Mid-Ohio Psychological Services, Inc. Staff Training: Psychopharmacology

1. Mid-Ohio Psychological Services, Inc. Staff Training:Psychopharmacology Daniel DiSalvo, CNP February 8, 2008

2. Outline • Welcome, Introduction & Lunch • Content • Pharmacodynamics/kinetics & Basic Principles • Antidepressants • MAOIs, TCAs • SSRIs • SNRIs • Other • Mood Stabilizers • Antipsychotics • Discussion • Question & Answer • Conclusion

3. Psychopharmacology • The study of the effects of drugs on affect, mood, cognition and behavior and the use of drugs to treat disorders of the central nervous system where it is the expressed intent to alter mood, thought or behavior.

4. The Concept of Chemical Imbalance NTin deficitin excess acetylcholinememory impairment/delirium aggression/depression dopamine dementia/depression psychosis/anxiety/ confusion/aggression serotonindepression/impulsivity/anxiety anxiety norepinephrinedepression/anxiety/dementia anxiety/aggression GABA anxiety/impulsivity cognitive/motor slowing glutamate cognitive slowing/dementia seizures/neuronal degeneration

5. The Basis of Psychopharmacology Correcting the chemical imbalance – either increasing or decreasing activity of that NT. • For disorders associated with hypofunctioning: • Stimulate NT release • Use chemical (drug) that mimics NT • Block metabolic inactivation of NT • Block reuptake • For disorders associated with hyperfunctioning: • Inhibit or reduce NT release • Block target receptors

6. Antidepressants • >8 different pharmacological MOAs • >2 dozen ADs • Most block monoamine reuptake • Some block alpha-2 receptors • Others might work on the enzyme MAO • Some have direct actions on only one monoamine NT system, while others work on multiple monoamine NT systems • The immediate pharmacological actions of all ADs eventually have the effect of boosting the levels of monoamine NTs

7. Why Does It Take So Long? • Down Regulation: no matter what their initial actions on receptors and enzymes, ADs eventually cause a desensitization of key NT receptors in a time course consistent with the delayed onset of AD action of these drugs. • Delayed actions of ADs may not only explain the delay in onset of therapeutic action of ADs; they may also explain why some patients fail to respond to ADs, as… • It is possible that in such patients the initial pharmacological actions are not translated into the required delayed pharmacologic and genetic actions.

8. Function • Pharmacokinetics: How the body acts on the drug. • Pharmacodynamics: How the drug acts on the body, especially the brain. • Drug is absorbed and delivered through the gut wall to the liver to be biotransformed so that it can be excreted. • CYP450: enzyme in the gut wall or liver converts the drug substrate into a biotransformed product in the bloodstream. • After the passing through the gut wall and liver, the drug will exist partly as unchanged drug and partly as biotransformed drug.

9. CYP450 Systems

10. Classical ADs: MAOIs & TCAs • MAOIs – the very first! 1950s, 1960s • Anti-TB drug • Great for panic and social phobia • Used to stop ‘em…dead! • Subtypes: A (depression – 5-HT, NE), B (anti-neurodegenerative - Parkinson’s) • Hypertensive crisis

11. MAOI Diet • Cheese pizza, sour cream, yogurt, and all cheeses except cream and cottage • Beef and chicken livers, unrefrigerated fermented sausage, summer sausage, bologna, salami, pepperoni, tofu, pickled fish/herring, lox caviar, dried salted herring/other smoked fish • Broad bean pods, fava beans, Italian green beans, snow pea pods, sauerkraut, avocados • Chocolate cake, cookies, ice cream, pudding, chocolate candy • Chianti, sherry, red, burgundy, ale, beer, vermouth, Reisling, liqueurs • Salad dressings with cheese or MSG • Brewer’s yeast/yeast extract (e.g., some soups, sauces, gravies), MSG, meat tenderizers , soy sauce.

12. MAOI Medication Interactions • Sympathomimetics • General anesthetics • Local or spinal anesthetics w/ epi (e.g., Novocaine) • OTC cough, cold and sinus w/ sympathos (e.g., Actifed, Sudafed, Contact, Dristan, Afrin, NyQuil, Dimetapp, Triaminic, etc.) • Demerol and other narcotics containing codeine, morphine, hydrocodone (e.g., Percocet, Percodan) • Cocaine • Macrolantin • Other ADs

13. MAOIs-A

14. MAOIs-B & RIMAs • Selegiline – parkinsonism… • Emsam (selegiline): greater affinity for B, but works on both at AD doses • 6/9/12mg transdermal/qd – no restrictions at 6 • RIMAs not available in US • Manerix – few dietary restrictions

15. Pharmacological Actions - MAOIs • Readily absorbed through GI • Peak plasma in 2hr. • T ½ is 2-3hr. • Irreversibly inactivate MAOs – i dose can last for 2w.

16. Therapeutic Indications –MAOIs • Depression, esp. that associated with mood reactivity, extreme sensitivity to interpersonal loss or rejection, prominent anergia, hyperphagia, hypersomnia (atypical features) • Also great for panic, PTSD, AN, BN, SP and pain syndromes. • Refractory • Panic (high) • OCD (none) • GAD (moderate) • BDD (moderate)

17. Precautions & Adverse Reactions – MAOIs • Orthostasis, insomnia, weight gain, edema, sexual dysfunction • (divide dose, increase fluids/salt, support stockings, take in a.m., add sleep agent, or…switch) • HTN crisis w/o tyramine (Parnate) – avoid • Taper and wait for >2w w/ a switch • Paresthesias, myoclonus, muscle pains • Pyridoxine 50-150mg/d • Less cardiotoxic, epileptogenic compared to TCAs • Caution, though, w/ renal, CV and hyperthyroidism • May alter dosage of a hypoglycemic agent • Associated w/ induction of mania in pts. in depressed phase of BPAD I and triggering psychotic decompensation in scz • Contraindicated in pregnancy/nursing

18. Precautions & Adverse Reactions – MAOIs • OD: agitation  coma w/ hyperthermia, HTN, tachypnea, tachycardia, dilated pupils and hyperreflexia, involuntary movements (face, jaw) • Asymptomatic 1-6hrs. • acidify urine, dialyze • Multi-drug (esp. 5-HT) – increase effects

19. Precautions & Adverse Reactions – MAOIs • Labs: • DM meds (hypoglycemia) • minimal, false elevation of TFTs • Periodic LFTs

20. TCAs • Wide range: MDD, Panic, GAD, PTSD, OCD, EDs, Pain Syndrome • Yet, very toxic and we have alternatives • Significant FPE • Peak plasma 2-8hrs • T ½ 10-70hrs • 2D6: (Is) quinidine, cimetidine, fluoxetine, sertraline, paroxetine, phenothiazines, carbamazepine, some antiarrhymics (propafenone, flecainide) • Block reuptake of NE, 5-HT • Competitive antagonists of muscarinic acetylcholine, H1, alpha-1, -2 • Use if cannot tolerate anxiety/GI upset (SSRIs)

21. TCAs – Approved / Off-Label Uses • MDD: induce mania in susceptible pts. (compared to bupropion, SSRIs) • Panic: imipramine, yet anxiogenic, so start low, go slow • GAD: doxepin, imipramine • OCD: clomipramine (2-4w…4-5m) and depressed pts. w/ marked obsessive features • EDs: imipramine, desipramine, clomipramine • Pain: any • Enuresis: imipramine • Peptic ulcer: doxepin • Others: narcolepsy, nightmare d/o, PTSD, sometimes for ADHD, sleepwalking, separation anxiety, sleep terrors, premature ejaculation, movement d/os

22. Precautions & Adverse Reactions – TCAs • Anticholinergic, sedation, orthostasis, seizure, conduction abnormalities, weight gain • Can induce mania (over SSRIs, bupropion) • May exacerbate psychotic d/os • Confusion, delirium • Tachycardia, flattened T waves, prolonged QTc intervals, depressed ST segments • Don’t use w/ cardiac pts., unless other agents have failed (monitor) • Sore throat in initial stages – monitor • Transient increase in LFTs vs. hepatitis

23. Drug Interactions – TCAs • MAOIs • Antihypertensives • Esimil, Ismelin (block reuptake) • propranolol, clonidine (also block) • Aldomet + TCA = agitation • DA blockers • perphenazine = doubling of plasma [ ] of both products (add to anticholinergic SE profile, too) • Sympathomimetics • Serious CV effects • CNS depressants • Opioids, EtOH, anxiolytics, hypnotics, OTC cold remedies • Oral contraceptives • BCPs may decrease TCA plasma [ ] through the induction of hepatic enzymes • Diamox, ASA, cimetidine, thiazide diuretics, fluoxetine, sodium bicarbonate = increase, while ascorbic acid, ammonium chloride, barbiturates, cigarette smoking, carbamazepine, chloral hydrate, lithium decrease levels

24. TCA Labs • Can get levels, though • Should be clinically driven

25. TCA Dosages / Clinical Guidelines

26. Clinical Guidelines of TCAs • Prior to tx: PE, CBC w/ diff, lytes, LFTs, EKG (esp. women >40, men >30) • Contraindicated in pts. w/ a QTc >450msc • Consider using newer agents 1st, esp. if pt. has an interfering medical dx • In kids, elderly – avoid, but if need to use, EKG should be monitored frequently • Those w/ chronic pain might be sensitive to initial dosing, but may benefit later • Taper to avoid cholinergic rebound syndrome

27. Dosing & Levels – TCAs

28. TCAs & OD • Serious, can easily be fatal • NRF, <1w quantity for those at risk • amoxapine – most fatal • OD Sx: • agitation, delirium, convulsions, hyperreflexia, bowel/bladder paralysis, dysregulation of BP, T and mydriasis…coma, respiratory depression • cardiac arrhythmias may not be correctable, and are at risk for up to 4d s/p OD d/t long T ½

29. SSRIS(the ones we know and love) • fluoxetine – 1987 • Rapidly eclipsed the MAOIs/TCAs • Don’t necessarily work better, but are safer and have a less (different) SE profile • Subtle differences between compounds: T 1/2 , potency for reuptake inhibition and affinity for some other receptors • Overall, less effects on adrenergic, histaminergic and cholinergic

30. Pharmacologic Actions – SSRIs • Selectively block the reuptake of 5-HT presynaptically • Slightly different pharmacokinetic profiles, as each drug is structurally different from the others • Many are highly protein bound • Varying T ½ - 24hr to several days • fluoxetine (active metabolite) = 7-15d • citalopram = 1.5d • sertraline / paroxetine = 1d • All are well absorbed and not generally affected by food administration except for sertraline (level may be increased w/ food) • No correlation between T ½ and time to onset • All eliminated in urine as active metabolites • citalopram / escitalopram – more selective for 5-HT receptor blockade

31. Indications For / Off-Label Use of SSRIs • MDD – acute, single, recurrent, prevention, etc. • DD, PD • OCD (may need more, take longer) • GAD, SP, PTSD • AN, BN (APA recommends use for persistent depression after pt.’s gained wt.) • BDD • PMDD • Children • Repetitive-type abnormalities, e.g., autism, ADHD (as adjunct), MR/DD, chronic enuresis • Other complex behavioral d/os • Obesity (high dose fluoxetine) • Binge eating (sertraline) • Substance abuse • Decrease aggressive behaviors – impulsivity / uncontrolled anger in all ages • Migraine / cluster HAs • Diabetic neuropathy, facial pain, fibrositis, arthritis, RLS

32. Pharmacokinetic Profiles – SSRIs

33. Basics – SSRIs

34. Precautions & Adverse Reactions – SSRIs • ¾ of pts. experience no SEs • ¼ have SEs in first 2w, usually subside • 10-15% are unable to tolerate • Sexual dysfunction: 50-80%, might not go away… • Decrease dose; switch (bupropion, nefazodone); add (bupropion) • GI: sertraline, fluvoxamine, citalopram • N, V, D, anorexia, dyspepsia – transient? • Weight gain: initially lose, but 1/3 will gain (>20lbs.); paroxetine (d/t anticholinergic SE) • HAs: 18-20% (fluoxetine – most); alternately, SSRIs are wonderful for tension HAs/migraines

35. Precautions & Adverse Reactions – SSRIs • CNS • Anxiety: fluoxetine (most), but then tx it • Insomnia/sedation: ¼ have insomnia (fluoxetine – take in a.m.); sertraline = fluvoxamine; citalopram/paroxetine – sedation • Tx w/ trazodone, BDZ, other off-labels • Nightmares: small amount of pts. (resolves) • Seizures: 0.1 - 0.2% of all pts. txd w/ SSRIs (comparable to other ADs/placebo) • EPS: • Tremor 5-10% • TD (exceptionally rare) • Pts. w/ well-controlled Parkinson’s – acute worsening of their motor symptoms • Bruxism (buspirone) • Most common w/ fluoxetine

36. Precautions & Adverse Reactions – SSRIs • Anticholinergic: • paroxetine (mild) • opposite of S.L.U.D. • Dry mouth (up to 20%) • Dose-dependent • Hematologic: • Can decrease plt. function = bruisability • paroxetine, fluoxetine (reversible neutropenia – rare, usually if concurrent w/ clozapine) • Electrolyte / Glucose: • Hypoglycemia (rare – DM pts. need to be careful) • Hyponatremia/ADH release (also rare) – if diuresing/H2O deprived • Endocrine / Allergic: • Decrease prolactin/galactorrhea (breast changes may take several months to correct) • Various rash types – 4% (d/c)

37. Precautions & Adverse Reactions – SSRIs • 5-HT Syndrome: • SSRI + MAOI or SSRI + L-tryptophan or SSRI + lithium = can raise 5-HT concentrations to toxic levels, causing cascade of: • D • Restlessness • Extreme agitation • Hyperreflexia • Autonomic instability • Myoclonus • Seizures • Hyperthermia • Uncontrollable shivering, rigidity • Delirium • Coma • Status epilepticus • CV collapse • Death

38. Precautions & Adverse Reactions – SSRIs • 5-HT Syndrome Tx: • D/C offender • Supportive care • Nitro • Cyproheptadine • Methysergide • Cooling blankets • Chlorpromazine • Dantrolene • Benzodiazpines • Anticonvulsants • Mechanical vents • Paralyzing agents

39. Precautions & Adverse Reactions – SSRIs • SSRI W/D: • Abrupt discontinuation, esp. w/ a shorter T ½ (paroxetine, fluvoxamine) • After 6w; ends by 3w • dizziness, weakness, N, HA, rebound depression, anxiety, insomnia, poor concentration, UR Sx, paresthesias, migraine-like Sx • Tx: don’t abruptly stop; use fluoxetine

40. SSRIs & Labs • None

41. SNRIs • “3rd Generation” ADs • 5-HT, NE – equal affinity • duloxetine, venlafaxine, mirtazapine • Differences among the three: • mirtazapine – antagonist of central presynaptic alpha2-adrenergic receptors; potent antagonist of H1 • venlafaxine – a little faster onset w/ rapid dose increase; great for severe MDD w/ melancholy; 1st non-bdz drug (other than buspirone) to be approved for GAD • duloxetine – compared w/ venlafaxine, it has a greater effect on 5-HT reuptake in vitro; approved for diabetic neuropathic pain

42. Other ADs • bupropion (DA, NE) – late 80’s • augmentation, SEs, off-label, etc. • be careful w/ OD and EDs – sz d/o • trazodone • structurally related to nefazodone, structurally unrelated to SSRIs, TCAs, MAOIs • active metabolite is mCPP (5-HT2c agonist), is especially sedating (off-label use), blocking H1 • priapism (1:6000; surgical intervention in 33%) • nefazodone • mixed 5-HT antagonist/reuptake inhibitor • great for anxiety • less sedation, hypotension than TCAs, trazodone • atomoxetine (NOT approved for depression) – NRI; could use off-label

43. Special Considerations in the Selection of an AD • Gender: • women have less gastric acid / slower emptying = slower GI absorption • volume distribution = more adiposity than lean muscle • H2O retention associated w/ menses = affects volume distribution, too • PO contraceptives can alter hepatic metabolism (TCAs)

44. Special Considerations in the Selection of an AD • Ethnicity: • AAs slow metabolizers compared to Europeans d/t metabolic enzyme expression • AAs have higher plasma levels per dose of AD (demonstrated most w/ TCAs) • Asians are slower to metabolize nortriptyline than other groups • Minorities were less likely than nonminorities to be offered AD treatment, independent of dx (study of CMHCs’ prescribing practices in Westchester County, NY)

45. Special Considerations in the Selection of an AD • Age: • Elderly? Steady-state [ ] are minimally affected by age (except paroxetine) • Remember: start low, go slow • Comorbidities: • Renal – dose adjustment (except fluoxetine, sertraline) • Liver – can increase levels of TCAs (monitor); give lower doses of SSRIs; don’t use nefazodone • Pregnant Women and Nursing Mothers: • Risks vs. benefits • Generally safe, but be careful of w/d for neonate

46. Mood Stabilizers • Agents that are geared at affecting one phase of illness w/o worsening any other phase(s) • 3 families: • lithium • anticonvulsants • atypicals

47. Lithium • 1970 • Used the longest, quite frequently and is excellent for mania, maintenance – all phases • Yet non-response rate can be as high as 40% • Narrow TI • Structurally simple = Li+ • MOA: unclear if NTs are involved, like they are in depression tx; occurs intracellularly w/ second-messenger systems • A monocovalent cation – a direct competitior of Mg+ @ regulatory enzyme, IMPase = reduces intracellular Ca+/protein kinase C activation

48. Lithium • lithium carbonate, Lithobid, Eskalith CR = immediate and extended (better tolerated, convenience) • Peak plasma 1-4h • T ½ 18-36h • Rapid, complete absorption • Low protein binding • No first-pass effect • 95% drug excretion by kidneys • Can remit mania in many cases, but clinically an antiepileptic or atypical is also used

49. Lithium – Labs / Pre-Treatment Testing • CBC • Lytes • KFTs • TFTs • EKG • Pregnancy • Check level q3-6mos, as well as associated labs/EKG • Normal range: 0.5-1.5mEq/L

50. Lithium • 150mg, 300mg, 600mg cap • $15.54, $17.77, $42.30 (#100) • Eskalith CR 450mg cap • $81.97 (#180)