Monitoring after starting an atypical antipsychotic

✽ BMI monthly for 3 months, then quarterly

• Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

• Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% initial weight

• Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

✽ Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

• EKGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

• Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

• Patients with low white blood cell count (WBC) or history of drug-induced leucopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and amisulpride should be discontinued at the first sign of decline of WBC in the absence of other causative factors

AMISULPRIDE: SIDE EFFECTS

How Drug Causes Side Effects

• By blocking dopamine 2 receptors in the striatum, it can cause motor side effects, especially at high doses

• By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

• Mechanism of weight gain and possible increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown

Notable Side Effects

✽ Extrapyramidal symptoms

✽ Galactorrhea, amenorrhea

✽ Atypical antipsychotics may increase the risk for diabetes and dyslipidemia, although the specific risks associated with amisulpride are unknown

• Insomnia, sedation, agitation, anxiety

• Constipation, weight gain

• Rare tardive dyskinesia

Life-Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome

• Rare seizures

• Dose-dependent QTc prolongation

• Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis

Weight Gain

• Occurs in significant minority

Sedation

• Many experience and/or can be significant in amount, especially at high doses

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

• For motor symptoms, add an anticholinergic agent

• Take more of the dose at bedtime to help reduce daytime sedation

• Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

• Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

• Benztropine or trihexyphenidyl for motor side effects

• Many side effects cannot be improved with an augmenting agent

AMISULPRIDE: DOSING AND USE

Usual Dosage Range

• Schizophrenia: 400–800 mg/day in 2 doses

• Negative symptoms only: 50–300 mg/day

• Dysthymia: 50 mg/day

Dosage Forms

• Different formulations may be available in different markets

• Tablet 50 mg, 100 mg, 200 mg, 400 mg

• Oral solution 100 mg/mL

How to Dose

• Initial 400–800 mg/day in 2 doses; daily doses above 400 mg should be divided in 2; maximum generally 1200 mg/day

• See also the Switching section below, after Pearls

Dosing Tips

✽ Efficacy for negative symptoms in schizophrenia may be achieved at lower doses, while efficacy for positive symptoms may require higher doses

• Patients receiving low doses may only need to take the drug once daily

✽ For dysthymia and depression, use only low doses

✽ Dose-dependent QTc prolongation, so use with caution, especially at higher doses (>800 mg/day)

✽ Amisulpride may accumulate in patients with renal insufficiency, requiring lower dosing or switching to another antipsychotic to avoid QTc prolongation in these patients

• Treatment should be suspended if absolute neutrophil count falls below 1,000/mm³

Overdose

• Sedation, coma, hypotension, extrapyramidal symptoms

Long-Term Use

• Amisulpride is used for both acute and chronic schizophrenia treatment

Habit Forming

• No

How to Stop

• See Switching section of individual agents for how to stop amisulpride

• Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

• Elimination half-life approximately 12 hours

• Excreted largely unchanged

Drug Interactions

• Can decrease the effects of levodopa, dopamine agonists

• Can increase the effects of antihypertensive drugs

• CNS effects may be increased if used with a CNS depressant

• May enhance QTc prolongation of other drugs capable of prolonging QTc interval

• Since amisulpride is only weakly metabolized, few drug interactions that could raise amisulpride plasma levels are expected

Other Warnings/Precautions

• Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

• If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

• Because amisulpride may dose-dependently prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

• Because amisulpride may dose-dependently prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

• Use only with caution if at all in Parkinson’s disease or Lewy body dementia, especially at high doses

Do Not Use

• If patient has pheochromocytoma

• If patient has prolactin-dependent tumor

• If patient is pregnant or nursing

• If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide; thioridazine; selected antiarrhythmics such as quinidine, disopyramide, amiodarone, and sotalol; selected antibiotics such as moxifloxacin and sparfloxacin)

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

• If patient is taking cisapride, intravenous erythromycin, or pentamidine

• In children

• If there is a proven allergy to amisulpride

AMISULPRIDE: SPECIAL POPULATIONS

Renal Impairment

• Use with caution; drug may accumulate

• Amisulpride is eliminated by the renal route; in cases of severe renal insufficiency, the dose should be decreased and intermittent treatment or switching to another antipsychotic should be considered

Hepatic Impairment

• Use with caution, but dose adjustment not generally necessary

Cardiac Impairment

• Amisulpride produces a dose-dependent prolongation of QTc interval, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amisulpride

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid amisulpride in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure