1. Pharmacologic Considerations in the Treatment of Bipolar Affective Disorder
Presented by: Ann M. Wheeler, PharmD, BCPP
Date: 11/3/2016 1

2. Learning Objectives Disclosures and Learning Objectives
Be able to recognize common adverse effects of mood stabilizers
Be able to identify common drug interactions associated with mood stabilizers
Be able to discuss differences between the available mood stabilizers
Disclosures: Dr. Ann Wheeler has nothing to disclose. 2

3. Pharmacologic Treatment of Bipolar Disorder
Review treatment guideline recommendations
Review properties of mood stabilizers including:
adverse effects
drug interactions
dosing
monitoring parameters
comparative cost 3

4. Guideline Recommendations
Acute Treatment
Manic or mixed episodes
Lithium or valproate + antipsychotic (limited duration)
For less ill, monotherapy is recommended with lithium, valproate, or an antipsychotic
Severely ill patients may require short-term use of a benzodiazepine as adjunctive treatment
For mixed episodes, valproate may be preferred over lithium
Antidepressant should be tapered and discontinued if possible
Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic
Breakthrough episode: optimize maintenance medication

5. Guideline Recommendations
Acute Treatment
Depressive episodes
Lithium or lamotrigine
Antidepressant monotherapy is not recommended
ECT is a reasonable alternative for severe illness, suicidality, psychosis, or pregnancy
Breakthrough episode: optimize maintenance medication
Second line:
Addition of lamotrigine or bupropion
Depressive episodes with psychotic features usually require adjunctive treatment with an antipsychotic medication

6. Guideline Recommendations
Acute Treatment
Rapid Cycling
Identify and treat medical conditions that may contribute to cycling (e.g. hypothyroidism, substance use)
Taper antidepressant if possible
Initiate treatment with lithium or valproate. Valproate generally more effective in rapid cycling

7. Guideline Recommendations
Maintenance Treatment
Maintenance Treatment is recommended following a manic episode and should be strongly considered in those with bipolar II disorder.
Best evidence with lithium and valproate
Alternatives include lamotrigine, carbamazepine or oxcarbazepine
Assess need for ongoing antipsychotic treatment; antipsychotics should be discontinued unless they are required for control of persistent psychosis. Data supports mood stabilizers over maintenance atypical antipsychotics.
Maintenance ECT may also be considered

8. NICE Guideline Recommendations
Prior to Acute Episode
Acute Episode
Maintenance Phase
Nothing
Lithium
Haloperidol, olanzapine, quetiapine, risperidone
Check Li level and optimize treatment. Consider adding AP.
Fluoxetine + olanzapine or quetiapine
Alternatives: olanzapine or lamotrigine
Check Li level and optimize treatment. If maximized, add alternative from above.
*Lithium*
If ineffective, consider adding valproate
If poorly tolerated or CI, consider valproate or olanzapine; or quetiapine (depression)
Acute Mania
Acute Depression

9. Treatment Recommendations
Acute Mania
Acute Depression
Rapid Cycling
Maintenance
Stop antidepressants (or inciting agents)
Use a mood stabilizer first:
Lithium, Valproate
Carbamazepine, Oxcarbazepine
If psychosis occurs, use an antipsychotic:
Olanzapine, Risperidone, Asenapine
Aripiprazole, Ziprasidone, Quetiapine
Consider short -term use of a benzodiazepine
Start with lithium or lamotrigine (alternatives include: quetiapine, olanzapine/fluoxetine)
“Antidepressant monotherapy is not recommended.”
Add lamotrigine or bupropion if needed
ECT if severely depressed or pregnant
CBT and Behavioral Activation
Identify and treat comorbid contributors such as hypothyroidism or drug/alcohol use
Taper contributing medications
Valproate often preferred (alternatives include carbamazepine, lithium, or lamotrigine)
Combination treatment often required
Continue agent that helped in acute phase
Taper benzodiazepines
Taper antipsychotics when mood stable
Lamotrigine and lithium may help ward off depression
Lithium may be best at warding off mania
Valproate, olanzapine, carbamazepine, oxcarbazepine also evidence-based

10. Lithium

11. Lithium Adverse Effects
Common: Leukocytosis (most patients), Polyuria/polydipsia (30- 50%), Dry mouth (20-50%), Hand tremor (45% initially, 10% after 1 year of treatment), Confusion (40%), Decreased memory (40%), Headache (40%), Muscle weakness (30% initially, 1% after 1 year of treatment), Electrocardiographic (ECG) changes (20-30%), Nausea, vomiting, diarrhea (10-30% initially, 1-10% after 1-2 years of treatment), Hyperreflexia (15%), Muscle twitch (15%), Vertigo (15%)
Less common: Extrapyramidal symptoms, goiter (5%), Hypothyroidism (1-4%), Acne (1%), Hair thinning (1%)
Black Box Warning: Toxicity with higher plasma concentrations
Pregnancy Category D
Toxicity is closely related to serum lithium concentrations and may occur at dosages close to therapeutic levels; monitor therapy by measuring serum lithium

12. Lithium Drug Interactions
Caution with medications known to prolong the QT interval
Caution with other medications that may increase serotonin levels
Caution with medications/conditions that affect renal clearance (e.g. thiazides, pregnancy)

13. Lithium Dosing Immediate release: 900-2400 mg/day PO divided q6-8hr
Extended release: mg/day PO divided q12hr
Lower initial dosage may be used to minimize adverse drug reactions

14. Lithium Monitoring Lithium levels
T1/2 = hours; ss 4-5 days; draw levels 12 hours post-dose, usually prior to the morning dose
Target level = mEq/L; should not exceed 1.5mEq/L
LiCp < 1.5 mEq/L (mild toxicity and transient effects) = Fine hand tremor, GI upset (N/V/D/anorexia), mild polyuria, polydipsia, muscle weakness
LiCp = 1.5 – 2.5 mEq/L (moderate toxicity) = Course hand tremor, twitching, reoccurrence of GI upset, slurred speech, vertigo, confusion, sedation, lethargy, hyperreflexia
LiCp > 2.5 mEq/L (severe toxicity) = Seizures, stupor, coma, cardiovascular collapse, death
Other common monitoring parameters: pregnancy test at baseline; Ca, Cr, urinalysis, TSH at baseline, then at least q6-12mo; serum drug levels 2x/wk until stable, then q2mo until chronic steady dose, then q6-12mo; ECG at baseline in pts >40 yo or if cardiovascular dz, then q6-12mo; consider CBC at baseline

15. Valproate

16. Valproate Adverse Effects
Common: Headache (31%), Asthenia (27%), Somnolence (27%), Tremor (25%), Dizziness (25%), Diplopia (16%), Amblyopia/blurred vision (12%), Nausea (48%), Vomiting (27%), Abdominal pain (23%), Diarrhea (13%), Anorexia (12%), Flu syndrome (12%), Infection (12%)
Less Common: Dyspepsia (8%), Ataxia (8%), Nystagmus (8%), Fever (6%), Emotional lability (6%), Thinking abnormal (6%), Alopecia (6%), Weight loss (6%), Constipation (5%), Amnesia (5%), Bronchitis (5%), Rhinitis (5%)
Black Box Warnings: Hepatotoxicity, teratogenicity, pancreatitis
Pregnancy Category: D
Hepatotoxicity: Hepatic failure resulting in fatalities has occurred. Children younger than 2 years are at increased risk for fatal hepatotoxicity, particularly patients on multiple anticonvulsants, as well as those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease. Increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-gamma (POLG) gene (eg, Alpers Huttenlocher Syndrome). If used in children with these conditions, it should be administered with extreme caution as a sole agent. Hepatotoxicity usually occurs during the first 6 months of treatment and may be preceded by malaise, weakness, lethargy, facial edema, anorexia, and vomiting.
Teratogenicity: Do not use in women of childbearing age unless the drug is essential to the management of the medical condition; all non-pregnant women of childbearing potential should use effective birth control if taking valproate products. May cause neural tube defects
Children exposed in utero have increased risk for lower cognitive test scores compared with those exposed in utero to other antiseizure medications
Alternative medications that have a lower risk for adverse birth outcomes should be considered. Patients should not stop taking valproate without talking to a health-care professional. Women should use effective contraception while taking valproate derivatives
Pancreatitis: Cases of life-threatening pancreatitis have been reported in children and adults. Some cases have been described as hemorrhagic with a rapid progression from initial symptoms to death.

17. Valproate Drug Interactions
CYP 450: CYP2C9 inhibitor, weak; 3A3/4 inhibitor, weak
antiplatelet effects
CNS depression
hyperammonemia
hyponatremia
uridine glucuronyl transferases (UGTs) catalyse glucuronidation via two enzyme families, UGT1 and UGT2, each with eight isoenzymes identified

18. Valproate Dosing Depakote initial dose: 750 mg/day PO in divided doses
Depakote ER initial dose: 25 mg/kg PO once daily. Increase as rapidly as possible to achieve the lowest therapeutic dose that provides desired clinical effect or plasma concentration
Doses should not exceed 60 mg/kg/day

19. Valproate Monitoring Valproate Levels
Target plasma levels = or 150 mcg/mL
Draw level prior to giving a dose
SS within 1-4 days; draw level after 3rd or 4th day
Other common monitoring parameters: LFTs at baseline, then frequently, especially during 1st 6mo or if suspected hereditary mitochondrial dz; Plt, coagulation tests at baseline, then periodically, also before planned surgery; serum drug levels; ammonia; s/sx depression, behavior changes, suicidality

20. Lamotrigine

21. Lamotrigine Adverse Effects
Common : Dizziness (38%), Diplopia (26-30%), Headache (29%), Ataxia (22%), Blurred vision (16-20%), Rhinitis (11-15%), Somnolence (14%)
Less Common: Insomnia (6-10%), Fatigue (8%), Chest pain (5%), Peripheral edema (2-5%), Suicidal ideation (2-5%), Dermatitis (2- 5%), Dry skin (2-5%), Increased libido (2-5%), Rectal hemorrhage (2-5%), Weakness (2-5%), Agitation (1-5%), Dysarthria (1-5%), Edema (1-5%), Fever (1-5%), Migraine (1-5%), Abnormal thoughts (1-5%), Urinary frequency (1-5%), Tremor (4%)
Black Box Warnings: Serious rash (Stevens-Johnson syndrome)
Pregnancy Category: C
Serious rashes requiring hospitalization (including Stevens-Johnson syndrome) and discontinuation of treatment have occurred in 0.8% of pediatric patients (<16 years) and in 0.3% of adult patients who have received the drug as adjunctive therapy for epilepsy with valproic acid
The risk of serious rash caused by treatment with lamotrigine XR is not expected to differ from that with the immediate-release formulation; however, the relatively limited treatment experience with lamotrigine XR makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with the drug; lamotrigine XR is not approved for patients younger than 13 years
Almost all life-threatening rashes have occurred within 2- 8 weeks of lamotrigine therapy, but they have also occurred after prolonged treatment; duration cannot be relied on as a means to predict the potential risk heralded by the first appearance of a rash
Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Thus, the drug should be discontinued at the first sign of rash unless the rash is clearly not drug related
Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring

22. Lamotrigine Drug Interactions
Not a CYP inhibitor or inducer, but metabolism is affected by inhibitors and inducers.
Caution when used in combination with valproate/valproic acid
Dose adjustment also necessary when given with carbamazepine

23. Lamotrigine Dosing
Monotherapy (without enzyme inducers or valproic acid)
Dose: 200 mg PO qd; Start: 25 mg PO qd x2wk, then 50 mg PO qd x2wk, then 100 mg PO qd x1wk; Max: 200 mg/day; Info: taper dose over 2wk to D/C
Enzyme-inducing AED adjunct
Dose: 200 mg PO bid; Start: 50 mg PO qd x2wk, then 50 mg PO bid x2wk, then 100 mg PO bid x1wk, then 150 mg PO bid x1wk; Max: 400 mg/day; Info: enzyme-inducing AEDs incl. carbamazepine, phenytoin, phenobarbital, primidone; taper dose over 2wk to D/C
Valproate adjunct
Dose: 100 mg PO qd; Start: 25 mg PO qod x2wk, then 25 mg PO qd x2wk, then 50 mg PO qd x1wk; Max: 100 mg/day; Info: applies to any regimen containing a valproic acid derivative; taper dose over 2wk to D/C

24. Lamotrigine Monitoring
No specific plasma concentration monitoring
Other common monitoring parameters: Cr at baseline; ophthal. exams if prolonged tx; s/sx depression, suicidality, clinical worsening if bipolar disorder, and/or unusual behavior changes

25. Carbamazepine

26. Carbamazepine Adverse Effects
Common : Ataxia (15%), Dizziness (44%), Drowsiness (32%), Nausea (29%), Vomiting (18%)
Less Common: Dry mouth (8%)
Rare: MI, Stevens-Johnson syndrome, Hepatic failure, Punctate cortical lens opacities, Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Black Box Warnings: Serious and sometimes fatal dermatologic reactions; aplastic anemia, agranulocytosis
Pregnancy Category: D
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported during treatment with carbamazepine; studies in patients of Chinese ancestry found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene; HLA-B*1502 is found almost exclusively in patients of Asian ancestry, with populations across broad areas of Asia producing such descendants; patients testing positive for the allele should not be treated with carbamazepine unless the benefit clearly outweighs the risk; patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiation of treatment with carbamazepine
Aplastic anemia and agranulocytosis reported; patients with a previous history of adverse hematologic reaction to any drug may be at increased risk

27. Carbamazepine Drug Interactions
CYP 450
CYP2C8 substrate, CYP3A4 substrate; CYP1A2/2A6 inducer, minor; CYP2B6 inducer, minor;CYP2C8 inducer, minor; CYP2C9 inducer, minor; CYP3A4 inducer, major; UGT1A4 inducer;P-gp (MDR1) inducer;
CNS depression
GI absorption enhanced by GLP-2 receptor agonist
hyperammonemia
hyponatremia
increases thyroid hormone clearance
serotonergic effects, weak

28. Carbamazepine Dosing Initial: 200 mg PO q12hr
Increase by increments of 200 mg/day; not to exceed mg/day

29. Carbamazepine Monitoring
Target plasma concentration is 8-12 mcg/mL
Toxic Levels: >12 mcg/mL
Timing: before morning dose
Time to Steady State: >1mo
Other common monitoring parameters: BUN/Cr, CBC w/ diff, LFTs, urinalysis, ophthal. exams at baseline, then periodically; serum drug levels; s/sx depression, behavior changes, suicidality

30. Oxcarbazepine

31. Oxcarbazepine Adverse Effects
Common : Dizziness (30-50%), Diplopia (30-50%), Headache (26-30%), Nausea/vomiting (26-30%), Nystagmus (26-30%), Somnolence (26-30%), Ataxia (10-30%), Abnormal gait (16-20%), Tremor (16-20%), Abdominal pain (11-15%), Fatigue (11-15%), Vertigo (11-15%), Vision abnormalities (11-15%)
Less Common: Dyspepsia (5-6%), Rash (4%), Insomnia (2-4%), Abnormal thinking (<4%), Hyponatremia (1-3%), Muscle weakness (1-2%), Hypotension (<2%), Speech disorder (1%), Asthenia
Post-marketing reports: Angioedema, Anaphylaxis, Bone marrow depression, agranulocytosis, aplastic anemia, pancytopenia, neutropenia, Pancreatitis and/or lipase and/or amylase increased, Folic acid deficiency, hypothyroidism, Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, Multiorgan hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia, and arthralgia
Pregnancy Category: C

32. Oxcarbazepine Drug Interactions
CYP2C19 inhibitor, moderate
CYP3A4 inducer, minor
CNS depression
Hyponatremia
Serotonergic effects, weak

33. Oxcarbazepine Dosing
300 mg/day PO initially; may titrate to mg/day maximum

34. Oxcarbazepine Monitoring
No specific target plasma concentration recommendations
Other common monitoring parameters: Cr at baseline; Na; s/sx depression, behavior changes, suicidality

35. Mood Stabilizer Costs Drug Average Cost* Lithium $9 $
$9 $
Lithobid (lithium er)
$18
Depakote (divalproex)
$20
Depakote ER (divalproex er)
$105
Lamotrigine $9
Lamictal XR (lamotrigine er)
$186
Carbamazepine
$6 $
Equetro (carbamazepine)
$72
oxcarbazepine
$27
*GoodRx.com price comparison; $= On $4/$10 generic lists at retail pharmacies

36. Place in Therapy for Atypical Antipsychotics
Acute manic, mixed or depressive episodes with psychotic features usually require treatment with an antipsychotic
Adjunctive treatment in acute manic episode
Optimal duration may be 24 weeks
(Mol Psychiatry Oct 13. doi: 10/1038/mp )
Maintenance treatment
Need to weight benefits vs. risks (metabolic abnormalities)
May be the better choice in patients with psychotic features

37. Place in Therapy for Atypical Antipsychotics
Approved FDA Bipolar Indication
Saphris (asenapine)
Acute treatment of manic or mixed episodes associated with Bipolar I Disorder; >9 years
Latuda (lurasidone)
Depressive episode associated with Bipolar I Disorder (Bipolar Depression); Adults
Zyprexa (olanzapine)
Bipolar I Disorder (Manic or Mixed Episodes (mono or adjunctive therapy); >13 years
Depressive episodes associated with BD I (with fluoxetine)
Risperdal (risperidone)
Bipolar mania; >12 years
Seroquel (quetiapine)
Seroquel XR
Bipolar mania; >9 years
Bipolar disorder, depressive episodes
Maintenance tx of BD I as adjunct to Li or VPA
Geodon (ziprasidone)
Bipolar I Disorder (acute mixed or manic and maintenance as adjunct to Li or VPA); Adults
Abilify (aripiprazole)
Bipolar I Disorder (acute or maintenance); >10 years
Agitation associated with bipolar mania; Adults

38. Detecting Anxiety Disorders
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