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 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, 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

• Although U.S. manufacturer recommends 6-month eye checks for cataracts, clinical experience suggests this may be unnecessary

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

Quetiapine: side effects How Drug Causes Side Effects

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

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

• By blocking muscarinic 1 receptors, it can cause dry mouth, constipation, and sedation

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

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

Notable Side Effects

✽ May increase risk for diabetes and dyslipidemia

✽ Dizziness, sedation

• Dry mouth, constipation, dyspepsia, abdominal pain, weight gain

• Tachycardia

• Orthostatic hypotension, usually during initial dose titration

• Theoretical risk of tardive dyskinesia

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

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

• Rare seizures

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

Weight Gain

• Many patients experience and/or can be significant in amount at effective antipsychotic doses

• Can become a health problem in some

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

Sedation

• Frequent and can be significant in amount

• Some patients may not tolerate it

• More than for some other antipsychotics, but never say always as not a problem in everyone

• Can wear off over time

• Can reemerge as dose increases and then wear off again over time

• Not necessarily increased as dose is raised

What to Do About Side Effects

• Wait

• Wait

• Wait

• Usually dosed twice daily, so take more of the total daily dose at bedtime to help reduce daytime sedation

• Start dosing low and increase slowly as side effects wear off at each dosing increment

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

• Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

QUETIAPINE: DOSING AND USE

Usual Dosage Range

• 400–800 mg/day in 1 (quetiapine XR) or 2 (quetiapine) doses for schizophrenia

• 400–800 mg/day in 1 (quetiapine XR) or 2 (quetiapine) doses for bipolar mania

• 300 mg once daily for bipolar depression

Dosage Forms

• Tablets 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg

• Extended-release tablets 50 mg, 150 mg 200 mg, 300 mg, 400 mg

How to Dose

• (According to manufacturer for quetiapine in schizophrenia): initial 25 mg/day twice a day; increase by 25–50 mg twice a day each day until desired efficacy is reached; maximum approved dose 800 mg/day

• In practice, can start adults with schizophrenia under age 65 with same doses as recommended for acute bipolar mania

• (According to manufacturer for quetiapine in acute bipolar mania): initiate in twice daily doses, totaling 100 mg/day on day 1, increasing to 400 mg/day on day 4 in increments of up to 100 mg/day; further dosage adjustments up to 800 mg/day by day 6 should be in increments of no greater than 200 mg/day

• Bipolar depression for quetiapine and quetiapine XR: once daily at bedtime; titrate as needed to reach 300 mg/day by day 4

• Quetiapine XR in schizophrenia and acute mania: initial 300 mg once daily, preferably in the evening; can increase by 300 mg/day each day until desired efficacy is reached; maximum approved dose 800 mg/day

• See also the Switching section below, after Pearls