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

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

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

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 www.psychiatryonline.org

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 www.psychiatryonline.org

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 www.psychiatryonline.org

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 www.psychiatryonline.org

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 www.nice.org.uk

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

Lithium

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

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)

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

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

Valproate

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.

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

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

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 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

Lamotrigine

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

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

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

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

Carbamazepine

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

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

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

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

Oxcarbazepine

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

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

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

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

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

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. 2015 Oct 13. doi: 10/1038/mp.2015.158) Maintenance treatment Need to weight benefits vs. risks (metabolic abnormalities) May be the better choice in patients with psychotic features

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

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