New Psychiatric MedicationsKnowledge is Power

Gregory T. Bogart, Pharm.D., BCPPClinical Psychiatric PharmacistUniversity of Maryland, School of Pharmacy Springfield Hospital Center Sykesville, MD

Jennifer Miller, Pharm.D., BCPPClinical Psychiatric PharmacistWilkes-Barre VAMCWilkes-Barre, PA

ObjectivesDiscuss clinical indications of new and emerging psychiatric medications Compare and contrast the role of new medications with existing medicationsImplement strategies to learn about new psychiatric medications

Antipsychotics

Oral Antipsychotics

1st Generation2nd GenerationThorazine (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 Generation2nd GenerationHaloperidol decanoateRisperdal ConstaFluphenazine decanoateInvega SustennaZyprexa RelprevvAbilify Maintena

NEW ORAL ANTIPSYCHOTICS

Iloperidone = Fanapt

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

Iloperidone - Efficacy6-week trial with placebo and risperidone showed superiority over placebo and comparable efficacy of risperidone at 6 weeks4-week trial with placebo and ziprasidone found superiority over placebo and similar efficacy to ziprasidone at 4 weeksFanapt [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014.

Iloperidone Possible Side EffectsMetabolic changes weight gain, cholesterolNot as significant as other 2nd gen drugsExtrapyramidal symptoms (EPS)QTc prolongationOrthostasis, low blood pressure, and dizzinessRarer side effects priapism, seizure, agranulocytosis

Iloperidone - DosingStarting dose 1 mg twice dailyTarget dosage range 6-12 mg twice dailyIncrease by no more than 2 mg twice daily every day until target rangeSlow titration due to increased risk of low blood pressure, dizziness, and fallsMaximum dose of 12 mg twice daily Fanapt [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014.

Iloperidone Role in therapyNew second generation antipsychotic choiceLower risk for EPS and weight gain than other optionsHigher risk of orthostasis, dizziness, and falls especially during the initial titration phaseSlow titration phase and twice daily dosing may be difficult for some patients to work with

Asenapine=saphrisFDA approved in 2009IndicationsTreatment of schizophrenia in adultsAcute treatment, either as monotherapy or adjunctive, or manic or mixed episodes of bipolar I disorder in adultsMechanism of action thought to be a combination of dopamine D2 and serotonin 5HT2 receptor blockadeSaphris [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine Efficacy in SchizophreniaShort term studiesA 6-week trial comparing asenapine to placebo showed superior efficacy asenapine at 6 weeksA 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 dosingA 6-weeks trial comparing asenapine to placebo olanzapine showed that asenapine and placebo failed to separate and that olanzapine was superior to bothSaphris [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine Efficacy in Bipolar I DisorderMonotherapyTwo 3-week trials of asenapine and placebo showed that asenapine was superior to placebo for controlling acute maniaAdjunctiveA 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 weeksSaphris [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine Possible Side EffectsMetabolic changes and weight gainNot as significant as other 2nd gen drugsEPS higher rates of akathisiaQTc prolongationSedation or somnolenceHeadacheRarer side effects agranulocytosis, seizures, and orthostasis

Saphris [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine - DosingAsenapine is supplied as sublingual tabletsDo not swallow tabletsDissolve under the tongueNo food or drink for 10 minutes after doseSaphris [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

IndicationStarting DoseDosage RangeMaximumSchizophrenia5 mg twice daily5-10 mg twice daily10 mg twice dailyAcute Bipolar I10 mg twice daily5-10 mg twice daily10 mg twice daily

Asenapine Role in TherapyCan be utilized in both schizophrenia and bipolar disorderUnique sublingual administrationRelatively small metabolic side effectsHigher rates of sedation and akathisia than other agents

Lurasidone=latudaFDA approved in 2010IndicationsTreatment of schizophrenia in adultsTreatment of depressive episodes in bipolar disorder in adults as both monotherapy and adjunctive therapyMechanism 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 SchizophreniaFive total trials, all 6 weeks longTwo trials of fixed dose lurasidone vs. placebo showed superior efficacy of lurasidoneOne trial of 40 mg, 80 mg, and 120 mg lurasidone vs. placebo showed that only the 80 mg dose was superior to placeboOne trial of lurasidone, olanzapine and placebo showed that both lurasidone and olanzapine were superior to placeboOne trial of lurasidone, quetiapine ER, and placebo showed both lurasidone and quetiapine ER were superior to placeboLatuda [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone Efficacy in Bipolar DepressionAs monotherapyA 6-week trial vs placebo for symptom reduction in bipolar depression showed that both doses of lurasidone studied were superior to placebo at 6 weeksAs an adjunctA 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 groupLatuda [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone Possible Side EffectsMetabolic changes and weight gainPossibly the most weight and metabolic neutralEPS akathisia more common than othersQTc prolongationSedation or somnolenceNausea and vomitingRarer side effects agranulocytosis, seizures, and orthostasis Latuda [package insert]. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

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

Lurasidone Role in TherapyCan be utilized in schizophrenia and bipolar depressionHas a very favorable long-term metabolic profileOnce daily dosing is most patient friendlyAppears to be the most rigorously studied of the newer agents

LONG ACTING INJECTIONS(LAIS)

RationaleLAIs are options to improve complianceLess frequent administration than oral agentsDoses converted from stable oral regimensGuaranteed drug level in the body post-injectionImproved clinician contact

Available Options

1st Generation2nd GenerationHaloperidol decanoateRisperdal ConstaFluphenazine decanoateInvega SustennaZyprexa RelprevvAbilify Maintena

Zyprexa RelprevvFDA approved in 2009Long acting intramuscular injection of olanzapine intended for gluteal injection onlyIndicated for the treatment of schizophreniaDesigned to be initiated after a stable regimen of olanzapine is establishedZyprexa Relprevv [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Zyprexa Relprevv - DosingNote: No oral medication overlap is requiredZyprexa Relprevv [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Oral dose of olanzapineDose of Zyprexa Relprevv for the first 8 weeksMaintenance dose of Zyprexa Relprevvafter 8 weeks10 mg/day210 mg every 2 weeks or405 mg every 4 weeks150 mg every 2 weeks or300 mg every 4 weeks15 mg/day300 mg every 2 weeks210 mg every 2 weeks or405 mg every 4 weeks20 mg/day300 mg every 2 weeks300 mg every 2 weeks

Adverse EventsAdverse events are similar to oral olanzapineMetabolic syndrome and weight gainSedationOrthostasis and dizzinessAlso has Post-Injection Delirium/Sedation Syndrome (PDSS) risk

Zyprexa Relprevv [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

PDSSSigns and symptoms associated with olanzapine overdoseSedation and/or delirium possibly leading to comaDizziness, confusion, disorientation, slurred speech, weakness, difficulty walkingOccurred in

Zyprexa Relprevv REMSPrescriber, patient, facility, and pharmacy must all registerMedication cannot be dispensed directly to patientMedication must be administered in a registered facility with access to emergency response servicesPatients must be observed by a healthcare worker for at least 3 hours after injection for signs of PDSSPatients may not leave the facility by themselvesPatients should not drive the remainder of the dayZyprexa Relprevv [package insert]. Indianapolis, IN; Eli Lilly and Company; Revised July, 2011.

Abilify MaintenaFDA approved in 2013Long acting intramuscular injection of aripiprazole intended for gluteal injection onlyIndicated for the treatment of schizophreniaDesigned 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 DosingRecommended starting dose in 400 mg monthlyContinuation of oral aripiprazole 10-20 mg/day is necessary for 14 days after initial injectionMaintenance dose is also 400 mg monthlyDose reduction to 300 mg can be used if 400 mg dose is intolerableAbilify Maintena [package insert]. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

Adverse EventsVery similar to oral aripiprazoleSlight metabolic changesSome EPS mostly akathisiaAnxietyHeadacheOrthostasisAbilify 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 Irenka DR (duloxetine)Lexapro (escitalopram)Effexor (venlafaxine)Prozac Sarafem (fluoxetine)Pristiq (desvenlafaxine)Paxil (paroxetine)Savella (milnacipran)Luvox (fluvoxamine)Fetzima (levomilnacipran)Zoloft (sertraline)Brintellix (vortioxetine)Viibryd (vilazodone)

Antidepressants

Tricyclic AntidepressantsAtypical AntidepressantsMonoamine Oxidase Inhibitors (MAOIs)Elavil (amitriptyline)Wellbutrin (bupropion)Nardil (phenelzine)Anafranil (clomipramine)Remeron (mirtazapine)Parnate (tranylcypromine)Tofranil (imipramine)Serzone (nefazodone)Eldepryl (selegiline)Pamelor (nortriptyline)Desyrel Oleptro (trazodone)Marplan (isocarboxazid)*Norpramin (desipramine)Sinequan (doxepin)Vivactil (protriptyline)

NEW ORAL ANTIDEPRESSANTS

Viibryd (Vilazodone) Year Approved2011

IndicationMajor Depressive DisorderImage from www.viibryd.comViibryd [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd (Vilazodone) Mechanism of ActionSelective Serotonin Reuptake Inhibitor (SSRI)Activity at serotonin receptor

EffectivenessDecreased depressive symptoms in 8 week trials better than placeboViibryd [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd (Vilazodone)

SafetyContraindicationsUse with MAOI

WarningsSerotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuationViibryd [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd (Vilazodone)

SafetyDrug interactions

Adverse EffectsNausea, diarrhea, dizziness, sleep disturbance, sexual dysfunctionViibryd [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Viibryd (Vilazodone)Considerations for UseTake with foodDose titrationNo dose adjustment for agePregnancy, nursing, or children

Medication RoleNo clear advantage over SSRIs for depressionViibryd [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised December, 2012.

Fetzima (Levomilnacipran) Year Approved2013

IndicationMajor Depressive DisorderImage from www.fetzima.comFetzima [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima (Levomilnacipran) Mechanism of ActionSerotonin Norepinephrine Reuptake Inhibitor (SNRI)

EffectivenessDecreased depressive symptoms in 8 week trials better than placebo

Fetzima [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima (Levomilnacipran) SafetyContraindicationsAllergic reaction, uncontrolled narrow-angle glaucoma, use with MAOI

WarningsSerotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuationFetzima [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima (Levomilnacipran)SafetyWarnings (cont.)High blood pressure & heart rate, narrow-angle glaucoma, urinary hesitation or retention

Drug interactions

Adverse EffectsNausea, vomiting, constipation, sweating, increased blood pressure & heart rate, sexual dysfunction

Fetzima [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Fetzima (Levomilnacipran)Considerations for UseAdjust dose for kidney impairmentNo dose adjustment for agePregnancy, nursing, children

Medication RoleNo clear advantage over SNRIs for depression No established effectiveness for fibromyalgia/ pain

Fetzima [package insert]. St. Louis, MO; Forest Laboratories, Inc.; Revised July, 2013.

Brintellix (Vortioxetine) Year Approved2013

IndicationMajor Depressive DisorderImage from us.brintellix.comBrintellix [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix (Vortioxetine) Mechanism of ActionSSRIActivity at various serotonin receptors

EffectivenessDecreased depressive symptoms in 6-8 week trials & longer time to recurrent depression in 64 week trial better than placeboBrintellix [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix (Vortioxetine) SafetyContraindicationsAllergic reaction, use with MAOI

WarningsSerotonin syndrome, suicidality, mania, bleed, low sodiumBrintellix [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix (Vortioxetine) SafetyDrug interactions

Adverse EffectsNausea, vomiting, constipation, dizziness, sexual dysfunction

Brintellix [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Brintellix (Vortioxetine)Considerations for UseAvoid in severe liver impairmentNo dose adjustment for agePregnancy, nursing, children

Medication RoleNo clear advantage over SSRIs for depression

Brintellix [package insert]. Deerfield, IL; Takeda Pharmaceuticals America, Inc.; Revised July, 2014.

Miscellaneous Medications

Miscellaneous Medications

Images taken from www.quillivantxr.com; www.intermezzorx.com; www.zubsolv.com

Learning Strategies

Resources NAMI.orgMedication fact sheetsFDA.govDrugs.comMedlinePlusNarsad.org

*Also paxil cr, luvox cr and effexor xr*Doxepin has greatest AH**Partial 5HT-1A agonist

Decreased depressive symptoms in two 8 week RCT trials of outpatients*Suicidality In children, teenagers & young adults 80mg/day; other medications which can increase BP & HRNo 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 bpmtrials excluded patients with significant CVD*Pregnancy decreased birth weight and possibly mortality in rats at supratherapeutic doses.Nursing present in rat milkChildren 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*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 effectShort term studies with outpts and were RCTs; Longterm study was open label with inpts and outpts**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 weeksNo changes in weight or vital signs observed in pre-marketing trials*-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 ads)

No dose adj for geri, race, ethnicity, (like other ads) up to severe renal dys, but unknown with severe hepatic disease*Methyl 2012Zolpid - 2011*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 illnessNational Alliance for Research on Schizophrenia and Depression the Brain and Behavior Research Foundation*