approach to bipolar disorder jon davine, md, ccfp, frcp(c) associate professor, mcmaster university...
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Approach to Bipolar Disorder
Jon Davine, MD, CCFP, FRCP(C)Associate Professor, McMaster UniversitY
OCFP Annual Scientific AssemblyToronto, OntarioNovember 30, 2013
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Faculty/Presenter DisclosureFaculty/Presenter Disclosure
• Faculty: Jon Davine
• Program: 51st Annual Scientific Assembly
• Relationships with commercial interests:Lundbeck, Canada:
Educational presentations
Advisory Board member
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Disclosure of Commercial SupportDisclosure of Commercial Support
• This program has received NO financial support • This program has received NO in-kind support
• Potential for conflict(s) of interest:– NONE
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Mitigating Potential BiasMitigating Potential Bias
• I am not discussing any of Lundbeck Canada’s drugs in this presentation
• When discussing pharmacotherapy, I will be using CANMAT guidelines
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Objectives• Learn how to make the diagnosis of bipolar in a time
efficient manner• Learn how to use psychopharmacology to treat Bipolar
Disorder, using current guidelines• Learn about issues of psychopharmacology and
pregnancy
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• MANIC• 7 days or more, unless hospitalized• Interferes with life greatly• Increased mood• Increased energy• Decreased sleep
• HYPOMANIC• 4 days or more• Somewhat interferes with life, seen by others as uncharacteristic• Same features as manic, no marked impairment in functioning
• IMPORTANT: Separate Bipolar II from Axis II, cluster B mood lability• Remember time line, days vs. hours or a day• Out of the blue vs. response to stressors
Bipolar Disorder
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Bipolar I vs. Bipolar II• Bipolar I
• Manic phase(s) +/- depression phase(s)• 1% lifetime prevalence
• Bipolar II• Hypomanic phase(s) + depression phase(s)• 1.1% lifetime prevalence
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• Mean age of onset - early to mid 20's • Peak age is 15-19
• Usually 3-10 year lag between onset and treatment• Initially
• Depression in women• Mania in men
• Twin studies and first degree relative studies support the fact of heritability
Bipolar Disorder
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Bipolar Terms• Bipolar
• Manic phase• Hypomanic phase• Depressed• Mixed phase - depression and mania essentially coexist,
switching over hours, or every 1 - 2 days. Also has been called ultra rapid cycling. Must last at least one week. Causes marked impairment in functioning.
• Rapid Cycling• 4 or more episodes/year• Going from manic to depressed - counts as two episodes
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THINGS TO DO:THINGS TO DO:• Assess for organicity• Harm to others (e.g., driving)• EtOH/Substance abuse
• High co-morbidity rate• Can worsen
• Suicidality • 17-19% lifetime prevalence of completed suicide• More often in depressed state
• Educate• Inadequately treated patient may have 10 or more episodes• Intervals between episodes narrows as person ages• Sleep deprivation can provoke hypomanic/mania
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Levels of Evidence• Level 1
• Meta-analysis or replicated RCT with placebo
• Level 2• At least one RCT with placebo or active comparison condition
• Level 3• Uncontrolled trial with 10 or more subjects
• Level 4• Anecdotal reports or expert opinion
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Treatment Recommendations• 1st line (A)
• Level 1 or 2 evidence plus clinical support for efficacy and safety
• 2nd line (B)• Level 3 evidence or higher plus clinical support for efficacy
and safety• 3rd line (C)
• Level 4 evidence or higher plus clinical support for efficacy and safety
• Not Recommended• Level 1 or 2 evidence for lack of efficacy
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• Anti-manic• 78% response rate• Level I evidence
• Anti-depressant• 79% response rate• Level I evidence
• Prophylaxis• 6 fold decrease in subsequent episodes• Level I evidence
Lithium – Indications
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• Half-life = 14-30 hours• Not metabolized
• Cleared by kidney (mind renal function)• Not protein bound
Lithium – Pharmacology
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• Polyuria, polydipsia (Diabetes Insipidus)• Treat with diuretics if necessary
• * Increase weight• Cognitive problems• * Tremor
• Treat with Beta-Blockers
• Sedation• * GI distress• Increase WBC• ECG changes
• Usually benign• Rarely conduction abnormality
Lithium – Side Effects
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• Hypothyroid (5-35%)• More females after 6-18 month treatment• Generally reversible• Can replace with thyroxine
• Nephrotoxicity• Controversy, but appears to be
Lithium – Other Effects
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• 0.4-0.6 mmol/L• Decreased side effects• Increased risk of episodes
• 0.6-0.8 mmol/L• Most often chosen• Not well studied
• 0.8-1.1 mmol/L• Deceased risk of episodes• Increased side effects
• Balance must be chosen between efficacy and side effects
Lithium – Levels and Side Effects
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• >1.5 mmol/L = Toxic• coarse tremor• Vomiting• Blurred vision• Vertigo• Confusion• Increased DTR
• > 2.5 mmol/L = Life threatening
• Treatment: hemodialysis
Lithium – Overdose
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• Workup – repeat every 6-12 months• ECG• CBC• TSH• Creatinine, ‘lytes, u/a• Pregnancy test if applicable
• Blood lithium levels• 5 days after starting, and then 5-7 days after dosage
changes• Get 2 therapeutic serum levels, then repeat q3months.
Lithium – What to do before starting:
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• Start at 300 mg PO BID• Increase by 300 mg/day depending on levels• Usual dosage 900-1500 mg/day• Measure "trough" levels
• Patient to have blood test 12 hours post last dose
Lithium - Dosage
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• Manic – 56% response rate (near Lithium effectiveness)• Level I evidence (A for mania and mixed states)
• Bipolar Depression – Few studies for bipolar depression• Level III evidence (B)
• Prophylaxis• Level II evidence (A)
Valproic Acid – Indications
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• 2 forms• Valproate and Divalproex sodium• Divalproex sodium (Epival) has less GI side effects, and
is therefore preferred
• Half-life = 6-16 hours• Metabolized by liver• Protein bound
Valproic acid - Pharmacology
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• * GI distress (use divalproex sodium)• Sedation• * Benign increased ALT, increased AST• Tremor• Hepatotoxicity• Decreased platelets, WBC• *Increased appetite, weight• Agranulocytosis• Polycystic ovarian disease – contraindicated
Valproic Acid – Side Effects
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• Workup before starting• History And Physical• LFT'S • CBC with platelets• Do initially, then at 4 weeks, repeat q 3-6 months
• Starting Dose 250 mg BID• Increase by 250 mg Increments weekly • + teratogenic
• Levels• 350-700 μmol/L3
Valproic Acid – When you start:
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Lamotrigine• Especially helpful from down-up
• More effective in preventing depression
• Less weight gain• Watch for any rash
• (5-10%) Stevens-Johnson syndrome a possibility, (1/5000), thus D/C.
• Start at 12.5-25 mg PO OD• Increase by 12.5-25 mg PO q1-2weekly• Levels – Usually 50-200 mg/day
• No blood level monitoring necessary
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Lamotrigine – Indications• Mania
• Level III evidence (D)• Depression
• Level I evidence (A)• Prophylaxis
• Level I evidence (A)
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• Mania • Level I evidence, but (C) due to s/e, drug interactions
• Bipolar depression• Level II evidence (C)
• Prophylaxis
• Level II evidence (C)
Carbamazepine - Indications
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Carbamazepine - Pharmacology• Half-life is ultimately 5-26 hours
• Metabolized by the liver• Protein bound
• Carbamazepine induces the CYP 450 enzyme system, resulting in:• Decreased neuroleptic level• Decreased benzodiazepines• Decreased TCA• Decreased anti-convulsants• Auto-induction
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• Diplopia• Blurred vision• Fatigue, drowsiness• Ataxia, dizziness• Nausea, vomiting• Less common
• Rashes• Decreased WBC• Decreased platelets• Increased LFTs• Hyponatremia
Carbamazepine – Side Effects
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• Idiosyncratic, rare:• Agranulocytosis• Aplastic anemia• Hepatic failure• Exfoliative dermatitis (Stevens-Johnson Syndrome)• Pancreatitis
• Toxicity symptoms:• Dizziness• Ataxia• Sedation• Diplopia• Stupor, coma, decreased LOC, convulsions
Carbamazepine – Adverse Reactions
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• Workup before starting• History and Physical• CBC with diff, platelets• LFT's
• Start at 100 mg BID• Increase by 200 mg q5d with levels
• 800-1000 mg/day• Range: 200-1800 mg
Carbamazepine - Starting
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• Therapeutic levels not established• We use same as for seizure• 17-42 μmol/L• Labwork
• CBC, platelets q2weeks for first 2 months• LFT's• Then q3months along with carbamazepine levels
Carbamazepine – Follow up
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Olanzapine• Has been HPB approved as anti-manic, but also as
monotherapy in bipolar• I would not go this route due to effects of increased weight,
increased glucose, triglycerides, and lipids
• Olanzapine and clozapine have more weight gain than risperidone and quetiapine
• Possible link to diabetes type 2
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Olanzapine – Indications• Mania
• Level I evidence (A)
• Depression• Level I evidence (B)
• Prophylaxis• Level I evidence (A)
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Gabapentin, Topiramate• For mania, depression, and prophylaxis:
• Level III (D)
• Not recommended or prescribed
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• Acute treatment duration = 2 to 10 weeks• Rule out organic
• Cushing's• Thyroid• MS• Steroids• *antidepressants - controversy • Substance abuse
Acute Treatment of Mania
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• History and physical• Labwork
• CBC with diff• Lytes, creatinine• LFT's• TSH• EKG (if >40)• U/A• Pregnancy test if relevant
Acute Treatment of Mania, Mixed State, Rapid Cycling
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CANMMAT (09):1st Line Treatments for Mania• Monotherapy: Lithium, divalproex, Risperidone,
Olanzapine, Quetiapine, Ziprasidone, Aripiprazole• Combination: Lithium or divalproex plus Atypicals,
except Ziprasidone (increases response by 20%)• Rapid Cycling/Mixed: Divalproex• **Discontinue antidepressant, stimulant meds
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• Risperidone, Olanzapine, and Quetiapine are all approved for use as anti manic agents
• Risperidone--1-4 mg/day• Olanzapine 5-20 mg/day• Quetiapine 200-800 mg/day• Aripiprazole 10 -15 mg/day• Ziprasidone 20-80 mg BID• Anti-manic, anti-psychotic
Atypical Neuroleptics
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Bipolar Depression• 20% of Bipolar Depressive Episodes run a chronic course• Mild depressive symptomatology may be successfully treated with
CBT or IPT• Lithium
• Response rates from 64% to 100%. Level I (A) evidence
• Antidepressants• Level I (B) evidence. • Watch for flips (more common with tricyclics) • Use with concomitant mood stabilizer to avoid flips
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Lamotrigine in Bipolar Depression• Lamotrigine
• Sometimes added to lithium as mood stabilizer• It works better from the “bottom up”• Lithium and Epival work better from the “top down”
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Atypical Neuroleptics in Bipolar Depression• Atypical Neuroleptics can be used as acute
antidepressants• Olanzapine has level 1 evidence as monotherapy for acute
depression• Quetiapine now approved for bipolar depression
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CANMMAT (09):1st Line Treatments for Bipolar Depression• Monotherapy:
• Lithium, lamotrigine, quetiapine• Combination Therapy:• Lithium and divalproate• Lithium or divalproate plus SSRI or buproprion• Olanzapine and SSRI
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• Usually lasts 6-12 weeks• Continue with psychoeducation/counseling
• Develop relationship• Helps compliance• Deal with stressors
Continuation Phase of Treatment
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• If Benzos were used, try to wean off• No evidence for them as prophylactic agents
• If Atypical Neuroleptics were used, gradually wean and discontinue unless:• (1) persistent psychosis, or (2) adjunctive prophylaxis
• If antidepressants used, once depression has past, if asymptomatic for 6-12 weeks, gradually wean off over several weeks.
Drugs in Continuation Phase
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• Risk of recurrence? not sure, but:• Mood stabilizers help with moderate-severe illness• But there is a subgroup of patients with mild illness who may
not need prophylaxis• Hard to identify this group
• Indefinite maintenance pharmacotherapy has been supported by “decision analysis”, which analyzes:• “costs”(e.g., lithium exposure)• “benefits”- (i.e., decreased risk of relapse)
Maintenance/Prophylactic Phase
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CANMMAT (09):1st Line Treatments for Maintenance• Monotherapy:
• Lithium, divalproate, lamotrigine, risperidone LA, olanzapine, quetiapine, aripiprazole
• Combination: • Lithium or divalproate plus risperidone LA, quetiapine, or
ziprasidone
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CANMMAT (09):1st Line Treatments for Bipolar II
• Depression: Quetiapine • Level 1 evidence
• Maintenance: Lithium, Lamotrigine • Level 2 evidence
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• All mood stabilizers are teratogenic• Risk vs. benefit
• Lithium lower risk (Ebstein's anomaly, 0.1%)• Tricuspid valve displacement
• If illness not that severe, consider planned pregnancy without meds• 4 week medication-free period pre-conception
• ECT, SSRI, Neuroleptics all lower risk in 1st trimester
Therapy in Pregnancy
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Epival in Pregnancy• Epival (sodium valproate) much more problematic
• Neural tube defects may increase to 5%• Try to avoid in women of child bearing age, especially weeks 1-10.
• Can use folic acid 5 mg. PO OD• Can do serial ultrasounds examining the neural tube
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Lamotrigine in Pregnancy• Cleft lip and palate• Possible less teratogenic
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Dosage in Pregnancy• May need to increase dose
• Especially lithium during this time• Then decrease dose after delivery (re: GFR)
• Post partum has >50% risk of an episode• Recommend re-start therapy after delivery
• All secreted through breast milk• Data suggests no immediate risk• No data regarding later behavioural effects• Speak to Motherisk or Womens Health Concerns about concerns
surrounding breastfeeding
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Disability Issues• Stable bipolar is not disabling
• Most people should hit their normal “life arc”, including working• Let patients know this!
• A minority of treatment resistant cases may require disability
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MDQ: Mood Disorders Questionnaire• Self report for bipolar• 5 questions
• 13 items on question 1