bipolar waters

what are the symptoms of mania/hypomania?

DIG FAST

- distractibility

- indiscretions (excessive pleasure activities)

- grandiosity

- flight of ideas

- activity increase

- sleep deficits

- talkativeness

what are 4 common comorbidities seen with bipolar disorder?

- anxiety

- SUD

- ADHD

- medical comorbidities

describe the comorbidity of bipolar + anxiety

worse prognosis

- higher risk of relapse

- increased time to recovery

- treatment nonresponse

- suicidality

describe the comorbidity of bipolar + SUD

- most common = AUD

- AUD high risk with women

- more likely with bipolar type 1

describe the comorbidity of bipolar + ADHD

- children with ADHD have a 10x increased risk in being diagnosed with bipolar disorder

- worse prognosis = more depressive episodes, significant comorbid anxiety and SUD

describe common medical comorbidities seen with bipolar disorder

- increased metabolic and cardio disorders

- diabetes, dyslipidemia, obesity, CV disease

describe the young mania rating scale

- 11 item clinical rated scale

- assesses the following factors: mood, motor activity, sexual interest, sleep language, appearance, insight, speech, thought, thought content, disruptive behavior

describe genetic risk factors for bipolar disorder

- very high rate = 7x increase with first degree relative

- 50% of pts have a family history

what are 4 childhood risk factors for bipolar disorder?

- trauma

- abuse

- anxiety

- subsyndromal conduct disorder

describe the prevalence of bipolar type 1/2

- type 1 = equally present in males and females

- type 2 = females more likely

describe how episodes of bipolar disorder may change with each additional episode

- episodes may become more frequent and harder to treat with each episode

- episodes may respond better earlier on

what are 4 non pharmacologic tretament options for bipolar disorder?

- adequate sleep

- psychotherapy (adjunct)

- ECT

- bright light therapy (adjunct)

why must we be cautious when using ECT or bright light therapy for bipolar disorder treatment?

there is a possible risk of switching depressive state (that it is treating) to a manic state

what are the goals of acute bipolar disorder treatment?

- rapid control of behavioral symptoms

- sleep restoration

- mood stabilization

what ar the goals of maintenance therapy for bipolar disorder?

after mood stability has been achieved for 3 months:

- continue improvement of functioning

- prophylaxis against future mood episodes

- may initially use all meds used in successful acute treatment, with goal of monotherpay

what are 4 treatment goals for acute manic, hypomanic and mixed episodes?

- reduce agitation, aggression and impulsivity

- prevent harm to self or others

- pharmacological recommendedations vary by guideline

- antidepressants should be tapered or discontinued when possible

why is it recommended to discontinue antidepressants when treating bipolar disorder?

- they are not 1st or 2nd line for bipolar disorder

- there is a risk of pt going into a mixed or manic state when using

what should be done if we continue use of an antidepressant when pt has bipolar disorder?

use in combination with mood stabilizer

what are the 6 first line treatment options for manic/hypomanic episode treatment with bipolar disorder?

- lithium

- VPA

- SGAs

- lithium + SGA

- VPA + SGA

- haloperidol

what are the 3 second line options for manic/hypomanic episode treatment with bipolar disorder?

- alt first line agent

- carbamazepine

- ECT

what are the 3 first line options for mixed episode treatment with bipolar disorder?

- VPA

- carbamazepine

- SGAs = especially olanzapine

what is the second line option for mixed episode treatment with bipolar disorder?

alt first like agent

describe the treatment of psychotic features with bipolar disorder

- most common in manic episodes

- antipsychotics should be used first line, can be used as mono therapy or in combination with mood stabilizer

- consider ECT

what are the 8 first line options for treatment of acute depressive episodes in bipolar disorder?

- lithium

- lamotrigine

- 3 specific SGAs (quetiapine IR or ER, lurasidone, olanzapine/fluoxetine)

- VPA

- carbamazepine

- lithium + VPA

out of the first line treatments for acute depressive episodes in bipolar disorder, what 3 specific SGAs are considered?

- quetiapine IR or ER

- lurasidone

- olanzapine/fluoxetine

out of the first line treatments for acute depressive episodes in bipolar disorder, which 2 agents have limited data?

- VPA

- carbamazepine

(still used just not as recommended)

out of the first line treatments for acute depressive episodes in bipolar disorder, what is generally considered for bipolar type 1?

combination of lithium + VPA

what are 4 second line treatment options for acute depressive episodes in bipolar disorder?

- alt first line agent

- combo of 2 first line agents (just not 2 SGAs)

- caripraszine

- ECT

describe the use of SGAs in bipolar depression

- not all SGAs are equally effective

- aripiprazole and ziprasidone should NOT be used

describe the treatment continuation for bipolar disorder

medication used for acute treatment should be continued for 2-4 months after response to acute episode

what are 6 first line options for maintenance therapy for bipolar disorder?

- continue med used to treat acute episode

- lithium

- lamotrigine

specific SGAs:

- quetiapine

- olanzapine

- LAI risperidone

what are 3 second line options for maintenance therapy for bipolar disorder?

- lithium + VPA or lamotrigine

- carbamazepine

- alternative SGA

describe the duration of therapy for meds that treat bipolar disorder

duration of therapy is lifelong unless:

- worsening mood ir inadequate response

- change in diagnosis

- non adherence

- adverse effects

- intolerance

describe the dosing and total range for lithium

- dose adjusted to target goal concentration OR titrated to effect

- titration = 600-1800 mg/day in divided doses

- total range = 0.6-1.2 mEq/L

what is the target serum for lithium in acute mania treatment?

0.8-1.2 mEq/L

what is the target serum for lithium in maintence therapy?

0.6-1.0 mEq/L

describe the steady state levels of lithium

- steady state occurs after 5 days of stable dosing

- monitor using trough levels

- may check levels earlier if thoughts of DDIs or toxicity

- steady state follows 1st order kinetics, concentration changes proportionally with dose change

describe clearance of lithium

can be affected by dehydration, sodium depletion, cardiac and renal dysfunction

describe dosing frequency of lithium

- generally dosed BID

- but can be given as a single dose if tolerated to reduce risk of renal toxicity, polyuria and improve adherence

describe onset of action for lithium

- mania = 6-10 days

- depression = 1 month

what boxed warning is associated with lithium?

lithium toxicity

what 4 additional warnings and precautions are seen with lithium?

- decreased renal ability to concentrate urine = NDI

- caution in pts with significant fluid loss

- avoid meds that significantly alter lithium concentration

- increased risk of fetal malformation = ebsteins anomaly

what are 3 dermatologic ADEs seen with lithium?

- acne

- psoriasis

- alopecia

describe ADE of acne with lithium

more common in ages 20-30

describe ADE of psoriasis with lithium

more common in ages 50+

describe ADE of alopecia with lithium

more common in women

what 2 CV ADEs are seen with lithium?

- AV block or other conduction issues

- bradydrrhythmias

describe ADE of AV block with lithium

may be safely continued unless 3rd degree heart block occurs

describe ADE of bradyarrhythmia with lithium

may result from sinus node dysfunction

what 2 GI ADEs are seen with lithium?

- nausea

- dry mouth/thirst

describe ADE of nausea with lithium

- may occur early in therapy

- switching to ER formulation may reduce nausea

describe ADE of dry mouth/thirst with lithium

counsel about adequate hydration, artificial saliva and hard candy

what 3 genitourinary ADEs are seen with lithium?

- polyuria

- AKI

- CKD

describe ADE of polyuria with lithium

- if occurs we may need to target a lower serum concentration or use once daily dosing

- urine output less than 1.5 L may indicate NDI

describe ADE of AKI with lithium

- rare unless during acute toxicity

- may be use to direct tubular epithelial damage

describe ADE of CKD with lithium

may cause modest decrease in CrCl over several years

what 3 endocrine/metabolic ADEs are seen with lithium?

- hypothyroidism

- hyperparathyroidism

- weight gain

describe ADE of hypothyroidism with lithium

- may alter conversion of T4 to T3 or directly affect TH release

- may add levothyroxine if needed

describe ADE of hyperparathyroidism with lithium

baseline and routine calcium serum concentration monitoring is recommended

describe ADE of weight gain with lithium

- often within first 2 yrs of treatment

- average = 4-6 kg

describe the neurologic ADEs seen with lithium

concentration dependent

- tremor, seizures, coma, delirium, confusion

describe nephrogenic diabetes insipidus

- chronic lithium may contribute to ADH resistance

- reduced ability to concentrate urine = polyuria, polydipsia

- may be irreversible

with NDI, why doe lithium accumulation in cells interfere with the ability for ADH to increase water permeability?

Lithium may substitute for Na+ entering cells of collecting duct through Na+ channels

describe the treatment of NDI

- discontinue lithium if possible

- if need to continue lithium, add amiloride

how does amiloride work?

for NDI

- potassium sparing diuretic that inhibits sodium channel in collecting tubule

- minimized further accumulation of lithium

describe the signs and symptoms of early presentation of lithium toxicity

- fine hand tremor

- polyuria

- mild thirst

(but they also occur at normal levels)

describe the signs and symptoms of mild-moderate (1.5-2 mEq/L) lithium toxicity

- diarrhea

- vomiting

- drowsiness

- muscle weakness

- decreased coordination

describe the signs and symptoms of moderate-severe (2-2.5 mEq/L) lithium toxicity

- ataxia

- blurred vision

- tinnitus

- EKG changes (t wave flat, heart block, arrhythmia)

describe the signs and symptoms of severe (3 mEq/L +) lithium toxicity

- neurological changes

- coma

describe the management of lithium toxicity

- supportive care

- NOT effective = activated charcoal and forced diuresis

- hemodialysis is effective in removing lithium

describe how hemodialysis is used to remove lithium and when it is recommended

- significant decrease in concentration after 1 session, but may have rebound effect as intracellular is redistributed to vasculature

recommend when:

- levels greater than 4 mEq/L

- levels greater than 2.5 mEq/L with serious cardio or neuro symptoms

what 5 agents can cause a DDI that causes increased lithium levels?

- NSAIDs

- ACEIs/ARBs

- thiazide diuretics

- loop diuretics

- reduced sodium intake

describe the DDI between lithium and NSAIDs

- inhibit prostaglandin synthesis = decreased renal blood flow = increased sodium and lithium reabsorption

- very rapid increase in lithium

describe the DDI between lithium and ACEIs/ARBs

- decreased Na reabsorption causes sodium loss and volume depletion and an increase in lithium reabsorption

- interaction may not be apparent for 3-5 weeks

describe the DDI between lithium and thiazide diuretics

increases lithium level by 25-40^%

describe the DDI between lithium and loop diuretics

over diuresis may lead to lithium toxicity

describe the DDI between lithium and reduced sodium intake

increases sodium and lithium reabsorption

what 5 agents can cause a DDI that causes decreased lithium levels?

- theophylline

- verapamil

- osmotic diuretics

- caffeine

- sodium, sodium bicarbonate antacids

describe the DDI between lithium and theophylline

30-60% lithium level reduction

describe the DDI between lithium and osmotic diuretics

increases lithium clearance by 40%

describe the DDI between lithium and caffeine

30% reduction in lithium levels

describe the DDI between lithium and sodium/sodium bicarbonate antacids

decrease sodium and lithium reabsorption

what 4 factors are monitored for lithium safety?

LITH

- levels

- insipidus

- TSH/tremor

- hydration status

What is the overall mechanism of valproic acid in bipolar disorder?

Increases GABA concentrations

describe the kindling theory in bipolar disorder

- early mood episodes may be triggered by acute stressors

- Over time the brain becomes sensitized = kindled

- Pathways are reinforced if episodes are untreated

- future episodes occur more easily, even without triggers

What is the treatment goal when dosing valproic acid for bipolar disorder?

- control manic/mixed episodes

- Avoid significant ADEs

Note: not effective for bipolar depression

What is the onset of effect for valproic acid when using a loading strategy?

onset within 3 days

Describe the valproic acid loading dose strategy

- 20 mg/kg/day (25 mg/kg if ER)

- may use 30 mg/kg for 2 days then decrease to 20 mg/kg (or 25 mg/kg if using ER)

Describe the valproic acid titration strategy

- initiate 500 or 750 mg QMs with rapid titration to 20 mg/kg/dose

- may titrate by 500 mg/day

what 4 salt forms of VPA exist?

- divalproex sodium ER

- divalproex sodium DR

- valproate sodium IR

- valproic acid IR

what formulation does divalproex sodium ER come in? what is its dosing frequency?

- tablets

- once daily

what formulation does divalproex sodium DR come in? what is its dosing frequency?

- tablets (enteric coated)

- sprinkle capsules

- BID

what formulation does valproate sodium IR come in? what is its dosing frequency?

- IV

- oral solution

- BID

what formulation does valproic acid IR come in? what is its dosing frequency?

- capsule

- BID

what are therapeutic serum levels for VPA?

50-125 mcg/mL

(but 70-90 is preferred)

how should VPA levels be monitored?

- draw trough levels 4-5 days after ignition or change in dosing

- levels greater than 125 = increased risk of ADEs

what are the 3 contraindications for VPA?

- Hepatic disease or significant hepatic dysfunction

- Urea cycle disorders

- Pregnancy (when used for migraine)

What are the 3 boxed warnings for VPA?

- Hepatic failure

- Pancreatitis

- Teratogenicity = neural defects and decreased IQ

what are 4 additional warnings seen with VPA?

- dose related thrombocytopenia

- hyperammonemia/encephalopathy

- hypothermia

- DRESS

what 2 dermatologic ADEs are seen with VPA?

- rash

- alopecia