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Bipolar Disorder & How to Treat

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Tonya Smith

on 5 July 2017

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Transcript of Bipolar Disorder & How to Treat

Bipolar Disorder & How to Treat
The role of antidepressants (or lack thereof) in bipolar disorder continues to be debated...
Focus on
Acute Bipolar Depression

Shannon Drayton, PharmD, BCPP
List the various treatment options for bipolar disorder
Explain the role of mood stabilizers, antipsychotics, antidepressants, and benzodiazepines in bipolar disorder
Compare and contrast the mood stabilizers with regard to efficacy, tolerability, and place in therapy
- Identify the 3 most commonly used mood stabilizers and list their adverse effects, dosing, drug interactions, monitoring parameters, and patient counseling points.
- Identify other second line mood stabilizers and give their adverse effects, drug interactions, monitoring parameters,
and patient counseling points
Design a therapeutic regimen for a patient with bipolar disorder (mania and depression), incorporating patient and medication specific factors along with a monitoring plan and counseling points for the selected regimen

As high as 50% in the first year
– Loss of “high”; who’s in control
– Side effects of medications
– Lack of insight into disease/unreasonable expectations
– Dual diagnosis

Ways to improve compliance
– Increases with t1/2 of drug
– Decrease dose
– Educational effort/counseling

Goals of Treatment
Resolution of symptoms
Prevention of future episodes or decrease in frequency of episodes
Reduction in severity and duration of episodes
Minimize side effects of medications
Compliance with treatment
Patient education re: disease/treatment
Avoidance of stressors

Treatment of BPAD
Treatment Guidelines
Canadian Network for Mood and Anxiety Treatments (CANMAT)
International Society for Bipolar Disorders (ISBD)

Selecting Medications
Phase specific considerations
Prior response and tolerability
Medical and psychiatric co-morbidities
Side effects
Drug interactions
Patient preferences

Treatment Options
Valproic Acid
Electro-convulsive therapy (ECT)
New anticonvulsants

Bipolar Depression
Evidence does not support the use of antidepressants in acute bipolar depression (STEP BD)
Lamotrigine does not help treat bipolar depression
It is, however, good as a maintenance medication for prevention of future episodes of mania and depression
Best for preventing depression, so good option in BPAD type II patients

Quetiapine in
Bipolar Depression
BOLDER I and II Study
8 weeks of monotherapy with 300 or 600 mg/day vs. placebo
– 53% of quetiapine
– 28% on placebo
Core symptoms of depression improved on quetiapine
Treatment-emergent mania in 3.2% vs 3.9%

Lurasidone in
Bipolar Depression
Bipolar Depression
Mood stabilizers are foundational agents and should be considered first line treatments
Strong evidence supporting the use
of lithium
Second generation antipsychotics provide benefit in acute bipolar depression
Strongest evidence supporting the use
of quetiapine or lurasidone monotherapy or the olanzapine plus fluoxetine combination

Lurasidone in
Bipolar Depression - PREVAIL I
PREVAIL I Study, adjunct
6 weeks of combination tx with li or vpa (n=183) vs placebo (n=165)
20 – 120 mg/d
– 42% of low dose
– 40% on high dose

Lurasidone in
Bipolar Depression - PREVAIL II
6 weeks of monotherapy
20-60mg/d or 80-120mg/d
Actual reduction in MADRS scores
Lurasidone 15.4 vs placebo 10.7
No difference seen between low and high dose lurasidone groups
Treatment-emergent mania
1% low dose
0% high dose

Effectiveness of treatments and their impact on bipolar disorder
Enrolled patients with all subtypes, severity, and demographic groups
– Bipolar disorder is a major public health concern
– Prevalence estimates 1-3% of U.S. population
– Costly disorder, accounts for 21% of mental health illness costs directly
– Is not a single study
– Platform designed to carry out a variety of clinical trials

New England Journal of Medicine 2007
Data from NIMH sponsored STEP-BD trials
Are adjunctive antidepressants effective?
Patients randomized (26 weeks)
Lithium, valproate, or carbamazepine PLUS bupropion or paroxetine OR
Lithium, valproate, or carbamazepine PLUS placebo
Adjunctive Antidepressants
Primary outcome was 8 consecutive weeks of euthymia
– 23.5% in MS + AD
– 27.3% in MS + placebo
Adjunctive Antidepressants
No significant difference in effectiveness
No significant difference in side effects
No significant difference in patients who discontinued treatment early
No significant difference in bupropion vs paroxetine groups
Rates of affective switch were similar
Adjunctive Antidepressants
Pro’s and Con’s
Old but still unsurpassed
Evidence and clinical opinion support its use
Evidence in all stages of Bipolar Disorder
Side effects

Anticonvulsants in Bipolar Disorder
Evidence to support:
– Divalproex sodium
– Valproic Acid
– Carbamazepine
– Oxcarbazepine
– Lamotrigine

Second Generation Antipsychotics
FDA approved for the treatment of an acute manic episode BPAD type I:
– Aripiprazole
– Olanzapine
– Risperidone
– Quetiapine
– Ziprasidone
– Asenapine
- Cariprazine

FDA approved for maintenance treatment:
– Olanzapine and aripiprazole and risperdal consta

FDA approved for bipolar depression:
– Quetiapine
– Lurasidone
– Olanzapine/fluoxetine combination
Evidence lacking or negative:
– Tiagabine
– Levetiracetam
– Gabapentin
– Topiramate
– Zonisamide

The details...

Valproic acid (VPA)

Carbamazepine (CBZ)

Lithium - Indications & Uses
bipolar disorder: acute and maintenance, augmentation for depression, aggression in MR, organic brain syndromes

Lithium - Dosing
Young, healthy: 900-2400mg/day divided

Adjustment required for geriatrics and renal dysfunction

Lithium - Dosage Forms
Immediate release: tid dosing recommended
– Li carbonate caps: 150, 300, 600mg
300mg = 8.12mEq
– Li carbonate tabs: 300mg, associated with more GI effects and stomatitis

Controlled release: bid dosing but once daily dose is tolerated
– Eskalith CR: 450mg tab
– Lithobid: 300mg tab

Syrup (citrate): 300mg/5ml or 8mEq/5ml

Lithium - Kinetics
Renally excreted, not dependent on hepatic metabolism

Check trough levels after 5 days
Therapeutic range: 0.5-1.5mEq/L

Pregnancy category D: crosses placenta freely; maternal = fetal conc.

Lithium - Side Effects
Dose-related: fine tremor, nausea, vomiting, diarrhea, sedation, dizziness, weight gain, nystagmus

Others: polydipsia, polyuria, hypothyroidism, leukocytosis, thrombocytosis, arrythmias, flattened/inverted T waves, sinus node dysfunction, edema, diabetes insipidus, exacerbation of psoriasis, rash, NMS

Lithium - Toxicity
Mild (levels 1.5-2.0mEq/L)
– nausea, vomiting, loose stools, lethargy, confusion, coarse hand tremor, drowsiness, lightheadedness

Moderate (levels 2.0-2.5mEq/L)
– severe N/V/D, dysarthria, worsening confusion, ataxia, blurred vision, profound lethargy, tinnitus, apathy

Severe (levels >3.0mEq/L)
– severe N/V/D, seriously impaired consciousness, increased DTR, stupor, seizures, coma, death

Lithium - Drug Interactions
Increase Li levels:
– ACE inhibitors
– angiotensin receptor blockers
– loop and thiazide diuretics
– spironolactone
– COX-2 inhibitors
Decrease Li levels:
– caffeine, theophylline, aminophylline
– acetalzolamide
– mannitol

Lithium - Cautions/Considerations
Renal Failure
Dehydration risk / Na depletion
Concurrent use during ECT
Lithium Monitoring (outpatient)
BUN, SCr: baseline and q3months if renal dysfunction, or as clinically indicated
Pregnancy test
Electrolytes: hyponatremia may cause toxicity
ECG: flattened/inverted T waves are reversible
Target levels
– acute mania: 0.8-1.2 mEq/L
– prophylaxis: 0.6-0.9 mEq/L
– augmentation in depression/geriatrics: 0.4-0.6 mEq/L
– obtain weekly for 4 weeks then monthly X 3 months, then q3 months or as indicated
– leukocytosis peaks at 2 weeks
TFTs: hypothyroidism
– incidence: 7-8%
– women at higher risk
– monitor at baseline, Q3-6 mo if TFTs change, otherwise TSH annually

VPA - Dosage Forms
Valproic acid (Depakene®) 250mg tab

Sodium valproate syrup
(Depakene®) 250mg/5ml

Divalproex sodium, delayed release tab
– must swallow whole, cannot chew

VPA - Kinetics
Protein binding: 80-90% (dose related)
Metabolized extensively in liver
– glucuronide conjugation, oxidation via CYP 450 2C9, 2C19

Therapeutic range 50-125mcg/ml (epilepsy)
Check trough levels after 3 days

VPA - Side Effects
GI: Anorexia, N/V/D, dyspepsia
Neuro: Somnolence, dizziness, tremor, ataxia, nystagmus, parkinsonism
Hematological: thrombocytopenia (dose related)
Asymptomatic elevation of transaminases (dose related)
Increased appetite, weight gain
Rash/Stevens-Johnson Syndrome
Severe hepatic dysfunction
– rare, idiosyncratic, majority of cases occur in first 3 months
– RF: age <2, multiple anticonvulsants
– no hepatic fatalities in pts over age 10 on monotherapy

VPA - Drug Interactions
VPA: 2C9/19 substrate, 2C9/2D6 inhibitor, weak 3A3/4 inhibitor
CBZ, LTG, PTN may induce VPA metabolism
VPA may increase, decrease, or have no effects on CBZ and PTN
VPA may increase conc of CBZ-epoxide

VPA inhibits LTG metabolism significantly thru glucuronidation

VPA - Indications/Uses
Acute mania, behavioral disorders and aggression
in MR/DD and AD patients, seizures

VPA - Dosing

– LD strategy: 15-20mg/kg/day (not shown to be more efficacious vs. standard dosing)
– Normal dosing: 750mg/d to start, titrate up according to efficacy
and tolerability
– Lower doses used in geriatrics/organic brain disease
– Maximum recommended dose: 60mg/kg/d

VPA - Monitoring (Outpatients)
Pregnancy test
CBC/PLT count at baseline, then monthly for 6 months, then every 6 months as clinically indicated
LFTs - same as above
Amylase/lipase is suspect pancreatitis
PT/PTT at baseline, then every 6 months as clinically indicated
NH4 if suspect encephalopathy
VPA levels generally 1-2 weeks after initiation, then every 3 months or as indicated

Divalproex sodium, sprinkle (Depakote Sprinkle®)

– may be mixed with semisolid food but particles must be swallowed whole, not chewed

Divalproex extended release (Depakote ER®)

CBZ - Indications/Use
Generally second line therapy in BPAD
Patients intolerant of or unresponsive to Li or VPA
Aggressive behavior/episodic dyscontrol
Eating disorders, anxiety disorders
Behavioral disturbances in dementia/MR/DD
Pain syndromes
Good for complex partial seizures/temporal lobe epilepsy

CBZ - Dosing
Initial dose: 200mg bid with meals, increase by 200mg/d weekly until desired response (faster inpatient)

CBZ - Kinetics
Autoinducer of metabolism through CYP450 3A3/4

Maximal enzyme induction occurs within 2-4 weeks (level should be at steady state)

Any change in dose will require at least 4 days for concentrations to reflect new SS level

Studies fail to show correlation's between CBZ level and response to BPAD (>12mcg/ml toxic)
CBZ - Adverse Effects
Aplastic anemia: incidence 1/50,000
Rash/Stevens Johnson
CBZ - Toxicity
CBZ - Drug Interactions
CYP2C8/9, 3A3/4 substrate

CYP1A2, 2C8/9, 2C18/19, and potent 3A3/4inducer

Urinary retention
Respiratory depression
CBZ - Precautions/Contraindications
Breast feeding
Pregnancy (1st trimester)
Liver dysfunction
Hypersensitive reaction to other drugs, including other anticonvulsants
Increased intraocular pressure
Patients with a history of atypical absence seizures
History of adverse hematological reaction to any drug
Hypersensitivity of CBZ or tricyclic antidepressants
History of bone marrow suppression
Concomitant use of MAOIs
CBZ - Monitoring (outpatient)
CBC with diff, PLT count: baseline, then qweek for 4 weeks, then qmonth X 3 mo, then q3months or as indicated
Electrolytes: baseline, then as indicated
LFTs: baseline then yearly or as indicated
BUN, SCr: baseline then yearly or as indicated
ECG if patient over age 40 or has pre-existing cardiac disease
Pregnancy test
Other treatment options
Calcium Channel
Three prospective studies have assessed clinical outcomes of treatment of acute mania with ECT
Baseline rating of depressive symptoms is a strong predictor of clinical response
Case reports suggest that ECT may be helpful in mixed states
Short-term, adjunctive treatment may be helpful in manic or mixed episodes
May benefit patients that are severely ill or agitated
Lorazepam is used most often

Calcium Channel Antagonists
Little support for calcium channel blocker efficacy in bipolar disorder
Verapamil has been studied
Nimodipine has been studied in ultra-rapid cycling

Treatment Options

– 600-2400 mg/day in divided doses

Side effects
headache, drowsiness, dizziness, ataxia, tremor, hyponatremia, weight gain, diplopia, nausea, vomiting, rash, Stevens-Johnson Syndrome

serum Na concentrations, efficacy and side effects

Drug interactions
Increases the metabolism of oral contraceptives and lamotrigine
Inhibits the metabolism of phenytoin when doses exceed 1200 mg/d
Phenobarbital increases the metabolism of oxcarbazepine by about 25%

Titration of dose, rash, CNS effects

Drug interactions
Carbamazepine, phenobarbital, and phenytoin all increase the metabolic clearance
Valproic acid reduces the metabolic clearance by 60%

Best studied of the third generation anticonvulsants

– 25-500 mg/day
- goal about 200mg/day

Side effects:
– Dizziness, sedation, ataxia, diplopia, and rash, Stevens-Johnson syndrome (incidence 0.16%)

Which of the following medication/therapeutic serum levels is correct?

a. Valproic acid 10-20mcg/mL
b. Lithium 0.6-1.2mEq/mL
c. Carbamazepine 50-150mcg/mL
d. Valproic acid 0.5-1.5mEq/mL

ED is a 25 yr old female, recently diagnosed with BPAD. She comes to you and asks about starting oral contraceptives. Which of the following mood stabilizers may be taken with oral contraceptives without decreasing its effectiveness?

a. Valproic acid
b. Nefazodone
c. Carbamazepine
d. Oxcarbazepine

AB is a 35 yo woman with a history of BPAD who comes to you complaining that all of the medications she has taken for BPAD have caused weight gain (from 20-40lbs depending on the agent). What medication could you initiate that may help a little with her mood as well as attenuate her weight gain?

a. Valproic acid
b. Lithium 0.6-1.2mEq/mL
c. Carbamazepine 50-150mcg/mL
d. Topiramate

BC is a 20yo male who was recently discharged form the hospital on carbamazepine. He had been hospitalized for the treatment of acute mania. One day prior to discharge his serum carbamazepine level was within normal limits and his mood was under good control. He presents today, approximately 4 weeks after discharge, and seems a bit hyper. Of note, he also has a history of smoking 1 pack per day and drinks “a few beers” occasionally. The only other medication he takes are nonprescription analgesics.

Which of the following symptoms would be most consistent with a return to mania in BC?

a. Paranoia, delusions, auditory hallucinations
b. Decreased sleep, rapid/pressured speech, hyperactivity
c. Restlessness, muscle tension, excessive worrying
d. Decreased energy, concentration, appetite

You check a level and find out that it is much higher than the day before he left the hospital and almost out of range. What is a likely cause of this change in serum level?

a. Auto-induction of metabolism is complete
b. Inhibition of elimination by ibuprofen
c. Induction of metabolism by cigarette smoke
d. Inhibition of metabolism by alcohol

A patient with BPAD ask how long he will need to stay on the antidepressant the doctor put him on during a depressive episode? You answer:

a. For life
b. Only while depressed
c. You shouldn’t ever be on an antidepressant
d. All of the above

He then ask how long he will need to be on his lithium? You respond:

a. For life
b. Only while manic
c. You shouldn’t ever be on lithium
d. You can stop it in a few months

Mr. B. comes into your pharmacy with a new prescription for gabapentin for his BPAD. He ask if you think it will help keep him from becoming manic or depressed? From the list below which medication has the most data to support its used in BPAD?

a. Topiramate
b. Gabapentin
c. Lamotrigine
d. Gabatril

A patient comes in complaining that the new medication “Lithium Carbonate” is causing him to have diarrhea. He ask what he could do about it?

a. Increase the dose
b. Change to lithium citrate
c. Change to the Eskalith CR
d. Change to Lithobid

After adding depakote to a patients regimen for BPAD the medical student on your team ask how long he should wait to get a level? He also states they need it as soon as possible. You reply:

a. 10 days
b. Levels correlate with efficacy in BPAD, so 5 days
c. 3 days
d. 7 days

Carbamazepine is a potent inducer at what cytochrome P450 isoenzyme?

a. 1A2
b. 2D6
c. 2C8/9
d. 3A3/4

A doctor calls to ask when adding valproic acid to a patient already on lamotrigine how should I begin?

a. 50mg qday
b. 100mg qod
c. 12.5mg qday
d. 25mg qday

Of the medications listed below which medication levels correlate with it’s efficacy in BPAD?

a. Lithium
b. Valproic Acid
c. Carbamazepine
d. Gabapentin

A patient comes in with ataxia and is on carbamazepine. You check a level to see if the patient may be toxic. What is the therapeutic range of carbamazepine?

a. 50-100mg/mL
b. 0.6-1.2mEq/mL
c. 6-12mcg/mL
d. 15-24mcg/mL

JV is a 34 yr old male brought to the emergency room by the police after neighbors called. He was standing in his front yard in boxer shorts preaching to people as they came home from work. His mother contacted the hospital and said he had been behaving strangely for about a week. He had bought 3 new cars and a $5000 entertainment center for his small 2-bedroom home.

Which of the following laboratory tests is most likely to determine a possible cause of JV’s symptoms?

a. Amylase and lipase
b. UDS
c. LFTs
d. PSA

Further history reveals that JV has had 2 major depressive episodes, but has never been treated for mania. The last depressive episode (4/03) was so severe he continues to take sertraline. He is a successful pharmacy student at the top of his class, and works 10-20 hrs per week. Over the past month, he has also started tutoring children in reading and joined 2 recreational baseball teams. He has not felt the need for more than 1-2 hours of sleep, and loves the extra energy. All laboratory values are WNL.

Which of the following is the BEST course of therapy for this patient (after discontinuing the sertraline)?

a. Gabapentin and diphenhydramine
b. Carbamazepine and methylphenidate
c. Lamotrigine and haloperidol
d. Topamax and lorazepam

Sertraline should be discontinued in JV because it:

a. Can induce mania
b. Is likely to interact with other medications
c. Should only be taken for 1 month anyway
d. May impair memory which will interfere with studying

All options for medication are considered, and the treatment team decides to start lithium in JV. What laboratory tests do you want prior to initiating lithium?

a. AST, ALT, Alk Phos
b. Mg, Ca, PO4

JV asks what side effects are most likely to happen with lithium. You tell him:

a. Insomnia, decreased appetite, and constipation
b. Leukopenia, aplastic anemia, Stevens-Johnson syndrome
c. Weight gain, hepatotoxicity, thrombocytopenia
d. Sedation, hand tremor, diarrhea

What medication should JV avoid since it can increase lithium levels?

a. Ibuprofen
b. Caffeine
c. Theophylline
d. Atenolol

Which of the following medication/therapeutic serum levels is correct?

a. Valproic acid 10-20mcg/mL
b. Lithium 0.6-1.2mEq/mL
c. Carbamazepine 50-150mcg/mL
d. Valproic acid 0.5-1.5mEq/mL

Carbamazepine would be contraindicated in a patient with:

a. Active psychosis
b. A history of leukemia
c. A sulfa allergy
d. Thyroid deficiency

The treatment of choice for a patient with severe toxicity to lithium treatment is:

a. Dialysis
b. Activated charcoal
c. Normal saline bolus
d. Potassium chloride

If lamotrigine is initiated in a patient receiving valproic acid (VPA), the starting dose of lamotrigine should be:

a. Lower than if started in a patient no receiving VPA
b. Higher that if started in a patient no receiving VPA
c. The same as in a patient not receiving VPA
d. Lamotrigine is contraindicated in patients receiving VPA

RG is a 27 yo male who is brought to the ER by his wife. She states that he has not slept in 4 days, and is continuously pacing. She says he has been talking non-stop and jumping from topic to topic. Further, he has spent all the money in their savings account. She is convinced he is using drugs, but a drug screen comes back negative. After admission to the psychiatric ward, it is determined that this is his first manic episode. Which of the following medications would be appropriate initial treatment for RG?

a. Gabapentin
b. Fluoxetine
c. Lithium
d. Topiramate

Lithium is a mood stabilizer which has the following pharmacokinetic properties:

a. Distributed primarily in adipose tissue
b. Metabolized to an inactive metabolite
c. Metabolized to an active metabolite
d. Excreted unchanged in the kidney
e. Excreted unchanged via the biliary system

Which of the following is NOT true for lithium carbonate?

a. Lithium is excreted renally
b. Lithium can cause hypothyroidism
c. Lithium decreases white blood count (leukopenia)
d. Lithium can cause GI upset
e. Lithium is metabolized by the liver

The main difference between Bipolar Disorder Type I vs Type II is that there are more depressive episodes in Type I.

True or False

Which of the following may induce a manic episode?

a. Fluoxetine
b. Cocaine
c. Hyperthyroidism
d. Nortriptyline
e. All of the above

Lab monitoring for valproic acid treatment includes:

a. Liver function tests
b. Complete blood count
c. Ammonia levels
d. One of the above
e. All of the above

All of the following may be used to treat acute mania EXCEPT:

a. Olanzapine
b. Gabapentin
c. Risperidone
d. Valproic Acid
e. Lorazepam

Which adverse effect is more frequently associated with oxcarbazepine than carbamazepine?

a. Ataxia
b. Nausea and vomiting
c. Stevens-Johnson Syndrome
d. Hyponatremia
e. Aplastic anemia

Which of the following combinations would result in a significant drug-drug interaction?

a. Olanzapine + Lithium
b. Gabapentin + Carbamazepine
c. Risperidone + Topiramate
d. Valproic Acid + Lamotrigine
e. None of the above

Which of the following is a dose related side effect of valproic acid?

a. Pancreatitis
b. Thrombocytopenia
d. Stevens-Johnson Syndrome

Lab monitoring for valproic acid treatment includes:

a. Liver function tests
b. Complete blood count
c. Ammonia levels
d. One of the above
e. All of the above

Acute Mania
Patients are usually on combination treatment during acute mania
Mood stabilizer (li or depakote)
Depending on severity of episode
Over time, most patients require combination therapy (kindling)
Treatment of Acute Mania
Lithium and depakote are mainstay of treatment
Antipsychotics can be used as monotherapy or as adjunctive therapy
Most SGAs have data a monotherapy and adjunct
FGAs have data as adjunctive therapy
Carbamazepine should be used as 2nd, 3rd line after patients fail li or depakote

Antipsychotics can be used to treat the mania itself and to treat the psychosis that comes along with mania
Benzodiazepines are used short term to help break the mania
Benzodiazepines typically started inpatient at high doses and then tapered as the mania resolves

Mania should begin to resolve within a few days of starting medications
Medications are typically started at a rapid pace and at high doses to break the mania
Doses of medications can be tapered and some medications may be discontinued after the mania resolves
Outpatients with mania and hypomania may not need the aggressive treatment that inpatients need because they are not as sick

Treatment of Acute Mania
Treatment of Acute Mania
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Treatment of Acute Mania
Biological Psychiatry 2003;53:1028-1042
British Journal of Psychiatry 1994;164:806-810
Archives of General Psychiatry 1988;45:727-732
Journal of Clinical Psychiatry 1996;57:543-546. Psychiatry Res. 1993;49:257-272.
Sachs GS, Nierenberg AA, Calabrese JR, et al. NEJM 2007;356:1711-22.
Sachs GS, Nierenberg AA, Calabrese JR, et al. NEJM 2007;356:1711-22.
Sachs GS, Nierenberg AA, Calabrese JR, et al. NEJM 2007;356:1711-22.
The big picture....
not used for the treatment of BPAD, but useful to counteract weight gain associated with many of the treatment agents
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