1. Pharmacologic Considerations in the Treatment of Bipolar Affective Disorder Presented by: Ann M. Hamer, PharmD, BCPP Date: 11/6/2014

2. Disclosures and Learning Objectives 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 Hamer has nothing to disclose.

3. Pharmacologic Treatment of Bipolar Disorder Review adverse effects Review drug interactions Review dosing Review monitoring parameters Review comparative cost

4. Treatment Recommendations Acute Mania Acute Depression Rapid Cycling 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 benzo 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 Maintenance 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 better at warding off mania Valproate, Olanzapine, Carbamazepine, Oxcarbazepine also evidence-based

5. Lithium

6. 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

7. 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)

8. Lithium Dosing Immediate release: 900-2400 mg/day PO divided q6-8hr Extended release: 900-1800 mg/day PO divided q12hr Lower initial dosage may be used to minimize adverse drug reactions

9. Lithium Monitoring Lithium levels T1/2 = 18-24 hours; ss 4-5 days; draw levels 12 hours post-dose, usually prior to the morning dose Target level = 0.6 -1.2 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

10. Valproate

11. 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

12. Valproate Drug Interactions CYP 450: CYP2C9 inhibitor, weak; 3A3/4 inhibitor, weak UGT2B7 inhibitor antiplatelet effects CNS depression hyperammonemia hyponatremia

13. 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

14. Valproate Monitoring Valproate Levels Target plasma levels = 50 - 125 or 150 mcg/mL Draw level prior to giving a dose SS within 1-4 days; draw level after 3 rd or 4 th 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

15. Lamotrigine

16. 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

17. 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 UGT1A4 substrate

18. Lamotrigine Dosing Monotherapy or without enzyme inducers or valproic acid Initial: 25 mg PO qDay for 2 weeks, then 50 mg PO qDay for 2 weeks; 100 mg PO qDay for 1 week; Double dose qWeek to maintenance at 200 mg/day PO With AED regimen without valproic acid Initial: 50 mg PO qDay for 2 weeks, then 100 mg/day PO divided q12hr for 2 weeks; Increase by 100 mg qWeek to 400 mg/day PO divided q12hr With valproic acid Initial: 25 mg PO qOD for 2 weeks, then 25 mg PO qDay for 2 weeks; Double dose qWeek to maintenance at 100 mg/day PO

19. 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

20. Carbamazepine

21. 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

22. 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

23. Carbamazepine Dosing Initial: 200 mg PO q12hr Increase by increments of 200 mg/day; not to exceed 1600 mg/day

24. 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

25. Oxcarbazepine

26. 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

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

28. Oxcarbazepine Dosing 300 mg/day PO initially; may titrate to 1800-2400 mg/day maximum

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

30. Mood Stabilizer Costs DrugAverage Cost* Lithium$9 W Lithobid (lithium er)$18 Depakote (divalproex)$20 Depakote ER (divalproex er)$105 Lamotrigine$9 Lamictal XR (lamotrigine er)$186 Carbamazepine$6 W Equetro (carbamazepine)$72 oxcarbazepine$27 *GoodRx.com price comparison; W=Walmart $4/$10 generic

31. STEP-BD NIMH-funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is a long-term outpatient study designed to find out which treatments, or combinations of treatments, are most effective for treating episodes of depression and mania and for preventing recurrent episodes in people with bipolar disorder.

32. STEP-BD N= 4360 total (Bipolar I, II, NOS, cyclothymia); assigned to “STEP-BD- certified psychiatrist” Major findings: After up to two years of best practices treatment, 58.4% of patients met criteria for full recovery. 48.5% had a recurrence (72% with a depressive episode; 28% with a manic, hypomanic, or mixed episode). Residual sx was assoc with an ↑chance of recurrence. Adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone in bipolar depression. www.nimi.nih.govwww.nimi.nih.gov; CNS Neuroscience & Therapeutics 2012; 18(3): 253-9; Am J Psychiatry 2008; 165:370-377

33. STEP-BD Major findings: Lamotrigine appears to be more effective than risperidone in treatment- refractory patients with bipolar depression. Study assigned pts to one of three adjunctive treatments: lamotrigine (up to 250 mg QD), inositol (up to 25 g QD), or risperidone (up to 6 mg QD) for up to 16 weeks. The recovery rates were: lamotrigine, 23.8%; inositol, 17.4%; risperidone, 4.6% (findings not ss). Valproate is associated with PCOS. Study evaluated 230 women (ages 18- 44) for the development of PCOS sx (menstrual irregularities, hirsutism, acne, hair loss, ↑testosterone). They found PCOS symptoms in 9 of 86 women on valproate (10.5%) compared to only 2 of 144 women on a nonvalproate anticonvulsant or lithium (1.4%). Prevention of rapid cycling recurrences may require early intervention and restricted use of antidepressants. www.nimi.nih.govwww.nimi.nih.gov; CNS Neuroscience & Therapeutics 2012; 18(3): 253-9; Am J Psychiatry 2008; 165:370-377

34. The End! Next Week: Looking forward to Dr. Betlinski’s return