Use of atypical antipsychotics in the elderly: a clinical review

Figures & data

Table 1 Receptor binding profiles and plasma half-life (t_1\2) of antipsychotic drugs

Drug class	Second-generation antipsychotics								First-generation antipsychotics
Receptor	AMI	ARI	ASE	CLO	OLA	PALI	RIS	QUE	SER	ZIP	HAL	PER
D2	1.3b	0.66a,b	1.3b	210	20	2.8	3.77	770	2.7	2.6	2.6	1.4b
5-HT1A	>10,000c	5.5a,b	2.5b	160	610	480	190	300	2,200	1.9a,b	1,800	421
5-HT2A	2,000c	8.7b	0.06b	2.59	1.5	1.2	0.15	31	0.14	0.12	61	5b
5-HT2C	>10,000c	22b	0.03b	4.8	4.1	48	32	3,500	6.0	0.9	4,700	132b
α1	7,100c	26b	1.2b	6.8	44	10	2.7	8.1	3.9	2.6	17	10
α2	1,600c	74a	1.2b	158	280	80	8	80	190	154	600	500
H1	>10,000d	30b	1.0b	3.1	0.08	3.4	5.2	19	440	4.6	260	8
M1	N/A	6,780b	8128b	1.4b	2.5b	>10,000b	>10,000b	120b	5,000	300b	>10,000b	1,500
M2	N/A	3,510b	4.5b	204b	622b	>10,000b	>10,000b	630b	N/A	>3,000b	>10,000b	N/A
M3	N/A	4,680b	4.67b	109b	126b	>10,000b	>10,000b	1,320b	2,692b	>1,300b	>10,000b	1,848b
M4	N/A	1,520b	5.09b	27b	350b	>10,000b	>10,000b	660b	N/A	>1,600b	>10,000b	N/A

Notes: Adapted with permission from Correll CU, From receptor pharmacology to improved outcomes: individualizing the selection, dosing, and switching of antipsychotics, Eur Psychiatry, 2010;25(Suppl 2):S12–S21, Copyright © 2010, Elsevier Masson SAS. All rights reserved.⁷⁹ Data represented as the equilibrium constant (Ki; nM), ie, nanomolar amount of the antipsychotic needed to block 50% of the receptors in vitro. Therefore, a lower number denotes stronger receptor affinity and binding.

a Partial agonism.

b Data from cloned human brain receptors.

c Data extracted from rat.

d Data extracted from guinea pig.

Abbreviations: AMI, amisulpride; ARI, aripiprazole; ASE, asenapine; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; PALI, paliperidone; PER, perphenazine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; N/A, not applicable.

Table 2 Possible isoforms of CYP involved in atypical antipsychotic drugs metabolism

Enzyme	Substrates	Inhibitors	Inductors
CYP1A2	Antipsychotics: clozapine,* olanzapine, asenapine, haloperidol Antidepressants: imipramine, amitriptyline, clomipramine, fluvoxamine, mirtazapine Methylxanthines: theophylline, caffeine Various drugs: paracetamol, R-warfarin, tacrine	Ciprofloxacin Fluvoxamine	Barbiturates Carbamazepine Phenytoin Rifampicin Tobacco
CYP3A4	Antipsychotics: clozapine,* risperidone, ziprasidone,^ sertindole, quetiapine, aripiprazole, asenapine, haloperidol Antidepressants: venlafaxine, clomipramine, citalopram, mirtazapine Benzodiazepines: diazepam, bromazepam Non-benzodiazepine anxiolytics: buspirone Antiepileptics: carbamazepine, felbamate, tiagabine Calcium antagonists: nifedipine, diltiazem, verapamil Various drugs: terfenadine, astemizole, cyclosporine, erythromycin, clarithromycin, tamoxifen, amiodarone, quinidine	Erythromycin Fluconazole Fluvoxamine Grapefruit juice Itraconazole Ketoconazole Nefazodone	Barbiturates Carbamazepine Felbamate# Hypericum Oxcarbazepine# Phenytoin Rifampicin Topiramate#
CYP2D6	Antipsychotics: risperidone, clozapine, olanzapine, aripiprazole, asenapine zuclopenthixol, haloperidol, thioridazine, perphenazine, fluphenazine Antidepressants: amitriptyline, clomipramine, imipramine, desipramine, fluvoxamine, nortriptyline, fluoxetine, paroxetine, fluvoxamine, citalopram, venlafaxine, mirtazapine, mianserin Opioids: codeine, dextromethorphan, tramadol β-blockers: metoprolol, timolol, pindolol, propranolol Antiarrhythmics: encainide, flecainide, propafenone Various drugs: debrisoquine, sparteine, phenformin	Asenapine° Fluoxetine Paroxetine Perphenazine Propafenone Quinidine Thioridazine	No known agent

Notes:

* Also metabolized via CYP2C19.

^ Also metabolized via aldehyde oxidase.

° Weak inhibitor.

# Weak enzymatic inductors.

Abbreviation: CYP, cytochrome P450.

Table 3 Side effects associated with atypical antipsychotics

Side effects	Amisulpride	Clozapine	Risperidone	Olanzapine	Quetiapine	Ziprasidone	Aripiprazole	Paliperidone	Asenapine
EPS	−/+	−	−/++	−/+	−	−/+	−/+	−/++	+
Tardive dyskinesia	+	−	?	−/+	−/+	?	−/+	?	−/+
Seizures	−	+++	?	−/+	−/+	?	−/+	?	−/+
Sedation	++	+++	+	+	+	?	−/+	+	+
NMS	+	+	+	?	?	?	?	+	?
Hypotension	+	−/++	+	+	+++	−/+	−/+	−/++	−/++
QTc	−/+	−	−/+	−	+++	−/+	−	−/+	−/+
Gastrointestinal (nausea, vomiting, constipation)	−/+	−/+	−/+	−	+	−/+	−	−/+	−
Anticholinergic	−	+++	−	+	+	−/+	−	−	−
Hematological	−	+++	−	−	−	−	−	−	−
Other effects	−/+	−/+ *	−/+	−/+	−/+	−/+	−/+	−/+	−/+
Diabetes	−	+	−/+	+ ?	−	−	−	−/+	−/+
Hypertriglyceridemia	−	+	−/+	+	−	−	−	−/+	−/+
Hepatic	−/+	−/+	−/+	−/+	−/+	−/+	−	−/+	+
Prolactin increase	+	−	−/++ ^	−	−	−	−/+	−/++ ^	−/+
Weight gain	−/+	+++	+	++	++	−/+	−	+	+

Notes:

* Polyserositis, acute interstitial nephritis, increased occurrence of infections, myocarditis;

^ dosage dependent;

− indicates no effect;

+ indicates mild effect;

−/+ indicates uncertain effect;

−/++ indicates probable dosage-dependent effect;

++ indicates moderate effect;

+++ indicates severe effect;

? indicates no conclusive evidence.

Abbreviations: EPS, extrapyramidal symptoms; NMS, neuroleptic malignant syndrome; QTc, corrected QT.

Table 4 Pharmacokinetic parameters of atypical antipsychotics

Drugs	Bioavailability (%)	Plasma half-life (hours)	Active metabolites	Dosage forms
Amisulpride	48	12–17	Yes	Capsules, tablets
Aripiprazole	87	48–68; dehydroaripiprazole: 46–75	Yes	Tablets, orally disintegrating tablets, liquid solution
Asenapine	35	24 In elderly patients approximately 30% higher than in younger adults.	Yes	Sublingual tablets
Clozapine	12–81	11–105	Yes	Tablets, orally disintegrating tablets
Olanzapine	80	20–70	Yes	Tablets, orally disintegrating tablets
Paliperidone extended release	28	23	No	Extended-release tablets
Quetiapine	5–13	7	Yes	Tablets, prolonged-release tablets
Risperidone	68	3–24	Yes	Tablets, orally disintegrating tablets, liquid solution
Risperidone long-acting		72–144 (3–6 days)	Yes	Long-acting injectable
Ziprasidone	59	4–10	No	Tablets, capsules

Table 5 Mean recommended dosages (mg/day) of some atypical antipsychotics in different diseases in the elderly (schizophrenia, Parkinson’s disease, and Alzheimer’s disease)

Drugs	Schizophrenia	Parkinson’s disease	Dementia (off-label use)
Amisulpride	200–400 mg	Insufficient evidence	Little evidence 200–400 mg
Aripiprazole	15–30 mg	Little evidence 10–15 mg	Little evidence 10–15 mg
Clozapine	50–150 mg	25–100 mg	25–100 mg
Olanzapine	10–20 mg	5–7.5 mg	5–7.5 mg
Paliperidone extended release	3–12 mg	3–6 mg	3–12 mg
Quetiapine	200–300 mg	25–200 mg	25–200 mg
Risperidone	2–3 mg	0.25–1 mg	0.25–2 mg

CorrellCUFrom receptor pharmacology to improved outcomes: individualizing the selection, dosing, and switching of antipsychoticsEur Psychiatry201025Suppl 2S12S2120620881

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