4.2 Antipsychotics: Typical vs Atypical

Antipsychotic medications are organized into two generations based on receptor-binding profile, and the PMH-BC exam expects nurses to match each generation — and each specific agent — to its expected benefit, its dominant side-effect profile, and the monitoring it requires.

Typical (First-Generation) Antipsychotics

First-generation antipsychotics (FGAs) work primarily by blocking dopamine D2 receptors. They effectively treat positive symptoms of psychosis (hallucinations, delusions, disorganized thought) but have limited effect on negative symptoms. FGAs are further divided by potency, which predicts their side-effect pattern:

Because D2 blockade in the nigrostriatal pathway is not selective, FGAs — especially high-potency agents — carry a significant risk of EPS (acute dystonia, akathisia, pseudoparkinsonism) and, with long-term use, tardive dyskinesia (covered in Section 4.6).

A critical prescribing safety flag applies to both generations: all antipsychotics — typical and atypical alike — carry an FDA black-box warning for increased mortality in older adults with dementia-related psychosis, largely from cardiovascular and infectious causes. Antipsychotics are not FDA-approved for this indication, and the nurse should expect careful risk-benefit discussion and the lowest effective dose whenever one is used off-label in this population.

Atypical (Second-Generation) Antipsychotics

Second-generation antipsychotics (SGAs) block D2 and serotonin 5-HT2A receptors. The added serotonin blockade reduces EPS risk relative to FGAs and gives SGAs meaningful efficacy against negative symptoms (flat affect, avolition, anhedonia, social withdrawal) as well as positive symptoms. Common agents include risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, lurasidone, and clozapine (reserved for treatment-resistant illness — see Section 4.6).

The trade-off for lower EPS is a substantially higher risk of metabolic syndrome: weight gain, hyperglycemia/new-onset diabetes, and dyslipidemia. Olanzapine and clozapine carry the highest metabolic risk; aripiprazole and ziprasidone carry the lowest risk among commonly used SGAs.

Required metabolic monitoring (ADA/APA consensus protocol) includes weight/BMI and waist circumference, blood pressure, fasting glucose or HbA1c, and a fasting lipid panel — obtained at baseline, again at 12 weeks, and at least annually thereafter; weight is checked more frequently in the first three months (for example, at weeks 4, 8, and 12) because early weight gain predicts long-term metabolic risk.

Other monitoring priorities:

• QT prolongation: Several antipsychotics — ziprasidone in particular — prolong the QT interval; obtain baseline and follow-up ECGs in patients with cardiac risk factors or on other QT-prolonging drugs.
• Prolactin elevation: Risperidone (and its metabolite paliperidone) raises prolactin more than other agents, producing galactorrhea, amenorrhea, gynecomastia, and sexual dysfunction — assess and report these symptoms rather than dismissing them.
• Sedation and orthostatic hypotension: Quetiapine and olanzapine are notably sedating; instruct patients to rise slowly and avoid driving until tolerance develops.

Partial Agonism: Aripiprazole and Brexpiprazole

Aripiprazole and brexpiprazole act as partial agonists at D2 receptors rather than full antagonists — sometimes described as "dopamine stabilizers" because they dampen dopamine activity where it is excessive while providing weak stimulation where it is low. This mechanism explains their distinct side-effect profile: lower metabolic risk and less sedation than most SGAs, but a comparatively higher relative risk of akathisia. A patient can therefore develop restlessness and an inner urge to move on aripiprazole despite it being one of the lowest-metabolic-risk antipsychotics available — a pattern the nurse should anticipate and screen for rather than attribute to anxiety.

Long-Acting Injectable (LAI/Depot) Antipsychotics

For patients with limited insight, a history of nonadherence, or a preference for less frequent dosing, LAI formulations deliver medication over an extended interval per injection: haloperidol decanoate and fluphenazine decanoate (roughly every 2-4 weeks), risperidone microspheres (every 2 weeks), paliperidone palmitate (monthly, with a longer-interval formulation available), and aripiprazole LAI (monthly, with a longer-interval formulation available). LAIs reduce relapse and rehospitalization associated with missed oral doses, but patients still require the same metabolic and EPS monitoring as their oral counterparts, and the nurse must observe for injection-site reactions and, with olanzapine LAI specifically, post-injection delirium/sedation syndrome, which requires a mandatory 3-hour post-injection observation period at a certified facility.

Choosing between agents also means weighing long-term movement-disorder risk: FGAs and higher-EPS SGAs carry greater tardive dyskinesia risk with sustained use, which is why ongoing AIMS screening (Section 4.6) is part of routine follow-up for any patient on a long-term antipsychotic, oral or injectable.

Clinical Application

A patient on haloperidol who develops a stiff, mask-like face and shuffling gait is showing pseudoparkinsonism from D2 blockade — an FGA-typical finding. A patient on olanzapine who has gained 15 pounds and has a fasting glucose of 140 mg/dL needs immediate metabolic evaluation, not reassurance that "all antipsychotics do this." Matching the agent's receptor profile to its expected risks lets the nurse anticipate — and teach patients to recognize — the adverse effects most likely to occur.