Schizophrenia/Antipsychotics: The Need-to-Knows

Which drugs can cause drug-induced psychosis by increasing dopamine?

- Cocaine

- Amphetamines

- Methylphenidate

- Levodopa

- Amantadine

- Dopamine Agonists

Which NMDA-antagonists can cause psychosis?

- Ketamine

- Memantine

- PCP

What are the four major positive symptoms of schizophrenia?

- Hallucinations

- Delusions

- Disorganized speech/thinking

- Disorganized behavior

What type of hallucination is most characteristic of schizophrenia?

Auditory hallucinations

What type of delusion is most common in schizophrenia?

Persecutory/paranoid delusions

What are the major negative symptoms of schizophrenia?

- Flat affect

- Avolition (lack of motivation)

- Alogia (lack of speech)

- Anhedonia (lack of enjoyment)

How do positive and negative symptoms differ?

- Positive = something is added that should not be there

- Negative = something normally present is diminished or absent.

What receptor do first-generation antipsychotics primarily block?

D₂ receptors

What dopamine pathway is associated with EPS when D₂ receptors are blocked?

Nigrostriatal pathway

What dopamine pathway is associated with hyperprolactinemia when D₂ receptors are blocked?

Tuberoinfundibular pathway

What adverse effects result from H₁ blockade?

Sedation and weight gain

What adverse effects result from M₁ blockade?

Anticholinergic effects such as dry mouth, constipation, and urinary retention

What adverse effect results from α₁ blockade?

Orthostatic hypotension

What determines the potency of a first-generation antipsychotic?

How strongly it blocks D₂ receptors

What are the major adverse effects of high-potency FGAs?

EPS and hyperprolactinemia

What are the major adverse effects of low-potency FGAs?

- Sedation

- Anticholinergic effects

- Orthostatic hypotension

What are examples of a low-potency FGA?

- Chlorpromazine

- Thioridazine

What are examples of a mid-potency FGA?

- Loxapine

- Perphenazine

- Molindone

What are examples of a high-potency FGA?

- Haloperidol

- Fluphenazine

- Thiothixene

- Trifluoperazine

Which FGA is the major "poster child" for QT prolongation?

Thioridazine

Which second-generation antipsychotic is most associated with cardiometabolic adverse effects?

Olanzapine

Which second-generation antipsychotic is most associated with EPS and hyperprolactinemia?

Risperidone

Which second-generation antipsychotic is especially sedating and has relatively low EPS risk?

Quetiapine

Which second-generation antipsychotic is most associated with QT prolongation?

Ziprasidone

What counseling point is important for Ziprasidone?

Take it with food to increase absorption (~500 calories BID)

What is Paliperidone?

The active metabolite of Risperidone

What major adverse effect is associated with Paliperidone?

Hyperprolactinemia

What major drug-interaction issue is associated with Lurasidone?

It is highly susceptible to CYP3A4 inhibitors and inducers

What major adverse effects are associated with Aripiprazole?

- Activation

- Akathisia

- Insomnia

Why is Aripiprazole different from most other antipsychotics?

It is a partial D₂ agonist

Which antipsychotics are the two biggest offenders for weight gain, dyslipidemia, and hyperglycemia?

Clozapine and Olanzapine

Which antipsychotic is the next major cardiometabolic offender after Clozapine and Olanzapine?

Quetiapine

What should be monitored for cardiometabolic adverse effects of antipsychotics?

- Weight

- Waist circumference

- Blood pressure

- Glucose

- Lipids

Which antipsychotic is the most effective for treatment-resistant schizophrenia?

Clozapine

After how many failed adequate antipsychotic trials should Clozapine be considered?

- Two failed trials

- Clozapine should generally be the third trial

Which antipsychotic has evidence/approval for reducing suicidal behavior in schizophrenia or schizoaffective disorder?

Clozapine

What serious hematologic adverse effect is associated with Clozapine?

Severe neutropenia

What laboratory value is monitored with Clozapine?

Absolute neutrophil count (ANC)

How often is ANC monitored during the first 6 months of Clozapine therapy?

Weekly

How often is ANC monitored during months 7–12 of Clozapine therapy?

Every 2 weeks

How often is ANC monitored after the first year of Clozapine therapy?

Monthly

What ANC threshold is used for the general population receiving clozapine?

≥1,500 cells/mm³

What ANC threshold is used for patients with Benign Ethnic Neutropenia (BEN)?

≥1,000 cells/mm³

What are the four major types of EPS?

- Acute dystonia

- Akathisia

- Drug-induced Parkinsonism

- Tardive dyskinesia

What are the characteristic features of acute dystonia?

Acute, painful muscle contractions, commonly affecting the head and neck

Who is at higher risk for acute dystonia?

Younger males, particularly after high-potency antipsychotics or injections

What is the preferred treatment for an acute dystonic reaction?

IM benztropine

What is akathisia?

Physical inner restlessness with inability to sit still, pacing, or repetitive leg movements

What is a preferred medication for antipsychotic-induced akathisia?

Oral propranolol

What are characteristic symptoms of drug-induced Parkinsonism?

Tremor, bradykinesia, shuffling/festinating gait, and decreased arm swing

What is a common treatment for antipsychotic-induced Parkinsonism?

An oral anticholinergic such as benztropine

Which EPS is treated with an IM anticholinergic because rapid relief is needed?

Acute dystonia

What is tardive dyskinesia?

A late-onset movement disorder characterized by involuntary movements that may be irreversible

What movements are characteristic of tardive dyskinesia?

Lip pursing, tongue darting, cheek puffing, grimacing, jaw movements, and other involuntary oral-facial movements

What medications are used to treat tardive dyskinesia?

Valbenazine and Deutetrabenazine

What drug class are valbenazine and deutetrabenazine?

VMAT2 inhibitors

How do VMAT inhibitors decrease dopamine?

They prevent dopamine storage in presynaptic vesicles → dopamine remains in the cytoplasm → MAO metabolizes it → ↓ dopamine

What important psychiatric adverse effect can occur with VMAT inhibition?

Depression and potentially suicidality

How often should AIMS generally be performed?

- TD = Every 6-12 months

- High-Risk FGA = Every 6 months

- Patient receiving an atypical antipsychotic = Every 12 months

Which antipsychotics are especially associated with hyperprolactinemia?

- High-potency FGAs

- Risperidone

- Paliperidone

Which antipsychotic has a particularly low risk of hyperprolactinemia?

Aripiprazole

Which electrolyte abnormalities increase the risk of QT prolongation?

Hypokalemia and Hypomagnesemia

What QTc value is considered the major danger threshold?

≥500 ms

Which antipsychotics/drug situations should especially make you think about QT prolongation?

- Thioridazine

- Pimozide

- IV haloperidol

- Ziprasidone

What boxed warning is shared by antipsychotics when used in older adults with dementia-related psychosis?

Increased risk of mortality

Which second-generation antipsychotics are broadly available as long-acting injectables?

- Aripiprazole

- Olanzapine

- Risperidone

- Paliperidone

Which first-generation antipsychotics are available as long-acting injectables?

- Haloperidol

- Fluphenazine

Why should oral tolerability be established before giving an LAI?

Once the long-acting injection is given, the medication cannot be removed and remains in the body for an extended period

Which LAI second generation antipsychotic is given as a one-time dose?

Aripiprazole (Aristada Initio)

Which LAI second generation antipsychotic is given at 6 month intervals?

Paliperidone (Invega Hafyera)

What are the two major safety-monitoring areas for antipsychotics?

- Cardiometabolic adverse effects

- Extrapyramidal/movement disorders

How is antipsychotic efficacy generally monitored?

Improvement in symptoms such as hallucinations, delusions, suspiciousness, and overall psychosis