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% of 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 those 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 suspected hematologic abnormalities may require a white blood cell count before initiating treatment

• Monitor liver function tests in patients with established liver disease

• Should check blood pressure in the elderly before starting and for the first few weeks of treatment

• 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 zotepine should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Zotepine: side effects How Drug Causes Side Effects

• By blocking alpha 1 adrenergic receptors, it can cause dizziness, sedation, and hypotension

• By blocking histamine 1 receptors in the brain, it can cause sedation and weight gain

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

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

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

Notable Side Effects

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

• Agitation, anxiety, depression, asthenia, headache, insomnia, sedation, hypo/hyperthermia

• Constipation, dry mouth, dyspepsia, weight gain

• Tachycardia, hypotension, sweating, blurred vision

• Rare tardive dyskinesia

• Dose-related hyperprolactinemia

Life-Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome

• Rare seizures (risk increases with dose, especially over 300 mg/day)

• Blood dyscrasias

• Dose-dependent QTc prolongation

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

Weight Gain

• Many experience and/or can be significant in amount

Sedation

• Many experience and/or can be significant in amount

What to Do About Side Effects

• Wait

• Wait

• Wait

• 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

• Reduce the dose

• Switch to a first-line atypical antipsychotic

Best Augmenting Agents for Side Effects

• Benztropine or trihexyphenidyl for motor side effects

• Sometimes amantadine can be helpful for motor side effects

• Benzodiazepines may be helpful for akathisia

• Many side effects cannot be improved with an augmenting agent

ZOTEPINE: DOSING AND USE

Usual Dosage Range

• 75–300 mg/day in 3 divided doses

Dosage Forms

• Tablet 25 mg, 50 mg, 100 mg

How to Dose

• Initial 75 mg/day in 3 doses; can increase every 4 days; maximum 300 mg/day in 3 doses

Dosing Tips

• Slow initial titration can minimize hypotension

• No formal studies, but some patients may do well on twice daily dosing rather than 3 times daily dosing

✽ Dose-related QTc prolongation, so use with caution, especially at high doses

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

Overdose

• Can be fatal, especially in mixed overdoses; seizures, coma

Long-Term Use

• Can be used to delay relapse in long-term treatment of schizophrenia

Habit Forming

• No

How to Stop

• Slow down-titration (over 6 to 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

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

• If antiparkinson agents are being used, they should be continued for a few weeks after zotepine is discontinued

Pharmacokinetics

• Metabolized by CYP450 3A4 and CYP450 1A2

• Active metabolite norzotepine

Drug Interactions

• Combined use with phenothiazines may increase risk of seizures

• Can decrease the effects of levodopa, dopamine agonists

• Epinephrine may lower blood pressure

• May interact with hypotensive agents due to alpha 1 adrenergic blockade

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

• Plasma concentrations increased by diazepam, fluoxetine

• Zotepine may increase plasma levels of phenytoin

• May increase risk of bleeding if used with anticoagulants

• Theoretically, dose may need to be raised if given in conjunction with CYP450 1A2 inducers (e.g., cigarette smoke)

• Theoretically, dose may need to be lowered if given in conjunction with CYP450 1A2 inhibitors (e.g., fluvoxamine) in order to prevent dangers of dose-dependent QTc prolongation

• Theoretically, dose may need to be lowered if given in conjunction with CYP450 3A4 inhibitors (e.g., fluvoxamine, nefazodone, fluoxetine) in order to prevent dangers of dose-dependent QTc prolongation