Quick Reference Medication Facts By Terence A. Ketter, M.D, Po W. Wang, M.D.

General Facts

■ More aggressive initiation and higher final dosages are needed and tolerated in acute manic and mixed episodes compared with other illness phases.

■ Most agents are more effective at combating mood elevation compared with depressive symptoms, with the notable exceptions of lamotrigine, which does the opposite, and quetiapine, which has comparable efficacy for mood elevation and depression.

■ Combination therapy is common, but only a few two-drug combinations are supported by evidence.

■ Gradual titration and weighting dosage toward bedtime may help limit adverse effects.

■ Most common adverse effects involve the central nervous system and gastrointestinal system.

Mood Stabilizer Facts

■ All mood stabilizers have at least one boxed safety warning.

Lithium

■ A boxed safety warning is provided regarding risk of lithium toxicity that can occur at dosages close to therapeutic levels.

■ The U.S. Food and Drug Administration (FDA) has approved lithium monotherapy for acute mania and longer-term treatment in bipolar disorder patients, but as of early 2009, not for acute mixed episodes.

■ The FDA has approved lithium for combination therapy with olanzapine, risperidone, quetiapine, or aripiprazole for acute mania, and with quetiapine for longer-term treatment.

■ Lithium is effective in pure mania and psychotic mania, but less so in mixed episodes or dysphoric mania.

■ In treating acute mania, lithium is started with low divided doses (e.g., 300 mg two or three times a day) and increased, as necessary and tolerated, by 300 mg/day every 1–4 days.

■ Gradual titration can decrease risks of central nervous system, gastrointestinal, and other adverse effects.

■ Lithium serum concentrations are classically 0.8–1.2 mEq/L in acute mania monotherapy, but mean concentrations were only 0.70–0.82 mEq/L in combination therapy acute mania trials.

Divalproex

■ Boxed safety warnings are provided for divalproex regarding risks of 1) hepatotoxicity, 2)teratogenicity, and 3) pancreatitis.

■ Monotherapy FDA indications are provided for divalproex for acute manic (delayed- or extended-release formulation) and mixed (extended-release formulation) episodes.

■ The FDA has approved divalproex for combination therapy with olanzapine, risperidone, quetiapine, and aripiprazole for acute mania, and with quetiapine for longer-term treatment.

■ As of early 2009, divalproex lacked a monotherapy FDA indication for longerterm treatment in patients with bipolar disorder, but was commonly used for longer-term treatment (often in combination with other agents).

■ Divalproex has a broader efficacy spectrum than lithium, with greater benefits in mixed episodes and dysphoric mania.

■ In treating acute mania, divalproex is started at 20–30 mg/kg/day (single daily dose with extended release), and the dosage is adjusted as necessary and tolerated.

■ Contemporary valproate serum concentrations are 85–125 µg/mL (with more adverse effects above 100 µg/mL) for acute mania monotherapy, but mean concentrations were only 64–104 µg/mL in combination therapy acute mania trials.

Carbamazepine

■ Boxed safety warnings are provided for carbamazepine regarding the risks of serious dermatological reactions and the HLA-B*1502 allele, as well as aplastic anemia (16/million patient-years) and agranulocytosis (48/million patient-years).

■ Carbamazepine has received a FDA monotherapy indication for acute manic and mixed episodes.

■ As of early 2009, carbamazepine lacked FDA indications for combination therapy and longer-term treatment in patients with bipolar disorder.

■ Carbamazepine has a broader efficacy spectrum than lithium, with greater benefits in mixed episodes and dysphoric mania.

■ In treating acute mania, carbamazepine should be started with low divided doses (e.g., 200 mg twice a day) and increased, as necessary and tolerated, by 200 mg/day every 1–4 days.

■ Gradual titration can decrease the risk of central nervous system and other adverse effects.

■ Therapeutic acute mania serum concentrations are not yet established, so dosage should be increased gradually until efficacy is attained, adverse effects supervene, or serum concentration exceeds 12 µg/mL.

■ Metabolic induction decreases concentrations of multiple medications (including carbamazepine itself, but not lithium), potentially decreasing efficacy of divalproex, lamotrigine, and second-generation antipsychotics, as well as other agents. Controlled studies failed to demonstrate additional benefit from adding risperidone or olanzapine to carbamazepine in acute mania.

■ Patients should be monitored clinically (and with laboratories as indicated) for blood dyscrasia.

Lamotrigine

■ A boxed safety warning is provided for lamotrigine regarding the risk of rare, serious rashes requiring hospitalization, which have included Stevens- Johnson syndrome, that require hospitalization.

■ Lamotrigine has been proven ineffective in acute mania, but has a bipolar longer-term monotherapy treatment FDA indication and possible modest efficacy in acute bipolar depression.

■ Gradual titration (25 mg/day for 2 weeks, 50 mg/day for 2 weeks, 100 mg/day for 1 week, and then 200 mg/day) is necessary to attenuate the risk of rash. Titration kits facilitate gradual initiation.

■ The FDA-recommended lamotrigine dosage is 200 mg/day, but dosages as high as 400–500 mg/day may be tolerated and yield benefit.

■ Lamotrigine dosages must be halved with divalproex and doubled with carbamazepine because of pharmacokinetic interactions.

■ Final lamotrigine dosages with concurrent hormonal contraceptives, compared to without, may need to be higher because of a pharmacokinetic interaction.

Second-Generation Antipsychotic Facts

■ All antipsychotics have boxed safety warnings regarding the risk of increased mortality in older adults with dementia-related psychosis.

■ All second-generation antipsychotics have safety warnings regarding the risks of hyperglycemia and diabetes mellitus, and require baseline assessment and longitudinal monitoring for these problems.

Clozapine

■ Boxed warnings are provided regarding risks of 1) agranulocytosis, 2) seizures, 3) myocarditis, 4) other adverse cardiovascular and respiratory effects, and 5) increased mortality in older adults with dementia-related psychosis (an antipsychotic class warning).

■ Clozapine lacks an FDA indication for bipolar disorder (as of early 2009).

■ Clozapine is a possible option in treatment-resistant bipolar disorder.

■ In treating acute mania, clozapine should be started at a low bedtime dose (25 mg/day) and gradually increased (daily by 25 mg/day) to attenuate adverse effects.

■ Final dosages of clozapine in bipolar disorder are commonly below 300 mg/day, lower than in schizophrenia.

■ Gradual titration can decrease the risk of orthostasis and other adverse effects.

■ Adverse effects (e.g., agranulocytosis, weight gain, sedation, seizures) limit the utility of clozapine.

■ Patients taking clozapine should have clinical and blood monitoring for agranulocytosis.

Olanzapine

■ The FDA has approved olanzapine for monotherapy and adjunctive (added to lithium or valproate) treatment of acute manic and mixed episodes, and combined with fluoxetine for acute bipolar depression.

■ Olanzapine has received a monotherapy FDA indication for longer-term treatment in patients with bipolar disorder.

■ A rapid-acting intramuscular formulation of olanzapine has a FDA indication for agitation in acute mania.

■ In treating acute mania, oral olanzapine formulations should be started at 10–15 mg at bedtime and may be increased rapidly to 20 mg at bedtime.

■ Olanzapine is slightly more effective than divalproex but has slightly more acute adverse effects (e.g., sedation, weight gain).

■ Chronic olanzapine adverse effects (e.g., sedation, weight gain, metabolic problems) may ultimately require discontinuation.

Risperidone

■ The FDA has approved risperidone for monotherapy and adjunctive (added to lithium or valproate) treatment of acute manic and mixed episodes.

■ As of early 2009, risperidone lacked a FDA indication for longer-term treatment in patients with bipolar disorder.

■ As of early 2009, the long-acting injectable formulation of risperidone had FDA approval for schizophrenia but not for bipolar disorder.

■ In treating acute mania, risperidone should be started at 2–3 mg at bed-time and increased as necessary and tolerated daily by 1 mg/day to as high as 6 mg/day.

■ Higher risperidone dosages increase the risk of extrapyramidal adverse effects.

Quetiapine

■ The FDA has approved quetiapine for acute manic episodes (immediate and extended-release formulations) and acute mixed episodes (extended-release formulation), both as monotherapy and as adjunctive (added to lithium or valproate) treatment.

■ Monotherapy efficacy has been demonstrated for acute mania not only at 3 weeks (as with other agents) but also at 12 weeks.

■ Quetiapine immediate- and extended-release formulations have received FDA approval for adjunctive therapy (added to lithium or valproate) in longer-term treatment in patients with bipolar disorder.

■ In treating acute mania, quetiapine immediate-release formulation should be started at 100 mg/day (label recommends divided doses, but clinically the daily dosage is commonly taken at bedtime) and increased daily, as necessary and tolerated, by 100 mg/day to as high as 800 mg/day. In acute mania, quetiapine extended-release formulation is started at 300 mg at bedtime, increased the next day to 600 mg at bedtime, and thereafter dosed between 400 and 800 mg at bedtime.

■ In treating acute bipolar depression, quetiapine immediate- and extended- release formulations are commonly initiated at 50 mg at bedtime, and increased by 50-100 mg, as necessary and tolerated, with final dosages of 300 or 600 mg/day in controlled trials, but commonly lower in practice.

■ Gradual titration can decrease risks of sedation, orthostasis and other adverse effects.

Ziprasidone

■ The FDA has approved ziprasidone monotherapy for acute manic and mixed episodes.

■ As of early 2009, the FDA had not approved ziprasidone for combination /therapy, acute bipolar depression, and longer-term treatment in patients with bipolar disorder.

■ A rapid-acting intramuscular ziprasidone formulation has been indicated for agitation in schizophrenia but not (as of early 2009) for acute mania.

■ Ziprasidone monotherapy was ineffective in controlled trials in acute bipolar depression.

■ In treating acute mania, ziprasidone should be started with at least 80 mg/day and then abruptly increased (e.g., to 160 mg/day) to attenuate the risk of akathisia emerging on lower dosages. Some patients may benefit from dosages over the recommended 160 mg/day maximum (e.g., 240–320 mg/day). The label recommends two divided doses, but single daily doses with dinner or at bedtime with a snack may be more feasible.

■ Taking ziprasidone with food is crucial, as this doubles absorption.

■ Compared with olanzapine, risperidone, and quetiapine, ziprasidone has less risk of sedation and weight gain but more risk of akathisia.

■ Adjunctive lorazepam may decrease problems with akathisia.

Aripiprazole

■ The FDA has approved aripiprazole for monotherapy and adjunctive (added to lithium or valproate) treatment for acute manic and mixed episodes.

■ Aripiprazole has received a FDA monotherapy indication for longer-term bipolar disorder treatment.

■ A rapid-acting intramuscular formulation of aripiprazole has been indicated for agitation in acute manic and mixed episodes.

■ Aripiprazole monotherapy was ineffective in controlled trials in acute bipolar depression.

■ In treating acute mania, oral formulations of aripiprazole should be started at 15 mg once daily and, if necessary, increased to 30 mg once daily.

■ Compared with olanzapine, risperidone, and quetiapine, aripiprazole has less risk of sedation and weight gain but more risk of akathisia.

■ Adjunctive lorazepam may decrease problems with akathisia.

First-Generation Antipsychotic Facts

■ First-generation antipsychotics have been superseded by second-generation antipsychotics, which appear better tolerated and have more evidence of efficacy in bipolar disorder.

■ All antipsychotics have a boxed safety warning regarding the risk of increased mortality in older adults with dementia-related psychosis.

■ The utility of chlorpromazine, the only first-generation agent with an acute mania indication, is limited by sedation and hypotension.

■ Haloperidol has substantial contemporary evidence of acute antimanic efficacy when used as monotherapy or when combined with lithium or divalproex.

Newer-Anticonvulsant Facts

Oxcarbazepine

■ Although lacking any FDA bipolar disorder indications, oxcarbazepine is the only newer anticonvulsant with evidence of possible efficacy in acute mania.

Gabapentin, Topiramate, Tiagabine, Levetiracetam, Zonisamide

■ Gabapentin and topiramate monotherapy have been proven ineffective or lack evidence of efficacy in acute mania.

■ Some newer anticonvulsants may have utility in comorbid conditions (e.g., anxiety disorders, eating disorders, alcohol use disorders).

Adjunctive Antidepressant Facts

■ Adjunctive fluoxetine (combined with olanzapine) is the only antidepressant FDA-approved for acute bipolar depression, but use of this combination is complicated by sedation and weight gain.

■ No adjunctive antidepressant has FDA approval for longer-term treatment of bipolar depression.

■ Adjunctive antidepressant efficacy is controversial, and tolerability (switch risk) may be problematic, particularly with venlafaxine and tricyclic antidepressants.

■ If the optimized lithium serum concentration is less than 0.8 mEq/L, then an adjunctive antidepressant may yield benefit.

Other Medication Facts

Adjunctive Thyroid Hormones

■ The FDA has not indicated adjunctive thyroid hormones for bipolar disorder.

■ Limited data suggest that adjunctive (most often added to antidepressants) L-triiodothyronine (T3) in physiological dosages may accelerate treatment response in nonrefractory depression and enhance treatment response in treatment-resistant depression.

■ Limited data suggest that L-thyroxine (T4) in supraphysiological dosages may yield benefit in treatment-resistant rapid-cycling bipolar disorder.

Adjunctive Pramipexole

■ Although adjunctive pramipexole has not received a FDA bipolar indication, two small controlled trials have suggested adequate efficacy and tolerability in acute bipolar depression.

■ Pramipexole has risks of nausea and sedation, and it may destabilize mood.

■ To enhance tolerability in treating acute bipolar depression, pramipexole should be started at 0.125 mg/day at bedtime and increased every 4 days, as necessary and tolerated, by 0.125 mg/day to a target range of 1.0–2.0 mg/day, with a maximum of 4.5 mg/day.

Adjunctive Modafinil

■ Adjunctive modafinil has received no FDA bipolar indication, but a controlled trial suggested adequate efficacy and tolerability in acute bipolar depression.

■ Modafinil may cause rare serious rash; may destabilize mood; and modestly induces cytochrome P450 enzymes 3A4, 2B6, and 1A2.

■ In treating acute bipolar depression, modafinil should be started at 100 mg each morning and increased weekly, as necessary and tolerated, by 100 mg/day to as high as 200–400 mg/day.

Consulted Sources:

- Handbook of Diagnosis and Treatment of Bipolar Disorders by Terence A. Ketter, M.D., Appendix B