Bipolar Disorder

Question 1

Which treatments are FDA approved adjunctive treatments in bipolar II depression?

Answer 1

Quetiapine
Adults: 50 mg orally once a day on day 1, then 100 mg once daily on day 2, then 200 mg once daily on day 3, then 300 mg once daily on day 4, all doses given at bedtime, then maintenance dose 300 mg/day; patients requiring higher doses should receive 400 mg on day 5, increased to 600 mg on day 8

Question 2

Which treatment is FDA approved for acute mania with agitation?

Answer 2

Olanzapine
Adults: Initial, 10 mg IM; lower dose of 5 mg or 7.5 mg may be used if indicated; usual effective dosage range is 2.5 mg to 10 mg. Subsequent doses are up to 10 mg IM; maximum of three 10 mg doses given 2 to 4 hours apart; monitor for orthostatic hypotension prior to the administration of repeated doses

Question 3

What state do most patients with bipolar disorder spend their time?

Answer 3

Depressed state - 70-80%

Bipolar II - depressed state even greater time spent in depressed state

Question 4

What are the 4 A’s of mixed features in bipolar disorder? These can be applied to hypomania, depression, and mania.

Answer 4

The 4 A’s: Anxiety, agitation, anger, attentional disturbance - distractibility. These are highly indicative of mixed features, which affects 1/3 to 1/2 of patients with depression. Antidepressants will not likely work in these patients. In fact, antidepressant resistance is a predictor of bipolar disorder.

Question 5

What percent of patients with bipolar disorder also have metabolic syndrome?

Answer 5

A little over 50% of patients with bipolar disorder have elevated triglycerides, high waist circumference (abdominal fat), hyperglycemia, HTN

Question 6

What treatments are FDA approved for bipolar depression?

Answer 6

Cariprazine, lurasidone, quetiapine, lumateperone, olanzapine/fluoxetine combination

Question 7

What treatments are FDA approved for acute mania?

Answer 7

Lithium, divalproex, carbamazepine, aripiprazole, asenapine, cariprazine, haloperidol, olanzapine, quetiapine, ziprasidone, risperidone, and combination treatment with either aripiprazole, asenapine, olanzapine, quetiapine, or risperidone and lithium or divalproex

Question 8

What treatments are FDA approved for maintenance in bipolar disorder?

Answer 8

Lithium, aripiprazole (oral and LAI), asenapine, lamotrigine, quetiapine (adj.), olanzapine, risperidone (LAI)

Question 9

What is the ideal duration of continuing adjunctive treatment for an acute manic episode in bipolar I patients in remission?

Answer 9

Yatham LN, Beaulieu S, Schaffer A, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer
following remission of a manic episode: A CANMAT randomized double-blind trial. Molecular Psychiatry 2016; 21(8):1050-1056 showed that recently remitted manic patients conferred remission benefits when continuing adj. antipsychotic treatment through 24 weeks vs. stopping immediately, but did not confer benefits through 52 weeks vs 24 weeks, and experienced greater weight gain through 52 weeks vs. 24 weeks.

Question 10

What is the DSM V definition of rapid cycling?

Answer 10

Presence of at least 4 mood episodes in the prior 12 months that meet criteria for mania, hypomania or major depression, excluding substance-induced episodes (e.g. stimulants, steroids, antidepressants).

Question 11

What is lithium’s efficacy in rapid cycling in bipolar disorder vs. non-rapid cycling subsets of bipolar disorder?

Answer 11

According to Step-BD analysis, an NIHM funded study (Systematic Treatment Enhancement Program) circa 2004, patient’s with RC cycling had a comparable response to lithium in terms of time spent ill as compared to patients with non RC subtypes of bipolar disorder. RC has a lifetime freq of 15.6% and 12 month rates of 20-38%; gender and bipolar II associations are not clear.

Question 12

What are 6 poor prognostic factors in bipolar disorder?

Answer 12

Rapid cycling, ≥20 lifetime mood episodes; comorbid anxiety; substance use disorders; h/o physical or sexual abuse; onset prior to age 19

Question 13

What are the success rates of lithium, divalproex, and carbamazepine on rapid cycling (RC) bipolar disorder in “Clinical Correlates of Sustained Response to Individual Drugs” study? (Post et al. 2016)

Answer 13

i. Lithium 49.3%
ii. Carbamazepine 39.9%
iii. Divalproex 34.8%

Question 14

In the study by Post et al. 2016, “Clinical Correlates of Sustained Response to Individual Drugs”, what insights were there regarding antidepressant efficacy in RC bipolar disorder?

Answer 14

Antidepressants had low success rates overall across all patients, especially in those with comorbid anxiety compared to those without anxiety (10.4% vs. 20.9%, p=.013).

Question 15

What is the drug interaction between lamotrigine and valproate, and dosing recommendation?

Answer 15

Lamotrigine dose should be reduced by perhaps 50% if used with valproate, as valproate inhibits metabolism of lamotrigine and raises lamotrigine plasma levels, theoretically increasing the risk of rash

Question 16

What medications does valproate inhibit the metabolism of, and thus raise levels?

Answer 16

Valproate inhibits metabolism of ethosuximide, phenobarbital, and phenytoin, and can thus increase their plasma levels.
No likely pharmacokinetic interactions of valproate with lithium or atypical antipsychotics

Question 17

Why should ammonia levels be drawn in patients taking valproate who present with lethargy, vomiting, or mental status change?

Answer 17

Reports of hypothermia and hyperammonemia with or without encephalopthay in patients taking topiramate combined with valproate, though this is not due to a pharmacokinetic interaction; in patients who develop unexplained lethargy, vomiting, or change in mental status, an ammonia level should be measured

Question 18

What are the notable side effects of valproate?

Answer 18

• Sedation, dose-dependent tremor, dizziness
• Abdominal pain, nausea, vomiting, diarrhea, reduced appetite, constipation, dyspepsia, weight gain
• Ataxia, asthenia, headache
• Alopecia (unusual)
• Polycystic ovaries (controversial)
• Hyperandrogenism, hyperinsulinemia, lipid dysregulation (controversial)
• Decreased bone mineral density (controversial)

Question 19

What is the bioavailability of Depakote DR vs. Depakote ER?

Answer 19

extended-release valproate is only about 80% as bioavailable as immediate-release valproate, producing plasma drug levels 10–20% lower than with immediate-release valproate
Thus, extended-release valproate is dosed approximately 8–20% higher when converting patients to the ER formulation

Question 20

Drug interactions with valproate - what medications raise valproate levels?

Answer 20

Aspirin may inhibit metabolism of valproate and increase valproate plasma levels.
Plasma levels of valproate may also be increased by felbamate, chlorpromazine, fluoxetine, fluvoxamine, topiramate, cimetidine, erythromycin, and ibuprofen

Question 21

What medications lower valproate levels?

Answer 21

Plasma levels of valproate may be lowered by carbamazepine, phenytoin, ethosuximide, phenobarbital, rifampin

Question 22

What signs of hepatotoxicity require immediate attention?

Answer 22

malaise, weakness, lethargy, facial edema, anorexia, vomiting, yellowing of the skin and eyes

Question 23

What is the pharmacodynamic interaction or result between topiramate and divalproex?

Answer 23

The exact mechanism is unknown, but there have been ~7 case reports of stuporous encephalopathy and hyperammonemia (levels ranging from 62 to 146 mcmol/L) when valproic acid was added to a topiramate regimen or beginning a combination of topiramate and valproic acid. Drug discontinuation resulted in recovery (ranging from 3-10 days) and ammonia levels decreased WNL (~3 days).

Question 24

What is the lamotrigine titration schedule for patients with bipolar disorder (monotherapy; not on an inhibitor like valproate or an inducer)?

Answer 24

Week 1 and 2: 25 mg/day
Week 3 and 4: 50 mg/day
week 5: 100 mg/day
week 6: 200 mg/day

Question 25

When should the lamotrigine titration start over again (how many days missed)?

Answer 25

After 5 days of being off of lamotrigine, the taper should begin again at 25 mg/day due to the risk of rash.

Question 26

What are patient counseling points when starting lamotrigine?

Answer 26

Advise patient to avoid new medications, foods, or products during the first 3 months of lamotrigine treatment in order to decrease the risk of unrelated rash; patient should also not start lamotrigine within 2 weeks of a viral infection, rash, or vaccination