Schizophrenia: Treatment and Goals

• Schizophrenia is a disorder of thought with various symptom clusters
• The dopamine hypothesis is a key element in understanding schizophrenia

Treatment Goals

• Treatment goals are patient-specific and provider-specific
• Patient-specific goals are individualized, focusing on quality of life, feelings of control, and functioning
• Provider-specific goals include relieving signs and symptoms, providing continuous treatment, minimizing side effects, maintaining adherence, and ensuring life-long care

Treatment Options

• Non-pharmacologic options, such as psychosocial interventions, electroconvulsive therapy (ECT), and transcranial magnetic stimulation (TMS), can be used adjunctively to pharmacologic treatment
• Pharmacologic options include antipsychotics: first-generation, second-generation, and "first-in-class"
• First and second-generation antipsychotics target the dopamine hypothesis, while "first-in-class" targets acetylcholine.

Antipsychotics - General Principles

• Use the lowest effective antipsychotic dose
• Be aware that the effects of antipsychotics are not instant
• Involve the patient in decision-making to improve adherence
• Use patient-specific factors to narrow down options
• Avoid polypharmacy

Timeline of Effects

• Initially, antipsychotics address aggression, agitation, and motor activity
• Within 1-2 months, they improve functioning, disorganization, and suspiciousness
• After 2-4 months, they target hallucinations and delusions

First Generation Antipsychotics (FGAs)

• Includes Haloperidol (Haldol®), Fluphenazine (Prolixin®), Trifluoperazine (Stelazine®), Thiothixene (Navane®), Loxapine (Loxitane®), Perphenazine (Trilafon®), Thioridazine (Mellaril®), Chlorpromazine (Thorazine®)

FGAs - General Mechanism

• D₂ receptor antagonism leads to therapeutic effect, extra-pyramidal symptoms, and prolactin elevation
• M₁ receptor antagonism causes anticholinergic effects like xerostomia, dry mouth, urinary retention, and confusion
• H₁ receptor antagonism results in sedation and weight gain
• α₁ receptor antagonism leads to syncope, reflex tachycardia, and orthostasis

FGAs - Categorization of Potency

• High potency FGAs include haloperidol, fluphenazine, trifluoperazine, and thiothixene
• Intermediate potency FGAs include loxapine and perphenazine.
• Low potency FGAs include thioridazine and chlorpromazine
• The higher the potency of a drug, the less is needed to have action at the receptor
• High potency drugs will have the same effects as low-potency drugs, but at much different doses (e.g. 2mg vs 100mg)

Second Generation Antipsychotics (SGAs)

• Commonly used SGAs are Risperidone (Risperdal), Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon), and Aripiprazole (Abilify)
• Less commonly used SGAs are Paliperidone (Invega), Asenapine (Saphris), Iloperidone (Fanapt), Brexpiprazole (Rexulti), Cariprazine (Vraylar), Lumateperone (Caplyta), and Olanzapine/Samidorphan (Lybalvi)

SGAs - General Mechanism

• Second-generation antipsychotics (SGAs) are similar to first-generation antipsychotics but have some key differences
• SGAs have increased D₂ receptor dissociation
• SGAs exhibit high affinity for serotonin 5HT₂a receptors, reducing movement disorders and prolactin issues D₃
• SGAs provide receptor blockade, improving cognitive effects

SGAs - Unique Mechanisms

• Aripiprazole and Brexpiprazole are D₂ and 5HT₁a partial agonists and 5HT₂a antagonists; partial agonism increases dopamine to reduce EPS; brexpiprazole is more potent at serotonin receptors to reduce akathisia observed with aripiprazole
• Cariprazine is a D₂, D₃, and 5HT₁a partial agonist and 5HT₂a antagonist; D₃ partial agonism > D₂ partial agonism may be beneficial for cognitive, negative symptoms
• Lumateperone is a pre-synaptic D₂ partial agonist and D₂ & 5HT₂a antagonist, augmenting NMDA/AMPA; its activity decreases positive feedback, increases dopamine, and enhances glutaminergic transmission
• Olanzapine/Samidorphan contains samidorphan which is a µ-opioid antagonist and reduces weight gain and waist circumference associated with olanzapine

"First-in Class" Medication

• Cobenfy™ is a combination of Xanomeline and Trospium
• It acts as an agonist at muscarinic (M) receptors M₁ and M₄
• M₁ activation decreases acetylcholine release and dopamine levels in the brain; it also modulates GABA, glutamate, and dopamine
• Peripherally, M₁ activation can cause gastrointestinal side effects and syncope

Dosing

• D₂ receptor blockade increases with dose/plasma concentration, exceeding thresholds for prolactin and EPS

FGA - Dosing

• Haloperidol's usual dosage range is 5mg-20mg (max: 100mg) with an equivalent dose of 2mg
• Fluphenazine's usual dosage range is 5mg-20mg (max: 40mg) with an equivalent dose of 2mg
• Thiothixene's usual dosage range is 15mg-30mg (max: 60mg) with an equivalent dose of 4mg
• Trifluoperazine's usual dosage range is 15mg-20mg (max: 40mg) with an equivalent dose of 5mg
• Perphenazine's usual dosage range is 8mg-64mg (max: 64mg) with an equivalent dose of 8mg
• Loxapine's usual dosage range is 20mg-60mg (max: 250mg) with an equivalent dose of 10mg
• Thioridazine's usual dosage range is 200mg-800mg (max: 800mg) with an equivalent dose of 100mg
• Chlorpromazine's usual dosage range is 200mg-800mg (max: 1-2gm) with an equivalent dose of 100mg

SGA - Dosing

• Risperidone's usual dosage range is 2mg-6mg (max: 8mg)
• Clozapine's usual dosage range is 300mg-600mg (max: 900mg)
• Olanzapine's usual dosage range is 5mg-20mg (max: 20mg)
• Quetiapine's usual dosage range is 400mg-800mg (max: 800mg)
• Ziprasidone's usual dosage range is 40mg-160mg (max: 160mg)
• Aripiprazole's usual dosage range is 10mg-30mg (max: 30mg)
• Lurasidone's usual dosage range is 40mg-160mg (max: 160mg)
• Paliperidone's usual dosage range is 3mg-12mg (max: 12mg)
• Asenapine's usual dosage range is 10mg-20mg (max: 20mg)
• Iloperidone's usual dosage range is 12mg-24mg (max: 24mg)
• Brexpiprazole's usual dosage range is 1mg-4mg (max: 4mg)
• Cariprazine's usual dosage range is 1.5mg-6mg (max: 6mg)
• Lumateperone's usual dosage range is 42mg (max: 42mg)
• Olanzapine/Samidorphan's usual dosage range is 5mg/10mg-20mg/10mg (max: 20mg/10mg)

Xanomeline/Trospium - Dosing

• Initiation dose: 50mg/20mg BID for at least two days
• Usual dose: 100mg/20mg BID for at least five days, can increase to 125mg/30mg

Pharmacokinetics - FGAs

• Haloperidol has a half-life of 14-37 hours and interacts with 2D6*, 3A4*, 1A2
• Fluphenazine has a half-life of 14-16 hours and interacts with 2D6
• Perphenazine has a half-life of 9-12 hours and interacts with 2D6*, 1A2, 3A4
• Loxapine has a half-life of 12-19 hours and interacts with 1A2, 2D6, 3A4
• Chlorpromazine has a half-life of 30 hours and interacts with 2D6*, 1A2, 3A4
• *Major interactions designated

Pharmacokinetics - SGAs

• Risperidone has a half-life of 20 hours and interacts with 2D6
• Clozapine has a half-life of 4-66 hours (~12 hours) and interacts with 1A2*, 3A4, 2D6
• Olanzapine has a half-life of 21-54 hours and interacts with 1A2*, 2D6
• Quetiapine has a half-life of IR: 6 hours, XR: 7 hours and interacts with 3A4
• Ziprasidone has a half-life of 7 hours and interacts with 3A4, 1A2, aldehyde oxidase
• Aripiprazole has a half-life of 75 hours and interacts with 3A4, 2D6
• Lurasidone has a half-life of 18 hours and interacts with 3A4

Pharmacokinetics – SGAs (Cont.)

• Paliperidone has a half-life of 23 hours and interacts with 2D6, 3A4
• Asenapine has a half-life of SL: 24 hours, Patch: 30 hours and interacts with 1A2
• Iloperidone has a half-life of 18-37 hours and interacts with 2D6, 3A4
• Brexpiprazole has a half-life of 91 hours and interacts with 3A4, 2D6
• Cariprazine has a half-life of 48-96 hours and interacts with 3A4, 2D6
• Lumateperone has a half-life of 18 hours and interacts with UGT, 3A4, 1A2
• Olanzapine/Samidorphan has a half-life of 21-54 hours and interacts with 1A2

Pharmacokinetics – Xanomeline/Trospium

• Xanomeline has a half-life of 5 hours
• Trospium has a half-life of 6 hours
• Substrate of: CYP2D6, CYP2B6, CYP1A2, CYP2C9, and CYP2C19

Formulations - FGAs

• All FGAs are supplied in tablets or capsules
• FGAs available as solutions are Haloperidol and fluphenazine
• FGAs available as short-acting injections are Haloperidol, fluphenazine, and chlorpromazine
• Long-acting injections of FGAs include haloperidol and fluphenazine
• Loxapine is available as an inhalant

Formulations - SGAs

• All SGAs are supplied in tablets or capsules
• Asenapine is available as a sublingual formulation
  • It is only an oral formation
• Orally disintegrating tablets
  • Include olanzapine, risperidone, and clozapine
• Solution -Cloazpine, risperidone, aripiprazole
• Olanzapine and ziprasidone are available as short-acting injections
• Risperidone, paliperidone, aripiprazole, and olanzapine are available as long-acting injections
• Asenapine is available as a patch
• Aripiprazole is available as a film

Medication Pearls

• Risperidone is a common first-line choice due to multiple formulations and ease of dosing

  • It has high potency
  • It exhibits more hyperprolactinemia and EPS than other SGAs
  • It keeps doe ≤6mg
  • It is renally eliminated
  • Use caution, especially with long-acting injectables

• See a section on clozapine

• Olanzapine is often trialed prior to clozapine

  • Time to discontinuation has a longer duration
  • It has extreme metabolic effects
  • Not recommended as first-line
  • It has greater potency compared to other options
  • Somnolence/sedation, anticholinergic
  • There are multiple formulations

• Quetiapine

  • Low potency
  • A helpful choice for EPS
  • It has somnolence/sedation, orthostasis, and metabolic side effects
  • Need to titrate to a dosage range of 400-800mg daily
  • Available in IR and XR formulation
  • IR is often given once daily
  • Shows little difference

• Ziprasidone

  • Low metabolic effects and less EPS
  • Must administer with at least 500 calories and dosed twice daily
  • It is available in a short-acting injection
  • QTc Prolongation exists
  • See side effects section

• Arirpiprazole

  • Used for first-break psychosis
  • Favorable side effect profile
  • Less metabolic. prolactin, and EPS side effects
  • Exception: akathisia
  • More activation and nausea
  • Long-acting injectable formulations

• Lurasidone

  • Take with 350 calories
  • Less metabolic, more EPS and prolactin side effects
  • Use with caution if patients have hepatic and renal impairment
  • Potential dose adjustments needed

• Paliperidone

  • The active metabolite of risperdone is 9-OH-risperidone
  • Exhibits a similar side effect profile to risperidone
  • May result in less orthostasis
  • A preferred LAI over risperidone
  • Dose adjustments may be needed if patients have renal impairment

• Asenapine

  • It is administered sublingually
  • Not the same as ODT
  • Effectiveness is lowered if you swallow it
  • Do not eat or drink 10 min after consumption
  • Do not take will other medications
  • Has adherence problems
  • Exhibits Oral Numbness and poor taste
  • Patches are expensive

• Iloperidone

  • Rarely used
  • Exhibits orthostasis among other side effects
  • Twice-daily dosing
  • Caution in hepatic impairment
  • potential Dose adjustments may be needed

• Brexpiprazole

  • Brand Name is costly
  • Similiar to aripiprazole
  • mechanism, akathsia, long half-life
  • More metabolic complications
  • The dose may need to be adjusted with hepatic and renal impairments

• Cariprazine

  • Brand Name is costly
  • Causes some EPS
  • Hepatic and renal impairments
  • Use may not be recommend if it's severe

• Lumateperone

  • Brand Name is costly
  • Takes only one dose
  • Has fewer EPS but increases somnolance/sedation
  • Should be avoided if you have moderate to severe hepatic impairments
  • Should be avoided with valproic acid
  • Can increase lumateperone exposure

• Olanzapine/Samidorphan

  • Brand Name is costly
  • It's effects range beyond weight gain
  • Somnolence
  • Anticholinergic
  • Glucose intolerance
  • Lipid abnormality

• Xanomeline/Trospium

  • Brand name is costly
  • Take two doses daily without food
  • DO not use if you have hepatic or renal impairment
  • Contraindications
    • Urinary retention
    • Gastric retention
    • Uncontrolled narrow-angle glaucoma

FGAS vs SGAS- Review

• Both drugs antagonize dopamine D2 receptors
• SGAS drugs exhibit have a higher 5HT2a affinity
• Differing Side Effect Profiles include - FGAS results in more EPS and hyperprolactinemia - SGAS results in more metabolic
• Neither drugs assists with negative symptoms
• Both equally effective

Long-Acting Injectables (LAIs)

• LAIs consist of first-generation and second-generation options
• FGAs include haloperidol decanoate and fluphenazine decanoate
• SGAs include risperidone, paliperidone, aripiprazole, and olanzapine
• FGA and SGA options exist for LAIs

FGA LAIS

• Haloperidol decanoate has a dose of 50mg - 450mg over four weeks
  • It also has a load of 20X the PO Dose
  • Peak time within ~7 days
  • The halflife is 3 weeks
  • Steady state occurs at 15 weeks
  • Oral overlap isn't needed if loaded. otherwise it may take up to 3-4 months if patient has not been fully loaded.
• Fluphenazine decanoate is 12.5-75 mg Q2 - Q4 Weeks
  • It peaks at 24 hours
  • A half-life of 2 weeks
  • To establish at a steady state it requires 10 weeks
  • Requires 10 weeks of oral overlap
• The location to administer using the Decanoate Administration – Z-Track

SGA LAIS

• Risperidone (Risperdal Consta®) has a dose of 25mg-50mg Q2weeks

  • Peaks at 5 Weeks
  • T1/2 is 6 days
  • Steady State is 8 weeks
  • Requires 3 weeks (PI) and 4-6 Weeks of oral overlap

• Risperidone (Perseris®) has a dose of 90mg to 120mg Q4weeks

  • Peaks at 4-6 hours
  • 9-11 Day T1/2
  • Steady state is ~4 Weeks
  • Contains no oral overlap Risperidone (Uzedy®) has a dose of 25mg-50mg Q2weeks
  • 50mg-125mg Q4weeks or 100mg-250mg Q8Weeks
  • Peaking within 6-24 hours
  • Day T 14-22 T1/2
  • Two months until it reaches its steady state
  • Contains no oral overlap

• Paliperidone palmitate (Invega Sustenna®) has a dose of 234mg Day 1, 156mg Day 8, or 39mg-234mg Q4weeks

  • Peaks Within 13 Days
  • Within 25-49 Days T1/2
  • The Steady State is 18-35 Weeks
  • Contains no oral overlap

• Paliperidone palmitate (Invega Trinza®) has a dose of 273mg-819mg Q12weels

  • Peaks within 30-33 Days
  • Within 84-139 Days T1/2 - The Steady State is 14-24 Months
  • Contains no oral overlap

• Paliperidone palmitate (Invega Hafyera®) has dose of 1092mg to1560mg Q6months

  • Peaks within 29to 32 Days -T1/2 Withing

• Aripiprazole (Abilify Maintena®) has a dose of 300-400mg Q4weeks

  • It peaks at 5-7 days
  • T1/2 30-46.5 days
  • a steady state within 21-33 Weeks
  • Requires 2 weeks of oral overlap Aripiprazole lauroxil (Aristada®) has a dose of10mg PO to 441mg Q4weeks or 15mg PO = 662mg Every 4 Q6weeks or 1064 mg Q8weeks
  • Peaks is 4 days
  • a T1/2 29 to -35
  • Steady State within 21-25 week
  • 3 with its oral overlap

• Aripiprazole (Abilify Asimtufii®) requires the dose of 720mg to 960 g Q8 weeks

  • Peak at 1 -49 Days day
  • Unavaliable T1/2
  • Steady State is reach Within 6 months
  • Oral overlap is 2 weeks

• Olanzapine pamoate (Zyprexa Relprevv®) has a dose from 150mg to 405mg -It Peaks Within 7Days -a T1/2 after 30days

  • Steady state takes 13 week
  • No Oral Olver lap.

LAI Considerations

• Many LAIs are expensive
• Do not use if patients have had h/o NMS
• Locations to give LAI; most gluteal or the deltoid -risperdeone must be given as a subq
• Must ensure your patients can tolerate and is effective to use by establishing those effects
• Giving LAI is not a better adherence if it's spread out injections
• LAI is also given by pharmacists in Maryland

Side Effects

• Side effects include seizures, blood dyscrasias, thermal dysregulation, NMS, QT prolongation, metabolic issues, orthostasis, cardiotoxicity, sedation, somnolence, EPS, hyperprolactinemia, sialorrhea, and anticholinergic effects
• Not all antipsychotics have all of these side effects

FGAs

• Refer to slide 14 for details of potency
• Spectrum of dopamine-related side effects vs. "the big three”
• Less metabolic, more EPS/hyperprolactinemia.

SGAS

• Side effects of all SGAs are to be on a spectrum
• Include anticholinergics, sedation, EPS,and metabolic

Xanomeline/Trospium

• Does not display classic Side Effects
• Has side effect such as the following
  • EPS
  • Metabolic -Sedation
• Cardiovascular also includes hypertension too
• Gastrointestinal also includes the following: Indigestion, nausea, vomiting and constipation

Addition Side Effects

• Neuropleptic malignant Syndrome its Rare,but its life Threatening

  • Risks
    • the Use of Antipsychotics(Antagonist Of Dopamine), First month to use or the increase
    • High dose, more on the Young and Itramuscular
      • prior history
      • Withdrawal Of Dopamine Agonist
      • All Antipsychotics can be a cause. -Rigidity
        • Lead - pipe
  • Mental Status Changes - Confusion, Fluctuations in conscious, And agitited. - Autonomic dysfunction - Labile blood pressure and heart rate
  • Other sings of Symptoms -CPK -ELevated Respiratory Rate. more then 20 - Diaphoresis - Leukocytes - Mutism - Tremors

  -Discontinue all medication.

Side Effects: Metabolic

• Having three criteria the patients is now considered to suffer from a metabolic affect :
  • Waist Circumference
    • Men- 40 Inches - More Then 30 in F
    • 130 over 85 in Pressure
      • • or regiving treat for *
  • Fasting Blood - more then 100
    • Men. - 40.
    • FL = 50

Additional Side Effects: QT Prolongation

• Caution is Pre-exisiting ABNormalities
  • average 76 to 100msec . Recommended annually K MCa
  • Thiorid azine is most commonly used 5.7 - Haloperidol = 14.5
  • Range 3 to-5.

Additional Side Effects

• Dementua has and boxed a warning.
  • and meta -analysis 1.6 is more likable
    • sudden death. and infection as pnewmina

Extrapyramidal symptoms and movements that lead to problems

• movement problems

Clozapine

• in Schizophrenia the best anti drug. Treatment resistance

• Time for treatment is equal because it is longer do high eps

side effects: clazopine

• REMS program is an issue. Feb 2025

  • neutrophil
  • sezizers =Hypotension -Tachy- cardia -Meta bolic

• The Kane trial 1 dosage above 2

  • A adequate to tolerate

How To Use this drugs

• 12.5 with 25- 50 Retitrate
• monothoery

Side Effects: Neutropenia

• Neutropenia is extream. its can cause a death
• Montoring the the account is needed . in the first with a year montoring is needed

Sezire Management

• If valporic it works to the liver it could cause

Myocarditis Symptoms and care

• Rare and more then 8 weeks and troponin -discontine and Recommedded

• HYpertention for all the range of all there problems use these

Final thoughs.

Antipsychotics are mainstay -Eps Side effect tends to have

• symptoms and they assist with sign.

Enable patient

• stabilise and to feel troubled

Do you. need is there a treatmeant

• Antipsychotics are prefer
• after at least two you can look at
• for clozapine what has
• A patient but