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Home , Cariprazine, Iloperidone, Lurasidone, Mesoridazine, Molindone, Ziprasidone

THE GROWING USE OF : AN UPDATE ON INDICATIONS, MONITORING AND COUNSELING

Karen Moeller, PharmD, BCPP Clinical Associate Professor The University of Kansas, School of Pharmacy Objectives

. Discuss common FDA indications and off- label uses for antipsychotics . Compare and contrast both typical and atypical antipsychotics’ side effects, drug interactions and monitoring parameters . Provide recommendations to patients, caregivers, and healthcare providers for managing side effects and monitoring parameters Case

.20 year old male presents with 2 new prescriptions

. (Zoloft) 50 mg PO QAM . (Seroquel) 100 mg PO QHS

What is his Diagnosis? Second Generation Antipsychotics (SGA) Indications / Bipolar Bipolar Irritability in Schizoaffective Depression adjunct Autism disorder Apripirazole# Aripiprazole Aripiprazole Asenapine Quetiapine Brexipiprazole Brexipiprazole Quetiapine ER Cariprazine # + Quetiapine Risperidone Lurasidone # Olanzapine * Quetiapine Risperidone Ziprasidone

* Also indicated for schizoaffective #Also approved for Bipolar Maintenance + Clozapine indicated for treatment resistant Schizophrenia and reducing Pharmacist Letter, Feb 2015 TCPR, June 2011, suicidal behaviors in schizophrenia and schizoaffective Schizophrenia Off-label uses for SGA

 Treatment-Refectory Depression

 Anxiety, PTSD, OCD

 Personality disorders (borderline personality disorder)

 ADHD

 Eating disorders

 Autism

 Substance abuse

AHRQ. Off-label use of Atypical Antipsychotics: An update. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf Antipsychotics 1st Generation 2nd Generation Thorazine® () Clozaril® (clozapine) Mellaril® () Risperdal® (risperidone)* Loxitane® () Geodon® (ziprasidone) Trilafon® () Seroquel® (quetiapine) Stelazine® (trifluperazine) Zyprexa® (olanzapine)* Navane® (thiothixene) Abilify® (aripiprazole)* Prolixin® ()* Invega® (paliperidone)* Haldol® () * Fanapt® (Iloperidone) Saphris® (Asenapine) Latuda® (Lurasidone) Rexulti® (Brexiprazole)

*Available in a Long Acting Injection Vraylar® (Cariprazine) Pharmacologic Properties

First Generation Antipsychotics Second Generation Antipsychotics (FGA) or Typicals (SGA) or Atypicals

Dopamine (D2) (D2) / (5-HT2A) Muscarinic Muscarinic Alpha Alpha Adrenergic Histamine

Receptor Effect by blocking the receptor Dopamine Mesolimbic – relief of positive symptoms Nigrostriatal – movement disorders, EPS Tuberoinfundibular – hyperprolactinemia Mesocortical – increase negative symptoms

Muscarinic side effects Alpha Adrenergic Orthostasis, Histamine , Sedation Typical Antipsychotics

Agent (MG) chlorpromazine (Thorazine) 100 Low thioridazine (Mellaril) 100 potency (Serentil) 50 loxapine (Loxitane) 10 (Moban) 10 perphenazine (Trilafon) 8 (Stelazine) 5 thiothixene (Navane) 4 High fluphenazine (Prolixin) 2 Potency haloperidol (Haldol) 2 Atypical Antipsychotics (SGA)

®  Asenapine (Saphris ) ®  Aripiprazole (Abilify )* ®  Clozapine (Clozaril )*  (Rexulti®) ®  Iloperidone (Fanapt )  Cariprazine (Vraylar®) ®  Lurasidone (Latuda ) ®  Olanzapine (Zyprexa )* ®  Paliperidone (Invega ) ®  Risperidone(Risperdal )* ®  Quetiapine(Seroquel )* ®  Ziprasidone (Geodon )*

* Generic formulation Oral disintegrating tablets ≠ sublingual

Long acting Injection (e.g. Monthly) Immediately Release Injection (e.g. work right away!) Dosage Formulations Tablet/ Oral Injectable Long acting Capsule Disintegrating (IM) Injectable Rapid Acting Aripiprazole* Tablet Yes Yes Yes Asenapine SL tablet Brexpiprazole Tablet Cariprazine Capsule Clozapine* Tablet Yes Iloperidone Tablet Lurasidone Tablet Olanzapine* Tablet Yes Yes Yes Quetiapine* Tablet Risperidone* Tablet Yes Yes Paliperidone Capsule Yes Ziprasidone* Capsule Yes * Generic formulations General Comparison

FGA > SGA SGA> FGA

• Extrapyramidal • Weight gain Side Effects • Diabetes • Neuroleptic • Hyperlipidemia malignant syndrome Extrapyramidal Side Effects

Dystonia 's Severe Blank facial Restlessness expression Muscle Can’t sit still Involuntary Spasm Rigidity movement Pacing Tremors Shuffling Gait Tx. Monitor and Tx. prevent -Tx: Benztropine or Diphendydramine Main Side Effects for SGA

. Weight gain . abnormalities . Glucose intolerance / Diabetes

. Weight gain of up to 25-50 pounds is common with clozapine, olanzapine

. Agents with minimal weight gain – aripiprazole, lurasidone, ziprasidone Overall Side Effects of Antipsychotics

. Cardiovascular side effects  QTc prolongation  Consider baseline EKG in all patients

. Increase Prolactin  Galactorrhea, gynecomastia, amenorrhea  FGA and risperidone/paliperidone

. Drowsiness  Some are more than other  Usually resolves in a few week Overall Side Effects of Antipsychotic

. Anticholinergic Side Effects  Dry Mouth  Constipation  Urinary retention  Blurred vision  Increase heart rate  Decreased sweating – can be deadly

. Weight Gain

.

. Typical Antipsychotics Comparison

Agent Sedation Anticholin Cardiac EPS ergic Orthostasis chlorpromazine (Thorazine) High High High Low thioridazine (Mellaril) mesoridazine (Serentil) loxapine (Loxitane) molindone (Moban) perphenazine (Trilafon) trifluoperazine (Stelazine) thiothixene (Navane) fluphenazine (Prolixin) haloperidol (Haldol) Very low Very low Very low Very High Atypical Comparison High Risk Low Risk EPS/TD Risperidone Clozapine Paliperidone Quetiapine Akathisias Aripiprazole Clozapine Lurasidone Quetiapine Weight Gain Clozapine Aripiprazole, lurasidone, Glucose intolerance Olanzapine ziprasidone Lipid abnormalities Hyperprolactinemia Risperidone Aripiprazole Paliperidone QTc prolongations Ziprasidone Aripiprazole Iloperidone Olanzapine Orthostatic Clozapine Hypotension Iloperidone Sedation Clozapine Risperidone Quetiapine Iloperidone Lurasidone Pharmacist Letter, Feb 2015; TCPR, June 2011, Schizophrenia Specific adverse effects

. Aripiprazole – impulse control disorder . Asenapine – severe allergic rx (anaphylaxis, , rash, etc.) . Clozapine – agranulocytosis, myocarditis . Olanzapine long acting injection  Sedation- Delirium syndrome . Severe skin reaction  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)  Ziprasidone and Olanzapine Black Box Warnings

. Increased Mortality in Elderly Patients with Dementia Related

 Causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

 All antipsychotics . Increase suicidally in adolescents and young adults < 25 years old

 Antipsychotics with bipolar depression or adjunct depression indications Monitoring

Baseline Follow-up Blood Pressure/ X Every visit Orthostatic hypotension Weight X Monthly for 1st 3 months, then quarterly Waist Circumference X Annually Glucose intolerance X At 3 months, then annually (if normal) Hyperlipidemia X At 3 months, then annually (if normal) Prolactin X Assess through interview at each visit; if symptoms present – order prolactin level EPS Akathisia X Every visit (Barnes Akathisia Scale) Parkinsonism X Every visit (Simpson Angus Scale) Tardive Dyskinesia X Every 3 month – FGA; Every 6 months SGA (AIMS or Discus rating scale) EKG X Consider cardiac risk factors

Schizophrenia treatment guidelines 2010; Diabetes Care, 27(2), 2004 Second Generation Antipsychotics (SGA) Indications Schizophrenia/ Bipolar Mania Bipolar Depression Irritability in Schizoaffective Depression adjunct Autism disorder Aripiprazole Apripirazole# Lurasidone Apripirazole Apripirazole Asenapine Asenapine Quetiapine Brexipiprazole Risperidone Brexipiprazole Cariprazine Quetiapine ER Cariprazine Olanzapine# Clozapine+ Quetiapine Iloperidone Risperidone Lurasidone Ziprasidone# Olanzapine Paliperidone* Quetiapine Risperidone Ziprasidone

* Also indicated for schizoaffective #Also approved for Bipolar Maintenance + Clozapine indicated for treatment resistant Schizophrenia and reducing Pharmacist Letter, Feb 2015 TCPR, June 2011, suicidal behaviors in schizophrenia and schizoaffective Schizophrenia SGA: D2 / 5-HT2a Antagonist

PO dosing CYP 450 Comments Metabolism Asenapine 10 – 20 mg 1A2 - Sublingual tablet (Saphris) - No food or drink 10 minutes after dose - Odd taste - DO NOT SWALLOW - Akathisia and - Unit dose packing may make it hard for people to open Iloperidone 12-24 mg 3A4 - Slow titration due to orthostatic (Fanapt) 2D6 hypotension -Significant QTc prolongation Lurasidone 40-160 mg 3A4 -Contraindicated with strong CYP3A4 (Latuda) inhibitors and inducers - Must take with 350 calories of food - Akathisia (recommended to take at night to minimize side effect) SGA: D2 / 5-HT2a Antagonist PO CYP 450 Comments dosing/day Metabolism Olanzapine 10 – 20 mg 1A2 -High weight gain (Zyprexa) -Long acting injection - must monitor for 3 hrs (Sedation/delirium syndrome); restricted distribution -Avoid parental benzos with rapid acting IM Paliperidone 3-12 mg N/A - Active metabolite of risperidone (Invega) - Ghost tablets will appear in stool - Long acting monthly and three-month injection - May increase prolactin - Good for patients with hepatic dysfunction Risperidone 1-6 mg 2D6 - May increase prolactin (Risperdal) - Every two week long-acting injection - Dosages greater than 6 mg increase EPS Quetiapine 150- 800 3A4 - Sedation (Seroquel) mg - XR take with light meal or snack Ziprasidone 40-160 mg 3A4 - QT prolongation (Geodon - Take with food Partial D2 agonist / 5-HT2a Antagonist

The may help stabilize the dopamine system without causing hypo conditions PO dosing CYP 450 Comments Metabolism Aripiprazole 5-15 mg 3A4 Adjunctive depression (Abilify) 2D6 Akathisia Considered the most “activating” SGA Brexipiprazole 1-4 mg 3A4 Adjunctive depression (Rexulti) 2D6 Similar to aripiprazole Possibly less activating Cariprazine 1.5 – 6 mg 3A4 Similar to aripiprazole (Vraylar) 2D6 Possibly less activating Not recommend to be use with 3A4 inducers

dosing recommendations with inhibitors and inducers Clozapine (Clozaril)

. Reserved for treatment resistant patients . Reduces the risk of in Schizophrenia . Many Side effects  Agranulocytosis (REMS program)  Seizures at doses > 600 mg/day  Orthostatic hypotension – must titrate slowly  Myocarditis  Sedation  Weight gain, diabetes  Sialorrhea

. Must me a registered pharmacy to dispense . Monitor ANC weekly x 6 months, then every 2 weeks X 6 months, then monthly . www.clozapinerems.com Atypical Drug Interactions Drug Major Increase AP Decrease AP CYP450 Concentration Concentration Metabolic Enzyme Aripiprazole 3A4, Protease inhibitors (PI), , 2D6 , Clozapine 1A2 , , Cigarette Smoking 2C19, 2D6, paroxetine, fluoxetine 3A4(minor) Lurasidone 3A4 PI, ketoconazole, clarithromycin, Rifampin, diltiazem Carbamazepine Olanzapine 1A2 Fluvoxamine, ciprofloxacin Cigarette Smoking Risperidone 2D6 Paroxetine, fluoxetine Quetiapine 3A4 PI, clarithromycin, ketoconazole carbamazepine Ziprasidone 3A4 PI, clarithromycin, ketoconazole carbamazepine Other Drug interactions

QTc prolonging drugs

 Antiarrhythmics  Stimulants

 Enhance dopamine release  Flecainide  Increase psychosis, mania 

 Antibiotics

 Clarithromycin, Erythromycin 

 Fluconazole  Levodopa

 Quinolones  If patient has Parkinson's and psychosis, consider a  Others weak dopamine blocker  (e.g. quetiapine)

Choice of Antipsychotic . Need to consider  History of prior response

 Cost/ability to obtain medication

 Matching patient-specific characteristics with adverse effect profile of selected agent

 Efficacy

 Side effects Efficacy: Are SGA better than FGA

. Clozapine is considered the most effective antipsychotic . Controversial topic . Most guidelines recommend SGA before FGA . SGA are often viewed as safer than SGA

. Landmark Studies  Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).  Cost Utility of the latest Antipsychotic Drugs in Schizophrenia (CUtLASS) Lieberman JA, et al. N Engl J Med 2005;353:1209-23 Jones RB, et al. Arch Gen Psychiatry. 2006; 62 (10):1079-87 CATIE and CUtLASS: Key findings CATIE CUtLASS

1493 patients - FGA vs SGA • 277 patients, FGA vs SGA Primary endpoint: all-cause • No difference in QOL discontinuation • Significant improvement in Pts stayed on olanzapine symptoms with clozapine longer than other AP over other SGA Olanzapine-highest rates of metabolic abnormalities No difference in QOL and cognitive symptoms

Conclusion: SGA and FGA are similar in effectiveness, compliance and QOL Controversies with Antipsychotic

. Off label uses

. Multiple Antipsychotics

. High dose Antipsychotics

. Use in children Off-label uses for SGA

 Treatment-Refectory Depression

 Insomnia

 Anxiety, PTSD, OCD

 Personality disorders (borderline personality disorder)

 ADHD

 Dementia

 Eating disorders

 Autism

 Substance abuse

 Nausea / Vomiting AHRQ. Off-label use of Atypical Antipsychotics: An update. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf Evidence for off-label antipsychotics use

Promising Lack of Studies/ Efficacy . General anxiety disorder . Insomnia - quetiapine . Substance abuse . OCD – risperidone . Eating disorders ADHD Modest/mixed . . PTSD- risperidone . Personality disorders . Dementia – aripiprazole, olanzapine, risperidone

AHRQ. Off-label use of Atypical Antipsychotics: An update. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf Antipsychotic Polypharmacy

. Use of two or more antipsychotics together  Common practice  Controlled trials do not support combined use  Increased side effects than efficacy  Increase mortality  Short term use during AP switch may be appropriate  Last-line opinion in guidelines  Rationale for use of AP polypharmacy must be documented on discharge from psychiatric hospitalizations

Current Psychiatry July 2008 High dose antipsychotics

. Rationale for use  Patients in clinical trials are not “usual patients”  Treatment response is consider ~ 20% symptoms reduction in clinical trials  Up to 30% of patients are treatment refectory  Allows for monotherapy versus polypharmacy . Common agents dosed above the max  Aripiprazole, Olanzapine, Quetiapine, Ziprasidone  Mixed evidence on efficacy

PCN Frontier Review 2015 Antipsychotics in Children

. 2 – 4 fold increase in last 15 years . Risk factors: Minorities, Medicaid enrollees, foster care . Efficacy in psychosis, , autism . Lack of efficacy in behavior or ADHD . Long term effects are unclear  Metabolic effects may be higher than adults  Hyperprolactinemia effects?  EPS tends to be higher  Cardiovascular safety – limited data

Schenider, C et al. Journal of Psychopharmacology 28(7): 2014 Five DON’T to prescribing AP

Don’t  Prescribe AP to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring  Routinely prescribe 2 or more antipsychotics concurrently  Use antipsychotics as 1st choice to treat behavioral and psychological symptoms of depression  Routinely prescribe antipsychotic as 1st line intervention for insomnia in adults  Routinely prescribe an AP medication to treat behavioral and emotional symptoms of childhood mental disorders in the absence of approved or evidence supported indications http://www.choosingwisely.org/wp-content/uploads/2015/02/APA-Choosing-Wisely-List.pdf Final Thoughts Treatment Adherence

. Very low in psychiatric patients

. 70-80% of patients admitted to the hospital stopped their medication

Remind patients that adhering to treatment/ medications helps to prevent relapse Treatment Success Treatment Side Failure Effects

Non Adherence Complex Denial of Dosing illness regimen

Cost Family How can pharmacist help?

. Counseling points  Side effects often go away  Some side effects can be treated  What to do with specific SE  Medication take time to work. Be patient  You may still have symptoms while on the medication but your symptoms should be diminished  Long term treatment is necessary – even when they feel better  Give them tools to remember to take their medications  Pill box; bubble packs Summary

. Antipsychotics are useful for many indications . SGA have significant metabolic effects and patients should be monitored annually . Tardive dyskensia should be assessed every 3 months for FGA and every 6 months for SGA . Important to make sure that safe prescribing practices are occurring (remember the 5 don’t) . Important that patients understand the value of their medication . Resources for pharmacists  National Alliance on Mental illness (NAMI) www.nami.org  College of psychiatric and neurologic pharmacists (CPNP) www.cpnp.org