These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific

conditions. Clinical data in a particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are

institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Optima Health

Management of Bipolar Disorder

Guideline History

Date

Approved 5/02

Date

Revised 1/06, 1/09, 1/11

Date

Reviewed 5/06, 1/08, 1/13, 1/15

Next

Review

Date 1/17

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical

data in a particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed

recommendations and are not intended as a substitute for clinical judgment.

Key Points

NOTE: Upon the recommendation of our Medical Care Review Committee (MCRC),

Optima Health does not support the following components contained in this

guideline:

1. Use of lamotrigine as monotherapy for bipolar depression (p. 19)

2. Maximum dose of 60 mg citalopram (due to FDA warning regarding

QT interval prolongation) (Appendix D, p. 61)

The lifetime prevalence of bipolar I disorder is estimated at 0.8% of the adult population,

with a range between 0.4% and 1.6%. Bipolar II disorder affects approximately 0.5% or

more of the population. Bipolar II disorder is more common in women; bipolar I disorder

appears to be evenly distributed between men and women.

Bipolar disorder is often comorbid with a range of other mental disorders such as substance

misuse and anxiety disorders.

Patients with Bipolar disorder can present with: a major depressive episode, manic episode,

hypomanic episode or a combination of manic and depressive symptoms (mixed episode).

This guideline contains separate algorithms based on presentation.

A complete clinical assessment should include: medical comorbidities, psychiatric

comorbidities, psychosocial status, current medications, response to past medications,

medication compliance and substance use.

Medications for mania and mixed episodes may take 5-10 days to begin showing a

significant positive effect. After any change in medication or dose, monitor the patient for

both positive and adverse effects. Reassess every 1-2 weeks for at least 6 weeks.

DSM-IV-TR defines Full Remission as “a period of at least 2 months in which there are no

significant symptoms” of mania or depression.

Patients with bipolar disorder who achieve a satisfactory clinical response (symptom

remission) should continue maintenence treatment.

Patients being prescribed an atypical antipsychotic should be monitored for possible

metabolic effects. (Our guideline “Monitoring Clients on Atypical Antipsychotics and

Management of Metabolic Effects” is available on the Optima website.) Communicate

and coordinate care with patient’s primary care physician (PCP) as needed.

Recent studies indicate positive benefit of psychoeducation and psychotherapy to address

stressors and comorbidities, symptom management, coping strategies and medication

adherence.

VA/DaD Clinical Practice GuidelineforManagement of Bipolar Disorder in Adults

Management of Persons with Bipolar DisordersA: Current Mania, HypomanIa or Mixed Episode A

Person me.ets DSM-l\! criteri"for bipolar manic, hypomanic

or mixed episode[AIJ Sidebar A: Clinical Status Assessment

2

No

Medicsl smj P5yd1iatric romerbidit1

Psyd10seda I .tstu.Current sndpsstmee! ication

Adhersnce te therspySuidde ris,SubstanO? use

Complete assessm..ntRe...i~w current medication

Assess risk fo.r suicide

[A2]

Is patient takingantidepressants or

mania-inducingmedication?

[ ,0.3 ]

Reduce/stopantidepres5<",ts

["'3 J

Se'.'ere mani" orpsychotic Features

present?[M]

- Ref..r for hospitalization- Initiate/adjust tr.;tament with

combination of antipsychotic andantimanic medications

- Reassess every 2-5 days untilsyptoms improve

[,0.5 J

[A6 ]

Is patient recei'.'ingdin lea I e ffeetivemedcaitons For

bipolar mani,,/mixed[Al]

y.,

No3

Initiate/adjust tretarnent ",ithan anti manic medication

[A9]

Modif',' dose or medication if indicated[A8J

"0

Is patient respondingto ther"p~'?

[Ail]

Ccntinu e current tr"atment

f'.lonitor regularly for 8 "",eks

NoIs patient in full

remission[ A12]

Ye..14

Ass"ss adh"rence, n"eds For psychosocialand/or family interventions.,

adverse "FFeets; and p.sI'chasodalbarri"rs to th"rapy .

Assess risk for suicide

[ ,0.13]

No

f~,

Add/change anti manicmedication until stable or

consider alternative therap',[ ,0..14 J

'eIs. patient in Full

remission?[Ali ]

Ye"

17N

R"evaluat" diagnosis and treatemntConsider hospitalizahon and orconsultationConsider ECT

C,mtinue to Module CMaintenance ThErapy

22:YYC,

Module A: Current Mania, Hypomania,or Mixed Episode

VAlDoD Clinical Practice Guideline forManagement of Bipolar Disorder in Adults

Management of Pel'sons with Bipolar DisordersB: Current Bipolar Depressive Episode

Person meets D5M-IV <rite ria fo,bipolar depre.,.;,e episode

[ 101 )

2

Complete asse.smentRe,iew.wrrent medications

A,sess risk for sukide[62 ]

Is the patient athigh ri.k of harm;ne

-self or others? -[63 ]

Refer for hospitalization [ 64 ]

No

Is pati..nt currentlyrH..iving dinical

e,f..di"... m..dieation.for bipolar depre.sion?

[ 65 ]

No

Initiat.. p"armacob..rapy ,',it;,medication ..ffecti',e fo, biod.r

d..pre.sion [66 ] .

B

Sidebar A; Clinical Status Asse..ment

Medical and ".vchiatrio comorbidit--",.,cho.ocial .t~tu. .Current and paot medic.tionA.dherence to therapySuidde ri.kSubstanc.. us..

Yu

Modify dose or medication if inoiotedusing medications effedive for bipola,d..pression [67 ]

~

Pro,'ide p.ycho"ducation,a"rchab"rapy and familyinte""ntion as indioated

[ 69 ]

,'JIs pati"nt r"".pending to

treatment?[ 610 ]

No

'J;"sess adher..nce, side eff..ds and

pS',ohesocial barri..rs to therapyAss..ss risk for suioid..

[ Bl2 ]

Augment or combin.. drugs [E!t]Consider 6CT or altemativ.. therapies [Bl3]Ensur.. p, ntion of induced m.nia

15Is patient in full

remission?[ 611]

:e No

Reevaluate diagnosis and treatmentConsid..r hospitalization and orconsultationCOMid"r ECT

Yu

Yu

No

Yu

Continue on Module CMaintenanc<: Th",apy

Module B: Bipolar Acute Depressive Episode

VAlDoD Clinical Practice Guideline forManagement of Bipolar Disorder in Adults

1Ilanagement of Pel'sons with Bipolar'Disorders [BDJModule C: Maintenance c

I'"""tt PE""" with hipolEr dIS"'<:H insimptcm"ticrEmission '" se!o3).oc{cm", aftE'

an acctE manldhypcms.oidmixec "'fcEp'"",iv" "'plsooe

iC1!

Sid..b2r A: CHnica.1 Status Aasessm..nt

AssESS rocrse d IIIness, ""atment

hist",", s"ccw,ent dioiesl st.w.(.e", sld~baf ,A,j

D.2

M..dical and Ps.ychiatric comorbldftyPsychosocial status,C"rrent and past medicationAdh..r..n<:e to tn..rapySuicide riskSubslanc," us,"

3

Is pstlent "'eEI>;hg tclHSbl.. aoddlnl"".1 ~ffEdivE meeiD!!ti,,", kr

maintaining th"r~mlssi"n? IC3!,/'"

YES

Nc

losmut", mE"t"nEOeE m;;diesti':nthat ha'f" d..m"nsirat"d dlnl"",1

"mcaey f", at 1"5;; e mcnth[C4I

Gontine" rr,alntenance mEdicationfo, ,at I"as' " m':oth

~

"ro'ii"" !,->yd1""ceostice, psy&':thS'ap"i Endlamlli 1","NEnti"n as indiest,,"

I Ct)

;'.$,:".>5'''.p"ns. aftS' ,-3 m"eths, On,g"icg a""..m.nt>at 1.5st In six -nt"" (X mcrE clt.n if dioies.llyn.cessa,,!- Mcnitcr Ell m.dication ano n,.ea.g" adv.,," Eff.ct>- Mcnitcand .nrours-g..adh",.no;,- Dis,",ss with pati..nt ,is. and O;""..frt ot 10"9 tS'm

ph~"m~ ""th.,apy[CT)

, IsthS'.. any meeical '"~fxiatic =mo,bidi!y?

(e,.g, SUD, ."xl"t';', suiddEJiiy)fC<8!

10

y", TI.st as di,icarlyIndicat,,"

N:

!1 13M.nag. acct plsod.,

Mooel. A (Manic Eplsod.)MOdel. 5 (D"",""lv", Epiooo,,)

I. pali",,,!in '.Iapo.. ,m..",,,o-it6io kf blpolar"piS:'<i",

ICe]

YES

r-lc

Do", p~ti"nt ,till h"v.sympt:ms", IntdeJabi.. ,id",

.ff.::;is?

,4

y.s Optimiz" ""'dlesti:, '''9i"",nane 1"')'''''''10,''''10/IntiON..nti"ns

iC10]

rb

1:, Censid"" disrontinuing m..dicatic" net critical for meedstabilizati"" "hi!.. msln'"ieing oymptomatic and

functional ,,,mlssi,,n

Continue tonC"""p to pt,="..nt ,..I~1OSE'and p'""",te'''C:>;''-':; am! ,,,habilitEtion

IC,1 j

Module C: Maintenance

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a

particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Description of Algorithm Steps for Management of Bipolar Disorder:

Current Mania, Hypomania or Mixed Episode

Step 3 Antidepressants or other manic inducing substances should be stopped in patients experiencing a manic,

hypomanic, or mixed episode. Antidepressant medications known to be associated with discontinuation

syndromes may be tapered over 3 to 5 days rather than being abruptly stopped.

Step 6 Patients with severe mania should be treated with a combination of antipsychotics and lithium or valproate.

These antipsychotics include olanzapine, quetiapine, aripiprazole, or risperidone and may include

ziprasidone.

Patients with severe mixed episode should be treated with a combination of antipsychotics and lithium or

valproate. These antipsychotics include aripiprazole, olanzapine, risperidone or haloperidol and may

include quetiapine or ziprasidone.

Clozapine, with its more serious side effect profile, may be added to existing medications for severe mania

or mixed episode if it has been successful in the past or if other antipsychotics have failed.

Patients who are not hospitalized should be reassessed every 2-5 days until symptoms improve.

Step 8 If patient is having intolerable side effects, switch to another effective treatment.

Assess compliance and blood serum concentration to assess if medications are in therapeutic range.

a. The serum trough concentration of lithium should be maintained between 0.8-1.2mEq/L.

b. The serum trough concentration of valproate should be maintained between 50-125mcg/ml.

c. The serum trough concentration of carbamazepine should be maintained between 4-12mcg/ml.

Medications without known therapeutic plasma concentrations should be increased until significant

improvement is seen, side effects become intolerable or the dose reaches the manufacturer’s suggested

upper limits.

Step 9 Pharmacotherapy for bipolar mania or mixed episode should start with initiation or optimization of a

medication that has been shown to be the most effective in treating bipolar manic episodes while

minimizing the potential risks.

Consider using the agent(s) that have been effective in treating prior episodes of mania or mixed episode.

Patients with mania should be started on one of the following: lithium, valproate, carbamazepine,

aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone.

Patients with mixed episode should be started on one of the following: valproate, carbamazepine,

olanzapine, aripiprazole, risperidone, or ziprasidone.

Clozapine, haloperidol and oxcarbazepine may be considered in patients with mania or mixed episode.

Lithium or quetiapine may be considered in patients with mixed episode.

Medications NOT recommended in patients with mania or mixed episode include topiramate, lamotrigine,

and gabapentin.

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a

particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Step 14 Escalating pharmacotherapy may be considered for patients whose mania/mixed episode or hypomania

does not respond to monotherapy. The possible options for escalating pharmacotherapy include:

a. Switching to another monotherapy may be considered if the patient did not respond to the first

medication.

b. In patients with mania/hypomania who do not respond to monotherapy, consider combining a

non-antipsychotic mood stabilizer (lithium or valproate) and a second generation

antipsychotic such as aripiprazole, olanzapine, quetiapine, or risperidone or ziprasidone.

c. In patients with mixed episode who do not respond to monotherapy, consider a combination

of a non-antipsychotic mood stabilizer (lithium or valproate) and a second generation

antipsychotic such as aripiprazole, olanzapine, or risperidone or quetiapine or ziprasidone.

Clozapine, with its more serious side effect profile, may be combined with valproate or lithium as a

treatment of severe mania or mixed episode, if it has been successful in the past or if other antipsychotics

have failed.

Adjust medications if there is no response within 2-4 weeks on an adequate dose of medication.

Electroconvulsive therapy (ECT) may be considered for patients with severe mania or patients whose

mania is treatment resistant, those patients who express a preference for ECT, and patients with severe

mania during pregnancy.

Risks and benefits of long-term pharmacotherapy should be discussed prior to starting medication and

should be a continued discussion item during treatment.

Description of Algorithm Stages for Management of Bipolar Disorder-

Currently Depressed

Step 6: Monotherapy

Quetiapine, lamotrigine, or lithium monotherapy should be considered as first-line treatment for adult patients

with bipolar depression.

Olanzapine/fluoxetine combination (OFC) should be considered for treatment of bipolar depression, but its

adverse effects (weight gain, risk of diabetes, hypertriglyceridemia) places this combination as a second-line

treatment.

There is insufficient evidence to recommend for or against the use of valproate, carbamazepine, topirimate,

risperidone, ziprasidone, or clozapine for bipolar depression.

Aripiprazole is NOT recommended for monotherapy in the treatment of acute bipolar depression, unless there is

a history of previous good response during depression without switch to mania or a history of treatment

refractory depression.

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a

particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Combination Strategies

Combining lithium with lamotrigine can be considered for patients with bipolar depression who do not respond

to monotherapy.

When patients do not respond to treatment options that have shown better efficacy, antidepressant augmentation

with SSRI, SNRI, bupropion, and MAOI can be considered for short-term treatment monitoring closely for

triggering of manic symptoms.

Clozapine can be considered for augmentation, using caution regarding metabolic or other adverse effects.

There is insufficient evidence to recommend for or against use of augmentation with aripiprazole, olanzapine,

risperidone, haloperidol, oxcarbazepine, topirimate, ziprasidone, valproate, or carbamazapine for the treatment of

bipolar depression.

Gabapentin and the tricyclic antidepressants (TCA’s) are NOT recommended for monotherapy or augmentation

in the treatment of acute bipolar depression, unless there is a history of previous good response during depression

without switch to mania or a history of treatment refractory depression.

Step 7 Partial response

Adjust medications if needed within 2-4 weeks on an adequate dose of medication.

Adjustments may include:

a. Augmenting with additional agent(s)

b. Discontinue the current agent and switch to another effective medication

c. If multiple trials of switching medications or augmentation strategies have not been effective,

consider ECT.

Any discontinuation of medication used to treat bipolar depression should be tapered and the patient should

be monitored for antidepressant discontinuation syndrome and mood destabilization.

Step 9 Psychoeducation, psychotherapy and Family Intervention

Give simple educational messages regarding medication therapy (e.g., take daily, understand gradual nature of

benefits, continue even when feeling better) in order to increase adherence to treatment.

Educate patient and family about the risk of switching to mania or hypomania that may occur naturally or as a

result of medications.

Consider psychoeducation and care management for patients with bipolar disorder. For best effect consider

offering in a structured group setting with ongoing care/disease management.

Patients who are currently in a depressive episode and are at high risk for non-adherence to medication, should

be considered for one of the following evidence-based psychotherapeutic interventions:

a. Cognitive behavioral therapy (CBT)

b. Family Therapy

c. Interpersonal and Social Rhythm Therapy (IPSRT)

Step 13 Electro-convulsive therapy (ECT) should be initiated in patients with severe or refractory bipolar depression who

consent and have no absolute medical contraindications.

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a

particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Management of Persons with Bipolar Disorder: Maintenance

Step 1 Patients who have had an acute manic episode should be treated for at least 6 months after the initial episode is

controlled and encouraged to continue on life-long prophylactic treatment with medication.

Patients who have had more than one manic episode or with one manic and one depressive episode, or three or

more depressive episodes, should be encouraged to continue on life-long prophylactic treatment.

If medications are to be discontinued, they should be slowly and gradually tapered over at least a 2 to 4 week

period, unless medically contraindicated, in order to prevent an episode of bipolar disorder and/or increased risk

of suicide.

Step 4 Maintenance Medication

Consider using the agent(s) that have been effective in the recent acute phase or in past mood episodes.

Consider reducing to a single medication (monotherapy) that has been shown to be most effective in

delaying/preventing relapse while minimizing the potential risks.

Lithium or olanzapine should be considered as first-line maintenance treatment for adults with bipolar disorder

to delay/prevent the recurrence of mania.

Risperidone long-acting IM injection should be considered for patients with frequent relapses.

Aripiprazole may be considered as a second line treatment to prevent or delay the recurrence of mania.

Lithium, or lamotrigine, should be considered as a first-line treatment to prevent or delay the recurrence of

bipolar depression. Olanzapine may be considered as a second line treatment to prevent/delay bipolar

depressive episodes.

Quetiapine augmentation of valproate or lithium should be considered a first-line maintenance treatment for

adults with bipolar disorder to maintain remission and prevent new episodes of all types.

Adding olanzapine to lithium or valproate may be used in maintenance treatment to delay or prevent

symptomatic relapse.

In patients with a history of severe or recent mania, lamotrigine should be used in combination with lithium,

olanzapine, or aripiprazole.

Valproate and carbamazepine may also be considered as alternatives for maintenance medication.

There is insufficient evidence to recommend for or against other antipsychotic or anti-epileptic agents in the

maintenance treatment of bipolar disorder.

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a

particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Recommended Pharmacotherapy Monitoring: Lithium, Antieptileptics

Starting Therapy Follow-up during Ongoing

Therapy (Stable Outpatient) Medication Baseline During Titration Lithium

0.6-1.2 mEq/L

sCr, eCrCl,

Electrolytes,

Thyroid profile

Pregnancy test***

Lithium serum concentration

q 4-14 days

Serum concentration q 6 mos

Annual sCr, eCrCl,*

Annual Thyroid profile**

Annual CBC w/ diff

Carbamazepine

4-12 mcg/ml

CBC w/ diff

LFT’s

CBZ concentration

q 2 wks for 3 mos

CBC w/ diff

LFT’s at 1 and 3 mos

Annual serum concentration

Annual CBC w/ diff

Annual LFT’s

Annual Electrolytes

Valproate

50-125 mcg/ml

CBC w/ diff

LFT’s

Valproate serum concentration no

sooner than 5-7 days after a

change in dose.

CBC w/ diff

LFT’s at 1 and 3 mos

Annual serum concentration

Annual CBC w/ diff

Annual LFT’s

Annual Electrolytes

sCr= serum createnine; eCrCl= estimated/calculated createnine clearance

* If sCr is elevated, even after a repeat check, then a 24-hour createnine clearance should be obtained every 6 months (q3-9

months) if sCr <2mg/dL. If sCr >2mg/dL then a 24 hour createnine should be obtained and the patient’s primary care provider

notified. Defer to the patient’s nephrologist if the patient is under the care of nephrology.

** Obtain annually (e.g., 9-15 months) for 5 years while on lithium. If after 5 years and no abnormalities, a thyroid profile should

be ordered when a patient’s clinical presentation warrants it.

*** For women of child-bearing potential

Electro-convulsive Therapy (ECT)

ECT for bipolar disorder is indicated as the primary therapy in the following:

a. Psychotic symptoms

b. Catatonia

c. Severe suicidality

d. Food refusal leading to nutritional compromise

e. History of prior positive response to ECT

ECT is considered as first line therapy for the following conditions:

a. Need for rapid, definitive treatment response on either medical or psychiatric grounds

b. Risks of other treatments outweigh the risks of ECT

c. Adequate trial of other treatment options has proven ineffective

d. Patient preference

ECT may be considered as augmented therapy in the following:

a. Treatment failure

b. Unavoidable adverse effects using alternative treatments

c. Deterioration of patient’s condition such that the first criterion is met.

VA/DoD Clinical PracTice Guideline forManagement of Persons with Bipolar Disorder

APPENDIX D: BIPOLAR DRUG TABLES-~~-"-~--""--""-"""'-"'---"-'~' _m",_,_,

Table D - 1. Dosing Parameters for Medications for Bipolar Medications

Lithium Carbonate

Cap: 150, 300, 600mEq

Tab: 300 mEq

Tab CR: 450 mEq

Syrup (citrate):8mEq/5mL

150 - 900 mg/day

Single (bedtime) or divided two orthree times a day. Increase doseby:so 150 mEq per day no soonerthan every 5 days.

;::5 Acute mania: 0.8-

1.2 mEq/L

Maintenance: 0.6

- 1.0Eq/L

Serum lithiumconcentrations should notexceed 1.2mEq/mL

Adjust dose:.CrClI0-50: 50%-

75% of normaldose

CrCI <10: 25%-50% of normaldose.Best to avoid inmoderate to severe

impairment.

None See renal

impairment;Initial dose no

greater than 600mg /day

-'---- - - - - - --

Medication Initial Oral Dose and Titration Days The,"apeutic Maximum Initial Dose Adjustment/ Guidanc,e in Special PopulationsFormulations and Between Range or Dose Renal Impairment Hepatic Geriatric

Strengths Dose Tm"get Daily ImpairmentAdjustment Dose

Lithium

.Anticpilcptics

Carbamazepine Initial: 100 -200 mg as a single 3-7 4 - 12 mcg/mL 1600 mg Adjust dose based Adjust dose based Adjust dose based

Cap ER: 100 mg, 200 dose. Increase by 100 mg/day on response and on response and on response and

mg, 300 mg weekly. Dosing should be two or serum serum serum

Tab: 200 mg three times a day based on concentration. concentration. concentration.

Tab chewable: 100formulation.

mg Tablet ER: 100mg, 200 mg, 400mg

Suspension, oral: 100mg/5 mL

VA/DaD Clinical Practice GuidelineforManagement of Persons with Bipolar Disorder

Medication Initial Oml Dose and Titration Days Therapeutic Maximum Initial Dose Adjustmentl Guidance in Special PopulationsFormulations and Between Range or Dose

Renal Impairment Hepatic GeriatricStrengths Dose Target Daily Impairment

Adjustment Dose

Valproate as Delayed release: 5 50 - 125 60 mg/kg/d None required. Required in mild- Lower doses mayDivalproex Inpatient: 20 mg/kg as a loading mcg/mL Increased moderate be required due

Delayed release: 125. dose in two or three divided unbound drug may impairment; to increased

250, 500 mg doses; 750 mg twice a day. make total Avoid if severe. unbound drug;

Extended release: Outpatient: 250 - 500 mg divided valproate Sedation more

250, 500 mg every 12 hours. Increase by 250 - concentration problematic

Liq:250/5mL 500 mg/day no sooner than every misleading

5 days.Inject. Maintenance: 20/mg/kg/day in two

divided dosesExtended release:

Inpatient: 25 mg/kg/day as a singledaily dose.

Outpatient: 250 - 500 mg as a singledaily dose. Increase by 250 - 500mg/day no sooner than every 5days.

Lamotrigine Not taking divalproex or CBZ: 25 7 -14 200 mg 400 mg Has not been Moderate to severe No specific ageTab: 25, 100, 150, mg once a day for 2 weeks, then studied, decreased impairment adjustment

200 mg 50 mg/day for 2 weeks, then 100 dosing may be without ascites required.mg/day for I week advised. decrease dose by

Taking divalproex: 25 mg every 7 -14 100 mg 200 mg 25%; with ascites

other day tor 2 weeks, then 25 decrease dose by

mg/day tor 2 weeks, then 5050%. Titrate

mg/day tor Ibased on clinical

week, then 100 mg/dayresponse.

Taking enzyme inducing drug (e.g., 7-14 300 - 400 mg 400 mgCBZ): 50 mg/day tor 2 weeks,then 100 mg/day for 2 weeks, then200 mg/day tor I week, then 300mg/day tor I week

VA/DaD Clinical Practice GliidelinejorManagement of Persons with Bipolar Disorder

Medication Initial Oml Dose and Titration Days

I Therapeutic I Maximum

Initial Dose Adjustment/ Guidance in Special PopulationsFormulations and Between Range or Dose Renal Impairment

Strengths Do'" .- ..

A(

Aripiprazole

130 mg 130mg I No adjustment 1 No adjustment I No specificTab: 5, 10, 15,20,30 required required

:ecommendationmg

Soln: I mg/mL

Clozapine 112.5 mg

1- 4 300 - 450 mg 900 mg No adjustment No adjustment No specificTab: 12.5,25, 100 mg required required recommendation

s

Olanzapine Acute Mania: 10 - 15 mg 2:1 5 - 20 mg 20 mg No adjustment Adjustment may be Lower initial

Tab: 2.5,5,7.5,10, required necessary; no doses and slower

15,20 mg specific titration, 2.5 - 5

Inj: 1Mrecommendations mg, may be

better tolerated.

Quetiapine

I Acute Mania: 50 mg twice a day on

2:1 400 - 600 mg 800 mg No adjustment Adjustment may be Reduced

Tab: 25, 100, 200, Day I, increase by 100 mg/day to required necessary; 25 clearance; lower

300 mg 200 mg twice a day on Day 4. mg/day. increase doses may be

Acute Depression: 300 mg 300 or 600 mg 600 mg by 25-50 mg per needed.

day to effectivedose based on

response.

Risperidone Oral: 2-3 mg >1 1-6mg 6mg Reduced clearance Reduced clearance; Initial dose 0.5 mgTab: 0.25, 0.5, 1, 2, 3, of active Starting dose 0.5 twice a day;

4mg Maintenance: 1M: 25 mg every 2 >4 weeks 25 - 50 mg every 50 mg every 2metabolite with mg twice a day increase no

SoIn: 1mg/mL weeks 2 weeks weeks moderate to severe greater than 0.5

Long-acting inj.impairment; mg twice a dayStarting dose 0.5 and no soonermg twice a day than once a

week at doses

> 1.5 mg/day

Ziprasidone

1 Acute Mania: 40 mg twice a day

2:1 120- 160mg 160 mg No adjustment No adjustment No adjustment;Cap: 20, 40 , 60, 80 recommended recommended lower doses maymg be sunicient

VA/DoD Clinical Practice GuidelineforManagement of Persons with Bipolar Disorder

Medication Initial Oral Dose and Tih"ation Days Therapeutic Maximum Initial Dose Adjustment/ Guidance in Special PopulationsFormulations and Between Range or Dose

Renal Impairment Heplltic GeriatricStrengths Dose Tm"get Daily Impairment

Adjustment Dose

OlanziFluoxetine Glanz6 mg/Fluox.25 mg Glanz 6-12 mg/ Glanz. 18 mg/ See individual agentsCap: 6/25,6/50, Fluox. 25-50 mg Fluox. 75 mg12/25, 12/50 mg

Antidepressants

Citalopram 20 mg once a day ;::1 10-60 mg/day 60 mg Avoid: CrCI < 20 t dose 10-20 mg

Escitalopram 10 mg once a day ;::1 10-20 mg 40 mg Avoid: CrCI < 20 10mg 5-10 mgFluoxetine 20 mg once a day ;::2 20-80 mg 80 mg No change tdose 50% 10mg

Fluoxetine weekly 90 mg once a week NA 90 mg 90 mg Avoid Avoid 90 mgParoxetine 20 mg once a day ;::1 20-50 mg 50 mg 10mg IOmg 10mgParoxetine CR 25 mg once a day ;::1 25 mg 62.5 mg l2.5mg 12.5 mg 12.5 mgSertraline 50 mg once a day 2:1 50-200mg 200 mg 25 mg t dose 25 mg

Duloxetine 20-30 mg twice a day ;::1 20-60 60 mg Avoid ifCrCl < 30 Avoid 20 - 40mgVenlafaxine IR 37.5 mg twice a day ;::1 37.5-225 mg 225-375 mg CrCIIO-70, t 50% t dose 50% 25-50 mgVenlafaxine XR 75 mg once a day ;::1 75-225 mg 225 mg CrCI 10-70, t 50% t dose 50% 37.5-75 mg

Severe:

Bupropion IR 100 mg twice a day ;::1 75-450 mg 450 mg Has not been 75 mg/day 37.5mg BID

Bupropion SR 150 mg once a day 2:1 100-150 mg 400 mg studied 100 mg / day 100 mg QD

Bupropion XR ISO mg once a day ;::1 150-300 mg 450 mg 150 mg /other day 150 mg QD

Trazodone 50 mg three times a day 2:1 75-600 mg 600 mg No change Unknown 25- 50 mgNefazodone 100 mg twice a day ;::1 300-600 mg/day 600 mg No change Avoid 50 mg BID

Mirtazapine 15 mg QHS 2:1 15-45 mg/day 45 mg CrCI <40 mL/min CI t 30% 7.5 mg QHS

Amitriptyline 50 mg QD- TID ;::1 75 mg QD 300 mg No changeLower dose and

10-25 mg HS

Impramine 25 mg QD - QID 2:1 50-150 mg/day 300 mg No change slower 10-25 mg HS

Nortriptyline 25 mg TID - QID >1 25 mg, 3-4/ day ISO mg No change titration 10-25 mg HS

Desipramine 25 mgTID-75 mgQD ;::1 100-200 mg/day 300 mg No change recommended 10-25 mg QD

Doxepin 25-75 mg QHS or BID ;::1 75 -ISO mg/day 300 mg No change 1-25 mg QHS

Isocarboxazid 10 mg BID-TID ;::1 10-60 mg 60 mg 10 mg BIDPhenelzine ]5 mg TID 2:1 60-90 mg 90 mg No change No change 7.5 mg QD

Selegiline patch 6mg/24h ;::2 6 mg/24 hours 12 mg/24h 6 mg/24h

Tranylcypromine 10 mg BID ;::] 30 mg/day 60 mg/day 10 mg BID

Adverse Medication Effects

Lithium:

Acne

Alopecia

Cognitive or memory impairment

Dermatologic (macular popular eruptions,

exfoliative dermatitis, follicular eruptions)

Polyuria/dypsia

Diabetes Insipidus

Drug interactions

Encephalopathy

GI complaints (nausea, vomiting, diarrhea,

anorexia)

Hypothyroidism

Increased parathyroid hormone

Leukocytosis

Muscle weakness (transient)

QRS widening

Renal complications (tubular acidosis, decreased

glomerular filtration rate, nephritic syndrome, and

possibly interstitial fibrosis, tubular atrophy or

glomerular sclerosis with long term exposure)

Teratogenic (Pregnancy category D)

Thrombocytosis

Toxicity

Tremor

T-wave changes

Weight gain

Signs, Symptoms and Management of Lithium Toxicity

Lithium Concentration

(12 hours post dose

unless specified)

Interpretation

Signs and Symptoms of Toxicity

Management

1.2-1.5 mEq/L Warning of potential serious toxicity

New onset or worsening of tremor,

nausea, vomiting, diarrhea,

drowsiness, sluggishness

Hold Lithium until concentration returns to

therapeutic range. Identify causes of toxicity:

drug-drug and drug-diet interactions, dosing

errors. If a cause cannot be identified, then

evaluate the patient’s kidney function.

1.6-2.5mEq/L Serious, but not considered life-

threatening

Coarse, irregular tremor, apathy,

sluggishness, drowsiness, sleepiness,

speech difficulty, smaller myoclonic

twitching, muscular weakness, ataxia,

and small increase in serum createnine.

Hold lithium; determine when last dose taken;

repeat lithium concentration <3 hours (if dose

not taken in the past 12 hours); assess fluid

status, electrolytes, and renal function.

Assess for drug-drug & drug-diet interactions.

Admission may be necessary to manage fluid

and electrolytes.

>2.5mEq/L Severe toxicity; >3.5mEq/L is a

medical emergency.

Nausea, vomiting, diarrhea, renal

failure, hyperreflexia, myoclonic and

choreoathetoid movements, ataxia,

dysarthria, coarse tremor, confusion,

delirium, hallucinations, seizures,

stupor, and coma.

Admit patient for management and

assessment.

Lithium Drug Interactions

↑Li Concentration ↓Li Concentration Other Interactions Thiazide diuretics

Furosemide

Caffeine via diuresis

Desmopressin

Angiotensin converting enzyme

inhibitors (ACEI’s)

Nonsteroidal anti-inflammatory drugs

(except sulindac)

Reduced sodium intake

Increased sodium intake

Sodium bicarbonate

Antacids

Theophylline

Verapamil

Osmotic diuretics

Neurotoxicity

Antipsychotics

Carbamazepine

Methyldopa

SSRI’s

MAOI’s

Diltiazem

Verapamil

Lithium effect on:

Amphetamines- decreased stimulatory effects

Chlorpromazine- reduced concentrations

Neuromuscular blocking agents- thyroid toxicity

Other drugs and diet can interact with lithium by affecting lithium clearance or through non-pharmacokinetic mechanisms.

Adverse Events of Anti-Epileptics

Intervention Significant Adverse Events or

may affect adherence

Serious or Life-Threatening

Adverse Events

Valproate Alopecia Tremor

Drug interactions Weight gain

Hepatotoxicity Pregnancy Category D

Hyperammonemia Stephens-Johnson syndrome

Pancreatitis Thrombocytopenia

Lamotrigine Cognitive impairment

Drug interactions Rash

Peripheral edema Headache

Vision changes

Pregnancy Category C

Stephens-Johnson syndrome

Topirimate Cognitive impairment

Weight loss Anorexia

Nystagmus Vision changes

Parasthesia

Decreased serum bicarbonate Purpura

Leukopenia Nephrolithiasis

Thrombocytopenia

Gabapentin Peripheral edema

Requires dose adjustment

based on renal function

---

Oxcarbazepine Ataxia

Drug interactions

Rash

Agranulocytosis SIADH/hypnatremia

Aplastic anemia Stephens-Johnson syndrome

AV block/bradycardia Thrombocytopenia

Pregnancy Category D

Carbamazepine Ataxia

Drug interactions

Rash

Agranulocytosis SIADH/hypnatremia

Aplastic anemia Stephens-Johnson syndrome

AV block/bradycardia Thrombocytopenia

Pregnancy Category D

Comparison of Relative Adverse Effects of the Second Generation Antipsychotics

Adverse Event Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone

Anticholinergic

effects

+ ++++ +++ + + +

Extrapyramidal

effects

+ 0 + 0 ++ +

Hyperglycemia + ++++ +++ ++ + 0

Hyperlipidemia + ++++ +++ ++ + 0

Hyperprolactinemia + + + + +++ +

Neuroleptic

Malignant Syndrome

+ + + + + +

Orthostatic

hypotension + ++++ + +++ ++ +

QTc prolongation 0 ++ + ++ ++ +++

Sedation + ++++ +++ +++ ++ +

Tardive dyskinesia 0 0 + 0 + +

Weight gain 0 ++++ +++ ++ ++ 0

Extrpyramidal effects include dystonia, akathisia, and pseudoparkinsonism

Incidence: 0= Zero-unlikely; += unlikely-low, possible; ++= low-moderate;

+++= moderate-high, probable; ++++= high, likely

Adverse Events of Antidepressants

Adverse Events

Drug Class Significant or may affect

adherence

Serious or Life-Threatening

SSRI GI complaints

Drug interactions

Headache

MAO Pyridoxine deficiency

Sedation

Drug/Food interactions

Hypotension

TCA Anticholinergic effects

Drug interactions

Orthostatic hypotension

Sedation

Cardiovascular

Overdose (lethal)

Risk of switching

These Guidelines are promulgated by Sentara Healthcare (SHC) as recommendations for the clinical management of specific conditions. Clinical data in a particular case may necessitate or permit deviation from these Guidelines. The SHC Guidelines are

institutionally endorsed recommendations and are not intended as a substitute for clinical judgment.

Reference

Adapted from VA/DoD Evidence Based Practice Clinical Practice Guideline on Management of

Bipolar Disorder in Adults, May 2010. http://www.healthquality.va.gov/bipolar/bd_306_sum.pdf

Accessed 1/2/13.

Resources for Patients/Families

Depression and Bipolar Support Alliance

http://www.dbsalliance.org

Mental Health America

http://www.mentalhealthamerica.net

National Institute of Mental Health

http://www.nimh.nih.gov

National Mental Health Information

Center http://mentalhealth.gov/