If It Doesn’t Work

• Try one of the other atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, iloperidone, asenapine, amisulpride, lurasidone)

• If 2 or more antipsychotic monotherapies do not work, consider clozapine

• Some patients may require treatment with a conventional antipsychotic

• If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

• Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

• Consider initiating rehabilitation and psychotherapy such as cognitive remediation

• Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

• Valproic acid (valproate, divalproex, divalproex ER)

• Other mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

• Lithium

• Benzodiazepines

Tests

• Baseline EKG, serum potassium, and serum magnesium measurements

• EKG should be repeated upon reaching steady state about 3 weeks after treatment initiation or upon reaching 16 mg/day, at 3 months, and then every 3 months for the duration of treatment

• EKG is recommended prior to and after any dose increase as well as after addition of any drug that can change sertindole concentration (e.g., CYP450 2D6 or 3A4 inhibitors)

Before starting an atypical antipsychotic

✽ Weigh all patients and track BMI during treatment

• Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

✽ Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

• Determine if the patient is

• overweight (BMI 25.0–29.9)

• obese (BMI >30)

• has pre-diabetes (fasting plasma glucose 100–125 mg/dL)

• has diabetes (fasting plasma glucose >126 mg/dL)

• has hypertension (BP >140/90 mm Hg)

• has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

• Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic

✽ BMI monthly for 3 months, than 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

• Should check blood pressure during titration and early maintenance treatment

SERTINDOLE: SIDE EFFECTS

How Drug Causes Side Effects

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

• 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 increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown

Notable Side Effects

✽ Orthostatic hypotension

• Dizziness, dry mouth, nasal congestion

• Weight gain, peripheral edema, decreased ejaculatory volume

✽ May increase risk for diabetes and dyslipidemia

• Rare tardive dyskinesia (much reduced risk compared to conventional antipsychotics)

Life-Threatening or Dangerous Side Effects

• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

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

• Rare neuroleptic malignant syndrome (much reduced risk compared to conventional antipsychotics)

• Rare seizures

Weight Gain

• Many experience and/or can be significant in amount

• May be less than for some antipsychotics, more than for others

Sedation

• Reported but not expected

What to Do About Side Effects

• Wait

• Wait

• Wait

• Anticholinergics may reduce motor side effects when present

• 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

SERTINDOLE: DOSING AND USE

Usual Dosage Range

• 12–20 mg/day

Dosage Forms

• Tablet 4 mg, 12 mg, 16 mg, 20 mg

How to Dose

• Initial 4 mg/day; increase by 4 mg every 4–5 days; maximum dose generally 24 mg/day

Dosing Tips

• A starting dose of 8 mg or a rapid increase in dose significantly increase risk of orthostatic hypotension

• Sertindole should be discontinued if QTc interval of more than 500 msec is observed during treatment

Overdose

• Fatalities have been reported; sedation, slurred speech, tachycardia, hypotension, transient QTc prolongation; torsade de pointes

Long-Term Use

• Not studied, but long-term maintenance treatment is often necessary for schizophrenia

Habit Forming

• No

How to Stop

• Down-titration, especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

• Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

• Terminal half-life approximately 3 days

• Extensively metabolized by CYP450 2D6 and 3A

Drug Interactions

• May increase effects of antihypertensive agents

• May antagonize levodopa, dopamine agonists

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

• Inhibitors of CYP450 2D6 (e.g., paroxetine, fluoxetine, duloxetine, quinidine) may significantly increase plasma levels of sertindole and require a dosage reduction of sertindole

• Inhibitors of CYP450 3A (e.g., nefazodone, fluvoxamine, fluoxetine, ketoconazole) can increase plasma levels of sertindole and concomitant use of these agents with sertindole is contraindicated