Bipolar Flashcards
Define mood
a pervasive and sustained emotion of feeling tone that influences a persons behaviour and colors his or her perception of the world
- can be labile, fluctuating or alternating rapidly between extremes
what is bipolar 1 disorder?
a distinct period of at least 1 week of full manic episode: abnormally and persistently elevated mood and increased energy
what is bipolar 2 disorder?
a current or past hypomanic episode and a current or past major depressive episode
men have more ______ episodes and women have more _____ or ______
manic; depressive; mixed
is there a cure for bipolar?
no but full recovery/maintenance is possible
what is the etiology of BD?
developmental, genetic, psychological, and neurobiologic factors may all contribute
risk factors for BD
drug or alcohol abuse
medical conditions
period of high stress
having a 1st degree relative
major life changes
which medical conditions are risk factors for BD?
hyperthyroidism
hormonal changes
CNS disorders
endocrine dysregulation
CVD
which medications can induce mania?
alcohol intoxication
antidepressants
DA-augmenting agents (CNS stimulants: amphetamines, cocaine, caffeine)
marijuana intoxication
steroids
thyroid preparations
when is the typical onset of bipolar?
typically before 25 yo
avg. 20-25
what happens for those who develop illness before age 19?
longer delay to treatment
greater depressive symptom severity
higher levels of comorbid anxiety/substance use
why is it important to get people are the right therapy early and keep them on it?
to slow down potential neurodegeneration
what comorbid conditions may worsen existing BD or make treatment challenging?
anxiety disorders(50-60%)
substance use disorder(60%)
ADHD(20%)
PTSD
what is the leading cause of death in BD?
suicide
what manual is used to diagnose bipolar?
DSM-5
what is the diagnostic criteria for mania relating to symptoms?
persistently and abnormally elevated mood(irritable or expansive) and energy, with at least 3 of the following changes from usual behaviour:
1. grandiosity/high self-esteem
2. decreased need for sleep
3. racing thoughts
4. increased talking/pressured speech
5. distractability
6. increased goal-directed or psychomotor agitation
7. excessive engagement in high risk behaviours
how long must symptoms be occurring to be considered a mania diagnosis?
nearly every day for at least 1 week
after considering symptoms what other criteria must be met for a mania diagnosis?
leads to significant functional impairment OR includes psychotic features OR necessitates hospitalization AND episode is not due to physiological effects of a substance or another medical condition
if mania was caused by a medication but stops after d/c that medication, does the patient have bipolar?
no
what is the pneumonic for mania symptoms?
DIGFAST
(slide 22)
what is the DSM-5 criteria for BDI?
manic episode REQUIRED for diagnosis
hypomanic episode or major depressive episodes may occur before or after manic episode but are NOT required for diagnosis
diagnostic criteria for hypomanic episode
same symptom criteria as manic episode but only lasting up to 4 days
unequivocal change in functioning or mood that is uncharacteristic of the individual and/or observable by others
hospitalization not required. no psychosis.
what is the DSM-5 criteria for BDII?
hypomanic episode AND major depressive episode (current or past episodes)
what is the diagnostic criteria for a major depressive episode?
5+ symptoms must be present nearly everyday during the same 2-week period and result in change in functioning and must include 1 or both of:
- depressed mood most of the day, nearly every day
- diminished interest or pleasure in all or most activities
what are the symptoms for diagnosing a major depressive episode?
S - sleep pattern changes
I - interests or activity changes
G - guilty feeling or increased worry
E - energy changes
C - concentration changes
A - appetite changes
P - psychomotor disturbances
S - suicidal ideation
what is the mood disorders questionnaire(MDQ)?
3 question, 13 item PATIENT RATED used to screen for possible BD
- most specific for identifying BDI
what is a positive MDQ score?
yes to 7/13 items from Q1
yes to Q2
“moderate or severe problem” for Q3
what is bipolar often misdiagnosed as?
MDD
what are some of the challenges in BD diagnosis and treatment?
delay to diagnosis
misdiagnosis
limited clinical trials
what is the response time for mania treatment?
1-2 weeks
full clinical benefit 3-4 weeks
what is the response time for depression treatment?
2-4 weeks
full clinical benefit 6-12 weeks
what is the non-pharm therapy for BD?
exercise, adequate sleep, healthy diet, decreased/abstinent substance use, decreased caffeine/nicotine/alcohol
bright light (depression)
relapse prevention plan
CBT, therapy
ECT
what is included in a wellness recovery action plan (WRAP)?
- early warning symptoms
- tools when threat of crisis starts
- what they have to do to stay well
- their responsibilities
- how they feel when they are well
- what they do and who they entrust to do things when in crisis
- list of people they can call in crisis
- their triggers
- post-crisis plan
what mood stabilizers are used in BD?
lithium
anticonvulsants ex. valproic acid & lamotrigine
atypical antipsychotics
what are the most commonly used mood stabilizers?
lithium
valproic acid/divalproex
lamotrigine
what are the indications of lithium?
BD - acute mania or prophylaxis/maintenance
schizoaffective disorder
unipolar depression - antidepressant augmentation
what is the bioavailability of lithium?
liquid: 100%
regular caps: 95-100%
ER tab: 60-90%
(very good F)
what side effects may be related to the onset and peak of lithium?
tremors or nausea
quick onset of 30-60 minutes
how does lithium act in the body?
distributes evenly in the total body water space - the body treats lithium like a salt
- very well absorbed
how is lithium metabolized?
it is eliminated mainly by the kidneys (95% renal elimination)
what decreased the clearance of lithium?
hyponatremia, dehydration, renal failure or dysfunction, decreased renal blood flow
which medications are associated with the potential for lithium toxicity?
ACEi
NSAIDs
thiazides
what is lithiums therapeutic range for acute mania? maintenance therapy? elderly?
acute mania: 1.0-1.2mmol/L
maintenance: 0.6-1.0mmol/L
elderly: 0.6-0.8mmol/L
at what lithium level would we start to see signs of toxicity?
> 1.5mmol/L - drowsy, ataxia, tremor, slurred speech, hypertonicity
2mmol/L - decreased HR, arrhythmia’s, seizures, myocarditis, coma, death
when should a lithium sample be taken?
12 hours post dose - usually in am after the evening dose
how frequently should lithium sampling be done?
5-7 days after starting therapy or changing dose, then once weekly until at a stabilized x 2 weeks, then monthly for up to 3 months, then at least every 6 months (once on long term therapy)
how can we minimized GI side effects of lithium?
give with food or divide dose BID
when is lithium CI?
in acute renal failure
do we need to adjust lithium doses in renal impairment?
yes once below 50mL/min
what factors can decrease lithium levels?
caffeine
sodium supplement
burns
pregnancy
excessive fluid intake
what factors can increase lithium levels?
NSAIDS
thiazide diuretics
ACEi/ARBs
dehydration
sodium loss
what medications increase the risk of neurotoxicity when used with lithium?
antipsychotics or carbamazepine
what are the drug interactions for lithium?
diuretics - potentially mixed effects
NSAIDs - increase Li concentration
ACEi - increase Li concentration
what are the adverse effects of lithium?
dose related:
- increased thirst
- fine tremors
- headache, sedation, weakness
- GI upset
more long term:
- skin changes
- alopecia
- weight gain (avg 4-6kg in first 2 years)
what are the serious (idiosyncratic) AE’s of lithium?
hypothyroidism
renal injury
nephrogenic diabetes insipidus medical emergency
what do we do if a toxic lithium level is observed?
hold dose
repeat plasma level next day
restart therapy when within target range
what are some monitoring parameters for lithium?
manic and depressive symptoms
CBC (with differential)
weight
electrolytes
thyroid function (TSH)
renal function (Scr, urea)
ECG
lithium concentrations
side effects
suicide risk
what are some important counselling points for lithium?
maintain consistent fluid, caffeine, and salt intake
avoid NSAIDs and check with pharmacist before starting any new meds
consider contraception if child-bearing potential
what are the benefits of once daily dosing HS for lithium?
less AEs and risk of renal injury
What are the indications of valproic acid?
Seizures
Bipolar disorder
What are the possible MOA’s of valproic acid for bipolar disorder?
- Inhibition of voltage-gated sodium channels - reduces release of glutamate
- Increasing action of GABA
- Modulates signal transduction cascades and gene expression
- May effect neuronal excitation mediated by the NMDA subtype of glutamate receptors
- Also effects serotonin, dopamine, aspartate, and t-type calcium channels
What is the protein binding for valproic acid?
85-90% bound to serum albumin
medications that compete for binding may increase toxicity
How is valproic acid eliminated?
> 95% hepatic metabolism via glucoronidation, b-oxidation, alpha-hydroxylation
What is the therapeutic range for valproic acid?
Total(free level) 350-700umol/L (50-150mcg/L)
When should you take a valproic acid level?
Steady state trough level 3-4 days after initial therapy
How is valproic acid dosed?
Uses weight based dosing
There can be a loading dose
Empiric maintenance dose generally 250mg BID for bipolar
What are the dosing principles for valproic acid?
Avoid in hepatic disease
Use lower initial doses in elderly
No dose adjustment necessary for renal impairment
What are the common forms of valproic acid?
Divalproex sodium (enteric coated tablets)
Valproic acid capsules
Valproate sodium syrup
Drug interactions for valproic acid
Drugs metabolized by CYP2C9, epoxide hydroxylase, UDPGT
Also subject to displacement interactions with other drugs and endogenous substances (like fatty acids)
Which drugs can increase valproate levels?
*Antibiotics (macrolides - clarithromycin, erythromycin)
*ASA/salicylates (ASA, salsalate, sodium salicylate)
Anticonvulsants (topiramate)
Which drugs can decrease valproate levels?
*Antibiotics (carbapenems - ertapenem, imipenem, meropenem)
Anticonvulsants (carbamazepine, phenytoin, phenobarbital)
What drugs will valproate increase the concentartaion of?
*Lamotragine - very severe interaction, increased by ~50%
Warfarin
TCA’s
What are the dose-related AEs of valproic acid?
GI(less with VPA): nausea, vomiting, anorexia, diarrhea, constipation
CNS: tremor, sedation, ataxia, dizziness
Thrombocytopenia
What are the idiosyncratic AEs of valproic acid?
Hepatotoxicity
Pancreatitis
Hyperammonemia
Skin rash (increased risk when combined with lamotragine)
What are the chronic AEs of valproic acid?
Weight gain (up to 60% of patients, mean 8-14kg)
Menstrual disturbances, polycystic ovaries
Alopecia
Can valproic acid be used in pregnancy?
No it is teratogenic - can lead to neural abnormalities
Patients need to be on reliable contraception
Monitoring parameters for VPA
Sedation - ongoing
CBC with diff and platelets, LFTs - baseline, monthly x 3 mo, then q 4-6 months
Ammonia - only if unexplained lethargy/confusion/vomiting
Rash - ongoing
Valproate level - 2-4 days after dose change or interacting drug started then in 1-2 weeks to ensure stable, then as needed
Counselling points for valproic acid
May take several weeks to see benefit
Check with pharmacist before starting any new medications
Use reliable contraception
Avoid excessive alcohol due to risk of hepatic injury
Can take with food to help with GI upset
When is lamotragine indicated in bipolar disorder?
Acute bipolar depression
Maintenance in BDI or II
Not a good manic agent
MOA of lamotragine
Alters signal transduction by binding to open channel conformation of the voltage-gated sodium channels reducing release of glutamate
Weak 5-HT3 receptor inhibitory effects
What is important about lamotragine dosing?
Titration MUST be done slow to prevent severe rash
Also important to advise patient not to start anything new to rule out other factors
Why is adherence important for lamotragine?
If you miss a dose for 5 days it would be out of your system and you must restart titration!
What would we do if a patient is on VPA/DVP and lamotragine?
Reduce dose of lamotragine by 50%
AEs of lamotrigine
Common: sedation, headaches, nausea, dizziness (all less then with DVP)
Dyspepsia, diarrhea, anxiety, peripheral edema, rash
Rare/serious: risk of SJS, aseptic meningitis, blood dyscrasias (neutropenia), hepatotoxicity
DI of lamotrigine
*VPA/DVP
Carbamazepine - decrease lamotrigine levels by 30-50%
Oral contraceptives - decrease lamotrigine levels by 50% (should be on a continuous contraceptive, no hormone free week)
Counselling points for lamotrigine
May take several weeks to see benefit, especially due to slow titration
Adherence is very important
Can take without regards to food or time of day
Self-monitoring for rash is very important - avoid trying new products
When is carbamazepine indicated for bipolar?
Acute mania treatment
Maintenance
MOA of carbamazepine
Stimulates release of ADH and potentiates its action in promoting reabsorption of water
How is carbamazepine eliminated and what is the major pathway?
> 99% hepatic metabolism
Major: CYP3A4
*induces its own metabolism via epoxide-diol pathway (AUTOINDUCTION)
What is the target range for carbamazepine?
17-51 umol/L
When would you take carbamazepine level?
Trough within 1 hour prior to dose
Dosing principles for carbamazepine
Initiate slowly due to early long half-life to minimize side effects
Best to give in divided doses
Best to dose at mealtime
Elderly: Lower initial doses and smaller dose increases
Liver disease: not recommended in decompensated, may need to reduce dose in stable liver disease
Renal impairment: no adjustment necessary
What formulations does carbamazepine come in?
Oral suspension
Immediate release tablet
Chewable tablets
Controlled release tablets
DIs for carbamazepine
CYP3A4 inhibitors(increase levels) and inducers(decrease levels)
Through was enzyme does carbamazepine induce its own metabolism?
CYP3A4
What drugs increase carbamazepine levels?
Macrolides - erythromycin, clarithromycin
antifungals(azoles) - fluconazole, ketoconazole
CCB - diltiazem, verapamil
* grapefruit juice*
VPA
Lamotrigine
Fluoxetine, trazadone
MAOI - CONTRAINDICATED
What drugs are decreased by carbamazepine?
MANY
warfarin
DOACs
Antipsychotics
Antidepressants
Methadone
Estrogen or progesterone contraceptives
What are the dose-related AEs of carbamazepine?
GI: nausea, vomiting, anorexia, dry mouth, constipation
CNS: lethargy, dizziness, sedation, headache, tremor
CV: tachycardia, hypotension
What are the idiosyncratic AEs of carbamazepine?
SIADH/hyponatremia
Blood dyscrasias
Hepatic: increased GGT, hepatitis
Menstrual disturbances
Weight gain
Photosensitivity
Rash and hypersensitivity reactions
carbamazepine should not be taken for patients with which positive genetic test?
Asian ancestry - HLA-B1502
Caucasian - HLA-A3101
What are the chronic AEs of carbamazepine?
Osteomalacia
Vitamin D deficiency
When is carbamazepine CI?
Hx of hepatic disease
CVD
Blood dyscrasias
Bone-marrow depression
concurrent use with clozapine
What monitoring is required for carbamazepine?
CBC with diff and platelets, electrolytes, LFT’s, renal function - baseline, then monthly x 3 mo, then q6-12mo
TSH, free T3/T4 - baseline, then q3-6mo
Sedation, tremor, cognitive changes, rash - ongoing
Bone mineral density - if taking for > 5 years
Counselling points for carbamazepine
Take with food to minimize GI upset
Report rash or flu-like symptoms right away
Recommend copper IUD for birth control
Recommend calcium and vitamin D supplementation
remember to check drug interactions!!
Are doses of antipsychotics for bipolar lower or higher then for psychosis?
Lower
What are the general AEs for antipsychotics?
EPS
Hyperprolactinemia, sexual dysfunction
Metabolic disturbances (weight gain, dyslipidemia, DM, CVD)
Anticholinergic: sedation, constipation, dry mouth, blurred vision, confusion
Antihistaminergic: sedation
Alpha1 blockade: hypotension, reflex tachy, dizziness, sedation
QT prolongation
Seizures
Should antidepressants be used in bipolar?
There is a risk of switching patient to mania but bipolar depression is very difficult to treat.
Avoid AD monotherapy - always in combo with mood stabilizer
Avoid TCAs and SNRIs
Bupropion >sertraline>fluoxetine or other SSRI (not paroxetine) > venlafaxine(?)
Taper off AD once asymptomatic for 6-12 weeks
What medications should be discontinued before starting treatment for acute mania?
Antidepressants
Stimulants
Alcohol
Nicotine
What are the 1st line monotherapy’s for acute mania?
Lithium
Quetiapine
Divalproex
Asenapine
Aripiprazole
Paliperidone
Risperidone
Cariprazine
What are the first line combo therapies for acute mania?
Li/DVP +
- quetiapine
- aripiprazole
- Risperidone
- asenapine
When would you expect to see improvements for treatment of acute mania?
50% will respond to monotherapy with significant improvement in mania in 3-4 weeks
- some improvement to mania should be seen in first week, especially with DVP or APs
What is the benefit of the 1st line combo therapies?
Greater efficacy than monotherapy with lithium to DVP alone, especially in more severe illness
- recommended when a response is needed faster, more severe manic episodes, patients at risk, or patients who only had partial response to monotherapy
When patient specific factor makes Divalproex a good choice?
Comorbid substance use disorder
When should a switch or add on therapy be considered for acute mania treatment?
If no response is observed within 2 weeks
Which agents do not work for acute mania?
Gabapentin
Lamotragine - good for depressed side
Omega 3 fatty acids
Topiramate
What are the 1st line treatments for bipolar I depression?
Quetiapine
Lurasidone + Li/DVP
Lithium
Lamotragine
Lurasidone
Lamotrigine (adj)
When do we expect to see a response to treatment for bipolar depression?
Can take 4-6 weeks for initial improvement to be observed (and may take longer for full resolution)
What is a limitation to trials for quetiapine in acute bipolar depression?
The trials were only 8 weeks
What agents are NOT recommended for bipolar I depression?
Antidepressant monotherapy (unless combined with mood stabilizer)
Aripiprazole
Ziprasidone
Lamotragine with folic acid
Mifepristone adjunctive
What are the benefits of effective maintenance treatment early in illness?
Reverse cognitive impairment
Preserve brain plasticity
May lead to improved prognosis and minimization of illness progression
What are the risk factors for relapses?
Younger age of onset
Psychotic features
Rapid cycling
More previous episodes
Comorbid anxiety
Comorbid substance use
What is the 1st line non-pharm option for maintenance therapy of bipolar?
Psychoeducation - should be offered to all patients as it decreases recurrence rates by ~15%
What are the 1st line maintenance therapies for bipolar?
Lithium
Quetiapine
Divalproex
Lamotragine
Asenapine
Quetiapine + Li/DVP
Aripiprazole + Li/DVP
Aripiprazole
What did the landmark bipolar clinical trial find?
Lithium was superior to VPA for maintenance and combo of Li + VPA was favoured over VPA
Does lithium or quetiapine have more real world evidence?
Lithium
If a patient is on combo therapy of lithium + AP when could we consider tapering off the AP?
After 6 months if the patient is stable
Info for bipolar treatment during pregnancy
Avoid: DVP/VPA, CBZ
Small increased risk in 1st trimester: Li
Least risk/appears safe: lamotragine
APs: least studied but risk appears neutral for quetiapine, risperidone, aripiprazole, olanzapine
Which medication has the most evidence for suicide prevention?
Lithium
