New Psychiatric Medications Knowledge is Power Gregory T. Bogart, Pharm.D., BCPP Clinical Psychiatric Pharmacist University of Maryland, School of Pharmacy Springfield Hospital Center Sykesville, MD Jennifer Miller, Pharm.D., BCPP Wilkes-Barre VAMC Wilkes-Barre, PA

Objectives Discuss clinical indications of new and emerging psychiatric medications Compare and contrast the role of new medications with existing medications Implement strategies to learn about new psychiatric medications

Antipsychotics

Oral Antipsychotics 1st Generation 2nd Generation Thorazine® (chlorpromazine) Clozaril® (clozapine) Haldol® (haloperidol) Risperdal® (risperidone) Prolixin® (fluphenazine) Geodon® (ziprasidone) Stelazine® (trifluperazine) Seroquel® (quetiapine) Trilafon® (perphenazine) Zyprexa® (olanzapine) Navane® (thiothixene) Abilify® (aripipirazole) Loxitane® (loxapine) Invega® (paliperidone) Mellaril® (thioridazine) Fanapt® (Iloperidone) Saphris® (Asenapine) Latuda® (Lurasidone)

Long Acting Injectable Antipsychotics 1st Generation 2nd Generation Haloperidol decanoate Risperdal Consta® Fluphenazine decanoate Invega Sustenna® Zyprexa Relprevv® Abilify Maintena®

New Oral Antipsychotics

Iloperidone FDA approved in 2009 Indicated for the treatment of schizophrenia in adults Mechanism of action – primarily dopamine (D2) antagonism with some serotonin (5HT2) antagonism Fanapt® [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014.

Iloperidone - Efficacy 6-week trial with placebo and risperidone showed superiority over placebo and comparable efficacy of risperidone at 6 weeks 4-week trial with placebo and ziprasidone found superiority over placebo and similar efficacy to ziprasidone at 4 weeks Fanapt® [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014.

Iloperidone – Possible Side Effects Metabolic changes – weight gain, ↑cholesterol Not as significant as other 2nd gen drugs Extrapyramidal symptoms (EPS) QTc prolongation Orthostasis, low blood pressure, and dizziness Rarer side effects – priapism, seizure, agranulocytosis

Iloperidone - Dosing Starting dose 1 mg twice daily Target dosage range 6-12 mg twice daily Increase by no more than 2 mg twice daily every day until target range Slow titration due to increased risk of low blood pressure, dizziness, and falls Maximum dose of 12 mg twice daily Fanapt® [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014.

Iloperidone – Role in therapy New second generation antipsychotic choice Lower risk for EPS and weight gain than other options Higher risk of orthostasis, dizziness, and falls especially during the initial titration phase Slow titration phase and twice daily dosing may be difficult for some patients to work with

Asenapine FDA approved in 2009 Indications Treatment of schizophrenia in adults Acute treatment, either as monotherapy or adjunctive, or manic or mixed episodes of bipolar I disorder in adults Mechanism of action thought to be a combination of dopamine D2 and serotonin 5HT2 receptor blockade Saphris® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine – Efficacy in Schizophrenia Short term studies A 6-week trial comparing asenapine to placebo showed superior efficacy asenapine at 6 weeks A 6-week trial comparing asenapine to placebo and haloperidol showed asenapine to be superior to placebo, but not haloperidol. It also showed no difference between 5 mg twice daily and 10 mg twice daily dosing A 6-weeks trial comparing asenapine to placebo olanzapine showed that asenapine and placebo failed to separate and that olanzapine was superior to both Saphris® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine – Efficacy in Bipolar I Disorder Monotherapy Two 3-week trials of asenapine and placebo showed that asenapine was superior to placebo for controlling acute mania Adjunctive A 12-week trial of asenapine or placebo added to lithium or valproic acid showed asenapine was superior to placebo at reducing manic symptoms at 3 weeks Saphris® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine – Possible Side Effects Metabolic changes and weight gain Not as significant as other 2nd gen drugs EPS – higher rates of akathisia QTc prolongation Sedation or somnolence Headache Rarer side effects – agranulocytosis, seizures, and orthostasis Saphris® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine - Dosing Asenapine is supplied as sublingual tablets Do not swallow tablets Dissolve under the tongue No food or drink for 10 minutes after dose Indication Starting Dose Dosage Range Maximum Schizophrenia 5 mg twice daily 5-10 mg twice daily 10 mg twice daily Acute Bipolar I Saphris® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine – Role in Therapy Can be utilized in both schizophrenia and bipolar disorder Unique sublingual administration Relatively small metabolic side effects Higher rates of sedation and akathisia than other agents

Lurasidone FDA approved in 2010 Indications Treatment of schizophrenia in adults Treatment of depressive episodes in bipolar disorder in adults as both monotherapy and adjunctive therapy Mechanism of action thought to be a combination of dopamine D2 and serotonin 5HT2 receptor blockade Latuda® [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone – Efficacy in Schizophrenia Five total trials, all 6 weeks long Two trials of fixed dose lurasidone vs. placebo showed superior efficacy of lurasidone One trial of 40 mg, 80 mg, and 120 mg lurasidone vs. placebo showed that only the 80 mg dose was superior to placebo One trial of lurasidone, olanzapine and placebo showed that both lurasidone and olanzapine were superior to placebo One trial of lurasidone, quetiapine ER, and placebo showed both lurasidone and quetiapine ER were superior to placebo Latuda® [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone – Efficacy in Bipolar Depression As monotherapy A 6-week trial vs placebo for symptom reduction in bipolar depression showed that both doses of lurasidone studied were superior to placebo at 6 weeks As an adjunct A 6-week trial of patients who were still symptomatic on lithium or valproic acid were given placebo or lurasidone. At 6 weeks, there was a superior symptom reduction in the lurasidone group vs. the placebo group Latuda® [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone – Possible Side Effects Metabolic changes and weight gain Possibly the most weight and metabolic neutral EPS – akathisia more common than others QTc prolongation Sedation or somnolence Nausea and vomiting Rarer side effects – agranulocytosis, seizures, and orthostasis Latuda® [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone - Dosing For schizophrenia, starting dose is 40 mg/day with a range of 40-160 mg/day For bipolar depression, starting dose is 20 mg/day with a range of 20-120 mg/day All doses should be taken with a meal of at least 350 calories to improve absorption Dosing is recommended in the evening due to the possibility of sedation and somnolence Latuda® [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone – Role in Therapy Can be utilized in schizophrenia and bipolar depression Has a very favorable long-term metabolic profile Once daily dosing is most patient friendly Appears to be the most rigorously studied of the newer agents

Long Acting Injections (LAIs)

Rationale LAIs are options to improve compliance Less frequent administration than oral agents Doses converted from stable oral regimens Guaranteed drug level in the body post-injection Improved clinician contact

Available Options 1st Generation 2nd Generation Haloperidol decanoate Risperdal Consta® Fluphenazine decanoate Invega Sustenna® Zyprexa Relprevv® Abilify Maintena®

Zyprexa Relprevv® FDA approved in 2009 Long acting intramuscular injection of olanzapine intended for gluteal injection only Indicated for the treatment of schizophrenia Designed to be initiated after a stable regimen of olanzapine is established Zyprexa Relprevv® [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Zyprexa Relprevv® - Dosing Oral dose of olanzapine Dose of Zyprexa Relprevv® for the first 8 weeks Maintenance dose of Zyprexa Relprevv®after 8 weeks 10 mg/day 210 mg every 2 weeks or 405 mg every 4 weeks 150 mg every 2 weeks or 300 mg every 4 weeks 15 mg/day 300 mg every 2 weeks 20 mg/day Note: No oral medication overlap is required Zyprexa Relprevv® [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Adverse Events Adverse events are similar to oral olanzapine Metabolic syndrome and weight gain Sedation Orthostasis and dizziness Also has Post-Injection Delirium/Sedation Syndrome (PDSS) risk Zyprexa Relprevv® [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

PDSS Signs and symptoms associated with olanzapine overdose Sedation and/or delirium possibly leading to coma Dizziness, confusion, disorientation, slurred speech, weakness, difficulty walking Occurred in <0.1% of all injections, 2% of all patients treated in 46 months Most patients recovered with supportive care within 72 hours Lead to the creation of a REMS program Zyprexa Relprevv® [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Zyprexa Relprevv® REMS Prescriber, patient, facility, and pharmacy must all register Medication cannot be dispensed directly to patient Medication must be administered in a registered facility with access to emergency response services Patients must be observed by a healthcare worker for at least 3 hours after injection for signs of PDSS Patients may not leave the facility by themselves Patients should not drive the remainder of the day Zyprexa Relprevv® [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Abilify Maintena® FDA approved in 2013 Long acting intramuscular injection of aripiprazole intended for gluteal injection only Indicated for the treatment of schizophrenia Designed to be initiated after a stable regimen of aripiprazole is established Abilify Maintena® [package insert]. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

Abilify Maintena® Dosing Recommended starting dose in 400 mg monthly Continuation of oral aripiprazole 10-20 mg/day is necessary for 14 days after initial injection Maintenance dose is also 400 mg monthly Dose reduction to 300 mg can be used if 400 mg dose is intolerable Abilify Maintena® [package insert]. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

Adverse Events Very similar to oral aripiprazole Slight metabolic changes Some EPS – mostly akathisia Anxiety Headache Orthostasis Abilify Maintena® [package insert]. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

Antidepressants

Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Celexa® (citalopram) Cymbalta® (duloxetine) Lexapro® (escitalopram) Effexor® (venlafaxine) Prozac® (fluoxetine) Pristiq® (desvenlafaxine) Paxil® (paroxetine) Savella® (milnacipran) Luvox® (fluvoxamine) Fetzima® (levomilnacipran) Zoloft® (sertraline) Brintellix® (vortioxetine) Viibryd® (vilazodone) Also paxil cr, luvox cr and effexor xr

Antidepressants Tricyclic Antidepressants Atypical Antidepressants Monoamine Oxidase Inhibitors (MAOIs) Elavil® (amitriptyline) Wellbutrin® (bupropion) Nardil® (phenelzine) Anafranil® (clomipramine) Remeron® (mirtazapine) Parnate® (tranylcypromine) Tofranil® (imipramine) Serzone® (nefazodone) Eldepryl® (selegiline) Pamelor® (nortriptyline) Desyrel® (trazodone) Marplan® (isocarboxazid)* Norpramin® (desipramine) Sinequan® (doxepin) Vivactil® (protriptyline) Doxepin has greatest AH

New Oral ANTIDEPRESSANTS

Viibryd® (Vilazodone) Year Approved 2011 Indication Major Depressive Disorder Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012. Image from www.viibryd.com

Viibryd® (Vilazodone) Mechanism of Action Selective Serotonin Reuptake Inhibitor (SSRI) Activity at serotonin receptor Effectiveness Decreased depressive symptoms in 8 week trials better than placebo Partial 5HT-1A agonist Decreased depressive symptoms in two 8 week RCT trials of outpatients Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd® (Vilazodone) Safety Contraindications Use with MAOI Warnings Serotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuation Suicidality – In children, teenagers & young adults <= 24 y/o. Monitored for change in mood, thoughts, behaviors, actions or feelings and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during initial few months and dose changes. Daily observation by family & caregivers. SS – GI upset, agitation, hallucinations, delirium, and coma, autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea Seizure – not studied Hyponatremia & bleed – no cases but with other SSRIs – headache, weakness, confusion Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd® (Vilazodone) Safety Drug interactions Adverse Effects Nausea, diarrhea, dizziness, sleep disturbance, sexual dysfunction DI - 3A4 substrate, NSAIDs, Serotonergic meds/MAOIs Transient vs chronic Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd® (Vilazodone) Considerations for Use Take with food Dose titration No dose adjustment for age Pregnancy, nursing, or children Medication Role No clear advantage over SSRIs for depression W/ food – or decrease [] by 50% Titration - 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then an increase to 40 mg once daily No human data in preg, lactation or children Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Fetzima® (Levomilnacipran) Year Approved 2013 Indication Major Depressive Disorder More active enantiomer of milnaciprin (approved in 2009 for fibromyalgia) More selective for NE - Tx norepinephrine deficiency symptoms - decreased concentration, lassitude, mental and physical slowing, and decreased self-care.3,4 Some authors claim that individual patients could experience improvement in their social and occupational functioning in addition to improvement in the core symptoms of depression.5 Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013. Image from www.fetzima.com

Fetzima® (Levomilnacipran) Mechanism of Action Serotonin Norepinephrine Reuptake Inhibitor (SNRI) Effectiveness Decreased depressive symptoms in 8 week trials better than placebo Decreased depressive symptoms in three 8 week RCT trials of outpatients (40-120mg all doses superior) Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima® (Levomilnacipran) Safety Contraindications Allergic reaction, uncontrolled narrow-angle glaucoma, use with MAOI Warnings Serotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuation Warnings not based on evidence directly from levomilnacipran Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima® (Levomilnacipran) Safety Warnings (cont.) High blood pressure & heart rate, narrow-angle glaucoma, urinary hesitation or retention Drug interactions Adverse Effects Nausea, vomiting, constipation, sweating, increased blood pressure & heart rate, sexual dysfunction These warnings are based off data with levomilnacipran Strong 3A4 inhibitors like ketoconazole; avoid doses > 80mg/day; other medications which can increase BP & HR No dose adjustment needed for 3A4 inducers (Other: serotonergic/MAOIs, drugs increasing BP & HR, drugs affecting homeostasis – NSAIDs) Alcohol accelerated drug release from ER capsules Urinary hestitation & erectile dysfunction were dose related Although BP avg increase was only 3mmHg and HR was 7 bpm…trials excluded patients with significant CVD Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima® (Levomilnacipran) Considerations for Use Adjust dose for kidney impairment No dose adjustment for age Pregnancy, nursing, children Medication Role No clear advantage over SNRIs for depression No established effectiveness for fibromyalgia/ pain Pregnancy – decreased birth weight and possibly mortality in rats at supratherapeutic doses. Nursing – present in rat milk Children – no data Once daily dosing; ER tablet – do not split, etc Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.2 NNT 6; NNT VNL was 8 Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Brintellix® (Vortioxetine) Year Approved 2013 Indication Major Depressive Disorder Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014. Image from us.brintellix.com

Brintellix® (Vortioxetine) Mechanism of Action SSRI Activity at various serotonin receptors Effectiveness Decreased depressive symptoms in 6-8 week trials & longer time to recurrent depression in 64 week trial better than placebo 5HT3, 1D, 7 antagonism, 1A agonism, 1B partial agonist 5mg not effective in 6-8 week trials; took 2 weeks for initial effect and about 4 weeks for full effect Short term studies with outpts and were RCTs; Longterm study was open label with inpts and outpts Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix® (Vortioxetine) Safety Contraindications Allergic reaction, use with MAOI Warnings Serotonin syndrome, suicidality, mania, bleed, low sodium Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix® (Vortioxetine) Safety Drug interactions Adverse Effects Nausea, vomiting, constipation, dizziness, sexual dysfunction The maximum recommended dose of BRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of BRINTELLIX by one half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. Consider increasing the dose of BRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. -------------------------------------------------------------------------- Nausea was dose related and resolved after ~ 2 weeks No changes in weight or vital signs observed in pre-marketing trials Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix® (Vortioxetine) Considerations for Use Avoid in severe liver impairment No dose adjustment for age Pregnancy, nursing, children Medication Role No clear advantage over SSRIs for depression -10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses -Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of BRINTELLIX 15 mg/day or 20 mg/day Developmental delays in rats; no adequate human trials; present in rat milk; no studies in peds; no dose adj needed for geri (like other 2 ad’s) No dose adj for geri, race, ethnicity, (like other ad’s) up to severe renal dys, but unknown with severe hepatic disease Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Miscellaneous Medications

Miscellaneous Medications Methyl – 2012 Zolpid - 2011 Images taken from www.quillivantxr.com; www.intermezzorx.com; www.zubsolv.com

Learning Strategies

Resources NAMI.org FDA.gov Drugs.com MedlinePlus Narsad.org Medication fact sheets FDA.gov Drugs.com MedlinePlus Narsad.org Seek info on the internet; talk with health care providers! NAMI – inform yourself at bottom left – about medications at bottom left FDA- a lot of links, but search function works well The site features FDA Consumer Update articles, videos, and slideshows.  Site users can get valuable access to information about new drug approvals, use a drug interaction checker to check the compatibility of using two drugs at the same time, identify drugs from their tablet and capsule markings, ask questions to other site users, join support groups, and much more. Site users can also subscribe to the Drugs.com electronic newsletter and also sign up to receive e-mail alerts from FDA's MedWatch.     MedlinePlus also offers a wide range of information about prescription drugs and dietary supplements.  Additionally, this site provides information about many medical conditions and health issues treated with prescription medications.  The site also provides a medical encyclopedia, a medical dictionary, an aid to find local health-related resources, and current health news and press announcements.  The site can be used on over 40 languages.  Narsad.org – “ask an expert”; blurbs about research and can search by mental illness National Alliance for Research on Schizophrenia and Depression – the Brain and Behavior Research Foundation