In this discussion, we will talk about the symptoms of schizophrenia, the mechanism of actions and side effects of FGAs and SGAs, and the treatment process of schizophrenia.

Etiology and Epidemiology of Schizophrenia

The exact cause of schizophrenia is unknown, but a genetic component and environmental factors are theorized to play a role.

It is one of the top 15 causes of disability worldwide because it also leads to a higher risk of cardiovascular disease, liver disease, diabetes, and dementia.

Substance Abuse concurrent with schizophrenia is extremely common. It also has the third-highest suicide rate among psychiatric disorders (after MDD and BD.)

Due to the increased risk of other diseases and suicide, patients with schizophrenia have a 15-20 shorter life expectancy.

Clinical Presentation

The schizophrenia course is littered with acute psychotic episodes. There is a significant deterioration within 5 years after the first episode, and most will never return to where they were before the first episode. While psychosis may cease, 5-15% of the patients will still experience continuous psychosis.

Schizophrenia is characterized by three different sets of symptoms: Positive, Negative, and Cognitive

Positive Symptoms

There are two primary symptoms are positive symptoms: psychosis and disorganization.

• Psychosis is characterized by hallucination and delusions
  • Hallucinations are perceptions of something that is not there.
  • Delusions are persistent false beliefs in something that is untrue.
• Disorganization is comprised of disorganized speech, disorganized thoughts, and disorganized behavior
  • Disorganized speech = word-salad, incoherent speech, loose associations
  • Disorganized thoughts = Loose association, thought blocking, circumstantial reasoning
  • Disorganized behavior = Agitation, silliness, purposeless movement

Positive symptoms are the most treatable target for pharmacologic therapies.

Negative Symptoms

These are symptoms that should be present but are not.

• Alogia
• Anhedonia
• Avolition
• Ambivalence
• Social withdrawal
• Catatonia (when they’re unable to respond to the world around them)

Cognitive Symptoms

These are deficits that affect functional thinking and memory.

• Memory problems
• Trouble with attention
• Communication difficulties
• Impaired skill acquisition
• Decreased executive dysfunction

While pharmacologic treatments can help improve negative and cognitive symptoms, the degree of helpfulness is much less than positive symptoms. FGAs are complete ineffective. SGAs work better than FGAs for negative symptoms. For cognitive symptoms, it’s better to rely on behavioral intervention instead of medications.

Review of Schizophrenia Pathophysiology

It all has to do with dopamine.

In the mesolimbic pathway, there is an excess of dopamine, leading to positive symptoms.

In the mesocortical pathway, there is a deficit of dopamine, leading to negative symptoms.

Cognitive symptoms are thought to be due to a decrease in cortical thickness.

Mechanism of Antipsychotics

The hallmark MoA is through the blockade of the mesolimbic dopamine D2 receptor. This leads to a decrease in positive symptoms. This mechanism, due to a lack of sufficient specificity, can lead to side effects. Some of which can be severe.

• A blockade of D2 receptors in the nigrostriatal pathway can precipitate extrapyramidal symptoms (EPS)
• A blockade of D2 receptors in the tuberoinfundibular (hypothalamus) can precipitate hyperprolactinemia.

Some agents increase DA production in the forefront cortex through the blockade of subcortical serotonin (5-HT2A) receptors. This leads to a decrease in negative symptoms.

Other receptors in the brain can be affected as well. Some agents hit other dopamine/serotonin receptors (5-HT1A, D2). Some also hit alpha-adrenergic, histaminergic, and muscarinic.

When thinking about what side effects the medication has, it’s good to think about what are the side effects of blockage of certain receptors.

For examples:

• Blocking SE
  • 1A: May improve cognition
  • 2A: This works on negative symptoms
  • 2C: This is where antidepressants hit. Weight gains.
  • 5-HT3: Anti-emetic
  • 5-HT7: Sleep and mood
• Blocking DA
  • This includes D2 and D3.
  • Decrease positive symptoms
  • Can cause movement disorders (EPS)
  • Can block prolactin release
• Blocking alpha-adrenergic
  • Alpha-1: dizziness, drowsiness, orthostatic hypotension
  • Alpha-2: Release of 5-HT and NE
• Blocking H1
  • Weight gain
  • Drowsiness
  • *Think diphenhydramine*
• Muscarinic
  • Anticholinergics: Urinary retention, constipation, dry mouth, dry eyes
  • Confusion
  • Tachycardia

And while medications are great, you might be surprised to know that they cannot fix everything. Patients with schizophrenia can and usually have residual features, such as anxiety, paranoia, lack of volition, lack of insight, lack of judgment, and lack of historicity.

General Treatment Approach

The cornerstone is pharmacotherapy. Patients are usually on treatment for life. It is important to know that no agent is perfect and some can cause a lot of problems.

Aside from pharmacotherapy, patient-centered psychosocial rehabilitation, such as supported housing and family psychoeducational, and active community treatment programs are important components as well.

Overview of Antipsychotic Agents

First-Generation (Typical) Antipsychotics (FGAs)

These agents work by blocking D2 receptors. Earlier agents, such as chlorpromazine and thioridazine, are less selective for D2 and have more off-target effects on H1, M1, and alpha-1. As such, they are referred to as low potency. Later agents, such as haloperidol and fluphenazine, are more selective for D2, but also have a higher risk for EPS and hyperprolactinemia. Because they have fewer off-target effects, they have a lower risk of sedation, anticholinergic effects, and orthostasis. These agents are referred to as high potency.

Chlorpromazine

This is a low-potency FGA that also blocks H1, M1, and alpha-1. It is indicated for schizophrenia (D2), bipolar (D2), agitation (D2), anti-emetic (H1), and intractable hiccups.

It has a lot of ADRs: high amount of weight gain, lower seizure threshold, orthostasis, and sedation.

The usual dose is 25-200mg/day in 2-4 divided doses.

It can be given as IM for acute agitation. (25-50 IM every 4-6 hours)

Chlorpromazine has the highest risk among FGAs for lower seizure threshold.

Haloperidol

This is a high-potency FGA. It is the most commonly use high-potency. It is indicated for schizophrenia, BD, agitation/delirium, and anti-emetic.

The dose is much lower than low-potency. We’re looking at 2-10 mg per day in 1-2 divided doses.

It can also be used for acute agitation. The dose is 2-10mg IM every 15 minutes.

It is a CYP3A4 and CYP2D6 substrate. It is also a CYP2D6 inhibitor.

Side effects are what we usually expect from high-potency FGAs (due to high affinity for D2 receptor): very high risk for EPS and hyperprolactinemia. Remember because we use it for emesis as well, it probably has histamine action, whose side effect is sedation, just not as much as chlorpromazine. QT prolongation is still a concern as well.

Second-Generation (Atypical) Antipsychotics (SGAs)

All of these agents work by blocking 5-HT2A which leads to an increase in dopamine levels in the prefrontal cortex. Some newer agents also work as partial agonists and D2 and 5-HT1A. Some also work on SERT.

The order of introduction is by the order they were approved by the FDA.

1993: Risperidone (Risperdal) – tablet, ODT, and liquid

“High EPS Risk”

MoA: Potent antagonist at 5-HT2A, D2, H1, alpha-1, and alpha-2

Indication: schizophrenia, BD, resistant MDD, resistant OCD, agitation/delirium

Dosing: Start with 1-2mg daily. May increase every 24 hours for the max of 8mg

Serious ADR: EPS (for dose above 4mg/day) and hyperprolactinemia (highest)

Common ADR: orthostatic hypotension (alpha-1), weight gain (H1), nausea/vomiting

1996: Olanzapine (Zyprexa) – tablet and ODT

“High metabolic effects – avoid as first-line”

MoA: Potent antagonist at 5-HT2A, 5-HT2C, D1-4, M1-5, alpha-1

Indication: schizophrenia, BD, MDD, agitation, anorexia, chemotherapy-induced nausea/vomiting

Dosing: Start with 5-10mg daily. may increase by 5mg weekly for a max of 20mg/day. If treating agitation, 5-10mg IM every 2-4 hours (max of 40). Hepatic dosing: 2.5-5mg daily

Metabolism: CYP1A2 – Smoking alert!

This medication is used a lot in inpatients because it works quickly and has a lot of off-target effects. It is not used as a first-line due to ADRs, but it is very effective.

Serious ADR: EPS

Common ADR: Metabolic syndrome/weight gain (H1), anticholinergic (M), orthostatic hypotension (alpha), and headache

1997: Quatiepine (Seroquel) – Tablet, ER tablet, and liquid

“Good, but very high sedation risk”

MoA: antagonist at 5-HT2A, D2, H1, alpha 1, and alpha 2. partial agonist at 5-HT1A. Quickly associate from D2 (low EPS)

Indication: schizophrenia, BD, MDD, GAD, PTSD, agitation/delirium

Dosing: 25mg BID. May increase 400mg/day for a max of 800mg/day. Must be hepatically adjusted to daily dosing instead of the BID.

Metabolism: CYP3A4 substrate

Serious ADR: None!

Common ADR: sedation (H1), weight gain (H1), orthostasis (alpha-1)

2001: Ziprasidone (Geodon) – tablet

“Must take with more than 500 calories”

MoA: antagonist at 5-HT2A, 5-HT2C, D2. Partial agonist at 5-HT1A

Indication: schizophrenia, BD, agitation, treatment, resistant MDD

Dosing: Start with 20-40mg BID. May titrate every 2 days to 80mg BID. For agitation, 10-20mg IM every 2-4 hours (max of 40.)

Serious ADR: EPS, QT prolongation

Common ADR: dizziness, nausea, and headache

Because it has a less metabolic effect, it is frequently used.

2002: Aripiprazole (Ability) – tablet, ODT, liquid, and Abilify Mycite

“Akathisia and impulse control disorders”

MoA: Antagonist at 5-HT2A. Partial agonist at D2 and 5-HT1A.

Indication: schizophrenia, BD, treatment-resistant MDD.

Dosing: 5-15mg daily. May increase by 5mg every 4-7 days (max of 30 per day)

Metabolism: Major CYP3A4 and 2D6 substrate

Serious ADR: Akathisia and impulse control issues

Common ADR: Insomnia

2006: Paliperidone (Invega) – tablet

“Prodrug of risperidone”

MoA: antagonist at 5-HT2A (lower affinity than risperidone), D2, H1, alpha-1, and alpha-2

Indication: schizophrenia and schizoaffective disorder

Dosing: 6mg once daily. May titrate by 3mg every 5 days (max 12mg/day). Renal dose adjustment: adjust for 10-80 SCr, and do not use in <10.

Serious ADR: EPS and hyperprolactinemia

Common ADR: Orthostasis (alpha-1) and nausea/vomiting

2009: Iloperidone (Fanapt) – Tablet

“High orthostasis risk”

MoA: antagonist at 5-HT2A, D2, alpha-1, and alpha-2.

Indication: Schizophrenia

Dosing: 1mg BID. May titrate every 24 hours by 4mg (max 24mg/day). Do not use in hepatic impairment.

Metabolism: CYP2D6 substrate – decrease dose by 50% if using with CYP2D6 inhibitors

Serious ADR: QT prolongation (one of the highest rates)

Common ADR: Orthostasis and dizziness (alpha)

2009: Asenapine (Saphris) – SL, patch

“Sublingual/patch only”

MoA: antagonist at 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, D2, alpha-1, and H1

Indication: schizophrenia, BD, agitation

Dosing: 5mg SL BID or 3.8mg patch QD. May titrate every 1 week. SL must avoid food/drink for 10 minutes. Hepatic: contraindicated in severe impairment

Serious ADR: Akathisia, oral ulcers/blisters

Common ADR: Mouth tingling

2010: Lurasidone (Latuda) – Tablet

“Must take with at least 350 calories”

MoA: antagonist at 5-HT2A, 5-HT7, D2-3, alpha-1. Partial agonist at 5-HT1A

This medication is very useful for patients with a depressive state.

Indication: schizophrenia, BD depression, MDD

Dosing: Start with 40mg QPM within 30 minutes of a meal. May titrate every 3 days by 40mg (max 160mg/day). Must dose adjust for renal and hepatic.

Serious ADR: EPS, akathisia, pseudo-parkinsonism

Common ADR: No weight gain!

2015: Cariprazine (Vraylar) – Tablet

“Akathisia risk”

MoA: antagonist at 5-HT2A, partial agonist at 5-HT1A and D2-3

Indication: schizophrenia, BD, MDD

Dosing: 1.5mg QD for 2 days, then 3mg QD. (max 6mg/day). Do not use in CrCl <30 or in severe hepatic impairment.

Serious ADR: EPS (horrible), pseudo-parkinsonism, and akathisia

Common ADR: Headache, insomnia, nausea

This is one of the best-tolerated SGAs.

2015: Brexpiprazole (Rexulti) – Tablet

“Depression and akathisia”

MoA: antagonist at 5-HT2A, partial agonist at 5-HT1A and D2-3

Indication: schizophrenia and MDD

Dosing: 1mg daily for 4 days, then increase to 2mg for 3 days, then 4mg daily if needed. Renal = CrCl 60 max 3mg. Hepatic = class B/C max of 3mg.

Metabolism: CYP3A4 substrate. Reduce dose in CYP2D6 poor metabolizers

Serious ADR: Akathisia

Common ADR: Terrible weight gain

2019: Lumateperone (Caplyta) – tablet

“Only comes in one dose!”

MoA: high-affinity antagonist at 5-HT2A, moderate affinity antagonist at D2 and alpha-1 and alpha-2. Also SERT.

Indication: schizophrenia and MDD

Dosing: 42mg once daily (this is the only dose). Caution in hepatic.

Metabolism: CYP3A4 substrate

Serious ADR: None

Common ADR: Drowsiness/sedation (alpha?) and headache

1989: Clozapine (Clozaril) – The Weird SGA

Mechanism: potent antagonist at 5-HT2A, H1, alpha-1, alpha-2, m1, weak at D2

Indication: schizophrenia, suicidality in schizophrenia/schizoaffective, resistant BD. First-line for resistant schizophrenia.

Clozapine is the most effective at reducing positive/engative symptoms

Dosing: 12.5mg 1-2 times daily. May titrate every 24 hours by 25-50mg. (Max 900mg/day). The usual dose is between 100-800mg/day.

Metabolism: Major CYP1A2 (smoking) and CYP3A4 substrate

Serious ADR: None! (Low D2 affinity)

Common ADR: Most weight gain (H1), most anticholinergic (m1), most sedation (H1), high metabolic syndrome risk, high orthostasis risk. Withdrawal effects and lower seizure threshold.

Unique ADR: Sialorrhea (drooling), constipation (m1), urinary incontinence (m1), neutropenia, agranulocytosis, cardiomyopathy, myocarditis.

Whew, there are a lot of ADRs – this is why it’s in the REMS program, which is mainly there for the risk of agranulocytosis.

ANC Baseline must be at least 1500 to initiate. And must check every month for the duration of therapy for the first 6 months, then q 2 weeks for 6 months, and q 4 weeks thereafter.

If the patient stops taking for more than 30 days, must restart the whole process over.

A quick review of ANC:

• Mild neutropenia is ANC 1,000-1,499 –> Continue treatment but monitor 3x weekly
• Moderate neutropenia is ANC 500-999 –> Interrupt treatment and monitor daily until >1000. May restart once above 1000.
• Severe neutropenia is ANC < 500 –> interrupt treatment and consult hematology. Do not rechallenge.
• Benign ethnic neutropenia (BEN): Same guideline as above.

Clozapine-Induced Myocarditis/Cardiomyopathy

This is infrequent but very serious. Patients need baseline ECHO.

Myocarditis usually presents in the first 4 weeks. Symptoms are flu-like symptoms, which can be difficult to diagnose. Early detection is important, otherwise, the mortality rate is 10-30%

Cardiomyopathy usually presents in 14 months. Symptoms are shortness of breath, palpitations, fatigue, and reduction in ejection fraction.

In these cases, STOP clozapine. DO NOT rechallenge.

Long-Acting Injectable Antipsychotics

These agents are becoming more prevalent in practice. They can help reduce hospitalizations and relapse of an episode, especially in patients with non-adherence. The primary barrier to these is the lack of insurance coverage and lack of familiarity.

Most of these agents require a stabilization period with oral antipsychotics. This is to ensure that the patients are responsive to the medication and prevent any hypersensitivity issues.

High-potency FGA: Fluphenazine decanoate (IM, SQ)

Frequency: 2-6 weeks

Oral overlap: Oral or short-acting injectable fluphenazine

Starting dose: 1.25x of the oral dose. Decrease the oral by 50% after the first injection, and discontinue by the second dose.

Titration: May increase the dose by 12.5 mg for the max of 100 mg

Injection location: Gluteal injection. Recommend a Z-track method to prevent the medication from leaking out.

High-potency FGA: Haloperidol decanoate (IM)

Frequency: Every month

Oral Overlap: Oral haloperidol

Starting dose: The first way is to use 10-20x of the oral dose, and the oral medication can be tapered by 25% weekly 2-3 months after the injection. The second way is to start with 20x of the oral dose, and do not use any oral overlap.

Titration: May titrate once a month for a max of 450 mg each week.

Location: IM

If you’re giving greater than 100 mg, the injection must be administer in multiples doses. This medication is the most likely to cause serious side effects, such as dystonia.

SGA: Risperidone (IM, SQ)

IM: Risperdal Consta

Frequency: Every 2 weeks

Oral Overlap: Oral risperidone

Starting dose: Start at 25 mg regardless. Oral medication is overlapped for 21 days

Titration: Increase by 12.4-24 mg every 4 weeks for a max of 50 mg per dose.

Injection site: Deltoid or upper gluteal area (alternating)

SQ: Perseris

Frequency: Once monthly

Oral overlap: Not required, but should establish tolerability with oral risperidone before

Starting dose: 90-120 mg

Titration: No titration is available. The dosing range is just 90-120 mg.

Injection site: IM (abdomen or back of upper arm)

Perseris comes in two synringes, a liquid and a powder. These must be mixed prior to injection. Patient should be in supine position.

SGA: Olanzapine (IM) – Zyprexa Relprevv

Frequency: every 2 or 4 weeks

Oral overlap: not required, but should establish tolerability with oral olanzapine

Starting dose: Dosing depends on the oral dose. The injection is available in 150 mg, 210 mg, and 300 mg.

Titration: Usually not needed, but the dose should reduce after the first 6 weeks.

Injection site: Gluteal administration only

Zyprexa Relprevv is part of the REMS program because it has a warning for post-injection delirium or sedation syndrome. These occurs when the medication got injected straight into the blood stream. Patients who receive this medication must be minitor for 3 hours after injection, which is why it is less likely to see this medication in practice.

SGA: Paliperidone (IM) – Three different agents

Invega Sustenna

Frequency: once monthly

Oral overlap: Not required, but should establish tolerability with oral paliperidone or oral risperidone

Starting dose: Loading dose of 234 mg on day 1, then decrease to 156 mg 1 week later in the opposite deltoid muscle.

Titration: There is a nice conversion factor between the oral dose and the injection dose. An example is if the patient is stable on paliperidone 9 mg/day, then the injection dose is 156 mg once monthly.

Injection site: Deltoid muscle or gluteal muscle. Needles are provided and must be used.

This formulation needs to be shaken for 10 seconds prior to the administration.

Invega Trinza and Invega Hafyera – *Patients must be on Sustenna for 2 months before starting these longer-acting agents*

Frequency: Trinza is every 3 months, and Hafyera is every 6 months.

Starting dose: Dosing is based on the current Invega dose for the same amount of times (stable for at least 2 months.) For example, if the patient is stable on 156 mg of Sustenna, then the dose for Trinza would be 546 mg (around 3x) and 1,092 for Hayfera (around 6x) Trinza requires at least 4 doses of Sustenna, and Hafyera requires at least 4 doses of Sustenna or at least 1 of Trinza.

Injection site: Same as Sustenna. Must use the provided needle.

Both Trinza and Hafyera must be shtaken for 15 seconds prior to administration, and must be inected within 5 minutes of shaking.

SGA: Aripiprazole (IM)

Abilify Maintena (monohydrate)

Frequency: Once monthly

Oral overlap: Oral aripiprazole or double injection start (if tolerability has been established already)

Starting dose: 400 mg monthly. Oral overlap for 14 days unless going with a double injection of 400 mg, then only a one-time dose of 20 mg aripiprazole is required.

Titration: Not usually needed, but in co-administration with CYP3A4 inhibitor or lack of tolerability, may reduce to 300 mg once monthly.

Injection site: deltoids or gluteal muscle (must be rotated)

Aristada / Aristada Initio (lauroxil)

Frequency: once every 4, 6, or 8 weeks

Oral overlap: Oral aripiprazole.

Starting dose: The first way: a single injection of 675 mg Aristada Initio + a single dose of oral 30 mg aripiprazole + the first dose of Aristada within 10 days. The second way: 21 days of oral overlap with Aristada

Titration: The maintenance dose depends on the oral dose, for example, if the patient is stabled on 15 mg/day of oral, then the injection is 662 mg every month, 882 mg every 6 weeks, or 1.064 mg every 2 months.

Injection site: deltoid or gluteal muscle

Aristada Initio should be avoided in CYP2D6 poor metabolizers. The injection needs to be tapped 10 times and shake vigorously for 30 seconds before administration.

Common Adverse Effects of Antipsychotics

Sedation – Ask each visit

All antipsychotics have H1 antagonism.

Highest risk: Clozapine and quetiapine

Lowest risk: aripiprazole, brexpiprazole, cariparzine, palperidone, and risperidone.

Treatment: Reduce dose, change agent, or wait for tolerance to build in a couple of days.

Orthostatic Hypotension – Ask each visit and perform BP both sitting and standing

This is due to alpha-1 antagonism. It increases fall risk, MI, and TIA risk.

Highest risk: low-potency FGAs, clozapine, quetiapine, paliperidone, iloperidone

Treatment: Switch to another agent, or wait until tolerance develops in 2-3 months.

Weight Gain – Monitor each visit

This is mainly through appetite stimulation, but MoA is unknown.

Highest risk: clozapine and olanzapine

Lowest risk: aripiprazole, lurasidone, and ziprasidone

Treatment: Switch agent, add metformin, weight interventions

If left untreated, this can lead to T2DM, lipid abnormalities, VTE risk

Metabolic Syndrome

To be diagnosed with metabolic syndrome, patients must have 3+:

• Waist circumference >40 in men and >35 in women
• TG > 150
• HDL <40 for men or <50 for women
• BP >130/85
• Fasting glucose >100

There are four components:

• A1c or fasting glucose: baseline, 3 months, then annually
• Lipid profile: baseline, every 3 months, then annually
• Blood pressure: every visit and at least every 6 months
• BMI/waist circumference: baseline and every 6 months

Anticholinergic Effects – Every visit

These are caused by muscarinic antagonism. Mostly concern older adults. Long-term use might be linked to an increased risk of Alzheimer’s and dementia.

Highest risk: low-potency FGAs, clozapine, and olanzapine

Treatment: Switch agent, lower doses, or wait for tolerance

Hyperprolactinemia – Don’t monitor unless s/s then check prolactin level

This is caused by D2 receptor antagonism in the tuberoinfundibular (hypothalamus) and resulted in a prolactin increase. This is secondary to mesolimbic D2 blockade.

Highest risk: high-potency FGAs like haloperidol, risperidone, and paliperidone

Lowest risk: aripiprazole, lurasidone, quetiapine, and clozapine

Treatment: switch agent, NO tolerance develops

Extrapyramidal Symptoms (EPS) – Every week until the antipsychotic is stable for 2 weeks

These are caused by D2 receptor antagonism in the nigrostriatal secondary to mesolimbic D2 blockage. Recalled that these dopamines inhibit ACh, and without DA, ACh runs free leading to Parkinsonian symptoms.

These include dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia.

In general, the highest risks are FGAs and risperidone. The lowest risks are iloperidone, quetiapine, and clozapine.

Treatment: stop the agent, anticholinergic agents, BZDs, and propranolol.

Dystonia – rapid onset abnormal muscle tonicity commonly in the cervical area.

Highest risk: FGAs

Treatment: IM or IV anticholinergics like benztropine 2mg or diphenhydramine 50mg – can taper after a few weeks. Prophylaxis is only considered in young males, with a history of dystonia, or high-potency FGAs.

Pseudo-Parkinsonism – Movement changes (akinesia, mask-like expression), Tremor (at rest, pill-rolling), Cogwheel rigidity (jerky movement), and Postural abnormalities (shuffling gate)

Highest risk: FGAs, risperidone, paliperidone, lurasidone, ziprasidone, and olanzapine

Treatment: Switch agent or treat with either anticholinergic (Benztropine/trihexyphenidyl) or dopamine agonist (Amantadine). May discontinue 6 weeks to 3 months after symptoms resolution.

Akathisia – pacing, shifting, fidgeting, and foot tapping – Use the Barnes Akathisia Scale

Highest risk: FGAs, aripiprazole, cariprazine, lurasidone, and asenapine

Treatment: Switch agent, propranolol 10 BID, or BZD short-term, or mirtazapine and trazodone.

Tardive Dyskinesia – lip smacking, tongue thrusting, can be irreversible

Highest risk: high-potency FGAs (haloperidol) – Monitor every 3 months in high risk and 12 months otherwise using AIMS (Abnormal Involuntary Movement Scale)

Treatment: Switch agent or VMAT2 inhibitors (deutetrabenazine or valbenzaine)

VMAT2 Inhibitors

MoA: Decrease the DA release by not transporting…

The dose must be adjusted with strong CYP2D6 inhibitors

Valbenazine (Ingrezza) 40mg QD. (Dose adjust for CYP3A4 inhibitors as well)

Deutetrabenzaine (Austedo) 6mg BID with food.

More Antipsychotic Adverse Effects

Patients with Dementia

ALL antipsychotics have a BBW for increase mortality in patients with dementia. This is usually due to stroke, myocardial infection, or sudden death.

This risk is highest in those with vascular disease. FGAs may have a higher risk than SGAs. As healthcare practitioners, we need to weigh the risks versus the benefits of treatment.

Thermoregulation Issues

This is caused by dopaminergic and muscarinic receptor antagonism. One of the symptoms is poikilothermia, which is when the body adjusts to ambient temperature because it cannot regulate temperature normally.

Patients should be cautioned that they are more susceptible to weather than most. During hot weather, they should ensure that they stay hydrated. Extreme temperatures should be avoided. This risk is the highest in older adults.

Highest risk: low-potency FGAs.

Electrocardiographic Changes

In some instances, these medications can cause QTc prolongation and increase the risk of torsade de pointes. This risk is included because patients taking antipsychotics have a 2x higher risk of sudden cardiac death. Generally, you shouldn’t have to worry about this unless the patients have risk factors, such as being female, taking cardiovascular medications, being over 50 years or having cardiovascular diseases. In these patients, you may consider obtaining a baseline QT.

Highest risk: haloperidol, chlorpromazine, ziprasidone, iloperidone

Lowest risk: aripripazole, brexpiprazole, cariprazine, and lurasidone

Treatment: Switch agent, and titrate agents carefully

Seizures

All antipsychotics decrease seizure threshold to a certain extent. This can be caused by too rapid titration or treatment initiation.

Highest risk: clozapine, chlorpromazine

Lowest risk: aripiprazole, risperidone, haloperidol

Treatment: reduce the dose. Do not start seizure prophylactic after the first med-induced seizure. This doesn’t mean they have seizures for the rest of their lives. Try to adjust the medication first and see if that fixes it.

Neuroleptic Malignant Syndrome (NMS)

This is an emergent clinical syndrome. Patients present with similarities to serotonin syndromes where there are mental status changes, rigidity, fever, and autonomic nervous system dysregulation. The patient’s temperature continues to climb until it kills the patient. This is seen in about 1% of antipsychotic users with a 10% mortality rate. Risk factors include FGAs, high doses, parenteral use, multiple antipsychotics, and older age.

Treatment: There is no treatment. Discontinue antipsychotics immediately and provide the patient with supportive care.

Catatonia

Catatonia is unique because it can be a symptom of both schizophrenia and antipsychotic medications. There are two primary ways that the symptoms manifest: extreme negativism and catatonic excitement.

This is one of the symptoms that can be worsened by dopamine block drugs. If left unaddressed, catatonia can progress to malignant catatonia, and then to the neuroleptic malignant syndrome. We must be extremely careful when increasing the antipsychotic dose, especially when unsure if catatonia is from the disease or medication.

Treatment: benzodiazepines. The preferred agent is lorazepam (1-2mg TID), usually 6-30 mg a day is required. If a benzodiazepine is not effective within 1 week, electroconvulsive therapy (ECT) may be considered. Side note, ECT is also the first line in malignant catatonia.

Treatment Process for Schizophrenia

Baseline lab: CBC, electrolytes, renal function, A1c, ECG, lipid, thyroid, urine drug screen

First phase: Initial Treatment of Acute Episode (first 7 days)

First-line: SGAs

• If agitated, olanzapine, haloperidol, and ziprasidone are preferred in the IM formulation. BZDs may be considered for severe symptoms.
• Otherwise: Aripiprazole, risperidone, ziprasidone

Goal: normalization of sleep and eating patterns

Monitoring:

• Titrate over the first few days. If no response in 2 weeks, change agent.
• Do not go straight for a higher dose with worse symptoms. This increases adverse effects without increasing efficacy.

Second phase: Stabilization Therapy (6-12 weeks)

• Continue that same dose as long as symptoms improve.
• If improvement stops can continue titration every 1-2 weeks.

Third phase: Maintenance Therapy (lifetime)

• Lifetime is important because the relapse rate after 1 year is 18-32% with medication and 60-80% with placebo.
• If can’t continue for a lifetime, should be at least 18 months.

Watch for polypharmacy because it usually increases adverse effects without improving outcomes or efficacy.

Treatment for Resistant Schizophrenia

This is when patients have moderate-severe symptoms, tried at least 2 agents for at least 6 weeks with adherence, and still fail.

Go for clozapine (also help with severe suicidality)

Drug-Drug Interactions

Be mindful of the enzymes for each agent. An enzyme inhibitor will increase substrate concentration, and an enzyme inducer will decrease substrate concentration. The key enzymes that we need to watch out for with antipsychotics are CYP2D6, CYP3A4, and CYP1A2.

Cigarette smoking impacted CYP1A2 and will decrease the serum concentration of antipsychotics.

HIV protease inhibitors (-navir) are CYP3A4 inhibitors and can increase the serum concentration of antipsychotics.

A combination of antipsychotics with SSRIs or metoclopramide can increase EPS risk.

Pregnancy and Lactation

Most antipsychotic medications are not ideal in pregnancy, but the risks and benefits need to be taken into consideration. If the medications are stopped, there are 50% risk of relapse and risk of smoking and alcohol use.

Not much data are available on which antipsychotics are safe right now. Haloperidol is probably not a major teratogen (used in hyperemesis gravidarum), but may increase preterm birth risk and neonatal EPS. SGAs have minimal data, but some may result in gestational diabetes or congenital malformation if used in early pregnancy.

For lactation, the safest agents seem to be olanzapine and quetiapine. Do NOT use clozapine if breastfeeding. Since stopping medication is not ideal either, an alternative method of feeding the infant should be utilized.

Last Note on Therapy

No antipsychotics have proven superior efficacy. Only Clozapine is superior in resistant schizophrenia.