Atypical Antipsychotics

With the introduction of the atypical antipsychotics, the 1990s were a time of significant resurgence in antipsychotic drug prescribing for elderly patients. These drugs were heavily promoted for a wide variety of indications, and the comfort level in prescribing them was high, even among nonpsychiatrists.

  • Indications for antipsychotic medications in the elderly population include schizophrenia, mania with psychotic symptoms, dementia with delusions and agitation/aggression, major depression with psy­chotic features, delusional disorder, delirium, and psychotic disorders secondary to medical conditions.
  • When antipsychotic medications are used to control psychosis, stand­ing rather than prn doses should be used.
  • All antipsychotics are substrates for CYP isoenzymes, mostly CYP2D6 and/or CYP3A4; in addition, several of the conventional antipsychotics are potent CYP2D6 inhibitors.
  • Initial titration of an antipsychotic should usually proceed at a rate of one to two dose increases per week; less for frail or medically com­promised elders.
  • In the treatment of acute psychosis in elderly patients with schizo­phrenia, there is no evidence favoring the “rapid neuroleptization” protocols formerly used to treat schizophrenic exacerbations.
  • Adverse effects that are particularly problematic for elderly patients include QTc prolongation, orthostasis/hypotension, sedation, anti-cholinergic effects, and metabolic effects (weight gain, glucose dsyregulation, and dyslipidemia) over the longer term.
  • The apparently increased risk of stroke and sudden death associated with atypical antipsychotics necessitates an increased threshold for their use in elderly patients, particularly those with dementia. The same caution should be used for conventional antipsychotics in the elderly.
  • Individual atypical antipsychotics differ substantially in the degree of associated risk for the development of the metabolic syndrome. In general, clozapine and olanzapine may confer the greatest risk and aripiprazole the least.
  • The prevalence of tardive dyskinesia among elderly patients after 3 years of treatment with conventional antipsychotics is 60%.

The following are approved and marketed in various parts of the world:


Generic name aripiprazole
Trade name Abilify
Class Quinolone derivative
Half-life 75 hours; 94 hours for dehydro-aripiprazole
Mechanism of action D2 partial agonist; 5-HT1A partial agonist; 5-HT2A antagonist
Available preparations Tablets: 5, 10, 15, 20, 30 mg
Oral solution: 1 mg/mL (150 mL)
Starting dose 5 mg/day
Titration Increase by 5 mg after 2 weeks
Typical daily dose 10 mg/day
Dose range 2.5–15 mg/day
Therapeutic serum level Not established

Comments: A recommended drug in elderly patients because of a favorable adverse-effect profile. As a dopamine D2 partial agonist at pre- and post-synaptic receptors, aripiprazole has prodopaminergic effects at low dopamine levels and dopamine-blocking effects at high dopamine levels. It is well absorbed orally, taken with or without food. Peak level in plasma in 3–5 hours (delayed by a high-fat meal). Bioavailability 87%. More than 99% protein bound. It is metabolized primarily via CYP2D6 and 3A4. The active metab­olite dehydroaripiprazole has D2 affinity similar to the parent compound. It has a very long half-life, with steady state reached in 14 days. Drug inter­actions: Aripiprazole interacts with CYP2D6 inhibitors and CYP3A4 inhib­itors and inducers. Like other atypical antipsychotics, confers a low risk of extrapyramidal side effects and tardive dyskinesia. Compared with other atyp-icals, aripiprazole has a relatively lower risk of prolactin elevation, QTc pro­longation, dyslipidemia, glucose dysregulation, and weight gain. Common adverse effects: Headache, agitation, anxiety, insomnia, somnolence, akathisia, light-headedness, weight gain, nausea, dyspepsia, constipation, and vomiting.


Generic name clozapine
Trade name Clozaril
Class Dibenzodiazepine
Half-life 12 hours (range 4–66 hours)
Mechanism Blockade of dopaminergic and serotonergic receptors
Available preparations Tablets: 12.5, 25, 100 mg (scored)
Orally disintegrating tablets: 25, 100 mg
Starting dose 6.25–12.5 mg/day
Titration Increase by 6.25–12.5 mg every 7 days (may be added to a high-potency typical antipsychotic, which is tapered when clozapine dose is at target or at 100 mg/day)
Typical daily dose Schizophrenia: 100 mg bid for acute treatment; lower dose for maintenance Psychosis in Parkinson’s disease: 6.25–50 mg
Dose range 6.25–400 mg/day (divided doses)
Therapeutic serum level 350–450 ng/mL (clozapine plus norclozapine) for adult patients with schizophrenia; no clear relationship between level and response

Comments: Highly effective for schizophrenia and psychosis in Parkinson’s disease and related disorders, but use is limited in elderly patients because of adverse effects. Boxed warnings regarding agranulocytosis, seizures, myocarditis, orthostasis, cardiorespiratory collapse with coadministration of benzodiazepines, and increased mortality in elders with dementia-related psychosis. Used for patients with schizophrenia who are resistant to other treatments, have severe movement disorders (e.g., tardive dykinesia), or have recurrent suicidal behaviors unresponsive to other interventions. Well absorbed orally, with no effect of food on bioavailability. 97% protein bound. Extensively metabolized in the liver to inactive metabolites. Peak level in 2.5 hours. Lowest doses (e.g., 6.25 mg) used for very elderly patients and patients with dementia. Divided doses are recommended. Not used prn. Latency to response may be seen; 6 weeks’ to several months’ latency is not uncommon in elderly patients. Response may not plateau for 12 months, especially for negative symptoms. Drug interactions: Potential interaction with benzodiazepines associated with sudden death; add benzodiazepines only after clozapine titration is complete. Other drug interactions mediated by CYP1A2, 2D6, and 3A4. Adverse effects: Agranulocytosis, Neuroleptic Malignant Syndrome, deep venous thrombosis and pulmonary embolism, glucose dysregulation, weight gain, increased serum creatine kinase, increased serum lipids (including triglycerides), seizures (plasma levels > 1,000 ng/mL), tachycardia, confusion, sedation, dizziness, and salivary pooling. See Routine white blood cell monitoring weekly for 6 months, then every other week if white blood cell and ANC values have been normal, then monthly if all counts normal for a second 6 months. To discontinue (for reasons other than leukopenia), decrease dose gradually over 4–6 weeks, and continue white blood cell monitoring for 4 weeks after discontinuation. For missed doses or if patient discontinues more than 48 hours, need to re-titrate, starting with lowest dose.


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