine gives reduced white blood cell counts and therefore needs weekly blood tests

7. ZYPREXA (olanzapine) is a more expensive version of clozapine $8/day, but 17 US veteran hospitals reported that haldol + benztropine (10 cents per day) is just as good

8. ANOTHER STATEGY: Selective Serotonin Re-uptake Inhibitors (SSRI’s) (first anti-depression drugs by design from 1980’s on) PROZAC (±) ZOLOFT PAXIL (1988, Lilly) (Pfizer) (Glaxo) > one million Rx/month 20-80 mg/day/once 50 mg/day/once 20 mg/day/once

10. COMT = catechol-O- methyl transferase MAO = Monoamine oxidase

11. ACTION: blocks serotonin re-uptake (binds 5-HT 1A receptors): serotonin stays around longer, nerve impulse more likely to be transmitted – overdose does not appear to be possible however Main side effects: nausea (Paxil < Zoloft < Prozac), dry mouth, dizziness, weight loss... PAXIL (SEROXAT in UK, paroxetine): only shows side effects early on but they diminish after a few weeks Sales increased 5x in less than a decade (2.7B$) ALL SSRI’s now have a black box warning: DO NOT GIVE TO PATIENTS ALSO USING MAO (monoamine oxidase) INHIBITORS DO NOT GIVE TO SUICIDAL PATIENTS, WITH EPILEPSY OR SEIZURES

12. Current Canadian Drugs in this Class and Related SSRI’s: citalopram, fluoxetine, paroxetine, sertraline fluvoxamine, venlafaxine (also SNRI) Monoamineoxidase inhibitors: phenelzine, tranylcypromine, moclobemide. Other: bupropion, trazodone, l-tryptophan SSRI's linked to serious lung disorder in newborns – avoid during pregnancy http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/2006_11_e.html Paroxetine [PAXIL] in First Trimester of Pregnancy May Have Small Increased Risk of Heart-Related Birth Defects, Compared to Other Antidepressants http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/paxil_4_pc-cp_e.html http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/paxil_4_pc-cp_e.html

13. RITALIN (Methylphenidate) (Novartis (CIBA)) (±) Stimulant for ADHD (attention deficit hyperactive disorder) Unruly children behave ‘properly’ within minutes Why a stimulant for ‘hyperactivity’? ADHD patients have decreased brain activity in areas critical to concentration ACTION: increases dopamine levels in brain, injected or orally, which activates motivation and drive (like ‘speed’!); main effect is on behaviour rather than body motor function Only tested on kids > 6 years age

14. Side effects: nervousness, insomnia, tics, loss of appetite, stomach pain; some suppression of growth with long-term use Not tested during pregnancy Dose: Children 5-10 mg, 3 x per day Adults 5-20 mg, 3 x per day About 5% of US kids estimated on drug!!! Also approved in Canada: dexamphetamine, atomoxetine

15. MANIC DEPRESSION - LITHIUM Suffer mood swings: 3 months ‘up’: excess drink, grand plans, impulse spending, quit job, give away possessions then 6-9 months ‘down’: rejection, suicidal feelings FIX: Li 2 CO 3 LITHANE (Pfizer) Lithium carbonate Mechanism not known but has many measurable effects: decreases dopamine in brain (changes metabolism), alters c-AMP formation, alters Na + transport in nerve & muscle cells DOSE: 3 x 600mg day is close to the toxic dose!