Antipsychotic Class Review

IOWA MEDICAID P&T COMMITTEE THERAPEUTIC CLASS REVIEW AUGUST 10, 2012

ANTIPSYCHOTICS CLASS REVIEW

[Literature Review search through July 16, 2012]

[Last Review Update: August 9, 2012]

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SYNOPSIS

Antipsychotics are also known as neuroleptic drugs, which comes from the Greek meaning "taking hold of one’s nerves". Antipsychotics are used to treat numerous psychiatric diagnoses including schizophrenia, bipolar disorder, aggression and irritability associated with autism and as augmentation agents for patients with major depressive disorder who fail to respond to antidepressant monotherapy. The first generation antipsychotics (FGAs), or the typical antipsychotics, have been in existence since the 1950s, while second generation antipsychotics, also known as the atypical antipsychotics (AAPs), have been available since the 1990s. The atypical antipsychotics are now considered 1st line treatment for schizophrenia and are one of the most widely prescribed drug classes.

Schizophrenia affects approximately 1.1% of the U.S. adult population. Schizophrenia is a severe, progressive, chronic brain disorder, with symptoms falling into one of three categories. The categories include: (1) positive symptoms, which are unusual thoughts or perceptions (delusions and hallucinations respectively); (2) negative symptoms, which are a loss or decrease in the ability to initiate plans, speak or find pleasure in everyday life; and (3) cognitive deficits.30

Bipolar disorder, also known as manic‐depressive illness, is also a chronic brain disorder that's characterized as a mood disorder with periods of depression and mania. Bipolar disorder can cause a dramatic shift in mood, energy, and a person’s ability to function in numerous domains. These severe symptoms can lead to difficulties in leading a productive life if not properly treated and managed. There are currently 5.7 millions adults in the U. S. that are diagnosed with bipolar disorder, which is approximately 2.6% of the population. Individuals with bipolar disorder have increased rates of substance abuse, divorce, unemployment, and arrest rates. Bipolar disorder typically develops in late adolescence or early adulthood.29

Major depressive disorder has a lifetime prevalence of 16 % in the United States. First line antidepressant treatment is often ineffective at relieving symptoms. Augmentation of antidepressants is a commonly employed strategy and certain atypical antipsychotics have been demonstrated to be efficacious.

Clozapine was first discovered in the 1950's, but was not used in clinical practice in the United States until 1990. Clozapine was found to be most effective for treatment resistant schizophrenia; however, associated adverse events limited its use. This led to the advent of newer atypicals with more tolerable side effect profiles compared with clozapine. Risperidone (Risperdal®) was the first of the newer atypicals, followed by olanzapine (Zyprexa®) and then quetiapine (Seroquel®) that were developed in the 1990's. Ziprasidone (Geodon®) and aripiprazole (Abilify®) became available in the early 2000’s. Paliperidone (Invega®) became available in 2006, while iloperidone (Fanapt®) and asenapine (Saphris®) became available in 2009. Most recently, the newest product that has been approved by the FDA is lurasidone (Latuda®). The frequency and severity of adverse events and drug‐drug interactions helps to differentiate the products from the earlier first generation antipsychotics such as haloperidol or perphenazine, with the atypicals.

The oral atypical antipsychotics included in this therapeutic class review include: aripiprazole (Abilify®), asenapine (Saphris®), clozapine (Clozaril®, Fazaclo®), iloperidone (Fanapt®), lurasidone (Latuda®), olanzapine (Zyprexa®), olanzapine/fluoxetine (Symbyax®), paliperidone (Invega®), quetiapine (Seroquel®), quetiapine XR (Seroquel XR®), risperidone (Risperdal®), and ziprasidone (Geodon®).

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The injectable atypicals included in this therapeutic class review include: aripiprazole (Abilify®), olanzapine (Zyprexa® IntraMuscular, Zyprexa® Relprevv), paliperidone (Invega® Sustenna), risperidone (Risperdal® Consta), and ziprasidone (Geodon®).

The oral typical antipsychotics included in this therapeutic class review include: chlorpromazine, fluphenazine, haloperidol (Haldol®), loxapine (Loxitane®), perphenazine, perphenazine/amitriptyline, pimozide (Orap®), thioridazine, thiothixene (Navane®), and trifluoperazine. Molindone (Moban®) is a typical antipsychotic used for schizophrenia. While there is no CMS term date, the manufacturer has recently discontinued this product and thus it will not be included in the review.

The injectable typical antipsychotics included in this therapeutic class review include: chlorpromazine, fluphenazine decanoate, haloperidol (Haldol®), and haloperidol decanoate (Haldol® decanoate).

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ATYPICAL ANTIPSYCHOTICS

FDA APPROVED INDICATIONS 1‐9, 32‐34, 67, 95‐99

Please note that the indications listed in the table below are for adults aged 18 years of age or older.

Adult Indications ARI ASE CLO ILO LUR OLA OLA/FLU PAL QUE QUE XR RIS ZIP

Bipolar I: Acute Mania, X X X X X X X Monotherapy Bipolar I: Acute Mania, Adjunct X X X X X X to valproate or lithium

Bipolar I: Depression X X X

Bipolar II: Depression X X

Bipolar I: Mixed, Monotherapy X X X X X X

Bipolar I: Mixed, Adjunct Therapy X X X X X to valproate or lithium Bipolar Maintenance: X X Monotherapy

Bipolar Maintenance: Adjunct X X X X

MDD Adjunct Therapy X X Schizoaffective Disorder: X Monotherapy & Adjunct

Schizophrenia X X X X X X X X X X

Treatment‐resistant Depression X

Treatment‐resistant Schizophrenia X

Recurrent suicidal behavior X w/Schizophrenia ARI‐aripiprazole (Abilify®); ASE‐ asenapine (Saphris®); CLO‐clozapine (Clozaril®, Fazaclo®); ILO‐iloperidone (Fanapt®); LUR‐lurasidone (Latuda®); OLA‐olanzapine (Zyprexa®); OLA/FLU‐ olanzapine/fluoxetine (Symbyax®); paliperidone (Invega®); QUE‐quetiapine (Seroquel®); QUE SR‐quetiapine SR (Seroquel® XR); RIS‐ risperidone (Risperdal®); ZIP‐ziprasidone (Geodon®).

The following table illustrates the current FDA approved indications for the injectables.

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Agitation with Drug Schizophrenia Bipolar I: Monotherapy Bipolar I: Adjunct schizophrenia/bipolar aripiprazole * X2 (Abilify®) olanzapine * X1, 3 (Zyprexa® IntraMuscular) olanzapine ** X (Zyprexa® Relprevv) paliperidone ** X (Invega® Sustenna) risperidone ** X X X (Risperdal® Consta) ziprasidone* X3 (Geodon®) 1 Bipolar I Mania 2Bipolar disorder, Manic or Mixed 3Schizophrenia *Short‐acting injectables (SAI); **Long‐acting injectables (LAI)

The following table illustrates the current FDA approved indications in the pediatric population.

Drug Schizophrenia Bipolar I: Acute Mania1 Bipolar I: Mixed1 Irritability associated with autism aripiprazole 13‐17 yrs 10‐17 yrs 10‐17 yrs 6‐17 yrs (Abilify®) olanzapine 13‐17 yrs 13‐17 yrs 13‐17 yrs ‐ (Zyprexa®) paliperidone 12‐17 yrs ‐ ‐ ‐ (Invega®) quetiapine 13‐17 yrs 10‐17 yrs ‐ ‐ (Seroquel®) risperidone 13‐17 yrs 10‐17 yrs 10‐17 yrs 5‐16 yrs (Risperdal®) 1 Monotherapy

DOSAGE FORMS, DOSE, MANUFACTURER1‐9, 32‐34, 67, 95‐99

Currently, the only generic versions available in this therapeutic class include clozapine (Clozaril®) and risperidone (Risperdal®). Daily doses may vary within the provided dose range based upon age and indication.

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Drug Dosage Forms Dose Manufacturer

Tablets: 2mg, 5mg, 10mg, 15mg, aripiprazole 20mg, 30mg (Abilify®) Orally Disintegrating Tablet: 10‐30mg QD Bristol‐Myers Squibb (Abilify® Disc) 10mg, 15mg Oral Solution: 1mg/ml asenapine Sublingual Tablets: 5‐10mg BID Schering‐Plough (Saphris®) 5mg, 10mg Tablets1: clozapine 25mg, 50mg, 100mg, 200mg Various generic manufacturers (Clozaril®) Orally Disintegrating Tablet: 100‐900mg divided as TID (Novartis) (Fazaclo®) 12.5mg, 25mg, 100mg, (Azur Pharma) 150mg, 200mg Tablets: iloperidone Initial dose of 1mg BID, 1mg, 2mg, 4mg, 6mg, 8mg, Vanda Pharmaceuticals (Fanapt®) target of 6‐12mg BID 10mg, 12mg lurasidone Tablets: 40‐160mg QD with food Sunovion Pharmaceuticals (Latuda®) 20mg, 40mg, 80mg (at least 350 calories) Tablets: olanzapine 2.5mg, 5mg, 7.5mg, 10mg, Various generic manufacturers (Zyprexa®) 15mg, 20mg 5‐20mg QD (Lilly) (Zyprexa® Zydis) Orally Disintegrating Tablet: 5mg, 10mg, 15mg, 20mg Capsules: olanzapine/fluoxetine 3/25mg, 6/25mg, 6/50mg, QPM dosing, max: 18/75mg Lilly (Symbyax®) 12/25mg, 12/50mg paliperidone Extended‐Release Tablets: 3‐6mg QD, max:12mg Janssen (Invega®) 1.5mg, 3mg, 6mg, 9mg Tablets: quetiapine QD to BID dosing, Various generic manufacturers 25mg, 50mg, 100mg, 200mg, (Seroquel®) max:800mg (AstraZeneca) 300mg, 400mg Extended‐Release Tablets: quetiapine XR 50mg, 150mg, 200mg, 300‐800mg QPM AstraZeneca (Seroquel® XR) 300mg, 400mg Tablets/M‐Tabs (ODT): risperidone 0.25mg, 0.5mg, 1mg, 2mg, QD to BID dosing, with Various generic manufacturers (Risperdal®) 3mg, 4mg effective dose range 4‐16mg2 ( Janssen) (Risperdal® M tab) Oral Solution: 1mg/ml

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Drug Dosage Forms Dose Manufacturer

ziprasidone Capsules: 20‐80mg BID, Various generic manufacturers (Geodon®) 20mg, 40mg, 60mg, 80mg Max daily dose: 200mg (Pfizer) 1Brand only available in 25mg and 100mg tablets; 2 Per manufacturer prescribing information; however, doses above 8mg/day for twice daily dosing were not shown to be more efficacious than lower doses, were generally associated with more EPS/other adverse events, and generally not recommended.

The following table includes the injectable dosage forms. There are currently no generic equivalents available. Olanzapine (Zyprexa® Relprevv), paliperidone (Invega® Sustenna), and risperidone (Risperdal® Consta) are all long‐acting injectables. Aripiprazole (Abilify® IM), olanzapine (Zyprexa® IM), and ziprasidone (Geodon® IM) are all to be used as acute treatments.

With olanzapine (Zyprexa® IntraMuscular), the contents of the vial should be dissolved using 2.1ml of sterile water for injection. This will provide a vial containing 10mg, with 5mg/ml of olanzapine. Olanzapine (Zyprexa® IntraMuscular) is indicated to be used for intramuscular use only. If agitation continues after an initial dose and a subsequent dose is warranted, up to 10mg may be given. The efficacy of repeated doses has not been studied in clinical trials. Furthermore, the safety of total daily doses exceeding 30mg or 10mg injections given more frequently than 2 hours after the initial dose and 4 hours after the second dose have not been studied. Lastly, the use of maximal dosing may be associated with significant orthostatic hypotension. It is therefore recommended that subjects be assessed for orthostatic hypotension prior to use.

It is recommended not to begin treatment with Zyprexa® Relprevv until there tolerability is established with oral olanzapine. Zyprexa® Relprevv should only be administered by a healthcare professional and is for deep intramuscular gluteal administration only; however, the Zyprexa® IntraMuscular injectable formulation should not be confused with Zyprexa® Relprevv. The use of Zyprexa® Relprevv for up to 24 weeks has been established in clinical trials.

Zyprexa® Relprevv has a box warning indicating there have been reports of post‐injection delirium/sedation syndrome. Signs and symptoms consistent with olanzapine overdose reported include sedation and/or delirium, EPS, dysarthria, ataxia, aggression, dizziness, weakness, hypertension, and convulsion. Therefore, Zyprexa® Relprevv must be given in a registered healthcare facility that has readily available emergency response services. After injection, subjects must be observed for a minimum of 3 hours at the healthcare facility by a healthcare professional. Due to this box warning, Zyprexa® Relprevv can only be obtained though a restricted distribution program called the Zyprexa® Relprevv Patient Care Program. The prescriber, the patient, the healthcare facility, and the pharmacy all need to enroll in this program.

It is recommended to not start taking Invega® Sustenna® until there tolerability is established with either oral paliperidone or oral risperidone. Invega Sustenna should only be administered by a healthcare professional for deltoid or gluteal administration. Concomitant use of Invega® Sustenna® with oral paliperidone (Fanapt®) or oral/injectable risperidone (Risperdal®/Risperdal® Consta) has not been studied.

It is recommended to not start treatment with Risperdal® Consta until there tolerability is established with oral risperidone (Risperdal®). Injections should be administered by a healthcare professional for either deltoid or gluteal administration. Use has been evaluated in clinical trials for up to 12 weeks. If titration is

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needed, it should not be done more frequently than every 4 weeks. Lastly, oral risperidone (Risperdal®) or other atypical should be given with the first injection and maintained for at least 3 weeks while the levels of the injectable are able to reach appropriate levels for adequate therapeutic effect.

Drug Dosage Forms Dose Manufacturer

5.25‐15mg IM; aripiprazole Vial: Max: 30mg daily or injections more Bristol‐Myers Squibb (Abilify®) 7.5mg/ml frequently than Q2H olanzapine Vial: 2.5‐10mg IM; Lilly (Zyprexa® IM2) 10mg per vial max 3 doses (30mg) 2‐4hrs apart olanzapine pamoate Powder for suspension, IM: 150‐300mg IM Q2 weeks OR Eli Lilly & Company (Zyprexa® Relprevv) 210mg, 300mg, or 405mg per vial 300‐405mg Q4 weeks paliperidone Extended‐release suspension, IM: 234mg IM day 1, 156mg a week Janssen (Invega® Sustenna) 39mg, 78mg, 117mg, 156mg, 234mg later, then monthly dose of 117mg1

risperidone Vial w/microspheres & Diluent: 25‐50mg IM Q2 weeks Janssen (Risperdal® Consta) 12.5mg, 25mg, 37.5mg, 50mg

ziprasidone Powder for solution, Single‐dose Vial: 10‐20mg IM, max 40mg/day given Pfizer (Geodon®) 20mg/ml as 10mg Q2H or 20mg Q4H

1 monthly dose range of 39‐234mg 2 IM‐IntraMuscular

PHARMACOLOGY 1‐9, 32‐34, 67, 95‐99

The exact mechanism of action of atypical antipsychotics (AAPs) for the treatment of bipolar disorder (BD) or irritability and aggression in autism is unknown. Even for schizophrenia, no single theory best describes

the mechanism of action of AAPs. It is theorized that dopamine type 2 (D2) in the cortical and limbic areas of the brain are crucial in the pathophysiology of schizophrenia for both typical antipsychotics (SGAs, e.g.,

chlorpromazine, perphenazine, and haloperidol) and for AAPs. By binding to D2 receptors in the basal

ganglia, extrapyramidal symptoms (EPS) may ensue and in binding to D2 receptors in the tuberoinfundibular, prolactin levels may increase. Both first and second generation antipsychotics act as antagonists or modulators at dopamine receptors.

One theory postulates that what distinguishes AAPs (that cause less EPS and prolactinemia) from typical

antipsychotics is their high ratio of serotonin (S2) 5HT2A receptor blockade to dopamine Type 2 (D2)

blockade. With postsynaptic serotonin antagonism providing a modulating effect on D2 receptors, dopamine is released in the nigrostriatal, meso‐cortical and tuberoinfundibular pathways. It is thought this decreases the frequency and severity of neurologic side effects of the SGAs in comparison to the FGAs, which lack intrinsic serotonin antagonism.

There appears to be at least 2 facts which contradict this theory; (1)‐although S2 blockade appears at low

dose AAP, it is at a dosage which is insufficient to treat psychosis; (2) whether S2 is blocked or not, both SGAs

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and AAPs have the same antipsychotic threshold D2 occupancy (i.e., 65%) in the brain. Another theory

holds that AAPs occupy D2 receptors only transiently and then “come off”‐ allowing normal D2 transmission and sparing EPS, prolactin elevation and cognitive deficits. This model known as “fast on, fast off” theory best describes the action of clozapine and Seroquel®, but not the other AAPs. In this model, EPS develops when the threshold occupancy is exceeded‐ at approximately 85% occupancy and tardive dyskinesia, a potentially irreversible movement disorder, occurs when there is long term D2 receptor blockade leading to compensatory up‐regulation of these receptors. Agents that rapidly dissociate from D2 receptors, such as quetiapine, are associated with a more benign neurologic side effect profile yet retain therapeutic efficacy. This also suggests that only transient D2 antagonism is required for therapeutic activity.

The exact mechanism of action of Symbyax®, the only combination product in this class, is unknown as well; however, it is postulated that there is activation of the 3 neural systems, including serotonin, norepinephrine, and dopamine.

AAPs also bind to many non‐D2 and S2 receptors including glutamate, histamine, alpha‐adrenergic and muscarinic receptors and each has a unique receptor profile that will determine their unique adverse effect profile.

PHARMACOKINETICS 1‐9, 32‐34, 95‐99

Pharmacokinetic properties are listed in the table below. Please note that Clozaril® tablets and Fazaclo® orally disintegrating tablets are considered bioequivalent.

Time to Peak Plasma Drug Time to Steady State Half‐Life Elimination Concentrations aripiprazole Urine: 25% 3‐5 hrs 14 days 75 hours (Abilify®) Feces: 55% asenapine Urine:50% 0.5‐1.5 hrs 3 days 24 hours (Saphris®) Feces: 40% clozapine 12 hours Urine 50% (Clozaril®) 2.5 hrs N/A [100mg BID dose] Feces: 30% (Fazaclo®) iloperidone 18‐23 hrs3 Urine: 45.1‐58.2% 2‐4 hrs 3‐4 days (Fanapt®) 31‐37 hrs4 Feces: 19.9‐22.1% lurasidone Urine: 9% 1‐3 hrs Within 7 days 18 hrs (Latuda®) Feces: 90% olanzapine Urine: 57% 6 hrs 7 days 21‐54 hours (Zyprexa®) Feces: 30% olanzapine1/fluoxetine2 Urine: 57%1 4 hrs/6 hrs 1 wk/4‐5 wks 21‐54 hrs/8.6‐9.3 days (Symbyax®) Feces: 30%1 paliperidone Urine: 80% 24 hrs 4‐5 days 23 hours (Invega®) Feces: 11%

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Time to Peak Plasma Drug Time to Steady State Half‐Life Elimination Concentrations quetiapine Urine: 73% 1.5 hrs Within 2 days 6 hours (Seroquel®) Feces: 20% quetiapine XR Urine: 73% 6 hrs Within 2 days 7 hours (Seroquel® XR) Feces: 20% risperidone 1 day3 3 hrs3 Urine: 70% 1 hr (Risperdal®) 5 days4 20 hrs4 Feces: 14% ziprasidone Renal: 20% 6‐8 hrs 6‐8 hours 7 hours (Geodon®) Feces: 66% 2 Fluoxetine is primarily eliminated via kidney. 3 Extensive metabolizers 4 Poor metabolizers

The following table includes data on the injectable formulations.

Systemic exposure of aripiprazole (Abilify® injectable) over a 24 hour period is similar after oral table administration; however, the area‐under‐the‐curve (AUC) in the first 2 hours after an IM injection was 90% greater than the AUC as the tablet,e using th same dose.

Additionally, the metabolic pathways for the injectable administration of aripiprazole (Abilify®) and ziprasidone (Geodon®) were not evaluated; however, it is not expected that the route of administration would alter the pathways.

With Riserpdal® Consta, a small initial release of medication occurs after an injection. This is followed by a lag time of 3 weeks, with the main release of medication starting from 3 weeks onward and sustained from 4‐6 weeks. It is for this reason that it is recommended to supplement with oral antipsychotic treatment during the first three weeks of treatment.

After intramuscular (IM) injection of paliperidone (Invega® Sustenna), paliperidone palmitate dissolves slowly prior to being hydrolyzed to paliperidone and then absorbed into systemic circulation. Release of paliperidone begins as quickly as day 1 and lasts for up to 126 days. When starting paliperidone injections in the deltoid muscle on day 1 and then again ony da 8, a rapid steady‐state concentration is achieved, thus not requiring use of oral antipsychotic supplementation.

Olanzapine (Zyprexa® Relprevv) is a practically insoluble salt, resulting in slow dissolution after deep IM gluteal injection and thus prolonged systemic plasma concentrations occur and are maintained for over several weeks to months. With olanzapine (Zyprexa® IntraMuscular), a rapid absorption occurs. In a study with healthy volunteers, a 5mg dose of intramuscular olanzapine resulted in, on average, a maximum plasma concentration that was about five times higher than the maximum plasma concentration that was produced with a 5mg oral dose of olanzapine.

Time to Peak Plasma Drug Time to Steady State Half‐Life Elimination Concentrations aripiprazole 1‐3 hrs 14 days 75 hours See note above (Abilify® IM)

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Time to Peak Plasma Drug Time to Steady State Half‐Life Elimination Concentrations olanzapine Urine: 57% 15‐45 minutes 21‐54 hours (Zyprexa® IntraMuscular) Feces: 30% Olanzapine Urine: 57% Within 7 days 30 days (Zyprexa® Relprevv) Feces: 30% paliperidone Urine: 80% 13 days After 2 injections 25‐49 days (Invega® Sustenna) Feces: 11% risperidone Urine 70% 4‐6 weeks after injection After 4 injections 3‐6 days (Risperdal® Consta) Feces: 14% ziprasidone 60 minutes 2‐5 hrs See note above (Geodon® IM)

CONTRAINDICATIONS 1‐9, 32‐34, 67, 95‐99 All medications in this therapeutic category carry a contraindication of hypersensitivity to their active ingredient or to any component of the compound.

Drugs that carry their own contraindications unique to the class are listed in the table below.

Drug Contraindication

clozapine Use with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of clozapine‐induced agranulocytosis severe granulocytopenia, severe central nervous system (Clozaril®) depression or comatose states from any cause. (Fazaclo®) Concurrent use with drugs known to cause agranulocytosis or suppress bone marrow function. lurasidone Concurrent use with strong CYP3A4 Inhibitors (ketoconazole) & strong CYP3A4 inducers (rifampin). (Latuda®) olanzapine/fluoxetine Concomitant use of an MAOI, or use within 14 days of discontinuing the MAOI, (Symbyax®) Concomitant use with pimozide and thioridazine. paliperidone (Invega®) Hypersensitivity to risperidone (Invega Sustenna®) ziprasidone Known history of QT prolongation (including congenital long QT syndrome) with recent acute MI, (Geodon®) or with uncompensated heart failure; Concurrent use with drugs that have QT prolongation.

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SPECIAL POPULATIONS 1‐9, 32‐34, 67, 95‐99

In the pediatric population, the safety and efficacy of using atypical antipsychotics has not been established, unless otherwise noted in the table below. The use of these medications during pregnancy and lactation requires a thorough risk/benefit analysis. Clinical worsening of psychiatric disorders typically does occur in the context of discontinuation of effective medications.

Pregnancy Dosage change with Dosage change with Drug Pediatrics Category Renal Insufficiency Hepatic Insufficiency aripiprazole ≥6 yrs1 C Not required Not required (Abilify®) asenapine Mild‐moderate: Not required No C Not required (Saphris®) Severe: Not recommended clozapine (Clozaril®) No B Use with caution Use with caution (Fazaclo®) iloperidone No C Not required Use not recommended (Fanapt®) lurasidone Moderate‐Severe: 20mg initially; Moderate‐Severe: 20mg initially; No B (Latuda®) Max 80mg/day Max 80mg moderate/40g severe. olanzapine ≥13 yrs1 C Not required Not required (Zyprexa®) olanzapine/fluoxetine Use with caution. No C Not studied/not required (Symbyax®) Initiate with ↓ dose paliperidone Mild: Initial dose 3mg Mild to Moderate: Not required ≥12 yrs1 C (Invega®) Moderate‐Severe: Initial dose 1.5mg Severe: Not studied quetiapine ≥10 yrs1 C Not required May be required (Seroquel®) quetiapine XR No C Not required May be required (Seroquel® XR) risperidone ≥5 yrs1 C Severe: 0.5mg BID & titrate prn Severe: 0.5mg BID & titrate prn (Risperdal®) ziprasidone No C Not required Not required (Geodon®) 1 Please refer to FDA approved indications section for specific age‐associated indication.

The following table contains information for the injectable versions.

Pregnancy Dosage change with Dosage change with Drug Pediatrics Category Renal Insufficiency Hepatic Insufficiency aripiprazole No C Not required Not required (Abilify®)

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Pregnancy Dosage change with Dosage change with Drug Pediatrics Category Renal Insufficiency Hepatic Insufficiency olanzapine (Zyprexa® IM) No C Not required Not required (Zyprexa® Relprevv) paliperidone Mild: 156mg/117mg/78mg maintenance2 Mild to Moderate: Not required1 No C (Invega® Sustenna) Moderate‐Severe: Not recommended Severe: Not studied1 risperidone Initiate 12.5‐25mg, titrate on PO med Initiate 12.5‐25mg, titrate on PO No C (Risperdal® Consta) before initiate 25mg Consta med before start 25mg Consta ziprasidone No C Not studied, but use with caution Not studied (Geodon®) 1Based on data from oral paliperidone 2Initiate at 156mg, then use 117mg 1 week later, then follow with monthly injects of 78mg

ADVERSE DRUG REACTIONS 1‐10, 32‐34, 67, 95‐99

The atypical antipsychotics demonstrate patterns of similar adverse events (AEs) compared with the typical

antipsychotics, especially those associated with D2 inhibition, but at varying degrees of incidence. Many of the AEs of this class are dose dependent and occur at a greater incidence when the dose is higher. Age and gender may also affect the risk of a particular AE. Typical antipsychotics have a greater likelihood of neurologic adverse effects than the atypicals. In contrast, the atypical antipsychotics are associated with a lesser degree of neurologic adverse effects but a substantially greater risk of weight gain and metabolic burden.

Neurologic adverse effects include extrapyramidal symptoms (EPS) such as: dystonia, neuroleptic induced Parkinsonism (NIP), akathisia, and withdrawal dyskinesias; and late onset syndromes: tardive dyskinesia and tardive dystonia. These AEs occur at different rates in different age groups, gender (e.g., male adolescents are at higher risk for acute dystonia), and underlying disease state. Atypicals are substantially less associated with neurologic toxicity. In the CATIE study, perphenazine had higher rates of EPS than did the atypicals.11 Risperdal® is the most likely and clozapine and Seroquel® are the least likely among atypicals to cause EPS owing to the former potent D2 binding affinity.28 Comparable rates of NIP between Risperdal® and fluphenazine exist18 demonstrating the overlap of risk between an individual typical and atypical.

Hyperprolactinemia is another example of an adverse event that may occur with this class and is most frequently found with risperidone, again related to its potent D2 binding affinity. Elevated prolactin levels are associated with gynecomastia, galactorrhea, and amenorrhea. Clozapine and Seroquel® are considered prolactin sparing, and Abilify®, a dopamine partial agonist, has been shown to reduce prolactin levels after other AAP‐based elevations.24

The most significant toxicities associated with the atypical antipsychotics are the development of weight gain and metabolic changes and these adverse effects are not typically associated with the typical antipsychotics. Although there is no single accepted definition of the Metabolic Syndrome, affected individuals have symptoms of increased abdominal girth, weight gain, hypertension, elevated glucose, and

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Clozapine and olanzapine (Zyprexa®) have the highest associated risk of metabolic syndrome. Ziprasidone (Geodon®) and aripiprazole (Abilify®) have the lowest risk and quetiapine (Seroquel®) and risperidone (Risperdal®) are intermediate. Monitoring guidelines have been established for tracking these parameters and should be followed on every patient treated with atypical antipsychotics. As such, weight, blood pressure, waist circumference, blood glucose and lipid levels should be monitored in all individuals receiving these medications.

Additional adverse effects are associated with specific receptor binding profiles. Seroquel® is associated with a risk of orthostatic hypotension mediated by blockade of alpha adrenergic receptors. This may lead to dizziness and falls, particularly in geriatric patients. Clozapine is associated with excessive salivation mediated by anticholinergic effects. It is also associated with agranulocytosis, a potentially fatal disorder. As such, white blood cell counts must be monitored weekly for the first six months of clozapine treatment. Every other week monitoring after six months is mandated. If there are no drops in white blood cell counts after one year, blood monitoring is done monthly.

Other common adverse effects seen with atypical antipsychotics include excessive hunger and sedation, thought to be mediated via H1 receptors. Dry mouth, urinary retention, constipation and blurry vision may occur and this is mediated by anticholinergic antagonism. Clozapine, Zyprexa® and Seroquel® show higher occurrence of these anticholinergic effects, while Abilify®, Risperdal®, and Geodon® have a lower risk of occurrence, if any at all since they have reduced potential to binding to these receptors.

Cardiovascular and cerebrovascular events in the elderly have also been reported with the use of this class. All medications in this class have a box warning of a potential for an increased risk of cerebrovascular events or death in those elderly patients with dementia‐related psychosis who are treated with atypicals. Atypicals are thought to be ineffective in the psychosis related to dementia. As such, their use is discouraged in patients with dementia related psychosis.

All antipsychotics (both typical and atypical classes) have been associated with causing sudden death in a dose dependent manner.66

Other miscellaneous side effects include sedation. Clozapine tends to have the highest risk of sedation and caution should be exercised when using concomitant medications. All of the atypicals reduce the seizure threshold. Those individuals with a history of seizure and with organic brain disorder should use this class with caution. Clozapine has the highest risk of occurrence of seizure, and currently has a box warning noting the potential risk of a greater likelihood of seizures.

Symbyax®, the one combination product in this class, carries a black box warning that warns of the potential for increased risk of suicidal thinking and suicidality in children, adolescents, and young adults in those with major depression disorder. This is due to the fluoxetine component of the product. Patients using olanzapine/fluoxetine (Symbyax®) should be closely monitored and observed for clinical worsening or unusual changes in behavior. Both Seroquel® XR and Abilify® also carry box warnings for increased risk of suicidality in children, adolescents, and young adults with major depressive disorder.

Property of IME and may not be reproduced without permission. Antipsychotics‐15

Lastly, recent studies suggest that quetiapine (Seroquel®, Seroquel® XR) use may result in dose‐related decreases in thyroid hormone levels in some subjects. In almost all cases, there was a reversal of effects upon discontinuation of therapy.7‐8

The following table summarizes the risk of occurrence for these major adverse events. As a reminder, most adverse events are dose dependent.10 Please note that asenapine (Saphris®), iloperidone (Fanapt®), and lurasidone (Latuda®) are new to the market and not enough information is available to determine the effects below.

Adverse Event ARI CLO OLA PAL5 QUE QUE SR8 RIS ZIP

Antimuscarinic ‐ +++ + ‐ + + ‐ ‐

Dyslipidemia ‐ +++ +++ ‐ ++ ++ ‐ ‐

Extrapyramidal symptoms + ‐ + + ‐ ‐ ++ +

↑ Prolacn ↓ ‐ + +++ ‐ ‐ +++ +

Postural Hypotension + +++ + ++ ++ ++ ++ +

QTc Prolongation + + + + + + + ++

Sedation ‐ +++ ++ ‐/+ ++ ++ + +

Seizures + +++ + + + + + +

Weight gain ‐ +++ +++ + ++ +/++ ++ ‐ + indicates small risk; ++ indicates moderate risk; +++ indicates high risk; ‐ indicates minimal risk; ↓ indicates decrease ARI‐aripiprazole (Abilify®); CLO‐clozapine (Clozaril®, Fazaclo®); OLA‐olanzapine (Zyprexa®); paliperidone (Invega®); QUE‐ quetiapine (Seroquel®); QUE SR‐quetiapine SR (Seroquel® XR); RIS‐ risperidone (Risperdal®); ZIP‐ziprasidone (Geodon®).

Other common side effects associated with Symbyax® occurring at an incidence of at least 5% include asthenia, edema, increased appetite, peripheral edema, pharyngitis, somnolence, abnormal thinking, tremor, and weight gain. Sexual dysfunction was also reported.

**In the following table, the results are adjusted so that they reflect only the extent that they exceed placebo.33, 67 **

asenapine lurasidone iloperidone Adverse Reactions (Saphris®) (Latuda®) (Fanapt®)1 Agitation 3%

Akathisia 3% 12% 0%

Anxiety 3%

Back pain 1%

Constipation 0% ‐ ‐

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asenapine lurasidone iloperidone Adverse Reactions (Saphris®) (Latuda®) (Fanapt®)1 Diarrhea ‐ ‐ 1%

Dizziness 1% 2% 3%

Dry mouth 1% ‐ 7%

Dyspepsia 2%

EPS 3% ‐ *

Fatigue 1%

Increased appetite >1% ‐ ‐

Increased weight >2% ‐ 0%

Insomnia 2% 1% ‐

Lethargy ‐ ‐ 2%

Nausea ‐ 6%

Nasopharyngitis ‐ ‐ 1%

Oral hypoesthesia 4% ‐ ‐

Orthostatic Hypotension ‐ ‐ 2%

Parkinsonism 6%3 ‐

Salivary hypersecretion >1%

Somnolence ‐ 12%2 4%

Vomiting 2% 110‐16mg/day dose 2Includes hypersomnia, hypersomnolence, sedation, and somnolence 3Includes bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor *EPS in clinical trials was divided out into akathisia (0%), bradykinesia (0.6%), dyskinesia (0.2%), dystonia (0.3%), Parkinsonism (0.2%), and tremor (0.6).

Data from several short‐term, placebo‐controlled studies was pooled to assess weight gain. Weight gain for those treated with lurasidone (Latuda®) was 0.75kg as compared with 0.26kg for placebo‐treated subjects. Specifically, lurasidone (Latuda®) 20mg had a ‐0.15kg change in weight from baseline, the 40mg strength had a 0.67 change in weight, a 1.14kg change in weight was seen with the 80mg, and a 0.68kg change in weight was seen with the 120mg daily dose. Additionally, the number of subjects with a ≥7% increase in body weight was 4.0% for the placebo group and 5.6% for the lurasidone‐treated group.

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Adverse events for the injectable versions are listed in the table below.

**In the following table, the results are adjusted so that they reflect only the extent that they exceed placebo for all medications except for ziprasidone (Geodon® IM). There was no placebo data from clinical trials available in the PI for ziprasidone (Geodon® IM). **

Adverse aripiprazole olanzapine olanzapine paliperidone3 risperidone ziprasidone1 Reactions (Abilify® IM) (Zyprexa® IM) (Zyprexa® Rel) (Invega® Sust) (Risperdal® Consta) (Geodon® IM) Akathisia 2% 5% ‐ 0% 0‐5% 0‐2%

Arthralgia ‐ ‐ 3% ‐ ‐

Asthenia ‐ 1% ‐ <1% ‐ 0‐2%

Bradycardia ‐ ‐ ‐ ‐ ‐ 0‐2%

Cough ‐ ‐ 0‐4% 0% 0‐1% ‐

Dizziness 3% 2% 0‐2% 3% 1‐5% 3‐10%

Dry Mouth ‐ ‐ 1‐5% 0% 0‐6% 0‐1%

EPS ‐ 4% ‐ 2% 0‐6% 0‐2%

Fatigue 1% ‐ 0‐2% 1% 3‐9% ‐

Headache 5% ‐ 5‐10% 3% 3‐9% 3‐13%

Hypotension 2% ‐ ‐ ‐ ‐ 0‐5%2

Increased Weight ‐ ‐ 0‐2% 0% 2‐3% ‐

Injection Site Pain ‐ ‐ 2‐3% 4%4 ‐ 7‐9%

Nasal Congestion ‐ ‐ 0‐4% ‐ 0‐2% ‐

Nausea 6% ‐ 2‐3% 0% 0% 4‐12%

Sedation 1% ‐ 1‐6% 1% 2‐3% ‐

Somnolence 3% 3% ‐ 1% ‐ 8‐20%

Tachycardia >1% ‐ ‐ ‐ ‐ ‐

Tremor ‐ 1% 0‐2% ‐ 0‐3% ‐

Vaginal Discharge ‐ ‐ 0‐4% ‐ ‐ ‐

Vomiting 2% ‐ 0‐4% 0% ‐ 0‐3%

1Range based on doses of 2mg, 10mg, and 20mg injection 2Report of postural hypotension 3Reported results based on 156mg dose 4Reported as injection site reactions EPS‐Extrapyramidal Syndrome

Property of IME and may not be reproduced without permission. Antipsychotics‐18

DRUG‐DRUG INTERACTIONS 1‐9, 32‐33, 67, 95‐99

There are some drug‐drug interactions that are pharmacodynamic in origin‐ occurring at the transmitter level or beyond. For instance, it is recommended that all medications in this therapeutic class be used with caution if used in combination with other antihypertensive medications, as well as centrally acting drugs, including alcohol. The hypotensive effect may be potentiated and concomitant use with centrally acting drugs may lead to additive side effects. Combination use of clozapine with anticholinergics or benzodiazepines can also cause additive effects and should be given with caution. It is also suggested that all medications in this class except for Abilify® and clozapine be used with caution if used in combination with levodopa/dopamine agonists. It is suggested that since there is antagonism, levels of levodopa may decrease. Geodon® should not be used with any drug that causes prolongation of the QT interval.

The following are tables that pertain to pharmacokinetic drug interactions that occur with particular medications within this class.

aripiprazole (Abilify®): metabolized by CYPs 3A4 and 2D6

Drug/Class Mechanism of Drug Interaction Clinical Recommendations CYP3A4 Inducers CYP3A4 ↑Abilify ®dose by 50% (Ex: carbamazepine) CYP3A4 Inhibitors CYP3A4 ↓ Abilify® dose by 50% (Ex: ketoconazole) CYP2D6 inhibitors CYP2D6 ↓ Abilify® dose by 50% (Ex: fluoxetine/paroxetine)

asenapine (Saphris®): Asenapine is primarily metabolized through direct glucuronidation by UGT1A4 and CYP450 enzymes, predominantly CYP1A2. Asenapine is a weak inhibitor of CYP2D6 and thus coadministration of substrates of CYP2D6 may result in increased levels of the substrate.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations Asenapine ↑ of AUC by 29%; fluvoxamine CYP1A2 inhibition Use combination with caution. CYP2D6 Inhibitors CYP2D6 Use combination with caution. (eg. paroxetine)

clozapine (Clozaril®, Fazaclo®): Clozapine is metabolized principally by CYP1A2, but it also has minor pathways: CYP3A4, flavin containing monooxygenase FMO3, and possibly CYP2D6, CYP2C9 and CYP2C19. It is glucuronidated by UGT1A4. It is a modest inhibitor of CYP2D6 and 3A4. As a result, Clozapine is particularly vulnerable to CYP1A2 inhibition (e.g., fluvoxamine, ciprofloxacin, oral contraceptives and others) and CYP1A2 induction (e.g., cigarette smoke, carbamazepine). Fluvoxamine increases levels of clozapine over 200% probably because it is a pan‐inhibitor and affects other pathways of Clozapine metabolism. CYP inhibitors of CYP2D6 or 3A4 variably increase levels of clozapine and are not easily explained. Neither

Property of IME and may not be reproduced without permission. Antipsychotics‐19

ketoconazole nor nefazodone (potent CYP3A4 inhibitors) have a significant effect on Clozapine concentration. Fluoxetine and paroxetine and citalopram increase clozapine concentration and sertraline variably may do so.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations CYP1A2 Inducers CYP 1A2 ↓ Clozapine by 50%. (Ex: Carbamazepine) CYP1A2 Inhibitors Cipro ↑clozapine 30%, but ﬂuvoxamine ↑ CYP system (eg: ciprofloxacin/fluvoxamine) ≥200%. Dose ↓ is required.

citalopram unknown ↑ Concentraon of Clozapine; dose↓.

Other CYP2D6 or3A4 Inhibitors ↑ Concentraon of Clozapine by over 30%; CY2D6 (Ex Fluoxetine, Paroxetine) ↓ Clozapine dose. Potential for ↑ risk of QT prolongaon; risperidone Additive effect Avoid combination.

iloperidone (Fanapt®): Iloperidone is metabolized by CYP3A4 and CYP2D6 enzymes.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations CYP3A4 inhibitors Iloperidone levels↑ by 50%; CYP3A4 (e.g. ketoconazole) ↓ dose of iloperidone by ½ and monitor. CYP2D6 Iloperidone levels ↑ 2‐3 fold; CYP2D6 (e.g. fluoxetine) ↓ dose of iloperidone by ½ and monitor. QTc interval prolongation drugs Additive effects Avoid combination. (e.g. quinidine)

lurasidone (Latuda®): Lurasidone is primarily metabolized by CYP3A4.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations

Strong CYP3A4 inhibitors CYP3A4 Combination Contraindicated. (e.g. ketoconazole) Strong CYP3A4 inducers CYP3A4 Combination Contraindicated. (e.g. rifampin) Moderate CYP3A4 inhibitors Use combination with caution and monitor; CYP3A4 (e.g. diltiazem) Max dose of 40mg/day with combination.

Moderate CYP3A4 inducers CYP3A4 Use combination with caution and monitor.

olanzapine (Zyprexa®, Zyprexa® Relprevv): It is principally metabolized via glucuronidation by UGT1A4. Minor pathways include CYP1A2, 2D6, ABCB1 (p‐glycoprotein) and flavin containing monooxygenase FMO3. As a result, probenecid, an inhibitor of UGT1A4 is known to increase the concentration of Zyprexa®, and it is likely that UGT1A4 inducers will decrease its concentration, but UGT‐based DDIs are poorly documented.

Property of IME and may not be reproduced without permission. Antipsychotics‐20

When assessing potential drug interactions for Zyprexa® Relprevv, the results from the studies of oral olanzapine should be used.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations UGT1A4 inhibitor UGT1A4 ↑ Likely and ↓ dose of Zyprexa® if necessary. (eg: Probenecid) UGT1A4 Inducer UGT1A4 Levels of olanzapine ↓ up to 70%; (eg. carbamazepine) CYP1A2 Olanzapine dose ↑ is required. CYP1A2 Inducers Olanzapine levels ↓ by 12‐40%; CYP1A2 (eg: Cigarette smoke) Dose ↑is required. CYP1A2 Inhibitors Olanzapine levels ↑ by 12‐64%; CYP1A2 (eg: fluvoxamine) Dose ↓ is required. CYP2D6 Inhibitors Some ↑ in olanzapine levels seen; CYP2D6 (eg. fluoxetine) Monitor combination. olanzapine/fluoxetine (Symbyax®): The risks of treating with Symbyax® in combination with other medications have not been extensively assessed. The drug‐drug interactions with the individual ingredients are applicable to Symbyax®. paliperidone (Invega®, Invega® Sustenna): Invega is a weak inhibitor of P‐glycoprotein (P‐gp). When assessing potential drug interactions for Invega® Sustenna, the results from the studies of oral iloperidone should be used.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations

↓ Paliperidone concentraons; carbamazepine CYP Monitor and ↑ dose if necessary. quetiapine (Seroquel®/Seroquel® XR): Seroquel ® is metabolized principally by CYP3A4 and CYP2D6 is a minor pathway.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations CYP3A4 Inducers Cmax of quetiapine is ↓ approximately 80%; CYP3A4 (eg: carbamazepine) ↑ Dose is required. Thioridazine Cmax of quetiapine is ↓ by 47%; ?CYP3A4 ?CYP3A4 Inducer Dose ↑ is required. CYP3A4 Inhibitors ↑ queapine levels, 84% ↓ clearance; CYP3A4 (eg: ketoconazole) Dose ↓ may be required. risperidone (Risperdal®, Risperdal® Consta): Risperidone is metabolized by CYP2D6, 3A4 and ABCB1 (p‐ glycoprotein), with modest inhibitor of CYP2D6. Formal drug‐drug interaction studies have not been done with Risperdal Consta; therefore, data is used from oral risperidone.

Property of IME and may not be reproduced without permission. Antipsychotics‐21

Drug/Class Mechanism of Drug Interaction Clinical Recommendations

CYP3A4 Inducers Risperidone levels ↓; CYP3A4 (eg: phenobarbital/phenytoin) ↑dosage is required. CYP3A4 Inhibitors Risperidone levels substantially ↑; CYP3A4 (eg: itraconazole) ↓ Dosage is required. CYP2D6 Inhibitors Risperidone levels substantially ↑; CYP2D6 (eg: fluoxetine/paroxetine) ↓ Dosage is required.

ziprasidone (Geodon®): principally metabolized through a Phase 1 enzyme aldehyde oxidase. CYP3A4 is only a minor pathway.

Drug/Class Mechanism of Drug Interaction Clinical Recommendations Potent CYP3A4 Inhibitors Cmax of ziprasidone ↑ by 30%; CYP3A4 (eg: ketoconazole) Monitor combination. Potent CYP3A4 Inducers Levels of ziprasidone may be ↓; CYP3A4 (eg: carbamazepine) Monitor combination & adjust dose if needed.

Property of IME and may not be reproduced without permission. Antipsychotics‐22

TYPICAL ANTIPSYCHOTICS

FDA APPROVED INDICATIONS183‐194

Drug CHLO1 FLU HAL LOX PER PER/AMI PIM THIOR THIOT TRI

Schizophrenia X X X X6 X7 X X

Manifestations of psychotic disorders X X X Manifestations of manic type of X manic‐depressive illness Severe behavioral problems in children2 X X9 Short‐term treatment of generalized X3 non‐psychotic anxiety Short‐term treatment of X X9 hyperactive children8 Control of tics & vocal utterances of X4 Tourette’s Disorder Control of nausea/vomiting X4 X4‐A Control motor/phonic tics of Tourette’s X5 Disorder: 2nd line treatment Moderate to severe Anxiety and/or X agitation and depressed mood For depression where anxiety and/or X agitation are severe For depression and anxiety associated X with chronic physical disease 1 Other indications includes: Relief of restlessness/apprehension before surgery; Acute intermittent porphyria; Adjunct treatment of tetanus; Relief of intractable hiccups 2 In children 1‐12 yrs of age marked by combativeness and/or explosive hyper‐excitable behavior, 3 Not as 1st line age, AND not to be used at doses of >6mg/day or for longer than 12 weeks, as it may cause persistent tardive dyskinesia that may prove irreversible 4 In adults and children 4‐A In adults only 5 Not for 1st line treatment or in for those whose tics are merely annoying or cosmetically troublesome, but for those whose development and/or daily life function is severely compromised who have failed to respond to standard treatment 6 In schizophrenic patients who have associated depressive symptoms 7 In those who fail to respond adequately to treatment with other antipsychotics, strongly recommended at least 2 trials with a different antipsychotic drug product at an adequate dose and for an adequate duration. 8 Who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. 9 Only after failure to respond to psychotherapy or medications other than antipsychotics.

Property of IME and may not be reproduced without permission. Antipsychotics‐23

The following table includes the injectable formulations of the typical antipsychotics and the approved indications. Tourette’s Disorder: Management of those with need for Drug Schizophrenia tics & vocal utterances prolonged parenteral neuroleptic therapy

chlorpromazine HCl1 fluphenazine decanoate X X haloperidol decanoate X X (Haldol®) haloperidol lactate X X (Haldol®) 1 Same indications as listed above with oral chlorpromazine

DOSAGE FORM, DOSE, MANUFACTURER183‐194

Dosage forms and specific dosages vary significantly by product and indication.

Haloperidol decanoate (Haldol® Decanoate) is the long‐acting injectable form of injectable haloperidol lactate (Haldol®), with the only difference between the two products being the duration of action.

Drug Dosage Form Manufacturer Tablets: 10mg, 25mg, 50mg, 100mg, 200mg chlorpromazine Various generic manufacturers Injectable: 25mg/ml Tablets: 1mg, 2.5mg, 5mg, 10mg Elixir: 2.5mg/5ml Oral Concentrate: fluphenazine Various generic manufacturers 5mg/ml Injection, decanoate: 25mg/ml Injection, HCl: 2.5mg/ml Tablets: 0.5mg, 1mg, 2mg, 5mg, 10mg, 20mg Oral Concentrate: haloperidol 2mg/ml Various generic manufacturers (Haldol®) Injection, lactate: (Janssen) 5mg/ml Injection, decanoate: 50mg/ml, 100mg/ml

Property of IME and may not be reproduced without permission. Antipsychotics‐24

Drug Dosage Form Manufacturer

loxapine Capsules: Various generic manufacturers (Loxitane®) 5mg, 10mg, 25mg, 50mg (Watson Labs) Tablets: perphenazine Various generic manufacturers 2mg, 4mg, 8mg, 16mg Tablets: perphenazine/amitriptyline Various generic manufacturers 2/10mg, 2/25mg, 4/10mg, 4/25mg, 4/50mg pimozide Tablets: Gate Pharma (Orap) 1mg, 2mg thioridazine Tablets: Various generic manufacturers (Mellaril®) 10mg, 25mg, 50mg, 100mg thiothixene Capsules: Various generic manufacturers (Navane®) 1mg, 2mg, 5mg, 10mg, 20mg (Pfizer) Tablets: trifluoperazine Various generic manufacturers 1mg, 2mg, 5mg, 10mg

PHARMACOLOGY183‐195

The exact mechanism of chlorpromazine, fluphenazine, and perphenazine are not known; however, they do have activity at all levels of the CNS.

All first generation antipsychotics bind to post‐synaptic D2 receptors, which is the mechanism thought to mediate their therapeutic effect. These agents vary in regards to their specific binding affinities with strong antagonists such as pimozide and haloperidol exerting the highest potency effect and chlorpromazine demonstrating the lowest potency. Perphenazine and thiothixene are mid‐potency agents. (The stronger the D2 antagonism, the lower dose needed to achieve a therapeutic effect.) Blockade of approximately 65 % of D2 receptors is associated with antipsychotic efficacy. High potency drugs, by virtue of their strong D2 antagonism, also have the highest rates of neurologic side effects. Such side effects occur when approximately 80 % of D2 receptors are blocked.

Lower potency agents such as chlorpromazine and thioridazine are associated with higher rates of sedation, anticholinergic side effects, and weight gain mediated by increased affinity towards H1 and cholinergic antagonism.

Thioridazine (Mellaril®) is piperidine phenothiazine. It is thought to work by blocking post synaptic dopamine (D2) receptors in the brain.

Thiothixene (Navane®) is from the thioxanthene series, with actions similar to the piperazine phenothiazines.

Trifluoperazine is a phenothiazine. It also exhibits anticholinergic activity, alpha‐adrenergic inhibition, and prolactin level elevation.

Property of IME and may not be reproduced without permission. Antipsychotics‐25

Amitryptiline is a tricylclic antidepressant and, when used in combination with perphenazine additive antidepressant effect is present.

PHARMACOKINETICS183‐195

Very limited information was found regarding the pharmacokinetics of the typical antipsychotics.

Time to Drug Half‐Life Excretion Peak Concentration chlorpromazine Data not found 6 hrs Renal: 23%

fluphenazine Data not found 33 hrs Not reported haloperidol IM: 3 weeks Renal: 33‐40% Data not found (Haldol®) IV: 14 hours Feces: 15% loxapine Renal: 50% 1.5‐3 hrs 4 hrs (Loxitane®) Feces: 50% perphenazine Data not found 8‐12 hrs Not reported per: 8‐12 hrs perphenazine/amitriptyline Data not found Renal: 18% ami: 27 hrs pimozide 4‐12 hrs 55 hrs Renal: major (Orap®) thioridazine Data not found 21‐24 hrs Renal (Mellaril®) thiothixene Data not found 34 hrs Not reported (Navane®) trifluoperazine Data not found 24 hrs Not reported

CONTRAINDICATIONS183‐195

Please refer to the table below for specific contraindications unique to each product.

Drug Contraindications

Hypersensitivity to phenothiazines; chlorpromazine In comatose states or in the presence of large amounts of CNS depressants. In those with suspected/established subcortical brain damage; In those receiving large doses of hypnotics; In comatose or severely depressed states; fluphenazine HCl In those with blood dyscrasia or liver damage; Cross‐sensitivity to phenothiazine derivatives; In those children less than 12 years of age (with Decanoate Injection ONLY).

Property of IME and may not be reproduced without permission. Antipsychotics‐26

Drug Contraindications

haloperidol In severe toxic CNS depression or comatose states; (Haldol®) Parkinson’s disease. loxapine In those with a known hypersensitivity to dibenzoxepine; (Loxitane®) In those comatose or in severe drug‐induced depressed states. In those comatose or greatly obtunded; In those receiving large doses of CNS depressants; perphenazine In presence of existing blood dyscrasias, bone marrow depression, or liver damage; Hypersensitivity to related compounds; In those with suspected/established subcortical brain damage. In depression of the CNS from drugs (ie barbiturates, alcohol, narcotics); perphenazine/ In presence of evidence of bone marrow depression; In those with hypersensitivity to phenothiazines or amitriptyline; amitriptyline Concomitant use with monoamine oxidase inhibitors; Use during the acute recovery phase following MI. In the treatment of simple tics or tics other than those associated with Tourette’s Disorder; In those taking drugs that may themselves cause motor/phonic tics; In those with congenital long QT syndrome, history of cardiac arrhythmias, taking other drugs which may prolong the QT interval, or those with known hypokalemia or hypomagnesemia; In those with severe CNS depression or comatose states from any cause; pimozide Hypersensitivity to related compounds/other antipsychotic drugs; (Orap®) Concomitant use with macrolide antibiotics (eg. clarithromycin, erythromycin, azithromycin); Concomitant use with Celexa®, Lexapro®, nefazodone, or sertraline; Concomitant use with paroxetine and other strong CYP2D6 inhibitors; Concomitant use with strong CYP3A4 inhibitors, including azole antifungals (itraconazole & ketoconazole) and protease inhibitors (eg ritonavir, saquinavir, indinavir, & nelfinavir); Other less potent CYP3A4 inhibitors should be avoided (eg zileuton, fluvoxamine). Concomitant use with other drugs known to prolong QTc interval; In those with congenital long QT syndrome or a history of cardiac arrhythmias; thioridazine Concomitant use with CYP2D6 inhibitors (ie fluoxetine and paroxetine); In those with a genetic defect leading to reduced levels of activity of CYP2D6. thiothixene In those with circulatory collapse; In those with comatose states or with CNS depression due to any cause; (Navane®) In those with blood dyscrasias. Hypersensitivity to phenothiazines; trifluoperazine Comatose or greatly depressed states due to CNS depressants; In cases of existing blood dyscrasias, bone marrow depression & pre‐existing liver damage.

SPECIAL POPULATIONS183‐195

Per the prescribing information of these products, the safety for use during pregnancy has not been established; however, the pregnancy ratings included below comes from MicroMedex®. Limited information was found regarding dose adjustment in those with renal impairment.

Property of IME and may not be reproduced without permission. Antipsychotics‐27

Dosage Adjustment with Dosage Adjustment with Drug Pediatrics Pregnancy Renal Impairment Hepatic Impairment Initiate ↓ doses, adjust chlorpromazine ≥6 mths C Use with caution gradually; monitor/use caution. Monitor closely; fluphenazine Yes C Not found discontinue if necessary haloperidol ≥3 yrs C Not reported Not reported (Haldol®) loxapine No N/E Not found ↓ Dose; monitor. (Loxitane®) Monitor closely; perphenazine ≥12 yrs C ↓ Dose; monitor. Discontinue if necessary perphenazine/amitriptyline No N/R Not found Use with caution.

pimozide ≥12 yrs C Monitor/use with caution ↓ Dose; monitor. (Orap®) thioridazine ≥2 yrs C Not found ↓ Dose; monitor. thiothixene ≥12 yrs C Not found ↓ Dose; monitor. (Navane®)

trifluoperazine ≥6 yrs C Not found ↓ Dose; monitor.

N/E‐ Not established; N/R‐ Use Not Recommended

ADVERSE DRUG REACTIONS183‐195

All antipsychotics have a boxed warning regarding the risk of increased mortality in elderly patients with dementia‐related psychosis. In a clinical study, the rate of death in drug‐treated patients was 4.5% with active treatment vs 2.6% with placebo, with most deaths being cardiovascular related (eg. heart failure, sudden death) or infectious (eg. pneumonia).

Thioridazine also has a boxed warning regarding the risk of prolongation of the QTc interval with use, in a dose‐related manner. Thioridazine has been associated with Torsades de pointes type arrhythmias and sudden death. Therefore, thioridazine should be reserved for those who need treatment and have not had an acceptable response to adequate courses of treatment with other antipsychotic drugs, either due to insufficient effectiveness of the inability to obtain an effective dose due to intolerable adverse events from these drugs.

Due to the amitriptyline portion of the product, a second boxed warning also exists for perphenazine/amitriptyline regarding the risk of suicidality with antidepressant use. In short‐term clinical trials, there have been reports of increased risk of suicidal thinking and behavior (suicidality) among children, adolescents, and young adults with antidepressant use vs placebo. Those initiating treatment with antidepressants should be closely monitored for clinical worsening, suicidality, or unusual changes in

Property of IME and may not be reproduced without permission. Antipsychotics‐28 behavior. Families and caregivers should also be educated of the need for close monitoring and for communicating with the prescriber.

Neuroleptic malignant syndrome (NMS), although rare, is associated with antipsychotic use. Symptoms include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (such as irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). If NMS is diagnosed, the antipsychotic should be discontinued, with intense monitoring and treatment of serious problems.

The risk of seizure is also associated with antipsychotic use, especially in those with EEG abnormalities or a history of such disorders.

Persistent tardive dyskinesia is associated with this class of medication. It is thought the risk is greater in the elderly. Symptoms, which may be irreversible in some, are characterized by rhythmical, involuntary movements of the tongue, face, mouth, or jaw, sometimes associated with involuntary movements of the extremities.

Dystonia is another class effect of antipsychotics, which is characterized by a prolonged abnormal contraction of muscle groups, with spasms of the neck muscles, sometimes progressing to tightness of the throat, in addition to difficulty in swallowing, difficulty breathing, and/or protrusion of the tongue. These effects may be of greater severity with high potency and at higher doses.

All typical antipsychotics have been associated with serious prolonged QT interval and, although rare, Torsades de pointes (except for chlorpromazine with the latter).

Adverse events associated with perphenazine/amitriptyline combination are those previously reported with perphenazine and amitriptyline. Please refer to the table below for perphenazine adverse events. Commonly reported adverse events with amitriptyline include weight gain, constipation, xerostomia, dizziness, headache, somnolence, and blurred vision.

The most commonly reported adverse events with the typical antipsychotics are listed in the table below. Placebo data was not available for comparisons.

Cardiovascular Adverse Event CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Hypotension ‐ √ √ √ √ √ √ √ √

Orthostatic Hypotension √ √ ‐ √ √ √ √ √ √

Tachycardia √ ‐ ‐ ‐ ‐ ‐ ‐ ‐

CHLO‐chlorpromazine; FLU‐fluphenazine; HAL‐haloperidol (Haldol®); LOX‐loxapine (Loxitane®); PER‐perphenazine; PIM‐pimozide (Orap®); THIOR‐thioridazine; THIOT‐thiothixene (Navane®); TRI‐trifluoperazine.

Dermatologic Adverse Event CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

↓Sweang ‐ √ ‐ ‐ √ √ √ √ √

Photosensitivity ‐ √ ‐ ‐ √ √ √ √ √

Property of IME and may not be reproduced without permission. Antipsychotics‐29

Gastrointestinal Adverse Events CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Constipation √ √ √ √ √ √ √ √ √

Nausea √ ‐ ‐ ‐ ‐ ‐ ‐ ‐

Xerostomia √ √ √ √ √ √ √ √ √

Neurologic Adverse Events CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Akathisia √ √ √ √ √ √ √ √ √

Dizziness √ √ ‐ √ √ √ √ √ √

Dystonia √ √ √ √ √ √ √ √ √

Extrapyramidal disease ‐ √ √ √ √ √ √ √ √

Parkinsonism √ √ ‐ √ √ √ √ √ √

Somnolence √ √ √ √ √ √ √ √ √

Tardive dyskinesia √ √ ‐ √ √ √ √ √ √

Tardive dystonia‐ drug induced ‐ √ ‐ √ √ √ √ √ √

Endocrine Adverse Events CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Ineffective thermoregulation √ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐

Heatstroke √ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐

Hypothermia √ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐

Miscellaneous Adverse Events CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Blurred vision ‐ √ √ √ √ √ √ √ √

Property of IME and may not be reproduced without permission. Antipsychotics‐30

Miscellaneous Adverse Events CHLO FLU HAL LOX PER PIM THIOR THIOT TRI

Epithelial keratopathy ‐ √ ‐ √ √ √ √ √ √

Eye/vision finding ‐ √ ‐ √ √ √ √ √ √

Nasal Congestion ‐ √ ‐ √ √ √ √ √ √

Retinitis pigmentosa ‐ √ ‐ √ √ √ √ √ √

Urinary retention ‐ ‐ √ √ √ √ √ √

DRUG INTERACTIONS34

Please refer to the Contraindications section for a complete list of drugs contraindicated with use with each specific agent.

Please refer to the tables below for drug‐drug interactions with specific agents in this class.

All antipsychotics:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↑ risk of EPS or NMS with concurrent use; Metoclopramide Concomitant use contraindicated

Chlorpromazine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Alcohol Additive effects and hypotension. Additive anticholinergic toxicity; Anticholinergics Use combo with caution and adjust dose as needed. ↓ eﬀect of oral ancoagulant; Anticoagulants Monitor and adjust as needed. Prolongs and intensifies the CNS depressants; CNS depressants Concurrent use with ↑ dose of CNS depressant is contraindicated. Drugs that prolong ↑ risk of QT prolongaon;

QT interval Some are contraindicated and others should be used with caution. May counteract antihypertensive effect; Guanethidine Monitor.

Property of IME and may not be reproduced without permission. Antipsychotics‐31

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↓ effects of levodopa; Levodopa Concomitant use not recommended. Possible ↑ risk of neurologic toxicity; Lithium If occurs, D/C treatment. ↓ effects of pergolide; Pergolide Monitor. ↑ levels of both; Propranolol Monitor and consider dose reduction of both agents. ↑ levels of chlorpromazine, ↑ effects including EPS & cardiac arrhythmias; SSRIs Monitor. If interaction occurs, consider ↓ dose or D/C one or both agents. ↑ plasma levels of both, with ↑ risk of toxicity; TCAs Monitor closely. Additive orthostatic hypotension effects; Thiazide diuretics Monitor. ↑ risk of seizure; Tramadol Avoid concomitant use. ↑ levels and effects of trazodone; Trazodone If interaction is suspected, ↓ trazodone dose.

Fluphenazine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↓ Effectiveness of fluphenazine & additive anticholinergic toxicity; Anticholinergics Use combo with caution and adjust dose as needed. Haloperidol may ↓ convulsive threshold; Anticonvulsants Monitor and adjust anticonvulsant dose as needed. ↓ effects of cabergoline; Cabergoline Co‐administration is not recommended. Potentiation of CNS depressants; CNS depressants Use of fluphenazine with large doses of hypnotics is contraindicated. Antihypertensive effect ↓; Guanethidine Avoid combination if possible. If not, monitor & adjust guanethidine dose. Prolonged QT interval & cardiac arrhythmias with combo; Haloperidol Use with caution and monitor. ↓ effects of levodopa; Levodopa Concomitant use not recommended. If use, monitor closely. ↓ fluphenazine effects & severe neurotoxicity been reported; Lithium Monitor. ↓ effects of pergolide; Pergolide Concomitant use is not recommended.

Property of IME and may not be reproduced without permission. Antipsychotics‐32

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↑ fluphenazine levels, ↑effects and adverse events; SSRIs Monitor and if interaction is suspected, ↓ dose or d/c one or both agents. ↑ risk of seizures; Tramadol Co‐administration is not recommended. ↑ levels and effects of trazodone; Trazodone Monitor and ↓ dose of trazodone as needed.

Haloperidol:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Effectiveness of haloperidol may be ↓; Anticholinergics Use combo with caution and adjust dose as needed. Haloperidol may ↓ convulsive threshold; Anticonvulsants Monitor and adjust anticonvulsant dose as needed. Antiparkinson agents Haloperidol contraindicated in those with Parkinson disease. (eg levodopa) ↑ levels of haloperidol and adverse events; Azole antifungals Monitor clinical response and adjust haloperidol dose as needed. Severe hypotension reaction with combination; Beta‐blockers Monitor and use supportive treatment if occurs. ↓ levels of haloperidol, ↑ levels carbamazepine; Carbamazepine Monitor clinical response and adjust dose as needed. Drugs that prolong Additive QT interval prolongation, ↑ risk of cardiac arrhythmias;

QT interval Monitor for QT prolongation. CNS‐depressant effects enhanced; Ethanol Avoid concomitant use. Toxic effects, including EPS syndrome, hyperthermia, unconsciousness; Lithium Effect is unpredictable, monitor for neurologic functions. D/C if occurs. ↑ CNS depressant effects; Opioids Use combination with caution and adjust dose as needed. ↓ haloperidol levels; Rifamycins Monitor for clinical response and adjust haloperidol dose as needed. ↑ levels of haloperidol, ↑ eﬀects and risk of toxicity; SSRIs Monitor and if toxic signs occur, d/c one or both agents. ↑ Risk of severe EPS; Tacrine Monitor and if interaction is suspected, d/c one or both agents. ↑ risk of seizures; Tramadol Co‐administration is not recommended.

Property of IME and may not be reproduced without permission. Antipsychotics‐33

Loxapine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Additive anticholinergic toxicity; Anticholinergics Use combo with caution. Reports of significant respiratory depression, stupor, hypotension; Lorazepam Monitor. ↑ sleep duraon and CNS depression; Sodium oxybate Sodium oxybate contraindicated with other sedative‐hypnotics. ↑ risk for seizures; Tramadol Concurrent use not recommended.

Perphenazine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Additive anticholinergic toxicity; Anticholinergics Use combo with caution. Anticonvulsants Perphenazine ↓ convulsive threshold;

(eg carbamazepine) Monitor and ↑ dose of anconvulsant medicaon as needed. Effects of cabergoline may be ↓; Cabergoline Co‐administration is not recommended. May enhance CNS depression so use with caution; CNS depressants Avoid alcohol; ↑ doses of CNS depressants contraindicated. ↓ Anhypertensive effecveness; Guanethidine Monitor blood pressure and adjust dose as needed. Effect of levodopa may be ↓; Levodopa If co‐administration cannot be avoided, monitor & adjust dose as needed. Perphenazine effects ↓ & risk of severe neurotoxicity; Lithium Monitor and adjust dose as needed. ↓ effects of pergolide; Pergolide Coadministration is not recommended. ↑ levels of perphenazine; SSRIs Monitor and adjust dose as needed. ↓ effects of tamoxifen, may ↑ increase risk of breast cancer recurrence; Tamoxifen If possible, avoid combination. ↑ levels of both agents, ↑ risk of adverse events; TCAs Monitor for clinical response and adjust dose/therapy as needed. ↑ risk for seizures; Tramadol Avoid concurrent use. ↑ levels of trazodone; Trazodone Monitor and adjust dose of trazodone if necessary.

Property of IME and may not be reproduced without permission. Antipsychotics‐34

Perphenazine/Amitriptyline:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Additive anticholinergic toxicity; Anticholinergics Combo may worsen schizophrenic symptoms & lead to tardive dyskinesia. May ↓ amitriptyline levels; Barbiturates Monitor. May ↓ amitriptyline levels; Carbamazepine Monitor. May ↑ amitriptyline levels; Cimetidine Monitor. May cause hypertensive crisis; Clonidine Monitor. May enhance CNS depression so use with caution; CNS depressants Monitor; Avoid alcohol. May ↑ amitriptyline levels; Fluoxetine Monitor. May ↑ amitriptyline levels; Haloperidol Monitor. Do NOT use with MAOI. MAOIs Wait 14 days when switch from MAOI & initiate new therapy. May ↑ amitriptyline levels; Oral contraceptives Monitor.

Pimozide:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction May prolong QT interval, ↑ risk of cardiac arrhythmias; Antiarrhythmic agents Do not co‐administer. Additive anticholinergic toxicity; Anticholinergics Use combo with caution. ↑ risk of life threatening cardiac arrhythmias; Azole antifungals Combination contraindicated. Additive depressant effects may occur with concomitant use; CNS agents Monitor. Pimozide is partially metabolized by CYP3A4, ↑ risk of arrhythmias; CYP3A4 inhibitors CYP3A4 pathway Avoid combination. Additive effects of QT interval prolongation, ↑ risk of cardiac arrhythmias; Dolasetron Do not co‐administer. Additive effects of QT interval prolongation, ↑ risk of cardiac arrhythmias; Droperidol Do not co‐administer.

Property of IME and may not be reproduced without permission. Antipsychotics‐35

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Drugs that cause Concomitant use is contraindicated. motor or phonic tics Additive effects of QT interval prolongation, ↑ risk of cardiac arrhythmias; Fluoroquinolones Avoid combination. Additive effects of QT interval prolongation anticipated; Haloperidol Avoid combination. ↑ levels of pimozide, thus ↑ risk cardiac arrhythmias; Nefazodone Combination is contraindicated. Prolong QT interval, thus ↑ risk of cardiac arrhythmias; Phenothiazines Thioridazine is contraindicated with concomitant use of pimozide. ↑ levels of pimozide, thus ↑ risk cardiac arrhythmias; Protease Inhibitors Combination is contraindicated. ↑ risk of life‐threatening cardiac arrhythmias, plus torsade de pointes; SSRIs Contraindicated with citalopram, fluvoxamine, paroxetine, sertraline. Prolong QT interval, thus ↑ risk of cardiac arrhythmias; Tacrolimus Do not administer combination. Potential additive effect on QT interval; TCAs Do not administer combination. ↑ pimozide levels & cause QT prolongaon, ↑ risk cardiac arrhythmias; Zileuton Combination contraindicated. ↑ risk of life‐threatening cardiac arrhythmias, plus torsade de pointes; Ziprasidone Combination contraindicated.

Thioridazine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Additive anticholinergic toxicity; Anticholinergics Use combo with caution and adjust thioridazine dose if necessary. Beta‐blockers ↑ levels of thioridazine. Not known if other b‐blockers act in same way;

(pindolol/propranolol) Concurrent use not recommended May potentiate CNS depressants; CNS depressants Monitor for severe respiratory depression and respiratory arrest. Drugs that prolong ↑ risk for QT prolongation;

QT interval Concomitant use contraindicated. ↑ risk cardiac arrhythmias; Duloxetine If co‐administer, Monitor and adjust dose of thioridazine as needed. ↓ eﬀect of levodopa; Levodopa Concomitant use not recommended. If use, monitor. ↓ eﬀects of pergolide; Pergolide Monitor combination.

Property of IME and may not be reproduced without permission. Antipsychotics‐36

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↓ levels of queapine potenally; Quetiapine Monitor combination. ↑ levels of risperidone; Risperidone Monitor closely, especially during initial stages of use. ↑ levels of thioridazine thus ↑ risk of eﬀects of EPS and cardiac; SSRIs Concomitant use of fluvoxamine/fluoxetine/paroxetine contraindicated. ↓ eﬀects of tamoxifen, may ↑ increase risk of breast cancer recurrence; Tamoxifen If possible, avoid combination. ↑ levels of both and risk for ↑ toxicity; TCAs Monitor combination. ↑ risk for seizures; Tramadol Avoid concurrent use. ↑ levels of trazodone; Trazodone Monitor and adjust dose of trazodone if necessary.

Thiothixene:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↑ ancholinergic effects; Anticholinergics Use combination with caution. ↑ clearance of thiothixene; Carbamazepine Monitor for reduced thiothixene effectiveness. May enhance CNS depression, especially impairment of motor skills; CNS depressants Use combination with caution and adjust dose if needed. Avoid alcohol. Antihypertensive effects may be counteracted; Guanethidine Monitor or consider alternative therapy. May potentiate hypotension; Hypotensive agents Monitor blood pressure. ↑ risk of neurotoxicity, including EPS; Lithium Monitor closely and reduce dose or discontinue treatment if needed. ↑ risk for seizures; Tramadol Avoid concurrent use.

Trifluoperazine:

Mechanism of Drug/Class Clinical Recommendations Drug Interaction ↓ eﬀect of oral ancoagulants; Anticoagulants Monitor and adjust dose of anticoagulant as needed. May ↓ convulsive threshold; Anticonvulsants Adjust dose of anticonvulsant if needed.

Property of IME and may not be reproduced without permission. Antipsychotics‐37

Mechanism of Drug/Class Clinical Recommendations Drug Interaction Additive depressant effects may occur with concomitant use; CNS agents Monitor. May ↑ risk of orthostac hypotension; Diuretics Monitor. Drugs that prolong ↑ risk to prolong QT interval & of life‐threatening cardiac arrhythmias. QT interval Antihypertensive effects may be counteracted; Guanethidine Monitor.

Property of IME and may not be reproduced without permission. Antipsychotics‐38

CLINICAL TRIALS

Clinical trials performed to obtain FDA approval confirmed all the medications in this therapeutic class to be superior in efficacy when compared with placebo, as well as showing the relative safety of the drug.

CATIE TRIAL:

One of the most influential comparative trials of AAPs in schizophrenia are the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which did not support superior clinical efficacy of AAPs over TAPs. Rather it showed a similar efficacy for treating psychosis and a lack of efficacy for impaired cognition for perphenazine and the available AAPs, as well as differing adverse events. Zyprexa® had the longest time to discontinuation, the proxy outcome of CATIE, but was associated with significant adverse events, especially weight gain and the Metabolic Syndrome (See Adverse Drug Reactions section). Additionally, the dosage of Zyprexa® was in the high range while some of the other AAPs were dosed in their low range.

In Phase 2 of CATIE, clozapine was noted to be as a superior agent for treatment resistant schizophrenia (TRS).13 Clozapine is clinically indicated after failure of two other antipsychotics. Similar conclusions were reached by the World Psychiatric Association after reviewing 1600 randomized controlled trials. Confirming the superiority of clozapine in TRS, they found no significant differences in the clinical efficacy of any other individual AAP.14,15 A meta‐analysis of AAPs has confirmed the superiority of clozapine compared to other AAPs in preventing suicide in schizophrenia16, and a head‐to‐head trial of clozapine to Zyprexa® also demonstrated the superiority of clozapine.17

In Jan 2009, results of the phase 3 CATIE schizophrenia trials were published.41 Subjects who discontinued antipsychotic therapy in phases 1 and 2 were able to participate in the phase 3 trial. The doctor and the subjects collaborated to determine which therapy would be most appropriate for use during the phase 3 trials, and the decision was based on clinical factors such as severity of symptoms, response to prior treatment, and health status. Available treatment options included aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long‐acting injectable fluphenazine decanoate, or a combination of any of the two treatments. Of the 270 subjects in the CATIE phase 3 trials, only 9 selected fluphenazine and 4 selected perphenazine. Furthermore, those who were most symptomatic chose either clozapine or combination therapy. Those with the highest body mass index chose either aripiprazole or ziprasidone. Therefore, generalizability of these findings may be limited. Nonetheless, results showed that all groups reported improvements in symptoms. Adverse reactions between treatment groups did fluctuate during the trial; however, only 7% overall discontinued therapy due to intolerability.

First generation Antipsychotics:

First generation antipsychotics all have activity in treating the symptoms of psychosis and schizophrenia, thought mediated by dopamine blocking activity. Head‐to‐head comparator studies are limited though all FGAs have demonstrated efficacy in treating schizophrenia. Clinical differences appear related primarily to side effect profile and potency of binding at the dopamine receptor. High potency agents such as haloperidol and fluphenazine may require concomitant treatment with an anticholinergic to prevent dystonic reactions in at risk populations such as young males. Lower potency agents such as chlorpromazine are associated with significant sedation. Mid potency agents such as perphenazine, have been compared to

Property of IME and may not be reproduced without permission. Antipsychotics‐39 atypical antipsychotics as described above. Indeed, midpotency antipsychotics offer an effective treatment option with less risk of weight gain and metabolic abnormalities than seen with many of the second generation agents.

Schizophrenia Reviews/Meta‐Analysis:

A meta‐analysis by Leucht et al36 published in 2009 included 78 randomized, blinded studies that compared the second‐generation antipsychotics as treatment for schizophrenia. The primary outcome was the change in total score on the Positive and Negative Syndrome Scale (PANSS). The antipsychotics included in the analysis were aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zotepine (not approved in the US). Differences in efficacy between treatments occurred for the positive symptoms (delusions and hallucinations) but not for the negative symptoms. Olanzapine was superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Furthermore, risperidone was more efficacious than quetiapine and ziprasidone; however, the effect sizes compared to others was small. In doses greater than 400mg per day, clozapine was superior to risperidone. The effect sizes of superior treatments compared to other treatments was small casting doubt regarding the clinical significance between treatments. The author’s concluded that while there are limitations to this meta‐analysis, including trial duration, study sponsorship, study quality, and dosages, the minimal superiorities in efficacy found should only be part of the equation when determining appropriate treatment for schizophrenia. Potential risk of adverse events and cost of the medication should also be taken into consideration.

An October 2009 Cochrane Review by Klinik et al80 (Level of Evidence 1a) included 9 randomized controlled trials with data comparing oral ziprasidone with oral forms of amisulpride, clozapine, olanzapine, quetiapine, and risperidone in subjects with schizophrenia or schizophrenia‐like psychoses. Overall, compared with olanzapine and risperidone, ziprasidone was found to be a less acceptable treatment. The data reviewed by the author’s suggested that ziprasidone was less efficacious then amisulpride, olanzapine, and risperidone. Even though there was limited data, it also suggested that there were no significant differences in tolerability between ziprasidone and amisulpride or clozapine. Less weight gain and a smaller increase in cholesterol was seen with ziprasidone compared with olanzapine, quetiapine, or risperidone. On the other hand, EPS side‐effects were reported slightly more with ziprasidone compared with olanzapine. Although an increased prolactin was reported more with ziprasidone than quetiapine, it was a smaller increase in prolactin when compared with risperidone.

An October 2009 Cochrane Review by Komossa et al81 (Level of Evidence 1a) included randomized trials comparing oral aripiprazole with amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine in subjects with schizophrenia or schizophrenia‐like psychoses. There were only four studies with two comparisons eligible for inclusion and review, which included comparisons with olanzapine and risperidone. The data suggests that aripiprazole was less efficacious than olanzapine in terms of general mental state, but was associated with less metabolic issues (cholesterol increase, weight gain) and other general effects, such as sedation and prolactin increase. Similar efficacy was seen when aripiprazole was compared with risperidone. Additionally, although tremor was reported more in the aripiprazole group compared with risperidone, dystonia, QTc abnormalities, prolactin, and cholesterol was reported less.

Property of IME and may not be reproduced without permission. Antipsychotics‐40

A 2010 Cochrane Review by Komossa et al82 (Level of Evidence 1a) included randomized trials comparing quetiapine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone, and zotepine in subjects with schizophrenia or schizophrenia‐like psychosis. Data from 21 trials were used, which compared quetiapine with clozapine, olanzapine, risperidone, and ziprasidone. The data reviewed by the author’s suggested that efficacy data favored olanzapine and risperidone when compared with quetiapine; however, the clinical meaning is unclear. Furthermore, clear mental state differences were not seen when quetiapine was compared with clozapine or ziprasidone. Quetiapine resulted in slightly fewer reports of movement disorders and less weight gain and glucose elevation compared with olanzapine, but there were more reports of QTc prolongation. Results suggested that quetiapine had slightly fewer movement disorders and less prolactin increase but more of an increase in cholesterol when compared with risperidone. Lastly, compared with ziprasidone, quetiapine was more sedating, caused more weight gain, and increased cholesterol levels.

A July 2009 Cochrane Review by Cipriani et al83 (Level of Evidence 1a) reviewed randomized controlled trials to help determine the efficacy and tolerability of using various antipsychotics in combination with clozapine for treatment resistant schizophrenia. Three small studies were eligible for inclusion. Results suggested that there was not one combination strategy superior to another. The author’s concluded that a longer, larger, and independent trial is required to help determine the most effective combination treatment.

A 2010 Cochrane Review by Klinik et al84 (Level of Evidence 1a) reviewed randomized controlled trials comparing the efficacy of oral olanzapine to oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, ziprasidone, or zotepine in subjects with schizophrenia or schizophrenia‐like psychosis. There were 50 studies eligible for inclusion and review, which included comparisons of olanzapine with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, or ziprasidone. Greater improvement in general mental state (PANSS total score) was seen with olanzapine as compared with aripiprazole, quetiapine, risperidone, and ziprasidone, but not more than amisulpride or clozapine. In the trials, there were fewer subjects that required re‐hospitalization in the olanzapine groups compared with the quetiapine and ziprasidone groups, but not in the clozapine group.

Safety and tolerability were also assessed. All products except for clozapine resulted in less weight gain compared with olanzapine. Furthermore, related metabolic issues such as glucose and cholesterol increases tended to be more prominent with olanzapine use. A slight increase in EPS side effects may be reported with olanzapine use compared with quetiapine, but less than with risperidone and ziprasidone. Prolactin increases may also be reported more with olanzapine use compared with aripiprazole, clozapine, and quetiapine, but less than risperidone. Overall, the authors concluded that due to the larger weight gain and other associated metabolic problems that may arise with olanzapine use, the benefit of its slight superiority in efficacy needs to be weighed against the other second generation antipsychotics, except for clozapine.

A meta‐analysis by Barak et al130 included nine trials with 784 subjects diagnosed with schizophrenia or schizoaffective disorder that were being treated with an antipsychotic and then substituted with aripiprazole. The primary outcome of the meta‐analysis was to assess the mean change from baseline weight when switched to aripiprazole. The distribution in which weight gain resulted upon use of an antipsychotic and thus resulted in a switch to aripiprazole included 46% for olanzapine (N=352), 30% for risperidone (N=226), 22% for typical antipsychotics (N=168), 2% sulpiride (N=17), 1% for clozapine (N=11),

Property of IME and may not be reproduced without permission. Antipsychotics‐41 and 1% for quetiapine (N=10). The mean weight for the group before changing to aripiprazole was 83.8kgs and the mean aripiprazole dose was 20.2mg/day.

Results demonstrated the minimal reduction in weight was 1.2kgs, with a range up to a reduction of 5.3kg. Weight reduction when switched to aripiprazole was statistically significant in the four largest studies (p<0.001). With the analysis, it was seen that there was a mean weight reduction of 2.55kg after switching to aripiprazole, which was statistically significant (p<0.001). Some studies did not have data regarding those with a ≥7% reduction in body weight (a clinically significant reduction); however, of the data available, it was reported that 10.7% had a ≥7% reduction in weight. 4.5% (22/484) had an increase of ≥7% in weight after the switch to aripiprazole. These were statistically significant changes (p<0.0004).

There was a statistically greater mean weight reduction in those diagnosed with schizophrenia (‐2.67kgs) than schizoaffective disorder (‐2.18kg; p<0.022). Lastly, those in the olanzapine group prior to switching to aripiprazole had the greatest mean weight reduction, which was statistically significantly different (‐2.74kgs; p<0.001). Overall, the authors concluded that in those patients exhibiting significant weight gain with an antipsychotic, switching to aripiprazole could be effective for it was a lower risk of weight gain.

A 2011 nationwide cohort study by Tiihonen et al140 included data from 2,588 subjects hospitalized for the first time in which schizophrenia was diagnosed. The primary endpoints included the risk of all‐cause discontinuation of the initial antipsychotic medication, the risk of rehospitalization for schizophrenia, and the risk of death. Only those who had taken any antipsychotic medication within the first 30 days of discharge were included in the analysis of all‐cause discontinuation.

After review of the data, the results suggest that the depot formulation of haloperidol, perphenazine, and risperidone had a significantly lower risk of discontinuation as compared with its oral formulation counterpart. The data was pooled to assess the difference between depot and oral antipsychotics (haloperidol, perphenazine, risperidone, and zuclopenthixol), and results suggest that the depot treatments was associated with a 59% decreased chance of discontinuation vs oral antipsychotics (p<0.0001).

Rehospitalization occurred in 57.8% (N=1,496) of the subjects due to a relapse of schizophrenia symptoms during a 2‐year follow‐up period. A smaller risk of rehospitalization was seen in those using an antipsychotic as compared with not using one. As compared with oral risperidone, only clozapine and olanzapine were associated with a significantly lower risk of rehospitalization. Significant differences were not seen in rehospitalization risk when comparing depot agents and their equivalent oral formulation; however, when the data was pooled, a significantly lower risk of rehospitalization was seen in those using depot antipsychotics as compared with oral antipsychotics (p=0.007), using data from haloperidol, perphenazine, risperidone, and zuclopenthixol depot and oral formulations.

A total of 160 deaths were reported during the follow‐up period, 64 deaths in those using any antipsychotics compared with 96 deaths in those who were not on an antipsychotic. The group using an antipsychotic was seen as having a lower risk of mortality. Due to the small number of deaths, statistically significant differences in mortality were not seen between individual antipsychotic medications.

The authors concluded that a significantly lower risk of rehospitalization was seen with those taking depot antipsychotics as compared with oral antipsychotics. GHS Comments: This study by Tiihonen et al is an observational cohort study. The results of this analysis are in direct conflict with those of Rosenheck et al111,

Property of IME and may not be reproduced without permission. Antipsychotics‐42 which suggests that there is not a significant difference between oral and depot antipsychotics for hospitalization rate. Although Tiihonen et al is an observational cohort study with results suggesting that the depot antipsychotics significantly lower the risk of rehospitalization as compared with the oral antipsychotics, Rosenheck et al is a randomized level 1a study which found no significant difference between the oral and the depot antipsychotics hospitalization rate.

Gopal et al141 performed a data analysis and found 8 randomized, placebo‐controlled studies that met criteria to assess the benefit‐risk ratio in subjects with schizophrenia. Data obtained from Medline included the first‐generation antipsychotic long‐acting injectables haloperidol decanoate, bromperidol decanoate, and fluphenazine decanoate. Information from a company database provided information on paliperidone palmitate, a newer second‐generation injectable. The information was used to determine the number needed to treat (NNT), the number needed to harm (NNH), and the likelihood of being helped or harmed (LHH).

Results suggest that the NNT for relapse prevention was similar between the medications, with a range between 2 and 5. Paliperidone had an NNT of 2 with 1 study and 3 with another study, while haloperidol had an NNT of 2 and fluphenazine had an NNT of 2 with one study, 2 with two studies, and 5 with one study. The NNT for relapse prevention was not available for bromperidol.

Results suggest that the NNH varied greatly. Compared with the first‐generation antipsychotics vs placebo, results suggested that paliperidone vs placebo had a lower incidence of extrapyramidal side effects, such as akathisia, tremor, and tardive dyskinesia. Additionally, paliperidone had a higher NNH for anticholinergic medication use and etardiv dyskinesia and the NNH favored paliperidone as compared with haloperidol.

Overall, the authors concluded that this analysis demonstrated paliperidone palmitate had a similar NNT to selected first‐generation long‐acting injectables and a more favorable NNH.

A 2010 Cochrane Review by Asenjo et al136 included at least single‐blinded randomized controlled trials assessing the use of clozapine as compared with other atypical antipsychotics for the treatment of schizophrenia or schizophrenia‐like psychoses. Twenty‐seven studies were found that met inclusion criteria, with twelve comparing clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone, and two with zotepine (this is not approved for use in the US).

Compared with olanzapine and risperidone, clozapine had a higher adverse event related discontinuation rate; however, fewer subjects in the clozapine group discontinued treatment early due to lack of efficacy as compared with risperidone.

Further results of the studies suggest that while clozapine was more efficacious than zotepine for improving general mental state, it was not consistently more efficacious when compared with olanzapine, quetiapine, risperidone, or ziprasidone. Significant differences were not seen between clozapine and olanzapine or risperidone regarding negative and positive symptoms of schizophrenia; however, two Chinese studies suggested that quetiapine was more efficacious than clozapine for treating negative symptoms.

Reports of adverse events varied between treatments. There were fewer reports of EPS effects with clozapine than with risperidone and zotepine. A greater decrease in white blood cells occurred with clozapine use as compared with olanzapine, more hypersalivation and sedation were reported as compared

Property of IME and may not be reproduced without permission. Antipsychotics‐43 with olanzapine, risperidone, and quetiapine, more weight gain was seen as compared with risperidone, and more seizures were reported as compared with olanzapine and risperidone. There were other differences reported in adverse events; however, these were less documented and further studies should be done to replicate them.

The authors concluded that additional trials are needed to more fully support/confirm the efficacy findings, but it is clear that the adverse reactions of clozapine differ from the other SGAs. Reviewing the side‐effect profile should also be a major part in determining which treatment is more appropriate over another for each patient.

A 2012 meta‐analysis by Taylor et al163 included 14 randomized, placebo‐controlled trials (N=734) to assess the efficacy of augmenting clozapine with a second antipsychotic in those diagnosed with refractory schizophrenia not fully responding to clozapine. Results suggest that a small benefit in efficacy was seen when clozapine was augmented with a second antipsychotic as compared with placebo (p=0.028). When an analysis was done by study duration, results suggested that the benefit of augmenting with a second antipsychotic was marginal, but was not statistically significant in studies with treatment of less than 10 weeks (p=0.47). Nevertheless, in those studies with treatment of 10 weeks or longer, a small but significant reduction in symptoms was seen (p=0.099). Regardless, the difference in effect size between those with less vs those with longer than 10 weeks duration was not statistically significantly different (p=0.424). The authors concluded that a modest benefit may be seen when augmenting clozapine with a second antipsychotic.

A retrospective cohort study by Azekawa et al169 included 703 outpatients from the Shioiri Mental Clinic diagnosed with schizophrenia or schizoaffective disorder to assess the time to discontinuation of those newly starting second‐generation antipsychotic (SGAs). Medical records were assessed to measure rates of continuation or discontinuation and adherence and non‐adherence. The primary outcome was all causes of treatment discontinuation, which is a global (and a proxy marker) measure of the effectiveness of a drug. The included medications were aripiprazole, blonanserin (not available in the US), olanzapine, quetiapine, perospirone (not available in the US), and risperidone.

Results suggest that there was a significantly longer time to discontinuation due to all causes for aripiprazole vs blonanserin (hazard ratio [HR] 0.63; p=0.008), olanzapine (HR 0.62; p=0.003), and risperidone (HR 0.58; p<0.58). While significant differences were not seen between aripiprazole and quetiapine or between aripiprazole and perospirone, there was a tendency toward longer use with aripiprazole vs quetiapine (HR 0.74; p=0.092) and vs perospirone (HR 0.68; p=0.086). Other than with aripiprazole, there were not significant differences seen between other comparisons of SGAs. The authors concluded that aripiprazole may be deemed as the best choice for long‐term treatment with an SGA of schizophrenia or schizoaffective disorder.

A 2012 systematic review and meta‐analysis by Soares‐Weiser et al180 included 60 randomized controlled trials (RCTs; N=33,360) and 27 observational studies (N=202,591) to compare the efficacy of olanzapine with other antipsychotics for the treatment of schizophrenia. Effectiveness is defined as the time to all‐cause medication discontinuation (primary outcome) and as all‐cause treatment discontinuation rates. Other antipsychotics included both first‐generation and second‐generation antipsychotics (FGAs and SGAs).

Property of IME and may not be reproduced without permission. Antipsychotics‐44

In the RCTs, there was a longer time to discontinuation for any cause with olanzapine as compared with aripiprazole (hazard ratio [HR] 0.81; N=1269), quetiapine (HR 0.68; N=2780), risperidone (HR 0.77; N=3980), ziprasidone (HR 0.73; N=1269), and perphenazine (HR 0.68; N=21,347). Significant differences were not seen between olanzapine and amisulpride (HR 0.87; N=1119), clozapine (HR 0.95; N=596), and haloperidol (HR 0.65; N=1651). In the observational studies, the time to discontinuation was longer for olanzapine as compared with amisulpride, risperidone, haloperidol, and perphenazine. Significant differences were not seen between olanzapine and aripiprazole, clozapine, quetiapine, and ziprasidone.

In the RCTs, olanzapine was associated with less discontinuation at endpoint as compared with aripiprazole (relative risk [RR] 0.87; N=2225), quetiapine (RR 0.69; N=2303), risperidone (RR 0.86; N=3646), ziprasidone (RR 0.81; N=19975), haloperidol (RR 0.75; N=2512), perphenazine (RR 0.78; N=691), and sulpiride (RR 0.56; N=108). Significant differences were not seen between olanzapine and amisulpride (p=0.27; N=859) or clozapine (p=0.64; N=1754). In the observational studies, olanzapine was associated with less discontinuation at the endpoint as compared with amisulpride and haloperidol and with a higher rate of discontinuation when compared to clozapine. Significant differences were not seen between olanzapine and aripiprazole, risperidone, ziprasidone, and perphenazine. The authors concluded that olanzapine appears to be more effective than most SGAs and FGAs (except for clozapine), as measured by the time to all‐cause medication discontinuation.

Bipolar Disorder/Bipolar Depression/Acute Mania Reviews/Meta‐Analysis:

A systematic review and meta‐analysis by Cipriani et al93 (Level of Evidence 1a) included five randomized controlled trials, four of which were conducted by the manufacturer Eli Lilly, comparing olanzapine with placebo or other active treatments to assess the effectiveness and tolerability of olanzapine for preventing recurrent mood episodes in bipolar disorder. The primary outcome was the efficacy of olanzapine for preventing further episodes of affective disorder. Results suggest that olanzapine was more effective than placebo in preventing further manic relapse only in patients who are olanzapine responders while in an acute manic or mixed state and who had not previously responded to lithium or valproate.

A 2010 systematic review by Vieta et al129 included randomized controlled trials to assess the effectiveness of treatments for bipolar depression. The mean change in the Montgomery‐Asberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAM‐D) total scores, and the rates of response/remission were the primary outcomes assessed. There were 19 studies identified that met inclusion for meta‐analysis, which consisted of adult subjects with bipolar I or bipolar II disorder and acute bipolar depression. The medications reviewed in the trials included quetiapine, lamotrigine, paroxetine, lithium, olanzapine, aripiprazole, phenelzine, and divalproex. The largest number of trials found was for quetiapine (5 trials) and lamotrigine (6 trials).

Results of the meta‐analysis suggest that quetiapine and the olanzapine‐fluoxetine combination had the greatest reduction in MADRS score. The greatest mean reduction in the HAM‐D score was seen with quetiapine. Several medications were not associated with significant reductions in MADRS/HAM‐D total scores vs placebo. These include lamotrigine, paroxetine, aripiprazole and lithium.

A significant improvement was seen with several medications for the relative risk (RR) of response rate as compared with placebo. These included quetiapine, lamotrigine, olanzapine, olanzapine‐fluoxetine

Property of IME and may not be reproduced without permission. Antipsychotics‐45 combination, imipramine, and divalproex. Paroxetine, lithium, phenelzine, and aripiprazole did not have significant effects compared with placebo for the RR for response rate. Furthermore, only quetiapine, olanzapine, and olanzapine‐fluoxetine combination resulted in having a significant effect on the RR for remission rate as compared with placebo. Although the olanzapine and the olanzapine‐fluoxetine combination had the highest RR for the remission rate, the RR for divalproex was not statistically significantly different when compared with placebo. The authors did note find that the RRs for response or remission with divalproex, imipramine, lithium, olanzapine, olanzapine‐fluoxetine, paroxetine, and phenelzine were based on one study each.

The authors concluded that although several treatments are superior to placebo for the treatment of bipolar depression, quetiapine and the olanzapine‐fluoxetine combination resulted in the greatest symptomatic improvements. Appropriate prescribing should also be balanced with safety and tolerability for the individual patient.

A meta‐analysis by Cipriani et al162 included 68 randomized controlled trials (N=16073) that compared multiple‐treatments to assess for the efficacy in treating adults with acute mania. The treatments included aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, paliperidone, quetiapine, risperidone, topiramate, and ziprasidone. The main efficacy outcomes included the mean change in the Young Mania Rating Scale (YMRS) and the number of subjects who dropped out of the allocated treatments after 3 weeks. At least one placebo‐controlled trial was included for all anti‐manic medication, and most were compared with at least 3 other medications.

Meta‐analysis of direct comparisons suggested that all anti‐manic treatments had significant efficacy as compared with placebo, except for topiramate and gabapentin. The mean difference was ‐0.56 for haloperidol, ‐0.50 for risperidone, ‐0.43 for olanzapine, ‐0.37 for lithium, ‐0.37 for quetiapine, ‐0.37 for aripiprazole, ‐0.36 for carbamazepine, ‐0.30 for asenapine, ‐0.20 for valproate, and ‐0.20 for ziprasidone, which were all significantly higher than placebo. The mean differences for lamotrigine, gabapentin, and topiramate were not significantly different compared wit placebo (were ‐0.08 for lamotrigine, 0.32 for gabapentin, and 0.07 for topiramate). Comparisons between active treatments suggested that olanzapine, lithium, and carbamazepine were more effective than valproate; haloperidol was more effective than lithium, quetiapine, and ziprasidone; olanzapine was more effective than asenapine; and lithium was more effective than topiramate. Overall, haloperidol, risperidone, olanzapine, lithium, quetiapine, aripiprazole, carbamazepine, asenapine, valproate, and ziprasidone were significantly more effective as compared with placebo, while gabapentin, lamotrigine, and topiramate were not.

In regards to discontinuaton rates, risperidone, olanzapine, and quetiapine had fewer drop‐outs as compared with placebo. Additionally, placebo had fewer drop‐outs as compared with topiramate. Haloperidol had fewer discontinuations than quetiapine; quetiapine less than lithium; and olanzapine less than risperidone and asenapine.

In regards to head‐to‐head comparisons for efficacy, results suggest that haloperidol was significantly more effective than lithium, quetiapine, aripiprazole, carbamazepine, asenapine, valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Furthermore, while risperidone and olanzapine were comparable in efficacy, they were more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin.

Property of IME and may not be reproduced without permission. Antipsychotics‐46

Lastly, topiramate and gabapentin were significantly less effective than all other anti‐manic medications included.

In terms of head‐to‐head comparisons for drop‐out rates, haloperidol was significantly inferior to olanzapine; lithium was inferior to olanzapine, risperidone, and quetiapine; lamotrigine was inferior to olanzapine and risperidone; gabapentin was inferior to olanzapine; and topiramate was inferior to others including haloperidol, olanzapine, risperidone, quetiapine, aripiprazole, carbamazepine, and valproate.

The authors concluded that the antipsychotic medications are significantly more effective than other mood stabilizers for the treatment of acute mania. Risperidone, haloperidol, and olanzapine should be included as among the most efficacious of existing treatment options.

Major Depressive Disorder Reviews/Meta‐Analysis:

A systematic review by Fleurence et al94 (Level of Evidence 1a) included 32 randomized control head‐to‐head trials assessing the effectiveness of augmentation strategies with different classes of medications in those who do not respond to first line treatment for major depression disorder. Trials assessing atypical antipsychotics included those with olanzapine, risperidone, quetiapine, and aripiprazole. Results demonstrated that there were greater response rates when using atypical antipsychotics as augmentation as compared with antidepressants alone; however, , there were also a greater number of withdrawals due to adverse events. Although this study was funded by Bristol‐Myers Squibb, as a class the atypicals proved to be efficacious, though with real risks of adverse events.

A 2010 analysis by Citrome128 included published registration studies to assess the safety and efficacy of adjunctive aripiprazole, olanzapine, and quetiapine for use in major depressive disorder (MDD). Three studies were identified for aripiprazole, five for olanzapine‐fluoxetine combination, and two for quetiapine extended‐release. The efficacy and safety of each product as compared to placebo was assessed by calculating the number needed to treat (NNT) and the number needed to harm (NNH).

In the aripiprazole studies, response was defined as a ≥50% decrease from the end of the prospective treatment phase in MADRS total score, while remission was defined as a MADRS total score of ≤10 and a ≥50% reduction in MADRS total score from the end of the prospective treatment. The NNT for response with the pooled aripiprazole studies was 7 and the NNT for remission was 8. Data from all three trials suggested superior rates of response and remission when aripiprazole is used as adjunctive treatment when compared with placebo. The NNH for discontinuation due to an adverse event was 43, while the NNH was 24 for weight gain of ≥7% from baseline and 6 for akathisia.

The definition for response with the olanzapine studies was the same as with the aripiprazole studies; however, the definition for remission was different for each study. The NNT for response with the pooled olanzapine studies was 11 and the NNT for remission was 10. These studies compared olanzapine/fluoxetine combinations with fluoxetine monotherapy. Furthermore, three of the five trials reviewed did not suggest a statistically significant advantage of olanzapine/fluoxetine combination in terms of response rates and two of the four studies did not suggest a statistically significant advantage for using olanzapine/fluoxetine in terms of remission. The NNH for discontinuation due to an adverse event was 12. The NNH for weight gain of ≥7% from baseline was 3, for increased appetite was 6, for dry mouth was 9, and 11 for somnolence.

Property of IME and may not be reproduced without permission. Antipsychotics‐47

The NNT for response in the pooled studies with adjunctive quetiapine XR was 14 for the 150mg daily dose and 9 for the 300mg daily dose. Furthermore, the NNT for remission in the pooled studies with adjunctive quetiapine XR was 11 for the 150mg daily dose and 7 for the 300mg daily dose. The NNH for discontinuation due to an adverse event with adjunctive quetiapine 150mg daily was 16 and for the 300mg daily dose was 8. Additionally, the NNH for weight gain of ≥7% from baseline was 81 for adjunctive quetiapine 150mg daily and was 25 for the 300mg daily dose,r fo somnolence was 6 (150mg dose) and 5 (300mg dose), and for dry mouth was 6 (150mg dose) and 4 (300mg dose).

The authors concluded that although the NNT for each of the three products suggest them to be efficacious when used as adjunctively with antidepressants, the risk of associated adverse events as seen with the NNH can vary greatly and should be taken into account when prescribing.

A 2010 Cochrane Review by Komossa et al134 included 28 randomized, double‐blind trials that compared the oral second generation antipsychotics (SGAs), used either as monotherapy or as adjunctive therapy, with placebo or other forms of active treatment to assess safety and efficacy for treatment of major depressive disorder (MDD) or dysthymia. Five SGAs were included: amisulpride (not available in the US), aripiprazole, olanzapine, quetiapine, and risperidone. Close to 30 studies were assessed.

Three studies met criteria for inclusion and they consisted of comparing aripiprazole with placebo when used as adjunctive therapy in those with MDD (treatment resistant depression). Aripiprazole was seen to have some benefit; however, adverse events were more commonly seen, including general EPS, akathisia, and weight gain.

Seven trials with olanzapine compared to placebo or an antidepressant in those with MDD wereincluded. Though fewer subjects discontinued treatment due to lack of efficacy in the olanzapine group vs placebo, no clear benefit was seen. There was no benefit for use in those with treatment‐resistant depression in terms of symptom reduction. When olanzapine was compared with an antidepressant, similar results in efficacy were seen. Weight gain and an increase in prolactin were reported more frequently with olanzapine as compared to antidepressant therapy. When olanzapine was compared with placebo as adjunctive therapy, there were reductions in depressive and anxiety symptoms. Based on the data reviewed, the authors indicated that there was no clear evidence of a benefit using olanzapine as monotherapy in those with MDD; however, there was a small benefit when used as adjunctive therapy when compared with placebo. Tolerability should be weighed against the positive treatment effects.

Of the seven quetiapine studies, four of them were as monotherapy, and the others were as adjunctive therapy. Data reviewed suggested that there was a benefit for using quetiapine for depressive and anxiety symptoms as either monotherapy or adjunctive therapy when compared with placebo. One study compared quetiapine with duloxetine, and there were no clear benefits seen with either treatment. In all studies, the tolerability and acceptability was lower with quetiapine owing to greater rates of sedation and weight gain. There was no data for the use of quetiapine in treatment‐resistant depression.

Data from four trials were reviewed that included subjects using risperidone adjunctively for treatment‐ resistant depression, and only limited evidence was seen. More subjects responded in the risperidone group compared with the placebo group and benefits were seen for reduction of depressive symptoms. Other than significantly higher prolactin levels, the tolerability of risperidone was similar to placebo.

Property of IME and may not be reproduced without permission. Antipsychotics‐48

There were five trials included with data regarding amisulpride compared to both placebo and to antidepressant treatment for dysthymia. There were significantly greater rates in improvement in depressive symptoms in the amisulpride group than with placebo. This improvement was less pronounced when compared with antidepressant therapy. Tolerability was less with amisulpride, das it tende to cause more menstrual disorder and weight gain.

Overall, while the authors reported that most SGAs were less tolerable, the efficacy of the SGAs varied among each treatment. It was suggested that quetiapine was more effective than placebo, aripiprazole and quetiapine adjunctive treatment were beneficial as compared with placebo (olanzapine and risperidone adjunctive treatment were partly beneficial), and there was some evidence to support beneficial effects of amisulpride in dysthymia.

Anxiety Reviews:

A 2011 systematic review by Samuel et al132 included eight trials, four randomized placebo‐controlled trials and four single‐arm studies to assess the use of treatments for refractory generalized anxiety disorder (GAD). The placebo‐controlled trials included pregabalin, olanzapine, quetiapine, and risperidone, while the single‐arm studies included aripiprazole, risperidone, quetiapine, and ziprasidone. All of the medications were used as adjunctive treatment to an SSRI, SNRI, or an anxiolytic, with the exception of ziprasidone. In the non‐comparator trial with ziprasidone, it was used as monotherapy after failure of the initial treatment due to inadequate efficacy.

Pregabalin was the largest sized trial, with over 350 subjects involved, and the quetiapine single‐arm trial was the next largest trial with over 70 subjects. The rest of the trials ranged from a sample size between 9 and 39 subjects. This small sample size is a limitation of the study. The authors noted that due to the small sample sizes and differences in the study design, a meta‐analysis and indirect analysis was not appropriate.

Results of the trials suggest that there was a significant reduction in the Hamilton Anxiety Scale (HAM‐A) with pregabalin (p=0.012) and risperidone (p=0.034) augmentation. Augmentation with olanzapine resulted in a significantly higher number of responders as compared with placebo. Significantly greater mean reduction in the HAM‐A scores was not seen with quetiapine augmentation as compared with placebo. The most frequently reported adverse events with olanzapine (91%) and quetiapine (54.5%) was sedation, and for risperidone it was somnolence (47.4%). Data from the single‐arm studies suggest that all four treatments significantly improved the HAM‐A scores when these scores were compared to the scores before augmentation or switching treatments. The authors concluded that larger randomized controlled trials with long‐term use are needed to validate the efficacy and safety of using these treatments as augmentation for those with refractory GAD.

A Cochrane Review by Depping et al133 included randomized controlled trials to assess the safety and efficacy of second‐generation antipsychotics (SGAs) used as either monotherapy or as adjunctive treatment in generalized anxiety disorder (GAD) or other anxiety disorders. Trials included in the review compared the SGAs with placebo, benzodiazepines, pregabalin, or antidepressants. Eleven studies met criteria for inclusion; nine assessed the use of SGAs in those with GAD and two assessed the use of SGAs in those with social phobia. Studies assessing the use of SGAs in those with panic disorder (PD) or other primary anxiety disorders were not found. The SGAs included in the studies were olanzapine, quetiapine, and risperidone.

Property of IME and may not be reproduced without permission. Antipsychotics‐49

Seven of the studies evaluated quetiapine when used in GAD. Results suggested a higher response rate for quetiapine compared with placebo; however, there was a higher discontinuation of therapy due to adverse events (such as weight gain, sedation, EPS effects) in the quetiapine group. When quetiapine was compared with antidepressants, significant differences in efficacy outcomes were not seen; however, the discontinuation rate was higher in the quetiapine group owing to adverse events. Two studies assessed the use of olanzapine; however, there was no difference found for efficacy outcomes. These were very small studies, with only 36 subjects which is a definite limitation to the results. Lastly, two trials that compared placebo with adjunctive risperidone treatment also found no difference in efficacy.

The authors concluded that due to the limited data found with olanzapine and risperidone, a conclusion for the use in those with anxiety disorders could not be drawn. However, while thee us of quetiapine monotherapy in those with GAD was efficacious and resulted in the reduction of symptoms, it had a lower tolerability that will need to be taken into account.

Miscellaneous Reviews:

A 2010 Cochrane Review by Komossa et al135 included eleven double‐blind, randomized, controlled trials (N=3696) to assess the use of second generation antipsychotics (SGAs) compared with an active treatment for use with those with obsessive compulsive disorder (OCD). The three SGAs that were reviewed included olanzapine, quetiapine, and risperidone, and they were compared with an antidepressant (typically an SSRI).

Use of olanzapine monotherapy as compared with an SSRI did not result in any difference in the primary outcome of response to treatment and other efficacy measures, but there were more reports of adverse events, specifically weight gain. Quetiapine, used as adjunctive treatment, was not found to be more efficacious than adjunctive placebo in regards to the primary outcome; however, it was significantly more effective than placebo in the mean Yale‐Brown Obsessive Compulsive Scale (Y‐BOCS) score at endpoint. Quetiapine was also seen to be beneficial for anxiety and depressive symptoms. Lastly, risperidone was more efficacious than placebo for the primary outcome, as well as with reducing anxiety and depressive symptoms. The authors concluded that overall, the limited data available precluded the ability to be able to draw any conclusions for the use of olanzapine in those with OCD. Although there is some evidence that supports adjunctive quetiapine and risperidone are effective, they were less tolerated.

Lyon et al85 conducted a very small (N=11) open‐label safety and tolerability 10‐week trial for use of aripiprazole as treatment of tics in children/adolescents with Tourette’s disorder (TD). The Yale Global Tic Severity Scale (YGTSS) was used to rate tic severity. YGTSS scores were reduced from 61.82 at baseline to 33.73 at the endpoint. The author’s concluded that use of aripiprazole should be further investigated as a treatment option as it was safe and seemed to reduce tics.

Injectable Reviews/Meta‐Analysis:

A study by Apiquian et al137 included data that was collected retrospectively for 12 months prior to baseline and prospectively every three months for 24 months to assess the effect of risperidone long‐acting injection (RLAI) on clinical outcome and the rate of hospitalization in adults diagnosed with schizophrenia (N=73) or schizoaffective disorder (N=6). Subjects were enrolled in the electronic schizophrenia treatment adherence registry in Latin America, which recorded the utilization of both RLAI and hospital services. All subjects eligible for inclusion must have experienced an acute or chronic episode and could benefit from RLAI

Property of IME and may not be reproduced without permission. Antipsychotics‐50 treatment. At six months, the mean dose of RLAI was 34.1mg. Efficacy and functionality were assessed using the Clinical Global Impression‐Schizophrenia scale (CGI‐SCH), Personal and Social Performance (PSP), and Global Assessment of Functioning (GAF) scores.

A significant reduction in the need for hospitalization services after being switched to RLAI treatment was noted. When comparing the six month retrospective evaluation with the six‐month prospective evaluation, there was a significant reduction in the number of subjects hospitalized, as it decreased from 28.2% to 5.1% (p<0.001), as well as a significant decrease in the duration of hospitalization, from 13 days to 2.1 days (p=0.002).

Significant improvements after six months of treatment were seen with the CGI‐SCH global score as compared with the initial phase (p<0.001). Additionally, significant improvements were seen with global functioning (p<0.001). A significant improvement in social functioning was also seen when compared with baseline, as assessed by the PSP scale. Furthermore, 33.8% of subjects reported being satisfied on RLAI treatment, 60% were very satisfied, and one patient was not satisfied with treatment. RLAI treatment was well tolerated, with only 20.2% (N=16) reporting adverse events, which were not serious in nature. Akinesia was the most frequently reported adverse event.

The authors concluded that the results suggest RLAI does improve symptoms and functionality in those diagnosed with schizophrenia while being well tolerated, in addition to decreasing the number and the length of stay of hospitalizations.

An analysis of data from two prospective observational studies was performed by Lambert et al143 in 2010 to assess the effectiveness of risperidone long‐acting injectable (RIS‐LAI) therapy for the treatment of schizophrenia in four countries (the US, Spain, Australia, and Belgium). Data was collected for 12 months pre‐baseline and 24 months post‐baseline. Twenty‐four months of treatment were completed and baseline Clinical Global Impressions‐Severity (CGI‐S) and Global Assessment of Functioning (GAF) information were collected at baseline and throughout the studies to assess for clinical improvements. Psychiatric hospitalization rates were also evaluated.

Results suggested that in every country, the mean CGI‐S scores significantly improved at all post‐baseline visits upd to the en of treatment (p<0.001). Similarly, changes from baseline with GAF scores were statistically significantly improved at all post‐baseline visits up to the end of treatment (p<0.001). Lastly, in all countries, the number of hospitalizations per person‐year significantly decreased, regardless of baseline hospitalization status (p<0.0001). In the US, there was a 54.9% decrease. When assessing data from outpatients only, the number of hospitalizations significantly decreased for subjects in US (55.9%) and Spain (56.8%). Decreases occurred in both Australia and Belgium; however, they were not statistically significantly different. The authors concluded that RIS‐LAI was an effective treatment that improved functioning and decreased psychiatric hospitalization rates in those with schizophrenia in four different countries.

In 2010, Leung et al142 performed a retrospective cohort study that included data from electronic records to establish an association between the use of short‐acting intramuscular (SAIM) antipsychotics for acute agitation with the length of hospital stay. Data from drug dispensing reports was utilized to place subjects into one of four groups based on the initial SAIM antipsychotic received during a psychiatric admission, which included SAIM haloperidol, SAIM olanzapine, SAIM ziprasidone, and SAIM aripiprazole. Although

Property of IME and may not be reproduced without permission. Antipsychotics‐51 subjects were placed into one of four groups, because of prescreening number estimations, the authors resolved to compare the haloperidol group with three second‐generation atypicals together (SGA group). The primary outcome of this study was the difference in the length of stay (LOS) between those receiving different SAIM antipsychotics, as well as the LOS from the time of the first injection until discharge, expressed as SAIM LOS.

Statistically significant differences were not seen between the haloperidol group (N=47) and the SGA group (N=89) in regards to LOS. The haloperidol group had an average of 16.98 LOS as compared with 17.59 with the SGA group (p=0.75). In regards to the SAIM LOS, statistically significant differences between groups were not seen (13.12 days with haloperidol vs 13.19 days with SGA; p=0.97). Data also showed that 14 subjects were administered multiple injections from multiple SAIM antipsychotics during the hospital stay. These subjects had an average 15‐day greater LOS. A statistically greater number of injections were given with the SGA group as compared with the haloperidol group (1.75 injections vs 3.14 injections, respectively; p=0.04). Lastly, a post‐hoc Bonferroni test was performed, and it suggested that there was a statistically significantly longer LOS in those being administered olanzapine as compared with ziprasidone (19.10 days vs 13.57 days, respectively; p=0.026). The authors concluded that the use of a second‐generation SAIM antipsychotic does not shorten the hospital stay and requires more injections as compared with SAIM haloperidol. In the analysis, the SGA SAIM antipsychotics were also found to cost more.

A clinical analysis by Aggarwal et al174 included patients from the Connecticut Mental Health Center diagnosed with schizophrenia or schizoaffective disorder to assess for concomitancy of long‐acting injectable (LAI) antipsychotic use with simultaneous oral antipsychotic use. Data was obtained from administrative records at the center, as well as reviews of pharmacy orders. It was found that there were 124 subjects on LAI medications, with 81.5% having a diagnosis of schizophrenia. Of these, 46% (N=57) also received concomitant oral antipsychotics. Of those receiving oral and LAI antipsychotics, 47% (N=27) were prescribed LAI haloperidol decanoate, 33% (N=19) were prescribed LAI fluphenazine decanoate, and 19% (N=11) were prescribed LAI risperidone. There were no significant differences found among these treatments for differences in rates of oral antipsychotic use. Furthermore, those on higher doses of LAI treatments were associated with a greater likelihood of using an oral antipsychotic. The authors concluded that while this data was only from one center that almost one‐half of subjects on LAI antipsychotics are on concomitant oral antipsychotics.

A 2012 Cochrane Review by Nussbaum et al179 included 5 randomized controlled trials (N=2215) to assess the safety and efficacy of paliperidone palmitate, a long‐acting intramuscular formulation, for the treatment of schizophrenia and schizophrenia‐like illnesses. Results suggest that there were less that discontinued treatment if they were randomized to paliperidone palmitate (PP). As compared with placebo, those in the PP group were less likely to have a recurrence of psychosis (relative risk [RR] 0.28). Use of PP resulted in fewer reports of agitation or aggression, and of using anxiolytic medications. Sexual dysfunction was not reported with PP use. Compared with placebo, there was a significantly greater increase in weight with PP use.

There were 2 studies which compared PP with risperidone long‐acting injection (RLAI; N=2052). Significant differences in the amount leaving the study early due to any reason were not seen between treatments. Compared with RLAI, those using PP were not statistically more likely to have recurrence of psychotic symptoms (RR 1.23). Significant differences between treatments were found in the number of deaths; there

Property of IME and may not be reproduced without permission. Antipsychotics‐52 were 5 deaths in the PP group vs 1 in the RLAI. The authors concluded that PP is superior to placebo and appears comparable in efficacy and tolerability to RLAI.

Use in Youth Reviews:

For youth with schizophrenia or bipolar disorder, there are insufficient clinical trials and no head‐to head comparator trials to draw any conclusions about the clinical superiority of any single AAP.19 Although there are more than 5 randomized controlled trials of Risperdal® and 1 RCT of Zyprexa® for treatment of irritability in autism, there are no head‐to‐head trials of AAPs.20 Additionally, Abilify® has demonstrated efficacy for the treatment of agitation associated with autism.90 In the treatment of bipolar disorder, there are insufficient head‐to‐head trials to conclude that there are drugs with superior outcomes; however meta‐analyses reveal that all of the AAPs demonstrate similar anti‐manic efficacy.21,22 A study of patients with bipolar disorder treated with Zyprexa®, Risperdal®, and Seroquel® showed no differences between them in regard to adherence and persistence, but all were demonstrated superior to TAPs.23

A comparative effectiveness review by Seida et al164 included 64 trials and 17 cohort studies to assess the safety and effectiveness of first‐ and second‐generation antipsychotics (FGA and SGA) in the population of children and young adults (≤24 years) diagnosed with psychiatric and behavioral conditions. Schizophrenia was the most common condition reviewed, with 31 studies found. There were 7 studies found using treatment for pervasive developmental disorders (PDD), 8 studies for disruptive behavioral disorders (DBD), 11 studies for bipolar disorder, 7 studies for Tourette syndrome, 4 studies for behavioral symptoms, and 9 studies treating multiple conditions. An overall strength of evidence (SOE) was assigned for studies per diagnosis.

Studies included comparisons of FGAs vs SGAs, FGAs vs FGAs, and FGAs vs placebo, all which had low or insufficient strength of evidence. For PDD, the SOE was low; however, some benefit vs placebo was seen with aripiprazole and risperidone for controlling obsessive‐compulsiveness and autistic symptoms. For DBD, the SOE was low with SGAs for aggression, anxiety, and medication adherence; however, a moderate SOE was seen with risperidone as being effective for measures on behavior symptoms and Clinical Global Improvements (CGI) vs placebo. For use in bipolar disorder, limited information was found and thus resulted in a low SOE. Nevertheless, a significant benefit was seen on CGI and manic symptoms as compared with placebo, but a lower medication adherence. For schizophrenia, the overall improvement on CGI was greater for those on SGAs vs FGAs; however, patient adherence was not different between the classes of medications. The efficacy for use in schizophrenia was comparable between all SGAs. For treatment with Tourette’s syndrome, there was a moderate SOE with risperidone and ziprasidone decreasing the frequency and severity of tics as compared with placebo. There was a lack of evidence for all other outcomes and comparisons. For the behavioral symptoms, while it was a low SOE, there was a greater improvement with risperidone vs placebo for the Aberrant Behavior Checklist. There was a lack of evidence for other comparisons and outcomes.

Adverse events were also compared between treatments. In comparing the SGAs and the FGAs, there were 12 studies found. Results suggested that significantly fewer extrapyramidal adverse events were seen with olanzapine and risperidone as compared with haloperidol; however, less weight gain was seen with haloperidol as compared with olanzapine. Prolactin‐related adverse events were not significantly different

Property of IME and may not be reproduced without permission. Antipsychotics‐53 between the two groups. The authors concluded that while the evidence is limited, a better adverse event profile was seen with some SGAs. Further head‐to‐head studies are needed.

A systematic review and meta‐analysis by Pringsheim et al165 included 35 randomized controlled studies to assess for specific metabolic and neurological adverse events associated with second generation antipsychotics (SGAs) when administered to children. This primary outcome, metabolic and neurologic adverse events, was measured by physical exams, rating scales, or laboratory tests. The SGAs included were risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone, and paliperidone.

Results suggested that olanzapine use had the highest weight gain (3.47kg), followed by risperidone (1.72kg), quetiapine (1.41kg), and aripiprazole (0.85kg). With cholesterol and triglycerides abnormalities, olanzapine and clozapine had the highest rates. Increases in prolactin were greatest with risperidone and olanzapine. Compared with placebo, there were higher odds of EPS in those treated with risperidone (odds ratio [OR] 3.55) and aripiprazole (OR 3.70), although olanzapine also had elevated rates. The authors concluded that as the evidence does support the risk of metabolic and neurologic adverse events with SGAs, monitoring of these events should be done and should be part of the standard of care with use.

Safety Reviews:

A 2010 meta‐analysis by Chung et al131 included data from numerous databases to assess the effects and risk of Bazett’s corrected QT interval (QTBc) prolongation for the most commonly prescribed second generation antipsychotics. There were sixteen randomized controlled trials providing data on QTBc prolongation. The six antipsychotics studied were amisulpride, aripiprazole, olanzapine, risperidone, sertindole, and ziprasidone.

Due to the lack of complete QTBc data reporting, quetiapine could not be included. Results suggested that the only second‐generation antipsychotic associated with both a statistically significantly lower risk to cause

QTBc prolongation (p=0.04) and a statistically significant less mean change in QTBc (p=0.03) was aripiprazole.

Sertindole, currently not available in the US, was seen to have a statistically significant mean QTBc prolongation (p<0.0001).

Hermes et al138 used data from the CATIE schizophrenia trial to assess the association between change in body mass index (BMI) and in total serum cholesterol and triglycerides with the Positive and Negative Syndrome Scale (PANSS) score. The original CATIE trial compared the effectiveness of several second generation antipsychotics (olanzapine 7.5‐30mg per day, risperidone 1.5‐6mg per day, quetiapine 200‐ 800mg per day, and ziprasidone 40‐160mg per day) with the first generation antipsychotic perphenazine, dosed at 8‐32mg per day, in an 18 month randomized, double‐blind multicenter trial. In the current study, Hermes et al used data from the first phase of this CATIE trial, from baseline to month 18, and completed two analyses. One analysis assessed the relationship of percent change in BMI from baseline to month 3 with the change in PANSS total score over that same time period. The second analysis used all available data from baseline up to 18 months measured with a different model than the first analysis to assess the same comparison.

In both of the analyses, statistically significant symptom improvements (greater reduction in PANSS scores) were seen with increased BMI (p=0.001). Results suggest a 0.28 point decrease with the 3 month analysis and 0.21 point decrease with the 18 month analysis in PANSS total score per 1% increase in BMI. Results also suggest that there was not a significant difference between the treatment groups for assessing the

Property of IME and may not be reproduced without permission. Antipsychotics‐54 relationship of PANSS with changes in BMI. Although the 3‐month analysis showed significant effects for olanzapine and perphenazine but not for the others, the 18 month analysis resulted in the association of symptoms and weight gain that was significant for all medications except for perphenazine. Lastly, there was not a significant association between percent change in total serum cholesterol or triglycerides and the change in PANSS score.

The authors concluded that while there was an inverse and statistically significant association between percent change in BMI and change in PANSS total score, it was not clinically important. Thus, it is improbable that switching to a medication that has less risk of metabolic effects will result in a consequential loss of clinical benefit.

A systematic review and subsequent meta‐analysis specifically on weight gain by De Hert et al139 included 31 randomized, placebo‐controlled trials N=3,595) assessing the cardiometabolic and endocrine side‐effects of second generation antipsychotics (SGAs) when used in children and adolescents. The SGAs that were assessed in the included trials were aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.

Except for ziprasidone, weight changes with all the SGAs were statistically significantly greater as compared with placebo. The mean weight change per individual studies ranged from ‐0.2kg (ziprasidone) to 4.3kg (olanzapine), whereas in a pooled analysis the mean weight change differed significantly and ranged from 0.5kg (ziprasidone) to 3.8kg (olanzapine). Additionally, a formal meta‐analysis was done with 24 of the studies. Results of this also suggest that ziprasidone (‐0.04kg) had the lowest weight gain, followed by aripiprazole (0.79kg), quetiapine (1.43kg), and risperidone (1.76kg) which were considered as intermediate weight gain, and then olanzapine (3.45kg) which had the highest rates of weight gain.

The effects of SGAs on hyperprolactinemia in children and adolescents were also reviewed. Results were similar to the effects in adults. The largest and dose‐dependent increase was seen with risperidone. There was an increase with olanzapine, mixed results with both quetiapine and ziprasidone, and a decrease with aripiprazole. Overall, the authors concluded that the data assessed warrants the need for monitoring of metabolic side effects if these products are to be used in children and adolescents.

A 2012 retrospective cohort study by Kales et al181 included data from a national database of US Department of Veterans Affairs regarding subjects with dementia who were ≥65 years of age taking antipsychotic treatment (N=33,604) that was used to assess the risk of mortality of specific treatments. The antipsychotics utilized were risperidone, olanzapine, quetiapine, or haloperidol. Valproic acid was also studied. Mortality data was obtained from the US National Death Index.

Results suggested that the 6‐month mortality rates were 20% for haloperidol, 12.6% for olanzapine, 12.5% for risperidone, 12.5% for valproic acid, and 8.8% for quetiapine. Relative risks suggested that haloperidol had the highest mortality risk (1.54; p<0.0001) while quetiapine had the lowest risk (0.73; p<0.0001). Risperidone was the reference (1.00), while the relative risk of olanzapine was 0.99 (p=0.8748) and valproic acid was 0.91 (p=0.2468). On average, the mortality risk was 1.5 times higher in the first 120 days than the subsequent 60 days with all medications, except for haloperidol. With haloperidol, the risk was highest in the first 30 days (relative risk 2.24 vs risperidone between 150‐180 days; p<0.001). The risk decreased significantly to no difference between 90‐120 days (relative risk 1.11 vs risperidone between 150‐180 days; p=0.65). The authors concluded that differences in mortality risk may exist with the various antipsychotics.

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A 2012 retrospective cohort study by Bhalerao et al182 also included data from the national department of Veterans Affairs registries regarding subjects ≥65 years of age (N=4,717) diagnosed with bipolar disorder with a new start of an atypical antipsychotic that was used to assess the risk of mortality of specific treatments. The treatments assessed were risperidone, olanzapine, and quetiapine, with valproic acid also being assessed. Mortality data was obtained from the US National Death Index.

Results suggest that the 6‐month mortality rates were 11.8 per 100 person‐years with risperidone. Risperidone had the highest mortality rate, with 58 deaths (total N=1027) within 180 days. This was followed by a mortality rate of 10.3 deaths per 100 person‐years with olanzapine, with 43 deaths (N=868) within 180 days. Quetiapine had a death rate of 5.3 per 100 person‐years, with 29 deaths (N=1119) within 180 days. Valproic acid had the lowest death rate of 4.6 per 100 person‐years, with 38 deaths (N=1703) within 180 days. Again, the authors concluded that differences may exist in mortality risks with various individual treatments. The authors did note that, “…a translation of these findings to clinical recommendations that suggest the use of one agent over another would be premature. The findings should be replicated in other samples.”182

The following table represents data from additional head to head comparative trials and other trials of interest.

After a careful review of the literature, the articles included in this therapeutic class review are not all inclusive. Key and pivotal studies that suggest one therapy is superior to another or a place in therapy of a specific product are included. Studies of low levels of evidence may not have been included in the review. Studies deemed of little relevance may also be excluded.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Fleischacker Multicenter, N=703 ‐Subjects ‐Compare efficacy ‐47% of the olanzapine group completed the ‐Compared with et al37 randomized, diagnosed with after 6 weeks of study compared with 39% of the aripiprazole aripiprazole, olanzapine 2009 double‐blind, schizophrenia therapy and group; time to discontinuation was was statistically significantly study experiencing weight gain significantly in favor of olanzapine (p<0.05). more efficacious, but also acute relapse liability after 26 was associated with aripiprazole 52 weeks weeks ‐A treatment difference of 4.9 points was significantly more weight Vs seen in the PANSS Total score (olanzapine, gain. olanzapine ‐A 6 week acute ‐29.5; aripiprazole, ‐24.6), with olanzapine

treatment phase being superior to aripiprazole. took place, and Clinical Global ‐Significantly more subjects experienced Impression‐ weight gain in the olanzapine group (40%) Improvement =1‐3 compared with the aripiprazole group (21%; or >20% reduction p<0.05). Significant differences were seen at in the Positive and week 3. Negative Symptom Scale ‐At week 26, significant weight changes were (PANSS). seen with olanzapine compared with aripiprazole (+13kg vs +4.30kg) respectively. Bastiaens Non‐ N=46 ‐Subjects with a ‐Measurement of ‐63% was the average improvement of the ‐Comparable efficacy was 200938 randomized, mean age of 11.9 Overt Aggression OAS. seen between aripiprazole open study with a variety of Scale (OAS) and ziprasidone when diagnoses, and ‐Clinical Global Impression‐Improvement treating aggressive with significant Scale was 2.1 +/‐1.2. behavior. aripiprazole 2 months aggressive Vs behavior ‐Statistically significant improvements were ziprasidone not seen between aripiprazole and ziprasidone.

‐The most reported side effect was sedation.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Kinon et al39 Randomized, N=604 ‐Hospitalized ‐Mean daily ‐Both olanzapine and aripiprazole treatment ‐Olanzapine and 2008 double‐blind patients change from groups (p<0.001) had significant aripiprazole exhibited study diagnosed with baseline in improvements from baseline in PANSS‐EC comparable efficacy for schizophrenia and Positive and score and secondary efficacy scores. treatment of agitation, but olanzapine 5 days agitation Negative the aripiprazole only had Vs Syndrome Scale‐ ‐Although more subjects in the aripiprazole minor increases in certain aripiprazole ‐Lorazepam was Excited group received lorazepam compared with the adverse events compared also given as Component olanzapine group at each visit, only a with olanzapine. needed (PANSS‐EC) score. significantly greater amount in the aripiprazole group obtained lorazepam at ‐Positive Visit 5 compared with olanzapine (41.2% vs symptoms and 31.0% respectively; p=0.033). safety were accessed as ‐The olanzapine treated group experienced a secondary significantly greater increase in fasting measures. glucose and triglycerides (p=0.030 and p<0.001, respectively).

‐A significant between‐group difference was seen with prolactin levels, increasing in the olanzapine group and decreasing in the aripiprazole group (p<.001). Karagianis Randomized, N=149 ‐Subjects ‐To determine the ‐Between treatment groups, there were no ‐Although appetite was et al40 multicenter, diagnosed with change in body statistically significant differences in mean decreased in the olanzapine 2009 double‐blind, schizophrenia, mass index (BMI) change from baseline in BMI, weight, or waist ODT group, this group double‐ schizoaffective in those who had circumference. showed comparable change dummy study disorder, related previously gained in weight and BMI from psychotic disorder weight with ‐Olanzapine ODT group obtained a significant olanzapine tablets. or bipolar disorder olanzapine tablets reduction in subjective appetite and better who taking 5‐ and continued treatment compliance as compared to the 20mg olanzapine with that therapy olanzapine tablets group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments olanzapine 16 weeks tablets compared with tablets PLUS those who sublingual switched to the placebo ODT Vs placebo tablets PLUS olanzapine orally dis‐ integrating tablets (ODT) Kolotkin Multicenter, N=55 ‐Subjects with ‐Weight and ‐At week 26, the aripiprazole group lost an ‐A decrease in weight et al42 randomized clinical symptoms weight‐related average of 1.7% weight compared with an change and improved WR‐ 2008 trial not optimally quality of life (WR‐ average of 2.1% weight gain with the SOC QOL was seen with the controlled and/or QOL), which were group (p<0.0001). aripiprazole group aripiprazole 26 weeks tolerability assessed at compared with other Vs problems with baseline, weeks 8, ‐A significantly greater improvement in standard therapy. Standard of current 18, and 26 physical function, self‐esteem, sexual life, and Care (SOC) medications WR‐QOL occurred with those in the aripiprazole group compared with SOC. (SOC included olanzapine, ‐Meaningful improvements in WR‐QOL were quetiapine, seen in 20.7% of the aripiprazole group and compared with 13.5% in the SOC group at risperidone) week 26. Newcomer Multicenter, N=173 ‐Overweight ‐Mean weight ‐Aripiprazole group reported significant ‐Weight and lipid levels et al43 randomized, subjects with change from decrease in weight compared with olanzapine significantly improved in 2008 double‐blind diagnosis of baseline. (‐1.8 vs +1.41; p<0.001). those who switched study schizophrenia or therapy from olanzapine to schizoaffective ‐Secondary ‐At all time points, % change in triglycerides aripiprazole. disorder on measure included were significantly different with aripiprazole previous % change from (decreases) compared with olanzapine

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments aripiprazole 16 weeks olanzapine baseline in fasting (increases). Vs therapy triglycerides olanzapine ‐Clinically relevant weight loss (≥7%) was seen in more subjects in the aripiprazole group (11.1%) compared with the olanzapine group (2.6%; p=0.038).

‐Clinically relevant weight gain was seen less in the aripiprazole group (2.5%) compared with the olanzapine group (9.1%; p=0.082).

‐Significant differences with % changes in fasting total cholesterol and HDL were seen in the aripiprazole group compared with the olanzapine group.

‐No change to minimal improvement was the range for both treatment groups assessed by the Clinical Global Impressions‐Improvement (CGI‐I) scores.

‐CGI‐I scores were statistically significantly better in those in the olanzapine group compared with the aripiprazole group (p<0.001).

‐36% of the aripiprazole group discontinued therapy compared with 26% of the olanzapine group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Harvey et al44 Multicenter, N=130 ‐Subjects ‐Cognitive ‐Ziprasidone was seen to have statistically ‐Ziprasidone improved 2008 randomized, diagnosed with benefits were significant within‐group improvements in cognition comparable or double‐blind schizophrenia assessed using the learning and delayed recall on the RAVLT and greater than clozapine in comparator with a history of following: episodic on TMT Parts A and B. those with history of trial either failure to memory (RAVLT), treatment resistance or respond to or executive ‐Improvement on the RAVLT was seen with intolerance. clozapine 18 weeks intolerance of functioning the clozapine group, but not on the TMT. Vs previous adequate (Stroop test), and ziprasidone antipsychotic processing speed ‐Both groups experienced improvements with treatments (Trail‐making test cognition, but the ziprasidone improvements [TMT] Parts A & B) were higher Meltzer Randomized, N=40 ‐Subjects with ‐To compare ‐Both treatment groups showed significant ‐Use of higher doses of et al45 double‐blind, treatment‐ efficacy of high improvement in psychopathology, but no olanzapine resulted in 2008 parallel‐group resistant dose olanzapine significant differences were found between comparable efficacy when study schizophrenia or (25‐45mg/day) treatment groups except for the Global compared to clozapine for schizoaffective with clozapine Assessment of Functioning score, which was treatment‐resistance olanzapine 6 months disorder who had (300‐900mg/day), in favor of clozapine (p=0.01). schizophrenia, but greater Vs failed to respond including metabolic adverse events. clozapine to prior treatment psychopathology, ‐Significant improvements were also seen in with other cognitive some domains of cognition, but no significant ‐Limitations include small antipsychotic performance differences were seen between treatment sample size. drugs groups. ‐To compare tolerability ‐Adverse events reported included weight gain, which was significantly greater with olanzapine (p=0.01), and extrapyramidal symptoms.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Kryzhanov‐ International, N=107 ‐Inpatient and ‐To compare ‐68.1% of the olanzapine group completed ‐Although significant skaya multicenter, outpatient efficacy by the study compared with 42.9% of the symptom improvement was et al46 randomized, adolescents assessing last‐ placebo group (p=0.020). seen in the olanzapine 2009 double‐blind, (mean age 16.2) observation‐ treated adolescents, placebo‐ diagnosed with carried‐forward ‐Significantly bigger improvements in the significant increases in controlled schizophrenia mean changes Brief Psychiatric Rating Scale total (p=0.003), metabolic adverse events trial from baseline to the Clinical Global Impressions Scale‐Severity were also seen. endpoint on the of Illness (p=0.004), the PANSS total anchored version (p=0.005), and the PANSS positive score olanzapine 6 weeks of the Brief (p=0.002) were seen with the olanzapine Vs Psychiatric Rating group compared with placebo. placebo Scale for Children, Clinical Global ‐45.8% of the olanzapine group gained ≥7 of Impression Scale‐ their body weight compared with 14.7% in Severity of Illness, the placebo group, which is significantly more and Positive and (p=0.002). Negative Syndrome Scale ‐Prolactin and triglyceride levels were (PANSS) significantly higher in the olanzapine group compared with the placebo group.

‐At the endpoint, fasting glucose, cholesterol, and triglyceride significant changes were not different between treatment groups; however, high triglycerides were seen in more olanzapine treated patients at any point throughout the treatment. Schulz Randomized, N=314 ‐Subjects ‐To compare ‐Significant improvements were seen in both ‐Significant, but not et al47 double‐blind diagnosed with efficacy by groups, but they did not differ in degree at statistically different 2008 trial borderline assessing the end‐point (p=0.661). improvements of symptoms personality change from were seen with olanzapine

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments olanzapine 12 weeks disorder baseline to ‐64.7% of the olanzapine group reported a versus placebo as Vs endpoint on the response rate of 50% reduction in ZAN‐BPD treatment for borderline placebo Zanarini’s Rating compared with 53.5% in the placebo group personality disorder. Scale for (p=0.062). Borderline Personality ‐The olanzapine group had a significantly Disorder (ZAN‐ shorter time to response compared with BPD) using last‐ placebo (p=0.022). observation carried‐forward ‐Significantly more weight gain (p<0.001) and higher abnormal levels of prolactin was reported with the olanzapine group compared with placebo. Ruths et al48 Randomized, N=55 ‐Subjects in ‐To determine the ‐42 subjects resulted in stable or improved ‐A substantial amount of 2008 placebo‐ nursing home with effect of stopping symptom scores (NPI) (18/27 with subjects that discontinue controlled mean age of 84.1 long‐term intervention group vs 24/28 reference group; long‐term treatment do study years diagnosed antipsychotic p=0.18). well and remain stable. with dementia treatment continue 4 weeks (behavioral and assessed with the ‐Subjects with behavioral decline once therapy with psychological Neuropsychiatric antipsychotic therapy was discontinued either symptoms of Inventory (NPI) started with higher daily treatment doses at haloperidol, dementia (BPSD) Questionnaire to baseline compared with subjects that were risperidone, determine stable or had improved symptom scores or olanzapine changes in (p=0.42). Vs behavioral and cessation of psychological therapy symptoms.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Kumra et al49 Randomized, N=39 ‐Adolescents aged ‐To evaluate the ‐Compared with those treated with ‐The authors concluded 2008 double‐blind 10‐18 years who efficacy of up to olanzapine, significantly more met response that clozapine would be the comparison met criteria for 30mg/day of criteria in the clozapine group (33% vs 66%). treatment of choice in diagnosis of olanzapine by these adolescents with clozapine 12 weeks schizophrenia and measuring ‐For reducing psychosis cluster scores and treatment‐refractory Vs were resistant or response, a negative symptoms, clozapine was superior schizophrenia. olanzapine intolerant to at decrease of ≥30% compared to olanzapine. least two different in total Brief antipsychotic Psychiatric Rating ‐Weight‐gain and other metabolic drugs Scale score and a abnormalities were associated with both Clinical Global treatment groups Impression Scale improvement of 1‐2. Kelly et al50 Randomized, N=377 ‐Subjects ‐Monitoring of ‐The olanzapine group experienced greater ‐Both positive and negative 2008 double‐blind diagnosed with metabolic risks, increases in BMI compared with the metabolic changes were comparator schizophrenia or including weight, risperidone group (p<0.001). noted; therefore, trial schizoaffective BMI, HbA1C, total recommendations include disorder cholesterol (TC), ‐The olanzapine group reported increases in appropriate monitoring of risperidone 8 weeks LDL‐C, HDL‐C, and TC, LDL‐C, and TG; however, the risperidone weight and metabolic Vs triglycerides (TG). group reported significant changes in TC and status during the first olanzapine TG. several months of therapy.

‐Both groups had increases in BMI that were associated with study discontinuation (p=0.0002).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Faries Post‐hoc N=60 ‐Subjects with ‐Changes from ‐71.7% switched to olanzapine, with 86 days ‐The authors concluded et al51 analysis, using schizophrenia pre‐ to post‐ being the average duration of risperidone that if subjects required a 2008 data from either remaining medication switch treatment prior to switching. switch in therapy from randomized, on risperidone or and endpoint risperidone, olanzapine is a open‐label switching to comparisons ‐86% on olanzapine finished the 1‐year study. successful treatment study of 1 year olanzapine between patients option. risperidone switched from ‐Significant improvements on clinical (Brief arm and risperidone to Psychiatric Rating Scale) and social (Quality of compared to olanzapine and Life Inventory) factors were reported after those who patients who switched to olanzapine. switched to continued on olanzapine risperidone ‐Comparable amounts of subjects obtained remission status at endpoint compared with the risperidone subjects that didn’t require switch to olanzapine (41.9% vs 35.5%).

‐More weight gain was seen with those who switched to olanzapine (2.4kg while on olanzapine vs 0.4kg while on risperidone). Hatta et al52 Pseudo‐ N=90 ‐Subjects with ≥15 ‐To compare ‐A significant effect of time course on PANSS‐ ‐Olanzapine ODT and 2008 randomized, score on the efficacy and EC was seen (p<0.0001). risperidone oral solution open‐label, excited tolerability of resulted in comparable flexible‐dose component of the treatment groups ‐The amount of subjects requiring an efficacy as treatment for multicenter Positive and using the PANSS‐ additional injection due to worsening of acutely agitated patients. study Negative EC scale, assessed symptoms was comparable between groups Syndrome Scale every 15 minutes (11.8% olanzapine vs 9.4% risperidone). risperidone 2 months (PANSS‐EC) when oral solution assessed at ‐Extrapyramidal symptoms and overall Vs emergency room patient approval were comparable between olanzapine visits due to acute treatment groups. ODT agitation

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments associated with ‐Improvement in tachycardia did occur psychosis significantly more with the olanzapine group vs the risperidone group (p=0.03). Canuso et al53 Three double‐ N=198 ‐Subjects ‐To access efficacy ‐61.3% completed the study in the ‐Paliperidone was 2008 blind, placebo diagnosed with of paliperidone paliperidone group compared with 42.9% in significantly more effective controlled schizophrenia who after risperidone the placebo group. than placebo for reducing trials (post took risperidone treatment, using symptoms in subjects who hoc analysis) ≥4 weeks prior to the Positive and ‐Significant improvement was seen in the were still symptomatic after trial and still with Negative PANSS, CGI‐S, and PSPS with paliperidone at least 4 weeks of acute symptoms Syndrome Scale compared with placebo (p<0.05). risperidone. paliperidone 3‐ 6 week (PANSS), Clinical Vs trials Global ‐No significant changes were seen with either placebo Impressions‐ group with the Simpson‐Angus scale. Severity scale (CGI‐S), Personal ‐Most commonly reported adverse events and Social with paliperidone compared with placebo Performance Scale were headache (16.2% vs 16.1%), insomnia (PSPS), the (14.1% vs 16.1%), and agitation (8.5% vs Simpson‐Angus 10.7%). Scale ‐Discontinuation rates due to adverse events ‐Adverse events were 2.1% with paliperidone compared with were also 5.4% paliperidone. monitored Connor et al54 Randomized, N=19 ‐Adolescents with ‐Clinician‐assessed ‐For all clinician‐assessed measures and ‐Although further studies 2008 double‐blind, conduct disorder Clinical Global parent‐assessed quality of life rating scale, with larger samples are placebo‐ Impressions‐ quetiapine was superior to placebo. required, this pilot study controlled Severity (CGI‐S) indicates that quetiapine pilot study and Improvement ‐For the parent‐assessed OAS and CPRS‐CP may be useful as treatment with two (CGI‐I) scale. measures, no differences between quetiapine for conduct disorder in parallel arms and placebo were seen. adolescents. ‐Parent‐assessed

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine 7 week quality of life, the ‐Both treatment groups were well tolerated, Vs overt aggressions with a report of akathisia with quetiapine. placebo scale (OAS), and the conduct problems subscales of the Conners’ Parent Rating Scale (CPRS‐CP) were also assessed Addington Multicenter, N=139 ‐Subjects ‐Changes in ‐Statistical improvements from baseline were ‐Both treatment group’s et al55 randomized, diagnosed with Positive and seen with both treatment groups in PANSS demonstrated comparable 2008 double‐blind schizophrenia who Negative and CGI‐S scores, and no between treatment efficacy as long‐term extension had responded to Syndrome Scale group differences were seen. treatment for patients with study treatment for (PANSS) total schizophrenia, but the acute score and Clinical ‐Although not statistically significant, 41.6% ziprasidone group had less exacerbations in Global Impression of the risperidone group completed the study reported adverse events. ziprasidone 44 week an 8 week study Severity (CGI‐S) compared with only 33.9% of the ziprasidone Vs score. group. risperidone ‐Greater improvements in the Montgomery ‐Tolerability and and Asberg Depression Rating Scale was seen safety measures in the ziprasidone group compared with the were also risperidone group (p<0.05). assessed. ‐Less weight gain, EPS measures, and prolactin effect were reported with the ziprasidone group compared with the risperidone group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments DelBello Open‐label N=63 ‐Children and ‐Assessing ‐Reported adverse events were the highest ‐The tolerability results of et al56 study with a adolescents aged tolerability of during the titration period (1st 10 days of this study were as 2008 fixed‐dose 10‐17 years with ziprasidone using period 1) and in the high‐dose group expected. The authors period and a bipolar mania, movement rating (160mg/day). concluded that an initial flexible dose schizophrenia, or scales, lab test, dose of 20mg/day, titrated period schizoaffective and electro‐ ‐During Period 1, the most commonly to a maintenance dose of disorder. cardiograms reported adverse events included sedation 80‐160mg/day over a 2 Period 1: 27 weeks (32%), somnolence (30%), and headache week period is optimal. ziprasidone 80 ‐Assessed clinical (25%). or 160mg/day response using And the Young Mania ‐22% reported movement disorders during Period 2: Rating Scale, the Period 1 vs 16% during Period 2. ziprasidone Brief Psychiatric flexible doses Rating Scale‐ ‐Only 6% discontinued therapy due to of 20‐ Anchored Version, adverse events during Period 1 compared 160mg/day and the Clinical with 20% during Period 2. Global Impressions‐ ‐A gain of ≥7% of body weight was reported Severity scale. in 33% of subjects.

‐All patients reported reduction of symptoms. Cutler et al57 Multicenter, N=593 ‐Subjects with ‐Change from ‐Significant reduction in PANSS score was ‐Both active treatment 2008 randomized, acute baseline in the seen with the iloperidone (<0.01) and groups were effective placebo‐ exacerbations of Positive and ziprasidone (p<0.05) groups when both were treatments for acute controlled schizophrenia Negative compared with placebo. symptoms of schizophrenia study Syndrome Scale and both were well Total (PANSS) ‐Lower rates of sedation, somnolence, tolerated. ‐Trial period score extrapyramidal symptoms, akathisia, included 1 week agitation, and restlessness were seen with of titration and 3 iloperidone vs ziprasidone. weeks

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments iloperidone 4 weeks maintenance ‐Weight gain, tachycardia, orthostatic Vs hypotension, dizziness, and nasal congestion ziprasidone were reported higher with iloperidone. Vs placebo ‐QT prolongation reports were comparable between active treatment groups. Dunner et al58 Randomized, N=64 ‐Subjects not ‐The least squares ‐Improvement in MADRS total score for ‐Greater clinical efficacy 2007 open‐label responding to SSRI mean change on monotherapy was ‐4.45 +/‐ 2.03 (p=NS) was seen with ziprasidone pilot study monotherapy for the Montgomery‐ compared with adjunctive ziprasidone 80mg adjunct therapy compared 6 weeks prior Asberg Depression (‐5.98 +/‐1.87 and adjunctive ziprasidone with monotherapy Rating Scale 160mg (‐8.27 +/‐2.17). sertraline. sertraline 8 weeks (MADRS) total Vs score from ‐Ziprasidone 80mg adjunct group had a 19% ‐Further studies are sertraline baseline to end of response rate compared with 32% rate with required for use of PLUS study ziprasidone 160mg adjunct and 10% with ziprasidone in treatment‐ ziprasidone placebo (p=NS). resistance depression. 80mg Vs ‐Physical exams, lab tests and sertraline electrocardiogram reports did not have PLUS clinically significant changes with either ziprasidone adjunctive dose. 160mg Aman et al59 Double‐blind, N=38 ‐Subjects aged 5‐ ‐Compared tests ‐Performance did not decline in those in the ‐Although minimal, 2008 placebo‐ 17 years with of sustained risperidone group. risperidone was an controlled autism and severe attention, verbal effective treatment for parallel group behavioral learning, hand‐eye ‐Those in the risperidone group performed a word recognition, with no design disturbances and coordination, and verbal learning task (word recognition) and a detrimental effective on a mental age of spatial memory, cancellation task (number of correct cognition. risperidone 8 weeks ≥18 months which were detections) better than those in the placebo Vs assessed before, group. placebo during, and at end of study

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments ‐Spatial memory task was comparable between groups.

‐Significant differences were not seen between treatment groups with the hand‐eye coordination task of the timed math test. van Randomized, N=122 ‐Subjects ‐Mean baseline‐ ‐Olanzapine treatment resulted in greater ‐Compared with Nimwegen double‐blind, diagnosed with to‐endpoint decreases in Y‐BOCS total score (p<0.01) in risperidone, olanzapine et al60 study schizophrenia, change in total total group, in those with baseline Y‐BOCS significantly and clinically 2008 schizoaffective score on the Yale‐ total score > 0 (p<0.01), and in those with decreased Y‐BOCS scores. olanzapine 6 weeks disorder, or Brown Obsessive‐ baseline Y‐BOCS total score >10 (p=0.032) Vs schizophreniform Compulsive Scale compared with the risperidone group. risperidone disorder (Y‐BOCS). Ganguli Randomized, N=123 ‐Subjects with ‐To assess short‐ ‐The group with the slowest olanzapine dose ‐Gradual reduction in dose et al61 open‐label, schizophrenia or term results of reduction (Gradual 2) had the lowest all‐ over 2 weeks resulted in 2008 rater‐blinded schizoaffective strategies for cause treatment discontinuation (12%), and it higher rates of retention study disorder on a discontinuation of occurred at half the discontinuation rate with when switching from stable dose at one treatment the other two groups (25% in the Abrupt olanzapine to risperidone (1)Abrupt 6 weeks least 30 days prior when starting group and 28% in Gradual 1). compared with abrupt or strategy (d/c to study who were another less gradual olanzapine intolerant or had ‐Compared with the Abrupt and Gradual 1 discontinuation. when start had a suboptimal treatment groups, the relative risk of early risperidone) response to at discontinuation was 0.77 with the Gradual 2 Vs least 30 days of group. (2)Gradual 1 olanzapine strategy (↓ ‐Improvements in PANSS total score olanzapine (p<0.0001), as well as PANSS positive 50% X 1 wk (p<0.0001), negative (p=0.171) and after start anxiety/depression (p=0.0005) subscale risperidone & scores were seen after medication change. then d/c) Vs

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments (3)Gradual 2 strategy (dose olanzapine at 100% x 1 wk, then ↓50% X 1 wk after risperidone started, & then d/c olanzapine) Sikich et al62 Randomized, N=119 ‐Children and ‐Response to ‐Response rates were not significantly ‐2nd generation 2008 double‐blind, adolescents with treatment, different between treatment groups (50% antipsychotics showed multicenter early‐onset defined as a molindone, 34% olanzapine, and 46% comparable efficacy to comparator schizophrenia or Clinical Global risperidone) or symptom reduction molindone, a 1st trial schizoaffective Impression (CGI) magnitude. generation antipsychotic disorder improvement for early‐onset olanzapine 8 weeks score of 1 or 2 and ‐Weight gain was significantly higher with schizophrenia; however, Vs ≥20% reduction in risperidone and olanzapine use compared reports of weight gain and risperidone Positive and with molindone. other metabolic effects in Vs Negative the youth are a concern. molindone Syndrome Scale ‐The greatest risk of weight gain was seen (PANSS) total with olanzapine, as well as significant score increases in fasting cholesterol, LDL, insulin, and liver enzymes.

‐Akathisia was reported more with molindone compared with the other 2 treatment groups.

‐Other adverse events were reported but differed among the medications.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Hanssens Open‐label, N=555 ‐Subjects with ‐Mean total score ‐SOC included olanzapine, quetiapine, or ‐The authors concluded et al63 multicenter, schizophrenia of the Investigator risperidone. that patient compliance 2008 randomized Assessment may increase with study Questionnaire ‐Improvements in sexual function were seen aripiprazole use due to the (IAQ) in both treatment groups from baseline; possibility of reduction in aripiprazole 26 weeks however, the aripiprazole group experience sexual dysfunction. Vs ‐Other measures significantly greater improvement at week 8 standard of were prolactin compared with the SOC group (p=0.007). care (SOC) levels and sexual function, based on ‐Prolactin levels at baseline were similar the Arizona Sexual (43.4mg/dl aripiprazole vs 42.3mg/dl SOC; Experience scale p=NS). (ASEX). ‐Decreases in prolactin level was significantly greater with the aripiprazole group compared with the SOC group (p<0.001). Ganesan Multicenter, N=477 ‐Subjects ‐% obtaining ‐77.6% that were switched to quetiapine XR ‐Clinical benefit with good et al64 open‐label switching to clinical benefit therapy completed the treatment, with 62.8% tolerability was seen when 2008 study quetiapine XR that when switched achieving a clinical benefit (p<0.0001). subjects were switched to were on a antipsychotic quetiapine XR. quetiapine XR 12 weeks different therapy ‐Improvements in CGI‐I and change in PANSS antipsychotic (improvement on total scores were significant (both p<0.001). experiencing the Clinical Global suboptimal Impression‐ ‐Reported adverse events included efficacy or Clinical Benefit somnolence (17.8%), sedation (15.1%), tolerability [CGI‐CB) scale) dizziness and dry mouth (both 14.0%), and ‐Other endpoints EPS (8.0%)> included CGI‐ Improvement (CGI‐I), Positive and Negative

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Syndrome Scale (PANSS) total score, and tolerability McIntyre Multicenter, N=489 ‐Subjects ≥ 18 yrs ‐The change from ‐On day 2, significantly greater least squares ‐For patients with bipolar et al68 randomized, with a primary baseline to day 21 (LS) mean changes in YMRS scores were seen disorder experiencing acute 2009 double‐blind, diagnosis of in the Young with asenapine (‐3) and olanzapine (‐3.4) vs manic episodes, asenapine placebo‐ bipolar disorder Mania Rating placebo (‐1.5; both p<0.01). is fast acting, efficacious, controlled, experiencing Scale (YMRS). and well tolerated. LOE‐1a parallel‐group manic or mixed ‐This was maintained until the end of the study episodes ‐Secondary study on day 21 (‐10.8 asenapine, ‐12.6 with endpoints include olanzapine vs ‐5.5 with placebo; both asenapine 3 weeks ‐A single‐blind changes from p≤0.0001). flexible dose placebo run‐ baseline in mania Vs period for 7 days or mixed states ‐A significantly greater response (42.3%) and placebo was done to allow severity measured remission (40.2%) was seen in the asenapine Vs for washout of using the Clinical group vs placebo (25.2% and 22.3% olanzapine medications Global Impression respectively; both p<0.01). for Bipolar Disorder (CGI‐BP), ‐For asenapine treated subjects, the NNT change from (Number Needed to Treat) versus placebo baseline in was 6 for both YMRS response and remission. depressive ‐The olanzapine group also had a significantly symptoms using greater response compared with placebo for the Montgomery‐ response/remission (50%/39.4% asenapine vs Asberg Depression 25.2%/22.3% placebo; p<0.0001/p=0.0041). Rating Scale (MADRS), % ‐For olanzapine treated subjects, the responders with a respective NNT for YMRS response and 50% decrease in remission were 5 and 6. YMRS score from baseline

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Safety and ‐Asenapine and olanzapine were superior to tolerability of placebo with CGI‐BP mania severity scores as adverse events early as day 2 of treatment and continued (AE) through the end of the study (p<0.002 asenapine vs placebo and p<0.0001 olanzapine vs placebo).

‐The LS mean changes from baseline to days 7 and 21 were ‐2.7 and ‐3.2 with asenapine (both p=NS vs placebo), ‐3.1 and ‐4.2 with olanzapine (p<0.05 and p<.005 vs placebo), and ‐1.4 and ‐1.8 for placebo.

‐Treatment emergent/treatment related events reported with asenapine were 73.7%/60.8%, 71.4%/52.9% with olanzapine, and 61.0%/36.2% with placebo.

‐Adverse events reported by ≥5 of asenapine subjects and at more than twice the frequency of placebo included (results adjusted to only extent that they exceed placebo): sedation (13.8%), dizziness (8.1%), fatigue (6.9%), and oral hypoesthesia (4.2%).

‐7.2% of asenapine subjects reported extrapyramidal symptoms vs 7.9% with olanzapine and 2.9% with placebo.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments McIntyre Double‐blind N=504 ‐Subjects with ‐The change from ‐Significant differences in YMRS total score ‐Asenapine was seen to be et al69 extension bipolar I disorder baseline to day 84 were not seen between asenapine and efficacious and was non‐ 2009 study experiencing on the Young olanzapine in both the pp population and the inferior to olanzapine with acute manic or Mania Rating intent‐to‐treat (ITT) population, thus extended treatment in LOE‐2 asenapine 9 weeks mixed episodes Scale (YMRS) asenapine was non‐inferior to olanzapine. those with bipolar disorder, 5 or 10mg BID who completed totals score (in the as well as being well Vs either of two 3‐ per‐protocol ‐The % of subjects in the asenapine and tolerated. olanzapine week, double‐ population [ppp]). olanzapine groups meeting criteria for YMRS 5‐20mg QD blind trials. response and YMRS remission were not Vs ‐These results significantly different (all p>0.05). placebo ‐The blinding were used to continued during establish non‐ ‐The rates of response with asenapine and this extension inferiority of olanzapine were 90% and 92% respectively study and those in asenapine vs for the pp population and 77% and 82% the olanzapine olanzapine. respectively for the ITT population. and asenapine continued with ‐Safety and ‐The rates of remission with asenapine and those treatments, tolerability were olanzapine were 88% and 91% respectively but those in the assessed. for the pp population and 75% and 79% placebo group respectively for the ITT population. were blindly switched to ‐There were no marked between‐group asenapine. differences in the reports of treatment‐ related adverse events.

‐Significant weight gain was reported in 19% of the asenapine group, 31% of olanzapine group and 10% of the placebo group.

‐EPS was reported in 15% of asenapine group, 13% of olanzapine, and 10% of placebo.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Grootens Multicenter, N=76 ‐Subjects ages 18‐ ‐To compare ‐A similar decrease in PANSS total score was ‐The authors concluded et al70 randomized, 40 years with a efficacy, assessed seen with both groups compared with that although both 2009 double‐blind, diagnosis of by a reduction in baseline, with a score of ‐17.15 difference olanzapine and ziprasidone parallel‐ schizophrenia, the total score of from baseline to end of study with olanzapine resulted in similar LOE‐1a group, schizoaffective the Positive and and ‐14.86 with ziprasidone (p=0.68). therapeutic efficacy, though controlled disorder, or Negative their side effect profile study schizophreniform Syndrome Scale ‐61% in the olanzapine group showed a differed. disorder (PANSS), the clinical response compared with 60% in the olanzapine 8 week Clinical Global ziprasidone group (p=1.00). 10‐20mg Impression Vs Improvement ‐35% of olanzapine group met remission ziprasidone (CGI‐I) scale. criteria vs 40% of the ziprasidone group 80‐160mg (p=0.80). ‐Safety ‐Significant differences with the CGI‐I scale were not seen between treatment groups.

‐Significantly more weight gain and increased appetite was reported with olanzapine use vs ziprasidone.

‐Decreased levels of triglycerides and cholesterol were seen with ziprasidone but these parameters increased in the olanzapine group (p<0.05).

‐Significant differences were not seen between groups with fating glucose or prolactin levels, or in cardiac or sexual side effects.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Boter et al71 Multicenter, N=498 ‐First‐episode ‐≥50% response ‐Within 12 months, 37% if the haloperidol ‐Within 12 months, 2009 open patients aged 18‐ and remission group had a ≥50% response within 12 clinically meaningful randomized 40 years with within 12 months, months, compared with 67% for amisulpride response and remission LOE‐2 study schizophrenia by measured with and olanzapine, 46% for quetiapine, and 56% rates were seen in those meeting DSM‐IV the Positive and for ziprasidone. with first‐episode patients haloperidol 12 months criteria. Negative with schizophrenia. Vs Syndrome Scale. ‐There was a statistically significant between Compared to haloperidol, amisulpride group difference for response (p=0.001), and the amount of response Vs was statistically lower with the haloperidol‐ and remission was higher olanzapine treated patients compared to the second most second‐generation Vs generation antipsychotics (except for antipsychotics (SGAs). quetiapine quetiapine). Vs ziprasidone ‐By the end of the study, 17% of the haloperidol remitted compared with 40% of the amisulpride group, 41% with olanzapine, 24% with quetiapine, and 28% with ziprasidone.

‐There was a statistically significant between group difference with remission (p=0.012), with less haloperidol‐treated patients reaching remission compared to those treated with the second generation antipsychotics.

‐15% of the amisulpride‐treated patients and 36% of the olanzapine treated patients had not responded to treatment, which was less than haloperidol‐treated patients. Also, higher amounts of patients on these

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments medications responded very well (24‐35% vs 13% haloperidol). At 12 months, these between group differences were statistically significant (p=0.016).

‐Those on amisulpride, olanzapine, or ziprasidone showed a ≥50% response when compared with haloperidol. Kane et al72 Multicenter, N=323 ‐Subjects ≥18 ‐The mean change ‐There were no statistically significant ‐Although generally well 2009 randomized, years with from baseline to differences between the aripiprazole group tolerated and safe, the double‐blind, chronic, stable end of study in and the placebo group in the change of addition of aripiprazole to LOE‐ 1a placebo‐ schizophrenia or the Positive and PANSS total score. risperidone or quetiapine controlled. 4‐ schizoaffective Negative did not offer additional arm study disorder on a Syndrome Scale ‐Changes from baseline to end of study were improvement in psychiatric stable dose of (PANSS) total similar in both groups (‐8.8 adjunctive symptoms. aripiprazole 16 weeks either quetiapine score aripiprazole vs ‐8.9 adjunctive placebo; PLUS or risperidone for p=0.942). risperidone ≥4 weeks but with ‐Mean change in Vs an inadequate Clinical Global ‐Statistically significant between‐ group placebo PLUS response Impressions‐ differences were not seen in CGI‐S scores risperidone Severity (CGI‐S) Vs was the key ‐With a subgroup analysis, improvement in aripiprazole secondary PANSS total scores with aripiprazole vs PLUS endpoint placebo was greater in patients with quetiapine schizoaffective disorder (‐13.6 vs ‐8.1; Vs ‐Safety was also p=0.145) than in those with schizophrenia (‐ placebo PLUS assessed 7.3 vs ‐8.5; p=0.505), but not statistically quetiapine significant.

‐Fatigue (8.3%), headache (7.1%), and insomnia (6.5%) were the 3 most common

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments adverse events with the aripiprazole group. The 3 most common with the placebo group were headache (8.5%), insomnia (8.5%), and akathisia (7.2%).

‐Fewer treatment‐emergent adverse events were reported with the adjunctive aripiprazole group vs placebo (4.7% vs 12.4%).

‐EPS adverse events were reported by 8.3% of the aripiprazole group vs 12.4% placebo.

‐Significant differences in median changes from baseline to end of study in fasting glucose, total cholesterol, fasting triglycerides, LDL cholesterol, or HDL cholesterol were not seen between treatment groups.

‐Weight change between aripiprazole and placebo were similar (1.3kg vs 1.1kg; p=0.728).

‐Clinically relevant weight gain was seen in 13.4% of those in the aripiprazole group compared with 9.9% of the placebo group (p=0.445).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Suppes Multicenter, N=280 ‐Subjects aged ‐The change from ‐After one week of treatment, a significantly ‐Use of quetiapine XR daily et al73 randomized, between 18 and baseline to end of greater reduction in MADRS total score was as monotherapy was 2010 double‐blind, 65 years with a study in the seen in the quetiapine XR group compared significantly more effective parallel‐ clinical diagnosis Montgomery with placebo. This reduction was consistently than placebo for treating LOE‐ 1a group, of bipolar I or II Asberg Depression seen through the end of the study (p<0.001 episodes of depression in placebo‐ disorder, most Rating Scale vs placebo). bipolar I controlled, recent episode (MADRS) total Phase III study depressed. score vs placebo ‐The mean changes in MADRS total score from baseline to week 8 were ‐17.4 for the ‐MADRS total quetiapine XR group and ‐11.9 for the quetiapine XR 8 weeks score in placebo group (p<0.001). 300mg QD subgroups of Vs patients based on ‐In the subgroups with bipolar I and II placebo diagnosis (bipolar disorder, significantly greater improvements I or bipolar II) and were seen in the quetiapine XR group disease course, compared with placebo. and MADRS individual item ‐Compared with placebo, quetiapine XR was scores were also significantly more effective (p<0.01) in assessed. subjects with/without a rapid cycling disease course. ‐Safety was assessed ‐Compared with placebo, quetiapine ER was associated with significantly greater improvement (p<0.05) in 8 of the 10 individual MADRS item scores.

‐A significantly greater amount of subjects responded to treatment in the quetiapine ER group compared with placebo, as seen by a ≥50% reduction in MADRS total score.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments ‐Significantly more in the quetiapine ER group achieved remission from week 1 onward compared with placebo (p<0.05 at all time points).

‐EPS adverse events were reported by 4.4% of the quetiapine ER group compared with 0.7% of the placebo group.

‐88.3% reported adverse events (AE) in the quetiapine ER group vs the placebo group, and the amount withdrawing from the study due to AEs was higher in the quetiapine ER group vs placebo (12.14% vs 1.7%).

‐The mean weight change in the quetiapine ER group was +1.3kg vs ‐0.2kg with placebo.

‐The mean change in serum glucose levels in the overall safety population was similar between groups; however, the rise in fasting glucose levels to clinically important levels at the end of study was greater in the quetiapine ER group (5.8%) vs placebo (2.1%). El‐Khalili Multicenter, N=446 ‐Subjects aged 18‐ ‐The change from ‐A significantly greater mean change in ‐The author’s concluded et al74 randomized, 65 years with a randomization to MADRS total score was seen with the that using quetiapine XR 2010 double‐blind, diagnosis of Major end of study in quetiapine XR 300mg/day group vs placebo 300mg as an adjunct placebo‐ Depression Montgomery‐ (‐14.7 vs ‐11.7; p<0.01). Although the therapy in those with an LOE‐ 1a controlled, Disorder (MDD) Asberg Depression quetiapine 150mg group also reduced the inadequate response to an Phase III study with a Hamilton Rating Scale MADRS total score, it was not statistically antidepressant was a safe Depression Rating (MADRS) total significant vs placebo (‐13.6; p=0.067). and effective treatment.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine XR 6 weeks Scale (HAMD) score. 150mg/day total score ≥ 20. ‐At the end of study, the MADRS remission GHS Comments: Number Vs Patients were ‐Quality of Life rates were 35.0% (quetiapine XR 150mg; Needed to Treat (NNT) for quetiapine XR required to have Enjoyment and p=0.059) and 42.5% (quetiapine XR 300mg; response was 18 and 8 300mg/day an inadequate Satisfaction p<0.01) vs 24.5% (placebo). respectively for quetiapine Vs response during Questionnaire‐ XR dosages of 150 mg and ‐Statistical significance was not seen between placebo their current Short Form (Q‐ 300 mg. quetiapine XR and placebo for the Q‐LES‐Q‐ (all adjunct to depressive LES‐Q‐SF) was also SF; quetiapine XR 150mg (10.37; p=0.606), an anti‐ episode to an assessed. NNT for remission was 10 quetiapine XR 300mg (11.82; p=0.789), and depressant) antidepressant. and 6 respectively for placebo (11.32). ‐Safety was quetiapine XR dosages of assessed ‐The overall incidence of adverse events (AEs) 150 mg and 300 mg. was 66.9% for the placebo group, 82.4% for the 150mg group, and 87.2% for the 300mg group. Most were mild to moderate in intensity.

‐0.7% withdrew from study in placebo group due to AEs, compared with 11.5% in the 150mg group, and 19.5% in the 300mg group.

‐Somnolence was reported by 4.1% of the placebo group, compared with 29.1% in the 150mg group, and 28.9% in the 300mg group.

‐Dry mouth, sedation, dizziness, constipation, nausea, headache, fatigue, increased appetite, and increased weight were the most commonly reported AEs.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Narula et al75 Parallel, N=72 ‐Drug‐naïve, 1st‐ ‐To assess efficacy ‐Compared to baseline, the olanzapine ‐The author’s concluded 2010 double‐blind, episode subjects of topiramate to resulted in a significant increase in weight that a low dose of randomized, aged 18‐65 years prevent and BMI (p<0.001). topiramate used in those LOE‐See GHS placebo‐ with olanzapine‐ treated with olanzapine Comments controlled schizophrenia induced weight ‐A statistically significant decrease in weight was able to prevent prospective gain and (within group p=0.003; between group olanzapine associated study metabolic p=0.05) and BMI (within group p=0.004; weight gain. Furthermore, it abnormalities. between group p=0.017) with topiramate. was able to prevent the olanzapine 12 weeks development of an adverse PLUS ‐Weight, body ‐Weight at baseline for topiramate group was metabolic profile. topiramate mass index (BMI), 54 kg compared with 52.73 (‐1.27kg) at end (100mg/day) fasting blood of study. Weight for olanzapine group was GHS Comments: This is a Vs glucose (FBG), 52.82kg at baseline and 58.85 at end of study significant finding given the olanzapine insulin, insulin (+6.03kg). high risk of weight gain and PLUS placebo resistance, lipids, metabolic problems blood pressure ‐BMI at baseline with topiramate group was associated with this class. (BP) were 20.56 and was 20.1 at end of study, Additionally, other studies assessed at compared with 20.2 in olanzapine group at have suggested that baseline and week baseline and 22.55 at end of study. metformin attenuates 12. antipsychotic associated ‐The topiramate group resulted in a decrease weight gain. ‐Clinical in FBG, TC, HDL, triglycerides, and BP evaluation was (p>0.05). A decrease in leptin was seen LOE‐ As there was no done using (p<0.001). A marginal increase in insulin, LDL, information provided about Positive and and VLDL levels were seen (p>0.05). the handling of drop‐outs in Negative the study (eg. last Syndrome Scale ‐Significant between‐groups changes in FBG observation carried), this (PANSS). (p<0.001), TC (p=0.008), LDL cholesterol study could not be rated. (p=0.009), and BP changes (systolic p=0.014; Attempts were made to ‐Safety was also diastolic p=0.014) were seen. contact the author without assessed. success.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Significant increases in FBG, insulin, leptin, TC, triglycerides, and LDL cholesterol were seen in the olanzapine group (p<0.001).

‐A significant reduction in PANSS symptom scores were seen in both groups.

‐The between group difference for the change in PANSS (total; p=0.001) and the general psychopathology scale score (p<0.001) was significant, with a greater response seen in the topiramate group.

‐Weight gain was seen in all subjects treated with olanzapine compared to only 9 patients in the topiramate group. Cutler et al76 Multicenter, N=593 ‐Subjects aged 18‐ ‐The change from ‐Significantly greater improvements were ‐For acute exacerbation of 2008 double‐blind, 65 years with baseline in PANSS seen in PANSS‐T scores in the iloperidone schizophrenia, iloperidone prospective, diagnosis of total (PANSS‐T) group vs placebo (‐12 vs ‐7.1; p<0.01). The was safe and effective. LOE‐1a randomized, schizophrenia and scores. ziprasidone group also obtained significantly placebo‐ and an overall Positive greater improvements compared with active‐control and Negative ‐ Mean change in placebo (‐12.3; p<0.05 vs placebo). phase III study Syndrome Scale Clinical Global (PANSS) total Impressions‐ ‐Significantly greater reductions in CGI‐S iloperidone 4 weeks score of ≥70 at Severity (CGI‐S) scores were seen with iloperidone vs placebo Vs screening and was a secondary (‐0.65 vs ‐0.39; p=0.007), as did subjects ziprasidone baseline endpoint receiving ziprasidone (‐0.67; p= 0.013 vs Vs placebo) placebo ‐Safety was (2:1:1 ratio) assessed ‐The most commonly reported treatment‐

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments emergent adverse events (TEAEs) with iloperidone were dizziness, sedation, weight increase, tachycardia, dry mouth, increase heart rate, nasal congestion, and orthostatic hypotension. 5% of the iloperidone discontinued treatment due to TEAE’s vs 8% of both the ziprasidone and placebo groups.

‐Similar degrees of QTC prolongation were seen with iloperidone and ziprasidone (p<0.001 vs placebo).

‐Mean weight increases from baseline for iloperidone, ziprasidone, and placebo were 2.8, 1.1, and 0.5kg, respectively. Clinically significant weight increases were seen with 21% of the iloperidone group, 7% with ziprasidone, and 3% with placebo.

‐1% of iloperidone group reported akathisia, vs 7% of ziprasidone and 0% of placebo. Kane et al77 Pooled data N=1644 Subjects aged 18‐ ‐The time to ‐Relapse rates between treatments differed ‐The author’s concluded 2008 from 3 (initial 6 65 years with relapse during the only slightly (43.5% iloperidone vs 41.2% that iloperidone use multicenter, week phase) diagnosis of long‐term phase. haloperidol). resulted in similar efficacy prospective, N=489 schizophrenia or (Relapse: increase with haloperidol while also randomized, (main‐ schizoaffective of the PANSS‐T ‐Mean time to relapse was 89.8 days with having a favorable long‐ double‐blind, tenance disorder and a score ≥25%) iloperidone vs 101.8 days with haloperidol; term safety profile. flexible‐dose, phase) Positive and however, this was not statistically significant parallel‐group Negative ‐Change from (p=0.8411). long‐term Syndrome Scale baseline to end of studies total (PANSS‐T) study in PANSS, ‐Similar results for PANSS‐T score were seen between groups (‐16.1 for iloperidone vs ‐

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments score ≥60. Brief Psychiatric 17.4 for haloperidol), which was not iloperidone 3‐six week Rating Scale, and statistically significant (p=0.338). Vs stabilization Clinical Global haloperidol phases, Impressions of ‐PANSS‐negative scores were ‐4.7 for each followed by Change (CGI‐C) group (p=0.981) and the PANSS‐positive 46 week scores. scores were ‐4.2 for iloperidone and ‐5.3 for main‐ haloperidol (p=0.006). tenance ‐Safety was ‐65% in the iloperidone group resulted in phase assessed improvement in CGI‐C scores vs 66% for the haloperidol group.

‐Changes in Brief Psychiatric Rating Scale scores were ‐9.0 for iloperidone and ‐9.6 for haloperidol (p=0.390).

‐The most commonly reported adverse events with both treatments were insomnia, headache, anxiety, agitation, dizziness, and restlessness.

‐Muscle rigidity (21.1 vs 4.1), akathisia (18.6 vs 3.5), tremor (22.1 vs 3.3), bradykinesia (6.0 vs 1.3), dystonia (7.2 vs 1.1), and EPS (7.7 vs 0.6) were reported more with haloperidol vs iloperidone in the 6 week initial phase.

‐A more favorable metabolic profile was seen with iloperidone in both the long‐ and short‐ term studies.

‐68.4% of the total weight gain seen with iloperidone was during the 1st 6‐weeks,

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments compared with 26.1% with haloperidol (2.6kg vs 0.6kg, respectively at end of 6 wks; compared with 3.8kg and 2.3kg respectively at end point).

‐Slight increases in total cholesterol, triglycerides, and glucose levels were seen with iloperidone with long‐term treatment. Sacchetti Multicenter, N=147 ‐Subjects aged 18‐ ‐The change from ‐PANSS total score changes from baseline to ‐The author’s concluded et al78 randomized, 65 years with baseline to end of end of study were similar between that while ziprasidone and 2009 double‐blind, diagnosis of study with PANSS treatments (‐25.0 ziprasidone vs ‐24.5 clozapine resulted in double‐ schizophrenia, total score. clozapine), with no significant between‐group comparable efficacy LOE‐1a dummy trial who are resistant differences seen at endpoint. coupled with satisfactory and/or intolerant PANSS (positive, general safety and ziprasidone 18 weeks to at least 3 acute negative, and ‐A progressive decrease from baseline was tolerability for treatment of 80mg BID x3 cycles with general seen starting at visit 1 (day 11) onward with difficult to treat days then flex different psychopathology both treatment groups (p<0.001, except schizophrenia, ziprasidone dose of 80‐ antipsychotic subscales, CGI‐S p=0.003 in the clozapine group at day 11). has a more favorable 160mg/day treatment in the completed at metabolic profile. Vs previous 5 years, baseline and ‐The rates of patients with a change in PANSS clozapine with a ≥80 score weekly thereafter, total score ≥20%, ≥30%, or ≥40% were similar GHS Comments: This is a 25mg/day up on the Positive Clinical Global between treatments. level 1a trial; however, a to 300mg/day and Negative Impression flaw of this study is that over 10 days Syndrome Scale Improvement ‐The proportion of responders failed to there is no placebo group. X7 days then total (PANSS‐T) (CGI‐I) scale and differentiate the two treatments, with one flex dose of score and a ≥4 on Calgary exception of a higher frequency (p=0.007) of 250‐600mg the Clinical Global Depression Scale patients with a PANSS total score Impression for Schizophrenia improvement of 20% or more in the Severity (CGI‐S) was also assessed. ziprasidone group (97.8% vs 77.8% with scale at baseline. clozapine). ‐Safety was assessed. ‐Significant improvements from baseline to

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments end of study in PANSS positive, negative, and general psychopathology were seen with both treatment groups, with no significant differences between groups.

‐A significant improvement in CGI‐S scores was seen with both groups, with no difference seen between treatments.

‐71% of the ziprasidone group reported treatment‐emergent adverse events (TEAEs), with insomnia being the most common. 79.5% of the clozapine group reported TEAEs, with salivation, tachycardia, dizziness, and somnolence being the most common.

‐The clozapine group resulted in a 0.8kg weight gain, while the ziprasidone group resulted in a 2.6kg weight loss, with a significant between group difference (p<0.001).

‐Median changes from baseline to end of study with fasting total cholesterol, LDL, and triglycerides significantly favored ziprasidone compared with clozapine, with ziprasidone have decreases in these parameters and clozapine having increases.

‐Median fasting glucose levels were unchanged in the ziprasidone group

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments compared with baseline but increased by 6mg/dL in the clozapine group, which resulted in a significant between group difference (p=0.003).

‐Significant changes in blood pressure were not seen with treatments. Clozapine increased heart rate by +8.0 bpm while ziprasidone increased by +2.0 bpm, but were not significantly different.

‐Significant treatment‐emergent ECG abnormalities were seen, with mean QTc change not significantly different between treatment groups. Alptekin Multicenter, N=287 ‐Subjects aged 18‐ ‐The change from ‐Suboptimal efficacy was the main reason for ‐The author’s concluded et al79 open‐label, 65 years treated baseline in total switching in 61, 56, and 53% of the subjects in that switching to 2009 non‐ with haloperidol, Brief Psychiatric the haloperidol, olanzapine, and risperidone ziprasidone is an effective randomized, olanzapine, or Rating scale pre‐switch groups, respectively. option for stable patients LOE‐2 baseline‐ risperidone for ≥3 (BPRS) score with schizophrenia or controlled, months before ‐At week 12, non‐inferiority of ziprasidone schizoaffective disorder single‐ baseline and with ‐Change from over all three medications was seen with the experiencing suboptimal treatment, a diagnosis of baseline in the BPRS. effect with haloperidol, flexible dose schizophrenia or Clinical Global risperidone, or olanzapine. study schizoaffective Impression‐ ‐Additionally, significant improvements in disorder Severity (CGI‐S) BPRS total score were seen with ziprasidone GHS Comments: This is a score, Clinical at the end of the study (p<0.0001 vs level of evidence 2 study Global baseline), but with the greatest amount of since it is an open‐label ziprasidone 12 weeks Impression‐ change happening during the first 2 weeks of study. Furthermore, a flaw 80‐160mg Improvement treatment. of this study is the fact that (CGI‐I) score, there is no placebo group. PANSS, MADRS, ‐Patients switched from haloperidol and

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Global risperidone resulted in a greater Assessment of improvement in BPRS than those switching Functioning (GAF), from the olanzapine group. and Drug Attitude Inventory (DAI) ‐In all three groups that switched to were also ziprasidone, significant improvements were assessed. seen on the CGI‐S, PANSS total, positive, and negative scores, and the MADRS, except for ‐Safety was the olanzapine group on the MADRS. assessed ‐Significant improvements were seen on the GAF (p≤0.002) at week 12 in all three pre‐ switch groups, as well as the DAI in the haloperidol and risperidone pre‐switch groups (p<0.05) but not in the olanzapine pre‐switch group.

‐52.1% had treatment‐emergent adverse events (TEAEs). Somnolence, dizziness, insomnia, headache, nausea, and anxiety were most commonly reported.

‐The haloperidol pre‐switch group had the highest baseline score on all three EPS symptoms rating scales, followed by risperidone and olanzapine. Improvements from baseline were seen in all three groups, with statistically significant improvements seen after switching from haloperidol or risperidone, but not olanzapine.

‐The pre‐switch olanzapine group resulted in significant mean weight loss of 2kg at week

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments 12; however, the pre‐switch risperidone group resulted in non‐significant weight reduction of 0.6kg and the pre‐switch haloperidol group resulted in a non‐ significant 0.4kg weight increase.

‐A neutral effect was seen with metabolic parameters and prolactin with switching to ziprasidone. Wang et al86 Multicenter, N=404 ‐Subjects ‐To compare ‐Risperidone decreased the time to relapse This study demonstrates 2010 open‐label, diagnosed with relapse between when administered at full dose (initial optimal that the dose used for randomized schizophrenia treatment groups. therapeutic dose) compared with a group initial treatment is the best LOE‐2 controlled clinically stabilized maintained at 50 % the initial optimal dose. dose for maintenance in trial after an acute relapse prevention. episode risperidone 1 year GHS Comment: Though an IOTD with no‐ open label study, this trial dose ↓ (IOTD‐ initial provides strong support Vs optimal that maintenance risperidone therapeutic treatment in patients with IOTD X4 wks, dose) schizophrenia is best then 50% achieved with the dose of dose ↓ medication used for acute Vs treatment. risperidone IOTD X26 wks then 50% dose ↓

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Berman Multicenter, N=1,147 ‐Subjects aged 18‐ ‐The mean change ‐Aripiprazole associated with significant ‐Limitation is the short term et al87 randomized, 65 years from end of the decreases in depressive symptoms assessed nature (6 weeks) of this 2009 double‐blind, diagnosed with prospective using the MADRS Total score. study. placebo‐ major depressive treatment to the LOE‐1a controlled disorder (MDD) end of the ‐Remission rates greater in adjunctive GHS Comment: Though trial and an inadequate randomized, aripiprazole than placebo. derived from a response to a double‐blind trials manufacturer sponsored aripiprazole 8 weeks previous in the ‐Aripiprazole well tolerated with akathisia study, this is a robust Vs antidepressant Montgomery‐ being most common treatment emergent effect. placebo Asberg Depression adverse event. Rating (MADRS) ‐NNT of 6 for remission and 5 for response. Moreno Naturalistic, N=90 ‐Children or ‐To compare ‐Significant differences in baseline weight and ‐Weight gain and metabolic et al88 uncontrolled adolescents weight and other metabolic measurements were not changes occur in youth 2010 comparator receiving a new metabolic seen. treated with second‐ trial prescription for differences in generation antipsychotics LOE‐2 olanzapine, youth with ‐Significant increases in weight and BMI were irregardless of diagnosis. risperidone, or different seen as a whole, and for each of the different bipolar 3 months quetiapine for no diagnoses 3 groups. 71.1% of the sample had significant disorder more than 30 days months after weight gain, with 75% of the bipolar group, Vs prior starting treatment 76.9% the other psychotic disorders group, other and 62.1% the nonpsychotic disorders group. psychotic disorders ‐Differences in weight increases were not Vs seen between patients in the three groups, or Other non‐ in differences in % of patients with ≥0.5 psychotic increase in BMI z‐score, with weight increase disorders ≥5%, or with BMI ≥85th percentile.

‐Total cholesterol significantly increased in those with bipolar (p=0.02) and other

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments psychotic disorders (p=0.01), and LDL increased significantly only in the bipolar group (p=0.02). Trivedi Integrated N=1,146 ‐Subjects with a ‐To compare the ‐Of the 5 studies included in the review, 3 ‐Those with treatment et al89 analysis of 5 diagnosis of major efficacy by way of compared OFC with fluoxetine and resistant depression 2009 randomized, depressive Montgomery olanzapine, 1 study compared OFC with treated with olanzapine‐ double‐blind disorder (MDD) Asberg Depression fluoxetine, olanzapine, and nortriptyline, and fluoxetine combination LOE‐1a comparator that were Rating Scale 1 study compared OFC with fluoxetine, resulted in significantly studies treatment (MADRS) total olanzapine, and venlafaxine. improved depressive resistant (prior 2 score symptoms compared with olanzapine 8 weeks treatment ‐A significantly greater change in MADRS total those taking either PLUS failures) ‐Safety score was seen with the OFC group (‐13) vs olanzapine or fluoxetine fluoxetine the fluoxetine group (‐8.6; p<0.001) and the alone combination olanzapine group (‐8.2; p<0.001). (OFC) GHS Comments: NNT of 6 Vs ‐Clinical response rates were significantly for response and 9 for fluoxetine higher for the OFC group (40.3%) vs the remission with OFC Vs fluoxetine group (27.8%; p<0.001) and the compared to olanzapine olanzapine olanzapine group (23.1%; p<0.001). monotherapy. NNT of 8 for response and 13 for ‐Clinical remission rates were significantly remission with OFC higher for the OFC group (25.5%) vs the compared to fluoxetine fluoxetine group (17.3%; p=0.006) and the monotherapy. olanzapine group (14.0%; p<0.001).

‐A significantly higher rate of discontinuation due to adverse events was seen with the OFC group (11.6%) vs fluoxetine (2.6%; p<0.001); however, it was not significantly different from the rate for the olanzapine group (13.8%; p=0.394).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Reported adverse events in ≥10% of the OFC patients were weight gain, increased appetite, dry mouth, somnolence, fatigue, headache, and peripheral edema.

‐Weight change in the OFC group was +4.42kg compared with +4.63 for olanzapine group (p=0.381) and ‐0.15 for the fluoxetine group (p<0.001), which the fluoxetine group was statistically significantly different with the OFC.

‐40.4% of the OFC group gained ≥7% body weight vs 42.9% of the olanzapine group (p=0.515) and 2.3% of the fluoxetine group (p<0.001), which the fluoxetine group was statistically significantly different vs OFC.

‐Mean change in cholesterol levels were Owen et al90 Multicenter, N=98 ‐Children and ‐The mean change ‐A significantly greater decrease in caregiver‐ ‐The authors concluded 2009 randomized, adolescents aged from baseline to rated ABC score was seen in the aripiprazole that aripiprazole was a safe double‐blind, 6‐17 years end point in the group (‐12.9) vs placebo (‐5.0; p<0.001). This and effective treatment in LOE‐1a placebo‐ diagnosed with caregiver‐rated was seen as early as week 1. this age group as treatment controlled, autistic disorder Aberrant Behavior for irritability associated parallel group and demonstrated Checklist (ABC) ‐Statistically significantly greater with autism. study behaviors such as irritability improvement in CGI‐I scores were seen with tantrums, subscale score. aripiprazole vs placebo beginning at week 1 aggression, self‐ (p<0.001) and continued through end of injurious behavior ‐Clinical Global study (p<0.001). or a combo Impression‐

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments aripiprazole 8 weeks Improvement 5mg , 10mg or (CGI‐I) score was ‐Significantly more in the aripiprazole group 15mg also assessed responded to treatment starting at week 2 vs Vs placebo (30.4% vs 4.1%; p<0.001) and placebo ‐Safety continued through end of study (52.2% vs 14.3%; p<0.001).

‐Discontinuation rates due to adverse events were 10.6% for aripiprazole and 5.9% for placebo.

‐Only mild to moderate adverse events were reported, no serious events were reported.

‐Compared with placebo, the aripiprazole group reported greater mean weight change at end of study (0.8kg vs 2kg; p<0.005). A greater incidence of clinically significant weight gain was also seen with the aripiprazole group vs placebo (28.9% vs 6.1%; p<0.01). Johnsen Randomized, N=213 ‐Subjects ≥18 ‐To assess the ‐The time until discontinuation of the drug, ‐The authors concluded et al91 prospective, years admitted to effectiveness with the time until discharge from index that quetiapine would be a 2010 rater‐blind, the ER for regards to time admission, and the time from discharge from good treatment to start naturalistic, symptoms of until drug index admission until readmission were not with in this population LOE‐3 head‐to‐head psychosis and had discontinuation different between treatment groups. admitted to the ER due to comparator diagnosis of for any cause, the psychosis. trial schizophrenia, time until ‐Outcomes related to symptom reduction and major depressive discharge from increased functioning resulted in significant GHS Comments: This study disorder with index differences among the treatment groups. has numerous limitations, psychotic hospitalization, including small sample size

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments risperidone 24 months features, or other and time until ‐Quetiapine was superior to risperidone and and non‐blinded design. Its Vs psychosis readmission olanzapine for reducing PANSS total score findings are at variance olanzapine and the positive sub‐score. with studies of larger Vs ‐Symptoms sample sizes (eg. CATIE quetiapine assessed Positive ‐Quetiapine was superior to the other study). Vs and Negative treatment groups for decreasing the PANSS ziprasidone Syndrome Scale general psychopathology sub‐score, (PANSS), Clinical decreasing the CGI‐Severity of Illness (CGI‐S) Global scale, and for increasing the GAF‐F score. Improvement (CGI), the Calgary ‐Ziprasidone was superior to risperidone for Depression Scale decreasing PANSS positive symptoms sub‐ for Schizophrenia score and the CGI‐S score, and for increasing (CDSS), and the the GAF‐F score. Global Assessment of ‐Weight gain and adverse influence on Functioning‐Split cholesterol and triglycerides was the most Version; Functions consistent difference between the groups in scale (GAF‐F). regards to adverse events. Most all other tolerability outcomes were similar between ‐Safety treatments. Peuskens Post hoc N=197 ‐Clinically stable ‐The time to first ‐The study ceased early because the interim ‐Quetiapine XR maintains et al92 analysis of a patients from the schizophrenia analysis demonstrated quetiapine XR to be remission in patients with 2010 multicenter, prior 16‐week relapse after statistically superior to placebo in the time to schizophrenia. randomized, open‐label randomization schizophrenia relapse. LOE‐1a double‐blind, stabilization parallel‐ period (who were ‐A significantly longer time to relapse was group, switched from seen with those treated with quetiapine XR vs placebo‐ their current placebo (p<0.001). controlled antipsychotic to study open‐label

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine XR 1 year quetiapine XR). 400mg, These subjects 600mg, or had documented 800mg schizophrenia for Vs at least 2 years. placebo Young Multicenter, N=802 ‐Subjects aged 18‐ ‐Change from ‐For improving MADRS total scores, both For treatment of episodes et al100 randomized, 65 years meeting baseline in doses of quetiapine were significantly better of acute depression in 2010 double‐blind, DMS‐IV criteria for MADRS total score than placebo. Numerically greater but not bipolar disorder, quetiapine parallel‐ bipolar I or II statistically significant improvements were was more effective than LOE‐1a group, disorder and who ‐Response (≥50% seen with the lithium group compared with placebo, while lithium did placebo‐ were experiencing reduction in placebo throughout the study. not differ significantly from controlled, a recent major MADRS total placebo on the main fixed‐dose depressive score) and ‐Significant improvements in MADRS total efficacy measures. study episode prior to remission (MADRS score were seen with quetiapine 600mg (but entry total score ≤12) not quetiapine 300mg) compared with GHS Comments: A quetiapine 8 weeks rates and Clinical lithium from day 8 through week 8 limitation of this study is 300mg or Global (difference of ‐2.49 points at week 8; that there were sub‐ 600mg QD Impressions‐ p=0.013). therapeutic blood levels of Vs Bipolar‐Change lithium in 34.9% of lithium lithium 600‐ were also ‐Both doses of quetiapine significantly treated subjects. 1800mg/day assessed improved MADRS scores in those with bipolar Vs I as compared with placebo (‐3.61 points placebo ‐Safety and treatment difference for quetiapine 300mg tolerability [p=0.006]; treatment difference of ‐5.28 points for quetiapine 600mg [p<0.001]).

‐In those with bipolar II, both doses of quetiapine showed numerically greater improvements in MADRS total scores compared with placebo; however, the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments between treatment differences were not statistically significantly different (quetiapine 300mg difference was ‐3.19 points [p=0.051]; 600mg difference was ‐2.43 points [p=0.131]).

‐Those without a rapid‐cycling disease showed significantly greater improvements when treated with both doses of quetiapine vs placebo (p<0.001), but not with lithium (p=0.066).

‐Significantly more treated with quetiapine met response criteria compared with those treated with placebo: 68.6% for quetiapine 300mg/day (p<0.05) and 69.6% for quetiapine 600mg/day (p<0.01) vs 55.8% placebo. The authors concluded that the NNT for the 300mg dose was 8 and for the 600mg dose was 7.

‐Those in the lithium group showed a numerically greater response than placebo, but was not statistically significantly different (62.5%; p=0.279). The authors reported an NNT of 15.

‐Significantly more in the quetiapine groups met remission criteria (300mg group was 69.8% and the 600mg group was 70.3%) as compared with placebo (55.0%; p<0.01 both doses). 62.5% of those in the lithium group

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments met criteria for remission, which was not statistically significantly different from placebo (p=0.228 vs placebo). The authors reported the NNT for quetiapine 300mg, 600mg, and lithium to be 7, 7, and 13.

‐The reported incidence of serious adverse events was low in all groups and similarly distributed across the treatment groups. The majority reported were mild to moderate in severity, with the most frequently reported being somnolence, dry mouth, and dizziness with both doses of quetiapine and nausea with lithium. Schoemaker Multicenter, N=1225 ‐Subjects aged 18 ‐To assess long‐ ‐Changes from baseline in PANSS total score ‐After 1 year of treatment, et al101 randomized, years of age or term use and were similar between treatments at week 6 asenapine was well 2010 double‐ older diagnosed changes in various (‐17.9 asenapine vs ‐19.0 olanzapine); tolerated, causing less dummy, with symptom domains however, a statistically significant difference weight gain than LOE‐1a double‐blind, schizophrenia or and overall was seen in favor of olanzapine at endpoint olanzapine; however, flexible‐dose, schizoaffective disease severity (‐21.0 asenapine vs ‐27.5 olanzapine; although both showed phase III trial disorder with a using the PANSS, p<0.0001). improvements in PANSS PANSS total score CGI‐improvement total scores, a greater asenapine 1 year ≥60 and a clinical (CGI‐I), and CGI‐S ‐At endpoint, CGI‐I scores were 2.9 asenapine improvement was seen 5mg BID global impression‐ and 2.4 olanzapine. 48% of the asenapine with olanzapine. Vs severity of illness ‐Safety and group and 34% of the olanzapine group had olanzapine (CGI‐S) score of tolerability CGI‐I scores ≥3 (indicating minimal 10mg QD ≥4. Those with a improvement, no change or worsening), history of whereas 52% of the asenapine group and inadequate 66% of the olanzapine group had scores <3 response to or (indicating much or very much improvement). intolerable adverse effects ‐38% of the asenapine group completed the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments with olanzapine trial as compared with 57% of the olanzapine were excluded. group, which was significantly different (p<0.0001).

‐The incidence of treatment‐emergent adverse events was 82% in both groups, with most reported adverse events rated as mild or moderate.

‐Mortality rates were <1% in both treatment groups, with 7 deaths in the asenapine group (5 suicides among 11 attempts) and 1 death in the olanzapine group (by suicide among 6 attempts).

‐Changes in weight were greater with olanzapine vs asenapine, with a mean change in weight at endpoint of 1.6kg with asenapine compared with 5.6kg with olanzapine. Weight gain was reported by 14% of the asenapine group vs 31% of the olanzapine group.

‐In both treatment groups, plasma prolactin levels decreased, with no notable changes or between‐group differences seen.

‐EPS‐like symptoms, which were usually mild, were reported by 18% of the asenapine group as compared with 8% of the olanzapine group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments McElroy Multicenter, N=740 ‐Subjects aged 18 ‐The change from ‐For reducing MADRS total score from week 2 ‐Quetiapine 300 or 600mg, et al102 randomized, years of age or baseline to the onward, quetiapine 300mg and 600mg was but not paroxetine, were 2010 double‐blind, older with clinical end of the study significantly more effective than placebo more effective than parallel‐ diagnosis of in MADRS total (p<0.05); these improvements were placebo for treating acute LOE‐1a group, bipolar I or II score maintained to the end of the 8 weeks depressive episodes in placebo‐ (p<.001). bipolar I and II. controlled ‐Response study (defined as ≥50% ‐Statistically significant improvements in GHS Comments: This decrease from MADRS total score was not seen with finding is consistent with a quetiapine 8 weeks baseline in paroxetine as compared with placebo at any vast literature supporting 300mg or MADRS total time point during the 8 weeks (p=0.313). the lack of efficacy of anti‐ 600mg/day score) and depressants in bipolar Vs remission (MADRS ‐Significantly greater improvements were depression. paroxetine total score ≤ 12) seen with both doses of quetiapine vs 20mg QD were also paroxetine in MADRS total score at week 8 Vs assessed (‐2.43, p=0.017 for 300mg; and ‐2.55, p=0.012 placebo for 600mg). ‐Safety and tolerability ‐At week 8, a significantly greater amount in the quetiapine group were classified as responders (66.8% and 67.2% for 300mg and 600mg respectively) as compared with placebo (52.9%; p=0.01 and p<0.01 respectively). The authors reported an NNT of 7 for both strengths.

‐The amount of those in the paroxetine treated group classified as responders was not significantly different from placebo (p=0.735, with an NNT of 46).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐A significantly greater amount of the quetiapine 600mg group achieved remission at week 8 as compared with placebo (68.5% vs 55.4%; p<0.05 and an NNT of 8).

‐The remission rates among those in the quetiapine 300mg (64.6%; p=0.081 with an NNT of 11) and paroxetine group (56.8%; p=0.828 with an NNT of 71) did not differ significantly from placebo.

‐Significant improvements were seen with paroxetine for the Hamilton Anxiety Rating Scale score as compared with placebo (p<0.05), but not with the Hamilton Depression Rating Scale score.

‐ The most commonly reported adverse events with quetiapine includes dry mouth, somnolence, sedation, and dizziness. Dry mouth, sedation, headache, insomnia, and nausea were most common with paroxetine. Kane et al103 Multicenter, N=458 ‐Subjects 18 years ‐The change from ‐ Compared to placebo, asenapine 5mg BID ‐In this population, 2010 randomized, of age or older a baseline in the and haloperidol were superior to placebo in asenapine 5mg BID was an double‐blind, clinical diagnosis total score on the regards to change in PANSS total score, with effective treatment of LOE‐1a placebo‐ of schizophrenia PANSS statistically significant differences seen from acute schizophrenia, with controlled with an acute day 21 onward. No advantage over placebo potential efficacy at day 42 trial exacerbation of ‐PANSS subscale was seen with asenapine 10mg BID. for 10mg BID as well. psychotic score and PANSS symptoms at responders ‐In the PANSS positive subscale score,

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments asenapine 6 weeks study enrollment asenapine 5mg BID and haloperidol were GHS Comments: The 5mg BID and a ≥60 PANSS ‐Safety superior to placebo from day 21 onward. haloperidol group did not Vs total score Asenapine 10mg BID showed advantage at receive adjunctive asenapine day 42 and study endpoint. In the PANSS prophylactic 10mg BID negative subscale, none of the treatments anticholinergics, thereby Vs were superior to placebo. likely increasing the adverse placebo events in the haloperidol Vs ‐Significantly more PANSS responders were group haloperidol seen with asenapine 5mg BID (55%; p<0.001) 4mg BID and 10mg BID (49%; p<0.05) as compared with placebo (33%). Advantages with asenapine 5mg was seen from day 21 onward and with 10mg were seen at day 42. Haloperidol did not show any statistically significant advantage over placebo at day 42 (44% vs 33%) or endpoint (42% vs 33%).

‐Treatment‐related adverse events were reported in 44%, 52%, 57%, and 41% of the asenapine 5mg, 10mg, haloperidol, and placebo groups.

‐No more than 5% of subjects had clinically significant weight change. 15%, 18%, 34%, and 10% of the asenapine 5mg, 10mg, haloperidol, and placebo group reported extrapyramidal symptoms.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Fleischhacker Multicenter, N=207 ‐Subjects aged 18‐ ‐The mean change ‐A significantly greater mean decrease in ‐In this population, the et al104 randomized, 65 years of age in body weight body weight was seen with the adjunctive combination of clozapine 2010 double‐blind, with a diagnosis of from baseline to aripiprazole group as compared with placebo and aripiprazole resulted in placebo‐ schizophrenia week 16. (‐2.53kg vs ‐0.38kg; p<0.001). This statistically significant improvement in LOE‐1b controlled being treated for significant difference was seen from week 6 weight, BMI, and fasting treatment on an outpatient ‐Clinical efficacy, through the end of the study. cholesterol. These phase of 16 basis and had body mass index reductions may lower the weeks and an been receiving a (BMI), and waist ‐A post‐hoc analysis of the data was done and risk of metabolic effects open‐label stable dose of circumference it revealed that there was not a significant associated with clozapine extension clozapine 200‐ were also difference in the amount of subjects with therapy. Symptom phase of 12 900mg/day for at assessed. clinically relevant (≥7% from baseline) weight improvement, however, did weeks least 3 months but gain at week 16 between the two groups not improve. not optimally ‐Safety (2.0% placebo vs 1.9% aripiprazole; p=0.908). clozapine 28 weeks controlled on PLUS clozapine. Were ‐There was a significantly greater amount in aripiprazole 5‐ required to have the aripiprazole with clinically relevant weight 15mg experienced loss as compared with placebo (15.3% vs 3% Vs ≥2.5kg weight gain respectively; p<0.001). clozapine during clozapine PLUS placebo treatment ‐Median reductions in BMI (0.8kg/m2; p<0.001) and waist circumference (2.0cm; p=0.001) were seen with aripiprazole as compared with no changes in the placebo group, which were statistically significantly different.

‐The mean change in body weight from the end of the double‐blind phase through the extension phase was greater in those that were in the adjunctive placebo group (from the double‐blind phase) vs the aripiprazole

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments group. (‐1.74kg vs ‐0.47kg).

‐Significant decreases in total cholesterol and low‐density lipoprotein (LDL) were seen with adjunctive aripiprazole vs placebo. Significant differences were not seen between groups in regards to high‐density lipoprotein (HDL), triglycerides, or fasting glucose.

‐A 30% improvement from baseline in PANSS total score was seen with 7% of the placebo group vs 9% of the aripiprazole at week 16. This was not a statistically significant difference (p=0.370).

‐Those who were in the placebo group during the double‐blind period results in increases in PANSS total score when these subjects were switched to aripiprazole during the open‐ label extension phase.

‐Some improvement in both treatment groups were seen in the mean CGI‐ scores at week 16, in favor of aripiprazole (p=0.037).

‐68.8% in the aripiprazole group reported adverse events during the double‐blind period as compared with 58.2% of the placebo group. Most reported were mild or moderate in nature.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐The most frequently reported adverse events differentiating placebo vs aripiprazole were headache (13.3% vs 9.2%), nausea (4.1% vs 16.5%), and anxiety (5.1% vs 13.8%).

‐4.1% of the placebo group reported extrapyramidal symptoms (EPS) as compared with 9.2% of the aripiprazole group. Liebowitz Time‐to‐ N=776 ‐Adult subjects ‐The time to ‐There were three treatment phases before ‐In this population, et al105 event, double‐ with diagnosis of recurrence of randomization took place: Enrollment phase maintenance therapy with 2010 blind, single episode or depressive events (up to 28 days, N=1,876), an open‐label run‐in quetiapine XR significantly multicenter, recurrent Major (relapse) from of 4‐8 weeks (N=1,854), and an open‐label reduced the risk of a LOE‐1a randomized, Depression randomization. stabilization period (N=787 completed this depressive episode, and placebo‐ Disorder (MDD) phase) of 12‐18 weeks. Those that met was tolerated similar to controlled and required a ‐Changes from randomization criteria (stable ≥12 weeks) quetiapine IR. study total score of ≥20 randomization in were randomized to continue quetiapine or on the 17‐item MADRS total switch to placebo. Hamilton score, CGI‐S score, quetiapine XR Up to 52 Depression Rating Hamilton Anxiety ‐As compared with placebo, quetiapine XR 50‐300mg per weeks max Scale (HAM‐D), a Rating Scale significantly reduced the risk of a depressive day Montgomery‐ (HAM‐A) total event, as assessed by increased time to an Vs Asberg Depression score, and the event (p<0.001). The risk was reduced by 66% placebo Rating Scale Pittsburgh Sleep in those randomized to continue quetiapine (MADRS) score Quality Index vs those switched to placebo. ≤12, and a Clinical (PSQI) global score Global were some also ‐Doses of 50mg, 150mg, and 300mg Impression‐ assessed. quetiapine XR significantly increased the time Severity of Illness to a depressive event. (CGI‐S) score ≤3 ‐Safety and tolerability ‐14.2% of the quetiapine XR reported a

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments depressive event as compared with 34.4% of the placebo group.

‐As compared with placebo, time to any discontinuation was significantly increased with quetiapine XR (p<0.001). 45.2% of the quetiapine XR group and 60.7% of the placebo group discontinued for any reason.

‐Significantly greater effects were seen with quetiapine XR for MADRS total, CGI‐S, HAM‐A total, PSQI secondary measures as compared with placebo (p<0.001 for all).

‐The reports of adverse events were similar in both treatment groups. Headache and insomnia were the most frequently reported events (≥10% of any group). Vieta et al106 Multicenter, N=493 ‐Adults aged 18‐ ‐The change from ‐Those in the placebo group switched to ‐For the treatment of acute 2010 randomized, 65 years with baseline in YMRS paliperidone ER during the maintenance mania in this population, double‐blind, diagnosis of total score at the phase. Of the 493 initially randomized, 371 paliperidone ER was LOE‐1a placebo‐ and bipolar I disorder 3‐week endpoint. entered into the maintenance phase of effective and safe. It was active‐ and experiencing paliperidone ER (N=219) compared with found to be non‐inferior to controlled acute manic or ‐The change from quetiapine (N=152). quetiapine over a 12 week trial with a 3‐ mixed episodes baseline in Global period. week acute and one Assessment of ‐Benzodiazepines were used by 64% of the treatment documented Functioning (GAF) subjects at baseline, and this decreased to phase and a 9‐ manic or mixed score, PANSS 53% of the subjects at the end of the 12 week week DB, episode requiring score, and the study period. During the acute treatment maintenance treatment within Clinical Global phase, use was more frequent in the placebo phase the three years Impression‐ group (63%) than the paliperidone ER group

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments prior to screening Bipolar Disorder‐ (54%) or the quetiapine group (46%). Acute phase: 3 weeks for and a Young Severity (CGI‐BP‐ paliperidone acute phase Mania Rating S) score was also ‐From baseline to end of the acute phase, the ER Scale *YMRS) accessed mean change in YMRS total score was ‐7.4 Vs 9 weeks for score of at least with placebo, ‐13.2 with paliperidone ER, and placebo MTP 20 ‐Safety ‐11.7 with the quetiapine group. Vs quetiapine ‐These results suggest that paliperidone ER was superior to placebo for reduction in Maintenance YMRS scores (treatment difference of ‐5.5; phase (MTP): p<0.001). A statistically significant difference paliperidone was also seen between quetiapine therapy Vs and placebo (treatment difference of ‐4.2; quetiapine p<0.001), but was not seen between paliperidone ER and quetiapine (treatment difference of 1.5; p=0.099).

‐At the end of 12 weeks, the mean change in YMRS total score was ‐15.2 in the paliperidone ER group vs ‐13.5 with the quetiapine group, with a treatment difference of 1.7. These results suggest that paliperidone ER is non‐inferior to quetiapine.

‐The mean change from baseline to the end of week 3 in the GAF scores was 6.7 with placebo, 12.2 with paliperidone ER, and 11.6 with quetiapine.

‐These results suggest that both paliperidone ER and quetiapine had statistically

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments significantly greater improvements in GAF scores as compared with placebo (p<0.001).

‐The GAF score at the end of 12 weeks was 14.9 for the paliperidone ER group and 15.8 for the quetiapine group. This treatment difference of 0.9 was not seen as significant, resulting in no difference between the two treatments.

‐Both the PANSS and the CGI‐BP‐S scores showed significantly greater improvements in both treatment groups as compared with placebo.

‐At the end of the 12 week period, no differences were seen with the PANSS and CGI‐BP‐S scores between paliperidone ER and quetiapine.

‐Statistically significant changes in YMRS total scores were seen as early as day 2 in both the paliperidone ER and quetiapine group.

‐There was a significantly higher % of responders in the paliperidone ER group vs placebo at the end of the acute phase (55.8% paliperidone ER vs 34.6% placebo; p<0.001). 49% of the quetiapine group was considered responders. The authors reported an NNT of 5 for quetiapine ER and an NNT of 7 for

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine in regards to response for this 3‐ week period.

‐At the end of the 12 weeks period, 64.7% of the paliperidone ER and 57.8% of the quetiapine group were considered responders. No difference in response rate was seen between treatments.

‐A significantly higher % of remitters was seen with paliperidone ER (52.1%) vs placebo (28.8%; p<0.001) at the end of the 3‐week period. 47.4% of the quetiapine group were remitters. The authors reported an NNT of 5 for paliperidone ER and an NNT of 6 for quetiapine in regards to remission for this 3‐ week period.

‐At the end of 12 weeks, 62.1% of the paliperidone ER group was remitting vs 56.3% of the quetiapine group, which was seen as not statistically different.

‐The most frequently reported treatment‐ emergent adverse event with paliperidone ER were headache, somnolence, and akathisia, while with quetiapine they were somnolence, sedation, dry mouth, headache, and dizziness.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Pavuluri Randomized, N=66 ‐Children and ‐To compare the ‐Although final scores did not significantly ‐The results suggest that et al107 double‐blind, adolescents aged Young Mania differ between treatment groups, the while both drugs were safe, 2010 double‐ 8‐18 years with a Rating Scale risperidone group resulted in a quicker risperidone was seen to dummy, diagnosis of (YMRS) between improvement as compared with divalproex have been associated with LOE‐1a outpatient bipolar I disorder treatments. (p<0.05). a quicker improvement, treatment (mixed or manic better reduction in manic trial episodes) who ‐Other efficacy ‐There was a 78.1% response rate on the symptoms, and was better were medication measures YMRS with risperidone as compared with tolerated vs divalproex. risperidone 6 weeks free or currently assessed included 45.5% with divalproex, which was statistically PLUS placebo clinically unstable Child Depression significantly different (p<0.01). GHS Comments: The NNT Vs on medication. Rating Scale‐ for both response and divalproex Those on Revised (CDRS‐R), ‐There was a 62.5% remission rate with remission comparing PLUS placebo medication had to Clinical Global risperidone group as compared with 33.3% risperidone vs divalproex go through a Impression Scale with the divalproex group, which was was 4. washout period. for Bipolar statistically significantly different (p<0.05). Disorder (CGI‐BP), Overt Aggression ‐Significantly greater improvements were Scale (OAS), and seen with the risperidone group on the CDRS‐ the Brief R as compared with divalproex (p<0.05). Psychiatric Rating Scale for Children ‐For some other secondary measures (BPRS‐C). including CGI‐BP, the BPRS‐C and the OAS, there were significant improvements ‐Safety and throughout the study for all subjects; tolerability however, similar outcomes were reported with each treatment group.

‐A significantly higher discontinuation rate was seen with divalproex as compared with the risperidone group (48% vs 24%, respectively; p<0.05).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Increased appetite (25% risperidone vs 31.3% divalproex) , stomach discomfort (18.8% vs 15.6%), sleepiness (15.6% vs 12.5%), and fatigue/tiredness (15.6% vs 12.5%) were the most commonly reported adverse events. Canuso Multicenter, N=399 ‐Subjects aged 18‐ ‐The difference in ‐During the 4 week additive therapy phase, ‐Paliperidone ER improved et al108 randomized, 65 years the mean total psychotropic medications, including symptoms earlier and to a 2009 double‐blind, diagnosed with change score on antipsychotics, could be added with the greater degree in this placebo‐ schizophrenia that the Positive and exception of risperidone, additional population compared to LOE‐1a controlled had been Negative paliperidone ER or quetiapine, and other quetiapine. trial with 2 experiencing an Syndrome Scale meds that interacted. phases: 2 acute (PANSS) at the 2‐ week mono‐ exacerbation for week ‐87.5% of the PAL ER group completed the therapy phase <4 weeks but >4 monotherapy monotherapy phase vs 84.9% of the followed by a days and were phase. quetiapine group and 82.5% of the placebo. 4‐week inpatients additive‐ ‐The severity and ‐Greater improvements in the mean PANSS therapy phase change scores of total change score from day 5 through the 2‐ the Clinical Global week monotherapy was seen with PAL ER as paliperidone 6 weeks Impressions scale compared with quetiapine (p<0.001) and ER 9‐12mg/ (CGI‐S, CGI‐C, placebo (p≤0.001). However, quetiapine day respectively) were resulted in significantly greater improvement Vs also assessed. vs placebo at day 9 quetiapine 600 or ‐Safety ‐PAL ER resulted in greater mean changes on 800mg/day four out of five PANSS factor (negative and Vs positive symptoms, disorganized thoughts, placebo and hostility/excitement) as compared with quetiapine and placebo (p≤0.008).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Significantly greater improvements on the CGI‐S and the CGI‐C were seen with PAL ER as compared with both quetiapine (p=0.002) and placebo (p<0.001); however, quetiapine was not statistically different from placebo at the end of the 2‐week monotherapy phase.

‐For the entire study of 6 weeks, the all‐cause discontinuation rate was lower for PAL ER (21.5%) as compared with quetiapine (33.3%; p=0.036) and placebo (36.3%; p=0.032).

‐Comparable amounts received one or more additional psychotropic medications during the additive‐therapy phase, with 52.9% in the PAL ER group and 55.4% in the quetiapine group. Olanzapine and haloperidol were the most frequently prescribed adjunctive medication.

‐The PAL ER group had greater improvements in the mean PANSS total score change at the end of the study as compared with quetiapine (p=0.023) or placebo (p=0.002). Change with quetiapine compared with placebo was non‐ significant. However, the change in PANSS total score was not significantly different between treatments during the additive‐ therapy phase only.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Through the entire 6 week study period, a greater improvement in PANSS factor scores for negative symptoms, disorganized thoughts, and uncontrolled hostility/ excitement (all p<0.050) was seen with PAL ER as compared with quetiapine or placebo.

‐Improvements in PANSS positive factor were greater with PAL ER vs placebo (p=0.014), but was comparable between PAL ER and quetiapine (NS).

‐For the CGI‐S score, PAL ER was significantly better than quetiapine and placebo at the study end; however, there were no differences between quetiapine and placebo.

‐ For the CGI‐C score, PAL ER was significantly better than placebo at the study end; however, there were no differences between quetiapine and placebo or between PAL ER and quetiapine.

‐During the monotherapy phase, the most frequently reported adverse events with PAL ER, quetiapine, and placebo were tremor (13.9%, 5.0%, and 7.5%), somnolence (8.9%, 11.9%, and 1.3%), insomnia (10.1%, 9.4%, and 11.3%), and headache (12%, 7.5%, and 13.8%).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Berwaerts Multicenter, N=469 ‐Adult subjects ‐The change from ‐All strengths of paliperidone showed ‐For the improvement of et al109 randomized, aged 18‐65 years baseline to the improvements from baseline to the end of manic symptoms in those 2010 double‐blind, with a diagnosis of last post‐baseline study in the YMRS total score; however, with bipolar I disorder, placebo‐ bipolar disorder assessment in the statistical superiority was seen with paliperidone ER was seen to LOE‐1a controlled with at least one YMRS total score paliperidone ER 12mg compared with placebo be superior to placebo in trial documented (p=0.005). This improvement with the 12mg the 12mg/day group only. manic or mixed ‐The change from dose was seen starting at day 2 and was Furthermore, paliperidone paliperidone 3 weeks episode requiring baseline to maintained at every time point (p<0.05). ER did not differ from ER 3mg, 6mg, treatment with endpoint in the placebo among patients or 12mg QD the 3 years before Global ‐Improvements in YMRS were dose‐ from the United States. Vs screening and a Assessment of dependent. YMRS total score was significantly placebo Young Mania Functioning (GAF) greater with the 12mg dose vs the 3mg dose Rating Scale score was also (p<0.001); however, the 12mg dose did not (YMRS) total score assessed. differ statistically from the 6mg dose (p=0.10) of ≥20 or between the 6mg and 3mg dose (p=0.09). ‐Safety ‐GAF scores improved for all treatment groups. The improvements were again dose‐ dependent; however, the differences between the treatment group and placebo were not statistically significantly different.

‐The % of responders in the treatment groups was not statistically significantly different from placebo.

‐70% of the placebo group reported treatment‐emergent adverse events as compared with 61% in the paliperidone 3mg group, 75% in the 6mg group, and 87% in the 12mg group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐The adverse event with the highest report of incidence was headache (17% paliperidone ER Vs 12% placebo). Addington Randomized, N=1,460 ‐Adult subjects (in ‐To assess the ‐Subjects with tardive dyskinesia were ‐Differences on the impact et al110 double‐blind the overall CATIE impact of excluded from the randomization. of depressive symptoms 2011 study study sample) perphenazine between perphenazine and diagnosed with compared with a ‐ In all groups, the total CDSS score improved second‐generation LOE‐1a perphenazine 18 month schizophrenia who second generation over time; however, there was no overall antipsychotics were not Vs follow‐up were able to take atypical on significant difference seen between seen. one of 4 2nd oral antipsychotic symptoms of treatments. generation treatments depression using atypical the Calgary (olanzapine, Depression Scale risperidone, for Schizophrenia quetiapine, or (CDSS) score. ziprasidone)

Rosenheck Randomized, N=369 ‐Adults 18 years of ‐Hospitalization in ‐All subjects were seen by their psychiatrist ‐The authors concluded et al111 controlled age or older in the a VA or non‐VA and nurse every month. that LA injectable 2011 study Veterans Affairs psychiatric risperidone was not (VA) system with a hospital between ‐Of those randomized to treatment, 40% superior to oral LOE‐1a risperidone 3 years, diagnosis of oral vs injectable were hospitalized at randomization, 55% antipsychotics in those with injectable with 2 years schizophrenia antipsychotic were hospitalized within the previous 2 years, schizophrenia or 25‐50mg Q2W of follow‐up disorder or and 5% were at risk for hospitalization. schizoaffective disorder Vs schizoaffective ‐Symptoms, that were at a high rate of oral disorder and at quality of life, and ‐After randomization, the rate of hospitalization; however, antipsychotic risk for psychiatric functioning were hospitalization was not significantly lower the LA injectable treatment of hospitalization or also accessed via among those receiving the long‐acting (LA) had more reports of psychiatrists who had been blinded video‐ injectable vs those receiving the oral extrapyramidal adverse choice hospitalized conference events and injection site

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments within the interviews antipsychotics (39% after 10.8 months vs 45% reactions. previous two after 11.3 months). Therefore, the LA years or who were injectable risperidone was not superior to at imminent risk oral treatment in regards to the time of for hospitalization hospitalization (p=0.39).

‐40% of those receiving LA risperidone injection also received concomitant oral antipsychotics during the first 6 weeks. During the remainder of the trial, 32% also received oral antipsychotics.

‐Significant improvement in psychiatric symptoms, quality of life, scores on the Personal and Social performance scale of global functioning, and neurologic side effects were not significantly different in those taking the LA injectable vs the oral antipsychotics.

‐The LA injection was not superior to oral treatment in the duration of adherence (p=0.19).

‐12% of those receiving oral antipsychotics switched to the LA injectable approximately 152 days after randomization.

‐Significant differences were not seen between groups for reasons of treatment discontinuation.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐The LA injectable was not superior to oral treatment in regards to the change in PANSS total score (p=0.72).

‐For adverse events, there were more subjects in the LA injectable risperidone group who had administration site conditions and general disorders (p=0.04), as well as ‘nervous system disorders (including headache, extrapyramidal signs and symptoms; p<0.001) than oral treatments. Berwaerts Multicenter, N=76 ‐Adults aged 18‐ ‐A non‐inferiority ‐There was a one‐week open‐label, placebo ‐With the doses prescribed et al112 randomized, 75 years comparison washout period before the double‐blind in this population, the 2010 double‐blind, diagnosed with between treatment. elevation of serum parallel‐group schizophrenia and treatments of the prolactin levels was similar LOE‐1b study symptomatically concentration‐ ‐On day 1, both treatment groups resulted in between treatments. stable while taking time profiles of rapid increases in mean serum prolactin paliperidone 6 days risperidone serum prolactin concentrations. GHS Comments: Both the ER 12mg days immediate‐ small number of subjects in 1‐6 release for at least ‐Compared with the paliperidone ER group, the study and the short Vs one month the mean prolactin Cmax was higher in the period of time that the risperidone risperidone group; however, the mean study medications were 2mg day 1, prolactin AUC0‐24H was higher in the used were limitations to then 4mg paliperidone group. the study. days 2‐6 ‐At day 6, similar mean serum concentration‐ time profiles were seen between treatment groups.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Weiner Double‐blind, N=69 ‐Adult subjects ‐To assess the use ‐Subjects maintained the clozapine dose at ‐A modest benefit may be et al113 placebo‐ ages 18‐65 years of risperidone as baseline throughout the study. Dosage seen with the use of 2010 controlled, diagnosed with adjunctive adjustments were not allowed throughout risperidone adjunctive to randomized schizophrenia or therapy for the the study. clozapine in treatment‐ LOE‐1a trial schizoaffective Brief Psychiatric resistant subjects. disorder and who Rating Scale ‐In the ITT group, a greater decrease in the risperidone 16 weeks have had an (BPRS) positive BPRS positive symptoms items was seen with 4mg adequate trial of symptom item the risperidone group vs placebo; however, Vs clozapine total score this treatment difference was a numerical, placebo but not statistically significant difference ‐The Scale for the (p=0.09). Assessment of Negative ‐In the completer group, there was a Symptoms (SANS) statistically significant greater positive and the Clinical symptom decrease in the risperidone group Global Impression vs the placebo (p=0.02). (CGI) severity of illness score was ‐In the ITT group, similar results were seen also assessed with the BPRS total score. A numerical, but not statistically significant difference was ‐Safety and seen with risperidone having a greater tolerability decrease as compared with placebo (p=0.06).

‐In the completer group, there was a statistically significant greater positive decrease in the risperidone group vs the placebo (p=0.03).

‐A significant treatment difference with the SANS total score was seen with risperidone vs placebo for negative symptoms (p=0.02), with

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments a small decrease seen in the risperidone group and a small increase seen in the placebo group.

‐The risperidone group had significantly elevated prolactin as compared with placebo. In general, risperidone was well tolerated. Findling A double‐ N=54 ‐Subjects aged 8‐ ‐To compare the ‐Only 26% (N=14) of the youth completed the ‐In this population, there et al114 blind 19 years of age PANSS, the Brief trial. The most common reason for was not one treatment that 2010 extension diagnosed with Psychiatric Rating discontinuation was adverse events (N=15), exhibited superior efficacy, phase of study schizophrenia, Scale for Children, inadequate efficacy (M=14), and non‐ and reports of adverse LOE‐1a referenced as schizophreniform and the Clinical adherence to the study‐related procedures events were seen with all #62 by Sikich disorder, or Global (N=8). treatments, including et al schizoaffective Impression‐ weight gain. Efficacy was disorder who Severity scores ‐As similar to the acute 8‐week study, there maintained throughout this molindone 10‐ 44 weeks were enrolled in between were no statistically significant differences maintenance period. 140mg/ day the acute 8‐week treatments between groups in the clinical outcomes. Vs trial GHS Comments: A olanzapine ‐Safety and ‐However, the change in the Child and limitation of this study is 2.5‐20mg/ ‐Those in the tolerability Adolescent Functional Assessment Scale 8 the small sample size. day molindone group total score was higher in the risperidone Vs also received group (mean change was 29.4 for risperidone, risperidone benztropine 3.3 for olanzapine, and 0.7 for molindone). 0.5‐6mg/day 0.5mg BID for EPSs while others ‐The PANSS total score and other clinical received matching outcome measurements did not vary much placebo. throughout this 44 week maintenance period, and there were no significant change in outcomes during this period. However, the significant differences seen during the acute 8‐week trial was maintained during this 44

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments week maintenance period (p≤0.05 for all).

‐83% reported at least one adverse event during this study.

‐Weight gain (39% total) and anxiety (26% total) were the two most frequently reported adverse events, and the rates between treatment groups were not significantly different. McIntyre Multicenter, N=218 ‐Subjects with ‐Safety and ‐86.1% reported treatment‐emergent adverse ‐Asenapine was efficacious et al115 double‐blind, bipolar mania who tolerability events (TEAEs) in the asenapine group, as for long‐term maintenance 2010 double‐ completed either compared with 71.9% in the treatment in this dummy, of two 3‐week ‐Efficacy placebo/asenapine group and 79.4% in the population with bipolar LOE‐1a parallel‐group efficacy trials and assessments olanzapine group. mania, as well as being well extension a subsequent 9‐ included changes tolerated and having study of those week double‐blind from baseline of ‐Headache, somnolence, insomnia, nausea, clinically significantly less eligible extension trial the 3‐week Parkinsonism, tremor, and constipation were weight gain. were eligible for efficacy trials on most frequently reported with the this trial (refer to the YMRS total placebo/asenapine group. Insomnia, asenapine 40 weeks reference #68 & score, Clinical sedation, depression, headache, somnolence, 5‐10mg #69 by McIntyre Global Impression increased weight, dizziness, nausea, and Vs et al) for Bipolar (CGI‐ akathisia were most common in the placebo/ BP) mania asenapine group. Increased weight, asenapine ‐The placebo/ severity, and the somnolence, sedation, headache, insomnia, Vs asenapine group Montgomery and akathisia were most common in the olanzapine consisted of those Asberg Depression olanzapine group. 15‐20mg who took placebo Rating Scale in the 3‐week trial (MADRS) total ‐Shifts from low/normal fasting blood sugar and were then score. to high levels were reported in 10% of the switched to placebo/asenapine group, 26% in the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments asenapine in the asenapine group, and 22.2% of the 9‐week extension olanzapine group. trial, with the blinding ‐Clinically significant weight gain of a ≥7% unbroken. increase in weight from baseline was reported in 21.9% of the placebo/asenapine group as compared with 39.2% of the asenapine group and 55.1% of the olanzapine group.

‐The mean change in YMRS total score at endpoint (using last observation carried forward method) was ‐25.8 for asenapine vs ‐26.1 for olanzapine. The rates of YMRS remission and response at endpoint were 93.4% for asenapine and 95.2% for olanzapine.

‐The mean change from baseline in the CGI‐ BP mania severity score was the same for both asenapine and olanzapine (‐3.2±1.3 Vs ‐3.2 ±1.1 at endpoint. Kramer Open‐label N=235 ‐Adult subjects ‐Long‐term safety ‐5 % (N=12) discontinued treatment due to ‐The results suggest that et al116 extension diagnosed with and tolerability treatment emergent adverse events (TEAEs). the long‐term safety with 2010 study to a schizophrenia who paliperidone ER use is double‐blind had completed ‐Long‐term ‐Serious TEAEs were reported in 6% of the consistent with results LOE‐2 placebo‐ the double‐blind efficacy as study group (N=13). There were no reports of seem from previous controlled phase (placebo vs assessed with the neuroleptic malignant syndrome (NMS) or placebo‐controlled trials, symptom paliperidone) or mean Positive and glucose‐related TEAEs. while continuing to be recurrence who came from Negative efficacious. study the run‐in or Syndrome Scale ‐The most commonly reported EPS‐related

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments stabilization phase (PANSS) total TEAEs included tremor (13%, N=31) and paliperidone 52 weeks of the earlier score. akathisia (11%, N=25). ER 3‐15mg QD study ‐37% needed an anti‐EPS medication or antihistamine during this open‐label extension (OLE) period as compared with 26% at baseline.

‐Somnolence was reported by 3% (N=6) and sedation was reported by 2% (N=5).

‐Subjects who were taking paliperidone ER in the earlier study reported additional improvement from OLE baseline to endpoint in PANSS total scores; however, those in the placebo group in the earlier study now taking the paliperidone ER in the OLE had the most improvement in PANSS. Nakamura Multicenter, N=180 ‐Adult subjects ‐To compare the ‐A statistically significantly greater ‐The use of lurasidone in et al117 parallel‐ hospitalized for an BPRSd extracted improvement was seen with lurasidone in the this population appears 2009 group, acute from the PANSS BPRSd as compared with placebo (p=0.0118). safe and effective. randomized, exacerbation of This statistical difference was seen at day 3 LOE‐1a placebo‐ schizophrenia, ‐The PANSS total, and continued throughout the study end. controlled with minimum positive, and trial illness duration of negative scores, ‐A statistically significantly greater at least a year and the Montgomery‐ improvement was also seen in the PANSS lurasidone 6 weeks a Brief Psychiatric Asberg Depression total score (0.004), PANSS positive score 80mg Rating Scale Rating Scale (p=0.006), PANSS negative score (p=0.0250), Vs (BPRSd) total (MADRS) and the and the CGI‐S total score (p=0.0072) with the placebo score, extracted Clinical Global lurasidone group vs placebo. from the Positive Impressions‐

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments and Negative Severity of Illness Syndrome Scale scale (GCI‐S) score ‐Gastrointestinal symptoms were the most (PANSS) of at least were all assessed. frequently reported, including nausea, 42. vomiting, constipation, and dyspepsia. ‐Safety ‐There were 6 patients with reports of treatment‐emergent adverse events that lead to discontinuation of study. Selvi et al118 Two‐phase N=90, then ‐Adult subjects ‐To compare the ‐41 were considered refractory to high‐dose ‐Risperidone may be more 2010 study: a 12‐ 41 were diagnosed with effects on the SSRI treatment and were then randomized to effective than aripiprazole week refractory obsessive‐ Yale‐Brown either risperidone (N=20) or aripiprazole for augmentation in those LOE‐2 prospective and then compulsive Obsessive‐ (N=21). Seven subjects dropped out of the with OCD refractory to an period to randomized disorder (OCD), Compulsive Scale study for various reasons, with 4 from the SSRI. determine to atypical were drug free for (Y‐BOCS) between aripiprazole group and 2 from the risperidone resistance to treatment 2 weeks, and then treatments. group. GHS Comments: This study SSRI were refractory to is limited by absence of treatment, SSRI treatment ‐The Hamilton ‐A significant improvements in the Y‐BOCS‐ placebo group, small followed by a after 12 weeks of Depression Rating Obsession subscale were seen in the sample size, and lack of single‐blind, treatment Scale (HDRS) and risperidone groups as compared with the double‐blind design. randomized, the Clinical Global aripiprazole group, using the t‐test. augmenting Impressions (CGI) period with an scale were also ‐The Y‐BOCS total scores for the 8 weeks with atypical assessed. atypical use were significant in favor of risperidone vs aripiprazole (p<0.05), as risperidone 8 weeks ‐Safety assessed with t‐tests. 3mg QD PLUS SSRI ‐50% (N=8) in the aripiprazole group and Vs 72.2% (N=13) of the risperidone group met aripiprazole criteria of ≥35% improvement in Y‐BOCS at 15mg QD the end of the study. PLUS SSRI

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Strom et al119 Open‐label, N=18,154 ‐Adult subjects ‐To assess the ‐Differences between ziprasidone and ‐The results of the study do 2011 randomized, diagnosed with outcome of non‐ olanzapine were not seen regarding the not suggest that multicenter, schizophrenia suicidal mortality. primary outcome of non‐suicide mortality. ziprasidone, even with the LOE‐2 post‐ known risk of QTc marketing ‐Sudden death, ‐With regards to all‐cause mortality or prolongation, is associated trials suicide, all‐cause mortality due to sudden death, there were no with an increased risk of and differences seen between treatments. non‐suicidal mortality as cardiovascular compared with olanzapine. ziprasidone 1 year mortality, and all‐ ‐The relative risk for cardiovascular mortality Vs cause (fatal MI or fatal arrhythmia events) olanzapine hospitalization comparing ziprasidone (N=3; 0.03%) with were some olanzapine (N=8; 0.09%) was 0.38. However, secondary when cardiovascular mortality was expanded assessments to include events as having insufficient data, the relative risk increased to 1.6 (N=24 [0.3%] for ziprasidone and N=15 [0.2%] for olanzapine).

‐The relative risk with suicide for ziprasidone vs olanzapine was 1.19.

‐A statistically significant difference was seen between treatments in regards to all‐cause hospitalization, with 15.1% with the ziprasidone group vs 10.9% of the olanzapine group.

‐However, no differences between treatments were seen with hospitalization for MI or hospitalization for arrhythmia or arrhythmia reported during hospitalization

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments for other reasons. Even though there was not a significant difference between groups, there were still a greater number in the ziprasidone group that was hospitalized for arrhythmia or had arrhythmia reported during hospitalization compared with olanzapine. Crespo‐ Prospective, N=174 ‐Subjects aged 15‐ ‐Primary ‐The haloperidol group had a higher rate for ‐The results suggest that Facorro randomized, 60 years meeting effectiveness treatment discontinuation for any cause as while symptom reduction et al120 flexible‐dose, criteria for brief outcomes were compared with the olanzapine or risperidone was similar between the 2011 open‐label psychotic the % of group (p=0.014). The difference in three treatments, the time study disorder, discontinuation of discontinuation rates between risperidone to discontinuation was LOE‐2 schizophreniform the initially and olanzapine were not significant lower with haloperidol vs. olanzapine 1 year disorder, assigned (p=0.802). the atypicals. 5‐20mg QD schizophrenia, or treatment and the Vs schizoaffective mean time to ‐92.9% completed the 1‐year follow‐up and GHS Comments: risperidone 3‐ disorder and discontinuation. 42.9% continued the initially assigned Haloperidol treated 6mg QD having their first medication in the haloperidol group vs 89.1% subjects did not receive Vs episode of ‐The primary and 67.3% with olanzapine, and 82.5% and prophylactic haloperidol 3‐ psychosis, and efficacy outcome 65.2% with the risperidone group. anticholinergics. 9mg QD with no prior was the mean treatment with change from ‐Mean time to all‐cause discontinuation was anti‐psychotic baseline to end of 7.9 months with haloperidol, 10.01 months treatment (or 1 year in Brief with olanzapine, and 9.61 months with total lifetime Psychiatric Rating risperidone. treatment of less Scale (BPRS), the than 6 weeks) Scale for the ‐Significant differences in the total scores of Assessment of the BPRS (p=0.250) were not seen between Positive the three treatments between baseline and Symptoms (SAP), the end of the study. and the Scale for ‐There was a 44.4% reduction in symptoms the Assessment of with the haloperidol group, according to Negative

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Symptoms (SANS) changes in the BPRS total score, as compared with 47.3% for olanzapine and 45.5% for ‐Clinical Global risperidone. Impression (CGI) scale, the Young ‐ Significant differences in the total scores of Mania Rating the SAPS (p=0.273) or the CGI (p=0.270) were Scale (YMRS), the not seen between the three treatments Hamilton between baseline and the end of the study. Depression Rating Scale (H‐DRS), and ‐A significant difference between treatments the Calgary was seen with the rate of change in the SANS Depression Scale total score. Olanzapine had the greatest for Schizophrenia reduction (‐2.1 with haloperidol, ‐3.5 with (CDSS) were also olanzapine, and ‐0.7 with risperidone; assessed p=0.045).

‐Safety ‐Significant differences were not seen between treatment groups in regards to total scores of H‐DRS (p=0.823) and the YMRS (p=0.926).

‐Reports of akathisia were greater with haloperidol treated patients as compared with olanzapine or risperidone. Lindenmayer Prospective, N=60 ‐Adult subjects ‐To assess the ‐The run‐in phase was an open‐label trial and ‐In this population who did et al121 randomized, with diagnosis of safety of both use of other antipsychotics were cross not show an adequate 2011 double‐blind, schizophrenia or doses of tapered downwards and discontinued. response to quetiapine parallel‐group schizoaffective quetiapine by 600mg daily, the 1200mg LOE‐1a trial disorder with sub‐ change from ‐EPS were measured using the Simpson‐ daily dose, while being well optimal baseline in mean Angus Scale (SAS), Abnormal Involuntary tolerated, did not offer an treatment‐ extrapyramidal Movement Scale (AIMS), and the Barnes additional advantage for

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine IR 8 weeks response and a symptoms (EPS). Akathisia Scale (BAS). symptom relief. 1200mg/day after the PANSS total score Vs initial 4 of ≥60 at baseline ‐The efficacy of ‐The SAS showed a small non‐significant 0.7‐ quetiapine IR week run‐in of the run‐in each dose as point reduction from 3.6 in the 600mg group 600mg/day period phase. measured by the vs the 1200mg which basically remained PANSS total score unchanged from 4.8 (p=0.576). ‐To be eligible for was also assessed. randomization in ‐There was no change seen in the AIMS this study, scores for the 600mg group (p=0.343) or the subjects needed 1200mg group (p=0.341). to prospectively fail to show an ‐Significant differences in akathisia were not initial therapeutic seen between groups (p=0.358) or for each response during a group as compared with baseline. 4‐week run‐in phase of ‐Significant changes in vital signs or in ECG quetiapine 600mg measures (QT interval) were not seen within per day. and between groups from baseline to the end of the study.

‐A statistically significant overall increase was seen in the behavioral activity rating scale (BARS) from baseline to endpoint for both groups combined; however, there were no changes between groups (p=0.354).

‐A non‐significant increase in weight of 1.8 lbs was seen with the 1200mg/day group as compared with 0.2 lbs in the 600mg/day group.

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‐Significant differences were not seen for most lab measures; however, there was a significant decrease in triglycerides from baseline to endpoint for the 600mg/day group (p=0.019).

‐There was a non‐significant improvement in the PANSS total score for the 600mg group (92.11 at baseline to 87.13 at endpoint; p=0.331).

‐ There was a non‐significant improvement in the PANSS total score for the 1200mg group (84.5 at baseline to 83.48 at endpoint; p=0.449).

‐Significant changes between groups from baseline to endpoint were not seen in the PANSS positive subscale (p=0.338).

‐A significant decrease in the PANSS negative subscale was seen for both doses (1.45 point decrease for the 600mg, p=0.049; 1.38 point decrease for the 1200mg, p=0.032). However, there was not a significant between‐group difference (p=.0203).

‐The authors noted that a limitation to the study may be that even the 1200mg/day dose may not be high enough for true treatment

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments refractory schizophrenia.

Gafoor Single‐blind, N=72 ‐Subjects ages 18‐ ‐To compare ‐The median time to stopping therapy was ‐Both quetiapine and et al122 randomized 35 years with a efficacy by 65.3 days in the quetiapine group as risperidone are safe and 2010 study first episode of assessing compared with 82.5 days for the risperidone effective treatments in first‐ schizophreniform symptom severity, group. Although results suggest a statistically episode schizophrenia at LOE‐2 psychosis with <2 clinical recovery, non‐significant difference between lower doses than those quetiapine 12 weeks weeks of exposure and global treatments, there was a trend for a reduced used in those with long‐ 300‐750mg/ to an function as chance of nonadherence with risperidone term schizophrenia. day antipsychotic measured by the (p=0.08). Vs medication PANSS, CGI, risperidone 2‐ Global ‐The mean daily dose of quetiapine was 5mg Assessment Scale 375mg and was 2.72mg for risperidone. (GAF). ‐Statistically significant changes in PANSS, ‐To compare GAF, and CGI were seen with each treatment safety by group (all p<0.0001). However, there were no assessing 4 statistically significant differences seen adverse events: between treatments. parkinsonism, excessive weight ‐There were comparable reports of sedation gain, sedation, and parkinsonism between treatments. and sexual dysfunction. ‐When compared with the quetiapine group, the incidence of loss of libido was somewhat increased in the risperidone group.

‐For both treatment groups, the reports of sedation was the highest to begin with, but then decreased over time.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐The greatest amount of weight gain was reported in the first month of treatment, while the rate of weight gain decreased during the next 2 months.

Kane et al123 Multicenter, N=386 ‐Adult subjects ‐The time to ‐An initial 26 week open‐label flexible dose ‐For prevention of relapse 2011 randomized, with diagnosis of relapse or trial was done before the DB phase, during in this population, long‐ placebo‐ schizophrenia and impending relapse which subjects were cross‐titrated from term asenapine use was LOE‐1a controlled, a documented in double‐blind previous medication to asenapine. If more effective but as safe double‐blind, history of ≥1 prior (DB) period as remained stable during trial, then were when compared to placebo. phase III study acute measured by a eligible for the DB phase. 700 were initially schizophrenia rating‐scale enrolled in the open‐label phase. episode during criteria or GHS Comments: The NNT asenapine 26 weeks the 3 preceding investigators ‐During the DP phase, 29.5% (N=114) for asenapine for incidence Vs years and judgment (with a reported relapse/impending relapse. of relapse/impending placebo schizophrenia CGI‐I score≥4 for relapse is 3. needing ≥2 days within 1 ‐The incidence of relapse/impending relapse continuous week and a PANSS based on data from within ≤3 days of the last antipsychotic total score ↑ study medication dose was statistically treatment for ≥1 ≥20% from DB significantly higher for the placebo group vs year before baseline, a PANSS asenapine. The incidence was 12.1% with screening was item score ≥5 on asenapine and 47.4% with placebo required. ‘hostility’ or un‐ (p<0.0001). cooperativeness’, or a PANSS item ‐This data of relapse/impending relapse was score ≥5 on 2 based on investigator judgment (75%), rating items of ‘unusual scale criteria (23%), and both (2%). thought content’, ‘conceptual ‐Time to relapse/impending relapse was disorganization’,

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments or ‘hallucinatory significantly longer with asenapine vs placebo behavior’. (p<0.0001).

‐Time to early ‐30.4% of the asenapine group discontinued discontinuation, treatment early (for any reason) as compared PANSS total score with 62.5% with placebo. Additionally, time were also some to early discontinuation was longer with other items asenapine vs placebo (p<0.0001). assessed. ‐For PANSS total score and CGI‐S, statistically ‐Safety significant differences in favor of asenapine were seen in the change from baseline of the DB phase (both p<0.0001).

‐There were reports of serious adverse events from both treatment groups, and included worsening of schizophrenia (asenapine 1% vs placebo 4.7%), and paranoid schizophrenia (asenapine 1% vs 3.6% placebo).

‐There were more reports of extrapyramidal symptoms (EPS) with placebo (4.7%) than asenapine (3.1%).

‐Clinically significant weight gain (weight gain ≥7 increase from DB baseline) was reported in 3.7% of the asenapine group as compared with 0.5% of the placebo group).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Canuso Multicenter, N=311 ‐Adult subjects ‐The change in ‐Significantly greater improvements in the ‐Results of this study et al124 randomized, diagnosed with PANSS total score. change in PANSS total score was seen with suggest that paliperidone 2010 double‐blind, schizoaffective paliperidone ER as compared with placebo. ER is an effective placebo‐ disorder ‐Clinical Global Mean decreases at endpoint were ‐20.0 with treatment, used as both LOE‐1a controlled, experiencing an Impressions of paliperidone ER and ‐10.8 with placebo, with monotherapy and as parallel‐group acute Change for a mean treatment difference of ‐9.1; adjunctive treatment, for study exacerbation of <4 Schizoaffective (p=0.0001). psychotic and affective weeks but >4 days Disorder (CGI‐C‐ symptoms associated with before screening SCA), PANSS ‐Significantly greater improvements were also schizoaffective disorder. paliperidone 6 weeks with a PANSS total factor scores, the seen for all 6 PANSS factor scores and for the ER score ≥60 and YMRS, and the CGI‐S‐SCA overall and the CGI‐S‐SCA (flexible prominent mood Hamilton Rating positive/negative/depressive domains with dosing of swings (≥16 on the Scale for paliperidone ER vs placebo. A composite 3‐12mg/day Young Mania Depression (HAM‐ response was obtained by 40.5% of the until day 15) Rating Scale D) scores were paliperidone ER group vs 28.0% of the Vs [YMRS]). some others also placebo group, which was statistically placebo assessed. significantly higher (p=0.046). ‐Continuation of adjunctive therapy ‐Safety ‐As compared with placebo, paliperidone ER to mood was beneficial as monotherapy and as stabilizers (MS) adjunctive therapy to MS/AD. and/or antidepressants ‐The most frequently reported adverse events (ADs) were (≥5% in either group) with paliperidone ER vs allowed if dosage placebo were headache (15 vs 12.6%), had been stable dizziness (8.4 vs 5.3%), insomnia (6.5 vs within 30 days 5.3%), akathisia (6.1 vs 1.1%), and dyspepsia before screening. (5.6 vs 5.3%). Starting of new therapy was not ‐Extrapyramidal symptoms‐related adverse allowed. events were reported by 16.8% (N=36) of the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments paliperidone ER group and 9.5% (N=9) of the placebo group, with akathisia and hypertonia being the most commonly reported. Hsu et al125 Prospective, N=42 ‐Adult inpatients ‐To compare relief ‐At points 15, 30, 45, 60, 75, and 90 minutes ‐ Significant differences 2010 randomized, from an acute of agitation after injection, there were significant were not seen between the rater‐blinded care psychiatric between differences in the PANSS‐EC scores between atypical antipsychotics in LOE‐2 study ward after treatments as the 4 treatments, with a more significant regards to efficacy. Thus, admission of a measured by the difference resulting in the earlier period. results suggest that medical center in PANSS‐EC, the olanzapine IM and ODT and Taiwan diagnosed Agitation‐ ‐Those taking olanzapine IM or olanzapine risperidone OS are as olanzapine First 24 with Calmness ODT had significantly greater improvement in effective as haloperidol IM. 10mg IM hours after schizophrenia, Evaluation Scale PANSS‐EC scores as compared with those However, olanzapine IM Vs admission bipolar I disorder, (ACES), and the taking haloperidol IM at points 15, 30, 45, 60, and ODT were more olanzapine schizoaffective Clinical Global 75, and 90 minutes after start of treatment. effective in the early phase 10mg ODT disorder, Impression‐ of treatment as compared Vs delusional Severity (CGI‐S) ‐Significant differences in PANSS‐EC were not with haloperidol IM. risperidone disorder, or other Scale seen between olanzapine IM and risperidone 3mg solution psychotic disorder oral solution (OS), olanzapine ODT and GHS Comments: An Vs and an excited ‐Tolerability risperidone OS, risperidone OS and important limitation is the haloperidol component (EC) haloperidol IM, or olanzapine IM and study design, being single‐ 7.5mg IM score of ≥14 on olanzapine ODT at these same times points. blind, and having a small N. the PANSS‐EC. IM: intra‐ ‐After the 90 minute time point, there were musuclar; no significant differences found in the PANSS‐ EC among the four treatment groups. ODT: orally dissolving ‐Significant differences were not seen in the tablet mean ACES score changes between the four treatments at 15, 30, 45, 60, 75, 90, 105, 120 minutes and 12, 24 hours.

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‐Significant differences in the mean CGI‐S Scale scores were seen from baseline to 24 hours.

‐Drowsiness was the most frequently reported adverse event in all four treatment groups. Although more drowsiness was reported with olanzapine IM and ODT vs risperidone OS and haloperidol IM, the difference was not statistically significant. Pandina Multicenter, N=1,220 ‐Adult subjects ‐The change in ‐For days 1‐28, the RIS‐LAI received oral ‐The use of PP in this et al126 randomized, diagnosed with PANSS total score risperidone 1‐6mg/day during titration population was found to be 2010 double‐blind, schizophrenia for from baseline to period, while the PP group received oral non‐inferior to the use of double‐ at least 1 year the last post‐ placebo. RIS‐LAI (in combination LOE‐1a dummy, before screening, randomization with short‐term oral active‐ a PANSS total assessment. ‐From day 4 onwards, the mean change from risperidone). Both were controlled, score between 60‐ baseline in PANSS total score was similar reported to be safe and parallel‐group 120, and a BMI ‐Non‐inferiority between treatments. At endpoint, the mean well tolerated. non‐inferiority ≥17kg/m2 and was proven if the change from baseline was ‐18.6 with the PP study <40kg/m2. PANSS total scores group and ‐17.9 with the RIS‐LAI group. GHS Comments: The NNT [i.e. 5 points] was for responder rate with PP not worse in the ‐With these results, it was asserted that PP vs RIS‐LAI is 23. One PP group than the was non‐inferior to RIS‐LAI. limitation is the lack of a RIS‐LAI group. placebo group. ‐These results were from the per‐protocol ‐Clinical Global (PP) analysis set; however, the results were Impression‐ confirmed and consistent when done with the Severity (CGI‐S) intent‐to‐treat (ITT) analysis set. score, Personal and Social ‐The ITT analysis set was used for the Performance Scale

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments paliperidone 13 weeks (PSP), PANSS secondary outcome measures. palmitate (PP) subscale scores, deltoid 234mg and the responder ‐Similar results were seen between day 1, 156mg rate (% of subjects treatments for all secondary assessments (as day 8, then with a ≥30% ↓in listed in the assessed outcomes). QM deltoid or PANSS total gluteal day 36 scores) were some ‐53% in the PP group and 48.5% in the RIS‐LAI and 64 other group responded to treatment at endpoint. Vs assessments. risperidone ‐The overall rate of treatment‐emergent long‐acting ‐Safety adverse reactions (TEAEs) in the PP group was injectable 57.9% as compared with 52.8% in the RIS‐LAI (RIS‐LAI) group, with the incidence between gluteal 25mg treatments very similar. day 8 & 22, 25‐37.5mg ‐Three adverse reactions were reported at a days 36 & 50, ≥2% higher incidence in the PP group vs the 25‐50mg days RIS‐LAI: insomnia (9.4 vs 6.7%), injection site 64 & 78 pain (5.1 vs 0.8%), and anxiety (4.3 vs 2.1%).

‐ Only one adverse reaction was reported at a ≥2% higher incidence in the RIS‐LAI group vs the PP group: constipation (3.1 vs 0.8%). Crespo‐ Prospective, N=174 ‐Subjects aged 15‐ ‐To assess the ‐166 subjects were considered clinically ‐Results suggest that during Facorro randomized, 60 years meeting relapse rates and improved and regarded as being at risk of the first year of therapy, et al127 open‐label criteria for brief the time to the relapse. Of these, 19.3% (N=32) had ≥1 the three treatments had 2010 study psychotic first relapse. relapse in the 1 year follow‐up. Eight of these similar efficacy in disorder, had the relapse post treatment preventing relapse or for LOE‐2 schizophreniform ‐Relapse was discontinuation. achieving remission. disorder, defined as those schizophrenia, or who obtained ‐Significant differences in relapse rates were

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments haloperidol 1 year schizoaffective clinical not seen between treatments (6/54 or 11.1% GHS Comments: A 3‐9mg/day disorder and improvement and for haloperidol, 10/54 or 18.5% for limitation of this study is Vs having their first stability (Clinical olanzapine, and 8/58 or 13.8% for the small sample size and olanzapine episode of Global Impression risperidone; p=0.541). the open‐label design. 5‐20mg/day psychosis and (CGI) rating ≤4 Vs with no prior and a decrease of ‐Significant differences in mean time to risperidone treatment with ≥30% on the Brief relapse were not seen between treatments 3‐6mg/day anti‐psychotic Psychiatric Rating (p=0.857). Mean time to relapse was 10.9 treatment (or Scale (BPRS) total months for haloperidol, 10.78 months for total lifetime score, and all olanzapine, and 10.98 months for treatment of less BPRS key risperidone. than 6 weeks) symptom items rated ≤3 for >4 ‐The overall study sample was used for the consecutive remission analysis. Of the 174 subjects, 31.0% weeks. met criteria for remission.

‐Symptomatic ‐The amount in remission was higher with the remission rates olanzapine group (18/55 or 32.7%) and the were also risperidone group (22/63 or 34.9%) as assessed. compared with the remission rate of those with the haloperidol group (14/56 or 25%); however, this remission rate was not statistically significantly different between groups (p=0.479). Li et al144 Multicenter, N= 452 ‐Adult Chinese ‐The change in ‐The subjects in the RIS‐LAI were ‐This study demonstrated 2011 randomized, subjects PANSS total score supplemented with oral risperidone 1‐ that in the per‐protocol open‐label, diagnosed with from baseline to 6mg/day at the start of therapy and with RIS‐ population of the study PP LOE‐2 rater‐blinded, schizophrenia for the last post‐ LAI dose increases. The subjects were was non‐inferior to RIS‐LAI parallel‐group at least 1 year randomization administered once‐biweekly gluteal as treatment of acute study before screening, assessment. injections, flexibly doses at 25mg, 37.5mg, or schizophrenia, and was well and having acute 50mg. tolerated.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments paliperidone symptoms of ‐The changes from palmitate (PP) disease with baseline to ‐The PP group were administered a 150mg GHS Comments: The NNT injected QM Positive and endpoint in the equivalent (eq) deltoid injection on day 1 and for response to treatment Vs Negative Clinical Global day 8, then once monthly deltoid or gluteal with RIS‐LAI vs PPI was 13. risperidone Syndrome Scale Impression‐ injections flexibly dosed at 50mg, 100mg, or Additionally, the non‐ long‐acting (PANSS) total Severity (CGI‐S) 150mg eq. inferiority of PP to RIS‐LAI injectable score between 60 scale score, was not demonstrated in (RIS‐LAI) BIW and 120, and a personal and ‐Antiparkinson medications were allowed in the ITT population BMI of social case of emergence of worsening of ≥17.0kg/m2. performance (PSP) extrapyramidal symptoms (EPS). scale score, PANSS subscale scores, ‐For the change in PANSS total score, PP was and the responder non‐inferior to RIS‐LAI in the per‐protocol rates were some (PP) population. This non‐inferiority was seen other as early as day 8 (the first assessment) and assessments. was seen at every subsequent assessment.

‐Safety ‐In the intention‐to‐treat (ITT) population, PP was not seen to be non‐inferior to RIS‐LAI for the change in PANSS total score. Less improvement in PANSS total score was seen in the PP group, as well as an increased BMI and these assessments were not seen in the RIS‐LAI group.

‐In the PP population, similar improvements for CGI‐S, PSP, the PANSS subscale score, and the Marder factor scores were seen in both treatment groups.

‐At the end of the study, 70.7% of subjects

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments from the PP group responded to treatment (improvement in PANSS score by ≥30%) as compared with 78.4% from the RIS‐LAI group.

‐73.4% reported treatment‐emergent adverse events (TEAEs) in the PP group as compared with 74.9% of the RIS‐LAI group, with the most commonly reported being akathisia, tremor, and insomnia.

‐There were 3 reports of suicide‐related adverse events in the RIS‐LAI group and non in the PP group, and one subject died (completed suicide) during the study.

‐The authors note that the open‐label design of the study may be a limitation as it may lead to bias in those treated. Li et al145 Randomized, N=80 ‐Adult subjects ‐To compare the ‐Significant differences were found with both ‐In this population, 2012 parallel‐ aged 18‐60 years PANSS and CGI‐S groups in PANSS total scores and subscale ziprasidone was as effective design, open‐ with a diagnosis of scale scores scores of positive symptoms, negative as olanzapine, while both LOE‐2 label, “psychotic symptoms, and general psychopathology (all being well tolerated. controlled syndrome ‐Response rate p=0.000). trial convincible with was also assessed, first manifestation which was defined ‐Significant differences were not found ziprasidone 6 weeks of schizophrenia”. as a change in the between the 2 treatments in PANSS total 80‐160mg/day Were naïve 1st rate of PANSS scores and subscale scores (all p>0.05). Vs episode subjects total score by olanzapine and required to >50% ‐The mean change rate of PANSS total score 10‐20mg/day have total score was 66.3% in the ziprasidone group vs 67% in ≥60 on Positive ‐Safety and the olanzapine group, with no significant

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments and Negative tolerability between‐group differences (p>0.05). Syndrome Scale (PANSS) and a ‐The response rate at week 2, 4, and 6 for score of ≥4 on ≥2 ziprasidone was 5%, 32.5%, and 80% of 4 psychotic respectively vs 7.5%, 47.5%, and 82.5%, items, and ≥4 on respectively, with the olanzapine group. Clinical Global Significant differences were not found Impression‐ between the two treatments at any week (all severity (CGI‐S) p>0.05). scale. Were not allowed to be ‐The QTc interval increased in the ziprasidone involved in a group and decreased in the olanzapine group; weight loss however, significant differences were not program found between the 2 groups (p>0.05).

‐Body weight and BMI changes from baseline were significant in the olanzapine group (p=0.000) but not with the ziprasidone group.

‐There were 11 cases of EPS in the ziprasidone group vs 1 in the olanzapine group, which was statistically significantly different (p=0.003).

‐Significant differences in other adverse events were not found.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Barbui et al146 Multicenter, N=106 ‐Adult subjects ‐To compare the ‐Significant differences in discontinuation of ‐Significant differences 2011 randomized, diagnosed with withdrawal rates treatments was not seen between were not seen and thus no prospective, schizophrenia who within 3 months aripiprazole and haloperidol after 3 months additional benefits were LOE‐1a parallel‐ did not have an of treatment (13.2% vs 15.1%; p=0.780). seen between aripiprazole group, optimal response ‐The severity of and haloperidol when double‐blind to clozapine when symptoms on the ‐Reasons for discontinuations in the augmenting with clozapine superiority having been Brief Psychiatric aripiprazole group included lack of efficacy in regards to treatment study treated for at least Rating Scale (N=4), acceptability problems (N=2), and lack withdrawal and overall 6 months and thus (BPRS) and the of adherence (N=1), while reasons in the schizophrenia symptoms; aripiprazole 3 months needed Liverpool haloperidol group included lack of efficacy however, a better PLUS augmentation University (N=4), acceptability problems (N=3), and lack perception of adverse clozapine treatment Neuroleptic Side of adherence (N=1). events was seen with Vs Effect Rating Scale aripiprazole vs haloperidol. haloperidol (LUNSER) were ‐The change in the BPRS total score was not PLUS also assessed statistically significantly different between clozapine aripiprazole and haloperidol (‐5.9 vs ‐4.4; p=0.523).

‐A significantly greater decrease in the LUNSERS total score was seen with the aripiprazole group vs the haloperidol group (‐7.4 vs ‐2.0; p=0.006). Carlson Multicenter, N=351 ‐Adult subjects ‐To compare the ‐A 9‐24 week stabilization period occurred ‐While the results for the et al147 randomized, ≥18 years of age time from (N=787), where subjects took open‐label primary outcome were not 2012 double‐blind, with diagnosis of randomization to lamotrigine and single‐blind aripiprazole. significantly different, there placebo‐ bipolar I disorder, relapse into a Appropriate dose‐titration took place. Those was a numerical benefit for LOE‐1a controlled with a manic or manic/mixed who maintained stability for 8 consecutive maintaining relapse with study (with mixed episode in episode weeks were eligible for the double‐blind aripiprazole vs placebo in open‐label previous 3 period. this population. lamotrigine) months, with a ‐The mean Young Mania changes in the ‐A numerically longer, but not statistically

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments lamotrigine 52 weeks Rating Scale YMRS and the significantly longer time to manic/mixed PLUS [YMRS] total score MADRS total score relapse was seen for aripiprazole vs placebo aripiprazole of ≥16, with or were some other (hazard ratio [HR]‐0.6; p=0.058). Vs without psychotic assessments placebo PLUS features and with ‐11% of the aripiprazole group had relapse aripiprazole or without a ‐Safety rates at week 52 vs 23% of placebo (NNT per history of rapid author =9). cycling (≥4 but ≤7 mood episodes ‐Similarly, the time to any relapse was per yr) numerically longer but not statistically significantly different between treatments (HR=0.7; p=0.055). 27% of the aripiprazole group had any kind of relapse at week 52 vs 42% for placebo (NNT of 7, which was non‐ statistically significant).

‐The aripiprazole group had a statistically significantly superior change from baseline to endpoint in the YMRS total score, with a treatment difference of 2.48 (p<0.001).

‐Significant differences in other outcomes, including the MADRS total score, were not seen between treatments.

‐67.3% of the placebo group reported treatment‐emergent adverse event (TEAE) vs 70.5% of the aripiprazole group.

‐The 3 most frequently reported AEs with aripiprazole vs placebo were akathisia (10.8%

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments vs 6.1%), insomnia (7.4% vs 11.5%) and anxiety (7.4% vs 3.6%).

‐Reported mean weight changes were 0.43kg in the aripiprazole group vs ‐1.8kg with placebo, which was significantly different (p=0.001). Significantly more in the aripiprazole group (11.9%) had a clinically relevant weight gain (≥7%) vs the placebo group (3.5%; p=0.007). Meltzer Multicenter, N=473 ‐Adult subjects ‐To compare the ‐A significantly greater change from baseline ‐Lurasidone was found to et al148 randomized, aged 18‐75 years change from to week 6 in the PANSS total score was seen be a safe and effective 2011 prospective, hospitalized with a baseline in PANSS with the lurasidone (LUR) 40mg group (‐25.7; treatment for those with parallel‐ primary diagnosis total scores at p=0.002) and the LUR 120mg group (‐23.6; acute schizophrenia. LOE‐1a group, of schizophrenia week 6 p=0.022) vs placebo (‐16.0). The olanzapine Additional efficacy benefits double‐blind and an illness group also had a significantly greater score vs of higher dose lurasidone study duration of ≥1 ‐The change from placebo (‐28.7; p<0.001). (120mg) were not seen vs year, hospitalized baseline in CGI‐S the 40mg dose; however lurasidone 6 weeks for ≤2 weeks for score was the key ‐Compared with placebo (‐1.1), the change dose‐related adverse 40mg QD an acute secondary from baseline to week 6 with the CGI‐S score events were seen, including Vs exacerbation of outcome was significantly greater with LUR 40mg (‐1.5; akathisia. lurasidone psychotic p=0.011) and 120mg (‐1.4; p=0.040). This 120mg QD symptoms and a ‐Safety change was also significantly greater with Vs Clinical Global olanzapine vs placebo (‐1.5; p<0.001). olanzapine Impressions‐ 15mg QD severity (CGI‐S) ‐Statistically significant differences in the Vs score ≥4 and a MADRS score was not seen with either LUR placebo Positive and 40mg (‐3.5; p=0.324) or the LUR 120mg group Negative (‐3.5; p=0.571) vs placebo (‐2.8); however, Syndrome Scale the olanzapine group (‐5.0; p=0.003) had (PANSS) total statistically significant differences vs placebo. score ≥80

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Rates of discontinuation due to adverse events were 6.7% for the LUR group, 11.8% for the LUR 120mg group, 6.5% for olanzapine, and 8.6 for placebo.

‐11.8% of the LUR 40mg group reported akathisia, vs 22.9% with LUR 120mg, 7.4% with olanzapine, and 0.9% with placebo.

‐1.7% of both LUR groups had weight increased vs 20.5% with olanzapine and 5.2% with placebo.

‐The amount with a clinically significant weight gain of ≥7% was comparable between the LUR 40 (7.6%) and the LUR 120mg (4.2%) vs placebo (7.0%); however, it was significantly higher with the olanzapine group (34.4%). Krystal Multicenter, N=296 ‐Adult subjects ‐To compare the ‐Significant differences between treatments ‐Treatment with et al149 randomized, who participated total score on the were not seen on the change in CAPS total risperidone did not reduce 2011 double‐blind, in a military 34‐item CAPS score from baseline (‐16.3 with risperidone vs PTSD symptoms effectively placebo‐ combat theater ‐12.5 with placebo; p=0.11). more vs placebo in this LOE‐1a controlled and diagnosed for ‐The observer and population with military‐ trial military service‐ patient‐rated ‐Significant differences in other measured related PTSD. related chronic Clinical Global outcomes were not seen between risperidone up 6 months PTSD and had a Impression (CGI) treatments, including observer‐rated (p=0.49) to 4mg QD Clinician‐ scale, the and patient‐rated CGI (p=0.17), the HAMA Vs Administered Montgomery‐ (p=0.08), MADRS (p=0.16), and PANSS placebo PTDS Scale (CAPS) Asberg Depression positive score (p>0.10).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments score >50 and a Rating Scale clinical history of (MADRS), the ‐Reports of adverse events were low; intolerance of or a Hamilton Anxiety however, significantly more in the risperidone non‐response to Scale (HAMA), and group reported weight gain (15.3% vs 2.3% ≥2 the PANSS were placebo), fatigue (13.7% vs 0%), somnolence antidepressants, some other (9.9% vs 1.5%), and hypersalivation (9.9% vs with an assessments 0.8%). inadequate response to ‐Safety adequate SRI treatments Khan et al150 Multicenter, N=951 ‐Adult subjects ‐To compare the ‐Significant reductions in HAMA‐A total scores ‐In this population with 2011 randomized, aged 18‐65 years mean change in were seen with quetiapine XR 50mg (‐13.31; GAD, quetiapine XR 50mg double‐blind, with documented HAMA‐A total p<0.001) and XR 150mg (‐13.54; p<0.001) vs and 150mg daily were safe LOE‐1a placebo‐ diagnosis of score from placebo (‐11.10). There was a numerical and effective. controlled, generalized randomization at difference but not statistically significant phase 3 study anxiety disorder week 8 difference with quetiapine XR 300mg vs GHS Comments: The NNT (GAD) required to placebo (‐11.87; p=0.240). for response rates with quetiapine XR 8 weeks, have a Hamilton ‐Response rate quetiapine XR 50mg, 50mg/day with 2 Anxiety Rating (≥50% reduction ‐At week 1, the response rates for all 150mg, and 300mg were Vs weeks for Scale (HAM‐A) in HAM‐A total quetiapine doses were greater vs placebo; 11, 10, and 24. quetiapine XR tapering total score ≥20 score), change in however, they were not significantly 150mg/day with item 1 CGI‐S, and MADRS different. Vs (anxious mood) total scores were quetiapine XR and item 2 some other ‐At week 8, the response rates were 300mg/day (tension) score of assessments significantly greater with quetiapine XR 50mg Vs ≥2. Clinical Global (60.3%; p<0.05) and XR 150mg (61.5%; placebo Impression‐ ‐Safety p<0.05) as compared with placebo (50.7). The Severity (CGI‐S) response rate with quetiapine XR 300mg was score ≥4 numerically higher but not statistically different vs placebo (54.9% vs 50.7%; p=0.371).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐At week 8, the MADRS‐total score change was ‐4.7 for quetiapine XR 50mg (p<0.05), was ‐5.11 for XR 150mg (p<0.01), and was ‐4.04 for XR 300mg (p=0.272) compared with ‐3.45 for placebo.

‐At week 8, the CGI‐S total score change was ‐1.62 with quetiapine XR 50mg (p=0.105), ‐1.7 for XR 150mg (p<0.05), and ‐1.45 for XR 300mg (p=0.956).

‐The most commonly reported adverse events were dry mouth, somnolence, sedation, dizziness, headache, fatigue, nausea, constipation, increased appetite, diarrhea, and insomnia. Berwaerts Multicenter, N=383 ‐Adult subjects ‐To compare the ‐During the 3‐week acute phase, subjects ‐In this population, et al151 randomized, (amount in aged 18‐65 years time to first were randomized to paliperidone ER 3‐ paliperidone ER was safe 2012 double‐blind, main‐ who met criteria recurrence of any 12mg/day (N=617) or olanzapine 5‐20mg/day and effective, delaying the parallel‐group tenance for bipolar I mood symptoms (N=149). Responders continued for 12 weeks time to recurrence of any LOE‐1a study phase) disorder, most (ie manic or through the continuation phase. Those on mood symptoms. recent episode depressive) paliperidone (PAL) who achieved remission manic or mixed, were randomized to PAL (N=148) or placebo GHS Comments: Please paliperidone Until 140 with at least 2 ‐The time to the (N=152) during the maintenance phase. note that this study was ER (PAL ER) recurrences previous first recurrence of Those on olanzapine (N=83) continued on enriched, as only Vs occurred documented manic symptoms fixed dose. responders were included olanzapine among mood episodes was the main in the double‐blind portion Vs those needing secondary ‐There was a significantly longer time to of the study. Those not placebo originally in treatment within outcome recurrence of mood symptoms with PAL ER vs responding to paliperidone PAL ER 3 years before placebo (p=0.017), with the median time to ER were not included in the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments group screening and a ‐Safety recurrence of 558 days with PAL ER vs 283 double‐blind portion, with Young Mania days with placebo. the outcome of Rating Scale determining the first time (YMRS) score of ‐The recurrence rate at 12 months was 51.6% to recurrence of any mood ≥20 for placebo, 38.6% for PAL ER, and 15.8% for symptoms. Additionally, olanzapine. The authors calculated the NNT please see the NNTs for PAL ER vs placebo to be 8 and for calculated by the authors olanzapine vs placebo to be 3. for recurrence rate. While this was not a true head‐to‐ ‐The median time to recurrence was not head study, olanzapine had observed on olanzapine, as only 23% a lower NNT. reported recurrence of any mood symptoms. However, a post‐hoc analysis suggested that the time to recurrence of any mood symptoms was significantly longer with olanzapine vs either treatment (p≤0.001 for both comparisons).

‐A significantly longer time to recurrence of manic symptoms was seen with the PAL ER group vs placebo (p<0.001), with a hazard ratio [HR] of 2.06. This suggests that those on placebo were twice as likely to report recurrence of manic symptoms vs those on PAL ER.

‐During the maintenance period, reported treatment‐emergent adverse events (TEAEs) were higher in the olanzapine group (64%) vs the placebo (59%) or the PAL ER group (55%).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Jindal et al152 Randomized, N=60 ‐Adult Indian ‐To compare the ‐At the end of 6 weeks, both treatments had ‐In this population, 2012 double‐blind, subjects aged 18‐ % of subjects a significant reduction in the BPRS total aripiprazole and olanzapine controlled 65 years showing clinical scores. The aripiprazole group had a were equally effective for LOE‐1a study hospitalized with a improvement, reduction of 21.66 points (p<0.001), while the short‐term treatment of diagnosed of defined as a 40% olanzapine had a reduction of 19.55 points schizophrenia. While more aripiprazole 6 weeks schizophrenia (in reduction in the (p<0.001). weight gain was seen with 10‐20mg QD an inpatient Brief Psychiatric olanzapine, both were well Vs clinical setting) Rating Scale ‐While a greater amount of subjects had a tolerated. olanzapine (BPRS) total score reduction in BPRS score in the olanzapine 10‐20mg QD as compared to group vs the aripiprazole group, the baseline difference was not statistically significant (62.97% vs 57.7%; p>0.05). ‐The PANSS total score was also ‐Both treatments had a significant reduction assessed in the PANSS total score at the end of 6 weeks. The aripiprazole group had a mean ‐Safety change of 11.94 points (p<0.001), while the olanzapine group had a mean change of 5.4 points (p<0.001).

‐While not a significant difference, more subjects in the aripiprazole group required trihexyphenidyl use vs in the olanzapine group (7.69% vs 3.71%).

‐A significantly greater number of the aripiprazole group needed lorazepam use vs in the olanzapine group (73.1% vs 40.74%; p<0.05).

‐Significantly more in the olanzapine group

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments gained weight during use vs the aripiprazole group (22.22% vs 7.70%; p<0.05).

While more in the olanzapine group resulted in greater increases in mean cholesterol levels, the difference between olanzapine and aripiprazole was not significantly different. Findling Multiphase, N=60 ‐Pediatric subjects ‐To compare the ‐Phase 1 of this study was an open‐label ‐ In this population, while et al153 double‐blind, aged 4‐9 years time to stabilization period with aripiprazole for up to there may have been a 2012 placebo‐ with bipolar discontinuation 16 weeks. If met criteria to continue nocebo effect, results controlled disorder (I, II, due to a mood (tolerated medicine and met a priori response suggest that aripiprazole LOE‐1a study NOS, or event criteria), were randomized into double‐blind may be superior to placebo cyclothymia) phase 2 portion of the study. for the long‐term treatment aripiprazole, 72 weeks ‐The Young Mania of pediatric patients max 15mg QD Rating Scale ‐70% of the entire study group withdrew from following stabilization with Vs (YMRS) and the study during the initial 4‐week period of open‐label aripiprazole. placebo Clinical Global the double‐blind phase; 50% for aripiprazole Impressions‐ (N=15/30) vs 90% for placebo (N=27/30). 6 Severity of Illness subjects in the aripiprazole group and none in (CGI‐S) scale were the placebo group actually completed the also assessed study.

‐Safety ‐Compared with placebo, those taking aripiprazole were enrolled significantly longer until time to study discontinuation for any reason (25.93 mean weeks vs 3 mean weeks; p=0.003).

‐There was a significantly longer time until discontinuation due to a mood even with aripiprazole vs placebo (25.93 mean weeks vs

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments 3.10 mean weeks; p=0.005).

‐Significant differences between treatment groups were not seen over time with the YMRS and SGI‐S scores (both p >0.05).

‐Stomach and musculoskeletal pain were significantly more likely to occur with aripiprazole vs placebo (both p<0.01).

‐A significant difference in weight gain from time of randomization was seen with the aripiprazole vs placebo group (mean 2.61kg vs mean 0.42kg; p=0.006); however, after adjusting for the fact that children at this age are already growing and adjusting for time, the significant difference in weight gain was eliminated. Honer et al154 Multicenter, N=131 ‐Adult subjects ‐To compare the ‐All subjects were tapered off meds if not ‐Results suggest that 2012 randomized, aged 18‐65 years emergent or taking quetiapine. Then by day 14, everyone quetiapine doses >800mg double‐blind, with diagnosis of worsening of was on quetiapine 800mg. At the end of 28 does not produce a greater LOE‐1a placebo‐ schizophrenia or extrapyramidal days, subjects were then randomized to amount of EPS side effects controlled schizoaffective symptoms (EPS) either placebo or quetiapine 400mg. as compared with an study disorder and a 800mg/day dose, but total score of 70‐ ‐Safety and ‐There was a 3.1% greater frequency of causes greater weight gain 110 on the tolerability deterioration or emergence of parkinsonism and comparable symptom Positive and in the >800mg/day group vs the 800mg/day improvement. Thus, the use Negative ‐The total PANSS group (p=0.76). Significant differences of quetiapine doses about Syndrome Scale score was the between treatment groups were not seen. the approved dose range is (PANSS) and who main secondary not beneficial. had persistent efficacy outcome ‐The differences in the amount of EPS

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments quetiapine 8 weeks positive and/or symptoms, adverse events, and serious 800mg QD negative adverse events between treatments were not PLUS symptoms. Had to statistically significant. quetiapine have at least a 4 400mg QD on the Clinical ‐A significantly greater increase in weight was Vs Global seen in the >800mg/day group, with no mean quetiapine Impressions (CGI) change from day 29 with the 800mg/day 800mg QD scale group vs a 1.2kg mean change from day 29 PLUS placebo with the >800mg group (p=0.044).

‐A statistically significant difference between treatments was not seen with the total PANSS scores between randomization and the end of treatment; however, the total PANSS scores in both treatment groups were reduced. Buchanan Two N=949 ‐Adult subjects ‐To compare the ‐Higher discontinuation rates were seen with ‐The superiority of et al155 multicenter, ≥18 years of age 16‐item Negative asenapine vs olanzapine (EH: 35.3% vs 19.6%; asenapine over olanzapine 2012 randomized, diagnosed with Symptom WH: 50.4% vs 26.2%). was not demonstrated in double‐blind schizophrenia and Assessment Scale these studies; however, LOE‐1a studies a PANSS negative (NSA‐16) total ‐At week 26, while both treatments reduced discontinuation rates were (Eastern [EH] symptom subscale score negative symptoms, significant differences higher with asenapine vs and Western score of ≥20 who between treatments in the change from olanzapine. Hemisphere had to be clinically ‐The PANSS total baseline NSA‐16 total score were not seen [HE]), stable for 5 and subscale (EH: p=0.79; WH=0.72). followed by a months before scores, as well as 26‐week screening the Clinical Global ‐Significant between‐group differences were extension Impressions (CGI)‐ not seen in regards to the secondary efficacy study Severity and CGI‐ outcomes of the PANSS total and negative Improvement subscale scores, and the CGI‐S; however, a scores were some modest but statistically significant greater other assessments change in the PANSS positive score was seen

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments asenapine 26 weeks, ‐Safety with olanzapine vs asenapine at weeks 12‐26 Vs followed by in the EH and at weeks 20 and 26 in the WH olanzapine a 26‐week (p<0.05). extension period ‐During the extension study, there were not significant differences between treatments in NSA‐16 total score (asenapine score ‐16.9 vs olanzapine score ‐15.4; p=0.23).

‐Furthermore, there were not significant differences seen between treatments in the extension phase on the PANSS negative subscale, PANSS total or CGI‐S scores. While changes in the positive PANSS subscale were small, significant differences were only seen with olanzapine vs asenapine in the WH (p=0.04), but not in the EH.

‐The overall incidence of EPS symptoms were higher in the WH vs the EH. The incidence of EPS adverse events was higher with asenapine vs olanzapine in the EH (8.3% vs 3.3%) as well as in the WH (16.4% vs 12.1%). There were not any discontinuations due to EPS adverse events however.

‐Clinically relevant weight gain (≥7% increase from baseline to end point) was seen in the EH study of 7.9% with asenapine vs 24.6% with olanzapine.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Weight gain was statistically significant between treatments, with weight change at the end of week 26 being ‐1.0kg with asenapine vs 2.9kg with olanzapine (p<0.0001) in the EH.

‐Clinically relevant weight gain (≥7% increase from baseline to end point) was also seen in the WH study of 8.0% with asenapine vs 18.6% with olanzapine. CItrome Multicenter, N=629 ‐Adult subjects ‐To assess long‐ ‐Comparable amounts subjects in each ‐Lurasidone was safe and et al156 randomized, aged 18‐75 years term adverse treatment reported at least one adverse well‐tolerated, with 2012 double‐blind, with primary events, including event (84.5% lurasidone vs 84.7% minimal effects on weight active‐ diagnosis of glucose levels, risperidone). and prolactin levels, while LOE‐1a controlled schizophrenia or cholesterol, having comparable effects study schizoaffective prolactin, and ‐Compared with the risperidone group, a on PANSS and CGI‐S scores disorder and bone marker greater amount discontinued treatment with with risperidone. lurasidone 40‐ 12 months duration of illness turnovers lurasidone due to a treatment‐emergent 120mg QD for at least 1 year adverse event (TEAE; 21.5% vs 14.4%). Vs and who has been ‐Efficacy risperidone 2‐ clinically stable for assessments, ‐A greater amount of the risperidone group 6mg QD ≥8 weeks before including relapse reported at lease one metabolic‐related TEAE baseline (defined rate, PANSS, CGI‐ as compared with the lurasidone group by Clinical Global S, and the (20.8% vs 11.7%). Impression‐ Montgomery Severity [CGI‐S] Asberg Depression ‐The 3 most commonly reported AEs with score of up to 4) Rating Scale lurasidone (vs risperidone) were nausea (MADRS) (16.7% vs 10.9%), insomnia (15.8% vs 13.4%), and sedation (14.6% vs 13.9%). The 3 most commonly reported AEs with risperidone (vs

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments lurasidone) were increased weight (19.8% vs 9.3%), somnolence (17.8% vs 13.6%), and headache (14.9% vs 10%).

‐Statistically significant changes in changes in cholesterol levels were not seen between treatments, or in heart rate or blood pressure.

‐The median change in prolactin levels were significantly higher in the risperidone group vs lurasidone (p<0.001).

‐There was a significant difference in body weight and BMI between treatments (mean decrease of ‐0.97kg with lurasidone vs an increase of 1.47kg with risperidone for weight, p<0.001; and mean decrease in BMI of ‐0.33 with lurasidone vs an increase of 0.53 with risperidone, p<0.001).

‐A statistically significant difference in relapse rate was not seen between lurasidone vs risperidone (20% vs 16%).

‐PANSS total score decreased in both treatment groups. Significant differences between treatments were not seen during the 12‐month period (‐4.7 for lurasidone vs ‐6.5 for risperidone).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐Both treatment groups resulted in decreases from baseline to month 12 in the CGI‐S scores (‐0.4 with lurasidone vs ‐0.4 risperidone).

‐Significant differences in MADRS total score were not seen between treatments (‐0.8 with lurasidone vs ‐2.4 with risperidone). Crespo‐ Randomized, N=174 ‐Subjects aged 15‐ ‐To compare the ‐There was a significantly different treatment ‐After 3 years of treatment, Facorro prospective, 60 years with first % of discontinuation rate for any cause between a lower effectiveness et al158 open‐label episode of discontinuation of treatments (p=0.005), with a significantly (based on the co‐primary 2012 study psychosis and no the initially higher rate in the haloperidol vs the outcomes) was seen with prior treatment assigned risperidone and olanzapine group. The haloperidol as compared LOE‐2 haloperidol 3‐ 4 years with antipsychotic treatment and the difference in discontinuation between with olanzapine and 9mg QD medication or, if mean time to risperidone and olanzapine showed a risperidone (the SGAs); Vs previously discontinuation tendency towards significance (p=0.082). however, with those who olanzapine 5‐ treated, a total life continue treatment, a 20mg QD time of adequate ‐To compare the ‐With haloperidol, the mean time to all‐cause comparable efficacy was Vs treatment of <6 mean change discontinuation was 15.4 months, as seen between treatments risperidone 3‐ weeks and from baseline to 3 compared with 23.8 months for olanzapine, for positive, negative, and 6mg QD diagnosis of brief years in BPRS total and 20.7 months for risperidone. depressive symptoms. psychotic scores disorder, ‐Significant differences between treatments schizophreniform ‐Safety were not seen in the % of good adherence disorder, (83.3% with haloperidol, 68.2% with schizophrenia, or olanzapine, and 78.9% with risperidone; schizoaffective p=0.0605). disorder ‐Global function outcome was not significantly different between treatments (81.8% with haloperidol‐treated vs 63% with

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments olanzapine and 71.4% with risperidone; p=0.505).

‐Baseline total scores of the Hamilton Depression Rating Scale (HDRS) were not significantly different between treatments. Significant differences between treatments were not seen after 3 years.

‐Significant differences in the increment of EPS signs were not seen after 3 years between treatments (p=0.132), or with the % of subjects with treatment‐emergent parkinsonism (9.1% haloperidol, 0% olanzapine, 0% risperidone; p=0.114); however, a significantly greater increase in akathisia severity was seen with haloperidol (p=0.013). Szegedi Multicenter, N=324 ‐Adult subjects ‐To compare the ‐Asenapine was used as adjunctive treatment. ‐The use of asenapine as et al159 randomized, with primary change from adjunctive therapy to 2012 double‐blind, diagnosis of baseline in the ‐Significantly greater YMRS total score lithium or valproate was placebo‐ bipolar I disorder (YMRS total score improvements were seen with asenapine vs effective, and more LOE‐1a controlled with Young Mania at week 3 placebo at week 3. Statistical significance was effective than the mood core study Rating Scale also seen at weeks 2, 6, 9, and 12. stabilizer monotherapy. with 40‐week (YMRS) ≥20, a ‐To compare extension current manic or changes from ‐The least mean change from baseline in study mixed episode baseline in YMRS YMRS total score of asenapine vs placebo was that began ≤3 at week 12, rates ‐10.3 vs ‐7.9 (p=0.026) at week 3 and ‐12.7 vs months before of YMRS response ‐9.3 (p=0.0073) at week 12. screening and (≥50% decrease who had to have from baseline ‐While the response rate did not differ been treated YMRS total score),

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments asenapine 12 week continuously with remission (YMRS significantly at week 3 with asenapine vs 5mg QD core plus 40 lithium or total score ≤12), placebo (34.2% vs 27%), there was a Vs week valproate for ≥2 and change in CGI significant difference seen at week 12 (47.7% asenapine extension weeks before for Bipolar vs 34.4%; p=0.0152). 10mg QD study screening Disorder (CGI‐BP) Vs score for severity ‐Rates of YMRS remission were significantly placebo of mania greater with asenapine vs placebo at weeks 3 (33.5% vs 21.5%; p=0.0158) and weeks 12 (43.2% vs 30.1%; p=0.0148).

‐Of those in the extension trial, rates of YMRS response (68.4% vs 78.8% placebo) and remission (65.8% vs 78.8%) were not significantly different at week 52.

‐The mean decrease from baseline in the core study in CGI‐BP scores were significantly greater with asenapine vs placebo at weeks 3 (‐1.1 vs ‐0.8, p=0.005 for mania severity; ‐1.0 vs ‐0.7, p=0.0073 for overall illness severity) and at week 12 (‐1.5 vs ‐1.0, p=0.0006 for mania severity; ‐1.2 vs ‐0.8, p=0.0102 for overall illness severity).

‐73.4% rate of treatment‐emergent adverse events with asenapine vs 68.7% with placebo over the 52 week period.

‐Sedation, somnolence, depression/ depressive symptoms, oral hypoesthesia, and increased weight were reported by ≥5% of

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments the asenapine group and twice as much as placebo.

Zhang et al160 Multicenter, N=239 ‐Adult Chinese ‐To compare the ‐While both treatment groups had statistically ‐While ziprasidone was as 2011 randomized, subjects aged 18‐ PANSS total score significant improvements in PANSS total score effective as risperidone, it double‐ 65 years with compared with baseline, there were not had less weight gain and LOE‐1a dummy, diagnosis of ‐The Brief statistically significant differences seen less prolactin elevation. double‐blind, schizophrenia and Psychiatric Rating between treatments. active‐ required to have a Scale (BPRS), controlled, PANSS score ≥60 PANSS subscales, ‐At week 6, there was a 1.5 difference parallel‐group responder rates between treatments in PANNS total score, study (≥50% reduction with an improvement from baseline to week from baseline 6 in PANSS total score of ‐35.6 with ziprasidone 6 weeks PANSS total ziprasidone vs ‐37.1 with risperidone. Thus, 80‐160mg/day score), and Clinical non‐inferiority of ziprasidone was seen. Vs Global risperidone 2‐ Impression‐ ‐Statistically significant differences on all 6mg/day Severity and – PANSS subscales and BPRS were seen with Improvement both treatments vs baseline; however, scales (CGI‐S and significant differences between treatments CGI‐I) were some were not seen. other assessments ‐Responder rates increased over time. At the ‐Safety end of the study, 64.4% of the ziprasidone group achieved a response as compared with 71.9% of the risperidone group.

‐Both treatments had improvements on CGI‐I and CGI‐S scores; however, there was a significantly greater improvement seen in the

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments risperidone group on the CGI‐I scale vs ziprasidone (2.2 vs 2.6; p=0.039).

‐A significant weight gain of ≥7% was seen with 18 subjects in the risperidone group, as compared with only 5 in the ziprasidone group.

‐A significantly greater amount in the risperidone group had prolactin abnormalities vs the ziprasidone group. Overall, the ziprasidone group had a ‐3.5ng/ml mean change from screening vs an increase of 85.4ng/ml with risperidone.

‐79.7% of the ziprasidone group reported treatment‐related adverse events as compared with 71.1% of the risperidone group. Fleischhacker Multicenter, N=749 ‐Adult subjects ‐To compare the ‐Dosing in the PP group was 50mg eq. on days ‐Paliperidone palmitate et al161 randomized, with an change PANSS 1 and 8, and flexible dosing (25‐100mg eq) long‐acting injectable was 2012 double‐blind, established total score from once daily, while dosing with the RIS‐LAI not found to have double‐ diagnosis of baseline to the group was bi‐weekly injections of 25mg on comparable efficacy to LOE‐1a dummy, schizophrenia for end of study days 8 and 22, and flexible dosing (25‐50mg) risperidone long‐acting active‐ at least 1 year, a starting from day 36, with oral injectable. controlled, PANSS total score ‐The changes from supplementation. Phase III, between 60 and baseline to GHS Comments: This was parallel‐group 120, acutely endpoint in the ‐The mean change from baseline to endpoint an industry sponsored comparative symptomatic at Clinical Global in PANSS total score was ‐11.6 in the PP group study. Results described study screening, and a Impression‐ vs ‐14.4 in the RIS‐LAI group. These results were from the per‐protocol BMI ≥15kg/m2 Severity (CGI‐S) were from the PP population, and these (PP) population, which can

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments paliperidone 53 weeks score, Personal results suggest that PP as dosed in this study cause bias. Lastly, oral palmitate LA and Social was not found non‐inferior to RIS‐LAI. Results risperidone was used in injectable Performance scale with the ITT population were consistent these combination with the (flex‐dose) (PSP) score, and results. injectable. PLUS oral the responder placebo (PP) rate (≥30% ‐The ITT population was used for the Vs reduction in the secondary outcomes. risperidone LA PANSS total score injectable from baseline to ‐The reduction of schizophrenia symptoms, as PLUS endpoint) measured by the CGI‐S total score, was higher risperidone in the RIS‐LAI group vs the PP group. oral (RIS‐LAI) ‐Comparable changes in PSP scores were seen between treatments. 43% of the PP group and 46% of the RIS‐LAI group had improved PSP scores vs baseline.

‐44% of the PP group was considered responders as compared with 54% of the RIS‐ LAI.

‐76% of the PP group reported treatment‐ emergent adverse events (TEAEs) as compared with 79% of the RIS‐LAI group.

‐The most frequently reported TEAE from either group were insomnia (15% each), psychotic disorder (14% PP vs 12% RIS‐LAI), worsening or relapse of schizophrenia (12% PP vs 9% RIS‐LAI), anxiety (10% PP vs 15% RIS‐ LAI), and headache (9% PP vs 11% RIS‐LAI).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Singham Single‐blind, N=100 ‐Subjects aged 15‐ ‐To compare the ‐For the positive subscale score, both ‐While PANSS scores and et al166 prospective, 75 years total scores of the treatments were equally efficacious for positive PANSS subscores 2011 longitudinal diagnosed with PANSS, and the reductions in scores, with the mean score for were reduced similarly comparative schizophrenia who subscales of chlorpromazine being 9 and for risperidone between treatments, LOE‐2 study were not in positive and being 7. risperidone was more danger to negative scores effective for reducing the chlor‐ 3 months themselves ‐The mean score of negative symptoms was negative PANSS subscore promazine (suicidal) or others statistically significantly reduced with and had better compliance 100‐200mg risperidone as compared with the baseline as compared with the Vs score (27.34 baseline vs 7.36; p<0.000). The chlorpromazine. risperidone 3‐ mean score was reduced from baseline with 16mg chlorpromazine; however, the difference was not statistically significantly different (27.52 baseline vs 19.62; p=NS).

‐Risperidone had a significantly better effect on negative symptoms vs chlorpromazine (p<0.01).

‐Both chlorpromazine (61 baseline vs 20 at final visit) and risperidone (56 baseline vs 14 final visit) significantly decreased total PANSS score from baseline (p=0.0001). Both were considered to be comparable for reducing the PANSS total score.

‐Compliance was better with risperidone vs chlorpromazine.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Geller et al167 Multicenter, N=279 ‐Pediatric subjects ‐To compare the ‐For the primary outcome, 68.5% of the ‐For the initial treatment of 2012 randomized, aged 6‐15 years Clinical Global risperidone group had a rating of ≤2 as childhood mania, while controlled, with a diagnosis of Impressions for compared with 35.6% of the lithium group risperidone was more LOE‐2 open‐label, bipolar I disorder, Bipolar Illness and 24% of the divalproex group. Statistically effective, it resulted in parallel group manic or mixed Improvement‐ significant differences were seen between greater metabolic study episode for at Mania (CGI‐BP‐ risperidone and lithium (p<0.001) and abnormalities. least 4 weeks IM). Ratings of 1 between risperidone and divalproex lithium 1.1‐ 8 weeks preceding (very much (p<0.001); however, significant differences 1.3mEq/L baseline, with a improved) or 2 were not seen between lithium and Vs Children’s Global (much improved) divalproex sodium. divalproex Assessment Scale counted for sodium 111‐ (CGAS) score of response ‐The mean KMRS scores were significantly 125mcg/ml ≤60 at baseline lower in those treated with risperidone vs Vs and is in good ‐Kiddie Schedule lithium (16.4 vs 26.2; p<0.001) and vs risperidone 4‐ physical health for Affective divalproex (16.4 vs 27.6; p<0.001). 6mg QD who were Disorders and treatment naïve Schizophrenia (K‐ ‐Per the CGAS, a significantly higher response SADS) Mania rate was seen with the risperidone group vs Rating Scale the lithium (48.3% vs26.7%; p=0.004) or vs (KMRS) and the divalproex group (48.3% vs 17%; p<0.001). CGAS were also assessed ‐A significantly higher rate of absence of mania was seen with the risperidone group vs ‐Safety lithium (62.9% vs 41.1%; p=0.013) or vs divalproex (62.9% vs 26%; p<0.001).

‐There were higher rates of discontinuation with lithium vs risperidone.

‐Significantly greater weight gain, BMI, and prolactin levels were seen with risperidone vs

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments lithium (p<0.001 for all comparisons) and vs divalproex (p<0.001 for all comparisons).

Gaebel Multicenter, N=710 ‐Stable adults ≥18 ‐To compare the ‐Aripiprazole was used in those countries ‐A significantly longer time et al168 randomized, years of age with time from were it was available, and was given as a ratio to relapse was seen with 2010 open‐label, diagnosis of randomization to of 1:2:2 to quetiapine and RLAI. RLAI treatment as active‐ schizophrenia or documentation of compared with oral LOE‐2 controlled schizoaffective relapse (to meet ‐There was a significant difference in time‐to‐ olanzapine. study disorder and were one of 7 specific relapse for the RLAI group vs quetiapine candidates for criteria, such as (p<0.0001). For the quetiapine group, the 25th risperidone 2 years switching therapy psychiatric quartile of time‐to‐relapse was 248 days; long‐acting (oral risperidone, hospitalization, however, this could not be defined for RLAI as injectable oral olanzapine, or deliberate self‐ there was <25% experiencing relapse. (RLAI) 50mg conventional injury, significant Q2W max neuroleptics) due clinical ‐Statistical significance was not seen between Vs to insufficient deterioration with treatments for relapse. 16.5% of the RLAI had quetiapine symptomatic a CGI‐Change relapse as compared with 31.1% of the oral 750mg control, side score of 6 quetiapine group. Only 20.5% reported a daily max effects, or patient single reason for relapse. Vs request ‐PANSS total aripiprazole score, negative ‐PANSS total score were significantly better as oral and positive sub‐ compared with baseline for both treatments scores were also at each post‐treatment assessment (p<0.001). assessed ‐Statistical improvements in PANSS total ‐Safety score were seen with RLAI (p<0.001) at endpoint, but not with quetiapine (p=0.10). A significant difference was seen between RLAI and quetiapine at endpoint (p<0.001).

‐At the end of the study, PANSS improvement ≥20% was seen by 42% of the RLAI group vs

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments 30% of quetiapine, by ≥30% was 30% RLAI vs 17% quetiapine, by ≥40% was 15% RLAI vs 7% quetiapine, and by ≥50% was 7% RLAI vs 3% (p<0.05).

‐Reported adverse events with RLAI vs quetiapine included somnolence (20% vs 11%), EPS (10.3% vs 5.6%), parkinsonism (4.6% vs 1.8%), prolactin‐related adverse events (4.6% vs 1.5%), and weight gain (7% vs 6.2%). Potkin et al170 Multicenter, N=307 ‐Adult subjects ‐Safety ‐There were comparable discontinuation ‐Lurasidone was safe and 2011 randomized, aged 18‐70 years rates between treatments for all causes effective, with comparable double‐blind, with diagnosis of To compare the (32.5% vs 30.7%) and due to adverse events efficacy and changes in LOE‐1a fixed‐dose, schizophrenia or PANSS total score, (10.4% vs 11.1%). metabolic parameters as parallel‐group schizoaffective and positive and ziprasidone. study disorder with a negative subscale ‐Both treatments were well tolerated, with at minimum scores, as well as least one adverse event reported by 56.7% of GHS Comments: The short lurasidone 3 weeks duration of at the Clinical Global the lurasidone group and 65.5% of the duration of use is a 120mg/day least 6 months but Impression‐ ziprasidone group. limitation of this study. Vs not currently Severity scale ziprasidone experiencing an (CGI‐S) were some ‐Comparable effects with lurasidone vs 160mg/day acute other assessments ziprasidone were seen with total cholesterol exacerbation of (‐6.4 vs ‐4.4mg/dl) and decrease in weight psychosis and not (‐0.65 vs ‐0.35kg). Minimal effects were seen required in on blood glucose or HbA1c levels. patient treatment for 3 months prior ‐There was a +3.0ng/ml increase in prolactin to baseline with lurasidone vs +2.0ng/ml with ziprasidone. There was a higher rate of ‘marked’ elevation in prolactin with

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments lurasidone vs ziprasidone (27% vs 16%); however, there were no discontinuations of treatment due to elevated prolactin levels.

‐Clinically significant abnormalities in ECG parameters were not seen for either treatment.

‐Statistically significant improvements from baseline were seen with lurasidone and ziprasidone at week 3 for PANSS total score (‐6.3 vs ‐4.5; p=0.229); however, statistically significant differences were not seen between treatments.

‐Statistically significant differences were seen with lurasidone and ziprasidone as compared with baseline but not as compared between treatments at week 3 for PANSS positive subscale (‐1.7 vs ‐1.5; p=0.656) and for PANSS negative (‐1.7 vs ‐1.0; p=0.084).

‐Comparable improvements on the CGI‐S scale were seen between treatments. Chen et al171 Randomized, N=48 ‐Subjects aged 15‐ ‐To compare the ‐In those who could not tolerate haloperidol, ‐In this population who has 2012 rater‐blinded, 65 years change from trifluoperazine was given. Will refer to this been inadequately active‐ diagnosed with baseline to group as the FGA group. controlled with a prior trial LOE‐2 controlled schizophrenia endpoint in PANSS of a FGA, comparable study with good total score ‐Significant improvements from baseline efficacy was seen when compliance within were seen with all 3 treatments, with a mean switched to a different FGA 3 months prior to ‐The change from change of PANSS total score from baseline to as compared with switching

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments risperidone 8 weeks study but who had baseline to endpoint being ‐14.9 with FGA (p<0.01), ‐12.7 to risperidone or Vs been inadequately endpoint in the with risperidone (p<0.01), and ‐14.8 with olanzapine. olanzapine responsive to only PANSS positive olanzapine (p<0.01). Vs 1 line of first and negative sub‐ GHS Comments: The small haloperidol generation score were also ‐A statistical difference in PANSS score from sample size and open‐label antipsychotics assessed baseline was seen quicker with olanzapine design are limitations of (FGA) and risperidone (at 2 weeks), while occurring this study. Further double‐ ‐A ‘good at week 6 with the FGA group. blind, larger sample size responder’ was studies are needed. defined as a ≥20% ‐At week 8, statistically significant differences decrease in PANSS in PANSS total score were not seen between total score and treatments. CGI‐S score ≤3 at endpoint ‐All 3 treatments had significant improvements in PANSS positive sub‐score, ‐Safety being ‐5.5 with FGA (p<0.05), ‐5.8 with risperidone (p<0.01), and ‐3.5 with olanzapine (p<0.01).

‐Olanzapine was the only treatment that had significant improvements in the PANSS negative sub‐score, of ‐4.1 (p<0.05).

‐Significant differences between treatments were not seen with the PANSS sub‐scores and in the amount of treatment responders.

‐38% of the FGA group was considered treatment responders as compared with 25% of the risperidone group and 31% of the olanzapine group.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐A statistically significant reduction in the Extrapyramidal Symptom Rating Scale (ESRS) subjective total score was seen with olanzapine vs the risperidone and FGA treatments (p=0.020). While the ESRS parkinsonism total score was reduced greater with olanzapine vs FGA and risperidone, the differences were not statistically significant.

‐Significant differences between treatments were not seen in the change of ESRS dystonia total score, ESRS dyskinesia total score, and all of the ESRS global impression.

‐The mean dose of supplemented anticholinergics increased slightly in the risperidone group (p<0.05) and did not significantly change in the olanzapine group; however, doses increased substantially in the FGA group (p<0.01).

‐While a significant increase in body weight was seen with olanzapine from baseline (2.69kg; p=0.026), significant differences in body weight were not seen between treatments.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Katila et al172 Multicenter, N=338 ‐Adult outpatient ‐To compare the ‐MADRS total scores were significantly ‐Monotherapy quetiapine 2012 randomized, subjects ≥66 years change from reduced with quetiapine vs placebo (mean XR was safe and effective double‐blind, of age with randomization to change of ‐16.33 vs ‐8.79; p<.001). for improving depressions LOE‐1a placebo‐ diagnosis of single endpoint in symptoms in this elderly controlled, or recurrent major Montgomery ‐The MADRS total scores were obtained for a population. parallel‐ depressive Asberg Depression subgroup of adults aged >75 years of age. group, Phase disorder (MDD), Rating Scale Statistically significant differences were not III study confirmed by the (MADRS) total seen between treatment groups (mean Mini‐International score change of ‐12.95 with quetiapine vs ‐9.05 quetiapine XR 11 weeks (9 Neuropsychiatric with placebo; p=0.068). with flexible weeks Interview, and ‐MADRS response dosing of 50‐ randomized, who had a (≥50% reduction ‐In a subgroup with adults ≤75 years of age, 300mg/day 2 weeks Hamilton Rating in MADRS total the MADRS total score was significantly Vs post‐ Scale for score from reduced with quetiapine vs placebo (mean placebo treatment Depression 17‐ randomization) change of ‐16.98 vs ‐8.78; p<0.001). phase) item (Ham‐D17) and remission scale total score of (MADRS total ‐A significantly greater MADRS response was ≥22 score ≤8, ≤10, and seen with quetiapine XR vs placebo at weeks ≤12) rates at week 1 and 9. At week 9, the quetiapine group had 9 were also a 62.2% response as compared with 30.4% assessed with placebo (p<0.001).

‐Safety ‐For remission with quetiapine vs placebo, 45.1% vs 17% , respectively, had MADRS total score ≤8, while 56.1% vs 23.4%, respectively, had MADRS total score ≤10, and 62.2% vs 30.4% had total score ≤12 (p<0.001 for all comparisons).

‐9.6% of the quetiapine XR group discontinued treatment due to an adverse

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments event (AE) as compared with 4.1% of the placebo group.

‐Common adverse events included somnolence, headache, dry mouth, and dizziness. Schreiner Multicenter, N=459 ‐Adult subjects ‐To compare the ‐The mean endpoint change in TG/HDL vs ‐Significant differences in et al173 randomized, aged 18‐65 years mean change in baseline was significant for olanzapine (0.097; metabolic profiles of 2012 prospective, diagnosed with the ratio of serum p<0.0001, which reflects a worsening), but therapeutic doses were controlled, schizophrenia and triglyceride levels was not for different for paliperidone ER seen between paliperidone LOE‐2 open‐label, considered to to high‐density (‐0.17; p=0.4748). ER and olanzapine, with parallel‐group benefit from lipoprotein levels olanzapine significantly study either treatment. (TG/HDL) ‐The change between treatments at endpoint associated with more Were required to suggested that paliperidone was significantly weight gain, lipid changes, paliperidone 6 months have a PANSS ‐The PANSS less likely to have an undesirable metabolic and new‐onset metabolic ER 6‐9mg QD total score within scores, lipid effect vs olanzapine (p<0.0001). syndrome. Efficacy Vs range of 60‐100. metabolism, and between treatments was olanzapine Those on body weight were ‐Serum TH significantly increased at each non‐inferior. 10‐15mg QD concomitant lipid‐ some other assessment and endpoint (p<0.0001) and HDL lowering therapy assessments significantly decreased at month 3 could be enrolled (p=0.0588), month 6 (p≤0.0083), and at if were on stable ‐Safety endpoint (p≤0.0083); however, significant dose of statins, changes were not seen with the paliperidone niacin, ezetimibe, ER group. and resins for ≥4 weeks or fibrates ‐New onset of metabolic syndrome occurred for ≥12 weeks in 13.2% of the paliperidone ER group vs 23.3% of the olanzapine group. This between‐ treatment group difference was significant (p=0.0230).

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐At endpoint, mean body weight increased by 1.2kg with paliperidone ER and by 3.8kg with olanzapine. All within‐treatment group and between‐treatment group changes at endpoint were significant for body weight (p≤0.0001) and BMI (p≤0.0001).

‐At endpoint, the mean increase in waist circumference was 0.7cm with paliperidone ER, which was not significantly different (p=0.140). The increase with olanzapine was 3.4cm, which was significantly different (p<0.0001). The between‐treatment group change was statistically significant (p<0.0001).

‐Significant improvements in PANSS total and sub‐scale scores were seen at each assessment and at endpoint for both treatments (p<0.0001). At endpoint, PANSS total scores were decreased by 13.5 with paliperidone ER and 16.6 with olanzapine. This suggested treatment equivalence and non‐inferiority.

‐Comparable amounts of patients with improvement in PANSS total scores of ≥20% at endpoint vs baseline was seen.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments Kilian et al175 Multicenter, N=374 ‐Adult subjects ‐To compare the ‐Follow‐up periods were done at 6, 12, 18, ‐A lower risk of psychiatric 2012 prospective with first‐line rehospitalization and 24 months. inpatient re‐admission was observational diagnosis of of patients after seen with olanzapine use as LOE‐2 trial schizophrenia or discharge from ‐At each follow‐up visit, there was an average compared with quetiapine schizoaffective index of 28% of the study participants that was and risperidone; however, quetiapine Up to 24 disorder and a hospitalization admitted at least once to psychiatric inpatient differences in clinical Vs months clinical treatment. outcomes were not seen olanzapine recommendation ‐The number of between treatments. Vs of antipsychotic days remained on ‐The average 6‐month hospital re‐admission risperidone maintenance initial rate was lowest of those in the olanzapine treatment with antipsychotic was group. quetiapine, also assessed olanzapine, or ‐Upon analysis, the average re‐admission rate risperidone for a was significantly lower in the olanzapine minimum of 12 group vs the quetiapine group (Odds Ratio months [OR] 0.40; p=0.017) and with risperidone (OR 0.25; p=0.000).

‐Compared to the quetiapine group, those in the olanzapine (‐62.35; p=0.023) and risperidone group (‐120.75; p=0.001) were given significantly lower chlorpromazine equivalent dosages. Vieta et al176 Multicenter, N=398 ‐Adult subjects ‐To compare the ‐This was a 3 period study, which included a ‐A significant delayed time 2012 randomized, aged 18‐65 years time to 2‐week screening period. At the end of the to recurrence of elevated double‐blind, with diagnosis of recurrence of any screening period, eligible patients entered a mood episodes was seen LOE‐1a double‐ bipolar I disorder mood episode for 12‐week open‐label period (period 2) and all with risperidone LAI as dummy trial and confirmed by treatment groups received risperidone LAI. Acute patients also compared with placebo. the Mini received oral risperidone in weeks 1‐3 and International ‐To compare the then tapered off in weeks 4‐5. At the end of Neuropsychiatric Young Mania period 2, those who had responded to

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments risperidone 18 months Interview. All Rating Scale treatment (had not experienced a recurrence long‐acting were classified as (YMRS), event) were randomized to double‐blind injectable either acute or Montgomery‐ treatment. (LAI) 25, 37.5, non‐acute with at Asberg Depression or 50mg PLUS least one manic Rating Scale ‐Significant differences in the time to oral placebo episode within 4 (MADRS), and recurrence of any mood episode were not Vs months of Clinical Global seen between treatments (p=0.057). The placebo enrollment Impression (CGI) median time (25th centile) to recurrence was injectable were some other 198 day for placebo and was not reached in PLUS placebo assessments the risperidone LAI group. oral Vs ‐Safety ‐In the adjusted analysis, the time to first oral recurrence of any mood episode was olanzapine significantly longer in the risperidone LAI 10mg/day group vs placebo (p=0.031). PLUS placebo injectable (as ‐While there was a significant difference for active the time to recurrence of elevated mood comparator) episodes with risperidone LAI vs placebo (p=0.005), significant differences in depressive episodes were not seen (p=0.655).

‐Significant improvements from baseline in YMRS Scores occurred during period 2, as well as the MADRS and CGI‐S scores in those classified as ‘acute’. Significant improvements in only YMRS scores were seen in those non‐ acute patients.

‐During this double‐blind phase, YMRS scores deteriorated significantly in the placebo

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments group (p<0.001 vs baseline); however, significant changes were not seen in the risperidone LAI (p=0.237).

‐Increases in MADRS and CGI‐S scores were seen in both treatment groups (p<0.001 vs baseline; however, the change in CGI‐S was significantly greater in the placebo arm vs the risperidone arm (p<0.001).

‐The YMRS and MADRS scores did not significantly change from baseline in the olanzapine group (both p≤0.001 vs placebo).

‐The most frequently reported adverse events with the risperidone LAI group included weight increase, insomnia, and amenorrhea. The most frequently reported adverse events with the olanzapine group included weight increase, somnolence, and insomnia.

‐4% of the risperidone group discontinued treatment due to adverse events, as compared with 4% of the olanzapine group and 2% of the placebo group. Kane et al177 Multicenter, N=403 ‐Adult subjects ‐To compare the ‐There were 4 phases to this study. Phase 1 ‐The use of aripiprazole IM‐ 2012 randomized, aged 18‐60 years time to consisted of the oral conversion phase (4‐6 depot significantly delayed double‐blind, who require exacerbation of weeks). Those not on aripiprazole were cross‐ time to impending relapse LOE‐1a placebo‐ chronic psychotic titrated to oral aripiprazole monotherapy. as compared with placebo. controlled antipsychotic symptoms/ Phase 2 was the oral stabilization phase (4‐12 trial treatment with a impending relapse weeks). If subjects met criteria for oral

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments aripiprazole 52 weeks diagnosis of stabilization, then they were assigned to IM‐depot 300 schizophrenia for ‐The amount of single‐ blind aripiprazole IM depot (400mg) in or 400mg at least 3 years subjects meeting phase 3 (the IM‐depot stabilization phase, 12‐ Vs and a history of impending relapse 36 weeks). Oral aripiprazole was continued placebo IM‐ symptom criteria in phase 3 for 2 weeks during this phase. Those who met depot exacerbation or and the change in stability criteria were randomly assigned into relapse when not PANSS total score the maintenance treatment phase 4 (this receiving from the double‐ study reports on phase 4). antipsychotic blind baseline to treatment endpoint were ‐A significant delay in the time to relapse was some other seen in the aripiprazole‐IM‐depot (AIMD) assessments group vs placebo.

‐Safety ‐There were significantly lower relapse rates with AIMD vs placebo at endpoint (10% vs 39.6%; hazard ratio [HR] =5.03).

‐Reasons for relapse at endpoint for AIMD vs placebo were clinical worsening per CGI/PANSS (74.1% vs 86.8%), hospitalization (25.9% vs 9.4%), suicide risk (3.7% vs 1.9%), and violent behavior (3.7% vs 7.5%).

‐Mean PANSS total scores improved during the oral and AIMD stabilization phase. During the double‐blind phase, significant mean increases in PANSS total scores were seen in the placebo group vs the AIMD group (+11.6 vs +1.4; p<0.0001). Significant differences were seen as early as week 2.

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments

‐The mean change in CGI‐S scores was statistically significantly in favor of AIMD vs placebo (0.1 vs 0.7; p<0.000). This was seen at every assessment starting at week 4.

‐Insomnia, headache, and tremor occurred most frequently with AIMD and more than placebo.

‐7.1% of the AIMD group discontinued treatment due to AEs as compared with 13.4% of the placebo group. Covell et al178 Multicenter, N=62 ‐Adult subjects ‐To compare the ‐Subjects were randomly assigned to either ‐More frequent treatment 2012 open‐label, aged ≥18 years time to all‐cause stay on current injectable or switch to discontinuations were seen randomized with a diagnosis of medication risperidone microspheres. 29 subjects in those who switched from LOE‐2 controlled schizophrenia or discontinuation remained on their medication and 24 haloperidol or fluphenazine trial schizoaffective switched to risperidone). decanoate to risperidone disorder who ‐To compare LAI, and also had significant haloperidol 6 months, were currently psychiatric ‐During the initial 6 months, significant weight gain and increases in decanoate plus an taking haloperidol symptoms as differences in time to all‐cause treatment prolactin. Vs additional 6 decanoate or measured by the discontinuation were not seen between fluphenazine month fluphenazine PANSS total score, treatments (p=0.33). When the additional 6 decanoate naturalistic decanoate and and months of naturalistic follow‐up were Vs follow‐up who might benefit hospitalization included, the time to all‐cause treatment risperidone from a switch to discontinuation was significantly shorter for long‐acting risperidone ‐Safety those switched to risperidone vs those who injectable microspheres remained on the first generation (LAI) (specifically, those antipsychotic (FGA; p=0.01). with suboptimal response to ‐When switched from a FGA to risperidone, it

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Study & Level Design & Sample Size Patient Assessed Conclusions and Results of Evidence* Comparators & Duration characteristics Outcomes GHS Comments treatment due to resulted in treatment discontinuation more persistent often than did continuation on a FGA (31% psychopathology discontinued vs 10% discontinued). or significant side effects) ‐Significant differences in PANSS total score and PANSS positive sub‐score scales were not seen between treatments.

‐Significant differences in the likelihood of being hospitalized for psychiatric reasons or the time to first hospitalization for psychiatric reasons were not seen.

‐BMI was significantly increased as compared to those who remained on the FGA, with a mean gain of 1.0 MBI at 12 months in those who switched vs ‐0.3 BMI at 12 months in those who stayed.

‐Significant increases in prolactin levels were seen with those who switched vs those who remained on the FGA.

‐Significant differences in the incidence of sexual side effects and new‐onset EPS within 6 months were not seen between treatments.

*Please see Addendum for Level of Evidence ratings and definitions.

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SUMMARY

First generation antipsychotics all have activity in treating the symptoms of psychosis and schizophrenia, thought mediated by dopamine blocking activity. Head‐to‐head comparator studies are limited though all FGAs have demonstrated efficacy in treating schizophrenia. Clinical differences appear related primarily to side effect profile and potency of binding at the edopamin receptor. High potency agents such as haloperidol and fluphenazine may require concomitant treatment with an anticholinergic to prevent dystonic reactions in at risk populations such as young males. Lower potency agents such as chlorpromazine are associated with significant sedation. Mid potency agents such as perphenazine, have been compared to atypical antipsychotics as described above. Indeed, midpotency antipsychotics offer an effective treatment option with less risk of weight gain and metabolic abnormalities than seen with many of the second generation agents.

As treatment of several psychiatric disorders including schizophrenia, schizoaffective disorder, bipolar disorder, irritability and agitation related to autism, and treatment‐resistant major depressive disorder, the atypical antipsychotics are potentially more favorable than the first generation (typical) antipsychotics owing to less potential neurologic toxicity. However, the atypical antipsychotics are not without risk of potentially serious adverse effects. Results of a 2009 meta‐analysis that included most of the atypicals suggests that minimal superiorities in efficacy amongst the agents were seen; thus, when choosing appropriate therapy, potential risks and degree of potential adverse events should be taken into account.

Results of the phase III CATIE trial indicated that the medications included in the trial all improved symptom outcomes associated with schizophrenia. Results of CATIE phase I trial indicated that Zyprexa ® had the longest time to discontinuation, but was associated with more adverse events, specifically weight gain and metabolic syndrome. Even a more recent comparator trial resulted in Zyprexa® being only slightly more efficacious, but adverse events once again were more common. Clozapine has been shown to be superior in patients with treatment resistant schizophrenia who failed to respond to two antipsychotic trials and in the prevention of suicide in individuals with schizophrenia.

However, one of the newer atypicals, paliperidone ER (Invega®), was not included in the CATIE trial. One head‐to‐head study compared paliperidone ER (Invega®) with quetiapine (Seroquel®) in patients with schizophrenia. Paliperidone ER (Invega®) was found to be more effective.108 Another trial compared paliperidone ER (Invega®) with quetiapine in those with bipolar disorder. In this trial, paliperidone ER (Invega®) was found to be non‐inferior to quetiapine (Seroquel®).106

Furthermore, other newer atypicals, including asenapine (Saphris®), iloperidone (Fanapt®), and lurasidone (Latuda®) were also not included in the CATIE trial. One comparator trial comparing asenapine (Saphris®) with olanzapine (Zyprexa®) in patients with schizophrenia or schizoaffective disorder showed that at 6 weeks of treatment, the improvement in PANSS total score were similar; however, after one year of treatment, olanzapine (Zyprexa®) was found to have a statistically significantly greater improvement as compared with asenapine (Saphris®).101 Overall, the newer atypicals, including asenapine (Saphris®), iloperidone (Fanapt®), and lurasidone (Latuda®) have limited data to determine if one is superior to any other within this classs.

Several atypical antipsychotics are employed to augment antidepressants in patients with major depressive disorder not fully responsive to antidepressant monotherapy with ample high quality research establishing Property of IME and may not be reproduced without permission. Antipsychotics‐177 efficacy. Such use represents a significant advance in the treatment of major depressive disorder though careful risk/benefit analysis needs to be employed when deciding to use these medications, owing to their potential adverse reactions compared with other commonly used augmentation strategies. Many antidepressant augmentation strategies have been utilized for long periods eof tim and are not associated with the adverse effects of the atypical antipsychotics.

There are currently five atypicals with FDA approval for use in adolescents; two of these are also approved for use in children with irritability associated with autism. All five of these atypicals have been approved for use in children with schizophrenia, with paliperidone ER (Invega®) the most recently approved. Several are also approved for use in bipolar I acute mania or mixed. Limited data is available to support the use of one atypical over another in this population. Additionally, concern has been raised regarding the use of these agents in very young patients due to the aforementioned potential adverse effects. Cautious risk‐benefit analysis must be undertaken on a continuous basis, not just at the inititiation of treatment. High utilization rates of atypicals have been demonstrated in foster youth with overall utilization patterns of this drug class increasing markedly in children and adolescents. Much of that utilization is driven by treating aggression and irritability. Careful clinical assessment is required to discern the underlying etiology of aggression and irritability as such psychiatric diagnoses as attention deficit disorder and depression may present with such symptoms. Once an accurate diagnosis is arrived at, more specific psychopharmacologic treatment may be inititated towards the treatment of the underlying diagnosis. This can help decrease utilization of antipsychotics when more appropriate and safe treatments are indicated. Use of psychosocial interventions including psychotherapy, is critical in preventing unnecessary and harmful exposure to antipsychotic medication.

There are several atypical injectable formulations included in this review, consisting of three long‐acting injectables (LAI) and three short‐acting injectables (SAI). The LAI are all indicated for treatment of schizophrenia and one has approval for use in bipolar I, while the SAI are all indicated for relief of agitation associated with schizophrenia or bipolar disorder.

Olanzapine (Zyprexa® Relprevv) has a limited place in therapy due to potential adverse reactions and limitations of use. Comparator studies with olanzapine (Zyprexa® Relprevv) were not found. One comparator study found paliperidone LAI (Invega® Sustenna) to be non‐inferior to risperidone LAI (Risperdal®).126 Another study by Li et al also found paliperidone LAI (Invega® Sustenna) to be non‐inferior to risperidone LAI (Risperdal®); however, several limitations exist with this study. The first is that this was an open‐label study. Furthermore, these results were found in the per‐protocol (PP) population, and the same results were not found in the intention‐to‐treat (ITT) population. Less improvement in PANSS total score with increased adverse events were found in the ITT population with paliperidone LAI (Invega Sustenna®), which was not seen with risperidone LAI (Risperdal®).144

Several studies have been recently published that compared the risk of hospitalization due to schizophrenia in those using injectables vs oral medications. One review by Rosenheck et al111 suggested that risperidone LAI (Risperdal®) was not superior to oral antipsychotics, as the rate of hospitalization was not significantly lower in those receiving the LAI vs the oral antipsychotics. Furthermore, the LAI was not superior in regards to improvements in PANSS total score as compared with the oral antipsychotics.

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This study’s results were in direct contrast to a cohort study by Tiihonen et al140, which suggested that there was a significantly lower risk of hospitalization in those taking LAI antipsychotics as compared with oral antipsychotics. This study by Tiihonen et al was an observational cohort study, while the study by Rosenheck et al was a randomized level 1a study which found no significant difference between the oral and the depot antipsychotics hospitalization rate.

Some of these agents are employed for off‐label uses, such as insomnia and anxiety. The evidence base to support such use remains weak with a greater likelihood of harm than benefit compared with other available treatments Off‐label use of this drug class has extended to dementia related psychosis; however, the efficacy of these agents in dementia related psychosis is unclear and the atypical antipsychotics have been associated with an elevated risk of cardiovascular adverse events.

Overall, other than these caveats, there is insufficient evidence to suggest one agent is superior clinically to another within a given indication. The only exception is clozapine, which has data to suggest superiority in patients with treatment resistant schizophrenia unresponsive to two antipsychotics. Furthermore, the American Psychiatric Association guidelines do not single out use of a specific antipsychotic for the treatment of schizophrenia or bipolar disorder.65

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ADDENDUM

Levels of Evidence

Level of Evidence Criteria • Systematic review or meta‐analysis of high quality studies o Patient‐oriented outcomes (mortality, morbidity, symptom improvement, quality of life) • High quality randomized controlled trial o Patient‐oriented outcomes (mortality, morbidity, symptom improvement, 1a quality of life) o Double‐Blinded o Clearly defined appropriate endpoints o Intent‐to‐treat analysis in primary group, appropriate use of per protocol population if utilized o Appropriate handling of drop‐outs (e.g. LOCF, MMRM) • Systematic review or meta‐analysis of high quality studies o Disease‐oriented outcomes (physiologic or surrogate end points) • High quality randomized controlled trial o Disease‐oriented outcomes (physiologic or surrogate end points) 1b o Double‐Blinded o Clearly defined appropriate endpoints o Intent‐to‐Treat analysis in primary group, appropriate use of per protocol population if utilized o Appropriate handling of drop‐outs (e.g. LOCF, MMRM) • Low quality randomized controlled trial o Clearly defined primary outcome o Open‐label (non‐blinded) 2 o Appropriate handling of drop‐outs (e.g. LOCF, MMRM) • Non‐randomized controlled trial • Cohort study

3 • Case control study/Case series/expert opinion

Definitions

Intent‐to‐Treat: Inclusion of all subjects who received at least one dose of study medication or placebo

Last Observation Carried Forward (LOCF): Method of handling drop‐outs wherein the last measurement is utilized as the final outcome data point at study conclusion.

Mixed Model Repeated Measures (MMRM): A statistical model to handle drop outs. Uses repeated measures to define data point outcome trends.

Observed Cases: Method of handling drop‐outs, which only includes study completers.

Per‐Protocol population: A sub‐group of intention to treat population often used to enrich for compliance.

Number Needed to Treat (NNT): The number of subjects required to bring about one response on the primary outcome.

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REFERENCES

1 Abilify [package insert]. Princeton, NJ: Bristol‐Myers Squibb Company; 2011.

2 Clozapine [package insert]. East Hanover, NJ: Novartis; 2005.

3 Fazaclo [package insert]. Aliso Viejo, CA: Novartis Pharmaceuticals Corp; 2007.

4 Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010.

5 Invega [package insert]. Titusville, NJ: Janssen; 2011.

6 Risperdal [package insert]. Titusville, NJ: Janssen; 2010.

7 Seroquel [package insert]. Wilmington, DE: AstraZeneca; 2011.

8 Seroquel XR [package insert]. Wilmington, DE: AstraZeneca; 2011.

9 Geodon [package insert]. New York, NY: Roerig, a division of Pfizer; 2010.

10 Haddad PM, Sonu GS. Adverse Effects of Atypical Antipsychotics: Differential Risk and Clinical Implications. CNS Drugs. 2007; 21 (11):911‐936.

11. Casey DE.Implications of the CATIE trial on treatment: extrapyramidal symptoms.CNS Spectr ;11(7 Suppl 7):25‐31, 2006.

12. Carpenter WT, Buchanan RW. Lessons to take home from CATIE. Psychiatr Serv. 59(5):523‐5, 2008

13. Swartz MS, Stroup TS, McEvoy JP et al:What CATIE found: results from the schizophrenia trial. Psychiatr Serv. 2008 May;59(5):500‐6

14. Tandon R, Belmaker RH, Gattaz WF et al:World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res. 2008 Mar;100(1‐3):20‐38.

15. Pfeifer JC, Kowatch RA, DelBello MP.The use of antipsychotics in children and adolescents with bipolar disorders.Expert Opin Pharmacother. 2007 Nov;8(16):2673‐87

16. Hennen J, Baldessarini RJ.Suicidal risk during treatment with clozapine: a meta‐analysis. Schizophr Res. 2005 Mar 1;73(2‐3):139‐45.

17. Meltzer HY, Alphs L, Green AI, et al:Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003 Jan;60(1):82‐91. Erratum in: Arch Gen Psychiatry.2003 Jul;60(7):735.

18. Fischer‐Barnicol D, Lanquillon S, Haen E, et al:Typical and atypical antipsychotics‐‐the misleading dichotomy. Results from the Working Group 'Drugs in Psychiatry' (AGATE).Neuropsychobiology. 2008;57(1‐2):80‐7. Epub 2008 Jun 2

19. Sikich L.Efficacy of atypical antipsychotics in early‐onset schizophrenia and other psychotic disorders. J Clin Psychiatry. 2008;69 Suppl 4:21‐5

20. Posey DJ, Stigler KA, Erickson CA, et al. Antipsychotics in the treatment of autism. J Clin Invest. 2008 Jan;118(1):6‐14

21. Perlis RH.Treatment of bipolar disorder: the evolving role of atypical antipsychotics. Am J Manag Care. 2007 Nov;13(7 Suppl):S178‐88. Review. Erratum in: Am J Manag Care. 2008 Feb;14(2):76.

Property of IME and may not be reproduced without permission. Antipsychotics‐181

22. Derry S, Moore RA. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. BMC Psychiatry. 2007 Aug 16;7:40

23. Hassan M, Madhavan SS, Kalsekar ID, et al.Comparing adherence to and persistence with antipsychotic therapy among patients with bipolar disorder. Ann Pharmacother. 2007 Nov;41(11):1812‐8

24. Mir A, Shivakumar K, Williamson RJ, et al.Change in sexual dysfunction with aripiprazole: a switching or add‐on study. J Psychopharmacol. 2008 May;22(3):244‐53

25. Motlová L, Spaniel F, Höschl C, Balon R.Are there any differences in the efficacy among second generation antipsychotics in the treatment of schizophrenia and related disorders? Ann Clin Psychiatry. 2007 Apr‐Jun;19(2):133‐43. PMID: 17612853

26. Rochon PA, Stukel TA, Sykora K, et al:Atypical antipsychotics and parkinsonism. Arch Intern Med. 2005 Sep 12;165(16):1882‐8

27. Urichuk L, Prior TI, Dursun S, Baker G.Metabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug‐drug interactions. Curr Drug Metab. 2008 Jun;9(5):410‐8

28. Weiden PJ.EPS profiles: the atypical antipsychotics are not all the same. J Psychiatr Pract. 2007 Jan;13(1):13‐24

29. NIMH‐National Institute of Mental Health. Bipolar Disorder Publication. 2008. Web site: http://www.nimh.nih.gov/health/publications/bipolar‐disorder/summary.shtml Accessed September 2, 2008.

30. NIMH‐National Institute of Mental Health. Schizophrenia Publication. 2008. Web site: http://www.nimh.nih.gov/health/publications/schizophrenia/summary.shtml. Accessed September 2, 2008.

31. National Institute of Mental Health. Atypical Antipsychotics. Web site: http://www.nimh.nih.gov/health/publications/mental‐health‐medications/complete‐index.shtml. Accessed July 1, 2009.

32. Symbyax [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010.

33 Fanapt [package insert]. Rockville, MD: Vanda Pharmaceuticals, Inc; 2011.

34 Clinisphere [computer program]. Version 4.2. St. Louis, MO: Facts and Comparisons; June 2009 and August 2012.

35 Medscape Medical News. FDA Expert Panel approves use of atypical antipsychotic Drugs in Kids. Website: http://www.medscape.com/viewarticle/704271. Accessed June 26, 2009.

36 Leucht S, Komossa K, Rummel‐Kluge C, et al. A meta‐analysis of head‐to‐head comparisons of second‐generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009; 166(2): 152‐63.

37 Fleischhacker WW, McQuade RD, Marcus RN, et al. A double‐blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiatry. 2009; 65(6): 510‐7.

38 Bastiaens L. A non‐randomized, open study with aripiprazole and ziprasidone for the treatment of aggressive behavior in youth in a community clinic. Communitty Ment Health J. 2009; 45(1): 73‐7.

39 Kinon BJ, Stauffer VL, Kollack‐Walker S, et al. Olanzapine versus aripiprazole for the treatment of agitation in acutely ill patients with schizophrenia. J Clin Psychopharmacol. 2008; 28(6): 601‐07.

40 Karagianis J, Grossman L, Landry J, et al. A randomized controlled trial of the effect of sublingual orally disintegrating olanzapine versus oral olanzapine on body mass index: The PLATYPUS Study. Schizophr Res. 2009. [Epub ahead of Print]

Property of IME and may not be reproduced without permission. Antipsychotics‐182

41 Stroup TS, Leberman JA, McEvoy JP, et al. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res. 2009; 107(1): 1‐12.

42 Kolotkin RL, Corey‐Lisle PK, Crosby RD, et al. Changes in weight and weight‐related quality of life in a multicentre, randomized trial of aripiprazole versus standard of care. Eur Psychiatry. 2008; 23(8): 561‐6.

43 Newcomer JW, Campos JA, Marcus RN, et al. A multicenter, randomized, double‐blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry. 2008; 69(7): 1046‐56.

44 Harvey PD, Sacchetti E, Galluzzo A, et al. A randomized double‐blind comparison of ziprasidone vs clozapine for cognition in patients with schizophrenia selected for resistance or intolerance to previous treatment. Schizophr Res. 2008; 105(1‐3): 138‐43.

45 Meltzer HY, Bobo WV, Roy A, et al. A randomized, double‐blind comparison of clozapine and high‐dose olanzapine in treatment‐resistant patients with schizophrenia. J Clin Psychiatry. 2008; 69(2): 274‐85.

46 Kryzhanovskaya L, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6‐ week, randomized, double‐blind, placebo‐controlled trial. J Am Acad Child Adolesc Psychiatry. 2009; 48(1): 60‐70.

47 Schulz SC, Zanarini MC, Bateman A, et al. Olanzapine for the treatment of borderline personality disorder: variable dose 12‐week randomized double‐blind placebo‐controlled study. Br. J Psychiatry. 2008; 196(6): 485‐92.

48 Ruths S, Straand J, Nygaard HA, et al. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo‐controlled study‐the Bergen District Nursing Home Study (BEDNURS). Int J Geriatr Psychiatry. 2008; 23(9): 889‐95.

49 Kumra S, Kranzler H, Gerbino‐Rosen G, et al. Clozapine and “high‐dose” olanzapine in refractory early‐onset schizophrenia: a 12‐week randomized and double‐blind comparison. Biol Psychiatry. 2008; 62(5): 524‐9.

50 Kelly DL, Conley RR, Love RC, et al. Metabolic risk with second‐generation antipsychotic treatment: a double‐blind randomized 8 week trial of risperidone and olanzapine. Ann Clin Psychiatry. 2008; 20(2): 71‐8.

51 Faries DE, Ascher‐Svanum H, Nyhuis AW, et al. Switching from risperidone to olanzapine in a one‐year, randomized, open‐label effectiveness study of schizophrenia. Curr Med Res Opin. 2008; 24(5): 1399‐405.

52 Hatta K, Kawabata T, Yoshida K, et al. Olanzapine orally disintegrating tablet vs. risperidone oral solution in the treatment of actuely agitated psychotic patients. Gen Hosp Psychiatry. 2008; 30(4): 367‐71.

53 Canuso CM, Youssef EA, Bossie CA, et al. Paliperidone extended‐release tablets in schizophrenia patients previously treated with risperidone. Int Clin Psychopharmacol. 2008; 23(4): 209‐15.

54 Connor DF, McLaughlin TJ, Jeffers‐Terry M. Randomized controlled pilot study of quetiapine in the treatment of adolescent conduct disorder. J Child Adolesc Psychopharmacol. 2008; 18(2): 140‐56.

55 Addington DE, Labelle A, Kulkarni J, et al. A comparison of ziprasidone and risperidone in the long‐term treatment of schizophrenia: a 44‐week, double‐blind, continuation study. Can J Psychiatry. 2009; 54(1): 46‐54.

56 DelBello MP, Versavel M, Ice K, et al. Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. J Child Adolesc Psychopharmacol. 2008; 18 (5): 491‐9.

57 Cutler AJ, Kalali AH, Weiden PJ, et al. Four‐week double‐blind, placebo‐ and ziprasidone‐controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008; 28 (2 Suppl 1): S20‐8.

58 Dunner DL, Amsterdam JD, Shelton RC, et al. Efficacy and tolerability of adjunctive ziprasidone in treatment‐ resistance depression: a randomized, open‐label, pilot study. J Clin Psychiatry. 2007; 68(7): 1071‐7.

Property of IME and may not be reproduced without permission. Antipsychotics‐183

59 Aman MG, Hollway JA, McDougle CJ, et al. Cognitive effects of risperidone in children with autism and irritable behavior. J Child Adolesc Psychopharmacol. 2008; 18(3): 227‐36.

60 van Nimwegen L, deHaan L, van Beveren L, et al. Obsessive‐compulsive symptoms in a randomized, double‐blind study with olanzapine or risperidone in young patients with early psychosis. J Clin Psychopharmacol. 2008; 28(2): 214‐8.

61 Ganguli R, Brar JS, Mahmoud R, et al. Assessment of strategies for switching patients from olanzapine to risperidone: a randomized, open‐label, rater‐blinded study. BMC Med. 2008; 6:17.

62 Sikich L, Frazier JA, McClellan J, et al. Double‐blind comparison of first‐ and second‐generation antipsychotics in early‐ onset schizophrenia and schizo‐affective disorder: findings from the treatment of early‐onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry. 2008; 165(11): 1420‐31.

63 Hanssens L, L’Italien G, Loze JY, et al. The effect of antipsychotic medication on sexual function and serum prolactin levels in community‐treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study. BMC Psychiatry. 2008; 8:95.

64 Ganesan S, Agambaram V, Randeree F, et al. Switching from other antipsychotics to once‐daily extended release quetiapine fumarate in patients with schizophrenia. Curr Med Res Opin. 2008; 24(1): 21‐32.

65 American Psychiatric Association Practice Guidelines: Schizophrenia and Bipolar Disorder. Website: http://www.psychiatryonline.com/pracGuide/pracGuideHome.aspx. Accessed July 7, 2009.

66 Ray WA et al. Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death NEJM. 2009; 360: 225‐235.

67 Saphris [package insert]. Kenilworth, NJ: Schering‐Plough Corporation; 2011.

68 McIntyre RS, Cohen M, Zhao J, et al. A 3‐week, randomized, placebo‐controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009; 11(7): 673‐86.

69 McIntyre RS, Cohen M, Zhao J, et al. Asenapine versus olanzapine in acute mania: a double‐blind extension study. Bipolar Disord. 2009; 11: 815‐26.

70 Grootens KP, van Veelen NM, Peuskens J, et al. Ziprasidone vs olanzapine in recent‐onset schizophrenia and schizoaffective disorder: results of an 8‐week double‐blind randomized controlled trial. Schizophr Bull. 2009. DOI: 10.1093/schbul/sbp037.

71 Boter H, Peuskens J, Libiger J, et al. Effectiveness of antipsychotics in first‐episode schizophrenia and schizophreniform disorder on response and remission: An open randomized clinical trial (EUFEST). Schizophr Res. 2009; 115:97‐103.

72 Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double‐blind, placebo‐controlled, 16‐week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009; 70(10): 1348‐57.

73 Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010; 121(1‐2): 106‐15.

74 El‐Khalili N, Joyce M, Atkinson S, et al. Extended‐release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicenter, randomized, double‐blind, placebo‐controlled study. Int J Neuropsychopharmacol. 2010. [Epub ahead of print.] doi:10.1017/S1461145710000015.

75 Narula PK, Rehan HS, Unni KES, et al. Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia; A double‐blind, placebo‐controlled trial. Schizophrenia Research. 2010. doi: 10.1016/j. schres.2010.02.001.

Property of IME and may not be reproduced without permission. Antipsychotics‐184

76 Cutler AJ, Kalali AH, Weiden PJ, et al. Four‐week, double‐blind, placebo‐ and ziprasidone‐controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008; 28(2 Supp 1): S20‐8.

77 Kane JM, Lauriello J, Laska E, et al. Long‐term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol. 2008:28 (2 Suppl 1): S29‐35.

78 Sacchetti E, Galluzzo A, Valsecchi P, et al. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res. 2009; 113(1):112‐21.

79 Alptekin K, Hafez J, Brook S, et al. Efficacy and tolerability of switching to ziprasidone from olanzapine, risperidone, or haloperidol: an international, multicenter study. Int Clin Psychopharmacol. 2009;24(5): 229‐38.

80 Komossa K, Rummel‐Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2009, Issue 4. Art. No.: CD006627. DOI: 10.1002/14651858.CD006627.pub2.

81 Komossa K, Rummel‐Kluge C, Schmid F, et al. Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2009, Issue 4. Art. No.: CD006569. DOI: 10.1002/14651858.CD006569.pub3.

82 Komossa K, Rummel‐Kluge C, Schmid F, et al. Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.:CD006625. DOI: 10.1002/14651858.CD006625.pub2.

83 Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006324. DOI: 10.1002/14651858.CD006324.pub2.

84 Komossa K, Rummel‐Kluge C, Hunger H, et al. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.:CD006654.DOI:10.1002/14651585.CD006654.pub2.

85 Lyon GJ, Samar S, Jummani R, et al. Aripiprazole in children and adolescents with Tourette’s disorder: an open‐label safety and tolerability study. J Child Adolesc Psychopharmacol. 2009; 19(6): 623‐33.

86 Wang CY, Xiang YT, Cai ZJ, et al. Risperidone maintenance treatment in schizophrenia: a randomized, controlled trial. Am J Psychiatry. 2010. [Epub ahead of print].

87 Berman RM, Rava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double‐blind, placebo‐controlled study in patients with inadequate response to antidepressants. CNS Spectr. 2009; 14(4): 197‐206.

88 Moreno C, Merchan‐Naranjo J, Alvarez M, et al. Metabolic effects of second‐generation antipsychotics in bipolar youth; comparison with other psychotic and nonpsychotic diagnoses. Bipolar Disord. 2010; 12(2): 172‐84.

89 Trivedi MH, Thase ME, Osuntokun O, et al. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment‐resistant depression. J Clin Psychiatry. 2009; 70(3): 387‐96.

90 Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009; 124(6): 1533‐40.

91 Johnsen E, Kroken RA, Wentzel‐Larsen T, et al. Effectiveness of second‐generation antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone. BMC Psychiatry. 2010; 10:26.

92 Peuskens J, Trivedi JK, Brecher M, et al. Long‐term symptomatic remission of schizophrenia with once‐daily extended release quetiapine fumarate: post‐hoc analysis of data from randomized withdrawal, placebo‐controlled study. Int Clin Psychopharmacol. 2010. [Epub ahead of print].

93 Cipriani A, Rendell J, Geddes JR. Olanzapine in the long‐term treatment of bipolar disorder: A systematic review and meta‐analysis. J Psychopharmacol. 2009. [Epub ahead of print].

94 Fleurence R, Williamson R, Jing Y, et al. A systematic review of augmentation strategies for patients with major depressive disorder. Psychopharmacol Bull. 2009; 42(3): 57‐90.

Property of IME and may not be reproduced without permission. Antipsychotics‐185

95 Zyprexa Relprevv [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010.

96 Invega Sustenna [package insert]. Titusville, NJ: Janssen, Division of Ortho‐McNeil‐Janssen Pharmaceuticals, Inc; 2010.

97 Risperdal Consta [package insert]. Titusville, NJ: Janssen, Division of Ortho‐McNeil‐Janssen Pharmaceuticals, Inc; 2010.

98 Zyprexa IntraMuscular [package insert]. Indianapolis, IN: Lilly USA, LLC; 2010.

99 Latuda [package insert]. Marlborough, MA: Sunovion Pharmaceuticals, Inc; 2010.

100 Young AH, McElroy SL, Bauer M, et al. A double‐blind, placebo‐controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN 1). J Clin Psychiatry. 2010; 71(2): 150‐62.

101 Schoemaker J, Naber D, Vrijland P, et al. Long‐term assessment of asenapine vs olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry. 2010; 43(4): 138‐46.

102 McElroy SL, Weisler RH, Chang W, et al. A double‐blind, placebo‐controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010; 71(2): 163‐74.

103 Kane JM, Cohen M, Zhao J, et al. Efficacy and safety of asenapine in a placebo‐ and haloperidol‐controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010; 30(2): 106‐15.

104 Fleischhacker WW, Heikkinen ME, Olie JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double‐blind, placebo‐controlled trial. Int J Neuropsychopharmacol. 2010; 13(8): 1115‐25.

105 Liebowitz M, Lam RW, Lepola U, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo‐controlled trial. Depress Anxiety. 2010; 27(10): 964‐76.

106 Vieta E, Nuamah IF, Lim P, et al. A randomized, placebo‐ and active‐controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010; 12(3): 230‐43.

107 Pavuluri MN, Henry DB, Findling RL, et al. Double‐blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder. Bipolar Disord. 2010; 12(6): 593‐605.

108 Canuso CM, Dirks B, Carothers J, et al. Randomized, double‐blind, placebo‐controlled study of paliperidone extended‐release and quetiapine in inpatients with recently exacerbated schizophrenia. Am J Psychiatry. 2009; 166(6): 691‐701.

109 Berwaerts J, Xu H, Nuamah I, et al. Evaluation of the efficacy and safety of paliperidone extended‐release in the treatment of acute mania: A randomized, double‐blind, dose‐response study. J Affect Disord. 2010. [Epub ahead of print].

110 Addington DE, Mohamad S, Rosenheck RA, et al. Impact of second‐generation antipsychotics and perphenazine on depressive symptoms in a randomized trial of treatment for chronic schizophrenia. J Clin Psychiatry. 2011; 72(1): 75‐80.

111 Rosenheck RA, Krystal JH, Lew R, et al. Long‐acting risperidone and oral antipsychotics in unstable schizophrenia. NEJM. 2011; 364: 842‐51.

112 Berwaerts J, Cleton A, Rossenu S, et al. A comparison of serum prolactin concentrations after administration of paliperidone extended‐release and risperidone tablets in patients with schizophrenia. J Psychopharmacol. 2010; 24(7): 1011‐18.

113 Weiner E, Conley RR, Ball MP, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology. 2010; 35(11): 2274‐83.

Property of IME and may not be reproduced without permission. Antipsychotics‐186

114 Findling RL, Johnson JL, McClellan J, et al. Double‐blind maintenance safety and effectiveness findings from the treatment of early‐onset schizophrenia spectrum (TEOSS) study. J Am Acad Child Adolesc Psychiatry. 2010; 49(6): 583‐ 94.

115 McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long‐term treatment of bipolar disorder: A double‐blind 40‐week extension study. J Affect Disord. 2010; 126(3): 358‐65.

116 Kramer M, Simpson G, Maciulis V, et al. One‐year open‐label safety and efficacy study of paliperidone extended‐ release tablets in patients with schizophrenia. CNS Spectr. 2010; 15(8): 506‐14.

117 Nakamura M, Ogasa M, Guarino J, et al. Lurasidone in the treatment of acute schizophrenia: a double‐blind, placebo‐controlled trial. J Clin Psychiatry. 2009; 70(6): 829‐36.

118 Selvi Y, Atli A, Aydin A, et al. The comparison of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor‐refractory obsessive‐compulsive disorder: a single‐blind, randomized study. Hum Psychopharmacol. 2011. [Epub ahead of print.]

119 Strom BL, Eng SM, Faich G, et al. Comparative mortality associated with ziprasidone and olanzapine in real‐world use among 18,154 patients with schizophrenia: the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). Am J Psychiatry. 2011; 168 (2): 193‐201.

120 Crespo‐Facorro B, Perez‐Iglesias RO, Mata I, et al. Effectiveness of haloperidol, risperidone, and olanzapine in the treatment of first‐episode non‐affective psychosis: results of a randomized, flexible‐dose, open‐label 1‐year follow‐up comparison. J Psychopharmacol. 2011. [Epub ahead of print].

121 Lindenmayer JP, Citrome L, Khan A, et al. A randomized, double‐blind, parallel‐group, fixed‐dose, clinical trial of quetiapine at 600mg vs 1200mg/day for patients with treatment‐resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 2011; 31(2): 160‐8.

122 Gafoor R, Landau S, Craig TK, et al. Esquire trial: efficacy and adverse effects of quetiapine versus risperidone in first‐ episode schizophrenia. J Clin Psychopharmacol. 2010; 30(5): 600‐6.

123 Kane JM, Mackle M, Snow‐Adami L, et al. A randomized, placebo‐controlled trial of asenapine for the prevention of relapse of schizophrenia after long‐term treatment. J Clin Psychiatry. 2011; 72(3): 349‐55.

124 Canuso CM, Schooler N, Carothers J, et al. Paliperidone extended‐release in schizoaffective disorder: a randomized, controlled study comparing a flexible dose with placebo in patients treated with and without antidepressants and/or mood stabilizers. J Clin Psychopharmacol. 2010; 30(5): 487‐95.

125 Hsu WY, Huang SS, Lee BS, et al. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol. 2010; 30(3): 230‐4.

126 Pandina G, Lane R, Gopal S, et al. A double‐blind study of paliperidone palmitate and risperidone long‐acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(1): 218‐26.

127 Crespo‐Facorro B, Perez‐Iglesias R, Mata I, et al. Relapse prevention and remission attainment in first‐episode non‐ affective psychosis. A randomized, controlled 1‐year follow‐up comparison of haloperidol, risperidone, and olanzapine. J Psychiatr Res. 2010. [Epub ahead of print].

128 Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med. 2010; 122(4): 39‐48.

129 Vieta E, Locklear J, Gunther O, et al. Treatment options for bipolar disorder: a systematic review of randomized, controlled trials. J Clin Psychopharmacol. 2010; 30(5): 579‐90.

130 Barak Y, Aizenberg D. Switching to aripiprazole as a strategy for weight reduction: a meta‐analysis in patients suffering from schizophrenia. J Obes. 2011. Pii: 898013.

Property of IME and may not be reproduced without permission. Antipsychotics‐187

131 Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven second‐generation antipsychotics in the treatment of schizophrenia: a meta‐analysis. J Psychopharmacol. 2010. [Epub ahead of print].

132 Samuel M, Zimovetz EA, Gabriel Z, et al. Efficacy and safety of treatments for refractory generalized anxiety disorder: a systematic review. Int Clin Psychopharmacol. 2011; 26(2): 63‐8.

133 Depping AM, Komossa K, Kissling W, et al. Second‐generation antipsychotics for anxiety disorders. Cochrane Database of Systematic Reviews. 2010, Issue 12. Art. No.: CD008120. DOI: 10.1002/14651858.CD008120.pub2.

134 Komossa K, Depping AM, Gaudchau A, et al. Second‐generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database of Systematic Reviews. 2010, Issue 12. Art. No.: CD008121. DOI:10.1002/14651585.CD008121.pub2.

135 Komossa K, Depping AM, Meyer M, et al. Second‐generation antipsychotics for obsessive compulsive disorder. Cochrane Database of Systematic Reviews. 2010, Issue 12. Art. No.: CD008141.DOI: 10.1002/14651858.CD008141.pub2.

136 Asenjo Lobos C, Komossa K, Rummel‐Kluge C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews. 2010, issue 11. Art. No.: CD006633. DOI: 10.1002/14651858.CD006633.pub2.

137 Apiquian R, Cordoba R, Louza M. Clinical outcomes of long‐acting injectable risperidone in patients with schizophrenia: six‐month follow‐up from the Electronic Schizophrenia Treatment Adherence Registry in Latin America. Neuropsychiatr Dis Treat. 2010; 7:19‐26.

138 Hermes E, Nasrallah H, Davis V, et al. The association between weight change and symptom reduction in the CATIE schizophrenia trial. Schizophr Res. 2011. [Epub ahead of print].

139 De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and endocrine adverse effects of second‐generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry. 2011. [Epub ahead of print].

140 Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011. [Epub ahead of print].

141 Gopal S, Berwaerts J, Nuamah I, et al. Number needed to treat and number needed to harm with paliperidone palmitate relative to long‐acting haloperidol, bromperidol, and fluphenazine decanoate for treatment of patients with schizophrenia. Neuropsychiatr Dis Treat. 2011; 7: 93‐101.

142 Leung JG, Benedetti AM, Frazee LA, et al. Comparison of short‐acting intramuscular antipsychotic medication: impact on length of stay and cost. Am J Ther. 2010. [Epub ahead of print].

143 Lambert T, Olivares JM, Peuskens J, et al. Effectiveness of injectable risperidone long‐acting therapy for schizophrenia: data from the US, Spain, Australia, and Belgium. Ann Gen Psychiatry. 2011; 10:10.

144 Li H, Rui Q, Ning X, et al. A comparative study of paliperidone palmitate and risperidone long‐acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011. [Epub ahead of print].

145 Li YM, Zhao JP, Ou JJ, et al. Efficacy and tolerability of ziprasidone vs olanzapine in naïve first‐episode schizophrenia: a 6‐week, randomized, open‐label, flexible‐dose study. 2012. [Epub ahead of print].

146 Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment‐ resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011; 31(3): 266‐ 73.

Property of IME and may not be reproduced without permission. Antipsychotics‐188

147 Carlson BX, Ketter TA, Sun W, et al. Aripiprazole in combination with lamotrigine for the long‐term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double‐blind study (CN138‐392). Bipolar Disord. 2012; 14(1): 41‐53.

148 Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double‐blind, placebo‐ and olanzapine‐controlled study. Am J Psychiatry. 2011; 168(9): 957‐67.

149 Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressant‐resistance symptoms of chronic military service‐related PTSD: a randomized trial. JAMA. 2011; 306(5): 493‐502.

150 Khan A, Joyce M, Atkinson S, et al. A randomized, double‐blind study of once‐daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder. J Clin Psyhcopharmacol. 2011; 31(4): 418‐28.

151 Berwaerts J, Melkote R, Nuamah I, et al. A randomized, placebo‐ and active‐controlled study of paliperidone extended‐release as maintenance in patients with bipolar I disorder after an acute manic or mixed episode. J Affect Disord. 2012; 138(3): 247‐58.

152 Jindal KC, Singh GP, Munjal V. Aripiprazole versus olanzapine in the treatment of schizophrenia: A clinical study from India. Int J Psychiatry Clin Pract. 2012. [Epub ahead of print].

153 Findling RL, Youngstrom EA, McNamara NK, et al. Double‐blind, randomized, placebo‐controlled long‐term maintenance study of aripiprazole in children with bipolar disorder. J Clin Psychiatry. 2012; 76(1): 57‐63.

154 Honer WG, MacEwan GW, Gendrom A, et al. A randomized, double‐blind, placebo‐controlled study of the safety and tolerability of high‐dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012; 73(1): 13‐20.

155 Buchanan RW, Panagides J, Zhao J, et al. Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. J Clin Psychopharmacol. 2012; 32(1): 36‐45.

156 Citrome L, Cucchiaro J, Sarma K, et al. Long‐term safety and tolerability of lurasidone in schizophrenia: a 12‐month, double‐blind, active‐controlled study. Int Clin Psychopharmacol. 2012. 27(3): 165‐76.

157 Fava M, Mischoulon D, Iosifescu D, et al. A double‐blind, placebo‐controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT‐A Study). Psychother Psychosom. 2012; 81(2); 87‐97.

158 Crespo‐Facorro B, Perez‐Iglesias R, Mata I, et al. Long‐term effectiveness of haloperidol, risperidone, and olanzapine: results of a randomized, flexible‐dose, open‐label comparison in first‐episode nonaffective psychosis. Psychopharmacology (Berl). 2012; 219 (1): 225‐33.

159 Sz egedi A, Calabrese JR, Stet L, et al. Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12‐week core study and 40‐week extension. J Clin Psychopharmacol. 2012; 32(1): 46‐55.

160 Zhang H, Li H, Shu L, et al. Double‐blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia. Neuropsychiatr Dis Treat. 2011; 7: 77‐85.

161 Fleischhacker WW, Gopal s, Lane R, et al. A randomized trial of paliperidone palmitate and risperidone long‐acting injectable in schizophrenia. Int J Neuropsychopharmacol. [Epub ahead of print].

Property of IME and may not be reproduced without permission. Antipsychotics‐189

162 Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple‐treatments meta‐analysis. Lancet. 2011; 378(9799): 1306‐15.

163 Taylor DM, Smith L, Gee SH, et al. Augmentation of clozapine with a second antipsychotic‐ a meta‐analysis. Acta Psychiatr Scand. 2012; 125(1): 15‐24.

164 Seida JC, Schouten JR, Boylan K, et al. Antipsychotics for children and young adults: a comparative effectiveness review. Pediatrics. 2012; 129(3): e771‐84.

165 Pringhseim T, Lam D, Ching H, et al. Metabolic and neurologic complications of second‐generation antipsychotic use in children: a systematic review and meta‐analysis of randomized controlled trials. Drug Saf. 2011; 34(8): 651‐68.

166 Singham AP, Mamarde A, Behere PB. A single blind comparative clinical study of the effects of chlorpromazine and risperidone on positive and negative symptoms in patients of schizophrenia. Indian J Psychol Med. 2011; 33(2): 134‐40.

167 Geller B, Luby JL, Joshi P, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry. 2012; 69(5): 515‐28.

168 Gaebel W, Schreiner A, Bergmans P, et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long‐acting injectable vs quetiapine: results of a long‐term, open‐label randomized clinical trial. Neuropsychopharmacology. 2010; 35(12): 2367‐77.

169 Azekawa T, Ohashi S, Itami A. Comparative study of treatment continuation using second‐generation antipsychotics in patients with schizophrenia or schizoaffective disorder. Neuropsychiatr Dis Treat. 2011; 7: 691‐5.

170 Potkin SG, Ogasa M, Cucchiaro J, et al. Double‐blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. Schizophr Res. 2011; 132(203): 101‐7.

171 Chen JJ, Chan HY, Chen CH, et al. Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics. Pharmacopsychiatry. 2012; 45(2): 64‐71.

172 Katila H, Mezhebovsky I, Mulroy A, et al. Randomized, double‐blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder. Am J Geriatr Psychiatry. 2012. Epub ahead of print.

173 Schreiner A, Niehaus D, Shuriquie NA, et al. Metabolic effects of paliperidone extended release versus oral olanzapine in patients with schizophrenia: a prospective, randomized, controlled trial. J Clin Psychopharmacol. 2012; 32(4): 449‐457.

174 Aggarwal NK, Sernyak MJ, Rosenheck RA. Prevalence of concomitant oral antipsychotic drug use among patients treated with long‐acting, intramuscular, antipsychotic medications. J Clin Psychopharmacol. 2012; 32(3):323‐8.

175 Killian R, Steinert T, Schepp W, et al. Effectiveness of antipsychotic maintenance therapy with quetiapine in comparison with risperidone and olanzapine in routine schizophrenia treatment: results of a prospective observational trial. Eur Arch Psychiatry Clin Neurosci. 2012. [Epub ahead of print].

176 Vieta E, Montgomery S, Sulaman AH, et al. A randomized, double‐blind, placebo‐controlled trial to assess prevention of mood episodes with risperidone long‐acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol. 2012. Epub ahead of print.

177 Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52‐week, multicenter, randomized, double‐blind, placebo‐controlled study. J Clin Psychiatry. 2012; 73(5): 617‐24.

Property of IME and may not be reproduced without permission. Antipsychotics‐190

178 Covell NH, McEvoy JP, Schooler NR, et al. Effectiveness of switching from long‐acting injectable fluphenazine or haloperidol decanoate to long‐acting injectable risperidone microspheres: an open‐label randomized controlled trial. J Clin Psychiatry. 2012; 73(5): 669‐675.

179 Nussbaum AM, Stroup TS. Paliperidone palmitate for schizophrenia. Cochrane Database Systematic Rev. 2012; 6: CD008296.

180 Soares‐Weiser K, Bechard‐Evans L, Howard Lawson A, et al. Time to all‐cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: a systematic review and meta‐analysis. Eur Neuropsychopharmacol. 2012. [Epub ahead of print].

181 Kales HC, Kim HM, Zivin K, et al. Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry. 2012; 169(1): 71‐9.

182 Bhalerao S, Seyfried LS, Kim HM, et al. Mortality risk with the use of atypical antipsychotics in later‐life bipolar disorder. J Geriatr Psychiatry Neurol. 2012; 25(1): 29‐36.

183 Perphenazine [package insert]. Princeton, NJ: Sandoz Inc; 2010.

184 Fluphenazine [package insert]. Princeton, NJ: Sandoz Inc; 2011.

185 Chlorpromazine [package insert]. Princeton, NJ: Sandoz Inc; 2011.

186 Haloperidol [package insert]. Morgantown, WV: Mylan Pharmaceuticals, Inc; 2011.

187 Haldol injection [package insert]. Titusville, NJ: Ortho‐McNeil Neurologics, Division of Ortho‐McNeil‐Janssen; 2011.

188 Haldol decanoate [package insert]. Titusville, NJ: Ortho‐McNeil Neurologics, Division of Ortho‐McNeil‐Janssen; 2011.

189 Loxitane [package insert]. Corona, CA: Watson Pharma, Inc; 2010.

190 Orap [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; 2011.

191 Thioridazine [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc; 2010.

192 Navane [package insert]. New York, NY: Pfizer; 2010.

193 Trifluoperazine [package insert]. Princeton, NJ: Sandoz Inc; 2011.

194 Perphenazine/Amitriptyline [package insert]. Morgantown WV, Mylan Pharmaceuticals Inc; 2010.

195 Thomson Reuters: Micromedex 2.0. Website: http://www.thomsonhc.com/micromedex2/librarian/. Accessed July 2012.

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