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Day # 17: Side Effects of Specific Antipsychotics

During our last lesson we had a lengthy discussion about side effects in the antipsychotic class of medications. Today we are going to take one day and cover specific medications and provide a reference for the side effects that are most classically associated and highly testable on shelf and licensing exams.

We are not going to cover every single antipsychotic medication, but we are going to cover the most commonly used and tested medications. Let's jump right in.

Today's Content Level: Beginner; Intermediate

High Potency FGA's

•As discussed previously, high potency antipsychotics confer the highest risk of developing extrapyramidal symptoms (EPS), neuroleptic malignancy syndrome (NMS), and hyperprolactinemia. When used in emergency settings (IM or IV), consider co-administering with diphenhydramine or benztropine to prevent EPS.

•Haloperidol (Haldol): PO/IM/IV/LAI.

  • Higher risk of EPS.

  • Higher risk of QTc prolongation (along with Ziprasidone and Quetiapine).

•Fluphenazine (Prolixin): PO/IM/LAI.

  • Higher risk of EPS.

  • Also approved for non-psychotic anxiety

Mid Potency FGA's

•Perphenazine (Trilafon): PO/IM.

  • Action at multiple sites (dopamine, histamine, cholinergic)

  • May reduce nausea/vomiting

•Loxapine (Loxitane): PO/IM/IV.

  • Higher risk of seizures.

  • Metabolite is an antidepressant (potent serotonin 2A antagonist).

  • Can increase efficacy in clozapine partial responders when given together.

  • Weight gain less than other antipsychotics.

Low Potency FGA's

•Low potency FGA's + clozapine are highest risk for seizures. They also have increased antihistamine, anticholinergic, and alpha-adrenergic activity making them more susceptible to sedation, weight gain, postural hypotension, dizziness, and constipation than the high potency FGA's.

•Chlorpromazine (Thorazine): PO/IM/IV.

  • Commonly causes orthostatic hypotension and highly sedating.

  • Can cause blue-gray skin discoloration

  • Can cause photosensitivity + corneal reposts of the eye

  • Also used to treat nausea, vomiting, and intractable hiccups


  • This is no longer commonly used. The branded product (Mellaril) was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.

  • Sometimes still shows up on tests due to known side effect of irreversible retinal pigmentation with high doses.

Second-Generation Antipsychotics

•In this class of medications the serotonin 5-HT2 antagonism is actually more potent than dopamine (D2) antagonism in many cases. Has more of an antidepressant affect that FGA's. There is less overall risk for EPS, NMS, and hyperprolactinemia but increased risk for metabolic syndrome.

•Asenapine (Saphris): ODT.

  • Orally dissolving (sublingual) tablet is the only formation available.

  • High risk of akathisia among SGA's.

Clozapine (Clozaril): PO.

  • We will discuss Clozapine in detail in a few days, however here are some highlights.

  • Most effective antipsychotic, used in treatment refractory schizophrenia.

  • Less likely to cause tardive dyskinesia and EPS in general.

  • Can cause tachycardia and hypersalivation.

  • Most severe anticholinergic side effects.

  • Very sedating.

  • Clozapine and olanzapine most severe weight gain and metabolic syndrome.

  • Higher risk of hypotension among SGA's (along with quetiapine and risperidone).

  • Small risk of myocarditis.

  • 1% incidence of agranulocytosis.

  • Must be stopped if ANC drops below 1,500/microliter.

  • 4% incidence of seizures (highest of all antipsychotics).

  • Only antipsychotic shown to reduce the risk of suicide.

•Iloperidone (Fanapt): PO/LAI.

  • May see orthostatic hypotension (titrate slowly) and QT prolongation.

•Lurasidone (Latuda): PO.

  • Must be taken with food.

  • Watch out for akathisia, Parkinsonism, and sedation.

  • Less risk for weight gain.

  • Also approved for use in bipolar depression.

•Olanzapine (Zyprexa): PO/ODT/IM/LAI.

  • Olanzapine and clozapine most severe weight gain and metabolic syndrome.

  • Very sedating.

  • Most efficacious antipsychotic in CATIE trial (aside from clozapine)

•Paliperidone (Invega): PO/LAI.

  • Metabolite of risperidone.

  • Long-acting injectable form (Sustenna).

•Quetiapine (Seroquel): PO.

  • Much less likely to cause EPS.

  • Common side effects include sedation (used inappropriately sometimes as sleep aid) and orthostatic hypotension.

  • Higher risk of QTc prolongation (along with haloperidol and ziprasidone).

  • Higher risk of hypotension among SGA's (along with clozapine and risperidone).

  • Moderate weight gain.

•Risperidone (Risperdal): PO/ODT/LAI.

  • Can cause ↑ prolactin. Highest among SGA's.

  • Orthostatic hypotension and reflex tachycardia. Higher risk of hypotension among SGA's (along with clozapine and risperidone).

  • Long-acting injectable form named Consta.

  • Third most efficacious antipsychotic in CATIE trial (after clozapine and olanzapine)

•Ziprasidone (Geodon): PO/IM.

  • Less likely to cause significant weight gain.

  • Higher risk of QTc prolongation (along with haloperidol and quetiapine).

  • Must be taken with food (50% reduction in absorption without a 300 calorie meal)

•Aripiprazole (Abilify): PO/LAI.

  • Unique mechanism of partial D2 agonism with high-potency 5HT2A antagonism. Instead of blocking dopamine (D2) receptors, they are partial agonists but have high binding affinity which allows less dopamine to bind to the receptors. Sometimes called third generation due to different mechanism of action.

  • Can be more activating (akathisia) and less sedating. Highest risk of akathisia among SGA's.

  • Less potential for weight gain.

  • Unlike other antipsychotics, this may cause a decrease in the QTc interval which makes it an attractive option in ICU patients or others with multiple risk factors for prolongation.


Nice work. Today's information will not only be helpful with patients but there will definitely be a few questions on clerkship exams and licensing exams. Tomorrow we will discuss prescribing tips and some of the important landmark medication trials for antipsychotics. Later we will do dive a little deeper into treatment resistant schizophrenia and clozapine.

Resources for today's post include:

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