Medicine & USMLE

Atypical Antipsychotics

Psych Pharm
  1. Lithium
  2. Typical Antipsychotics
  3. Atypical Antipsychotics
  4. SSRIs
  5. SNRIs
  6. Tricyclic Antidepressants (TCAs)
  7. Monoamine Oxidase Inhibitors (MAOIs)
  8. Bupropion
  9. Mirtazapine
  10. Trazadone
  11. Vilazodone
  12. Vortioxetine
  13. Buspirone
  14. Varenicline


Atypical antipsychotics include the drugs aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone, and clozapine. These drugs work by blocking dopamine signaling in the brain. Clinically, atypical antipsychotics treat both the positive and negative symptoms of schizophrenia and are also used as mood stabilizers in bipolar disorder. Remember atypical antipsychotics share some side effects with typical antipsychotics, including hyperprolactinemia and neuroleptic malignant syndrome (NMS), but they are much less likely to cause extrapyramidal symptoms or anticholinergic effects. Atypical antipsychotics in general are associated with weight gain and metabolic syndrome. Specific high-yield side effects to know are agranulocytosis, seen with clozapine, and Long QT syndrome, seen with ziprasidone.

Key Points

  • Atypical Antipsychotics
    • Also known as the second-generation antipsychotics
    • Drug Names:
      • Aripiprazole
      •  -apine drugs:
        • Clozapine
        • Olanzapine
        • Quetiapine
        • Asenapine
      • -idone drugs:
        • Risperidone
        • Ziprasidone
        • Lurasidone
        • Iloperidone
        • Paliperidone
    •  Mechanism
      • D2 receptor antagonist
        • Weaker antagonism than typical antipsychotics
          • Fewer EPS and anticholinergic side effects than typical antipsychotics
            • Used in patients who develop EPS on typical antipsychotics
        • Blocks effects of dopamine released by dopaminergic neurons in the brain, primarily affecting the following known pathways:
          • Mesolimbic
            • This dopaminergic pathway is involved in reward-seeking and a dopaminergic imbalance in this region is thought to be the cause of psychosis.
          • Nigrostriatal
            • The nigrostriatal pathway plays a key role in regulating movement as part of the basal ganglia. Inhibiting the effects of dopamine in this pathway leads to movement abnormalities, including Parkinsonism.
          • Tuberoinfundibular
            • Dopamine released by the dopaminergic neurons of the tuberoinfundibular pathway normally act on the anterior pituitary to inhibit prolactin secretion. Blocking the effect of dopamine in this pathway leads to hyperprolactinemia.
        • ↑ cAMP
        • Aripiprazole – D2 partial agonist
      • 5-HT2, alpha, and H1 antagonism
        • Degree to which these receptors are affected is unclear
    • Indications
      • Schizophrenia (first line)
        • Treats positive AND negative symptoms
        • Clozapine used in treatment-resistant schizophrenia
          • The ‘big gun’ of antipsychotics for schizophrenia. schizoaffective disorder, and suicidality in schizophrenia
      • Bipolar Disorder
        • Antipsychotics like olanzapine and risperidone have mood-stabilizing properties and may be used in bipolar disorder
          • Used in acute mania (Bipolar Type I) as well as in bipolar depression (Bipolar Type I/II)
        • Often in conjunction with lithium
      • Other psychotic disorders
        • Major depressive disorder with psychotic features
        • Postpartum psychosis
      • Treatment-resistant tics in Tourette syndrome
      • Anxiety disorders
      • OCD
    •  Adverse effects:
      • Neuroleptic malignant syndrome (NMS)
        • Life-threatening reaction to antipsychotics characterized by
          • Fever
          • Muscle rigidity
            •  Often described as “lead pipe” rigidity
              • Tip: Can differentiate from serotonin syndrome by lack of hyperactive reflexes (i.e. no clonus/hyperreflexia)
            •  Often accompanied by an increase in creatinine kinase (CK)
            • May cause myoglobinuria
          • Altered mental status
          • Autonomic dysfunction
            • Unstable vitals (BP, HR)
        • Treatment:
          • Discontinue antipsychotic
          • Dantrolene
          • Dopamine agonists (ex. bromocriptine)
      • Metabolic syndrome
        • Particularly among -apine drugs (olanzapine, clozapine)
        • Weight gain (obesity)
        • Hypertriglyceridiemia
        • Hyperglycemia (insulin resistance)
      • Hyperprolactinemia
        • Most associated with risperidone
        • Disinhibition of prolactin secretion from lactotrophs of the anterior pituitary, leading to:
          • Galactorrhea
          • Gynecomastia
          • Oligomenorrhea/amenorrhea
          • Erectile dysfunction
          • Low libido
        • High levels of prolactin lead to the suppression of GnRH. Low GnRH in turn decreases levels of LH and FSH. With decreasing levels of LH and FSH, the gonads produce less estrogen and testosterone. This can impair fertility leading to a state of hypogonadotropic hypogonadism
      • Prolonged QT  
        • Most associated with ziprasidone
      • Agranulocytosis (clozapine)
        • Life-threatening depletion of granulocytes (e.g. neutrophils), seen in 1% of people
        • Requires frequent monitoring of WBC count
        • Clozapine can also cause:
          • Seizures
          • Myocarditis
          • Sialorrhea (drooling)