OHSU Presentation Template - White

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Pharmacologic Considerations in the Treatment of
Schizophrenia and Psychosis
Presented by Ann M. Hamer, PharmD, BCPP
Date 3/3/2016
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Disclosures and Learning Objectives

• Learning Objectives
• Be able to discuss first-line treatment
  recommendations for schizophrenia
• Be able to discuss benefits and risks of typical
  and atypical antipsychotics
• Be able to identify differences between available
  antipsychotics
• Disclosures Dr. Ann Hamer has nothing to
  disclose.

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Agenda

• Week 1
• Treatment selection recommendations and clinical
  trials
• Overview of available agents
• Week 2
• Role of receptor antagonism in adverse effect
  profiles
• Identifying and treating adverse effects
  associated with traditional and atypical
  antipsychotics
• Alternative dosage forms

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Role of Antipsychotic Medications
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Choosing an Antipsychotic

• The choice of antipsychotic medication should be
  made by the patient and provider together.
  Provide information and discuss the likely
  benefits and possible side effects of each drug,
  including
• metabolic (including weight gain and diabetes)
• extrapyramidal (including akathisia, dyskinesia
  and dystonia)
• cardiovascular (including prolonging the QT
  interval)
• hormonal (including increasing plasma prolactin)
• other (including unpleasant subjective
  experiences)

www.nice.org.uk
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Treatment Selection

• CATIE
• Clinical Antipsychotic Trials of Intervention
  Effectiveness (CATIE)
• Compared rates of all-cause discontinuation in
  1432 patients treated with either an SGA
  (olanzapine, quetiapine, risperidone, or
  ziprasidone) or the FGA perphenazine.
• Olanzapine showed a longer time to
  discontinuation for any reason compared with the
  other antipsychotics (9.2 months for olanzapine
  vs 3.5-5.6 months for the others).
• This difference was not significant when compared
  with perphenazine alone.
• Perphenazine showed effectiveness comparable to
  that of the other SGAs used in the study.

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Treatment Selection

• CATIE
• Patients with schizophrenia treated with
  olanzapine experienced higher rates of clinically
  significant weight gain (7 of body weight)
  compared with the other antipsychotics (30 with
  olanzapine vs 7 with ziprasidone, 12 with
  perphenazine, 14 with risperidone, and 16 with
  quetiapine P lt.001) and had greater increases in
  HbA1C, total cholesterol, and triglycerides.
• Other adverse effects seen were generally
  consistent with those observed in clinical
  practice. Risperidone was associated with the
  greatest increase in prolactin (P lt.001) and
  perphenazine had the highest rate of
  discontinuation due to EPS, although there were
  no significant differences in the rates of EPS
  between the different treatment groups.

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Treatment Selection

• CUtLASS
• European Cost Utility of the Latest Antipsychotic
  Drugs in Schizophrenia Study (CUtLASS 1).
• Examined improvement in quality of life as
  measured by the Quality of Life Scale (QLS) in
  185 patients who were treated over a period of 1
  year with either an FGA or an SGA.
• No significant difference was observed in the
  primary outcome (QLS) in either treatment arm,
  nor in any of the secondary outcomes, including
  symptom improvement, treatment adherence,
  attitudes toward medication, or extrapyramidal
  side effects.

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Treatment Selection

• EUFEST
• European First Episode Schizophrenia Trial
  (EUFEST)
• Examined 498 first episode patients over 1 year
  of randomized treatment with haloperidol,
  amisulpride, olanzapine, quetiapine, or
  ziprasidone.
• More patients discontinued haloperidol for any
  reason than the other antipsychotics (72 vs 40
  for amisulpride, 33 for olanzapine, 53 for
  quetiapine, and 45 for ziprasidone P lt.001).
• There were no differences in symptom improvement
  or rates of hospital admission between the
  treatment groups.
• Patients treated with haloperidol experienced the
  most EPSs, and patients treated with olanzapine
  experienced the most weight gain.

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Treatment Selection

• CAFE
• Comparison of Atypicals for First Episode
  Schizophrenia (CAFE)
• Patients treated with either olanzapine,
  quetiapine, or risperidone had similar all-cause
  discontinuation rates at 1 year, no differences
  in overall symptom severity measures, and side
  effects similar to those seen in other trials.

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Treatment Selection
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Treatment Selection

• Considerations
• patient preference
• prior treatment response (or first degree
  relative)
• side effect profile
• medical history and risk factors
• adherence

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Treatment Selection

• In patients with schizophrenia experiencing their
  FEP, the SGAs are generally preferred for initial
  treatment.
• These patients are also particularly vulnerable
  to the adverse effects of antipsychotic
  medications, such as weight gain and EPS, and are
  generally more responsive to lower doses than
  patients who have experienced multiple episodes.
• Therefore, the lowest possible dose, typically
  about half the dose used in patients with chronic
  schizophrenia, should generally be used in these
  patients.

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Antipsychotics

• Traditional
• Also referred to as first-generation
  antipsychotics, dopamine antagonists,
  conventional antipsychotics, typical
  antipsychotics, neuroleptics, or major
  tranquilizers.
• Neuroleptic refers to the ability of a drug to
  cause a syndrome known as neurolepsis. This
  syndrome has three main features psychomotor
  slowing, emotional quieting, and affective
  indifference.
• Typical antipsychotics drugs that do not have
  atypical properties are considered typical or
  conventional antipsychotics
• Atypical
• Also called second-generation antipsychotics.
  Considered atypical because they produce fewer
  extrapyramidal symptoms and have non traditional
  receptor binding profiles

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Receptor Binding Profiles of Antipsychotics

• Traditional

• Atypical

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Traditional Antipsychotics
Generic Brand
Chlorpromazine Thorazine
Thioridazine Mellaril
Mesoridazine Serentil
Loxapine Loxitane
Molindone Moban
Perphenazine Trilafon
Thiothixene Navane
Trifluoperazine Stelazine
Haloperidol Haldol
Fluphenazine Prolixin
Droperidol Inapsine
Prochlorperazine Compazine
Pimozide Orap
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Mechanism of Action
Mesocortical Can induce secondary negative sx and
cognitive effects Mesolimbic Improves symptoms
of psychosis Nigrostriatal Associated with
increased risk of EPS Tuberoinfundibular
Increase prolactin levels by promoting its
release in the pituitary gland
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Chemical Classification

• Phenothiazines
• Largest chemical group. Share the same
  three-ring chemical structure with different side
  chains joined at the nitrogen atom of the middle
  ring.
• Low/medium potency agents chlorpromazine,
  mesoridazine, thioridazine
• Medium/high potency agents perphenazine,
  fluphenazine, trifluoperazine,
• Non-phenothiazines
• Butyrophenones (high potency) droperidol,
  haloperidol
• Thioxanthenes (low/medium potency) thiothixene
• Dihydroindolones (low/medium potency) molidone
• Dibenzepines (low/medium potency) loxapine
• Diphenylbutylpiperidines (high potency) pimozide

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Dosing Equivalents (Low v. High Potency)
Drug Chlorpromazine Equivalents
Chlorpromazine 100 mg/d
Fluphenazine 2 mg/d
Trifluoperazine 5 mg/d
Haloperidol 2 mg/d
Pimozide 2 mg/d
Loxapine 10 mg/d
Molindone 10 mg/d
Perphenazine 10 mg/d
Prochloperazine 15 mg/d
Thioridazine 100 mg/d
Thiothixene 4 mg/d
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FGA Overview
FGA Usual Dose Range Initial Oral Dose Max Dose Formulations T1/2 Primary metabolism Enzyme Inhibition
Chlorpromazine 400-600 25-200 800 Tab, IM 30 2D6, gluc 2D6
Fluphenazine 2 -15 2-10 12 Tab, IM, LAI, soln 33 2D6 2D6
Haloperidol 2-20 2-10 30 Tab, IM, LAI, soln 20 2D6, 3A4, gluc 2D6, 3A4
Loxapine 20-80 20 100 Cap, soln, inhalation 12 1A2, 2D6, 3A4, gluc None
Perphenazine 12-24 8-16 24 Tab 9-12 2D6, 3A4, others 2D6
Pimozide 8-10 1-2 10 Tab 55 1A2, 2D6, 3A4, others 2D6
Thiothixene 10-20 5-10 30 Cap 33 1A2, others None
Thioridazine 200-600 150 600 Tab 21-25 2D6, others 2D6
Trifluoperazine 15-20 4-10 40 Tab 22 1A2 None
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Atypical Antipsychotics
Generic Brand
Aripiprazole Abilify
Asenapine Saphris
Brexpiprazole Rexulti
Cariprazine Vraylar
Clozapine Clozaril
Iloperidone Fanapt
Lurasidone Latuda
Olanzapine Zyprexa
Paliperidone Invega
Quetiapine Seroquel
Risperidone Risperdal
Ziprasidone Geodon
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Indications
Drug Generic Schizophrenia Schizoaffective Agitation Autism BPD (Manic/ Mixed) BPD (Depression) MDD Tourettes
Saphris No X gt10 yrs
Fanapt No X
Invega Yes gt12 yrs
Latuda No X X
Zyprexa Yes gt13 yrs IM gt13 yrs A A
Risperdal Yes gt13 yrs gt4 yrs gt10 yrs
Seroquel Yes gt13 yrs gt10 yrs X
Seroquel XR No gt13 yrs gt10 yrs X A
Geodon Yes X IM A
Abilify Yes gt13 yrs IM gt6 yrs gt10 yrs A X
Rexulti No X A
Vraylar No X X
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Risperidone (Risperdal)

• The pharmacokinetics of the oral formulations are
  all equivalent, with rapid absorption and 20-hour
  elimination half life.
• Risperidone has little activity at muscarinic
  receptors and no anticholinergic effects.
• Drug-drug interactions are infrequent, but its
  serum levels are modestly decreased by inducers
  of the cytochrome P450 system, such as
  carbamazepine, and are increased by inhibitors
  such as fluoxetine and ketoconazole.
• Although it is not necessary to adjust the dose
  of risperidone whenever such a medication is
  added or withdrawn, clinicians should be aware of
  the potential for a change in serum level with
  the simultaneous use of these medications.

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Risperidone (Risperdal)

• The drug is typically dosed once daily.
• Starting doses for adults are 1 to 2 mg/day, and
  maintenance doses are typically in the 2 to 6
  mg/day range, with 4 mg/day the average dose in
  the community. Doses above 6 to 8 mg/day are
  associated with higher rates of extrapyramidal
  symptoms.
• Titration should be done over the course of
  several days in order to minimize the emergence
  of extrapyramidal symptoms or akathisia.
• For the elderly population, doses typically start
  at 0.25 to 0.5 mg/day, average about 1 mg/day,
  and do not usually exceed 2 mg/day.

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Risperidone (Risperdal)

• Hepatic impairment results in increased serum
  levels and activity due to a 35 percent greater
  free fraction of the drug. Renal dysfunction
  reduces elimination of risperidone by 60. Both
  conditions may require dose reductions.
• The usual dose of the oral solution and
  rapid-disintegrating formulation of risperidone
  for acute agitation is 1 to 2 mg every 30 minutes
  to two hours, to a maximum of 4 mg/day. The
  primary side effects of risperidone are mild
  sedation, hypotension, akathisia, prolactin
  elevation, and weight gain.
• Preliminary data suggest that risperidone may be
  associated with an increased incidence of
  pituitary adenomas compared to other
  antipsychotic agents. At higher doses, the drug
  is associated with a somewhat greater risk of
  extrapyramidal symptoms than other atypicals.

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Olanzapine (Zyprexa)

• Generic olanzapine is available in standard
  tablets and orally disintegrating tablets
• Proprietary olanzapine is available in coated
  tablets, rapid-disintegrating tablets,
  short-acting injectable solution, and a
  long-acting injectable (depot) formulation,
  olanzapine pamoate.
• The oral formulations have gradual absorption and
  30-hour elimination half life. The drug is
  usually given once a day.
• Olanzapine has significant activity at histaminic
  and muscarinic receptors.
• Drug-drug interactions are not prominent with
  olanzapine, but olanzapine is dependent upon CYP
  1A2 for clearance.

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Olanzapine (Zyprexa)

• Coadministration of medications that strongly
  inhibit or induce CYP 1A2 can alter olanzapine
  levels. Olanzapine levels are decreased somewhat
  by cigarette smoking. This may be an issue when
  patients are stabilized on a specific dose of
  olanzapine while on a nonsmoking hospital unit
  and then resume smoking upon discharge, reducing
  serum levels of the drug.
• For adults, the starting dose of olanzapine is
  usually 5 to 10 mg/day.
• Maintenance doses of 15 to 30 mg/day are common
  and doses up to 40 mg/day can be useful in
  selected cases, though exceeding the
  manufacturer's recommended maximum of 20 mg/day.

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Olanzapine (Zyprexa)

• Doses for most non-treatment-refractory patients
  should not exceed 20 mg/day, as data have
  suggested equivalent efficacy of 10, 20 and 40
  mg/day, but worsened tolerability at doses of 40
  mg compared to 10 mg/day.
• The average dose for stable schizophrenia
  patients participating in an 18-month
  effectiveness study was about 20 mg daily. For
  the elderly population, doses begin at 1.25 to
  2.5 mg/day, average 5 mg/day, and may go up to 10
  mg/day.
• The usual dose of oral olanzapine for acute
  agitation is 5 to 10 mg, repeated every 30
  minutes to two hours to a maximum of 20 mg/day.
  There is no significant absorption of the
  rapid-disintegrating formulation of olanzapine
  across the oral mucosa.

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Olanzapine (Zyprexa)

• An intramuscular injectable form of the
  medication is available for the treatment of
  acute agitation. The recommended dose is 10 mg,
  repeated at intervals of two to four hours, up to
  a total of 30 mg/day.
• The most common side effects of olanzapine are
  weight gain, sedation, akathisia, hypotension,
  dry mouth, and constipation. Weight gain,
  hyperglycemia, and hyperlipidemia are greater
  with olanzapine than with other SGAs, and are
  particularly prominent in adolescents. The FDA
  has recommended that olanzapine be used with
  caution when treating this age group.
• No specific recommendations have been made
  regarding dosing changes for patients with renal
  or hepatic impairment.

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Quetiapine (Seroquel)

• Quetiapine is available as immediate or extended
  release tablets.
• The immediate release formulation is available as
  a generic
• It is rapidly absorbed and cleared with a six to
  seven hour elimination half life.
• The extended release tablets give a peak
  concentration at six hours, followed by a
  seven-hour clearance half life.
• For both formulations, an active metabolite,
  norquetiapine, represents about half of the
  active drug in circulation and has a 12 hour
  elimination half time.

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Quetiapine (Seroquel)

• Although the manufacturer recommends twice daily
  dosing for the immediate release tablets, both
  formulations are commonly used in the community
  on a once daily schedule without substantial
  problems.
• The drug has strong histaminic, cholinergic, and
  alpha-1-adrenergic binding, responsible for
  relatively high levels of sedation,
  anticholinergic effects, and orthostatic
  hypotension.
• Drug-drug interactions are not common with
  quetiapine, but serum levels are affected by
  induction or inhibition of the cytochrome P450
  system by drugs including carbamazepine,
  fluoxetine, and ketoconazole. In practice, dose
  adjustments with these medications are not
  commonly required.

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Quetiapine (Seroquel)

• The usual adult starting dose of immediate
  release quetiapine is 25 mg twice daily, followed
  by a relatively slow titration at the rate of 25
  to 50 mg/day to a total dose of 300 to 600
  mg/day.
• The titration of the drug may be even slower if
  the patient develops hypotension or excessive
  sedation.
• The manufacturer suggests a starting dose of
  quetiapine extended release to be up to 300
  mg/day, with titration to 600 mg/day by Day 2,
  and 800 mg/day by Day 3.
• Final doses of the two formulations are
  equivalent. The manufacturer recommends a maximum
  dose of 800 mg/day, but doses as high as 1200
  mg/day have been used and appear to be well
  tolerated.

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Quetiapine (Seroquel)

• For the elderly population, doses usually start
  at 12.5 to 25 mg twice daily and are titrated to
  doses substantially lower than for younger
  adults.
• The drug does not require renal function for
  clearance, but patients with hepatic impairment
  may experience an increase in serum levels
  necessitating dose adjustment.
• The main side effects of quetiapine are sedation,
  orthostatic hypotension, akathisia, dry mouth,
  and weight gain.
• Sedation is most often noted early in treatment
  and seems more closely related to treatment
  duration than to dose, so patients may find their
  sedation improving after several days, even if
  the medication dose is still being titrated.

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Quetiapine (Seroquel)

• Quetiapine causes QT prolongation in combination
  with other factors prolonging the QT interval
  use of the drug should be avoided in conjunction
  with other medications that prolong the QT
  interval or patient risk factors for QT
  prolongation.
• Quetiapine appears to cause less extrapyramidal
  symptoms than other antipsychotics, with the
  exception of clozapine or iloperidone, and is
  less likely to increase prolactin levels.

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Ziprasidone (Geodon)

• Ziprasidone is available in capsules and as a
  sterile solution for intramuscular injection.
• A generic preparation of the oral medication is
  also available.
• The oral formulation is absorbed slowly and
  cleared with an elimination half life of seven
  hours.
• The drug is approved for twice daily dosing, but
  once daily administration is commonly used in the
  community without apparent problem.
• Bioavailability in the absence of food is
  inconsistent. It has been estimated to be 50
  percent lower than when ziprasidone is taken with
  the recommended 500 calorie meal.

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Ziprasidone (Geodon)

• The drug has low histaminic and no appreciable
  muscarinic activity.
• Drug-drug interactions are of two types.
• First, serum levels respond modestly to
  concurrent treatment with inhibitors and inducers
  of the cytochrome P450 system, such as
  carbamazepine, fluoxetine, and ketoconazole .
• Second, the drug causes mild QT prolongation, not
  usually clinically significant in isolation, but
  use of the drug with other medications that
  prolong the QT interval is contraindicated.
• The recommended adult starting dose of oral
  ziprasidone is 20 to 40 mg twice daily, followed
  by titration over two to five days to the
  manufacturer's highest recommended dose of 80 mg
  twice daily.

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Ziprasidone (Geodon)

• In practice, doses up to 240 mg/day are common
  and well tolerated. A dose of at least 120 mg/day
  is believed to be necessary to achieve sufficient
  dopamine D2 blockade for therapeutic efficacy.
• The oral drug is not affected by renal
  impairment, but a component of the intramuscular
  preparation is cleared through the kidney,
  leading to the manufacturers recommendation that
  it be used with caution in that population.
• Hepatic impairment causes mild increases in serum
  levels and clearance time that may require dose
  adjustment.
• Injectable ziprasidone has been FDA-approved for
  acute agitation. It is recommended in 20 mg doses
  every four hours or 10 mg doses every two hours
  to a maximum of 40 mg/day.

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Ziprasidone (Geodon)

• Side effects include mild sedation early in
  treatment, nausea, weakness, nasal congestion,
  and mild QT prolongation.
• Ziprasidone appears to cause less weight gain,
  hyperglycemia, and hyperlipidemia than other
  second-generation antipsychotics.
• There are rare reports of severe
  hypersensitivity, including drug reaction with
  eosinophilia and systemic symptoms (DRESS), a
  potentially life-threatening reaction that begins
  as a rash.
• Despite the report of QT prolongation in clinical
  trials, this has not emerged as a clinically
  significant problem in post-marketing
  surveillance.

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Aripiprazole (Abilify)

• Aripiprazole is unique among the SGA in its
  pharmacology and pharmacokinetics, but is similar
  in clinical efficacy.
• Aripiprazole acts as a partial agonist at
  dopamine D2 receptors, activating the receptor
  but eliciting a reduced response compared to the
  natural neurotransmitter. The drug is also a
  partial agonist at serotonin 5HT1a receptors, but
  an antagonist at 5HT2a, H1, and
  alpha-1-adrenergic receptors.
• Aripiprazole is available as a standard and
  orally disintegrating tablet, as a sterile
  solution for intramuscular injection, and as a
  long-acting intramuscular formulation for monthly
  administration.

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Aripiprazole (Abilify)

• Oral aripiprazole is absorbed slowly and cleared
  with a 75-hour elimination half life.
• The injectable preparation shows significant
  clinical efficacy within 45 minutes, and reaches
  peak serum levels in one to three hours. Its long
  elimination half life has the advantage of
  creating relatively steady serum levels
  throughout the day, even with an occasional
  missed dose, but may slow the impact of a dose
  adjustment or transition to a different
  medication.
• Drug-drug interactions have not commonly been
  reported with aripiprazole, but it is metabolized
  via the cytochrome P450 system. A two-fold
  increase in dosing in the presence of metabolic
  inducers, and a 50reduction in dose with
  cytochrome P450 inhibitors, such as fluoxetine,
  quinidine, or ketoconazole.

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Aripiprazole (Abilify)

• Clinical trials of adults with schizophrenia
  started the drug at 10 to 15 mg daily,
  administered in a single dose. This dose proved
  to be adequate for many patients, but doses up to
  30 mg daily have been approved. The
  manufacturer's clinical trials for bipolar
  disorder started patients at 30 mg daily and
  lowered the dose only for side effects.
• The manufacturer does not recommend dose
  adjustment for patients with hepatic or renal
  insufficiency .
• The most common side effects of aripiprazole are
  headache, nausea, vomiting, insomnia, tremor, and
  constipation. Weight gain has been minimal in
  short and long-term trials. The drug has a lower
  risk of extrapyramidal symptoms, increases in
  lipid or prolactin levels, and sedation, compared
  to other atypicals in a small number of
  comparative trials.

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Aripiprazole (Abilify)

• Aripiprazole may be a cause of QT prolongation,
  based on a case report. Avoidance of
  aripiprazole is suggested in patients with
  congenital prolonged QT syndrome.
• Rates of akathisia are substantially higher for
  patients receiving aripiprazole for major
  depressive disorder and bipolar disorder compared
  to patients receiving aripiprazole for
  schizophrenia.
• The use of aripiprazole in conjunction with other
  antipsychotic medications is not generally
  recommended, because the combination of a partial
  agonist with an antagonist leads to unpredictable
  levels of receptor activity.
• Switching patients to aripiprazole should be done
  slowly because of aripiprazoles exceptionally
  high affinity for dopamine D2 receptors in the
  face of its partial agonism at this receptor.

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Paliperidone (Invega)

• Paliperidone is available in an osmotic delivery
  capsule to be swallowed whole, not crushed or
  chewed, and requires several days to achieve
  steady-state kinetics. It is also available as
  a LAI.
• The bioavailability of paliperidone is increased
  by about 50 when taken with a high calorie meal.
  
• Once absorbed, paliperidone has a 23-hour
  elimination half time.
• About 60 is excreted unchanged in the urine,
  with the remainder metabolized by cytochrome P450
  isoenzymes. The high level of urinary excretion
  of unmetabolized paliperidone makes it unique
  among antipsychotics in not requiring intact
  hepatic function for clearance.
• Thus, in contrast to other antipsychotics,
  paliperidone requires no dose adjustment with
  hepatic impairment. Significant drug-drug
  interactions have not been identified.

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Paliperidone (Invega)

• For non-elderly adults, paliperidone is typically
  started at 6 mg once daily and, if needed, can be
  increased in 3 mg/day increments at five day
  intervals. For elderly patients, or those with
  renal impairment, 3 mg per day may be used.
• The most common side effects are extrapyramidal
  symptoms, including parkinsonism, dystonia,
  dyskinesia, and akathisia. Other side effects
  include prolactin elevation and tachycardia.
• Paliperidone has a mild to moderate risk of
  weight gain comparative trials found that the
  increase in weight was less than that caused by
  olanzapine.
• Paliperidone can prolong the QT interval, and
  should not be used with other drugs with similar
  effects.
• These side effects are dose-dependent, more
  prominent at doses above 6 mg per day.

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Iloperidone (Fanapt)

• Iloperidone has antagonist activity at dopamine
  D2 and serotonin 5HT2a receptors, similar to
  other SGAs.
• Short-term studies of varying doses found optimal
  efficacy at 12 to 24 mg daily.
• Because of the propensity for orthostatic
  hypotension, dosing should be initiated at 1 mg
  BID with gradual titration, reaching 6 mg BID by
  Day 4.
• The elimination half life is 18 to 33 hours.
• Plasma levels increase with CYP 2D6 and CYP3A4
  inhibitors, leading to the recommendation that
  dose be reduced by 50 in the presence of
  medications such as fluoxetine.

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Iloperidone (Fanapt)

• Side effects include dizziness, orthostatic
  hypotension, tachycardia, weight gain, dry mouth,
  and sedation.
• Compared to other antipsychotics, iloperidone
  caused relatively few extrapyramidal symptoms, an
  intermediate degree of weight gain, and above
  average QT prolongation, though not to a degree
  that cardiac monitoring or avoidance of other
  drugs that prolong the QT interval has been
  recommended.
• The drug is not affected by renal insufficiency
  or mild hepatic impairment. Moderate hepatic
  impairment is associated with increased levels of
  drug metabolites, suggesting a lower dose may be
  needed. The manufacturer recommends against its
  use in patients with severe hepatic impairment,
  which has not been studied.

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Asenapine (Saphris)

• Asenapine has a broad range of receptor
  activities, including antagonism of dopamine,
  serotonin, adrenergic, and histaminic receptors,
  but minimal muscarinic activity.
• It is rapidly absorbed and has a 24-hour
  elimination clearance half-time.
• Its major route of metabolism is through CYP 1A2
  and glucuronidation, with no major active
  metabolites.
• Drug interactions tend to be mild and generally
  do not require an adjustment in dose.
• Asenapine is unique among antipsychotics in its
  sublingual administration, necessitated by its
  poor GI absorption.

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Asenapine (Saphris)

• Both the starting and maintenance doses of the
  medication are 5 to 10 mg BID. The maximum
  recommended dose is 10 mg BID.
• The drug dissolves and is absorbed quickly, but
  the patient should not eat or drink within 10
  minutes of administration.
• The most common side effects are sedation, weight
  gain, dizziness, EPS (especially akathisia), and
  oral hypoesthesia. Weight gain is intermediate
  among the SGAs.
• QT prolongation was limited to 2 to 5
  milliseconds at doses as high as 20 mg BID, a
  level not expected to be of clinical
  significance.
• Prolactin levels do not differ from those seen
  with placebo.

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Asenapine (Saphris)

• Rare reports of serious hypersensitivity
  reactions, including anaphylaxis, caused the
  issuance of a safety communication and product
  warnings by the FDA. Eight of 52 cases described
  in the communication occurred after only one dose
  of asenapine and 19 prompted emergency
  intervention or hospitalization.
• Systematic studies of asenapine in geriatric
  patients have not been reported, but caution is
  recommended early in treatment because of a
  mildly elevated risk of orthostatic hypotension
  and syncope.
• No data on use in children or adolescents have
  been reported.
• Severe hepatic dysfunction caused a 7-fold
  increase in serum levels of asenapine, leading
  the manufacturer to recommend against its use in
  that population.
• Renal impairment has no impact on drug levels or
  clearance.

50
Lurasidone (Latuda)

• Lurasidone shows high affinity for dopamine D2
  and serotonin 5-HT2A receptors, as is
  characteristic of other second-generation
  antipsychotics.
• It also has potent antagonism at 5-HT7 receptors
  of unclear significance.
• It has moderate affinity for 5-HT1A and alpha2
  adrenergic receptors, and minimal binding at
  alpha1 adrenergic, histamine H1, and muscarinic
  M1 receptors.
• Absorption of the drug occurs over one to three
  hours, followed by a serum half-life of 18 to 37
  hours.

51
Lurasidone (Latuda)

• Bioavailability increases two to three-fold when
  the drug is taken with a 350 calorie meal, but is
  not dependent on the fat content of the meal.
• Its major route of metabolism is via CYP3A4,
  which produces both active and inactive
  metabolites. Medications that are strong
  inhibitors or inducers of CYP3A4 substantially
  alter serum levels of lurasidone and their
  coadministration is contraindicated.
• Dose reduction is recommended in the presence of
  moderate CYP3A4 inhibitors, such as diltiazem.
• The drug is supplied as 20, 40, 80 and 120 mg
  tablets intended for once daily dosing with a
  meal.

52
Lurasidone (Latuda)

• The suggested initial dose is 40 mg daily for
  most patients dose titration was not employed in
  the efficacy studies. The maximum daily dose of
  160 mg received approval based upon results of a
  6 week efficacy trial. However, results of an
  unpublished trial that included 120 mg daily
  showed no benefit over and more adverse effects
  than 80 mg per day.
• Dose reduction is needed in the setting of
  moderate or severe renal or hepatic
  insufficiency.
• Common side effects include somnolence,
  akathisia, nausea, and parkinsonism. Less
  commonly reported adverse effects include acute
  dystonia, agitation, anxiety, and dizziness.

53
Lurasidone (Latuda)

• Weight gain was mild in short-term studies and
  was not observed in open-label extension studies
  of 24 to 52 weeks. Fasting glucose is more
  likely to be elevated with lurasidone (10 to 14
  of patients compared to 8.6 on placebo), but
  lipid levels show little difference compared to
  placebo treatment.
• Prolactin elevation occurs in 8.3 of women and
  1.9 of men on the drug, compared to 0.6 to 1 of
  those on placebo.
• The mean change in QT interval was -1.2
  milliseconds in the initial clinical trial and no
  other ECG abnormalities were reported
  subsequently
• The drug has not been tested in children or
  adolescents.
• Its pharmacokinetics appear unchanged in the
  elderly population, but no studies of its
  efficacy or safety in that group are available

54
Brexpiprazole (Rexulti)

• Mechanism thought to be related to combination of
  partial agonist activity at serotonin 5HT1A and
  dopamine D2 receptors and antagonist activity at
  5HT2A receptors.
• Peak plasma concentrations occur within 4 hours
  after administration. Absolute oral
  bioavailability is 95.
• Can be administered with or without food.
• Metabolism is mainly mediated by CYP3A4 and
  CYP2D6
• Available in 0.25, 0.5, 1, 2, 3 and 4 mg tablets
• Recommended starting dose is 1 mg once daily on
  Days 1 to 4. Titrate to 2 mg once daily on Day 5
  through Day 7, then to 4 mg on Day 8 based upon
  clinical response. The recommended target dose
  is 2 to 4 mg once daily. Maximum recommended
  daily dose is 4 mg.

55
Brexpiprazole (Rexulti)
56
Cariprazine (Vraylar)

• Mechanism thought to be related to combination of
  partial agonist activity at serotonin 5HT1A and
  dopamine D2 receptors and antagonist activity at
  5HT2A receptors. Cariprazine forms two major
  metabolites, desmethyl cariprazine (DCAR) and
  didesmethyl cariprazine (DDCAR), that have in
  vitro receptor binding profiles similar to the
  parent drug.
• Steady state between parent drug and metabolites
  occurs between 1 and 4 weeks (some up to 12
  weeks). Peak plasma concentrations occur within
  3-6 hours after administration. Absolute oral
  bioavailability is 95. Half life is 2-4 days
  for parent 1-3 weeks for active metabolites.
• Extensively metabolized by CYP3A4 and to a lesser
  extent by 2D6 to DCAR and DDCAR. DCAR is further
  metabolized into DDCAR by 3A4 and 2D6. DDCAR is
  then metabolized by 3A4 to a hydroxylated
  metabolite.

57
Cariprazine (Vraylar)

• Available in 1.5, 3, 4.5, 6 mg capsules
• Recommended starting dose is 1.5 mg once daily.
  Can be increased to 3 mg on Day 2. Depending
  upon clinical reponse and tolerability, further
  dose adjustments can be made in 1.5 or 3 mg
  increments. The recommended dose range is 1.5 to
  6 mg daily (with or without food).
• Effect from dose initiation or increase may take
  several weeks.
• If given with a strong 3A4 inhibitor, Vraylar
  dose should not exceed 3 mg daily.

58
Role of Clozapine

• Indications Treatment-resistant schizophrenia
  Reduction in the risk of recurrent suicidal
  behavior in schizophrenia or SAD.
• For patients who have failed treatment with
  adequately dosed trials (generally 4-6 weeks) of
  more than 1 antipsychotic medication, the most
  evidence-based treatment strategy is to initiate
  clozapine.
• Clozapine may be instituted earlier in the
  treatment of patients with schizophrenia who have
  persistent suicidality, aggression, or hostility,
  as these patient populations in particular seem
  to benefit from clozapine (as in 1 meta-analysis
  which demonstrated a 3-fold reduction in suicidal
  behaviors compared with other antipsychotics).
• The high risk of weight gain and other metabolic
  effects, and the risk for agranulocytosis,
  myocarditis, orthostatic hypotension, seizures,
  and other adverse effects limit the use of
  clozapine, but many experts agree that the agent
  is likely underutilized.

Schizophr Res. 200573(2-3) 139-145.
59
The End
Next Week Antipsychotics Part Deux