1. Psychopharmacology1 Anti Psychotic, Mood Stabilizer DR SEDDIGH

2. Classes of psychotropic medication n Antipsychotic medications n Mood-stabilizing drugs n Anti-anxiety medications n Antidepressant medications n Psychostimulants

3. Antipsychotic medications

4. Antipsychotics: Diagnostic Indications Psychiatric n Schizophrenia n Schizoaffective disorder n Mood disorders with psychosis n Delusional disorder Nonpsychiatric n Dementia/Delirium n Psychosis secondary to a nonpsychiatric medical disorder n Developmental disability with psychosis and/or aggression n Tourette’s disorder n Nausea, vomiting 4

5. Antipsychotic Agents n Antipsychotic agents have two major groups Conventional antipsychotics Block dopamine receptors Atypical antipsychotics Moderate blockade of dopamine receptors

6. ANTIPSYCHOTICS n Pre-90’s –“Typical”, conventional, traditional neuroleptics, major tranquilizors –Modeled on D 2 antagonism –EPS/TD n Post-90’s –“Atypical”, novel, 2 nd generation –Modeled on 5-HT2/D2 antagonism –Less EPS, prolactin effects –Weight gain, sedation, diabetes

8. Impact of antipsychotics..

9. Conventional Antipsychotic Agents n Classification –Low potency-Thioridazine –Medium potency-perphenazine –High potency-Halopridol n Mechanism of Action –Block receptors of dopamine, acetycholine, histamine, norepinephrine

10. n Typical antipsychotics –Phenothiazines e.g. chlorpromazine, fluphenazine, thioridazine –Butyrophenones e.g. haloperidol, droperidol –Thioxanthines e.g. chlorprotixen, thiothixene n Atypical antipsychotics Clozapin Risperidone Olonzapin Sertindole Quetiapine Classification of antipsychotic drugs

11. Overview of Antipsychotics Conventional Antipsychotics Chem. GroupGeneric NameTrade MarkDose (mg) Phenothiazines chlorpromazine LARGACTIL, MEGAPHEN, 200-800 thioridazine MELLERIL 100-600

12. Overview of Antipsychotics Conventional Antipsychotics Chem. GroupGeneric NameTrade MarkDose (mg) Phenothiazines Perphenazine PERFENAZIN, TRILAFON, PERATSIN 16-24 Prochlorperazine PROCHLORPERAZIN, STEMETIL 20-80 Fluphenazine MODITEN 2-16 trifluoperazine STELAZIN 10-50 Thioxanthenes flupenthixol FLUANXOL 6-18 Butyrophenones haloperidol HALOPERIDOL, HALDOL, APO- HALOPERIDOL 2,5-10 melperone BURONIL 50-300 Diphenylbutyl piperidines pimozide ORAP 2-10 fluspirilen IMAP 2-10 penfluridol SEMAP 2-60 Perathiepines oxyprothepin MECLOPIN 5-20

13. Antipsychotics of the 2 nd Generation Generic NameTrade MarkDose (mg) D2, D3 selective antagonists sulpirideDOGMATIL, PROSULPIN50-1200 amisulprideSOLIAN, DENIBAN50-1200 SDA risperidoneRISPERDAL, RISPEN, RISPERDAL QUICKLET 4-8 ziprasidoneZELDOX40-160 SertindoleSERDOLECT12-20 MARTA clozapineLEPONEX200-600 olanzapineZYPREXA i.m. inj. 10 mg5-20 quetiapineSEROQUEL300-600 zotepineZOLEPTIL75-300

14. Adverse Effects Summary Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy; dysphoria Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effect Hypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur Idiosyncratic reactions ‑ malignant neuroleptic syndrome Weight gain Neurological side effects - see next

15. REACTIONFEATURESTIME OF MAXIMAL RISK PROPOSED MECHANISM TREATMENT Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria 1 to 5 daysUnknownAntiparkinsonian agents are diagnostic and curative Akathisia Motor restlessness; not anxiety or "agitation" 5 to 60 daysUnknownReduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may help Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait 5 to 90 daysAntagonism of dopamine Antiparkinsonian agents helpful Neuroleptic malignant syndrome Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal Weeks; can persist for days after stopping neuroleptic Antagonism of dopamine may contribute Stop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effective Perioral tremor ("rabbit" syndrome) Perioral tremor (may be a late variant of parkinsonism) After months or years of treatment UnknownAntiparkinsonian agents often help Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia After 6 months or years of treatment (worse on withdrawal) Excess function of dopamine hypothesized Prevention crucial; treatment unsatisfactory a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day). Neurological Side Effects of antipsychotics

16. Phenothiazines - Side effects Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway) Sexual dysfunction result from NE and SE blockade erectile dysfunction in 23-54% of men retrograde ejaculation in loss of libido and anorgasmia in men and women Seizures - <1% for generalized grand mal

17. ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKS Placebo Molindone Ziprasidone Fluphenazine Haloperidol Non-pharmcontrol Risperidone Chlorpromazine Sertindole Thioridazine Olanzapine Clozapine 0 1 2 3 4 5 Mean change in body weight (kg)

18. Phenothiazines - Side effects Neuroleptic malignant syndrome (1-2% early in trt) combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up) can be fatal in 5-20% of cases if untreated treatment – discontinue meds; give trts for fever and cardiac problems

19. Sensitivity to sun some phenothiazines collect in skin (chlorpromazine) sunlight causes pigmentation changes – grayish-purple splotching (look bruised) can also occur in eye and cause brown in cornea(chlorpromazine) and retin (thioridazine) Jaundice – elevated bilirubin in liver - < ½%

20. Limitations Of Conventional Antipsychotics n Approximately one-third of patients with schizophrenia fail to respond n Limited efficacy against –Negative symptoms –Affective symptoms –Cognitive deficits n High proportion of patients relapse n Side effects and compliance issues

21. Antipsychotic Drugs – New Generations „atypical“ n clozapine n risperidone n olanzapine n sertindole n quetiapine etc.

22. Atypical antipsychotics MARTA (multi acting receptor targeted agents) n clozapine, olanzapine, quetiapine SDA (serotonin-dopamine antagonists) n risperidone, ziprasidone, sertindole Selective D2/D3 antagonists n sulpiride, amisulpiride

23. Clozapine (1989) Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway Also blocks NE More strongly blocks 5-HT2 receptors in Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

24. Clozapine Extrapyramidal side effects are minimal May help treat tarditive dyskinesia Still shows orthostatic hypotension effects, sedation, weight gain, increased heart rate Increased risk for seizures (2-3%) Agranulocytosis in 1% Agranulocytosis risks increase when co-administered with carbamazepine Interactions with SSRIs and valproic acid increase Clozapine levels and risks

25. Risperidone (Risperdal; 1994) Fewer side effects than Clozapine Marketed as first line approach to treatment Blocks selective D2, norepinephrine, and 5-HT2 Argued as effective for positive and negative symptoms (controversial) Extrapyramidal side effects low (but are shown at high doses) - controversial Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin No agranulocytosis risks May cause anxiety/agitation (possible OCD)

26. Olanzipine - Zyprexa – 1996 Same poorly supported arguments about improved negative symptom reduction Argued to be better than risperidone in extrapyramidal issues Does not cause prolactin elevation

27. Sertindole – Serlect – 1995 concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998 Quetiapine – Seroquel - 1997 in Iran Ziprasidone – 2001 Similar to advantages of others, but argued not to cause weight gain

29. n Mood Stabilizers

30. Mood Stabilizers n Lithium n Anticonvulsants –Valproic Acid [Depakote] –Carbamazepine [Tegretol] –New Anticonvulsants (?): Lamotrigine [Lamictal]Lamotrigine [Lamictal] Topiramate [Topamax]Topiramate [Topamax] Gabapentin [Neurontin]Gabapentin [Neurontin]

31. n Lithium

32. Lithium: History n Used since mid-XIX: gout, diabetes... n For BP since 1960’s, FDA ‘74 n Effective Antimanic, mood stab, BP depr. n If Discontinued relapse near 100% 2 yr n Therapeutic Levels: n 1-1.5 mEq/ml Acute mania n 0.4-0.8 mEq/ml Maintenance 0.3-0.8 mEq/ml in elderly –Narrow therapeutic index

33. Lithium: Pharmacology n Not liver metabolized. n Kidney excreted n Not protein bound n 70-80% reabsorb prox Tubule,  Na (dehydr, thiazide diuret)  Li level  Na (dehydr, thiazide diuret)  Li level n Excretion related to GFR:  elder  preg n Half-life 24 hrs (HS), steady state 5 days n Peak Levels 2 hrs, SR 4-4.5 –fast release: N/V, slow rel: diarrhea

34. Predictors: Good Li Response n Past Li response (personal or family) n Euphoric, pure (classic) mania n Sequence Mania-Depr-Euthymia n No psychosis n No Rapid Cycling

35. Predictors: Poor Li Response [Good response to anticonvulsants] n Mixed mania (adolescents) n Irritable mania n Secondary mania (geriatric) n Psychotic Sx n Rapid Cycling n Depression-Mania-Euthymia n Comorbid substance abuse

36. Lithium: Common Side Effects n GI distress n Polyuria / polydipsia n Sedation-lethargy n Cognitive (memory, concentr, slow) n Wt. Gain n Poor coordination, tremor n Skin (worse acne)

37. Lithium: Serious SE n Renal –nephrogenic diabetes insipidus –tubular interstitial nephritis n Hypothyroidism n Psoriasis (onset or worsening) n Cardiac: EKG flat T, SA dysfx, tachicardia n Li Tox. N/V/D, delirium, ataxia, stupor –Tx dyalisis if >3.0, correct fluid- electrolites

38. Li: Interactions & Use Li levels: n  Li levels: diuretics,diuretics, NSAIDs (ASA, sulindac OK)NSAIDs (ASA, sulindac OK) ACE-inhibitorsACE-inhibitors n Starting: –Baseline Renal, TFT, HCG, EKG >40yo, UA, weight, medical Hx –300-600 mg/day divided doses –Levels in 5 days –Increase 900-1200 mg/day

39. Valproate NA

40. Valproate [Depakote] n FDA Sz ‘78, BP ‘96 n Effective antimanic, BP depression n Therapeutic effect 2 d. level 50-125 mg/l –oral loading 20-30 mg/kg/day n Mixed, rapid cycling, schizoaffective n Closed had injury, EEG abnormality

41. VPA: Common Side Effects n GI distress n Sedation n Liver transaminase elevation n Tremor n Hair loss n Weight gain-increased appetite n Thrombocitopenia (elders n Thrombocitopenia (elders) n Teratogenic: neural tube, cranio- facial

42. VPA: Less Common SE n Neutropenia n Coagulopathies,  platelet Function n endocrine abnormalities –Amenorrhea, policystic ovary? –Hypothyroidism –Hypocortisolemia

43. VPA: Rare Dangerous SE n Idiosincratic Hepatic Failure –lethargy, anorexia, N/V, jaund, bleed, edema –Risk: <3 y.o., many anticonvuls, Dev. Delay –Remote risk in >10yo psychiatric patients n Acute Hemorrhagic Pancreatitis - Eatly 6 month,serum amylase level - Eatly 6 month,serum amylase level n Bone Marrow Supression

44. VPA Use n Baseline: –Medical Hx, CBC-diff, LFT (LDH, SGOT, SGPT, bili, Alk. Phos, GGT), HCG, PT,PTT if bleeding abnorm, amylase? –Warn about hepatic, pancreatic, hematologic, teratogenic risks n n Monitor LFT, CBC

45. n Carbamazepine

46. Carbamazepine [Tegretol] n FDA Trig Neuralg ‘68, TLE ‘74 n Effective antimanic, Tx-refract Depr n Onset 2 wks, antidepr 4-6 wk n Ther. Levels: 4-12 n Half life decreases to 12-17 hrs –p450 liver induction

47. CBZ: Side Effects n Less cognitive probl than Li n Less Wt gain, hair loss, tremor than VPA n Neuro: Diplopia,blurr vision, fatigue/sed n GI: Naus/diarr, Dry mouth n Leukopenia, thrombocitopenia, rash n  LFT n Agranulocytosis (, Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenic

48. CBZ: Use n Baseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritin n Start low: –100-400 mg/day, –  100-200 mg every several days, bid (occasionally qd) n Follow CBC, LFT –clinical monitoring more effective than labs

49. And Others … And Others … n New Anticonvulsants Lamotrigine: ?Effective BP & depr, 10%rash, levels  by CBZ,  by VPALamotrigine: ?Effective BP & depr, 10%rash, levels  by CBZ,  by VPA Topiramate: wt loss, 1.5% renal stonesTopiramate: wt loss, 1.5% renal stones Gabapentin: effective?? (open reports, add- on)Gabapentin: effective?? (open reports, add- on) Tiagabine, Vigabatril CaTiagabine, Vigabatril Ca n Others: Ca-channel blockersCa-channel blockers Tamoxifen Prot Kinase-C inhibitorTamoxifen Prot Kinase-C inhibitor

50. THANKS FOR YOUR ATTENTION