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Home , Brexpiprazole, Cariprazine

UTAH MEDICAID DUR REPORT DECEMBER 2020

NEWER ORAL

Brexpiprazole (Rexulti) (Vraylar) (Caplyta)

Report finalized: November 2020 Report presented: December 2020

Drug Regimen Review Center

Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanne LaFleur, Pharm.D., MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2020 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved Contents

Background on Medications ...... 3 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications ...... 6 Methods ...... 13 Guideline Recommendations for , and Autism Spectrum Disorder ...... 14 A. Schizophrenia ...... 14 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults ...... 18 B. Bipolar Disorder ...... 25 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder ...... 30 C. Autism Spectrum Disorder ...... 39 Table 4. Select Recent Autism Spectrum Disorder Related Treatment Guidelines ...... 40 Metabolic Side Effects (MSE) of Antipsychotics ...... 43 Table 5. Antipsychotic Approximate Relative Side Effects with Oral Formulations ...... 46 Recommendations related to MSE among selected schizophrenia and bipolar disorder guidelines ... 47 Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines ...... 49 Efficacy and Safety of Newer Antipsychotics (, cariprazine, lumateperone) ...... 54 Efficacy for schizophrenia and/or bipolar disorder ...... 54 Expert opinion about potential differences ...... 56 Safety ...... 57 Summary of Warnings and Precautions ...... 59 Table 9. Warnings and precautions for select FGAs and all SGAs ...... 61 Considerations for Prior Authorization Criteria ...... 64 Summary ...... 68 References ...... 70 Appendix A: Proposed Mechanism of Action and Receptor Binding Profile ...... 77 Appendix B: Literature Search Strategy ...... 79 Appendix C: Overview of Other Common Medications for Bipolar Disorder ...... 81 Appendix D: Summary of a Meta-analysis for Efficacy Measures with Cariprazine and Brexpiprazole for Schizophrenia ...... 83

2 Background on Antipsychotic Medications

Antipsychotics encompass a broad class of medications named for the ability to treat psychotic or related symptoms. Early antipsychotics (often referred to as first generation or “typical” antipsychotics [FGAs]), starting with , were pioneered in the 1950s.1 Since then, many more antipsychotics have been developed; the next “phase” of antipsychotics emerged in the 1980s, with the approval of .2 This next generation of antipsychotics is often referred to as second generation or “atypical” antipsychotics [SGAs]. More recently, newer antipsychotics with unique pharmacodynamic properties have emerged (starting in 2002 with ) that are sometimes referred to as third generation antipsychotics (TGA).3,4 For this report, we will use the terminology of FGAs and SGAs (with “TGA” included among SGAs).

SGAs were initially lauded as having a better side effect profile (primarily fewer extrapyramidal side effects such as dystonia, parkinsonism, and a lower propensity for tardive dyskinesia [TD]) with possibly greater efficacy for certain symptoms of schizophrenia incompletely treated with FGAs. However, now some of these distinctions are questioned, and most SGAs are known to have negative metabolic side effects. Although the FGAs and SGAs terminology are still commonly used, the medications are heterogeneous with some varying potential benefits and side effect profiles.1 In general, compared to FGAs, most SGAs are associated with fewer EPS and more metabolic side effects such as weight gain, hyperglycemia, and dyslipidemia.1,5

Most FGAs and SGAs seem similarly effective for psychotic and manic symptoms, but SGAs may have additional benefits for mood disorders.1 For the maintenance treatment of schizophrenia, SGAs are often a treatment of choice compared to FGA, perhaps due to concerns for the long-term risk of TD.1 However, both short-acting injectable FGAs and SGAs may be used for the acute treatment of agitation associated with schizophrenia or bipolar disorder.6,7 For bipolar disorder, SGAs are mainstay treatment options as first-line therapy for the treatment of acute symptoms and option for maintenance therapy. The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline specifies FGAs as third-line options for certain situations, but other guidelines by the British Association for Psychopharmacology (BAP) and National Institute for Health Care Excellence (NICE) include as a first-line option along with SGAs for the treatment of .8-10

There are approximately 27 unique chemical entities available in the US (12 FGAs, 15 SGAs) with common pharmacologic properties (eg, receptor antagonism and/or partial agonism) that can be referred to as “antipsychotics”; however, not all of these products are approved to treat psychotic symptoms. Table 1 lists antipsychotics available in the US, along with their approved indication and possible off-label uses (except for long-acting injectables, which will be discussed in a future report). Note that in some cases FDA-approval varies by formulation. Most antipsychotics are indicated to treat schizophrenia/psychotic disorders or agitation/aggression associated with schizophrenia or . Among those indicated for schizophrenia, clozapine is uniquely indicated for treatment- resistant schizophrenia and for reducing the risk of suicide associated with schizophrenia/schizoaffective disorders; and is indicated for schizoaffective disorder.2,11 Two dopamine antagonists are not FDA-approved for any psychiatric condition (ie, and which are approved for postoperative nausea and vomiting). Some additional indications (may vary by formulation; see Table 1) include Tourette’s syndrome (, haloperidol, aripiprazole); anxiety (, ); irritability associated with autism spectrum disorders (aripiprazole, );

3 adjunctive treatment of major depressive disorder (aripiprazole, brexpiprazole, extended- release) or treatment-resistant (/); and Parkinson’s disease associated psychosis ().3,12-20 Antipsychotic approval for treatment of bipolar I disorder varies based on the primary symptoms (ie, mania vs. depression), duration (ie, acute mania or depression vs. maintenance treatment), and as monotherapy or adjunctive use. The only FGA indicated for bipolar disorder [BD] (other than for agitation) is chlorpromazine, for bipolar mania.21 SGAs oral formulations indicated in adults for the treatment of bipolar disorder are as follows:

• BD I depression (acute) as monotherapy: cariprazine, , olanzapine/fluoxetine15,22,23

• BD I depression (acute) as adjunct to or : lurasidone22

• BD I/II depression (acute) as monotherapy: quetiapine13

• BD I mania/mixed (acute) as monotherapy: aripiprazole, , cariprazine, olanzapine, quetiapine (immediate-release is only labeled for mania), risperidone, ziprasidone3,23,24 12,25-27

• BD I mania/mixed (acute) as adjunct to lithium or valproate: aripiprazole, asenapine, olanzapine, quetiapine (immediate-release only labeled for mania), risperidone3,12,24-26

• BD I maintenance as monotherapy: asenapine, olanzapine, aripiprazole ( with sensor [Abilify Mycite])24,25,28

• BD I maintenance as adjunct to lithium or valproate: quetiapine, aripiprazole (tablet with sensor [Abilify Mycite]), ziprasidone26-28

Regarding off-label uses of the newer oral agents, Micromedex does not list any off-label indications. However, for cariprazine (Vraylar) Lexicomp includes augmentation of unipolar major depressive disorder in adults (data from a randomized, double-blind controlled trial) as an off-label indication.29 In addition, Lexicomp lists treatment of severe agitation/aggression/psychosis associated with dementia as possible off-label indications for brexpiprazole (Rexulti) and cariprazine (Vraylar) based on data from a randomized control trial for brexpiprazole, and for both agents, clinical practice guidelines that mention use of antipsychotics for this indication.29,30 Neither Micromedex nor Lexicomp include off-label indications for lumateperone (Caplyta).

Refer to Table 1 for agents with approval for pediatric use (age <18 years old). Drug moieties that do not have a pediatric FDA-approved indication or pediatric off-label use (per Micromedex) include , , amisulpride, brexpiprazole, cariprazine, clozapine, , lumateperone, pimavanserin.2,14,16,23,31-37 Nonetheless, it is apparent that the listed off-label uses in Micromedex are not exhaustive, as there is information, even guidelines proposing a place in therapy for some of these agent for certain pediatric conditions: clozapine as a last-line agent in children or adolescents with treatment- refractory schizophrenia; for Tourette’s disorder; and antipsychotics, especially risperidone, for aggression in youth with disruptive and aggressive behaviors.38-41 For further details about select off- label use in pediatric patients, please refer to the September 2019 DUR report, Antipsychotics in Children and Adolescents.

Antipsychotics are available in a wide variety of formulations, as oral preparations (ie, capsules, tablets, orally disintegrating tablets [ODT], sublingual tablet, oral suspension or elixir), injectable preparations

4 with either short-acting (ie, hours) or long-acting (ie, weeks+) properties, suppositories, powder for inhalation, and a transdermal patch. Refer to Table 1 for information about formulations excluding the long-acting injectables (a topic to be covered in a future report). Most chemical entities are available as an oral formulation except for the FGA droperidol and SGA amisulpride (both available as short-acting injectables).34,42 Among the SGAs, olanzapine, and ziprasidone also have short-acting injectable formulations.25,27 In addition, aripiprazole, clozapine, olanzapine, and risperidone are available as orally disintegrating tablets.2,3,12,25 Novel dosage forms include a transdermal patch for daily use (asenapine as Secuado) and a tablet with a sensor allowing for tracking of administration on a phone application (aripiprazole as Abilify MyCite).28,43

As of November 2020, Utah Medicaid includes the following antipsychotics as preferred on the preferred drug list (PDL): Abilify Maintena (LAI), aripiprazole tablet, Aristada (LAI), clozapine tablet, Invega Sustenna (LAI), Invega Trinza (LAI), Latuda (must fail another preferred agent first), olanzapine ODT and olanzapine, Perseris (LAI), quetiapine and quetiapine ER, risperidone solution and tablet, Saphris, and ziprasidone. FGAs are not included on the PDL except for prochlorperazine that is preferred for the treatment of gastrointestinal-related disorders. Other agents commonly used for bipolar disorder (ie, lithium, valproate [divalproex], , and ) are also preferred on the PDL.

Prior authorization (PA) is required for use of antipsychotics among children <6 years old, requiring psychosocial interventions first, trial and failure of at least one preferred antipsychotic and metabolic monitoring. In addition, PA is required for use of >1 antipsychotic concurrently for 45+ days among children up to 20 years old. Other pediatric-related restrictions for SGAs include agent-specific age and dose limits.

Brexpiprazole (Rexulti), cariprazine (Vraylar), and lumateperone (Caplyta) are each non-preferred and limited to adults only. Drug-specific PA is in place for Abilify MyCite, limiting use to adults who have failed an LAI antipsychotic; reauthorization requires patients to demonstrate >80% compliance.

The purpose of this report is to summarize FDA-approved and off-label uses for antipsychotics recognized by the compendia Micromedex and to review recent guideline recommendations for the place in therapy of antipsychotics in the treatment of schizophrenia, bipolar disorder, and autism spectrum disorder. In addition, this report will summarize recent systematic review (SR) level evidence regarding the risk of metabolic side effects, primarily among SGAs. Particular emphasis will be placed on some of the newest antipsychotics with oral formulations (brexpiprazole [Rexulti], cariprazine [Vraylar], and lumateperone [Caplyta]). Consult prescribing information for details about particular medications. As a previous drug utilization review (DUR) report focused on use of antipsychotics in children (September 2019), this report will focus more so on adult treatment. No Utah Medicaid utilization data will be included.

5

Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications Drug Entity Formulations FDA-approved indicationsa Possible Off-label Indications Included (brand name) in Micromedex31,b

(evidence supports efficacy or favors efficacy unless otherwise specified as inconclusive)

First Generation Antipsychoticse

Chlorpromazine21 Tablet; • Severe behavioral problems • Agitation associated with terminal (Thorazine) (children 1 to 12 years) cancer (IV formulation; adults, Solution for • Treatment of psychotic inconclusive evidence, B) injection (IM disorders (no age specified) • Anxiety before procedures (used with or IV) • Bipolar mania (no age specified) meperidine and • Schizophrenia (no age specified) pediatric, B) • Autonomic dysreflexia associated Also: acute intermittent porphyria, with spinal cord injury (IV or IM presurgical apprehension, formulation; adults, inconclusive intractable hiccups, nausea and evidence, C) vomiting, and as adjunct for • Symptoms of cholera (adults; tetanus inconclusive evidence, B) • Acute migraine (IV or IM formulation; adults, inconclusive evidence, B) • Opioid withdrawal symptoms in newborns (pediatric; inconclusive evidence, C) • Eye pain (injection; adults, inconclusive evidence, B) • Post-operative paralytic ileus (IM formulation; adults, inconclusive evidence, B) • Intractable phantom limb pain (oral formulation; adults, inconclusive evidence, C) • Sydenham’s chorea (adults; inconclusive evidence, B) • syndrome (IM formulation; adults, inconclusive evidence, C) Droperidol42 Solution for • Nausea and vomiting associated • Agitation associated with psychosis (Inapsine) injection (IM with procedures (age ≥ 2 years) (Adults, B) or IV) • Adjunct to general anesthesia (pediatric and adults, B) • Benign headache (adults, B) • Acute migraine (adults, B) Fluphenazine oral • Psychotic disorders (adults) • Agitation associated with dementia hydrochloride35c concentrate, “not been shown effective in the (adults; inconclusive evidence, C; use (Prolixin) oral elixir, management of behavioral only if benefits outweigh the risks, tablet, complications in patients with see BBW) mental retardation”

6 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications solution for • Chemotherapy-induced nausea and IM injection vomiting (oral formulation; adults, inconclusive evidence, B) • Huntington chorea (oral formulation; adults, inconclusive evidence, B) • IBS (in combination with ; adults, inconclusive evidence, C) • Diabetes associated neuropathy pain (oral formulation in combination with nortriptyline; adults, inconclusive evidence, B) • Tourette’s disorder (oral formulation; adults, inconclusive evidence, B) Haloperidol Tablet, oral Oral solution and tablet • Behavioral/psychiatric symptoms lactate17 solution, • Psychotic disorders (age ≥ 3 associated with dementia (oral tab solution for years) formulation; adults, inconclusive (Haldol) IM injection • Tourette’s disorder (age ≥ 3 evidence, B; use only if benefits years) outweigh the risks, see BBW) • Hyperactive children – short- • Management of opioid-induced side term, after failure of effects among cancer patients psychotherapy and medications (adults; no evidence strength other than antipsychotics provided) (children ≥ 3 years) • Delirium associated with critical • Severe behavioral disturbances illness (haloperidol lactate IV; adults, in children after failure of inconclusive evidence, A) psychotherapy and medications • Adjunct for postoperative nausea and other than antipsychotics vomiting (haloperidol lactate IV; (children ≥ 3 years) adults, B) Solution for injection • Schizophrenia (adults) • Tourette’s disorder (adults) Loxapine36,37 Inhalation Powder for inhalation • Severe MDD with psychotic features powder • Agitation associated with (loxapine succinate oral formulation; (Loxitane, (Adasuve), bipolar I disorder or adults, inconclusive evidence, B) Adasuve) capsule schizophrenia (adults) Loxapine succinate capsule

• Schizophrenia (adults) Molindone44 Tablet • Schizophrenia (age ≥ 12 years) No information available

(Moban)

Perphenazine45 Tablet • Schizophrenia (age ≥ 12 years) No information available (Trilafon) Also: nausea and vomiting (adults)

“not been shown effective for the management of behavioral complications in patients with mental retardation”

7 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications Pimozide18 Tablet • Tourette’s disorder after • Schizophrenia (adults, B) standard treatment failure (age • Anorexia (pediatric; inconclusive (Orap) ≥ 12 years) evidence, B) • Anxiety (adults; inconclusive evidence, B) • Huntington’s chorea (adults; inconclusive evidence, B) • OCD (adults, C) • Delusions associated with trigeminal trophic syndrome (adults; inconclusive evidence, C) Prochlorperazine1 Procl. Prochlorperazine edisylate Prochlorperazine edisylate injection 9,46 edisylate injection • Severe headache (adults, B) (solution for • Schizophrenia (weight ≥ 20 • Acute migraine +/- aura (pediatric (Compazine, injection) pounds & age ≥ 2 years) and adults, B); also suppository for Procomp, Also: severe nausea and vomiting adults Compro) Procl. (weight ≥ 20 pounds & age ≥ 2 • Tension headache (adults, B) maleate years) • Vascular headache (adults, B)

(tablet) Prochlorperazine maleate oral Prochlorperazine edisylate injection OR tablet prochlorperazine maleate orally Procl. • Schizophrenia (age ≥ 2 years) • Prophylaxis or treatment of (suppository) • Anxiety – non-psychotic, not postoperative nausea and vomiting first-line (adults) (adults; no SOE provided)

Also: severe nausea and vomiting • Treatment of radiation-associated (weight ≥ 20 pounds & age ≥ 2 nausea and vomiting (adults; no SOE years) provided, recommended as rescue Prochlorperazine suppository therapy in ASCO guideline) • Severe nausea and vomiting (adults) “not been shown effective in the management of behavioral complications in patients with mental retardation” Thiothixene47 Capsule • Schizophrenia (age ≥ 12 years) • Borderline personality disorder or (Navane) “have not been evaluated in the schizotypal personal disorder (adults; management of behavioral inconclusive evidence, B) complications in patients with mental retardation” Thioridazine48 Tablet • Schizophrenia unresponsive to • Behavioral problems associated with (Mellaril) other agents (adults and dementia or low IQ in children pediatric patients, age not (inconclusive evidence; pediatrics – B, specified) adults – A); use not recommended Efficacy for treatment refractory due to risks) schizophrenia is unknown • Borderline personality disorder (adults; inconclusive evidence, B) • Depression (adults in combination with ; inconclusive evidence, B; not FDA-approved due to risks, use not recommended)

8 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications • Unexplained female infertility (adults; inconclusive evidence, B) Trifluoperazine Tablet • Schizophrenia (adults, children No information available hydrochloride20 6-12 years) (Stelazine) • Non-psychotic anxiety, short- term (adult)

“not been shown effective in the management of behavioral complications in patients with mental retardation” Second Generation Antipsychotics Amisulpride34 Solution for • Prevention or treatment of No information available (Barhemsys) injection post-operative nausea and vomiting Aripiprazole3,28 Generic: oral ODT, tab, oral soln • Borderline personality disorder solution, • Irritability associated with (adults, B) Abilify [tabs, oral tablet, ODT autism (age 6-17 years) • Hyperprolactinemia induced by other soln], • Adjunct to Li or Val, or antipsychotics (adults, B) Oral tablet monotherapy for bipolar I • Abilify Discmelt Bipolar I disorder – maintenance with sensor mania/mixed (age ≥ 10 years) (dosage forms other than Abilify [oral dist. tab] • Tourette’s disorder (age 6-18 Mycite, no recommendation strength Abilify Mycited years) provided; based on at least 1 26- [oral tab with • Schizophrenia (age ≥ 13 years) week RCT) sensor]) • Adjunct to AD for MDD (adults) • Behavioral/psychiatric symptoms Tab with sensor associated with dementia (adults, B; • Adjunct to Li or DVP, or use only if benefits outweigh the monotherapy for bipolar I risks, see BBW) mania/mixed (adults) • Maintenance treatment of bipolar I disorder, as adjunct to Li or Val or monotherapy (adults) • Schizophrenia (adults) • Adjunct to AD for MDD (adults) Asenapine24 Sublingual Sublingual tablet No information available tablet, ER • Monotherapy for acute bipolar I Saphris (sl tab), transdermal mania/mixed (age ≥ 10 years) • Secuado (patch) patch Adjunct to Li or DVP for acute bipolar I mania/mixed (adults) • Maintenance treatment of bipolar I disorder as monotherapy (adults) • Schizophrenia (adults) Patch • Schizophrenia (adults) Brexpiprazole16 Tablet • Adjunct to AD for MDD (adults) No information available from • Schizophrenia (adults) Micromedex; see page 5 for information (Rexulti) from Lexicomp

9 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications Cariprazine23 Oral capsule • Bipolar I disorder – No information available from mixed/mania (adults) Micromedex; see page 5 for information (Vraylar) • Bipolar I disorder – depression from Lexicomp (adults) • Schizophrenia (adults) Clozapine2 Oral tablet • Treatment-resistant • Parkinson’s disease associated (generic, schizophrenia (adults) psychosis (adults, B) (Clozaril, FazaClo, Clozaril); ODT • Suicidal behavior associated • Parkinson’s disease treated with Verzacloz) (generic); with schizophrenia or levodopa – drug associated oral schizoaffective disorder (adults) dyskinesia (no recommendation suspension strength provided; “acceptable risk (Versacloz) Indicated for those who fail to with specialized monitoring” per respond to other antipsychotics, International Parkinson and or individuals with schizophrenia Movement Disorder Evidence-Based or schizoaffective disorder Medicine Committee) considered to be at chronic risk of • Behavioral/psychiatric symptoms suicide. associated with dementia (adults, B; use only if benefits outweigh the risks, see BBW) Iloperidone32 Oral tablet • Schizophrenia (adults) No information available (Fanapt) • Consider other agents first, due to QT interval prolongation risk. Lumateperone33 Oral capsule • Schizophrenia (adults) No information available (Caplyta)

Lurasidone22 Oral tablet • Schizophrenia (age ≥ 13 years) No information available (Latuda) • Bipolar I depression - adjunct to Li or Val (adults) • Bipolar I depression - monotherapy (age ≥ 10 years) Olanzapine25 Oral tablet, IM injection • Acute agitation with or without powder for • Agitation associated with dementia (adults; IV or IM (Zyprexa, Zyprexa IM solution, schizophrenia or bipolar I mania formulation, B) Zydis [ODT]) ODT (adults) • Anorexia (adults, B) Oral olanzapine alone • Treatment or prophylaxis of Olanzapine/ (generic); • Bipolar I mania/mixed (age ≥ 13 (moderate to highly emetogenic) fluoxetine15 Capsule (with years) chemotherapy induced nausea and (Symbyax) fluoxetine) • Bipolar I mania/mixed – adjunct vomiting (pediatric or adults, B) to Li/Val (adults) • Delirium (adults; oral or ODT • Bipolar I disorder – formulations, B) maintenance as monotherapy • Treatment refractory schizophrenia (adults) (adults, B) • Schizophrenia (age ≥ 13 years) • Adjunct treatment for MDD with Oral formulation with fluoxetine psychotic features (adults, B) • Bipolar I – acute depression • Behavioral/psychiatric symptoms (age ≥ 10 years) associated with dementia (adults, B; • Treatment resistant MDD use only if benefits outweigh the (adults) risks, see BBW)

10 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications Due to greater potential for • Cachexia associated with cancer (no metabolic side effects among recommendations, SOE low, per adolescents (vs. adults), ASCO guideline) prescribers may consider other • Prodrome period before agents first. schizophrenia (Adults; inconclusive evidence, B) (all for olanzapine alone; if not mentioned, a formulation was not specified in the review of evidence) Paliperidone11 ER tablet • Schizophrenia (age ≥ 12 years) • Bipolar I disorder – mania/mixed (Invega) • Schizoaffective disorder - (adults, B) monotherapy or adjunct to AD or mood stabilizers (adults) Pimavanserin14 Capsule, • Parkinson’s disease associated No information available (Nuplazid) tablet psychosis (adults)

Quetiapine13,26 Oral tablet, IR formulation: • Monotherapy for MDD (adults; (Seroquel, oral tablet ER • Schizophrenia (age ≥ 13 years) evidence based on XR formulation, B) Seroquel XR) • Bipolar I disorder – • Monotherapy for GAD (adults, B) o Mania as monotherapy (age • Bipolar I disorder – maintenance as ≥ 10 years) monotherapy (adults, B) o Mania adjunct to Li or Val • Delirium (adults; inconclusive (adults) evidence, B) o Maintenance as adjunct to Li • Treatment-refractory OCD (adults; or Val (adults) inconclusive evidence, A) • Bipolar I/II disorder – • Parkinson’s Disease associated o Depression as monotherapy psychosis (adults; inconclusive (adults) evidence, B) ER formulation: • Behavioral/psychiatric symptoms • Adjunct for MDD after AD failure associated with dementia (adults, B; (adults) use only if benefits outweigh the • Schizophrenia (age ≥ 13 years) risks, see BBW) • Bipolar I disorder – o Mania/mixed as No formulations otherwise specified monotherapy (age ≥ 10 years) o Mania/mixed adjunct to Li or Val (adults) o Maintenance as adjunct to Li or Val (adults) • Bipolar I/II disorder – o Depression as monotherapy (adults) Risperidone12 Oral soln, • Schizophrenia (age ≥ 13 years) • ASD (pediatric, B) oral tablet, • Irritability associated with • Behavioral disturbances associated (Risperdal, ODT autism (age 5-17 years) with intellectual disability (pediatric Risperdal M-tab • Bipolar I disorder – and adult, B) [ODT]) o Mania/mixed as • Delirium prophylaxis among cardiac monotherapy (age ≥ 10 surgery patients (adults, B; oral tab or years) ODT)

11 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications o Mania/mixed adjunct to Li or • Tourette’s disorder (pediatric and Val (adults) adults, B) • TD due to antipsychotics (adults, B) • Treatment-refractory depression (adults; inconclusive evidence, B) • Adjunct for chronic military-related PTSD (adults; inconclusive evidence, B) • Behavioral/psychiatric symptoms associated with dementia (adults, B; use only if benefits outweigh the risks, see BBW) No formulations otherwise specified Ziprasidone27 Oral capsule, IM injection: • Schizoaffective disorder (adults, B) solution for • Acute agitation associated with • Bipolar I disorder mania/mixed as Ziprasidone IM injection schizophrenia (adults) monotherapy (pediatric, 10-17 years; mesylate (ziprasidone Co-administration with oral B, at least 1 RCT) ziprasidone not recommended • Behavioral/psychiatric symptoms (Geodon) mesylate) associated with dementia (adults, B; Oral capsule: use only if benefits outweigh the • Schizophrenia (adults) risks, see BBW) • Bipolar I disorder – o Mania/mixed as monotherapy (adults) o Maintenance as adjunct to Li or Val (adults) Prescribers may consider the potential to prolong the QT interval when selecting treatment; may consider other options first Abbreviations: ASCO, American Society of Clinical Oncology; ASD, autism spectrum disorder; BBW, black box warning; ER, extended release; FDA, United States Food and Drug Administration; FGAs, first generation antipsychotics; IM, intramuscular; IV, intravenous; IQ, intelligence quotient; li, lithium; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; ODT, orally disintegrating tablets; Procl., prochlorperazine; PTSD, post-traumatic stress disorder; RCT, randomized controlled trial; sl, sublingual; SOE, strength of evidence; soln, solution; susp, suspension; tab, tablet; TD, tardive dyskinesia; val, valproate aFor bipolar disorder, treatment of mania or mixed (ie, concurrent mania and depression symptoms) means it was studied for acute use to treat the mood symptom. Treatment for depression generally also means it is used acutely to treat the mood; however, product labeling varies. For example, product labeling for olanzapine/fluoxetine is labeled as “acute depressive episodes associated with bipolar I disorder” whereas labeling for cariprazine is for “treatment of depressive episodes associated with bipolar I disorder.” A phase III trial for cariprazine enrolled patient who had a bipolar I depressive episode of ≥ 4 weeks and <12 months.49 An indication for maintenance treatment indicates it has been studied and approved for long-term use (ie, to prevent recurrence of full-blown acute mood episodes). bIBM Micromedex provides a rating about the strength of evidence for off-label indications. Category A refers to evidence from MAs of RCTs with homogenous results or multiple RCTs with many patients. Category B refers to MAs of RCTs with conflicting results, or RCTs with few patients and/or serious flaws. Category C refers to indications based on expert opinion or case reports/series. The last category is no evidence.

12 Table 1. Overview of Oral and Short-acting Injectable Antipsychotics Indications In some cases, a possible off-label use was listed (and a recommendation strength provided) but the evidence was considered inconclusive. All possible indications included within Micromedex as “Non-FDA Uses” were included, but in cases where the evidence was not conclusive, a note about “inconclusive evidence” is provided. CPossible off-label indications are only listed for fluphenazine hydrochloride. Other indications have been examined for the long-acting fluphenazine decanoate formulation: agitation associated with dementia (adults; inconclusive evidence, C; use only if benefits outweigh the risks, see BBW), Huntington chorea (adults; inconclusive evidence, B) and to reduce self-injury behaviors (adults; inconclusive evidence, B) dAbilify Mycite system is a tablet with a sensor + patch system that sends a signal to a phone application after ingestion of the tablet. Whether this improves patient compliance is not established, and the system should not be used to track ingestion in “real-time.” Use in pediatric patients is not established. eProduct labeling for most FGAs does not clearly specify an age group for use. Ages listed are taken from data or dosing information to provide general information about historical adult vs. pediatric use.

Appendix A discusses the mechanism of action and receptor binding profile for antipsychotics.

Methods To find information about metabolic side effects of antipsychotics, a literature search for systematic reviews and meta-analyses published in 2019 and 2020 was performed in Epistemonikos. The focus of results was on populations with either schizophrenia or bipolar disorder. A supplementary search for evidence (randomized controlled trials or systematic reviews) regarding switching antipsychotics and the impact on metabolic parameters was also performed in Epistemonikos. Reference lists of relevant studies were also screened for relevance. The literature search terms are provided in Appendix A. The Agency for Healthcare Research and Quality (AHRQ) evidence-based reports website (https://www.ahrq.gov/research/findings/evidence-based-reports/index.html) and Cochrane library were searched using the term “antipsychotic” to identify systematic reviews and meta-analyses regarding the efficacy and/or safety of antipsychotics among patients with schizophrenia or bipolar disorder. Additional studies were identified through references of included clinical practice guidelines.

Antipsychotic product labeling was obtained either from the FDA website, or from the dailymed website (https://dailymed.nlm.nih.gov/dailymed/). Information about off-label uses of antipsychotics was found in Micromedex and Lexicomp. Information about the newest oral antipsychotic, lumateperone, was obtained from FDA review documents on the FDA website, and from searching for “lumateperone OR caplyta” in Pubmed. References lists of review articles were checked for clinical trials. As systematic reviews included some information about efficacy and side effects of brexpiprazole and cariprazine, supplementary information (eg, expert review articles) for brexpiprazole and cariprazine were found from searching “brexpiprazole OR rexulti” or “cariprazine OR vraylar” in Pubmed.

Potentially relevant clinical practice guidelines for schizophrenia, bipolar disorder, and autism spectrum disorders were identified on the College of Psychiatric and Neurologic Pharmacist (CPNP) treatment guidelines website (https://cpnp.org/guideline/external). The American Academy of Neurology (AAN), American Academy of Pediatrics (AAP), American Academy of Child & Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), British Association for Psychopharmacology, Canadian Psychiatric Association (CPA), Canadian Network for Mood and Anxiety Treatments (CANMAT), National Institute for Health and Care Excellence (NICE), The Royal Australian and New Zealand College of Psychiatrists (RANZCP), and World Federation of Societies of Biological Psychiatry (WFSBP) were searched for clinical practice guidelines. For schizophrenia and bipolar disorder, relevant guidelines that

13 included overall management of the condition (eg, not only pregnancy) and were published in 2016 or later were included. For autism spectrum disorders, guidelines published since 2019 with a focus in children were included.

Guideline Recommendations for Schizophrenia, Bipolar Disorder and Autism Spectrum Disorder

A. Schizophrenia

Schizophrenia affects an estimated up to 0.75% of non-institutionalized persons worldwide; typically symptoms are persistent and a major cause of disability.50 Comorbidities are common; approximately half of patients also have a mental/behavioral health disorder, and the prevalence of diabetes and heart disease is higher than the general population.50,51 Major sources of mortality include suicide, cardiometabolic disease, and accidents.6 Symptoms usually present between late teens and early thirties (male onset is on the earlier end of this range). Onset before young adulthood is rare.50,51 Core symptoms of schizophrenia include: positive (psychotic) symptoms such as hallucinations, delusions, or disorganized speech; negative symptoms such as low motivation, lack of pleasure, and reduced facial expressions or speaking; and cognitive symptoms such as trouble with concentration, attention, or memory.52

Schizoaffective disorder is a schizophrenia spectrum disorder. It is less common than schizophrenia with a lifetime prevalence of about 0.3%. Onset is also typically during young adulthood, but may occur later in life. Individuals suffer from psychotic illness similar to schizophrenia; however, in addition to the positive/negative symptoms, there are also concurrent prominent major mood symptoms. Mood symptoms may be bipolar type (if mania occurs) or depressive type, and must be present for the majority of the duration of the illness. To distinguish from bipolar disorder or depression with psychotic features, at some point over a patient’s lifetime, delusions or hallucinations must occur independent of the mood disorder (for at least 2 weeks).51

Although schizoaffective disorder is a distinct diagnosis for which only 2 antipsychotics are specifically indicated (clozapine to reduce suicidality, paliperidone),2,11 some antipsychotic clinical trials also included patients with schizoaffective disorder.53 To our knowledge, there are not clinical practice guidelines specific to schizoaffective disorder. The Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline extends its recommendations to schizophrenia spectrum disorders which includes schizophrenia and schizoaffective disorder, in addition schizophreniform disorder (schizophrenia-like illness lasting for 1 to <6 months) and others.6 The British Association of Pharmacology (BAP) schizophrenia guideline provides one recommendation for the bipolar subtype of schizoaffective disorder: the antipsychotic selected should be individualized, based on expert opinion. BAP reports limited evidence about a particular antipsychotic for this subtype, and perhaps antipsychotics indicated for mania should be considered.54 The American Psychiatric Association (APA) guideline target condition is schizophrenia; however, authors note that some studies included for the evidence-based recommendations also included patients with schizoaffective disorder. However, it was not possible to separate information for patients with schizoaffective disorder to provide separate recommendations.55

14 Guideline recommendations for schizophrenia Recommendations for young people (children, adolescents)

Most clinical practice guidelines for schizophrenia are aimed at treatment of adults. The 2013 National Institute for Health and Clinical Excellence (NICE) guideline for youth recommends oral antipsychotics combined with psychological interventions for first episode psychosis. Selection of an antipsychotic should be based on benefits and possible side-effects. Prescribers should consider that olanzapine has a higher likelihood of weight gain than other SGAs. Aripiprazole is recommended for those ages 15-17 that do not respond to or cannot take risperidone.56 Canadian 2017 guidelines for youth offer similar recommendations to NICE other than any route of administration can be considered, “there is a lack of evidence for efficacy differences or clinical superiority between the various antipsychotic classes or generations (except for clozapine for treatment-refractory cases) or modes of administration.”57 The 2013 practice parameter for youth from American Academy of Child and Adolescent Psychiatry also recommends antipsychotics concurrently with psychological interventions with SGAs “typically being the treatment of first choice.”58 The 2019 DUR report on use of antipsychotics in children summarized additional information from treatment guidelines and from an SR59:

Antipsychotics, along with psychotherapy/psychosocial therapy, are considered a primary treatment for EOS [early onset schizophrenia] and COS [child-onset schizophrenia].57,58,60 Clinical practice guidelines recommend judicious use of antipsychotics for youth with a confirmed diagnosis of schizophrenia spectrum disorders,57,58 and initiation of an antipsychotic in consultation with a psychiatric specialist in child and adolescent mental health.57 Dosing should be initiated at the lower end of the dosage range and slowly titrated upward. If the agent is not approved for use in children, the 2017 Canadian clinical practice guideline recommends starting at a dose lower than the lowest dose approved in adults.57 Firm recommendations regarding duration of treatment are lacking (due to uncertainty in the diagnosis and treatment-related toxicities); but, in adults, antipsychotic treatment usually continues indefinitely.61

• The [2013] NICE guideline for treatment of schizophrenia in youth similarly recommends only using combined antipsychotics for a short duration (eg, during cross-tapering); trying clozapine monotherapy for patients with failure of 2 antipsychotic monotherapies; augmenting clozapine with a second antipsychotic upon inadequate response to clozapine monotherapy; assessing for reasons for treatment failure; and employing a multidisciplinary review prior to starting combined antipsychotic treatment.56

• A 2017 systematic review of the efficacy of antipsychotic medications in youth and young adults reported moderate-quality evidence from RCTs that SGAs (altogether) reduce negative symptoms and positive symptoms of schizophrenia and related psychoses, slightly improve functioning on the clinical global impressions (CGI) scales and improve response rates compared to placebo.38 Similar effects on negative and positive symptoms, response rates and functioning (based on CGI) were observed between FGAs and SGAs.38 FGAs and SGAs are considered similarly effective with the exception of clozapine, which has greater relative effectiveness among SGAs when compared to FGAs in adults. It is unclear if clozapine is more effective than other SGAs in youth.38

15 Rapid tranquilization may be performed in young people when their agitation is a threat to themselves or others. High-potency antipsychotics (commonly FGAs such as haloperidol) should be used cautiously due to the greater risk of acute dystonia compared to adults.56 Recommendations for adults

General goals of treatment

Goals of treatment of schizophrenia vary by phase of treatment (acute versus maintenance). During an acute exacerbation or initial onset of psychotic symptoms, goals include reducing symptoms. After the acute phase, goals include preventing symptom recurrence while maximizing functioning and quality of life.62

General approach to use of antipsychotics

Antipsychotics are a cornerstone treatment for schizophrenia. They may be used as-needed for acute treatment of agitation associated with schizophrenia (usually oral or short-acting intramuscularly [IM]), continuously for remission of an acute exacerbation (usually orally), or as maintenance treatment to prevent recurrence (oral or long-acting injectable). Other agents may be used with antipsychotics to target comorbidities/symptoms incompletely treated by an antipsychotic (eg, or anxiolytics), to treat acute agitation (eg, benzodiazepines), or to manage side effects related to antipsychotic use (eg, agents for acute dystonia, beta-blockers or benzodiazepines for ).62 In addition to antipsychotics, guidelines also recommend various evidence-based psychosocial and psychoeducation interventions.6,54,62 Table 2 includes adult guideline recommendations since 2016 from the American Psychiatric Association (APA), BAP, Canadian Psychiatric Association (CPA), and RANZCP.

When selecting an antipsychotic for first-time psychosis, the 2020 APA, 2019 BAP and 2017 CPA guidelines do not prefer a specific antipsychotic, class (ie, FGAs or SGAs), or formulation (though acute treatment will generally start with an oral formulation of the same medication planned for LAI therapy to establish tolerability).54,62,63 These guidelines recommend selecting an antipsychotic based on patient preference, anticipated side effect profile, antipsychotic receptor binding profile, available formulations, and comorbidities. This recommendation is based on the lack of conclusive evidence that any one antipsychotic is more effective than another for the first-episode of schizophrenia.54,62,63 Unlike other guidelines, the 2016 RANZCP guideline prefers starting an oral SGA over an FGA due to a better side effect profile (especially for EPS). Further, they recommend selecting an agent with the least risk of weight gain when possible.6 The algorithm for selecting an initial SGA recommends other agents before olanzapine.6 With regard to formulations, oral concentrates or oral disintegrating tablets may be considered for patients with trouble swallowing pills or who will not consistently swallow pills; short- acting injectables are usually limited to short-term use if a patient cannot take an oral medication or for acute agitation.62

An initial response to antipsychotic therapy is expected within 2-4 weeks, and an initial trial at up to the maximum dose may continue for about 6-8 weeks.54,62,63 If the initial antipsychotic is effective and well- tolerated without significant side effects, most guidelines recommend continuing the same antipsychotic for maintenance treatment.6,54,62 Switching to an alternative antipsychotic should be considered in patient-specific circumstances (eg, side effects, residual symptoms, plans to switch to a

16 LAI).62 Providers should explore contributing factors during an acute exacerbation (eg, nonadherence) and select an antipsychotic based on similar factors to the first-episode in addition to considering prior antipsychotic treatment history.6,54,62,63 The exact recommended duration of treatment varies. The risk of relapse should be balanced with the risks of ongoing treatment, as a patient-specific decision.54,62 After an initial response to treatment, the CPA recommends maintenance treatment for at least 18 months, BAP recommends a minimum of 2 years, and RANZCP recommends 2 to 5 years.6,54,63 Continuation of treatment after the first-episode of psychosis, may reduce the risk of relapse by about 50%.54 Many patients will require chronic treatment; long-term treatment is associated with lower mortality.62

Unlike other antipsychotics, the SGA clozapine is recommended under specific circumstances in the APA, BAP, CPA, and RANZCP guidelines: for treatment-resistant schizophrenia, and for consideration in cases of severe aggression that is not responding to other treatments.6,54,55,64 Although the definition may vary, treatment-resistant schizophrenia is usually considered as persistent symptoms of at least moderate severity (eg, with <20% reduction in one symptom domain on a standardized scale) after at least 2 trials of different antipsychotics at a therapeutic dose, duration of at least 6 weeks each, and with adequate (at least 80%) adherence.55 The APA also recommends clozapine for cases where the patient is at a high risk for suicide.55 Clozapine has a risk for a number of serious side effects and is only available under a risk evaluation and mitigation strategy (REMS).2

Additional notes on treatment of acute disturbances

The BAP and National Association of Psychiatric Intensive Care and Low Secure Units (NAPICU) published a guideline (2018) regarding de-escalation of acute disturbances (ie, agitation, aggression, violent behaviors) associated with physical or mental disorders. Treatment goals are to reduce violent/aggressive behaviors, for which as-needed medication may be used to preemptively deescalate behaviors, or for rapid tranquilization. Interventions for de-escalation include nonpharmacologic options (eg, altering the environment, reassuring or reframing, distractions). For rapid tranquilization, the following classes are often used: benzodiazepines (oral, IM, or intravenous [IV]), antipsychotics (oral, short-acting IM, or IV) and various other agents (eg, promethazine). After nonpharmacologic de- escalation strategies, oral options are recommended first (pre-rapid tranquilization). IM treatment for rapid tranquilization is generally reserved as a last resort after failure of oral options.65 RANZCP also recommends IM formulations if the patient’s symptoms are severe or dangerous, or if the patient refuses oral medications.6 The IM route of administration is a risk factor for acute dystonia, abnormal prolonged muscle contractions, that cause significant patient distress. IV options are considered last and must be administered in settings where close monitoring and resuscitation is feasible. Among antipsychotics, the following interventions have evidence of effectiveness and are recommended treatment options: oral aripiprazole (Ib, A), oral olanzapine (Ib, A), oral risperidone (Ib, A); oral haloperidol (III, C), oral quetiapine (III, C); IM aripiprazole (Ia, A), IM droperidol (Ib, A), IM olanzapine (Ia, A); IM haloperidol with IM promethazine (Ib, A), IM lorazepam with IM haloperidol (Ia, A); IV droperidol (Ib, A), IV olanzapine (III, C).65 Oral-inhaled loxapine is also effective (Ib, A), but cannot be used in patients with pulmonary disease and is only available under a REMS program.7,36 (see footnote of Table 2 for description of level of evidence).

17 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Practice Guideline for Evidence in guideline is based on the SR by McDonagh et al. 2017 that included the Treatment of some patients with schizophreniform disorder, and schizoaffective disorder. In Patients with addition, the authors concluded that evidence for antipsychotic treatment is Schizophrenia, 3rd most applicable to “adults (mean age 25 to 50 years), with mainly moderate-to- 53 edition; APA, 202062 severe disease”

Person-centered care, including pharmacologic and non-pharmacologic treatments (eg, psychosocial interventions) are recommended. Antipsychotic Pharmacotherapy Recommendations • Treat with an antipsychotic; monitor for efficacy and adverse effects (1A) • Continue antipsychotic treatment, if effective (1A) o Use the same antipsychotic (2B) • Clozapine for treatment-resistant schizophrenia (1B) • Clozapine if “the risk for suicide attempts or suicide remains substantial despite other treatments” (1B) • Clozapine if “the risk for aggressive behavior remains substantial despite other treatments” () • LAI antipsychotic if preferred by the patient, or history of nonadherence (2B) • Lowering the antipsychotic dose or switching to a different antipsychotic is recommended for management of antipsychotic-induced parkinsonism (2C; alternative: anticholinergic agent), or akathisia (2C; alternatives: add benzodiazepine or beta-blocker) Evidence-based Treatment of First Schizophrenia Episode Guidelines for the • Antipsychotic selection should be individualized based on side effect Pharmacological profile. Initial dose should be low to minimize adverse effects. (D) Treatment of • Antipsychotics are the first-line treatment. Doses at the lower end of the Schizophrenia; BAP, therapeutic range are recommended. (B) 201954 • Efficacy of various antipsychotics for the first-episode are expected to be similar (“though some agents [e.g., olanzapine, amisulpride, risperidone] might perform slightly better than others”). Selection should be primarily based on the potential adverse effects. (S) • Monitor efficacy using a comprehensive scale. Initial trial dose may be 2 weeks, and total trial length at up to max dose for about 6 weeks. (B) • Target should be symptom remission. Response is defined as at least 25% reduction in total symptom score or reduction by at least 1 point on the CGI (within 2 weeks), or 40-50% reduction or reduction by at least 2 CGI points after about 6 weeks. (B) • Consider another antipsychotic if insufficient response after 6 weeks (D) Maintenance Treatment • Treat patients in remission with the standard dose of an antipsychotic for at least 2 years to reduce the risk of relapse. (B) • Offer LAI, “given the evidence of a lower risk of relapse.” (B) • Review whether medication should be continued after 2 years if remission maintained and patient is without evidence of psychotic symptoms. (D) o Use shared decision-making and consider benefits and risks. (S)

18 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Acute Psychosis Antipsychotic • Similar criteria to first-episode, but also consider patient preferences (S) and past experience in terms of efficacy and side effects (S) Response Maintenance • Continue antipsychotic within target dose range; individualize selection based on prior treatment, side effects, medication adherence, and comorbidities (S) • Keep oral regimen simple (S); reduce dose cautiously and monitor closely (S) • Before switching treatments, ensure the antipsychotic had an adequate trial (dose, duration) (S) • Address risk factors for relapse including substance use, adherence, and environment (S) • Avoid using an intermittent treatment approach (B) o Ideal duration of treatment unclear; authors suggest assessing individualized risk: benefit of continuation • Consider LAI to monitor adherence or per patient preference (B) • Monitor effectiveness and side effects (S) Treatment-Resistant Schizophrenia (TRS) Treatment-resistance = failed response to 2+ adequate antipsychotic trials • “Clozapine should be the first-choice treatment” for patients with TRS (A) o An adequate trial should be clozapine alone at least 6 months (B) o Consider augmentation of clozapine only after a minimum of 3 months of clozapine at an optimized dose (S) • Consider high-doses or combinations of other antipsychotics only after exhausting other treatment options including clozapine (B) o Monitor patients on high-dose or combined antipsychotic regimens closely and only continue after 3 months if benefits outweigh risks (S) Treatment of Comorbidities/Specific Symptoms • Depression: Antipsychotic selection should be considered carefully along with other factors; evidence does not support switching from an FGA to SGA specifically for depression (D) • Mania/hypomania (eg, for schizoaffective disorders, bipolar type): Select antipsychotic based on patient characteristics (D); limited evidence supports using paliperidone o Consider mood stabilizers if manic symptoms persist after an adequate antipsychotic trial (D) • Substance use disorders: Ensure antipsychotic optimization; clozapine may be considered if symptoms persist (C) • Persistent hostility or aggression: Consider a trial of clozapine (B) Adherence Adherence “is the most common cause of relapse and associated with increased difficulty or delay in achieving remission”

19 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • When possible, account for risk of side effects, and patient-specific factors for tolerability concerns when selecting an antipsychotic (S) • Choose a simple regimen (S), assess tolerability (S), and assess for adherence in a non-judgmental way (S) • Consider using more objective measures (eg, pill counts, plasma levels) to assess adherence if nonadherence has been associated with relapse (S) • Consider an LAI if nonadherence is associated with relapse, by patient preference or if “avoidance of non-adherence is a clinical priority” (S) o After the first-episode of psychosis, LAI may be considered if poor adherence to oral medications occurs (B) Recommendations about Antipsychotics during Pregnancy: • No absolute evidence of safety, but “available evidence suggests [antipsychotics] are not major teratogens” (B) o Discontinuing antipsychotics during pregnancy is not recommended due risk of relapse (C) o “Avoid polypharmacy and use the lowest effective dose” (S) • Avoid starting olanzapine in women with risk factors for diabetes when planning a pregnancy (S) • May continue LAI if initiated prior to pregnancy and there is a high risk of recurrence (S), but avoid a new start of LAI during pregnancy due to poor flexibility (S) Recommendations about Antipsychotics while breastfeeding • Do not breastfeed while taking clozapine (D) • If starting a new antipsychotic, a less sedating antipsychotic is preferred (S) Guidelines for Guideline reviewed and adapted recommendations from 8 guidelines from Pharmacotherapy of other organizations (NICE, SIGN, AACAP, EPA), all published between 2011 and Schizophrenia in 2016. adults; CPA, 201763 Pharmacotherapy for Adults First Schizophrenia Episode • Antipsychotics are recommended (from NICE, strong) • Use shared decision-making for selecting an antipsychotic, incorporating discussion of possible side effects and efficacy (from NICE, strong) o Considers all antipsychotics to have similar efficacy; selection often based on side effect profile • During acute treatment, consider (from SIGN, grade D): o If tolerated, continue initial antipsychotic for at least 2 weeks o Consider changing the antipsychotic if no response by 4 weeks o Reassess partial response after 8 weeks Also consider formulation, “earlier use [of long-acting injections (LAIs)] in the course of treatment has been advocated…discussion regarding their use should not be confined to only those for whom nonadherence is a concern” • For dose, target the lower end of the effective dosage range. Select dose based on efficacy and tolerability (from SIGN, grade D) • Maintenance treatment (after controlling positive symptoms) should last at least 18 months (from SIGN, grade D) o Risk of relapse is high

20 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Acute Exacerbation • Increase dose /change antipsychotic; if tolerated continue at least 4 weeks; reassess partial response after 8 weeks (from SIGN, grade D) o LAI may be helpful if nonadherence Maintenance Treatment • Offer maintenance after acute treatment with an antipsychotic at a low to moderate dose (from SIGN, grade B) • Duration of maintenance after control of positive symptoms acutely, should be for at least 2 years and maybe for 5 years or longer (from SIGN, grade A) • Patients should be allowed either an oral or LAI (from SIGN, good practice) Treatment-Resistant Schizophrenia (TRS) • Offer clozapine (from SIGN, grade A) • Consider clozapine after non-response to 2+ antipsychotics (from SIGN, grade B) o Definition of non-response varies; sometimes response has been defined as at least 20% decrease in one of the symptom domains as measured by a scale o Resistance to antipsychotic treatment = “persistence of 2 or more positive symptoms with at least a moderate level of severity, or a single positive symptom with severe or greater severity, following 2 or more adequate trials with different antipsychotic drugs” o Adequacy of treatment (also include assessment of adherence including antipsychotic plasma level if applicable): § Oral: at least 6 weeks at middle or higher dose of therapeutic range § LAI: at least 6 weeks at steady state § Clozapine: at least 8 weeks, ideally 12 weeks at dose of 400 mg/d or greater Treatment of Schizophrenia Resistant to Clozapine • Insufficient evidence to recommend a specific treatment Treatment of Specific Symptoms • Aggression/hostility: Base treatment selection upon patient preference, past antipsychotics, adverse effects, and medical history. Clozapine is indicated for those also with TRS. (from SIGN, grade D) o Notes that SRs suggest clozapine is superior for treatment of aggression • Depressive symptoms: Treat depression according to guidelines for treatment of depression, including use of antidepressants (from SIGN, good practice) Clinical Practice Guideline applies to schizophrenia spectrum disorders including Guidelines for the schizophrenia, schizoaffective disorder, schizotypal disorder, management of schizophreniform disorder and “acute transient psychotic disorder” with schizophrenia and symptoms of schizophrenia. It does not include recommendations for related disorders; childhood-onset of schizophrenia. RANZCP, 20166

21 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • In addition to antipsychotics, many other interventions are recommended concurrently including psychosocial interventions, psychoeducation, and other support Pre-psychotic/prodromal phase • Do not consider antipsychotics unless positive psychotic symptoms present for at least 1 week, patient is at risk (self-harm or aggression), or when symptoms continue despite psychosocial treatments (EBR, III-1) Treatment of first episode of “non-affective psychosis” • Prefer SGAs to FGAs (due to better SE profile, especially EPS risk) [CBR] o Select agent based on: patient preference, previous response, tolerability, and potential long-term side effects (EBR, I) o Flow diagram recommends these SGAs first: oral amisulpride (not available in US), aripiprazole, quetiapine, risperidone, ziprasidone § If insufficient response (after 3 weeks), may consider olanzapine. “Where possible, medicines with the least risk of weight gain should be selected” § LAI (SGAs or low dose FGAs) may be considered for nonadherence “There is little evidence that the SGAs are more effective than the FGAs in the acute treatment of positive symptoms. However, there is some evidence that oral SGAs are more effective than oral FGAs in relapse prevention” • Avoid use of >1 antipsychotic “unless it has been clearly demonstrated that the person’s symptoms are resistant to monotherapy” (EBR, II) • Consider clozapine early if other interventions are not effective (EBR, I) • Recommends lifestyle interventions for weight gain prevention (EBR, II), and considering metformin for preventing SGA-related weight gain “when these risks cannot be adequately managed by switching medication” or by lifestyle (EBR, II) • Duration: recommended to continue for minimum of 2-5 years (EBR, II) Maintenance treatment • Usually continue treatment with same antipsychotic with response during acute phase (if benefits > risks, including side effects) o May consider switching if concerning side effects • If planning for LAI, select an oral option appropriate for transitioning (ie, same antipsychotic) • Stopping treatment: consider risks vs. benefits; patient should be well for at least 12 months before d/c Treatment of acute relapse • Consider alternative antipsychotic if no response after 2-3 weeks of treatment at the recommended dose (+adherent) [EBR, II] • Consider clozapine after 2+ antipsychotic trials (with at least one being a SGA) of adequate dose (300-1000 chlorpromazine equivalents) and duration (6+ weeks) [EBR, I] • LAI may be considered for poor adherence or patient preference (EBR, I) • Address poor adherence, side effects, other comorbidities, social environment (EBR, II)

22 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • If persistent symptoms after clozapine trial: adjunct to clozapine, or previous best regimen + add adjunct (EBR, II) Severe, persistent symptoms: • Use psychosocial interventions (CBR) • Clozapine = choice for treatment-resistant schizophrenia (EBR, I) o Trial for at least 12 months due to possible late-responders (EBR, I) • Clozapine: consider for persistent aggression that does not respond to other treatments (EBR, II) • Augmentation (ECT, or other medications) of clozapine considered if not effective alone (EBR, III-1) Combination antipsychotics • 2 antipsychotics “may be justifiable” if no response after monotherapy of 2 agents; requires monitoring (EBR, II) Considerations for comorbidities • Consider alternative antipsychotic with possible benefit for mood symptoms if the symptoms (ie, depression, anxiety) do not respond to psychological intervention (EBR, II) • AD/anxiolytics may be added for persistent symptoms after optimizing antipsychotic (EBR, II); consider agent without overlapping SE with the antipsychotic (EBR, IV) Pregnancy • Consider antipsychotics “associated with fewer fetal adverse effects in available registry data (eg, olanzapine, quetiapine, risperidone)” (EBR, III-3) Treatment of acute behavioral disturbances Consider pharmacologic treatment if non-pharmacologic treatment unsuccessful • Oral preferred to injectable treatment (CBR) • Prefer SGAs if an injectable must be used (EBR, II) o IM first line (if patient is refusing oral meds, highly aroused, or violent): olanzapine; IM second line: droperidol • Monitor and avoid overdosing when using as-needed medication (EBR, III-1) Abbreviations: AACAP, American Academy of Child and Adolescent Psychiatry; AD, ; APA, American Psychiatric Association; BAP, British Association of Psychopharmacology; CGI, clinical global impressions scale; d, day; d/c, discontinuation; ECT, electroconvulsive therapy; EPS, ; European Psychiatric Association (EPA); FGA, first generation antipsychotic; FGAs, first generation antipsychotics; IM, intramuscular; LOE, levels of evidence; MA, meta-analysis; MS, ; NICE, National Institute for Health and Care Excellence (NICE); RANZCP, Royal Australian and New Zealand College of Psychiatrists; RCT, randomized controlled trial; ROB, risk of bias; Scottish Intercollegiate Guidelines Network (SIGN); SE, side effect; SGA, second generation antipsychotic; SGAs, second generation antipsychotics; SR, systematic review APA Strength of Recommendation 1: Recommendation, benefits >harms; 2: suggestion, benefits > harms with some uncertainty APA Strength of Evidence A: high; B: moderate; C: low (all based on consistency of effect, directness of effect, precision, and ROB)

23 Table 2. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) BAP Strength of Recommendation A: direct level 1 evidence; B: direct level 2 or extrapolated from level 1 evidence; C: direct level 3 or extrapolated from level 1 or 2 evidence; D: direct level 4 or extrapolated from level 1, 2, or 3 evidence; S: “standard of good practice” BAP Levels of Evidence for Causal Relationships: Ia: MA of RCTs; 1b: 1+ RCT; IIa: 1+ non-randomized controlled study; IIb: 1+ other quasi-experimental study; III: other non-experimental or descriptive study; IV: expert reports or opinion RANZCP Strength of Recommendation CBR = consensus-based recommendation, based on collective expert opinion EBR = evidence-based recommendation when sufficient evidence RANZCP LOE I: SR of RCTs; II: RCT; IIII-1: pseudo-RCT; IIII-2: “comparative study with concurrent controls”; IIII-3: “comparative study without concurrent controls”; IV: case-series or pre/post test SIGN and EPA Grades of Recommendation (used in CPA) A: 1+ high or low risk of bias SRMAs of RCTs or RCT with consistent results that applies to the population; B: SRs of observational studies or high-quality case-control or cohort study with consistent results that applies to the population or extrapolated evidence from studies under grade A; C: case-control studies or cohort studies at a high risk of bias or extrapolated evidence from SRs of observational studies or high-quality case-control or cohort study with consistent results that applies to the population D: descriptive studies or expert opinion Good practice: based on clinical experience

Summary from the 2017 SR by McDonagh et al. regarding schizophrenia in adults (a main SR cited in the 2020 APA guideline) The main SR used to support the 2020 APA guideline for schizophrenia overall suggests comparable efficacy of antipsychotics. However, authors reported some slight differences among the antipsychotics based on low to moderate strength of evidence (SOE). The following comparative effectiveness information is primarily applicable to “…adults (mean age 25 to 50 years), with mainly moderate and moderate-to-severe disease…” treated for a first-episode 53:

• “Olanzapine, aripiprazole, risperidone, quetiapine, and ziprasidone were similar in function, quality of life, mortality, and overall adverse effects. Core illness symptoms were better with olanzapine and risperidone than asenapine, quetiapine, and ziprasidone, and with paliperidone than lurasidone and iloperidone.”

• “Haloperidol had similar benefits but more adverse effects than olanzapine and risperidone”

• Based on low quality evidence ziprasidone may improve quality of life better than haloperidol

• “Symptom response and remission were better with olanzapine than haloperidol, but no differences were found in response between haloperidol and aripiprazole, quetiapine and ziprasidone, or in remission between haloperidol and ziprasidone (low SOE).”

• “Core illness symptoms were improved significantly more with olanzapine and risperidone than haloperidol (moderate SOE) …”

24 • “Olanzapine improved negative symptoms significantly more than haloperidol (moderate SOE), and risperidone and aripiprazole improved negative symptoms significantly more than haloperidol (low SOE).”53 B. Bipolar Disorder

Major classes of bipolar disorder include bipolar I disorder and bipolar II disorder. Bipolar I disorder is characterized by the lifetime occurrence of a full manic episode (severe symptoms that last at least 7 days or require hospitalized care) whereas bipolar II disorder is characterized by at least one less severe manic episode that does not result in significant impairment, referred to as hypomania. In addition to hypomania, individuals also experience major depressive episodes and there should be an absence of psychosis.66 Depression predominates the disease course for most, and is a major source of disability over time.67 Mania is characterized by increased energy with an abnormally elevated or irritable mood during which time the individual also experiences certain symptoms such as reduced need for sleep, elevated self-esteem, or racing thoughts. Sometimes both manic and depressive symptoms occur during the same episode; this is referred to as “mixed features.” “Rapid cycling” is another modifier which is the occurrence of 4+ different mood episodes (ie, depression, hypomania, mania) within a given year.66 Overall, bipolar disorder is characterized by a relapsing-remitting course with periods of relapse and remission of mood symptoms.9

Bipolar disorders can result in severely impaired functioning; between 2001-2003, approximately 83% of adults with bipolar disorder reported serious impairment. Bipolar disorder carries a high risk of suicide; the rate is approximately 15 times higher than the general population.66 Risk of suicide is highest during depressive phases.10 Concurrent anxiety disorder (among up to 90% of individuals), and substance use disorders are common.9 Among young people, concurrent ADHD is common.10

In the US, over 12 months, an estimated 0.6% of individuals had bipolar I disorder, and between 0.0% and 0.6% had bipolar II disorder.66 Up to 4.4% of people may be diagnosed with a bipolar disorder in their lifetime.68 Onset of bipolar I disorder occurs at a mean age of 18 years old and onset of bipolar II disorder occurs at a mean of the mid-20s.66 Lifetime prevalence among US adolescents (13-18 years) is approximately 2.9%.68 Diagnosis during childhood is controversial and may require longitudinal monitoring.8 Mania symptoms leading to a diagnosis of bipolar I disorder rarely occur before puberty.9 Overview of treatment

Treatment of bipolar disorder includes a targeted phase to improve an emergent mood (ie, stabilizing mania or depressive symptoms) followed by a maintenance phase, generally at a euthymic mood, to prevent relapse.67 Medications used to treat bipolar disorder have several purposes. Some are used to treat specific symptoms (ie, acute mania, mixed mania and depression, or depression); others aim to treat residual symptoms and prevent relapse into an acute episode of mania or depression.10,67 Common medications used include anticonvulsants (valproate [divalproex], carbamazepine, lamotrigine) or lithium, antipsychotics, and possibly antidepressants. Anticonvulsants and the salt lithium are often called “mood stabilizers.” Antipsychotics, especially SGAs, are a mainstay of treatment of acute mania or mixed episodes. Other “antimanic” treatment options, that is medications which improve mania symptoms without typically causing a “switch” to depression, include valproate, carbamazepine, and lithium.9,10 Depression symptoms are often more resistant to treatment67; select SGAs (lurasidone, cariprazine, olanzapine/fluoxetine, quetiapine) have demonstrated efficacy.10 Other medications that

25 may be used for acute depression include lithium (li), lamotrigine, valproate (val), and antidepressants. For long-term maintenance treatment, various SGAs have demonstrated efficacy in preventing mood episodes either as monotherapy or in combination with lithium or valproate (quetiapine [monotherapy off-label] ± li/val, asenapine, aripiprazole ± li/val, olanzapine, risperidone long-acting injectable ± li/val, lurasidone ± li/val (off-label), paliperidone >6 mg (off-label), and ziprasidone ± li/val).10,22,26 In addition, lithium, valproate, lamotrigine, or carbamazepine may be used.10 Short-acting injectable antipsychotics may be used to treat severe agitation associated mania, but oral options are usually preferred if feasible.10

During acute treatment of mood episodes, monotherapy or combination therapy (often with a mood stabilizer + SGA) may be considered. In general, combination therapy may be preferred when symptoms are severe or when the patient has a history of partial response to monotherapy.10 Guidelines also recommend considering combination therapy when a patient presents for treatment of a new mood episode and is already on a maintenance treatment that has been partially effective (eg, adding an SGA to lithium).8-10 When choosing among monotherapy options, antipsychotics tend to have a faster onset of action than mood stabilizers, and may be useful when a rapid onset of effect is desired (eg, severe mania, high suicide risk).9,10 Short-term treatment for a mood episode is continued until remission of symptoms; this typically occurs within 3 months, but mood stability may require 6+ months. Clinicians may consider tapering off medications used acutely and/or continuing as maintenance therapy.9 Most patients will require long-term maintenance treatment.10 Continuation of medications effective during an acute phase, particularly if they are among first-line recommendations for maintenance treatment, should be considered (but not monotherapy with an antidepressant). When feasible, monotherapy maintenance treatment is preferred to limit polypharmacy. However, combination therapy may be considered based on patient history and response (eg, if subthreshold mood symptoms persist, or relapses occur).9 Over the lifetime, most patients will not be effectively treated with only monotherapy; short- or long-term combination therapy (often mood stabilizer + antipsychotic) may be required to better manage symptoms and prevent recurrence.10 According to clinical practice guidelines, lithium has the most robust evidence for maintenance treatment; it is effective at preventing depression, mania and reducing suicide risk.9,10

Appendix C Table C1 provides a summary of FDA-approved indications, black-box warnings and notes about medications, or medications classes other than antipsychotics used in the treatment of bipolar disorder.

A 2018 SRMA of RCTs, nonrandomized controlled trials, or prospective cohort studies for the treatment of bipolar disorder reported the following medications as having convincing evidence of efficacy among adults (mostly in patients with bipolar I disorder)69:

• “Modest improvement” of acute mania in bipolar I disorder compared to placebo: lithium, asenapine, cariprazine, olanzapine, quetiapine, risperidone, ziprasidone (low-SOE)

o The only antipsychotic with FDA approval that did not demonstrate benefit versus placebo was aripiprazole (“insufficient strength of evidence”). Haloperidol also had insufficient strength of evidence versus placebo. The insufficient evidence was due to study limitations and imprecision.

o Effect of olanzapine and divalproex/valproate were similar (low-SOE)

26 o Paliperidone, which is not FDA approved for bipolar disorder, also improved acute mania versus placebo at higher doses (median dose 9 mg, no benefit at 3 mg or 6 mg) (low-SOE)

o Insufficient evidence for various combinations (eg, asenapine, aripiprazole, quetiapine, olanzapine, risperidone, or ziprasidone + a mood stabilizer vs. a mood stabilizer)

o Insufficient evidence for various mood stabilizers for mania versus placebo: carbamazepine, valproate

• Maintenance treatment (increases time to recurrence of any episode versus placebo) for bipolar I disorder: lithium (low-strength evidence)

o Insufficient evidence for various antipsychotics versus placebo: aripiprazole, paliperidone, olanzapine, quetiapine, risperidone, aripiprazole LAI, risperidone LAI

• Depression associated with bipolar I & II disorder: “evidence was insufficient” for any agent

o However, no antipsychotic trials met inclusion criteria (due to <3 months of follow-up). Cariprazine was not included among the antipsychotics at the time of this study.

• Similar serious adverse effects. SGAs, except for quetiapine, were associated with more EPS vs. placebo. More EPS occurred with haloperidol versus other antipsychotics. More “clinically significant weight gain” occurred with olanzapine.

This SRMA is considered more “conservative” because they excluded studies with >50% attrition rates. Summary of treatment goals and recommendations from guidelines for adults

When choosing among treatment options for various phases, guidelines recommend selecting a treatment based on goals (eg, how fast a response is needed), patient preference, prior treatment history, anticipated side effects, and comorbidities.9,10 In general, there is a dearth of evidence for specific treatment of bipolar II disorder. Many trials may enroll both bipolar I&II patients without reporting separate data10; thus guidelines tend to recommend extending evidence from type I to type II based on expert consensus in the absence of specific studies.9,10 For example, recommendations for mania may be considered for hypomania that is causing enough impairment to require treatment.10 NICE does not make separate recommendations for bipolar II disorder, but states the intended disease states for the guidelines are all bipolar disorders including bipolar I, bipolar II and others.8

The goals of treating acute manic or mixed episodes include quickly reducing symptoms followed by achieving a stable mood. Although a single medication may be used, only approximately 50% of patients achieve symptom remission within 3-4 weeks with monotherapy, so in clinical practice, combination therapy is common for better response and improved remission.10 The combination of an antipsychotic and mood stabilizer is typically effective more quickly and induces a better response than either agent alone. The Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline notes that “in general, combination therapy is preferred to mood stabilizer (MS) monotherapy because clinical trials suggest that on average about 20% more patients will respond to combination therapy.”10 The combination (SGA + MS) may also perform better than SGA monotherapy but it is not well-studied.10 Response to antimanic treatments is expected within 1-2 weeks (lithium may have a slower onset).

27 Prescribers should consider switching to alternatives or adding an additional agent if no response within 2 weeks.10 The NICE guideline recommends treatment until symptom resolution, then assessing for the need of long-term therapy within 4 weeks of symptom resolution. If continued, therapy should be reviewed after 3-6 months.8 FGAs may have a greater risk of inducing a switch to depression relative to SGAs.10

Guidelines from the CANMAT 2018, NICE (update 2018), and BAP (2016) recommend antipsychotics, among other agents (ie, lithium, divalproex), with some differences in which antipsychotics are recommended first for the treatment of acute manic or mixed episodes.8-10

• CANMAT recommends various SGAs (quetiapine, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine) while BAP and NICE recommend haloperidol, olanzapine, quetiapine, or risperidone.8-10 NICE and BAP separate the treatment approach by whether the patient was already on a therapy.8,9 If patients are already on an appropriate maintenance monotherapy, optimization of that treatment may be considered first.9 An antipsychotic may be added to a MS if symptoms are severe or if the MS cannot be optimized. Otherwise, a recommended antipsychotic may be started alone.8,9

o CANMAT recommends other antipsychotics, olanzapine (monotherapy or combination therapy), ziprasidone monotherapy, and haloperidol as second-line options due to safety concerns.10

o CANMAT recommends combination therapy (first-line specific antipsychotics + lithium or divalproex) if a fast response is needed or if the patient has a history of partial response, and also for presentation with mixed features (specifically recommending SGA + valproate), or patients with possible schizoaffective disorder (specifically recommending antipsychotic + lithium/valproate).10 An exception to combination options is adding lithium or valproate to paliperidone and ziprasidone due to lack of evidence of added benefit.10 BAP also recommends combination therapy with a MS + antipsychotic if the symptoms are severe or after breakthrough symptoms on one of the treatments alone.9

• Several treatments are NOT recommended for acute mania: lamotrigine, gabapentin, topiramate8,25

The goal of treating acute depression is full remission of symptoms to achieve a stable mood. Antipsychotics recommended among the first-line options are in line with those with FDA approval for bipolar depression (except for cariprazine, which may be due to lack of data the time of publication of these guidelines). Antipsychotics, compared to mood stabilizers, tend to demonstrate faster improvement, and may be particularly helpful among patients in which a rapid response is needed (eg, suicide risk, medical complications).10 NICE guideline recommends treatment until symptom resolution, then assessing for long-term therapy within 4 weeks of symptoms resolution. If continued, it should be reviewed after 3-6 months.8

• Guidelines vary slightly in first-line recommendations for bipolar I acute depression. o CANMAT first-line options (select in this order based on tolerability, and consider patient history): quetiapine, lurasidone + lithium/valproate, lithium, lamotrigine, lurasidone, adjunctive lamotrigine (may be particularly helpful for lithium non-responders)10

28 § CANMAT considers cariprazine, and olanzapine/fluoxetine second-line due to tolerability concerns10

o NICE first-line options (either for those not on maintenance, or to add-on to maintenance therapy with lithium or valproate): olanzapine/fluoxetine or quetiapine8

o BAP first-line options (either for those not on maintenance, or to add-on to maintenance therapy with lithium or valproate): quetiapine, olanzapine, lurasidone, or olanzapine/fluoxetine (olanzapine alone is an alternative option)9

o CANMAT does not recommend a couple antipsychotics due to limited efficacy or negative evidence: aripiprazole monotherapy, ziprasidone monotherapy or adjunctive therapy10

• For bipolar II acute depression, CANMAT recommends quetiapine first-line.25 BAP notes that evidence for bipolar I can probably be extended to bipolar II disorder.9

The goal of maintenance treatment is to maintain prevent relapses, control any residual symptoms,9 and prevent poor outcomes (eg, lack of functioning, suicide).10 Patients are at high-risk for relapse, so as long as acceptable to the patient, long-term treatment is recommended.9 Some evidence supports starting long-term treatment, even after the index episode, to prevent neuroprogressive components (eg, worsening cognition, reduction in grey matter) that may occur with bipolar disorder. Psychosocial interventions as an adjunct to medications is recommended to improve long-term outcomes.10 CANMAT notes that in general, continuing medications that were effective acutely into the maintenance phase should be considered (except for perhaps antidepressants). This is particularly true if the patient received a medication for acute therapy that is also listed among first-line options for maintenance therapy. SGA combination therapy with lithium or valproate reduces the risk of recurrence when continued together for up to 6 months, but there is a lack of evidence regarding potential benefits after 6 months. Therefore, CANMAT recommends weighing the risks versus benefits of continuing the SGA.10 Medications considered for long-term maintenance vary in their established benefits (ie, for preventing mania, or depression). According to CANMAT guidelines, the antipsychotics quetiapine (as monotherapy or with lithium/valproate) and olanzapine have the highest level of evidence for preventing depression and mania. Most of the recommended antipsychotics align with FDA approved indications except quetiapine monotherapy is off-label; CANMAT second-line options of lurasidone, and paliperidone are also off-label.10,11,22 • The CANMAT, BAP and NICE guidelines all recommend lithium as first-line treatment for maintenance therapy for bipolar I disorder, or valproate as an alternative.8-10 o CANMAT also recommends the following agents/combinations as first-line after considering lithium (for consideration in this order): quetiapine, valproate, lamotrigine, asenapine, quetiapine + lithium/valproate, aripiprazole + lithium/valproate, aripiprazole, aripiprazole once-monthly LAI10 § CANMAT recommends olanzapine, risperidone LAI, adjunctive risperidone LAI, paliperidone (at dose >6 mg), lurasidone + lithium/valproate, and ziprasidone + lithium/valproate among second-line options due to either weaker efficacy evidence or tolerability concerns o NICE also recommends olanzapine as another first-line alternative to lithium8

29 o BAP also recommends antipsychotics that patients responded very well to during acute treatment9 • For maintenance treatment of bipolar II disorder, CANMAT recommends either quetiapine, lithium or lamotrigine first-line.10 BAP recommends either lamotrigine or quetiapine.9

Summary of guideline recommendations for youth

Principles and considerations are similar to adults, with greater emphasis on comorbidities and the tolerability of medications. Any polypharmacy should be considered judiciously. The risk of metabolic side effects with SGAs may be greater among adolescents than adults. More limited data is available regarding treatment of depression than acute mania.9,10 Children/adolescents may be at higher risk of switching to mania during depression treatment than adults.9 The NICE guideline recommends “not routinely continuing antipsychotic treatment” for >12 weeks (for treatment of mania or depression).8

• For acute mania in bipolar I disorder, both BAP and NICE recommend aripiprazole (for age 13+). Otherwise, they recommend selecting an antipsychotic recommended for adults.8,9 CANMAT recommends lithium, risperidone, aripiprazole, asenapine or quetiapine as first-line.10

o CANMAT recommends olanzapine and ziprasidone second-line due to tolerability concerns (CANMAT)10

• For acute depression, both NICE (for moderate-severe symptoms) and BAP recommend considering therapies used for adults.8,9 CANMAT recommends lurasidone as first-line.10

o CANMAT recommends Olanzapine/fluoxetine as 3rd line due to tolerability concerns, and quetiapine is also recommended 3rd line (noting that although studies of quetiapine in children were negative, this was likely due to methodological flaws)10

• For maintenance treatment, there is very limited data. NICE and BAP do not provide recommend pharmacologic treatments.8 9 CANMAT recommends aripiprazole, lithium and valproate first-line. Adjunctive lamotrigine may be considered for age 13+. CANMAT recommends asenapine, quetiapine, risperidone or ziprasidone as 3rd-line based on very limited evidence.10

Table 3 provides a summary of pharmacotherapy recommendations from recent clinical practice guidelines. Note that cariprazine received FDA approval for bipolar I depression after publication of these guidelines. The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) does include some information about its use for bipolar depression (placing it as a second-line option in adults).10 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Guidelines for the • Acute mania Management of o Acute agitation: oral medications with rapid onset first; if Patients with Bipolar persistent, severe, or patient refuses oral agents, consider IM Disorder; CANMAT and § 1st line: aripiprazole IM (LOE 2), lorazepam IM (LOE 2), ISBD, 201810 loxapine inhaled (LOE 1), olanzapine IM (LOE 2)

30 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) § Antipsychotic oral options: • Second line: asenapine SL (LOE 3), risperidone ODT (LOE 3) • Third line: haloperidol PO (LOE 4), quetiapine PO (LOE 4), risperidone PO (LOE 4) o Mania: Select monotherapy or combination; choose based on how fast a response is needed (combination therapy is usually faster), historical treatments and response, severity, tolerability concerns and patient preference. § 1st line monotherapy (in this order): li (LOE 1), quetiapine (LOE 1), DVP (LOE 1), asenapine (LOE 1), aripiprazole (LOE 1), paliperidone at dose >6 mg (LOE 1), risperidone (LOE 1), cariprazine (LOE 1) § 1st line combinations (in this order): quetiapine + Li/DVP (LOE 1), aripiprazole + Li/DVP (LOE 2), risperidone + Li/DVP (LOE 1), asenapine + Li/DVP (LOE 2) § May select a treatment based on clinical features (eg, family history of response to li, irritability, anxiety, mixed features; for example: • Mixed features: “Evidence supports the preferential use of atypical antipsychotics and divalproex in these cases, with combination therapy frequently required” • Psychotic features: no evidence of superiority of any first-line treatments; suggests combination therapy of Li/DVP + SGA for “mood-incongruent psychotic features” or patients with possible schizoaffective disorder • Acute bipolar I depression o Mediations are considered essential, but adjunct psychosocial interventions should also be offered o 1st-line (in this order): quetiapine (LOE 1), lurasidone + Li/DVP (LOE 1), Li (LOE 2), lamotrigine (LOE 2), lurasidone (LOE 2), adjunctive lamotrigine (LOE 2) o Not recommended (lack of efficacy): aripiprazole (level 1 negative), ziprasidone as monotherapy or combination (level 1 negative) o May select treatment based on presenting features: antipsychotic (quetiapine or lurasidone) if faster response needed; mixed symptoms (consider combination with OLA/FLX, asenapine, or lurasidone; avoid antidepressants); psychotic symptoms (clinical experience suggests antipsychotics or ECT); rapid cycling (consider Li, DVP, OLA, QUE)

31 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • Maintenance for bipolar I o Adjunctive psychosocial treatments to prevent recurrence o 1st-line recommendations (in this order)a: Li (LOE 1 for any mood, depression, mania), quetiapine (LOE 1 for any mood, depression, mania), DVP (LOE 1 for any mood, LOE 2 for depression, LOE 3 for mania), lamotrigine (LOE 1 for any mood and depression, LOE 2 for mania), asenapine (LOE 2 for any mood, depression, and mania), quetiapine +Li/DVP (LOE 1 for any mood, depression, and mania), aripiprazole+Li/DVP (LOE 2 for any mood and mania, no data for depression), aripiprazole (LOE 2 for any mood and mania, no data for depression), aripiprazole once monthly (LOE 2 for any mood and mania, no data for depression) o is not recommended due to emergent depressive symptoms and risk of side effects (level 2 negative) o Difficult to use clinical presentation to direct treatment; patients are expected to try different therapies in their lifetime. § Lithium responders: “gold standard for maintenance treatment” as effective for preventing mania and depression and against suicidality. § Lamotrigine responders: depressive symptoms predominate, comorbid anxiety (do not use if frequent manic symptoms) § Quetiapine responders: may be particularly useful for mixed features § Insufficient data to differentiate antipsychotic responders and non-responders. • Treatment-refractory o Ensure adherence and adequate previous trials o If non-adherence is a factor after using strategies to improve it, consider LAI: risperidone monotherapy or adjunctive (LOE 2), or aripiprazole once-monthly (LOE 2) o Limited evidence is available; adjunctive clozapine may be effective • Bipolar II o Acute depression § 1st line: quetiapine (LOE 1) o Maintenance § 1st line: quetiapine (LOE 1), lithium (LOE 2), lamotrigine (LOE 2) • Special Considerations: o Pregnancy § Collaboratively make decisions to discontinue medications § Psychosocial strategies are preferred in the first trimester when possible § DVP should be avoided (risk of neural tube defects, other abnormalities, and neurodevelopmental delays)

32 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) § For most agents, risk during pregnancy cannot be ruled out o Postpartum § Encourage initiation or optimization of maintenance treatment § Weigh breastfeeding risks vs. benefits; a SR “suggested quetiapine and olanzapine as preferred choices for breastfeeding, considering their relatively lower infant dosages” o Treatment of Children and Adolescents § Similar considerations for adults, with greater consideration for comorbidities (e.g., ADHD) and tolerability • Consider polypharmacy judiciously § Acute mania: • 1st-line: lithium (LOE 1), risperidone (LOE 1), aripiprazole (LOE 1), asenapine (LOE 2), quetiapine (LOE 2) § Acute depression: • 1st-line: lurasidone (LOE 2), there is a paucity of data § Maintenance: • 1st-line: aripiprazole (LOE 2), lithium (LOE 2), divalproex (LOE 2) o Older Age § Limited data; pay close attention to PK changes and DDIs § Acute mania • 1st-line: lithium (LOE 2), divalproex (LOE 2) § Acute Depression • 1st-line: quetiapine (LOE 2), lurasidone (LOE 2); however, lithium or lamotrigine may be considered before antipsychotics due to concerns about side effects (both LOE 4) § Maintenance • First-line: consider continuing what was effective acutely; also lithium (LOE 2), lamotrigine (LOE 2), divalproex (LOE 3) o Comorbidities: treatment should prioritize the most severe symptoms first (eg, mania, psychosis, suicidal ideations), then consider other treatments when the mood is more stable. Psychosocial interventions are also recommended, with most of evidence for interventions during acute depression and maintenance phase. • Maintenance phase: first line – psychoeducation (ie, education about the disease, education of family members) [LOE 2]; second-line – CBT (LOE 2), FFT (LOE 2)

33 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Bipolar Disorder: Recommendations for children, adolescents and adults, and for the spectrum Assessment and of bipolar disorders (ie, bipolar I, bipolar II, and other bipolar disorders). Management; NICE, Selection of treatment should be based on patient preference, previous 2018 (update to 2014)8 treatment response, side effects, and comorbidities. Note (2020 update): Valproate is not recommended among girls or women of child-bearing potential unless other options are not feasible due to risks of “fetal malformations, and adverse neurodevelopmental outcomes after any exposure in pregnancy.” (2) “Do not offer gabapentin or topiramate to treatment bipolar disorder” (2)

Psychological interventions (e.g., CBT or interpersonal therapy) are also recommended, particularly for depressive symptoms and relapse prevention. Among adolescents, psychological interventions are recommended for long- term management (while pharmacologic therapies should not be used “routinely,” but may be considered). Adult recommendations • Pharmacologic treatment of mania or hypomania or mixed state o If not on antipsychotic or MS already: haloperidol, olanzapine, quetiapine, or risperidone (2) o If on a MS (Val or other for prophylaxis) already: optimize MS; if no response, may add haloperidol, olanzapine, quetiapine, or risperidone (3) § If on Li, optimize Li and consider adding haloperidol, olanzapine, quetiapine, or risperidone (3) o If on an AD when (hypo)mania develops, consider stopping the AD o “Do not offer lamotrigine to treat mania”(2) o If initial antipsychotic is not effective or not tolerated (“including rapid weight gain”), consider an alternative antipsychotic (choose another of those recommended) [2]; if that fails, add Li or Val (if Li not appropriate or ineffective) (3) o Assess within 4 weeks of symptom resolution; if continue mania treatment, review again after 3-6 months (2) • Pharmacologic treatment of moderate to severe depression o If not on treatment: OLA/FLX, or QUE (2) § Alternatives: olanzapine monotherapy, or lamotrigine (3) § If no response (to OLA/FLX or QUE), then lamotrigine (3) o If on Li already: optimize Li; if Li maximized, consider OLA/FLX, or QUE § Alternatives: add OLA, or lamotrigine § If no response (to adding OLA/FLX or QUE), stop OLA/FLX or QUE and add lamotrigine (to Li) (3) Lurasidone was not yet licensed for bipolar depression, but authors thought It should be considered future guidelines o If on VAL already: optimize VAL dose; if limited response, add OLA/FLX or QUE § Alternatives: add olanzapine, or lamotrigine (3)

34 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) § If no response (to adding OLA/FLX or QUE), stop OLA/FLX or QUE and add lamotrigine (to VAL) (3) o Assess within 4 weeks of symptom resolution; if continue depression treatment, review again after 3-6 months (2) • Pharmacologic maintenance treatment o First-line: lithium (2) § Alternatives (if Li not tolerated or appropriate): valproate or olanzapine; if fails, then consider quetiapine (3) § If Li not effective: consider + Val (3) Recommendations for children and young people (age 13-18) Mania: average age among studies – 13 years (range 6-18) Depression: average age among studies – 15 years (range 10-18) Maintenance: average age among studies – 9 years (range 4-17) • Pharmacologic treatment of (hypo)mania o Consider treatment options as for adults; also consider aripiprazole for “moderate-severe mania in bipolar I disorder” (3) o “Do not routinely continue antipsychotic treatment for longer than 12 weeks” • Pharmacologic treatment of moderate to severe depression o Consider treatment options as for adults with concurrent psychological intervention (3) o “Do not routinely continue antipsychotic treatment for longer than 12 weeks” o Other treatment options recommended (eg, CBT, IPT for at least 3 months) [1st line for less severe symptoms] (2) • Pharmacologic maintenance treatment o Pharmacologic treatments not recommended for long-term management. Family/psychological interventions recommended. (3) Evidence-based Treatment of acute mania in patients not already receiving long-term Guidelines for Treating treatment: Bipolar Disorder, • For rapid treatment, consider oral antipsychotic (****) revised 3rd edition; o “haloperidol, olanzapine, risperidone, and quetiapine are BAP, 20169 particularly effective in short-term reduction of symptoms” o Alternatives: valproate (but not for women of child-bearing potential), other antipsychotics, carbamazepine, Li • “do not escalate the dose of a simply to obtain a sedative effect” (S) Treatment of acute mania in patients already receiving long-term treatment: • Assess potential cause; if “current presentation is due to inadequate symptom control,” maximize current treatment (S); increasing the dose of antipsychotics or valproate (IV) or targeting higher serum concentrations with Li (I) may be more effective. • Consider adding an antipsychotic or valproate to lithium (****)

35 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Treatment of severe acute mania or mania not controlled with optimized first- line treatments: • Add another agent: o Li or VAL + antipsychotic (****) o Clozapine “in more refractory illness (**) o ECT (for very severe, or treatment-resistant, or if severe and pregnant) Other acute mania considerations: treat mixed features like (hypo)mania (I); treatment for hypomania or less severe mania can be extrapolated from data for treatment of mania (IV) • Duration: after full symptom remission (typically occurs within 3 months, but may require 6+ months), may taper any medications only used for acute mania (over 4+ weeks) Treatment of acute depression in patients NOT receiving long-term treatment: • Quetiapine, olanzapine or lurasidone (***); olanzapine/fluoxetine (***) • Lamotrigine, usually with another treatment (****) • If “less severe” symptoms: Li (**) • Co-prescribe any AD with an anti-manic agent (ie, antipsychotic, Li, VAL) (S) o “Dual-action monoamine re-uptake inhibitors (, , , and (II)) carry a greater risk of precipitating a switch to mania than single action drugs” (especially SSRIs) (II) o For BP II: if use AD as monotherapy, increase dose gradually and closely monitor for hypomania/mixed state/agitation (IV) • ECT for more severe symptoms or if severe symptoms and pregnant (***) Treatment of acute depression in patients receiving long-term treatment: • Optimize treatments and ensure current long-term treatment prevents mania (ie, antipsychotic, Li, VAL) (S) • If no response to optimization, initiate treatment as recommended for patients NOT receiving long-term treatment Other acute depression considerations: • Use of AD is controversial (IV) • Most evidence is for BP I, but it probably can be applied to BP II (IV) • May taper antidepressants after 12 weeks of remission (*), but continuation is reasonable if relapse (IV) • Treatment-resistant depression: little information; consider ECT (***), augmentation strategies for unipolar depression. Ensure use of anti-manic agent (S). Maintenance treatment: • Suggested order of evidence of efficacy: “Li > VAL > olanzapine > lamotrigine > quetiapine > carbamazepine” (I) • “Consider lithium as initial monotherapy” (****) if patients are adherent o Good for preventing mania, depression, mixed, and for reducing suicide (I)

36 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • Other options (if Li ineffective, or cannot tolerate Li, or adherence is a concern): VAL, or antipsychotics (****) o If a patient responded very quickly/well during an acute treatment phase, long-term use as monotherapy may be considered (IV). “This may lead to preferential use of dopamine antagonists; active consideration of lithium as a better alternative should be promoted” (IV) o Lamotrigine or quetiapine for BP II monotherapy (***) o Lamotrigine with a long-term anti-manic agent for BP I (IV) • If poor monotherapy response or subthreshold symptoms: o For mania, combine 2 anti-manic agents (IV) o For depression, “a combination of lithium, lamotrigine, quetiapine, lurasidone, or olanzapine may be more appropriate” (IV) o Clozapine for refractory mania (**) o Possibly AD for minority of patients (**), ECT (*), psychotherapy (**) • Other maintenance treatment considerations: o Long-term term treatment should be considered after 1 manic episode (***) o Consider applying evidence from BP I to BP II (**) o LAI can be considered if preferred or poor adherence to oral (**); “only risperidone has RCT support”; for mania prophylaxis (II) o May add-on short-term therapies for acute stressors (eg, antipsychotics, anxiolytics) (IV) o No specific treatments for rapid cycling; consider other contributors (**), including AD (*) o Treatment discontinuation: there is a risk of relapse even after years (II); taper for at least 4 weeks (S); abrupt d/c of Li can provoke mania (I) Treatment of Young People Mania: • 1st-line: aripiprazole (because approved for those 13+ with BP I) (***) • Otherwise: follow recommendations for adults o “There is some primary evidence that olanzapine, quetiapine, and risperidone are efficacious in adolescents” (**) • “Be aware of the increased potential for a range of adverse reactions and effects, particularly weight gain” (S) Depression: • Consider psychotherapies and pharmacotherapy as recommended for adults (*) • Children/younger people be at higher risk of switching to mania with AD use than adults (II) Treatment of Elderly • Consider lower doses; consult medication prescribing info (*)

37 Table 3. Summary of Select Recent Clinical Practice Guidelines for Bipolar Disorder Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Pregnancy Considerations • Valproate and carbamazepine have teratogenic potential (I); do NOT use valproate in women of child-bearing potential (I) o Li has been associated with cardiac malformations, but “concerns about lithium and cardiac malformations appear to have been disproportionate (II)” • Antipsychotics seem to have low or no teratogenic risk, but “risks from new compounds are usually unknown and always justify caution” • Balance risks with benefits (S) Abbreviations: AD, antidepressant; BAP, British Association of Psychopharmacology; CANMAT, BP, bipolar disorder; CANMAT, Canadian Network for Mood and Anxiety Treatments; CBT, cognitive behavioral therapy; DVP, divalproex; ECT, electroconvulsive therapy; FFT, family-focused therapy; IM, intramuscular; ISBD, International Society for Bipolar Disorders; li, lithium; LOE, level of evidence; MA, meta-analysis; MS, mood stabilizer; NICE, The National Institute for Health and Care Excellence; OLA, olanzapine; OLA/FLX, combination of olanzapine and fluoxetine; PK, pharmacokinetic; QUE, quetiapine; RCT, randomized controlled trial; SGA, second generation antipsychotic; VAL, valproate aEvidence ranking is based on preventing any mood disorder, or specifically depression or mania for each first- line maintenance option.

CANMAT and ISBD Recommendation Ratings: First-line: efficacy = level 1 or 2 + clinical support for safety + no risk of switch Second-line: efficacy = level 3 (or higher) + clinical support for safety + low switch risk Third-line: efficacy = level 4 (or higher) + clinical support for safety Not recommended: lack of efficacy = level 1, or level 2 (with expert opinion) CANMAT and ISBD Level of Evidence Ratings: Level 1: precise MA OR “replicated double-blind (DB), randomized controlled trial (RCT) that includes placebo or active control comparison (n ≥ 30 in each active treatment arm)” Level 2: imprecise MA or 1 “DB RCT with placebo or active control comparison condition (n ≥ 30 in active treatment arm) Level 3: 1+ “DB RCT with placebo or active control comparison condition (n = 10-29 in active treatment arm or health system administrative data” Level 4: “uncontrolled trial, anecdotal reports, or expert opinion” BAP Evidence Grades High (****): RCTs or compelling observational data; moderate (***): RCTs with flaws or observational data; Low (**): RCTs with significant flaws or observational data; Very low (*): very poor quality RCTs, poor observational data or “case series/reports”; S: “standard of care” by expert consensus BAP Levels of Evidence I: MA of RCTs, or 1+ “large, good-quality, RCT” or “replicated smaller RCTs;” if observational study, “large representative population sample” II: 1 small RCT or quasi-experimental study data; if observation study, “small, well designed but not necessarily representative samples” III: Descriptive studies including case-control studies, case reports IV: expert opinion or experience NICE: Does not clearly label recommendation strength; the strengths listed in the table (1 to 3) were translated based on wording: (1) a “must”; applies to all patients, (2) a “should”; benefits > harms for most patients, and (3) a “could”; benefits> harms, but other similar options available, selection depends on preference

38 C. Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is type of neurodevelopmental disorder. Core symptoms include social deficits, and restricted/repetitive behaviors. Comorbidities among children with ASD commonly occur; examples include seizures, sleep disturbances, attention-deficit/hyperactivity disorder (ADHD), and mood disorders. Many children (about 30%) have an intellectual disability.70

ASD onset typically occurs by about age 2, but individuals with a more mild presentation may be diagnosed later when greater levels of social functioning are required.61 The 2014 estimated prevalence of ASD in the US was 16.8 per 1,000 children at age 8 years.71

Antipsychotics may be used as part of a multi-modal approach (including developmental/behavior therapy) to treat emotional and behavioral symptoms of ASD, but are not typically used to treat the core symptoms of ASD (eg, restrictive/repetitive behaviors).70,72 In 2018 the BAP recommended that SGAs should not be routinely used to treat repetitive behaviors.73 Treatment with medications should be considered only after ruling out other stressors (eg, environmental changes or medical causes such as pain), or irritability co-occurring from mood and anxiety disorders.73 The BAP recommended risperidone or aripiprazole for irritability associated with ASD only after failure of behavioral or educational approaches (strength of recommendation, A, based on “…the highest quality evidence”).73 According to the 2019 guideline by the American Academy of Pediatrics (AAP), SGAS (aripiprazole and risperidone are FDA-approved and have the most supportive evidence) may be used to treat irritability and severe disruptive behaviors. In addition, atypical antipsychotics may improve repetitive behaviors over the short-term, based on multiple double-blind placebo-controlled trials. However, they (risperidone and aripiprazole) are considered “more effective for targets of tantrums, aggression, and self-injurious behavior.”70 SGAs may also have a role in treatment of other psychiatric comorbidities (eg, mood dysregulation disorder or hyperactivity associated with ADHD), but they are not considered first-line therapies.70

A 2017 systematic review from the Agency for Healthcare Research and Quality reported that there is moderate quality evidence that SGAs “…probably decrease irritability, and decrease slightly lethargy/social withdrawal, stereotypy and inappropriate speech; they likely increase response rates and (slightly) clinical severity.”38 Limited evidence supports use of other pharmacotherapies (eg, methylphenidate, , ).74 Treatment of ASD in Adults

Few organizations have guidelines specific to management of ASD in adults.72,75 ASD is a lifelong disorder, and adults exhibit similar symptoms as children and adolescents with ASD. Diagnosis of an ASD during adulthood can be challenging due to significant overlap with many common comorbidities and difficulties assessing the adult presentation of symptoms.75 The NICE 2016 update guideline for adults does not recommend antipsychotics for core autism symptoms. Similar to children, psychosocial interventions are recommended first-line for “challenging behaviors” (eg, irritability, aggression). Antipsychotics may be considered when symptoms are so severe as it is not possible or safe to institute a psychosocial intervention, or as an adjunctive treatment with psychosocial interventions. No specific antipsychotic is recommended. In terms of duration, they recommend discontinuing the antipsychotic within 6 weeks if no significant benefits are observed. In contrast, anticonvulsants are “not routinely” recommended for challenging behaviors.75

39 The British Association of Pharmacology 2018 expert consensus-based recommendations for treating irritability recommend nonpharmacologic options (eg, behavioral interventions) first, and consider use of aripiprazole, risperidone, or an SSRI cautiously on a case-by-case basis. Antipsychotics are not mentioned as a treatment option for any other target symptoms.72

See Table 4 for a summary of pharmacotherapy recommendations from newer guidelines (since 2019) for autism spectrum disorder in children. Table 4. Select Recent Autism Spectrum Disorder Related Treatment Guidelines Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Identification, Treatment goals include improving core symptoms and maximizing functional Evaluation, and skills. Management of • Medications not effective for the core symptoms of ASD, but they may be Children with Autism used for “coexisting behavioral health disorders” or for “problem behaviors Spectrum Disorder; or symptoms causing significant impairment and distress” such as AAP, 202070 “aggression, self-injurious behavior, sleep disturbance, mood lability, anxiety, hyperactivity, impulsivity, inattention.” • Consider medications only after careful assessment of what may have triggered a behavior and treatment of any triggering medical conditions (eg, GERD, pain). Consider behavioral interventions first. • “children with ASD may be at greater risk for adverse effects” SGA (primarily risperidone or aripiprazole) are potential options to treat specific target symptoms: • Irritability and severe disruptive behaviors (eg, outbursts, aggression, self- injury) o Consider medications only if there is not an identified and treatable medical cause and if the irritability does not respond to behavioral interventions, or it is due to another disorder (eg, ADHD, anxiety) o “Medications most effective if combined with behavioral strategies addressing identified environmental causes” o “Strong support” from double-blind placebo-controlled trials for risperidone and aripiprazole § Other AP “such as olanzapine and quetiapine may have utility on the basis of their adverse effect profile” o Other medication options include alpha-2 agonists (based on small trials for irritability), SSRIs (fluoxetine and ; insufficient evidence), anticonvulsants (valproic acid and divalproex sodium; small studies for irritability, evidence inconclusive), and SNRIs (venlafaxine; very small study) • Hyperactivity, impulsivity, inattention, or distractibility o Consider medications if symptoms persist after behavioral approaches o 1st line: low-dose stimulant (for impulsivity, hyperactivity) o 2nd line or alternative: atomoxetine or alpha-2 agonists o Atypical antipsychotics (aripiprazole, risperidone) are an alternative later-line option as “they may decrease hyperactivity” but “their primary use is for irritability and aggression”

40 Table 4. Select Recent Autism Spectrum Disorder Related Treatment Guidelines Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • Repetitive behaviors (eg, compulsions, “stereotyped motor mannerisms”) o Multiple double-blind placebo-controlled trials (with aripiprazole, risperidone) showing improvement at least in the short-term o Other medication options include anticonvulsants (valproic acid or divalproex; “modest improvement,” “may have improvement with topiramate as a second agent with risperidone”), SSRIs (fluoxetine, ; not shown effectiveness for ASD repetitive behaviors, but may be used to treat anxiety or OCD) • “Mood dysregulation disorder,” anxiety, depression o Treat as recommended for the general population for the identified disorder § 1st line: CBT (strong RCT evidence for anxiety disorders in children with ASD; most effective treatment for general population with OCD, but may be less effective for those with ASD+OCD) § SGA or MS recommended for “mood dysregulation disorder” § Anxiety disorders may be treated with SSRIs (recommends , fluoxetine, citalopram, ) and/or benzodiazepine for “event related anxiety” § Alpha-2 agonists or beta-blockers may be considered for physiologic symptoms of anxiety Practice Guideline: Sleep disturbances among youth with ASD is common (affects an estimated 40- Treatment for 80%). The disturbances may adversely affect the functioning, including and worsening core ASD symptoms. disrupted sleep • There is minimal evidence to guide treatment. No studies identified in the behavior in children guideline SR (up to 2017) examined other pharmacologic treatments. and adolescents with Treatment Recommendations: autism spectrum • Ensure adequate treatment of co-occurring conditions that may affect sleep disorder; AAN, 202076 (level B) and assess for the impact of other medications (eg, stimulants) on sleep and consider adjustments (level B) • Implement behavioral interventions (eg, CBT, education, sleep training) [level B] If other strategies are not successful, consider melatonin (preferably pharmaceutical grade) [level B] Post-diagnostic This is a position statement with an overview of care of children with ASD. management and Detailed information about pharmacotherapy was not a goal. follow-up care for Goals of ASD treatment include: “improving social functioning, play, verbal and autism spectrum nonverbal communication, and functional adaptive skills, as well as reducing disorder; CPS, 201977 maladaptive behaviors, and promoting learning and cognition.” • Overarching steps for managing ASD include: (1) testing for related medical conditions, (2) assessing and managing comorbidities, (3) providing therapies for functional challenges (eg, speech-language therapy), (4) behavioral and developmental interventions to target ASD core symptoms, (5) managing “challenging behaviors,” and (6) providing family or other support

41 Table 4. Select Recent Autism Spectrum Disorder Related Treatment Guidelines Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) • Treating “maladaptive behaviors” (eg, aggression, self-injury): o Treatment options may include: behavioral interventions, parent- training, environmental interventions, pharmacotherapy, or a combination o 1st-line: nonpharmacologic treatments for the maladaptive behaviors; also ensure appropriate medical treatment for comorbidities o Consider medication + other treatment options for the following: “disruptive behaviors that are pervasive, severe, or interfere substantively with a child’s learning, socialization, health or safety, or the quality of family life” § For most children, consider medication only after exhausting other options. If used, medications should be combined with behavioral interventions. § Children with ASD may be more sensitive to side effects; “start low and go slow” § For difficult cases, consult a specialist (ie, child psychiatrist or developmental pediatrician) o Aripiprazole and risperidone are approved to treat irritability and aggression for those 5+ years old • Treating selected comorbidities: o No recommendations for antipsychotics for anxiety, depression, or sleep disturbances o ADHD: first-line therapy is stimulants; alternatives include atomoxetine or alpha-2 agonists combined with parent training § Recommendations from the CPS statement about ADHD with comorbid ASD78: • Treat those with ADHD + ASD the same as those with ADHD alone, but “children and youth with ASD+ADHD are more likely to be nonresponders and to have side effects” • Use “standard evidence-based interventions for ADHD” (eg, behavioral training) before starting medications • Physical activity helps reduce symptoms • Treatment with other therapeutic agents (e.g., antipsychotics, antidepressants) may be considered when there are comorbidities Abbreviations: AAP, American Academy of Pediatrics; ADHD, attention-deficit hyperactivity disorder; AAN, American Academy of Neurology; AP, antipsychotic; ASD, autism spectrum disorder; CPS, Canadian Pediatric Society; CBT, cognitive behavioral therapy ; GERD, gastroesophageal reflux disease; OCD, obsessive compulsive disorder; MS, mood stabilizer; RCT, randomized controlled trial; SGA, second generation antipsychotic; SNRI, serotonin- reuptake inhibitor; SR, systematic review; SSRI, selective serotonin reuptake inhibitor;

AAP: Clinical report for guidance. No information about levels of evidence or recommendation strength included. CPS: It is a position statement. No information about levels of evidence or recommendation strength included.

42 Table 4. Select Recent Autism Spectrum Disorder Related Treatment Guidelines Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) AAN Recommendation Strength: Level B – favorable risk to benefit; clinicians should consider doing this, but it is not as high as an “A” recommendation where clinicians “must” implement the recommendation. Level C is the lowest strength recommendation. Metabolic Side Effects (MSE) of Antipsychotics Background on metabolic risk in patients with schizophrenia or bipolar disorder

Individuals with schizophrenia and bipolar disorder have a higher risk of death (2-3 times higher for schizophrenia) than the general population. This results in a loss of 10-20 years compared to the general population.10,55 Mortality from cardiovascular disease is a major contributory cause.79 Schizophrenia and bipolar disorder are associated with a higher risk of metabolic syndrome, obesity, and diabetes.9,79 Many different factors may contribute to the risk of cardiovascular disease including lifestyle (eg, less exercise, higher rates of cigarette smoking, lower access to healthcare, greater and drug use), genetic causes, and medications.54,79,80 Genome-wide association studies have demonstrated shared metabolic risk pathways between psychotic disorders and metabolic syndrome.81 Indeed, various studies have demonstrated metabolic abnormalities, particularly in glucose homeostasis, in individuals with first- episode psychosis compared to controls with similar body mass index (before taking an antipsychotic).82 While antipsychotics may contribute to increased risk, prospective cohort studies have demonstrated that lack of antipsychotic treatment is associated with a higher risk of mortality than use of antipsychotics in patients with schizophrenia.54

Regarding antipsychotic-induced weight gain, the relative propensity for weight gain seems to vary among antipsychotics. Comparison (of mostly SGAs) via network meta-analysis suggests the greatest risk is with olanzapine and clozapine, while iloperidone, quetiapine, risperidone, and paliperidone may have moderate risk.83 Table 5 shows an approximate relative comparison among SGAs (and a couple FGAs) of selected side effects, including weight gain.5,83 A review article suggests antipsychotic-induced weight gain occurs in 3 stages: stage 1, during the first few months of treatment, where rapid accumulation of weight occurs; stage 2 (1+ years) where slower but steady weight gain continues; and stage 3, a weight- gain plateau phase where patients maintain a heavier weight. The time to stage 3 may vary by antipsychotic.84 A 2013 meta-analysis suggests that longer exposure to antipsychotics (measured out to >38 weeks) is associated with greater weight gain. In addition, nearly all included antipsychotics demonstrated some weight gain, including those with relatively lower liability such as aripiprazole and ziprasidone.84 The authors suggest that the first 6 weeks of treatment is the most important as many patients who gain weight in this time period maintain the gained weight. It should also be noted that significant variation of effects should be expected with a given antipsychotic; in clinical trials, while some patients gain weight, others also maintain or lose weight.84

Regarding other metabolic parameters, antipsychotics are also associated with insulin resistance, hyperglycemia, and diabetes. Short-term treatment can result in changes in insulin resistance and hyperglycemia, some of which may occur independent of weight gain. Long-term treatment is associated with other changes such hyperinsulinemia and type 2 diabetes.84 Table 5 includes approximate relative changes in glucose for SGAs from a network meta-analysis.83 This suggests

43 clozapine is the highest risk, followed by olanzapine and iloperidone. Lurasidone demonstrated reductions in glucose compared to placebo.83 A separate review reporting approximate risks for type 2 diabetes found olanzapine and clozapine to have the highest risk. In addition, this study supports that the risk may be dose-related for some antipsychotics; for quetiapine and risperidone, doses in the highest tertile but not lower doses, were associated with greater risk of diabetes.80

Regarding dyslipidemias, the network meta-analysis suggests the highest risk (primarily based on total cholesterol) is with clozapine, followed by olanzapine and quetiapine. In this analysis, some antipsychotics showed benefits on certain lipid parameters including a reduction in low-density lipoprotein (LDL) cholesterol with cariprazine, and increases in high-density lipoprotein (HDL) cholesterol with brexpiprazole and aripiprazole compared to placebo.83 Background on how antipsychotics may increase risk of MSE

Studies support that nearly all antipsychotics, including both FGAs and SGAs, can cause metabolic side effects (MSE).5,85,86 However, the exact mechanism through which it occurs is unknown. Various mechanisms have been proposed to account for the MSE including disruption of central regulation (eg, in satiety centers and hunger centers) and peripheral regulation (eg, at adipose tissues, insulin secretion/sensitivity). Weight gain can induce other changes such as impaired glucose and lipid metabolism. Impaired glucose and/or lipid metabolism may also be induced more directly by direct effects on the or pancreas, among other effects. Antagonism of certain receptors may drive some of this dysfunction. For example, antagonism of 5-HT2C, D2, and H1 is associated with weight gain and development of diabetes. This may occur due to disruptions to pathways in the hypothalamus that regulate food intake and peripheral changes such as increased decreased glucose uptake and decreased hepatic insulin sensitivity. Antagonism of other receptors (5-HT2A, M3, alpha1) may also cause similar dysregulation centrally and/or peripherally. Comparison among antipsychotics with the greatest propensity for weight gain and those with the least suggests that the lack of activity at certain receptors

(ie, 5-HT2C), antagonism at certain receptors (ie, alpha2A, D2/3) and/or partial agonism at others (5-HT1) may be beneficial (or at least less disruptive). Still the effects are diverse with some being negative such as disrupted insulin regulation and increased food intake.87 High affinity for the D2 receptor may result in changes to the dopamine reward pathway with food; this has been proposed as a reason for chronic metabolic changes with medications such as haloperidol.84 Beyond direct effects at receptors, antipsychotics may induce downstream changes that interfere with other functions related to metabolic homeostasis (eg, hormone secretion and signaling, gut microflora changes). Cumulatively, authors propose many mechanisms of antipsychotic-induced MSE, direct and indirect effects.85

The FDA requires that all SGAs include a warning for risk of metabolic changes that could include hyperglycemia, diabetes mellitus, dyslipidemia and weight gain. Cases of ketoacidosis, hyperosmolar coma or death have occurred among SGAs. Product labeling for brexpiprazole, cariprazine, and lumateperone notes there have been cases of hyperglycemia.16,23,30 Product labeling for lumateperone notes cases of hyperglycemia, yet lipid changes and weight gain occurred at rates similar to placebo.33 Product labeling for brexpiprazole reports hyperglycemia (in about 10% of patients), lipid changes at a similar rate to placebo, and changes in weight (20-30% of patients gained ≥ 7%, and 4-10% had a ≥ 7% decrease in weight).16 With cariprazine, hyperglycemia and dyslipidemia occurred at a similar rate in patients treated with placebo in clinical studies. In addition, in 3-6 week studies, the proportion of patients with ≥ 7% weight gain was 8% (vs. 5% with placebo) at recommended doses of cariprazine in

44 patients with schizophrenia; in patients with bipolar mania, was 1% with cariprazine vs. 2% with placebo; and was 1% with placebo vs. 3% in bipolar depression trials.23 A recent expert opinion review notes that knowledge of long-term MSE risks associated with newer agents (ie, brexpiprazole, cariprazine, lumateperone) is unknown or limited.88 Importance of MSE

Weight gain may drive development of metabolic syndrome and increase the risk for other obesity- related disease.54,55 In addition, weight gain may contribute to medication nonadherence. An expert consensus guideline about adherence among patients with severe mental illness point to weight gain in particular as a concerning side effect that may lead to nonadherence. Distress or fear of certain side effects were also listed as factors for nonadherence, among others.89 Risk factors for antipsychotic-induced weight gain

Younger age and/or first-time treatment with an antipsychotic are risk factors for greater weight gain.6,54,55 In addition, initial weight gain (within roughly the first 6-8 weeks) is predictive of long-term weight gain.79 Baseline obesity is a risk factor for poor metabolic outcomes with antipsychotics.9 A network meta-analysis examined baseline risk factors for metabolic changes; increases in fasting glucose were associated with a higher baseline body weight and a higher proportion of males. More substantial changes in total cholesterol were associated with a higher proportion of patients of non- white race. Interestingly, greater increases in several metabolic parameters (weight, total cholesterol, LDL cholesterol) and decreases in HDL cholesterol were associated with improvement in schizophrenia symptoms.83

45 Table 5. Antipsychotic Approximate Relative Side Effects with Oral Formulationsa Antipsychotic Weight Glucose Diabetes80 Lipid Akathisia5 Parkinsonism5 Sedation5 QTc Select Other55 generic name gain83 Abn83 Abnb83 Prolongation5 Select First-Generation Antipsychoticsc Chlorpromazine +++/++++ ND +++ ND ++ ++ ++ ++ TD, anticholinergic Haloperidol +/-d + + + +++ +++ +/++ +/++ ProL, TD Select Second Generation Antipsychotics with oral formulationsc Aripiprazole + + + +* ++ + + + Asenapine ++ + ND ND ++ + ++ ++ TDe Brexpiprazole ++ + ND +* + + + + Cariprazine + + ND +/-* +++ ++ +/- + Clozapine ++++ +++ +++ +++ +/- +/-* +++ +/++ Seizures, constipation, anticholinergic, increased salivation Iloperidone +++/++++ +/++ ND +/- +/- + + ++/+++ Lumateperone4,33 +/- (LD) +/- (LD) ND +/- (LD) + (LD) ++ (LD) ++ (LD) +/- (LD) Lurasidone + +/-* + + +++ ++ +/++ +/- TDe, dose-related ProL Olanzapine ++++ ++ +++ +++ + +/- ++ ++ Paliperidone +++ + + + + + + +/++ ProL,TDe Quetiapine +++ ++ ++ ++ +/- +/- +++ ++ Risperidone +++ + ++ + ++ ++ ++ ++ ProL, TDe Ziprasidone +/- + + +/- ++ + ++/+++ +++ Abbreviations: Abn, abnormalities; FGA, first generation antipsychotic; FGAs, first generation antipsychotics; LD, limited data; ND, no data; ProL, elevated prolactin; SGAs, second generation antipsychotics; TD, Tardive Dyskinesia; QTc, corrected QT interval aApproximate relative scores range from: -/+ (lowest risk/minimal changes) to ++++ (maximum risk/most significant changes). Highest risk is highlighted in red text, while lowest risk is highlighted in blue text. This data is a rough approximation, compiled primarily from review of comparisons to placebo from various SR/MAs/NMAs where results may vary,5,84 and much of the comparisons are of low or very low certainty. In most cases, the comparisons are from short-term RCTs of patients with schizophrenia. There can be considerable patient heterogeneity; this information should not be considered absolute. In addition, less information is available for newer agents and many FGA. Information for lumateperone was approximated from clinical trial data and expert opinion.4,90 bLipid abnormalities primarily based on changes in total cholesterol. Changes in other lipids may vary. cSelected FGAs included for comparison with SGAs. Most SGAs are included except for pimavanserin (indicated specifically for Parkinson’s disease-associated psychosis), and amisulpride, which is only available in the US as a short-acting injectable). dResults varied in other studies.5,86 Bak et al. report weight gain particularly with longer use (>6 weeks).86 eRisk likely lower than among FGAs, but may be higher risk than some other SGAs. *Beneficial effects observed vs. placebo: reductions in glucose with lurasidone, reductions in LDL cholesterol with cariprazine, increases in HDL cholesterol with brexpiprazole and aripiprazole,83 lower risk of using antiparkinsonian medications with clozapine.5

46 Recommendations related to MSE among selected schizophrenia and bipolar disorder guidelines

Overall, guidelines suggest that the relative propensity for various MSEs (especially weight gain) among antipsychotics should be a factor in both the selection of an initial agent, as well as a factor in later deciding to switch to another therapy during chronic treatment.6,9,10,54,62,79 However, they also note that it may be difficult to select a medication without any MSE risk. Proactive strategies to manage MSE include lifestyle interventions (ie, exercise, dietary interventions), metformin, switching to another antipsychotic that is considered lower risk, or possibly adding aripiprazole as an adjunctive treatment among those receiving olanzapine or clozapine.6,10,62,79 Guidelines consistently mention clozapine and olanzapine among the antipsychotics with the highest risk for MSE and amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, haloperidol, lurasidone, and ziprasidone as lower risk.6,9,10,62 Though, the CANMAT guideline for bipolar disorder states that weight gain with aripiprazole and asenapine may occur with long-term use. Further, among treatment options for bipolar disorder, it is important to note that non-antipsychotics are also associated with weight gain including lithium and valproate. Carbamazepine and lamotrigine are considered to have a lower propensity for weight gain.10 The APA guideline for schizophrenia recommends evaluating all medications that can contribute to weight gain for possible changes (eg, valproate) when weight gain occurs on an antipsychotic.62

Clinical practice guidelines for autism note that MSE are a risk with use of antipsychotics among patients with autism spectrum disorders (ASD), and the risks seem similar to those reported in other populations.75,91 However, the guidelines do not mention specific strategies for managing these adverse effects.75,91

See Table 6 for a summary of information about relative propensity for MSE, influence of the risk of MSE on treatment decisions and suggestions for managing the MSE from selected clinical practice guidelines. Evidence regarding switching antipsychotics to manage MSE

Various SRs or randomized controlled trials (RCTs) have examined metabolic changes and symptom control or discontinuation rates after switching from an antipsychotic with a higher MSE liability to a lower one. Cumulatively, evidence reviewed suggests potential benefits on various metabolic parameters (weight, cholesterol, triglycerides) over the short-term studies of roughly 26 weeks or less in primarily patients with schizophrenia or schizoaffective disorder who had already been treated with at least one antipsychotic.92-94The clinical significance of the magnitude of these changes is unclear. Most of the evidence reviewed was for switching from an antipsychotic among the highest MSE liability (olanzapine) to another antipsychotic with either medium MSE liability (quetiapine) or relatively low MSE liability (aripiprazole).92-94 One study showed benefits on weight loss when switching from risperidone (medium MSE liability) to lurasidone (low MSE liability) over 6 months and minimal changes in other metabolic parameters.95 Either switching from a high liability antipsychotic (olanzapine or clozapine) to a lower liability one (aripiprazole, ziprasidone, quetiapine) or adding adjunctive aripiprazole to olanzapine or clozapine may significantly reduce hemoglobin A1c among patients with a severe mental illness. However, this benefit was not observed in the subgroup analysis of the population without diabetes, which suggests the greatest benefits on hemoglobin A1c with adjunctive aripiprazole or antipsychotic switching may be among those with diabetes already.96

47 When considering switching as a therapeutic strategy for MSE, a recent expert opinion review article notes that knowledge of long-term MSE risks associated with newer agents (ie, brexpiprazole, cariprazine, lumateperone) is unknown or limited.88 Individual Summary of Various “Switch” Studies

An SR and meta-analysis (MA) from in 2013 concluded that in a small sample of RCTs (of 26 weeks or less) among patients with schizophrenia, switching from olanzapine to either aripiprazole or quetiapine demonstrated some benefits on metabolic parameters. However, discontinuation rates were higher in groups that switched therapies than those that stayed on olanzapine. The following differences were observed93:

• Switch to aripiprazole or quetiapine from olanzapine (2 RCTs): mean weight loss of 1.94 kg (CI -3.9 to 0.08)

• Switch from olanzapine to quetiapine (1 RCT): mean difference in BMI -0.52 (CI -1.26 to 0.22)

• Switch from olanzapine to aripiprazole (1 RCT): relative risk (RR) of clinically relevant BMI increase (>1 unit), 0.28 (CI 0.13 to 0.57)

• Switch to aripiprazole or quetiapine from olanzapine (2 RCTs): mean difference in fasting blood glucose of -2.53 (-2.94 to -2.11)

A SRMA from 2017 by Taylor et al. included RCTs of studies with various types of interventions (pharmacologic or nonpharmacologic) in adults with severe mental illnesses with glycemic outcomes. Antipsychotic switching (6 RCTs) demonstrated a significant reduction in mean hemoglobin A1c (-0.11, 95%CI -0.18 to -0.05). However, significant changes in mean difference of fasting blood glucose (mmol/L) were not seen. Subgroup analysis of studies that excluded patients with diabetes or included those with and without diabetes suggests the benefits on hemoglobin A1c were only seen in those with a combined population. Included studies evaluated either switching to aripiprazole, quetiapine or ziprasidone from olanzapine or clozapine, adjunctive treatment with aripiprazole in patients on olanzapine or clozapine, or switching to the olanzapine orally disintegrating tablet from the standard olanzapine tablet. Most studies were shorter than 6 months in duration and had an unclear or high risk 96 of bias on multiple factors assessed.

Stroup et al. 2011 performed an RCT, which was included among the 2013 Mukandan et al. SR, of a switch from either olanzapine (5-20 mg daily), quetiapine (200-1200 mg daily) or risperidone (1-16 mg daily) to aripiprazole (titrated to 5-30 mg daily) among adult patients (mean age about 41) with schizophrenia or schizoaffective disorder on a stable antipsychotic dose and overweight BMI (>=27, mean of 35) and non-HDL cholesterol >=130 mg/dL. All received lifestyle interventions. After 24 weeks, those who switched to aripiprazole had greater reductions in non-HDL-c (-20.2 vs. -10.8 mg/dL), weight (-3.6 kg vs. -0.7 kg, a significant difference of -2.9 kg, 95%CI -1.6, -4.2, p<0.001), body mass index (BMI) by -1.07 units (p<0.001) and serum triglycerides (least squares mean difference of -32.7, 95%CI -12.1, - 53.4, p = 0.002). No benefits were seen for glucose or insulin sensitivity. Benefits on laboratory parameters were seen after 1 month, while weight change occurred over 24 weeks. However, more patients who switched discontinued the antipsychotic (43.9% vs. 24.5%); while a similar percentage of patients had an efficacy failure (20.6% vs. 17%).92

48 Mattingly et al. 2020 conducted an open-label RCT extension study among patients with schizophrenia or schizoaffective disorder who completed a 12-month trial of lurasidone 40-120 mg/day or risperidone 2-6 mg daily who were switched to lurasidone 80 mg daily for 6 months after study completion. After 6 months, those that continued lurasidone experienced minimal changes in weight (weight loss of -0.6 kg, 6.4% with >=7% weight decrease while those that switched to lurasidone reported a weight loss of -2.9 kg (19.7% with >=7% weight decrease). There was little change in median total cholesterol, triglycerides, glucose, or hemoglobin A1c among those who continued lurasidone. Small changes (from baseline to 6 months) were observed in those that switched to lurasidone: -5.5 mg/dL in triglycerides, -3.0 mg/dL glucose, +4.5 mg/dL. Both groups of patients maintained clinical stability throughout the study, though numerically more patients who switched to lurasidone discontinued the study (25.3% vs. 19.1%).95

Correll et al. recently published the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) open-label RCT that evaluated either switching to aripiprazole [max 30 mg/day] (or or perphenazine [max 64 mg/day]) if previously taken aripiprazole), adding metformin (1000 mg twice daily), or continuing the same baseline antipsychotic. In addition, they receiving lifestyle interventions. Participants were children ages 8-19 years old with a severe mental illness (ie, schizophrenia spectrum disorder, bipolar disorder, or psychotic depression) that had gained weight (now obese or overweight) after receiving an SGA. Aripiprazole and risperidone were the most common medications at baseline. The primary outcome of BMI z-score significantly decreased (from baseline to week 24) with both metformin (-0.09 ± 0/03, p= 0.002) or switching antipsychotic (-0.11 ± 0.04, p = 0.003), unlike in the antipsychotic maintenance group (+0.04 ± 0.03). Both metformin and switching had greater changes in BMI than the maintenance group (p=0.002). Discontinuations were greatest in the perphenazine group (52.9%).97

Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines Guideline; Sponsoring Recommendation Organization, Year (level of evidence and/or strength of recommendation) Practice Guideline for MSE Onset the Treatment of • Onset is often early in treatment, but may still occur later Patients with • Weight gain: typically occurs within first 6 months but indefinite weight gain Schizophrenia, 3rd with long-term use is possible. Younger individuals and/or those treated for edition; APA, 202062 the first episode of psychosis may be more likely to gain weight. Influence on Antipsychotic Selection • Selection of an agent should take into account patient preferences (including history of nonadherence based on intolerance of a certain agent) and pre- existing conditions (eg, diabetes) [“choice of medication will need to consider the likelihood of exacerbating an existing health condition”] • Younger patients with the first psychosis – may consider that they may be more likely to experience metabolic effects when selecting treatment • “No medication appears to be devoid of possible side effects” • During long-term treatment, weight gain or development of metabolic syndrome or diabetes are “common reasons that a change to a different medication may be discussed” Hyperlipidemia: • Clozapine and olanzapine may increase risk

49 Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines Hyperglycemia/Diabetes • Clozapine and olanzapine particularly increase risk; FDA warning for all SGAs Weight gain • Given the increase in mortality and morbidity associated with excess weight, “prevention of weight gain should…be a high priority”; consider proactive steps with gain of 5-10 pounds o Assess for other contributors; d/c other likely contributing medications (eg, valproate) if possible o With significant weight gain, may consider switching to an alternative antipsychotic with a lower propensity for weight gain. Other treatment options can also be considered (eg, dietary interventions, exercise, metformin). § Make a shared decision with the patient, considering the risks: benefits of a medication change. • Weight gain (7% or more increase): olanzapine > other antipsychotics individually (aripiprazole, asenapine, clozapine, quetiapine, risperidone, ziprasidone) Metabolic syndrome • Olanzapine > risperidone (with follow-up of 6 weeks – 3 months), olanzapine > aripiprazole (with follow-up of 3.5 – 12 months) Post-diagnostic Onset Evidence-based • Metabolic changes including weight gain observed within 6-8 weeks of start Guidelines for the (“may average 3.8 kg by 12 weeks”) Pharmacological • Early weight gain predicts long-term weight gain Treatment of Influence on Treatment Selection Schizophrenia; BAP, • Patients treated for the first time are more sensitive to weight gain 202054 • Lower potential for further weight gain after switching agents among longer- term antipsychotic users (perhaps because already gained weight) • Avoiding all metabolic effects is unlikely due to affinity of antipsychotics for various receptors associated with metabolic affects within the typical dosage range • Side effect profile is a consideration for treatment selection Weight gain • Proposed grouping of propensity for weight gain based on MA of clinical trials: o Relatively high risk: clozapine, olanzapine o Medium risk: risperidone, quetiapine, paliperidone o Relatively low risk: amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, haloperidol, lurasidone, ziprasidone Other Metabolic Changes • Relative propensity for other effects (glucose, cholesterol) tends to follow individual agent risk for weight gain Guidelines for the Treatment Considerations Management of • Consider replacing antipsychotics with a higher propensity for metabolic Patients with Bipolar disorders with “medications with a more favorable profile” “if the Disorder; CANMAT therapeutic advantage of the high-risk agent over the alternative is minimal and ISBD, 201810 and metabolic/weight issues persist”

50 Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines • Consider likelihood of weight gain carefully. It is a very common reason for non-adherence. Weight Gain • Medications for BPD associated with weight gain: olanzapine, clozapine, risperidone, quetiapine, gabapentin, divalproex, lithium o Possible risk after long-term use: aripiprazole, asenapine • Medications for BPD with less weight gain: carbamazepine, lamotrigine, ziprasidone, lurasidone Metabolic syndrome including hyperglycemia, diabetes, dyslipidemias: • Greatest risk: clozapine, olanzapine • Moderate risk: quetiapine (also increases with higher doses), risperidone • Lower risk: aripiprazole, ziprasidone, asenapine, lurasidone • Treatment: consider d/c the medication when possible; treat as appropriate per the disorder Evidence-based Weight Gain Guidelines for • Problem with many medications for bipolar disorder Treating Bipolar Metabolic Indices Disorder, revised 3rd • Particularly problematic for olanzapine and quetiapine edition; BAP, 20169 • Lurasidone: “minimal changes in weight, blood lipids, or glycemic control” Clinical Practice Onset Guidelines for the • Weight gain usually occurs at start of treatment (early illness) Management of Treatment Selection Schizophrenia and • Side effect profile, especially risk of weight gain, should play a role in Related Disorders; selecting an antipsychotic. Selecting an antipsychotic with lower risk for RANZCP, 20166 weight gain is recommended when possible. Weight Gain • Consider switching to a “weight neutral antipsychotic” for weight gain concerns (EBR, LOE II) o Additional strategies include: § Metformin for prevention/reducing weight gain if starting treatment with an antipsychotic associated with weight gain when switching medications or lifestyle changes would be inadequate (EBR, LOE II) § Metformin for treatment, as an alternative to switching antipsychotics (EBR, LOE II) o Lifestyle interventions to treat weight gain (EBR, LOE III-1) o Lifestyle interventions to prevent weight gain (EBR, LOE II) • Weight gain may be higher in women than men Diabetes • Treatment strategy is to treatment diabetes as indicated (ie, hypoglycemic agents) Lipids/cholesterol elevation • Switching to an alternative antipsychotic with low risk for these elevations is mentioned is a treatment strategy o Additional strategies include treatment with a statin, diet, exercise

51 Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines Guidelines on the Recommendations targeted for adults due to limited data for younger groups. management of Onset weight gain, • Weight gain within first 6-8 weeks, which also predicts long-term weight metabolic gain (>5% gain within first 4 weeks predicts long-term gain) disturbances and Weight Gain cardiovascular risk • Antipsychotics weight gain risk categories: associated with o Low: Haloperidol, ziprasidone, lurasidone, aripiprazole, amisulpride, psychosis and asenapine antipsychotic drug o Medium: quetiapine, risperidone, paliperidone treatment; BAP, o Medium-high: chlorpromazine High: olanzapine, clozapine 201679 o • First-time antipsychotic treatment may have greatest liability for changes: “average increases of 7-8% for risperidone and 13% for olanzapine over 3 months” Glucose Dysregulation • Strongest evidence for risk: clozapine, olanzapine • Weight gain with antipsychotics does not always predict insulin resistance or diabetes Other Metabolic Changes • Risk for changes in glucose, cholesterol, and triglycerides are similar to risk categories for weight gain Interventions: • Clinical significance: weight gain ≥ 7%, weight loss ≥ 5%; “for every 1 kg/m2 increase in BMI in the general population, the risk of developing new-onset type 2 diabetes increases by 8.4%” • Recommendations for weight loss: o First-line: lifestyle interventions (A) – helpful for weight loss after initial gain on an antipsychotic (loss of about 3 kg), and may also help prevent some initial weight gain (B) o Metformin: “should be considered as an adjunct to attenuate or reduce weight gain following antipsychotic medication” (A) § short-term weight loss vs. placebo of 3 kg after antipsychotic-related weight gain (A); when started with an antipsychotic, minimized weight gain by 5 Kg (A) o Switching to a different antipsychotic (with lower weight gain risk): “a strategy that should be considered.”(B) Decision to switch should also consider the risk of relapse. (S) § Few RCTs directly looked at weight loss from switching; found about 3 kg weight loss after switching from olanzapine to quetiapine or aripiprazole. (B) o Adjunctive treatment with aripiprazole: “possible intervention for weight gain” specifically for those receiving clozapine or olanzapine (B) (in 3 RCTs, mean weight loss of 2 kg with adding aripiprazole) o Other treatments have been studied for weight loss in patients receiving an antipsychotic: , melatonin; other treatments effective in the general population may also be useful for patients receiving antipsychotics

52 Table 6. Selected Information about Relative Metabolic Side Effects in Schizophrenia and Bipolar Treatment Guidelines Treatment considerations for younger populations/children: • Relative weight gain risk seems similar to adults; proposed order of risk: olanzapine ≥ clozapine > risperidone ≥ quetiapine > aripiprazole = ziprasidone • NICE recommends avoiding olanzapine for first-time treatment of psychosis due to the relative magnitude of metabolic risks • Young people may at greater risk for weight gain, or possibly it appears this way because this more often reflects first time treatment with antipsychotics relative to studies in adults • Young people taking antipsychotics have a significantly increased risk for type 2 diabetes vs. healthy young people • Lifestyle interventions have been studied in young people, but no study data about adjunctive aripiprazole. Two studies on adjunctive metformin in young people showed conflicting results. Abbreviations: APA, American Psychiatric Association; BAP, British Association of Psychopharmacology; BMI, body mass index (1 unit = 1 kg/m2); D/c, discontinue; FDA, United States Food and Drug Administration; Kg, kilogram; MA, meta-analysis; MSE, metabolic side effects; RANZCP, Royal Australian and New Zealand College of Psychiatrists; RCTs, randomized controlled trials; SGA, second generation antipsychotic; SGAs, second generation antipsychotics;

APA Strength of Recommendation 1: Recommendation, benefits >harms; 2: suggestion, benefits > harms with some uncertainty APA Strength of Evidence A: high; B: moderate; C: low (all based on consistency of effect, directness of effect, precision, and ROB) BAP Strength of Recommendation A: direct level 1 evidence; B: direct level 2 or extrapolated from level 1 evidence; C: direct level 3 or extrapolated from level 1 or 2 evidence; D: direct level 4 or extrapolated from level 1, 2, or 3 evidence; S: “standard of good practice” BAP [both 2016 bipolar and metabolic disturbances guideline] Levels of Evidence for Causal Relationships: Ia: MA of RCTs; 1b: 1+ RCT; IIa: 1+ non-randomized controlled study; IIb: 1+ other quasi-experimental study; III: other non-experimental or descriptive study; IV: expert reports or opinion BAP [2016 metabolic disturbances guideline] Levels of Evidence for Observational Studies: I: “large representative population samples”; II: “evidence from small, well-designed, but not necessarily representative samples”; III: “non-representative surveys, case reports”; IV: “expert committee reports or opinions and/or clinical experience of respected authorities” RANZCP Strength of Recommendation CBR = consensus-based recommendation, based on collective expert opinion EBR = evidence-based recommendation when sufficient evidence RANZCP LOE I: SR of RCTs; II: RCT; IIII-1: pseudo-RCT; IIII-2: “comparative study with concurrent controls”; IIII-3: “comparative study without concurrent controls”; IV: case-series or pre/post test

53

Efficacy and Safety of Newer Antipsychotics (brexpiprazole, cariprazine, lumateperone) Efficacy for schizophrenia and/or bipolar disorder

Evidence from SRs and network/direct MA of randomized controlled trials suggest brexpiprazole, and cariprazine have similar efficacy to other antipsychotics for the treatment of adults with multiple episodes of schizophrenia.5,98 This evidence is primarily based on short-term treatment, and authors rated most of the evidence as fair, low, or very low quality.5,98 However, in one direct comparisons MA of short-term trials among treatment-experienced adults with schizophrenia, risperidone outperformed cariprazine on the mean difference in overall symptoms, and positive symptoms. Though the effect on negative symptoms was similar.5 In the same MA, superiority over placebo was demonstrated for overall, negative, and depressive symptoms with both brexpiprazole and cariprazine. For total symptoms and positive symptoms, cariprazine performed similarly to aripiprazole. Brexpiprazole performed similarly to aripiprazole and quetiapine for overall symptoms, and positive symptoms. No statistically significant differences were observed among direct comparisons on negative symptoms for aripiprazole versus cariprazine, risperidone versus cariprazine, aripiprazole versus brexpiprazole, or quetiapine versus brexpiprazole. Similarly, comparisons of aripiprazole versus cariprazine, and quetiapine versus brexpiprazole for depressive symptoms suggest similar efficacy.5 See Appendix D Table D1 for a summary of the direct comparisons results from the meta-analysis.

For treatment of bipolar I disorder mania, a SR reports similar efficacy of cariprazine to several antipsychotics and lithium for treating bipolar mania. Cariprazine was superior to placebo for acute mania or mixed features based on low-strength evidence.69 Short (3 weeks) RCTs cariprazine 3-12 mg daily among patients with bipolar I disorder with manic or mixed features demonstrated a statistically significant reduction in mania symptoms and remission rates compared to placebo.99 In an MA of the combined results versus placebo, cariprazine 3-6 mg/day improved mania symptoms moderately (standardized mean difference -0.52, 95% confidence interval [CI] -0.82 to -0.21). Similarly, by MA, patients receiving cariprazine 3-6 mg/day were twice as likely to achieve remission versus placebo (odds ratio 2.05, 95% CI 1.61 to 2.61). Authors noted that the effect size (ES) of -0.52 is comparable to previously published effects sizes of other SGAs for mania (pooled ES of 0.40), indirectly suggesting comparability of cariprazine to other SGAs.99

Regarding cariprazine for bipolar depression, short (6-8 weeks) RCTs of cariprazine 0.25 to 3 mg daily for bipolar I disorder depression (except 1 trial that included bipolar II disorder) demonstrated a statistically significant improvement in depression symptoms compared to placebo. One study (that also included the patients with bipolar II disorder) of lower doses (0.25 to 0.75) did not show superiority of cariprazine over placebo. Cariprazine 1.5 – 3 mg/day significantly reduced depression symptoms compared to placebo (for 1.5 mg/day: ES -0.26, 95%CI -0.49 to -0.02; for 3.0 mg/day: ES -0.21, 95%CI -0.41 to -0.01). Numerical results suggest improvements in depression remission and response rates with cariprazine over placebo; however, the statistical significance of these results depended on which depression rating scale was used. Results were significant with one, but not the other.99 Comparability of cariprazine to other SGAs for bipolar depression is uncertain. Indirect comparisons, which may not offer an accurate comparison, of the number needed to treat (NNT) by SR authors suggest slightly worse efficacy of

54 cariprazine (NNT = 10) versus other SGAs (olanzapine-fluoxetine NNT = 1.8; lurasidone NNT = 8.2; quetiapine NNT = 6). However, another author points out that there is some overlap in the confidence intervals for this comparison, the SGAs efficacy may be comparable.100 To our knowledge, there are not head-to-head comparisons of cariprazine with other medications for the treatment of bipolar disorder.101

Table 7 summarizes efficacy data (based on changes in total symptoms) from RCTs leading to FDA approval of lumateperone for schizophrenia. All studies were conducted among treatment-experienced adults with moderate to severe acute exacerbation of schizophrenia who had a history of response to a past antipsychotic. No patients with schizoaffective disorder were included.90,102,103 Comparisons were versus placebo other than 2 trials including a risperidone 4mg/day control arm. Lumateperone at the dose of 42 mg was superior to placebo in 2 of 3 trials, and appears relatively similar to risperidone for PANSS total score over 4 weeks.90,102,103 In the 6-week trial, risperidone 4 mg daily separated from placebo, but lumateperone did not which may be due to differences in drop-out rates; yet FDA reviewers contend that the reason for this remains a mystery.103

Table 7. Summary of results from lumateperone clinical trials for schizophrenia Trial Interventions Resultsa PANSSb Total Score Intervention Baseline LS mean change from baseline to week 4 Lum 42 mg Lum 42 mg 88.1 -13.2* (vs. PBO: -5.8, 95%CI -10.5 to -1.1) Lum 84 mg Lum 84 mg 84.6 -8.3 (vs. PBO: -0.9, 95%CI -5.6 to 3.8) Lieberman JA et Risp 4 mg Risp 4 mg 86.1 -13.4* (vs. PBO: -6.0, 95%CI -10.8 to -1.3) al. 201690 Placebo Placebo 86.3 -7.4

Metabolic Parameter Change (from day -7 to day 28): 4-week RDBCT Intervention TG [mmol/L] Glucose Weight [Kg] Weight (n = 335) (mean) [mmol/L] (mean (SD); change ≥

(mean) median) 7% (%) Age 18-55 years Lum 42 mg +<0.1 +<0.1 2.0 (3.10); 1.0 13%

Lum 84 mg -0.1 to -0.2 +0.1 to +0.2 1.9 (3.4); 1.1 17.4%

Risp 4 mg +0.1 to +0.2 +0.5 to +0.6 3.0 (3.7); 2.5 19.1% Placebo +<0.1 +0.1 to +0.2 0.8 (3.5); 0.8 6% Exact values for change in TG and glucose not reported. Changes are approximate with a range given (- indicates decrease, + indicates increase) PANSS Total Score Intervention Baseline LS mean change from baseline to week 4 Lum 28 mg Lum 28 mg 89.3 -12.9 (vs. PBO -2.6, 95%CI -6.2 to 1.1) Lum 42 mg Lum 42 mg 90.1 -14.5* (vs. PBO -4.2, 95%CI -7.8 to -0.6) Correll CU et al. Placebo Placebo 90.1 -10.3 2020102 Metabolic Parameter Change (from baseline to day 28):

Intervention TC [mg/dL] Glucose Weight Weight 4-week RDBCT (mean) [mg/dL] change ≥ (n = 449) (mean) 7% (%)

Age 18- 60 years Lum 28 mg -3 to -4 +1 to +2 +1.0 to +1.5 4.3 Lum 42 mg -4 to -5 +1 to +2 +1.0 to +1.5 8.4 Placebo -2 to -3 +2 to +3 +1.0 to +1.5 3.8 Exact values for change in TC, glucose, weight (kg) not reported. Changes are approximate with a range given (- indicates decrease, + indicates increase).

55 Table 7. Summary of results from lumateperone clinical trials for schizophrenia Trial Interventions Resultsa Trial in FDA PANSS Total Score review103 Intervention Baseline LS mean change from baseline to week 6 Lum 14 mg Lum 14 mg 88.5 -15.0 (vs. PBO 0.1, 95%CI -3.4 to 3.5) 6-week RDBCT Lum 42 mg Lum 42 mg 90.4 -14.6 (vs. PBO 0.5, 95%CI -2.9 to 3.8) (n = 696) Risp 4 mg Risp 4 mg 89.7 -20.5* (vs. PBO -5.4, 95%CI -8.9 to -1.9) Placebo Placebo 90.7 -15.1 Age 18-60 years

Abbreviations: CI, confidence interval; kg, kilograms; LS, least-squares; Lum, lumateperone; PANSS, positive and negative syndrome scale; PBO, placebo; RDBCT, randomized, double-blind, controlled trial; risp, risperidone; SD, standard deviation; TC, total cholesterol *Indicates statistically significant difference versus placebo aRisperidone arm included for “assay sensitivity,” but no direct statistical comparison. Risperidone treatment range for schizophrenia is from 4 to 8 mg. bThe PANSS is a well-established and accepted 30-item scale that assesses various schizophrenia symptoms (positive [7 items], negative [7 items], and general psychopathology [16 items]). Each item is scored from 1 (no symptoms) to 7 (severe symptoms), for a possible score range from 30 to 210. A total of 58 is roughly considered mild, 75 indicates marked illness, and 116 indicates severe illness. Change in PANSS scores from baseline is a common efficacy endpoint in schizophrenia trials. According to an SR by the AHRQ, in among patients with severe schizophrenia, a clinically important difference on the PANSS is 11.5 points. Other studies have reported an absolute difference of 5 to 15 (with the majority reporting 15) as a minimum clinically important difference; this corresponded to a 17 to 34 percent change from baseline.104

Expert opinion about potential differences

Brexpiprazole, cariprazine, and lumateperone all have unique receptor binding profiles that in theory could lend themselves to treating particular symptoms. While some of these potential benefits have been demonstrated in pre-clinical animal studies, most of the proposed benefits are either untested in humans, or suggested based on post-hoc analyses of clinical trials.4,105

Brexpiprazole seems to have a similar receptor binding profile to aripiprazole. It does have greater activity at alpha receptors than aripiprazole, which may make it more sedating. It is proposed that this would be beneficial for concurrent anxiety or irritability, particularly among patients with major depressive disorder.105 Brexpiprazole is FDA approved for use as an adjunctive therapy to antidepressants in adults with major depressive disorder (in addition to the indication for schizophrenia).16

Cariprazine is D3 and D2 receptor and antagonist, with greater preference for the D3 receptor (by 10-fold). This may allow for greater D3 receptor occupancy at lower doses. Further, its affinity for the D3 receptor exceeds that of dopamine; this differentiates cariprazine from other antipsychotics whose actions at D3 are reversible by dopamine.101 At lower doses it may act primarily as a partial agonist, while acting as an antagonist at higher doses.4 Researchers have theorized that the greater affinity for the D3 receptor may lead to benefits on cognition, depressive symptoms, and negative symptoms of schizophrenia.4 One randomized, double-blind trial compared cariprazine (4.5 mg target dose) dose to risperidone (4 mg target dose) over 26 weeks in adult patients with chronic (>2

56 years) stable schizophrenia with predominantly negative symptoms. Greater least-squares (LS) mean reductions in the positive and negative syndrome scale factor score for negative symptoms (PANSS- FSNS) were observed with cariprazine than risperidone (cariprazine -8.90 vs. risperidone -7.44; LS mean difference -1.46, 95%CI -2.39 to -0.53).106 This suggests possible benefits cariprazine over risperidone for negative symptoms.

Lumateperone has a greater affinity for 5-HT2A receptors than D2 receptors (by 60-fold), this may be associated with a lower risk for EPS. In addition, it has other unique effects including moderate affinity for the serotonin transporter and stimulation of a glutamatergic receptor. It has been proposed that this may lead to benefits on cognition, depression, and negative symptoms in schizophrenia. Superiority over other SGAs with respect to effect on these symptoms have yet to be conclusively proven.107 Safety

To facilitate a comparison of common side effects between the selected antipsychotics (brexpiprazole, cariprazine, lumateperone) and other similar SGAs, Table 8 includes common side effects (that occurred among at least 4% of patients and more frequently than placebo in clinical trials) for selected SGAs.

In the short-term trials, some adverse events that occurred more frequently than placebo (most at 2x the incidence) occurred in certain disease states but not others. For cariprazine and brexpiprazole, akathisia was frequently reported and appeared dose-dependent.16,23 Akathisia was also reported in clinical trials among some populations who received aripiprazole, lurasidone, and ziprasidone.3,22,27 Patients who received cariprazine also reported more frequent EPS vs. placebo which was also observed with aripiprazole and lurasidone, and ziprasidone in clinical trials.3,22,27 Weight gain was reported with brexpiprazole and lurasidone (among pediatric patients with bipolar disorder) more than placebo.16,22 Somnolence and dry mouth were reported with lumateperone more frequently than placebo.33

A 2019 expert opinion review article about cariprazine reported that studies evaluating the side effect profile of cariprazine have been for a maximum of 19 weeks. Additional long-term follow-up data would be helpful to better understand possible long-term safety risks.101

Expert opinion articles differentiate the dopamine partial agonists, aripiprazole, brexpiprazole, and cariprazine among patients with schizophrenia, as follows108:

• Greatest propensity for weight gain: brexpiprazole > aripiprazole > cariprazine

• Greatest propensity for somnolence: aripiprazole > brexpiprazole > cariprazine

• Greatest propensity for akathisia: cariprazine > aripiprazole > brexpiprazole

57 Table 8. Common Side Effects among Selected Oral SGAs in Adult Short-term Clinical Trialsa 3,16,22,23,27,33 Antipsychotic Schizophrenia Bipolar Disorder Major Depression Aripiprazoleb Adults Bipolar mania - adults Akathisia (25% vs. 4%) Akathisia (8% vs. 4%) Akathisia (13% vs. 4%) Restlessness (12% vs. 2%) Adolescents (13-17 years) Sedation (8% vs. 3%) Insomnia (8% vs. 2%) EPD (NR) Restlessness (6% vs. 3%) Constipation (5% vs. 2%) Somnolence (NR) Tremor (6% vs. 3%) Fatigue (8% vs. 4%) Tremor (NR) EPD (5% vs. 3%) Blurred vision (6% vs. 1%) Bipolar mania – 10-17 years Somnolence (23% vs. 3%) EPD (20% vs. 3%) Fatigue (11% vs. 4%) Nausea (11% vs. 4%) Akathisia (10% vs. 2%) Blurred vision (8% vs. 0%) Salivary hypersecretion (6% vs. 0%) Dizziness (5% vs. 1%) Brexpiprazolec Weight gain (4% vs. 2%) Weight gain (7% vs. 2%) Akathisia (9% vs. 2%) Somnolence (5% vs. 0.5%) Cariprazined EPS (15-19% vs. 8%) Bipolar Mania Akathisia (9-13% vs. 4%) EPS (26% vs. 12%) Akathisia (20% vs. 5%) Dyspepsia (7% vs. 4%) Vomiting (10% vs. 4%) Somnolence (7% vs. 4%) Restlessness (7% vs. 2%) Hypertension (5% vs. 1%) Bipolar depression Nausea (7% vs. 3%) Akathisia (6-10% vs. 2%) Restlessness (2-7% vs. 3%) EPS (4-6% vs. 2%) Lumateperonee Somnolence (24% vs. 10%) Dry mouth (6% vs. 2%) Lurasidonef Adults Bipolar depression-adults Somnolence (17% vs. 7%) Akathisia (9% vs. 2%) Akathisia (13% vs. 3%) EPS (7% vs. 2%) EPS (14% vs. 6%) Somnolence (11% vs. 7%) Nausea (10% vs. 5%) Bipolar depression – age 10- Adolescents (13-17) 17 years Somonolence (15% vs. 7%) Nausea (16% vs. 6%) Nausea (14% vs. 3%) Weight increase (7% vs. 2%) Akathisia (9% vs. 2%) Insomnia (5% vs. 2%) EPS-non-akathisia (7% vs. 4%) Rhinitis-80 mg dose (8% vs. 2%) Vomiting (8% vs. 2%)

58 Ziprasidoneg Somnolence (14% vs. 7%) Bipolar mania/mixed RTI (8% vs. 3%) Somnolence (31% vs. 12%) EPS (14% vs. 8%) EPS (31% vs. 12%) Dizziness (16% vs. 7%) Akathisia (10% vs. 5%) Abnormal vision (6% vs. 3%) Asthenia (6% vs. 2%) Vomiting (5% vs. 2%) Abbreviations: EPD, extrapyramidal disorder; EPS, extrapyramidal symptoms (may include dystonia, parkinsonian symptoms, EPD, hypokinesia, muscle rigidity, tardive dyskinesia, tremor, among others); NR, not reported; RTI, respiratory tract infection a Total incidence ≥ 5% (or 4% for brexpiprazole) and more frequent than placebo (incidence ≥ 2x placebo); percentages shown reflect the percentage with the antipsychotic versus placebo. Included data are for adults unless the age group is specified. bData for schizophrenia is from pooled data of 4-6 week trials with aripiprazole doses ranging from 2 to 30 mg. Data for bipolar disorder is based on aripiprazole monotherapy pooled data from 3-week trials for bipolar mania at doses of 15 to 30 mg. Data for MDD is for adjunct treatment of MDD with an antidepressant at a dose of 2 to 30 mg in trials up to 6 weeks long. For pediatric patients with bipolar disorder, data is based on one 4-week trial at a dose of 10 or 30 mg/day. For adolescents with schizophrenia, it is based on one 6-week trial at a dose of 2- 30 mg. cData based on 6-week trials for schizophrenia (dose range 1-4 mg) and MDD (dose range 1-3 mg). Rates of akathisia and restlessness were dose dependent (eg, akathisia 14% with 3 mg vs. 4% with 1 mg). dBased on 6-week trials for schizophrenia with doses from 1.5 mg to 12 mg (max recommended dose is 6 mg); eBased on 4-6 weeks trials at the approved dose of 42 mg daily. fBased on short-term studies (up to 6 weeks). Incidence of akathisia (eg, 5.6% at 20 mg vs. 22% at the highest dose) and EPS were dose-related. Incidence reported is the average across all lurasidone doses versus placebo. Bipolar studies were monotherapy. gBased on short-term trials (up to 6 weeks for schizophrenia, and up to 3 weeks of bipolar mania/mixed). Summary of Warnings and Precautions

Additional information about contraindications, warnings, and precautions, and use during pregnancy/lactation for brexpiprazole, cariprazine, lumateperone:

• Brexpiprazole16

o Contraindication: known hypersensitivity to the product

o Dose adjustments or a lower max dose are required with: moderate-strong, and strong CYP () 2D6 or CYP3A4 inhibitors; strong CYP3A4 inducers; moderate-severe hepatic impairment (Child-Pugh score ≥ 7); moderate-severe renal impairment (CrCl [creatinine clearance] <60 mL/minute); and among CYP2D6 poor metabolizers

o A unique warning (also with aripiprazole) is the risk for compulsive or impulsive behaviors such as gambling, sexual urges, or binge eating

o Pregnancy: Use caution; human risk unknown. In animal studies no teratogenicity was observed at doses exceeding human doses, though increased perinatal pup death occurred at very elevated doses. Antipsychotics in general have been associated with extrapyramidal/withdrawal symptoms in neonates exposed during the third trimester.

59 o Lactation: Consider risks vs. benefits of use; presence of brexpiprazole in human milk is unknown. It has been detected in rat milk.

• Cariprazine23

o Contraindication: known hypersensitivity to the product

o Avoid use concomitant with CYP3A4 inducers; or severe hepatic (Child-Pugh score of 10 to 15) or renal impairment (CrCl <30 mL/minute)

o Dosage adjustments required with strong CYP3A4 inhibitors

o A unique warning is the risk for a delay in onset of adverse effects. This is due to the very long half-life (up to 1-3 weeks) of a cariprazine metabolite. Monitor for possible events for several weeks.

o Pregnancy: Use caution; human risks unknown. Fetal harm occurred in animal studies (malformations, increased death, developmental delay in rats at doses within human range). Antipsychotics in general have been associated with extrapyramidal/withdrawal symptoms in neonates exposed during the third trimester.

o Lactation: Consider risks vs. benefits of use; presence of cariprazine in human milk is unknown. It has been detected in rat milk.

• Lumateperone33

o Contraindication: known hypersensitivity to the product

o Avoid use concomitant with CYP3A4 inducers, moderate to strong CYP3A4 inhibitors, UGT inhibitors, and with moderate to severe hepatic impairment (Child-Pugh class B or C)

o Warnings and precautions are similar to other SGAs

o Pregnancy: Use caution; human risk unknown. In animal studies no teratogenicity was observed at doses exceeding human doses, though increased perinatal pup death occurred at very elevated doses. Antipsychotics in general have been associated with extrapyramidal/withdrawal symptoms in neonates exposed during the third trimester.

o Lactation: “Breastfeeding is not recommended” due to possible risk to infants from exposure to an aniline metabolite (observed in animal studies) of lumateperone. The presence of lumateperone in human or animal breast milk is unknown.

Table 9 includes a summary of warnings and precautions from the product labeling for the FGA, haloperidol, and all SGAs, based on the oral dosage forms (except for amisulpride). Note that sometimes there is inconsistency among FDA product labeling; these comparisons give approximate relative differences, but some products may not have formal labeling for a warning or precaution expected to be true of all antipsychotics.

60

Table 9. Warnings and precautions for select FGAs and all SGAs (for oral dosage forms, except for AMI)2,3,11,12,14-17,21-27,32-34,43 Warning or Precaution HAL AMI ARI ASEa BRE CAR CLO ILO LUM LUR OLAb PAL PIM QUE RIS ZIP Increased risk of death in elderly with dementia-related X X X X X X X X X X X X X X X psychosisa Cerebrovascular adverse events in elderly with dementia- X X X X X X X X X X X X X related psychosis Suicidal thoughts or behavior in young people (age ≤ 24)c X X X X Xb X EPS symptoms that may be confused with another disorder Severe neutropenia; monitor ANC – REMS program requiredc X Potentially fatal myocarditis, cardiomyopathy, mitral valve X incompetencec NMS X X X X X X X X X X X X X X Tardive dyskinesia X X X X X X X X X X X X X X Metabolic disturbancesd X X X X X X X X X X X X X Leukopenia, neutropenia, and agranulocytosis X X X X X X X X X X X X X X Orthostatic hypotension/syncope X X X X Xc X X X X X X X X Seizures X X X X X Xc X X X X X X X X Cognitive/motor impairment X X X X X X X X X X X X X X Compulsive behaviors X X Suicide X X X X

Safety and effectiveness not established for pediatrics X Xc,e Xc Xc X Delay in adverse effects X QT interval prolongation Xf X X X X X X X Xg Priapism X X X X DRESS X X Anticholingeric effects Xh X X Elevated prolactin X X X X X X X X X Lab test monitoringi X X GI narrowing in patients with GI disease (risk of GI X obstruction) Falls X X X X X X X X X X X X X X Dysphagia with aspiration risk X X X X X X X X X X X X

61 Table 9. Warnings and precautions for select FGAs and all SGAs (for oral dosage forms, except for AMI)2,3,11,12,14-17,21-27,32-34,43 Warning or Precaution HAL AMI ARI ASEa BRE CAR CLO ILO LUM LUR OLAb PAL PIM QUE RIS ZIP TTP X Antiemetic properties X Body temp dysregulation X X X X X X X X X X X X X Switch to (hypo)mania X Adverse reactions among PD or lewy-body dementia X X X Cataracts X Increased BP in children/adolescents X Hypothyroidism X Discontinuation syndrome Xj X Contains (for PKU) Xk Rash, severe skin reactions (eg, SJS) X Patients with other illnessl X X X GI hypomotility, potential paralytic ileus X Pulmonary embolism X Hepatotoxicity X Eosinophilia Xm Fever Xn Hypersensitivity reactions Xo Pregnancy use Xp Encephalopathy when used with Li X Bronchopneumonia X Abbreviations: AMI, amisulpride; ANC, absolute neutrophil count; ARI, aripiprazole; ASE, asenapine; BBW, black box warning; BP, blood pressure; BRE, brexpiprazole; CAR, cariprazine; CHL, chlorpromazine; CLO, clozapine; DRESS, drug reaction with eosinophilia and systemic symptoms; EPS, extrapyramidal side effects or extrapyramidal symptoms; GI, gastrointestinal; HAL, haloperidol; ILO, iloperidone; Li, lithium; LOX, loxapine; LUM, lumateperone; LUR, lurasidone; NMS, neuroleptic malignant syndrome; OLA, olanzapine; PAL, paliperidone; PD, Parkinson’s disease; PIM, pimavanserin; PKU, phenylketonuria; QUE, quetiapine; REMS, risk evaluation and mitigation strategy; RIS, risperidone; SJS, Stevens-Johnson syndrome; temp, temperature; TTP, thrombotic thrombocytopenic purpura; ZIP, ziprasidone aASE is also available as a transdermal patch. Warnings and precautions are similar, + also: application site reactions at patch site, and external heat may increase absorption.

62 Table 9. Warnings and precautions for select FGAs and all SGAs (for oral dosage forms, except for AMI)2,3,11,12,14-17,21-27,32-34,43 Warning or Precaution HAL AMI ARI ASEa BRE CAR CLO ILO LUM LUR OLAb PAL PIM QUE RIS ZIP bWhen combined with fluoxetine, also has BBW for suicidal behaviors among young people. Additional warnings with fluoxetine include: serotonin syndrome, angle- closure glaucoma, allergic reactions, switch to (hypo)mania, abnormal bleeding, hyponatremia, and long half-life. cBlack box warning (BBW). The BBW for increased risk of death among elderly patients with dementia also notes the antipsychotic “is not approved for the treatment of patients with dementia-related psychosis.” Pimavanserin is not indicated for non PD-related psychosis in elderly patients. All antipsychotics with an indication for depressive symptoms (bipolar or unipolar) also have a BBW for the increased risk of suicidal thoughts or behaviors among young people taking antidepressants. Clozapine has additional BBW: the risk for severe neutropenia requires enrollment in a REMS program to receive clozapine; the dose must be titrated slowly due to risk of orthostatic hypotension, bradycardia and syncope; dose-related seizure risk; myocarditis, cardiomyopathy, mitral valve incompetence that may be fatal. dIncludes changes such as elevated glucose or development of diabetes, dyslipidemias or weight gain. All SGAs (atypical antipsychotics) have this warning even the risk profile varies by antipsychotic. eThis is specific to the tablet with sensor formulation [Abilify Mycite]. fQT interval prolongation can lead to Torsades de Pointes. Cases of sudden death have been reported among those receiving haloperidol. gMagnitude of QT interval prolongation shown to be greater than selected other agents (risperidone, quetiapine, olanzapine, haloperidol). Manufacturers also warn of the potential for sudden death related to this change, though an excess risk of death has not been observed relative to other antipsychotics. hClozapine has the potential for particularly potent anticholinergic effects; product labeling refers to it as “anticholinergic toxicity” iRefers to glucose and lipids for olanzapine; refers to magnesium and potassium for ziprasidone (related to minimizing risks with QT interval prolongation) jFor clozapine, this refers to a cholinergic rebound and possible psychosis recurrence following an abrupt stop in therapy. kSpecific to the ODT formulation (Risperdal M-Tab) lPaliperidone also warns of use among patients with recent severe cardiovascular disease event (eg, myocardial infarction) as these patients were not in clinical trials and risk of orthostasis with paliperidone. Ziprasidone also warns of limited information for use in patients with recent cardiovascular disease (due to QT prolongation and/or orthostasis), pediatric patients (safety and effectiveness not established), geriatric patients, renal and hepatic impairment. Additional precautions for haloperidol: use in CV disorders due to transient hypotension; may interfere with anticoagulants; EPS in patients with PD; potentiation of CNS depressants; for mania, may cause rapid swing to depression; severe neurotoxicity in thyrotoxicosis patients; co-administration with rifampin (increase haloperidol levels); decreased cholesterol and/or ocular changes observed with other chemically-similar AP; and limited clinical studies among older adults ages 65 or older. mUsually occurring in the first month of treatment, it may or may not be associated with other organ involvement. nTransient fever, usually early in therapy, and usually benign. However, need to evaluate for other causes (eg, severe neutropenia, infection, NMS) oHypersensitivity reactions including anaphylaxis, angioedema, swollen tongue, hypotension and other allergic hypersensitivity reactions have occurred. History of these reaction is a contraindication for future use. pExposure to antipsychotics during third trimester has been associated with withdrawal symptoms and/or EPS at birth. This may occur with other antipsychotics, but is listed as a warning for haloperidol. Haloperidol also notes that some teratogenic effects have been reported, those it is not known if it is causal. Use during pregnancy with caution.

63 Considerations for Prior Authorization Criteria

The board may consider implementing prior authorization criteria for the newer antipsychotics reviewed in this report.

Potential criteria for brexpiprazole (Rexulti), cariprazine (Vraylar), and lumateperone (Caplyta)

• Age ≥ 18 years old • Each antipsychotic is approved for use in adults, and the safety and effectiveness in those <18 has yet to be established16,23,33 (though clinical trials are ongoing)

AND

• Intended use aligns with the FDA-approved indication: • Brexpiprazole (Rexulti): schizophrenia, or as an adjunct to an antidepressant for major depressive disorder • Cariprazine (Vraylar): schizophrenia; acute treatment of mania or mixed episodes, or depression in bipolar 1 disorder • Lumateperone (Caplyta): schizophrenia

AND

• May consider one or more of the following: 1. Trial and failure1 or contraindication to a certain number of PDL-preferred second- generation antipsychotics [SGAs] drug moieties with the same indication or recommended use per a clinical practice guideline: § For schizophrenia – trial/failure/contraindication of 2 or 3 PDL-preferred indicated for schizophrenia (this PA consideration applies to Caplyta, Rexulti, and Vraylar) • Currently the following SGAs with a preferred status on the PDL share this indication: aripiprazole tablet, aripiprazole long-acting injectables (LAI), clozapine2, paliperidone LAI, lurasidone3, olanzapine, olanzapine orally disintegrating tablet, risperidone tablet, risperidone oral solution, risperidone LAI, quetiapine, quetiapine extended-release, asenapine sublingual tablet, ziprasidone

1Trial and failure may refer to lack of efficacy after an appropriate dose and duration of therapy, or development of clinically significant treatment-associated adverse effects.

2Indicated for treatment-resistant schizophrenia, and suicidal behavior associated with schizophrenia or schizoaffective disorder

3Preferred on PDL after step therapy that requires failure of another PDL-preferred SGA first

64 § For bipolar I disorder depression – trial/failure/contraindication to 1 or 2 PDL- preferred SGAs (this PA consideration applies to Vraylar) • Currently, the following SGAs with preferred status on the PDL share this indication: quetiapine immediate release or extended release, and lurasidone§ o The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline for bipolar disorder recommends both quetiapine and lurasidone among first-line options; cariprazine is recommended as a second-line option10 § For bipolar I disorder mania or mixed symptoms – trial/failure/contraindication to 2 or 3 PDL-preferred SGAs (this PA consideration applies to Vraylar) • Currently the following SGAs with preferred status on the PDL share this indication: aripiprazole, asenapine, olanzapine, quetiapine, risperidone, ziprasidone o The 2018 CANMAT guideline for bipolar disorder recommends quetiapine, asenapine, aripiprazole, cariprazine, and risperidone among first-line options; olanzapine and ziprasidone are second-line options10 § As an adjunct to an antidepressant for major depressive disorder – trial/failure/contraindication to 1-2 PDL preferred SGAs (this PA consideration applies to Rexulti) • Currently aripiprazole and quetiapine extended-release share this approved indication and have preferred status on the PDL. Additionally, risperidone is a guideline recommended first-line option and also with preferred status on the PDL. o The CANMET 2016 guideline for major depressive disorder in adults recommends the following agents for adjunctive treatment with an antidepressant (after non-response [<25% symptom reduction] or partial response [25-49% symptom reduction] to an antidepressant): aripiprazole, quetiapine, risperidone. Brexpiprazole, and olanzapine are among second-line options. Ziprasidone is among third-line options.109 § CANMAT recommends making a patient-specific decision about adjunctive treatment vs. switching to another antidepressant. Factors for selecting adjunctive treatment include: 2+ prior antidepressant trials, partial response to initial antidepressant, targeting residual symptoms, faster response needed, patient preference.109

Note: Available evidence (mostly short-term evidence) suggests brexpiprazole, cariprazine, and lumateperone have a low risk of metabolic side effects relative to some other SGAs (eg, olanzapine, clozapine, risperidone, quetiapine).4,83 Various other SGAs are also considered to have a lower likelihood for metabolic side effects that also share some overlapping indications with these newer SGAs (aripiprazole, asenapine, lurasidone, and ziprasidone; all currently PDL-preferred).6,9,10,62

65 OR

2. The patient is stable (ie, with positive response) on brexpiprazole, cariprazine or lumateperone AND the provider believes switching to an alternative preferred therapy could lead to destabilization • For example, a patient may be stabilized on a medication during a behavioral health admission. • Note that clinical practice guidelines for bipolar disorder do not include cariprazine (Vraylar) as a recommended treatment for long-term maintenance therapy.10 Its effectiveness in preventing recurrence of acute mood episodes has yet to be established.99 § For schizophrenia and bipolar disorder, in general, clinical practice guidelines support continuing treatments that were effective and tolerated during acute treatment.6,8,10,54,55However, for bipolar disorder, there are other treatments that have established efficacy for preventing mood recurrence that are considered first-line. CANMAT recommends the following as first-line options: lithium, quetiapine, valproate, lamotrigine, asenapine, quetiapine + lithium/valproate, aripiprazole + lithium/valproate, aripiprazole, aripiprazole once-monthly LAI.10 • If criteria similar to this is implemented, Utah Medicaid may wish to retrospectively evaluate use and consider peer-to-peer education about preferred alternatives as appropriate • Off-label uses • May consider allowing off-label use according to standard language supported by Utah Medicaid on other prior authorizations (eg, randomized controlled trial evidence published in specific journals) and/or may consider following suggestions in clinical practice guidelines • At least one clinical practice guideline (the Royal Australian and New Zealand College of Psychiatrists) extends its recommendations to all schizophrenia spectrum disorders, which includes schizoaffective disorder and others.6 The British Association of Pharmacology (BAP) guideline recommends individualizing selection of an antipsychotic for patients with the schizoaffective disorder bipolar subtype.54 The American Psychiatric Association guideline states that recommendations are applicable to patients with schizophrenia; however, some of the trials included for formulating recommendations also included patients with schizoaffective disorder.55 • The 2018 update to the National Institute for Health and Care Excellence (NICE) guideline extends its recommendations to the full spectrum of bipolar disorders, including bipolar II disorder. CANMAT recommends extending treatment recommendations for mania in bipolar I disorder to hypomania in bipolar II disorder that causes enough impairment to require treatment.10 BAP also recommends extrapolating recommendations for treatment bipolar I disorder to bipolar II disorder based in expert opinion when there is an absence of specific evidence to direct treatment of bipolar II disorder.9 • Additional consideration may be given to allowing providers to submit justification of use for related indications (eg, schizoaffective disorder, bipolar II disorder) if the patient has failed FDA-approved treatments for the indication and/or failed treatment with preferred SGAs as

66 required for use before brexpiprazole, cariprazine, or lumateperone for schizophrenia, bipolar I disorder, or adjunctive treatment of major depressive disorder per the prior authorization criteria • CANMAT recommends quetiapine (preferred on the PDL) as first-line for bipolar II depression, and notes that recommendations for mania can probably be extended to hypomania.10 § Cariprazine (Vraylar) is indicated for bipolar I depression, and bipolar I acute mania/mixed episode. Its efficacy for bipolar II depression is unclear; one phase 2 trial that included both bipolar I and bipolar II patients failed to meet the primary endpoint.100 Phase 3 clinical trials only included patients with bipolar I disorder.99,100 • Paliperidone is FDA-indicated for schizoaffective disorder and the long-acting injectable is preferred on the PDL. Clozapine, which is preferred on the PDL, is indicated specifically to reduce suicidality in patients with schizoaffective disorder. § Brexpiprazole (Rexulti), cariprazine (Vraylar), and lumateperone (Caplyta) are all indicated for treatment of schizophrenia • To our knowledge, their efficacy for treatment of schizoaffective disorder is unknown. Pivotal phase 3 clinical trials excluded patients with schizoaffective disorder.90,102,103,110-113

67 Summary

Antipsychotics, commonly classified as FGAs or SGAs, are heterogeneous with differing receptor binding and side effect profiles.1,55,85 In general, FGAs may be associated with more EPS. In contrast, SGAs may be more likely to cause MSE with short- or long-term use.114 Both FGAs and SGAs are effective in treating a number of mental health disorders. Evidence supporting use varies by agent. Both are mainstay treatment options for schizophrenia.54,55 However, particularly for long-term use, SGAs may be used more commonly.114 For bipolar disorder, with the exception of haloperidol for acute mania, SGAs are usually recommended.8-10 When selecting among treatment options, both schizophrenia and bipolar treatment guidelines support selecting a personalized treatment with decision-making based on the patient’s presentation, treatment history, available dosage forms, and the side effect profile of medications.9,10,54,55 The newer oral antipsychotics, brexpiprazole (Rexulti), cariprazine (Vraylar), and lumateperone (Caplyta) are all SGAs indicated for treatment of schizophrenia.16,23,33 Cariprazine is also indicated for acute treatment of bipolar I disorder mania/mixed or depressive episodes.23 Brexpiprazole is additionally indicated as an adjunctive treatment to antidepressants after failure of an antidepressant in patients with major depressive disorder (MDD).16 Lexicomp includes severe agitation/psychosis associated with dementia, and adjunctive treatment of MDD as possible off-label uses of brexpiprazole and cariprazine, respectively.29,30 These newer antipsychotics have yet to be approved for children.16,23,33

Although there may be some slight variation in the efficacy among antipsychotics for the treatment of schizophrenia,5,53 most clinical practices guidelines for adults consider all FGAs and SGAs (except for clozapine) to be similarly effective for the first-episode of psychosis.54,55,63 One prefers starting an SGA first due to the better side effect profile, and possibility of greater relapse prevention (based on oral use).6 Clozapine is recommended for treatment-resistant schizophrenia or severe aggression unresponsive to other treatments6,54,55,63; or for patients at high risk for suicide.55 If an antipsychotic is effective and well-tolerated during acute treatment, most guidelines recommend continuing the same antipsychotic for maintenance treatment.6,54,55 To our knowledge, there are not specific clinical practice guidelines for schizoaffective disorder. One guideline extends recommendations to all schizophrenia spectrum disorders6; other guidelines note the limited evidence for patients with schizoaffective disorder.54,55 Information about lumateperone was not included in clinical practice guidelines.6,54,55,63 Cariprazine and brexpiprazole were included in the two most recent schizophrenia guidelines.54,55

Antipsychotics (primarily SGAs) and mood stabilizers [MS] are major treatment options for bipolar disorder. Treatment of bipolar disorder includes an acute phase to improve an emergent mood (ie, stabilizing mania or depressive symptoms) followed by a maintenance phase to prevent relapse.9,67 During acute treatment, combination therapy (often with an SGA + MS) may be preferred to monotherapy when symptoms are severe or the patient has a history of partial response to monotherapy.9,10 SGAs are recommended for acute bipolar I mania in adults (CANMET recommends quetiapine ± lithium/valproate, asenapine ± lithium/valproate, aripiprazole ± lithium/valproate, paliperidone, risperidone ± lithium/valproate, and cariprazine as first-line options)10; the other guidelines also recommend haloperidol and olanzapine among first-line options.8,9 Fewer SGAs are recommended for acute bipolar I depression. SGAs among first-line agents per CANMET are quetiapine and lurasidone + lithium/valproate10; other guidelines also include olanzapine.8,9 The only clinical practice guideline that included information about cariprazine for depression, recommends cariprazine as a second-line option for bipolar I depression due to tolerability concerns.10 For maintenance therapy

68 of bipolar I disorder, all guidelines recommend lithium as first-line.8-10 CANMAT also recommends quetiapine ± lithium/valproate, asenapine, and aripiprazole among first-line options after considering lithium10; NICE considers olanzapine as an alternative.8 The BAP recommends considering continuation of antipsychotics for maintenance therapy if patients responded well acutely9; CANMAT also supports this, particularly if the acute treatment is among first-line options for maintenance treatment.10

Limited evidence is available to guide treatment of bipolar II disorder in adults. In general, in the absence of specific evidence, guidelines recommend extending evidence for bipolar I disorder to bipolar II disorder.8-10 Based on clinical experience, CANMAT recommends extending mania recommendations to bipolar II hypomania causing significant impairment.10 Among guidelines with specific bipolar II recommendations, one recommends quetiapine first-line.10 For maintenance treatment, two guidelines recommend quetiapine, or lamotrigine9,10; one additionally recommends lithium.10

Overall, guidelines suggest that the relative propensity for various MSEs (especially weight gain) among antipsychotics should be a factor in both the selection of an initial agent, as well as later deciding to switch to another therapy.6,9,10,54,62,79 Proactive strategies to manage MSE include lifestyle interventions, metformin, switching to lower risk antipsychotic, or possibly adding aripiprazole as an adjunctive treatment among those receiving olanzapine or clozapine.6,10,62,79 Guidelines consistently mention clozapine and olanzapine among the antipsychotics with the highest risk for MSE and amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, haloperidol, lurasidone, and ziprasidone as lower risk.6,9,10,62 Relative comparisons from NMA of primarily short-term (ie, 6-8 week) studies in patients with schizophrenia also support this.5,83 Preliminary information from short-term clinical trials for lumateperone also suggest it is at a lower risk of MSE.90,102 The long-term MSE risks of brexpiprazole, cariprazine, and lumateperone are relatively unknown.88

Brexpiprazole, cariprazine and lumateperone seem to have a similar side effect profile to many other SGAs.4,5,23,33 In clinical trials, more patients receiving cariprazine reported EPS, particularly akathisia, than with placebo.23 Lumateperone was well tolerated with somnolence as the most common side effect.33 Weight gain was reported more frequently with brexpiprazole than placebo.16 Each share the black-box warning for increased risk of death in patients with dementia-related psychosis.16,23 Cariprazine and brexpiprazole also carry a warning for risk of suicidal thoughts and behavior in young people with depression.16,23 A warning unique to brexpiprazole (and aripiprazole) is the increased risk of compulsive or impulsive behaviors such as gambling.3,16 Cariprazine carries a warning for the risk of delayed adverse effects due to a metabolite with a long half-life (approximately 1-3 weeks).23

Prior authorization (PA) criteria may be considered for brexpiprazole, cariprazine, and lumateperone. No drug-specific PA criteria are currently in place for these agents in Utah Medicaid. Each is non-preferred on the PDL; in contrast, many other SGAs are preferred. Considerations for PA criteria may include (1) the lack of safety/effectiveness in children, and/or (2) the FDA-approved indications for use. Because other SGAs with overlapping indications are preferred, additional PA criteria could include step-therapy requirements for trial, failure, or contraindication to between 1 and 3 preferred SGAs. The board may also consider requiring fewer failed SGAs for bipolar I depression (a consideration for cariprazine) as fewer SGAs are indicated or recommended in guidelines. The PA may also consider allowing continuation of patients already stabilized on one of these agents. The board may wish to discuss whether the PA criteria should also be extended to patients with similar indications (eg, schizoaffective disorder, bipolar II disorder) in light of some guideline recommendations.

69 References

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76 Appendix A: Proposed Mechanism of Action and Receptor Binding Profile

The exact mechanism of action of antipsychotics for the treatment of various mental health disorders is not known. However, antagonism (or partial agonism) of the dopamine D2 receptor is required for anti- psychosis effects. Among the FGAs, the amount of D2 receptor blockade correlates with antipsychotic efficacy. However, SGAs tend to exert more varied effects on other receptors that may contribute to their efficacy. For example, D2 antagonism is associated with a decrease in positive symptoms of schizophrenia, 5-HT2A antagonism may help treat negative symptoms, and partial agonism of 5-HT1A may have benefits for negative, cognitive, anxiety, and depressive symptoms.115 Newer antipsychotics (eg, aripiprazole, brexpiprazole [Rexulti], cariprazine [Vraylar]), sometimes called TGA, are centrally acting D2 receptor partial agonists that have varied effects based on the dopamine tone.115,116 This may allow for minimizing dopamine-related side effects, while maintaining enough activation of dopamine signals in the brain.116 Lumateperone (Caplyta) may also share these properties, but partial agonist activity was not conclusive in FDA review documents.103

The unique receptor binding profiles and locations of the activity (eg, for dopamine, whether it binds in the mesocortical, nigrostriatal, or tuberoinfundibular pathways) also predict some adverse effects.

Greater D2 receptor antagonism in the nigrostriatal pathway is associated with development of EPS, and blockade within the tuberoinfundibular pathway may elevate prolactin levels. Other varying effects are expected based on activity at other receptors.115

The mechanism of benefit of antipsychotics for treating bipolar disorder is incompletely understood. Mania may be characterized by a “hyperdopaminergic state” that responds to antagonism of dopamine D2/D3 receptors. Most antipsychotics studies have been shown to be effective for treating acute mania. However, treatment of bipolar depression does not seem to be a class effect. This suggests that benefit may occur from activity at receptors other than dopamine, but the exact mechanism of benefit is unknown.9

Appendix Table A1 provides an overview of the receptor binding profile for select agent. Cariprazine and brexpiprazole have unique binding profiles with some similarity to aripiprazole.85 Lumateperone is a

D2 (with inconclusive pre-synaptic agonist activity), with a binding profile similar to other antipsychotics except for additional binding to the serotonin transporter (SERT).33,103 Each have low or negligible affinity for several receptors associated with metabolic side effects.33,87

77 Appendix A Table A1. Comparison of Receptor Binding Profile of Various Antipsychoticsa,b33,64,85 * * * * * c Antipsychotic D1 D2 D3 D4 D5 5-HT1A 5-HT2A 5-HT2C 5-HT7 H1 M1 M3 α1 α2 Transporters generic name Select First-Generation Antipsychotics Chlorpromazine + +++ +++ ++ + - +++ ++ ++ +++ ++ ++ +++ +/++ Haloperidol + +++ +++ +++ + - ++ - + - - - ++ - Molindone - ++ ++ ------ND - + Perphenazine ++ ++++ ++++ ++ - +++ + ++ +++ - ND ++ + Select Second Generation Antipsychotics Aripiprazole + ++++ +++ + - +++ ++ ++ ++ ++ - - ++ ++ SERT Asenapine +++/+++ +++ +++ ++++ +++ +++ ++++ ++++ ++++ +++ - +++ + Brexpiprazole + ++++ +++ ++++ ++++ ++++ + +++ ++ +/? +++ ++/++++ SERT, NET Cariprazine ++++^ ++++^ ++ +++ ++ + + ++ - + Clozapine + + + ++ + + ++ ++ ++ +++ +++ ++ +++ ++ Iloperidone + +++ +++ ++ + + +++ ++ + + +++ +/++ Lumateperone ++ ++^d ++ ++++ - - - ++ SERT (++) Lurasidone + +++ +++ ++++ + ++++ - - ++ ++/+++ Olanzapine ++ ++ ++ ++ ++ +++ ++ ++ ++ ++ ++ +/++ Paliperidone + +++ +++ +++ ++ + +++ ++ +++ ++ +++ +++ Quetiapinee + + + - ++ ++ + ++ ++ + + ++ +/++ NET Risperidone + +++ +++ +++ + + ++++ ++ +++ +++ +++ ++/+++ Ziprasidone + +++ +++ ++ + +++ ++++ ++++ +++ ++ ++ +/++ SERT, NET Abbreviations: α, alpha receptor; 5-HT, serotonin receptor; D, ; FDA, US Food and Drug Administration; H, receptor; M, muscarinic receptor; ND, no data; NET, norepinephrine transporter; nM, nanomolar; PL, product labeling; SERT, serotonin transporter; a Binding strength: ++++: very strong (Ki <1 nM), +++: strong (1 nM ≤ Ki <10 nM), ++: moderate (10 nM ≤ Ki <100 nM, +: weak (100 nM ≤ Ki <1000 nM, -: negligible or very weak (Ki ≥ 1000 nM), +/?: some activity but strength of affinity unknown bPartial agonism is indicated by yellow, whereas other binding reflects antagonism or inverse agonism. c Binding profile may differ slightly by subtype of alpha2 receptor. If multiple binding profiles are indicated, this reflects differences by subtype. dMay have pre-synaptic partial agonist activity (commonly asserted in the literature), but per the FDA review, it is not certain and the PL lists antagonism.33 eBinding profile based on both quetiapine and its active metabolite norquetiapine87 *antagonism associated with metabolic side effects including weight gain and/or diabetes mellitus; however, the cause of metabolic side effects is complex and not fully understood. Downstream and peripheral effects may also contribute.85,117 ^Possible dose-dependence. Cariprazine is a partial agonist at lower doses while antagonist at higher doses.4

78 Appendix B: Literature Search Strategy

Search 1 of Epistemonikos on 10/21/20 for metabolic side effects related to antipsychotics:

(title:((title:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone)) OR abstract:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone))) AND (title:(safety OR tolerability OR harm OR harms OR "side effects" OR "side effect" OR weight OR diabetes OR lipids OR dyslipidemia OR glucose OR metabolic) OR abstract:(safety OR tolerability OR harm OR harms OR "side effects" OR "side effect" OR weight OR diabetes OR lipids OR dyslipidemia OR glucose OR metabolic))) OR abstract:((title:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone)) OR abstract:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone))) AND (title:(safety OR tolerability OR harm OR harms OR "side effects" OR "side effect" OR weight OR diabetes OR lipids OR dyslipidemia OR glucose OR metabolic) OR abstract:(safety OR tolerability OR harm OR harms OR "side effects" OR "side effect" OR weight OR diabetes OR lipids OR dyslipidemia OR glucose OR metabolic))))

Additional limits applied: limited to systematic reviews, and year to 2020

Search 2 of Epistemonikos on 10/21/20 for articles about switching antipsychotics: (title:((title:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone)) OR abstract:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone)))) OR abstract:((title:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR

79 amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone)) OR abstract:((antipsychotic OR antipsychotics OR neuroleptic OR neuroleptics) OR (chlorpromazine OR fluphenazine OR haloperidol OR loxapine OR molindone OR perphenazine OR pimozide OR prochlorperazine OR thiothixene OR thioridazine OR trifluoperazine OR amisulpride OR aripiprazole OR asenapine OR brexpiprazole OR cariprazine OR clozapine OR iloperidone OR lumateperone OR lurasidone OR olanzapine OR paliperidone OR pimavanserin OR quetiapine OR risperidone OR ziprasidone))))) AND (title:(switch OR switching) OR abstract:(switch OR switching))

80

Appendix C: Overview of Other Common Medications for Bipolar Disorder

Appendix Table C1. Overview of Other Common Medications Used for Bipolar Disorder Generic name or FDA-approved Other notes about use Black box warnings class indications

(brand name) Lithium118 BD mania • Toxicity can occur at • Reduces suicide risk BD maintenance near therapeutic levels. • Requires therapeutic drug monitoring Lithium Access to drug level (therapeutic range ~0.8 – 1.2 mEq/L) carbonate, monitoring is needed. • “Relative slowness of action”67; risk of Safety/effectiveness recurrence with abrupt d/c67 (Lithobid) in age <12 years not • Drug-drug interactions established • Other SE: GI upset, lethargy, fine hand tremor, polyuria/polydipsia, cognitive dulling • Risks with long-term use: decreased thyroid levels, possible loss of renal function Valproic Acid BD mania/mixed • Serious or fatal • Not recommended among girls/women Salts119a hepatotoxicity (in first 6 of reproductive potential8 Also: seizure months) – highest risk • Drug-drug interactions divalproex disorders, migraine age <2 years, • Total valproic acid level (for mania): 50- sodium headache prophylaxis mitochondrial disorders 125 mcg/mL (Depakote, • Use in patients with • Other AEs: abdominal pain, alopecia, Depakote ER, Studied in children mitochondrial disease tremor, weight gain, ataxia67 Depakote (10+ years for mania); (increased risk of liver • Risk of polycystic ovary syndrome8 Sprinkles) higher risk of failure) • Other warnings: bleeding disorders, hepatotoxicity at age • Fetal congenital suicidal behaviors, hyperammonemia, valproic acid <2 years. malformations and hypothermia, DRESS/multi-organ (Depakene [IR]) neurodevelopmental hypersensitivity reaction disorders valproate sodium • Life-threatening or fatal (Depacon – pancreatitis injectable) Carbamazepine120 BD I mania/mixed • Severe dermatological • Drug-drug interactions (inhibitor and reactions (Asian inducer of CYP3A4; auto-inducer) (Carbatrol, Epitol, Also: epilepsy, populations higher risk) • Use cautiously in women of childbearing Equetro, Tegretol, trigeminal neuralgia o Associated with HLA- age10; risk of congenital defects including Tegretol-XR, Teril) pain B*1502 allele. Testing spina bifida recommended among • Other AEs: blurred vision, dizziness, Equetro (ER Safety and those considered sedation, tremor, GI symptoms67 capsule) = dosage effectiveness in high-risk for having • Other warnings/precautions: DRESS, form studied in pediatric patients not the allele. Avoid use in possible fetal risk, hyponatremia, clinical trials for established (Equetro patients with the HLA- cognitive/motor impairment, liver BPD labeling); has been B*1502 allele damage, hepatic porphyria used in pediatrics for • Aplastic anemia, epilepsy agranulocytosis

81 Appendix Table C1. Overview of Other Common Medications Used for Bipolar Disorder Generic name or FDA-approved Other notes about use Black box warnings class indications

(brand name) Lamotrigine121 BD I maintenance • Serious rashes – can be • Not helpful for mania10 (Lamictal, life threatening • DDIs with valproate (requires lower dose) Lamictal ODT, “Treatment of manic o D/c if rash and carbamazepine (requires higher Lamictal XR, or mixed episodes is dose) Lamictal CD, not recommended” • Rash (among up to 10%) and TEN or SJS Subvenite) Also: epilepsy • Slow dose initiation required (limit rash risk) Safety/efficacy not • Other AEs: nausea, insomnia, fatigue established among • Other warnings/precautions: pediatric patients 10- hemophagocytic lymphohistiocytosis, life- 17 with bipolar threatening hypersensitivity reactions, disorder mania/mixed cardiac rhythm abnormalities, blood or depressed episode. dyscrasias, suicidal behavior, aseptic Indicated for seizure meningitis disorders for age 2+ Antidepressants varies by specific Increased risk of suicidality Use for bipolar disorder is controversial medication among adolescents and (due to risk of a “switch” to mania), but may young adults occur in clinical practice.67 Risks may be greater with certain classes (ie, AD). Evidence for or against use is limited.9 Guidelines do not recommend first-line (especially long-term), and if used, recommend use with an antimanic agent, particularly for BD I.9,10 BAP only recommends long-term use in cases of a high risk of severe depression relapse. Avoid use with rapid-cyclers or for mixed symptoms.9 Risks of switching may be lower for BD II. CANMAT recommends certain AD as second or third-line options for maintenance treatment of BD II: venlafaxine, escitalopram, fluoxetine.10 Abbreviations: AD, antidepressant; BAP, British Association of Psychopharmacology; BD, bipolar disorder; BD I, bipolar I disorder; BD II, bipolar II disorder; CANMAT, Canadian Network for Mood and Anxiety Treatments; D/c, discontinue; DDIs, drug-drug interactions; ER, extended release; IR, immediate release; L, liter; mEq, milliequivalents; ODT, oral disintegrating tablet; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysis; XR, extended release; aValproic acid is the active component. Divalproex sodium is a bonded compound of sodium valproate and valproic acid that dissociates in the GI tract.8,119,122

82 Appendix D: Summary of a Meta-analysis for Efficacy Measures with Cariprazine and Brexpiprazole for Schizophrenia

Appendix Table D1. Summary of direct comparisons of other antipsychotics or placebo with cariprazine or brexpiprazole in clinical trials for schizophrenia SRMA Results Huhn et al. 20195 Overall comparable efficacy among second generation antipsychotics, and select first generation antipsychotics for acute treatment of total symptoms, positive symptoms, and SR, NMA of RCTs negative symptoms among adults with multiple-episode schizophrenia. (head-head or vs. • Below is a summary of direct comparisons (ie, pairwise meta-analysis) that included placebo) of adults cariprazine, brexpiprazole. Lumateperone was not included at the time of this study. with acute Summary of studies among of antipsychotics Schizophrenia (or Antipsychotic Standardized mean difference or mean difference related disorders) Aripiprazole 27 studies (total n = 2361), 65% male, mean age 37 years, duration of symptoms 14.26 years, treatment duration = 5.85 weeks, mean dose = Excluded: 18.65 mg (olanzapine equivalents = 12.52 mg), 40.74% at high risk of bias treatment resistant Brexpiprazole patients, first-time 6 studies (total n = 1264), 60% male, mean age 40.15 years, duration of treatment, symptoms 15 years, treatment duration = 6 weeks, dose = 3 mg (olanzapine predominant equivalents: 15 mg), 16% high risk of bias negative/depressive Cariprazine 4 studies (total n = 1029), 70% male, mean at 37.9, duration of symptoms symptoms, relapse- 14.25 years, treatment duration = 6 weeks, mean dose = 4 mg (olanzapine prevention study equivalents: 13.8 mg), 0% high risk of bias only Risperidone 84 studies (total n = 4973), 64% male, mean age 36.55 years, duration of symptoms = 13.78 years, treatment duration = 6.91 weeks, mean dose = 5.82 mg (olanzapine equivalents = 19.39 mg), 32% at high risk of bias Quetiapine 33 studies (total n = 3496), 64.7% male, mean age 38.41 years, duration of symptoms = 13.78 years, treatment duration = 6.91 weeks, mean dose 519.52 mg (olanzapine equivalents = 14 mg), 33.33% at high risk of bias Summary of direct comparisons for overall symptoms (primary outcome) Comparison Standardized mean difference or mean difference (95% confidence interval) Aripiprazole vs. cariprazine 0.02 (-0.28 to 0.32) Risperidone vs. cariprazine -0.34 (-0.64 to -0.04) – favors risperidone Cariprazine vs. placebo -0.37 (-0.53 to -0.21) – favors cariprazine Aripiprazole vs. brexpiprazole -0.09 (-0.51 to 0.33) Quetiapine vs. brexpiprazole -0.21 (-0.54 to 0.11) Brexpiprazole vs. placebo -0.25 (-0.39 to -0.11) – favors brexpiprazole Summary of direct comparisons for positive symptoms Comparison Standardized mean difference or mean difference (95% confidence interval) Aripiprazole vs. cariprazine -0.01 (-0.30 to 0.28) Risperidone vs. cariprazine -0.39 (-0.68 to -0.10) – favors risperidone Cariprazine vs. placebo -0.32 (-0.47 to -0.16) – favors cariprazine Aripiprazole vs. brexpiprazole -0.26 (-0.66 to 0.15) Quetiapine vs. brexpiprazole -0.18 (-0.49 to 0.13) Brexpiprazole vs. placebo -0.17 (-0.31 to -0.04) – favors brexpiprazole

83 Appendix Table D1. Summary of direct comparisons of other antipsychotics or placebo with cariprazine or brexpiprazole in clinical trials for schizophrenia SRMA Results Summary of direct comparisons for negative symptoms Comparison Standardized mean difference or mean difference (95% confidence interval) Aripiprazole vs. cariprazine 0.08 (-0.18, 0.33) Risperidone vs. cariprazine -0.15 (-0.41, 0.10) Cariprazine vs. placebo -0.34 (-0.48 to -0.21) – favors cariprazine Aripiprazole vs. brexpiprazole 0.16 (-0.22 to 0.55) Quetiapine vs. brexpiprazole -0.16 (-0.44 to 0.12) Brexpiprazole vs. placebo -0.24 (-0.36 to -0.12) – favors brexpiprazole Summary of direct comparisons for depressive symptoms Comparison Standardized mean difference or mean difference (95% confidence interval) Aripiprazole vs. cariprazine -0.04 (-0.31 to 0.23) Cariprazine vs. placebo -0.37 (-0.63 to -0.10) – favors cariprazine Quetiapine vs. brexpiprazole -0.16 (-0.45 to 0.13) Brexpiprazole vs. placebo -0.17 (-0.31 to -0.04) – favors brexpiprazole Summary of weight gain Comparison Standardized mean difference or mean difference (95% confidence interval) Aripiprazole vs. cariprazine 0.00 (-1.40, 1.41) Placebo vs. cariprazine -0.78 (-1.59 to 0.04) Aripiprazole vs. brexpiprazole -0.91 (-2.30 to 0.48) Placebo vs. brexpiprazole -1.16 (-1.99 to -0.34) – favors placebo Comparisons among other antipsychotics with statistically significant difference: Ziprasidone < risperidone; haloperidol < quetiapine; lurasidone < quetiapine; haloperidol < iloperidone; ziprasidone < iloperidone; Olanzapine > each of the following (in no particular order): paliperidone, risperidone, haloperidol, aripiprazole, lurasidone, ziprasidone Overall summary of evidence ratings for symptom improvement (not reported for other outcomes) Comparison Quality of evidence ratings Aripiprazole vs. cariprazine mixed indirect and direct evidence: very low; “study limitations, serious imprecision, incoherence” Cariprazine vs. placebo mixed indirect and direct evidence: very low; “study limitations, publication bias, heterogeneity, serious incoherence” Cariprazine vs. risperidone mixed indirect and direct evidence: low; “study limitations, imprecision” Brexpiprazole vs. aripiprazole mixed indirect and direct evidence: very low; “study limitations, imprecision, heterogeneity, incoherence” Brexpiprazole vs. placebo mixed indirect and direct evidence: very low; “publication bias, heterogeneity, serious incoherence”

Abbreviations: CI, confidence interval; mg, milligram; vs.; versus Bolded comparisons indicate a statistically significant difference.

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