1. Pharmacologic Considerations in the Treatment of Schizophrenia and Psychosis Presented by: Ann M. Hamer, PharmD, BCPP Date: 3/19/2015

2. Disclosures and Learning Objectives Learning Objectives – Be able to discuss attributes of traditional antipsychotics – Be able to identify/manage EPS – Be able to monitor for metabolic side effects Disclosures: Dr. Ann Hamer has nothing to disclose.

3. Traditional Antipsychotics GenericBrand ChlorpromazineThorazine ThioridazineMellaril MesoridazineSerentil LoxapineLoxitane MolindoneMoban PerphenazineTrilafon ThiothixeneNavane TrifluoperazineStelazine HaloperidolHaldol FluphenazineProlixin DroperidolInapsine ProchlorperazineCompazine

4. FGA—Pharmacology Characterized by strong antagonism of dopamine D2 receptors in both cortical and striatal areas Their dopamine D2 binding is highly correlated with clinical potency The nonspecific localization of their dopamine binding is consistent with their risk of movement disorders and prolactinemia.

5. FGA Overview FGAUsual Dose Range Initial Oral Dose Max Dose FormulationsT1/2Primary metabolism Enzyme Inhibition Chlorpromazine400-60025-200800Tab, IM302D6, gluc2D6 Fluphenazine2 -152-1012Tab, IM, LAI, soln332D6 Haloperidol2-202-1030Tab, IM, LAI, soln202D6, 3A4, gluc2D6, 3A4 Loxapine20-8020100Cap, soln, inhalation121A2, 2D6, 3A4, gluc None Perphenazine12-248-1624Tab9-122D6, 3A4, others 2D6 Pimozide8-101-210Tab551A2, 2D6, 3A4, others 2D6 Thiothixene10-205-1030Cap331A2, othersNone Thioridazine200-600150600Tab21-252D6, others2D6 Trifluoperazine15-204-1040Tab221A2None

6. Comparison of Receptor Antagonism

7. FGA Side Effect Comparison

8. EPS

11. Parkinsonism Drug-Induced Parkinsonism consists of six separate sets of motor disturbances: Rigidity Tremor Reduced facial expression/speech Impaired gait/posture Postural instability Bradykinesia

12. Dystonia Dystonia is a movement disorder in which muscles are contracted and contorted. Symptoms may co-occur with dyskinesia. Symptoms may result in the patient’s assuming abnormal postures or positions. Dystonia may be present at rest and/or during action. Dystonia is usually first seen during action. In more advanced cases, symptoms may appear both at rest and during action

13. Akathisia Akathisia is subjective feelings of inner restlessness with the urge to move, and/or objective movements such as: Restless movement of one extremity Fidgeting Changing position The inability to sit down for long periods Pacing back and forth or marching in place Terminology used by the patient to describe these feelings may often be confusing and even idiosyncratic.

14. Scales Good EPS Review Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004713/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004713/ AIMS Rating Scale: http://www.psychiatrictimes.com/clinical-scales- movement-disorders/clinical-scales-movement- disorders/aims-abnormal-involuntary-movement-scale http://www.psychiatrictimes.com/clinical-scales- movement-disorders/clinical-scales-movement- disorders/aims-abnormal-involuntary-movement-scale Simpson Angus Scale: http://cpnp.org/_docs/ed/movement- disorders/scale/msas.pdf http://cpnp.org/_docs/ed/movement- disorders/scale/msas.pdf Barnes Akathisia Rating Scale: http://keltymentalhealth.ca/sites/default/files/BARS.pdf http://keltymentalhealth.ca/sites/default/files/BARS.pdf

15. Tardive Dyskinesia

16. About 5% of patients maintained on conventional antipsychotics will develop tardive dyskinesia every year (i.e., about 25% of patients by 5 years) The risk of developing tardive dyskinesia in elderly subjects may be as high as 25% within the first year of exposure to conventional antipsychotics. If D2 receptor blockade is removed early enough, tardive dyskinesia may reverse. This reversal is theoretically due to a “resetting” of these D2 receptors by an appropriate decrease in the number or sensitivity of them in the nigrostriatal pathway once the antipsychotic drug that had been blocking these receptors is removed.

17. Tardive Dyskinesia However, after long-term treatment, the D2 receptors apparently cannot or do not reset back to normal, even when conventional antipsychotic drugs are discontinued. Patients who develop EPS early in treatment may be twice as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic risk factors for developing tardive dyskinesia with chronic treatment using a conventional antipsychotic.

18. Metabolic Syndrome in Psychiatrically Hospitalized Patients Prevalence of metabolic syndrome w/ prior antipsychotic treatment = 29.5% Syndrome strongly associated with being overweight, older age, long treatment exposure, schizoaffective diagnosis, more illness- episodes or hospitalizations, polypharmacy, and higher total daily CPZ-equivalent doses Metabolic syndrome risk greater among young (<26 years) AP- treated patients Prevalence of metabolic syndrome w/o prior antipsychotic treatment = 7.20% Hum. Psychopharmacol Clin Exp. 2012;27:521-26

19. Metabolic Syndrome in Psychiatrically Hospitalized Patients Hum. Psychopharmacol Clin Exp. 2012;27:521-26

20. Glucometabolic hormones and CV risk markers in AP-treated patients Key Points: Antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised CV risk profile with an insulin resistant-like pattern including beta cell hypersecretion and elevated glucose- dependent insulinotropic polypeptide levels The appetite-regulating hormone GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment J Clin Psych. 2014; 75:9c

21. Hyperglycemia and Diabetes Indirect effect Secondary to weight gain Obesity is a risk factor for insulin resistance (precursor for type 2 diabetes) Direct effect Hyperglycemia and diabetes without significant weight gain has been identified Inhibition of glucose transport into cells, increase cellular levels of glucose transporters leading to hyperglycemia and an increase in insulin release. Prolonged hyperinsulinemia can eventually lead to insulin resistance.

22. Proposed mechanisms (in addition to lifestyle factors): Increased caloric intake Slowed basal metabolic rate 5HT2C plays a role in regulating appetite Blockade may increase appetite (olanzapine, quetiapine, clozapine) Psychotropics with greater ability to block H-1 receptors often show greater weight gain potential Possibly by deactivating brain satiety centers and increasing hunger Weight gain associated with atypical antipsychotic agents generally occurs within the first few months after initiation and may not stabilize for more than a year CNS Neuroscience & Ther. 2012;18:57-63 Weight Gain

23. Antipsychotic Comparison

24. MedicationAmount of Weight Gain Olanzapine (Zyprexa)2.3 kg/month average 4.2 - 12 kg total Quetiapine (Seroquel)1.8 kg/month 4.1 - 5.6 kg total Risperidone (Risperdal)1.0 kg/month Ziprasidone (Geodon)0.8 kg/month Asenapine (Saphris)0.9kg over 3 weeks Iloperidone (Fanapt)1.5-2.1 kg total Aripiprazole (Abilify)0.5 - 0.9 kg total Clozapine (Clozaril)1.7 kg/month 2.4 - 31.3 kg total Lurasidone (Latuda)0.75 kg CNS Neuroscience & Ther. 2012;18:57-63 Weight Gain

25. Metabolic Monitoring Protocol for Adult Patients on AAPs BC Med Journal. 2012;54(2)

26. Metabolic Monitoring Protocol for Children on AAPs

27. Lifestyle intervention improves AP-user health Patients randomized to STRIDE intervention or usual care for 6 months. The intervention included an additional 6-month reinforcement phase. Assessments conducted at baseline, 6 and 12 months MeasurementInterventionUsual Care Weight loss of at least 5% of baseline weight 40%17% Fasting blood glucose106.3mg/dL baseline to 100.4mg/dl at 12 mon 106mg/dL baseline to 109.5mg/dL at 12 mon Medical hospitalization6.7%18.8% Psychiatric hospitalization  Similar  Am J Psychiatry 2014; doi: 10.1176/appi.ajp.2014.14020173 Lifestyle Interventions

28. Treatment Options for Metabolic Syndrome Selective monoamine transport inhibitors Bupropion, psychostimulants Insulin-promoting agents Metformin Specific anticonvulsants with anti-obesity effects Topiramate, zonisamide Other agents with effects on appetite and body weight Orlistat, amantadine, modafinil, memantine CNS Drugs. 2009;23(12)

29. Treatment Options for Metabolic Syndrome Bupropion Minor benefits in limiting weight gain associated with other psychotropic, but may reduce serum cholesterol levels Caution with sympathomimetics (e.g. phentermine) CNS Drugs. 2009;23(12)

30. Treatment Options for Metabolic Syndrome Metformin Best evidence to support use Can be combined with antipsychotics to manage hyperglycemia by increasing insulin sensitivity and decreasing leptin levels, ideally in combination with weight control Lifestyle modification combined with metformin appears to be more effective for weight loss than either tx alone Metformin alone is more effective than placebo in improving insulin sensitivity Metformin 250mg tid, along with lifestyle modification, to promote weight loss and decrease insulin resistance in patients who gain >10% of their pretreatment body weight on antipsychotic medications is recommended. CNS Drugs. 2009;23(12) JAMA. 2008;299:185-193

31. Beneficial Effects of Metformin JAMA. 2008;299:185-193

32. Treatment Options for Metabolic Syndrome Topiramate Can promote weight loss; add on strategy has shown 10-15 lb weight loss in case studies Adverse effects include perceptual and cognitive abnormalities, metabolic acidosis, renal stones and glaucoma Dose range from studies 100-400mg/day. Zonisamide Some ability to reduce weight Effects on mood stabilization are weak CNS Drugs. 2009;23(12) CNS Neuroscience & Ther. 2012;13:57-63

33. Treatment Options for Metabolic Syndrome Orlistat Pancreatic lipase antagonist that inhibits absorption of dietary fats May be effective at treating psychotropic-induced weight gain. May improve dyslipidemia parameters and improve glycemic control. Dose typically 120mg TID. Must take a MVT. Amantadine May limit weight gain with antipsychotics Dose typically 300mg/day. CNS Drugs. 2009;23(12) CNS Neuroscience & Ther. 2012;13:57-63

34. Treatment Options for Metabolic Syndrome Modafinil May produce weight loss with antipsychotics, possibly with less risk of inducing mania or worsening psychosis than standard psychostimulants such as amphetamines or methylphenidate Memantine Uncompetitive glutamic acid NMDA receptor antagonist May contribute to weight control in addition to its cognition-enhancing effects CNS Drugs. 2009;23(12)

35. TREATMENT INITIATION Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Discuss and record the side effects that the person is most willing to tolerate. Record the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects. At the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range Justify/record reasons for dosages outside of normal dosage range. Record the rationale for continuing, changing or stopping medication, and the effects of such changes. Trial of the medication at optimum dosage for at least 4–6 weeks. MONITORING AIMS Rating Scale: http://www.psychiatrictimes.com/clinical-scales-movement- disorders/clinical-scales-movement-disorders/aims-abnormal-involuntary- movement-scalehttp://www.psychiatrictimes.com/clinical-scales-movement- disorders/clinical-scales-movement-disorders/aims-abnormal-involuntary- movement-scale Simpson Angus Scale: http://cpnp.org/_docs/ed/movement- disorders/scale/msas.pdfhttp://cpnp.org/_docs/ed/movement- disorders/scale/msas.pdf Barnes Akathisia Rating Scale: http://keltymentalhealth.ca/sites/default/files/BARS.pdf http://keltymentalhealth.ca/sites/default/files/BARS.pdf

36. FGAUsual Dose Range (mg) Initial Oral Dose (mg) Max Dose (mg) FormulationsT1/2 (Hrs) Primary metabolism Enzyme Inhibition Haloperidol2-202-1030Tab, IM, LAI, soln202D6, 3A4, gluc2D6, 3A4 Perphenazine12-248-1624Tab9-122D6, 3A4, others2D6 Ariprazole10-15 30Tab, ODT, IM, LAI, soln75-942D6, 3A4None Asenapine10-201020SL tab241A2, glucNone Clozapine150-60025-50900Tab, ODT, susp121A2, others, gluc 2D6 (mod) Iloperidone12—24224*Tab18-262D6, others3A4 (mod) Lurasidone40-8040+160 ++Tab29-373A4None Olanzapine10-205-1030Tab, ODT, IM, LAI30-38CYP1A2, glucNone Paliperidone6-12612ER tab, LAI23Excreted mainly unchanged# None Quetiapine150-750 IR 400-800 ER 50750 IR 800 ER Tab, ER tab6-12CYP3A4None Risperidone2-61-28Tab, ODT, LAI, soln202D6 to paliperidone 2D6 Ziprasidone40-16040-80200Cap, IM7 oral 2-5IM 3A4None *12 (CYP2D6 poor metabolizer or with 2D6 inhibitor +20 (renal or hepatic insufficiency) ++80 (mod or severe renal insufficiency, mod hepatic insufficiency); 40 (severe hepatic insufficiency) #Dose reduction necessary in renal insufficiency

37. The End! Next Week: Welcome Back Dr. Betlinski