Bipolar Disorder

which medications are the mainstays of treatment for both acute mania and prophylaxis for recurrent manic and depressive episodes?

lithium and valproate

which medications are alternative or adjunctive treatments for BPD depending on the phase of illness (mania, depression, or maintenance)?

anticonvulsants (like lamotrigine and carbamazepine) and SGA agents (like aripiprazole and quetiapine)

which medication is less favored for use d/t its ADR profile

carbamazepine

T/F: anticonvulsants may be more effective than lithium in several mood subtypes (like mixed states and rapid cycling)

true

what is considered first line treatment option for acute bipolar depression

lithium, valproate, or quetiapine

T/F: some patients can be stabilized on one mood stabilizer, but others may require combo therapy or augmentation agents during an acute mood episode

true

________________ approved for BPD can be used as mood stabilizers and prescribed as schedules doses

antipsychotics

facts regarding augmentation in bipolar disorder

If possible, the augmentation agent should be tapered and d/c when the acute mood episode remits and the pt is stabilized.

what are the possible augmentation agents?

benzos, other mood stabilizers, antipsychotics and/or antidepressants

T/F: antidepressants should only be used with a mood stabilizer in BPD

true

T/F: there is a limited selection of approved LAI for BPD

true

what are the challenges in diagnosing BPD?

MUST rule out organic causes of mania or depression. Accuracy in diagnosis is key and requires excellent history. Mania may be confused with ADHD related disorders (infection, endocrine, electrolytes, CNS are others...). Depression may appear to be unipolar. If improperly treated (misdiagnosed for MDD) antidepressants can cause switch to mania. Monitor and report for any extreme improvements with initial AD. Psychotic symptoms associated with bipolar I (generally)

how does BPD and MDD differ from each other?

Patients with BD experience episodes of depression which often leads to a misdiagnosis of unipolar depression, while MDD can present with different symptoms depending on the person, but for more people depressive disorder changes how they function day-to-day for more than two weeks.

what is bipolar I

an illness in which people have experienced one or more episodes of mania (mania and depression with hospitalization or psychosis)

what is bipolar 2?

a subset of BD in which people experience depressive episodes shifting back and forth with hypomanic episodes, but a full manic episode

what pharmacologic treatment interventions are unique to BPD with antidepressants?

monotherapy (“unopposed”) is not appropriate, and pts should avoid classes that may be more likely to contribute to mania (TCA, SNRI)

what pharmacologic treatment interventions are unique to MDD with antidepressants?

monotherapy is encouraged and SSRIs/SNRIs are first-line in most guidelines

T/F: the FDA boxed warning for suicide applies to all antidepressants regardless of indication for use

true

what pharmacologic treatment interventions are unique for BPD for antipsychotics?

considered essential mood stabilizers now (versus just “add-on treatment”), not all APS are approved for BPD

what pharmacologic treatment interventions are unique for MDD for antipsychotics?

APS for MDD are only for augmentation (add-on) not for monotherapy (lower doses), SSRIs/SNRIs are first-line in most guidelines

what are some similarities between BPD and MDD treatments with APS?

FDA approval for APS use in BPD or MDD do not always cover all formulations of that agent, APS approved by FDA for BPD and MDD inherit the suicide boxed warning, FDA boxed warning for dementia-related psychosis is not relevant when the APS is prescribed for a primary psychiatric disorder

T/F: no long-acting injectables are approved for MDD

true

T/F: only two APS are approved for use in BPD

true

which LAI are approved for BPD?

Aripiprazole (abilify maintena, abilify asimtufii) and risperidone (risperdal consta, rykindo)

what are aripiprazole’s FDA approved uses within BPD?

Acute Treatment of Manic and Mixed Episodes associated with Bipolar I adults and pediatric patients 10-17 years

what are asenapine’s FDA approved uses within BPD?

Acute monotherapy treatment of manic or mixed episodes, in adults and pediatric patients 10-17 years.

Adjunctive treatment to lithium or valproate in adults

Maintenance monotherapy treatment in adults

what are cariprazine’s (Vraylar) FDA approved indications within BPD?

Acute treatment of manic or mixed episodes associated with bipolar I in adults
Treatment of depressive episodes associated with bipolar I disorder-adults

what are Iloperidone’s (Fanapt) FDA approved indications within BPD?

Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults

what are lumateperone’s (Caplyta) FDA approved indications within BPD

Depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy or adjunctive with lithium or VPA

what are lurasidone’s (Latuda) FDA approved indications within BPD?

Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 -17 years) as monotherapy

Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate

what are the FDA approved indications for olanzapine PO within BPD?

Bipolar I disorder in adults: Acute treatment of manic or mixed episodes as monotherapy or adjunct to lithium or valproate.
Maintenance monotherapy treatment

what are the FDA approved indications for olanzapine + samidorphan (Lybalvi) within BDP?

Bipolar I disorder in adults: Acute treatment of manic or mixed episodes as monotherapy or adjunct to lithium or valproate.
Maintenance monotherapy treatment

what are the FDA approved indications for quetiapine (Seroquel) within BPD?

Depressive episodes associated with bipolar disorder.
Acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy to lithium or divalproex (& 10-17 years

what are the FDA approved indications for risperidone (Risperdal) within BPD?

Alone, or in combo with lithium or VPA, for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults, and alone in children and adolescents (10-17 years)

what are the FDA approved indications for ziprasidone (Geodon) within BPD

Acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder.
Maintenance treatment of bipolar I disorder as adjunct to lithium or VPA

what are the FDA approved indications for olanzapine (Zyprexa) IM short acting within BPD

PRN: Treatment of acute agitation in schizophrenia and bipolar I mania

T/F: the long-acting injectable form of olanzapine is only used for the treatment of schizophrenia

true

what is olanzapine + fluoxetine (Symbayax) PO used for?

treatment of depressive episodes associated with bipolar I disorder or treatment resistant MDD

what pharmacologic treatment interventions are unique to BPD with mood stabilizers?

Many options for mood stabilizers. Could utilize antipsychotics, lithium, valproate, or antiepileptic agents (not all are FDA approved for BPD)

what pharmacologic treatment interventions are unique to MDD with mood stabilizers?

not routinely recommended

T/F: use of augmentation to mood stabilizers can be used in treatment of refractory MDD or when BPD episodes require pharmacotherapeutic interventions

true

define hypomania

a period of abnormally, continually elevated, expansive, or irritable mood with increased activity or energy for at least 4 consecutive days

what are the first line agents for acute mania

Lithium or valproate monotherapy

SGA monotherapy (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, cariprazine)

Lithium or valproate + SGA (aripiprazole, asenapine, quetiapine, risperidone)

Mixed mania: no recommendations

what are the second line agents for acute mania

Alternative first-line agent, CBZ, ECT, haloperidol, olanzapine, ziprasidone, lithium + valproate.

Mixed mania: asenapine, cariprazine, VPA, aripirazole

what are the first line agents for acute depressive episodes in BPD?

Acute bipolar I: lithium, lamotrigine, quetiapine, quetiapine ER, lurasidone

Acute bipolar II: quetiapine, quetiapine ER

Mixed depression: no recommendations

what are the second-line agents for acute depressive episodes in BPD

Acute bipolar I: valproate, lithium or valproate or SGA + SSRI or bupropion, ECT, cariprazine

Acute bipolar II: lithium, lamotrigine, ECT, sertraline, venlafaxine, adjunctive bupropion

Mixed depression: cariprazine, lurasidone

what are the first line agents for maintenance treatment in BPD

Monotherapy: lithium, lamotrigine, valproate, olanzapine, quetiapine, asenapine, aripiprazole PO or LAI (mania prevention)

Adjunctive therapy: lithium or valproate + quetiapine or aripiprazole (mania prevention)

what are the second-line agents for maintenance treatment in BPD

olanzapine, risperidone, LAI, CBZ, paliperidone, adjunctive ziprasidone or lurasidone

T/F: no mood stabilizer is approved for use in depression of any kind

true

what is lithium well known for?

anti-suicide effects

T/F: neither lithium nor CBZ monotherapy is recommended for the treatment of bipolar depression

true

MOA of lithium

exact mechanism is not fully understood

clinical pearls for lithium

Steady-state concentration achieved after about 5 days of stable dosing. Serum concentration may be obtained sooner if suspicion for toxicity,
presence of a drug interaction, or development of electrolyte/renal
abnormalities. Serum concentration should be drawn in the morning as a 12-hour post-dose concentration.

PKPD of lithium:

follows first-order linear kinetics and is fully excreted not metabolized (no CYP interactions)

what is lithium clearance impacted by?

Dehydration, sodium depletion, hyperhidrosis, and cardiac and renal dysfunction resulting in lithium toxicity

adverse kidney changes are more prominent in patients who receive lithium in _________________

divided doses

T/F: once daily dosing of lithium reduces the occurrence of polyuria and may improve adherence

true

CI to lithium

severe/unstable renal or CVD, severe debilitation, dehydration or sodium depletion

which medications interact with lithium

NSAIDs, diuretics, ACEi/ARBs, methyl-xanthines, and others

what is the drug interaction between NSAIDs and lithium?

lithium levels are increased by 16-60% making concomitant use is not recommended

which NSAIDs may not influence lithium levels

aspirin and sulindac

what is the drug interaction between diuretics and lithium

lithium levels are increased by thiazides and decreased by mannitol

How should the drug interaction between diuretics and lithium be managed?

Avoid thiazides that increase lithium levels by 25-40%.

Loop diuretics may promote lithium clearance in a clinically insignificant manner however, over-diuresis with a loop diuretic can lead to toxicity.

Osmotic diuretics (e.g., mannitol) increases lithium clearance by 40%

Potassium-sparing diuretics have limited effects on lithium concentrations

what is the drug interaction between ACEi/ARBs and lithium

lithium levels are increased

clinical pearls for the drug interaction between ACEi/ARB and lithium:

ACEi and ARBs can increase lithium levels by 30-40%. This
interaction is delayed and may not be seen for 3-5 weeks.

Should consider alternative antihypertensive agent that does
not interact with Lithium when possible.

Non-DHP CCBs and antipsychotics have been associated with increasing
the risk of Li-induced neurotoxicity, but this is likely rare but possible.

what should be used for bp management if using lithium?

beta-blockers (after a cardio consult though!)

what is the drug interaction between methyl-xanthines and lithium

lithium levels may be decreased

clinical pearls for the drug interaction between methyl-xanthines and lithium

caffeine 300 mg reduce lithium by 30% and theophylline reduces lithium levels by >30-60% in a dose dependent manner

what are other drug interactions with lithium?

increased neurotoxicity — lithium is a risk factor for NMS when used with antipsychotics and lithium has been rarely reported with serotonin syndrome

BBW for lithium

lithium toxicity - concentration should be routinely monitored 

precautions/warnings for lithium:

May unmask Brugada syndrome which can asymptomatically increase risk of sudden cardiac death.

Decreased renal concentrating ability that may present as nephrogenic diabetes insipidus.

Acute and chronic reductions in GFR may occur

Use with caution in patients with significant fluid loss bc of increased risk of toxicity

Avoid meds that significantly alter lithium concentrations

T/F: lithium therapy increases the risk of fetal malformations

true

when does lithium start working for mania?

Relatively slow onset of action (6-10 days) compared with APS and VPA. Full resolution of symptoms may take up to 3 weeks

when does lithium start working for depression?

greater than one month may be required for maximal improvement

ADRs of lithium

Dermatologic - acne, psoriasis, alopecia/thinning hair

Cardiovascular - AV block, bradyarrhythmia, ECG changes w toxicity

GI - nausea early in tx, dry mouth/thirst

Genitourinary - polyuria, AKI, CKD

Hematologic - benign leukocytosis may be seen

Neurologic - concentration-dependent with tremor, seizures, coma, delirium, and confusion

why should thyroid functions be tested for patients taking lithium?

can cause lithium-induced hypothyroidism which causes hair changes

what can lithium toxicity do cardiovascularly?

ECG changes, arrhythmias, and QTc prolongation

how can you prevent/reduce nausea from lithium?

change to ER formulation 

__________________ lithium concentrations should be suspected with severe nausea, vomiting, and diarrhea

supratherapeutic

how can we prevent/treat dry mouth associated with lithium use?

educate patients on adequate hydration and the use of other non-pharmacologic techniques (e.g., hard candy) can help manage this side effects

how can you reduce risk of genitourinary ADRs from lithium?

target lower (0.45-0.75 mEq/L) and once daily dosing

clinical pearls for lithium genitourinary ADRs:

AKI is most common in setting of toxicity and possibly as a result of direct tubular epithelial damage. Other forms of kidney injury rarely occur. Creatinine clearance decreases modestly over years with an estimated annual loss of approximately 2 mL/min

clinical pearls of neurologic ADRs from lithium

Toxicity management depends on the severity and if acute or chronic. For toxicity related to overdose, dosage form ingested is important. Non-specific T-wave flattening is common and, depending on severity, heart block or arrhythmias may be seen

how does lithium toxicity present initially?

fine hand tremor, polyurria, mild thirst

how does serum lithium of 1.5-2 mEq/L present?

mild to moderate toxicities including diarrhea, vomiting, drowsiness, muscle weakness, and decreased coordination

how does serum lithium of 2-2.5 mEq/L present?

moderate to severe toxicities including ataxia, blurred vision, tinnitus, and ECG changes

how does serum lithium higher than 3 mEq/L present?

neurological changes, coma

Facts regarding interventions for toxic levels of lithium:

Activated charcoal is of little value in lithium overdose (does not bind).

Sodium polystyrene sulfonate has limited benefit (number of reports)

Forced diuresis is not recommended

Hemodialysis (HD) can be effective

facts regarding valproate

Has dose relate GI, tremor, and sedation. Early dose forms very GI irritating, and GI ADRs are transient (can give with food, lower doses, or ER forms to help), give dose at bedtime to reduce sedation, ER forms have lower bioavailability (more may be needed)

valproate is synergistic with which medications?

lithium, APS, benzos, CBZ

ADRs of valproate

prolonged bleeding (platelets), thrombocytopenia, weight gain, hyperammonemia, alopecia (dose dependent).

what are the BBWs for valproate

pancreatitis and/or liver toxicity, hepatotoxicity, and urea disorders

T/F: DR and ER doses of valproate are interchangeable/equivalent

false

when converting from DR to ER valproate what may need to be done?

dose increase

MOA of lamotrigine

For psychiatric effects exact mechanism unknown: suggested: Blocks voltage sensitive sodium channels (among other MOA). Mood stabilizing AED

why does lamotrigine have a slow titration schedule?

risk of SJS/TEN

with concomitant valproate, the titration schedule dosing for lamotrigine is ____________ by 50%

reduced

with concomitant carbamazepine, phenytoin, or primidone (inducers), the titration schedule dosing for lamotrigine is ______________

doubled

Which mood stabilizer should be re-titrated if a dosing gap greater than 3-5 half-lives or 48 hours occurs while taking?

lamotrigine

how can you convert from IR to ER lamotrigine?

the initial ER dose should be equal to the TDD of IR given once/day