Bipolar Disorder Flashcards
What is dysthymia?
persistent depressive disorder
What is cyclothymia?
mood swings between short periods of mild depression and hypomania
What is the bipolar I disorder?
a distinct period of at least one week of full manic episode
what is bipolar II disorder?
a current or past hypomanic episode AND a current or past major depressive episode
T or F
a depressive episode is required for a bipolar I disorder diagnosis?
false
what are some risk factors for bipolar disorder?
drug or alcohol abuse
having a first degree relative
period of high stress
major life changes
medical conditions
what medical conditions can induce mania?
hyperthyroidism, hormonal changes, CNS disorders, endocrine dysregulation, CVD
what drugs can induce mania?
alcohol
drug withdrawal states
antidepressants
DA-augmenting agents – stimulants, sympathomimetics
NE-augmenting agents
steroids
thyroid preparations
herbal products (St. John’s Wort)
what is the average age of onset of bipolar?
20-25 years
what type of symptoms of bipolar do people typically develop before age 18?
depressive symptoms
what are the consequences of early onset bipolar?
longer delay to treatment
greater depressive symptom severity
higher levels of comorbid anxiety/substance use
what is a mixed episode of bipolar?
depressive and hypomanic symptoms occurring at the same time
what is the kindling theory of bipolar disorder?
abnormalities lead to more abnormalities
syndromal episodes increase vulnerability to more episodes
leads to neurodegeneration
and is neurodegeneration?
persistent neurocognitive deficits, increasing impairment, delayed functional recovery
what is the best predictor of functioning in bipolar disorder?
medication adherence
what percentage of bipolar patients discontinue their medications?
50%
usually due to adverse effects
what are some common comorbid conditions with bipolar disorder?
anxiety disorders (50-60%)
substance use disorder (60%)
ADHD 920%)
PTSD
medical comorbidities: diabetes, dyslipidemia, obesity, CVD
what is the most commonly abused substance in BD?
alcohol
what is the leading cause of death in BD?
suicide
what is the diagnostic criteria for mania?
persistently and abnormally elevated mood (irritable or expansive) and energy, with at least 3 of the following changes from unusual behaviour:
1. grandiosity
2. decreased need for sleep
3. racing thoughts
4. increased talking/pressured speech
5. distractibility
6. increased goal-directed or psychomotor agitation
7. excessive engagement in high risk behaviours
symptoms occur nearly every day for at least 1 week
leads to significant functional impairment OR includes psychotic features OR necessitates hospitalisation
episode is not due to physiological effects of a substance or another medical condition
what are the symptoms of mania?
DIGFAST
D: distractibility
I: irritability or indiscretion
G: grandiosity
F: flight of ideas (racing thoughts)
A: activity (or energy) increased
S: sleep decreased
T: talkativeness
what is the diagnostic criteria for a hypomanic episode?
same symptoms of a 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
impairment in social or occupational functioning is not severe. hospitalisation not required. no psychosis
the episode is not due to physiological effects of a substances or another medical condition
what is the diagnostic criteria for a major depressive episode?
5+ symptoms must be present nearly every day during the same 2-week period and result in change in functioning (SIG E CAPS):
S: changes in sleep pattern
I: changes in interests or activity
G: feelings of guilt or increased worry
E: changes in energy
C: changes in concentration
A: changes in appetite
P: psychomotor disturbances
S: suicidal ideation
must include one or both of the following:
1. depressed mood most of the day, nearly every day
2. diminished interest or pleasure in all or most activities
what does the MADRS measure?
clinician rated severity of depression
what does the HAM-D measure?
clinician rated severity of depression
what does the YMRS rate?
clinician rated screening and assessing severity of mania
what does the MDQ measure?
patient rated screening for possible BD
what is a positive MDQ screen?
yes to 7/13 items in question 1
yes to question 2
moderate to severe in question 3
what are some challenges in BD diagnosis and treatment?
delay to diagnosis
misdiagnosis
limited clinical trials
what is the most common misdiagnosis of BD?
depression
what is the average delay to treatment of BD?
8-12 years
how long does it take for bipolar mania to respond to medication?
response: 1-2 weeks
full clinical benefit: 3-4 week
how long does is take for bipolar depression take to respond to medication?
response: 2-4 weeks
full clinical benefit: 6-12 weeks
T or F
bipolar depression takes longer to respond to medication than bipolar mania
True
T or F
bipolar depression responds to medication faster than unipolar depression
false
what is a WRAP?
wellness recovery action plan
lists early warning signs
tools they can use when the threat of a crisis starts to come
what they have to do to stay well
what they will do and who they will entrust to do things for them - help take care of them - when they are in crisis
a list of people they can call when in a crisis
what their triggers are
post-crisis plan
what are the medical indications of lithium?
bipolar:
- acute mania treatment
- prophylaxis/maintenance
schizoaffective disorder
unipolar depression adjunct
T or F
lithium is highly protein bound
false
what is the half life of lithium?
12-27 hours
longer in elderly
how is lithium eliminated
95% renal
4% perspiration
what causes decreased clearance of lithium?
hyponatremia, dehydration, renal failure or dysfunction, decreased renal blood flow
what is chronokinetics?
varies with circadian rhythm
what are the lithium concentration therapeutic range for acute mania?
1.0 to 1.2 mmol/L
what are the lithium concentration therapeutic range in maintenance therapy?
0.6 to 1.0 mmol/L
0.6 to 0.8 mmol/L in elderly
when is time of sampling for lithium?
12 hours post dose level
stat if toxicity or non-adherence is suspected
when should lithium levels be taken?
5-7 days after starting therapy or changing doses, then once weekly until at a stabilized dose for 2 weeks, then monthly for up to 3 months, then at least every 6 months
during times of infection, debilitation, changes in diet, recurrences of symptoms, noncompliance, signs of toxicity
why is it best to give lithium once daily in maintenance therapy?
improves compliance
decrease in urine volume and decrease in renal toxicity
what should be done when lithium toxicity is suspected?
hold dose
repeat plasma level next day
restart therapy when within target range
T or F
lithium syrup contains lithium carbonate
False
syrup contains lithium citrate; caps and XR tabs contain lithium carbonate
what are some factors that can decrease lithium levels?
pregnancy
sodium supplementation
hemodialysis
peritoneal dialysis
burns
theophylline/aminophylline
caffeine
acetazolamide
sodium bicarb
what are some factors than can increase lithium levels?
dehydration
renal impairment
sodium loss
increased age
strenuous exercise
cirrhosis
NSAIDs
thiazide diuretics
ACEi/ARBs
SSRIs/SNRIs
chronic lithium use
what is the interaction between lithium and NSAIDs?
decreased lithium clearance = increased lithium concentrations
what is the interaction between lithium and ACEi/ARBs?
angiotensin II and decreased aldosterone levels = sodium depletion/lithium retention
vasoconstriction results in decreased renal perfusion, decrease lithium clearance = increased lithium level
what are some common AEs with lithium?
increased thirst and urinary frequency
fine tremors to hands/arms
headache, sedation, weakness
GI upset
skin changes
alopecia
weight gain
what is usually the first sign of lithium toxicity?
GI upset
what are some serious AEs of lithium?
hypothyroidism
renal injury
blood dyscrasias
bradycardia or conduction abnormalities
nephrogenic diabetes insipidus
what is nephrogenic diabetes insipidus?
cannot concentrate urine = polydipsia, polyuria
how can lithium cause nephrogenic diabetes insipidus?
lithium accumulation in collecting tubule
lithium interferes with antidiuretic hormone
volume depletion = lithium reabsorption = toxicity
what are the signs and symptoms of lithium toxicity?
mild: ataxia, fine tremors of the limbs, GI disturbances, muscle weakness, fatigue
moderate: sedation, lethargy, ataxia, dysarthria, headaches, increased reflexes, hyperthermia, coarse tremors, impaired sensorium, nystagmus
severe: coarse tremors, delirium, seizures, coma, respiratory complications, death
what concentration of lithium is toxic?
1.5 mmol/L +
toxicity can occur at doses close to therapeutic levels
what are the monitoring parameters for lithium?
manic symptoms
depressive symptoms
CBC with differential
weight
electrolytes
thyroid function
renal function
ECG
plasma lithium concentrations
lithium adherence
lithium side effects
suicide risk
T or F
lithium is safe in pregnancy
false
causes heart anomallys
what are the clinical indications of valproic acid?
seizures: generalised tonic clonic (grand mal), partial-onset, absense
bipolar disorder
- acute mania treatment
- maintenance
T or F
Vaproic acid is highly protein bound
TRUE
how is valproic acid eliminated?
> 95% hepatic metabolism via glucuronidation, B-oxidation, alpha-hydroxylation
major metabolism via UDGT-catalysed glucuronidation and B-oxidation
which metabolite of vaproic acid can cause liver toxicity?
4-ene-valproic acid
what is the half life of valproic acid?
12-18 hours
what is the therapeutic level of valproic acid?
350-700 umol/L
(total valproate levles)
what is the time of sampling of valproic acid?
trough
when are valproic acid levels taken?
steady state trough level – 3-4 days after initial therapy
seizure activity
suspected signs and symptoms of valproic acid toxicity
addition or withdrawal of other enzyme inducing drugs
suspected non-adherence
does lithium need to be adjusted for hepatic or renal impairment?
hepatic: no
renal: yes
does valproic acid need to be dose adjusted for hepatic or renal impairment?
hepatic: yes
renal: no
which enzymes are key to valproic acid drug interactions?
CYP2C9
epoxide hydroxylase
UDPGT
which drugs can increase valproate levels?
macrolides
topiramate
isoniazid
ASA/salicylates
which drugs can decrease valproate levels
carbapenems
anticonvulsants: carbamazepine, phenytoin, phenobarbital
rifampin
which drugs are increased by valproate?
anticonvulsants: carbamazepine, phenytoin, phenobarbital, lamotrigine
warfarin
TCAs
what is the interaction between valproate and lamotrigine?
valproate increases lamotrigine levels by 50%
enhances AEs of lamotrigine
labeling recommends 50% dose reduction when used with valproate
what are the AEs of valproate?
dose related
- GI: N/V/D/C, anorexia
- CNS: tremor, sedation, ataxia, dizziness
idiosyncratic
- increased transaminases and LDH
- hepatotoxicity
- hyperammonemia
- leukopenia
- skin rash (SJS, TENS, DRESS)
- hyponatremia
chronic
- weight pain
- menstrual disturbances, polycystic ovaries
- alopecia
is valproic acid safe in pregnancy?
no
causes neural tube defects
what are the monitoring parameters of valproic acid?
sedation
CBC with diff and platelets
LFTs
ammonia
rash
valproate levels
what are the clinical indications of lamotrigine?
seizures: partial onset (Adj), absence seizures, generalised tonic-clonic
bipolar disorder
- acute bipolar depression
- maintenance
what is the MOA of lamotrigine?
alters signal transduction via:
- binding to the open channel conformation of the voltage gated sodium channels
- reducing release of glutamate
weak 5-HT3 receptor inhibitory effects
what is the half life of lamotrigine?
25-33 hours
how is lamotrigine metabolised?
hepatic and renal
metabolised by glucuronidation and UGT enzymes
why is a slow titration so important with lamotrigine?
risk of SJS
what are the AEs of lamotrigine?
common: sedation, headache, N, dizziness
less common: dyspepsia, anxiety or emotional lability, chest pain, peripheral edema, dysmenorrhea, ataxia, rash (non serious)
rare/serious: risk of SJS, aseptic meningitis, blood dyscrasias, hepatotoxicity
what monitoring parameters are there for lamotrigine?
baseline: hepatic and renal function
ongoing: rash
no serum levels or lab monitoring required
what are the important DIs of lamotrigine?
VPA/DVP: increase lamotrigine 2-fold
carbamazepine, phenytoin, phenobarb, topiramate
oral contraceptives: decrease lamotrigine levels by 50%
what are the clinical indications of carbamazepine?
seizures: generalised tonic-clonic, partial onset
bipolar disorder
- acute mania treatment
- maintenance
neuropathic pain
trigeminal neuralgia
what is the MOA of carbamazepine?
signal transduction modulation (decrease repetitive action potential firing) and anti-kindling properties
stimulates the release of ADH and potentiates its action in promoting reabsorption of water
how is carbamazepine eliminated?
> 99% hepatic metabolism via CYP enzymes
what is the major metabolite of carbamazepine and is it active?
carbamazepine-10,11-epoxide
active and has therapeutic and toxic effects
what is unique about carbamazepines metabolism?
it induces its own metabolism via the epoxide-diol pathway (autoinduction)
why is carbamazepines clearance and half life variable depending on dosing?
due to autoinduction
what is the therapeutic range of carbamazepine?
17-51 umol/L
what is the time of sampling of carbamazepine?
trough within 1 hour prior to dose
when is carbamazepine levels taken?
until stabilised at target dose
- during autoinduction (every 1-2 weeks until on stable regimen)
- steady state through (after 5 weeks)
routine monitoring
- suspected non-adherence
- suspected s/sx of carbamazepine toxicity
- potential DIs or altered PK
- conversion between carbamazepine dosage forms
- to establish what concentration resulted in mood stability
how long does autoinduction of carbamazepine last?
around 5 weeks
is dosing adjustments of carbamazepine needed in renal or hepatic impairment?
renal: no
hepatic: yes
- not recommended in pts with decompensated liver disease
T or F
there is an IV formulation of carbamazepine
False
what is the primary mechanism of DIs in carbamazepine?
CYP3A4 inhibitors and inducers
CYP450 isoenzymes
which drugs increase carbamazepine levels?
macrolides
anticonvulsants: valproate acid, lamotrigine
antidepressants: fluoxetine, fluvoxamine, trazodone
- MAOIs: CI within 2 weeks of use
azoles
- voriconazole: CI
isoniazid
calcium channel blockers (esp. non-DHP)
cimetidine
grapefruit juice
propoxyphene
quinine
which drugs decrease carbamazepine levels?
anticonvulsants: phenytoin, phenobarbital, primidone
rifampin
theophylline
isotretinoin
which drugs are decreased by carbamazepine?
doxycycline
anticoagulants
- warfarin: monitor INR
- DOACs: use not recommended
anticonvulsants: phenytoin, valproic acid, lamotrigine, topiramate
antipsychotics
- lurasidone: CI
antiretroviral – NNRTIs: CI
estrogen OR progesterone contraceptives
methadone
what are the AEs of carbamazepine?
dose related
- GI: N/V, anorexia, dry mouth, constipation
- CNS: lethargy, dizziness, sedation, headache, incoordination, ataxia, blurred vision, diplopia, tremor
- CV: tachycardia, hypotension, cardiac conduction abnormalities (rare)
idiosyncratic
- SIADH/hyponatremia
- blood dyscrasias
- hepatic: increased GGT, hepatitis
- abnormal thyroid function tests: decreases free T3/T4
- diplopia, nystagmus
- menstrual disturbances
- weight gain
- photosensitivity
- rash (10% morbiliform) and hypersensitivity reactions
chronic: osteomalacia, vitD deficiency
what level of WBC warrants d/c of carbamazepine?
< 2x10^9/L
which genetic test should be done in Asian individuals before carbamazepine use and why?
HLA-B*1502
if positive at increased risk for SJS
what are the CI of carbamazepine?
hx of hepatic disease, CVD, blood dyscrasias, bone marrow depletion
concurrent use with clozapine
what are the monitoring parameters of carbamazepine?
sedation, tremor, cognitive changes
ocular exams
ECG
CBC with diff and platelets
electrolytes
LFTs
renal function
TSH, free T3/T4
BMD
rash
baseline pregnancy or allele testing if applicable
which contraception method is preferred with carbamazepine?
copper IUD, condoms (non hormonal)
decreases efficacy of hormonal methods of contraception
what is the primary mode of action of antipsychotics?
DA blockade
which antipsychotics are used in BD?
atypicals
which symptoms of antipsychotics are pts with BD at an increased risk of?
EPS
what are some AEs of 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 tachycardia, dizziness, sedation
QT prolongation
seizures
what are the monitoring parameters for antipsychotics?
BMI, vitals
A1C/FBG, lipids
ECG
liver function, renal function, electrolytes, CBC
prolactin
what was the objective of the STEP-BD study?
to determine if adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing risk of mania
what is the consensus with antidepressants in bipolar?
avoid AD monotherapy without an antimanic agent
use with caution in people with a hx of AD-induced mania, mixed features or rapid cycling
d/c use during acute manic episode
consider tapering off once depression symptoms eliminated for 3-4 mo.
which antidepressants seem to be the safest in BD?
bupropion > sertraline, then fluoxetine and other SSRIs (NOT paroxetine)
which antidepressants have the highest risk of switch in bipolar depression?
TCAs»_space; SNRIs
paroxetine also not recommended
what is the first line treatment for acute mania?
monotherapy:
- lithium
- quetiapine
- divalproex
- aripiprazole
- paliperidone (>6mg)
- risperidone
combination: lithium or divalproex + quetiapine, risperidone or asenapine
when is it recommended to start acute mania treatment off as combination therapy over monotherapy?
a response is needed faster, history of partial acute or prophylactic response to monotherapy or in those with more severe manic episodes
when is lithium preferred over divalproex?
in individuals who display classical euphoric grandiose mania, few prior episodes of illness, a mania-depression-euthymia course, and/or those with a family history of BD, especially with a family hx of lithium response
when is divalproex recommended?
those with multiple prior episodes, predominant irritable or dysphoric mood and/or comorbid SUD or those with a hx of head trauma
which medication regimens are recommended in BD with mixed features?
DVP or APs, especially AP + DVP
when should an add on or switch strategy be considered in acute mania treatment?
if not response within 2 weeks of starting a first line agent
what is second line treatment of acute mania?
2nd line monotherapy:
- olanzapine
- carbamazepine
- ziprasidone
- haloperidol
2nd line combination: olanzapine + lithium or divalproex
ECT
which agents are NOT recommended for acute mania?
gabapentin
lamotrigine
omega 3 fatty acids
topiramate
what is first line treatment of BD I depression?
quetiapine
lurasidone + Li/DVP
lithium
lamotrigine monotherapy or adj
lurasidone
what is the 2nd line treatment of bipolar I depression?
2nd line monotherapy: divalproex
2nd line add on therapy
- adj SSRI or bupropion (added to Li/DVP or AAP)
- olanzapine-fluoxetine
ECT
when is ECT considered in bipolar I depression?
refractory pts and if rapid response in needed (imminent suicide risk, catatonia, psychotic depression, medical stabilization)
which agents are not recommended in bipolar I depression?
antidepressant monotherapy
aripiprazole monotherapy
ziprasidone mono/adjunctive therapy
lamotrigine with folic acid
mifepristone adj
why is it important for maintenance treatment early in disorder?
- reverse cognitive impairment
- preserve brain plasticity
- may lead to improved prognosis and minimisation of illness progression
what are some risk factors for recurrence of episodes?
younger age at onset
psychotic features
rapid cycling
more previous episodes
comorbid anxiety
comorbid SUD
which psychosocial treatment is 1st line in bipolar I maintenance?
psychoeducation
what are the first line agents for BDI maintenance therapy?
lithium
quetiapine
divalproex
lamotrigine
asenapine or aripiprazole
quetiapine or aripiprazole + Li/DVP
what is 2nd line therapy for BDI maintenance therapy?
2nd line monotherapy
- olanzapine
- risperidone injectable
- carbamazepine
- paliperidone injectable
2nd line add on therapy: risperidone injectable adj
which agents are not recommended for BDI maintenance?
perphenazine
TCAs
which bipolar agents should be absolutely avoided in pregnancy?
DVP/VPA, CBZ
which agent has the least risk in pregnancy?
lamotrigine
which bipolar agent has evidence that it reduces suicide risk?
lithium
