Mood stabilizers Flashcards
what is considered the gold standard mood stabilizer for bipolar disorder
lithium
which has a more rapid anti-manic effect, lithium or valproate
valproate (therapeutic benefit seen in 3-5 days)
list medications that fall under the “mood stabilizers and anticonvulsants” label
lithium
valproate
carbamazepine
gabapentin
lamotrigine
levetiracetam
phenytoin
pregabalin
oxcarbazepine
what is the strictest definition of mood stabilizer
an agent that treats and prevents acute mania and depression
what is the broadest definition of mood stabilizer
an agent that is effective at either treating or preventing mania or in treating or preventing depression, and does not exacerbate symptoms
how long do mood stabilizers generally take for a good response
1-2 weeks
some initial effects can take place within 48 hours
why are antiepileptics used to treat bipolar disorders
bipolar disorder and epilepsy share common features including an EPISODIC course of illness and KINDLING phenomena
the AMYGDALA plays role in both disorders as well
however epilepsy and bipolar disorders are two distinct diseases
what is the mechanism of action of most mood stabilizers
most have multiple MOAs
include modulation of GABA-ergic and glutamatergic neurotransmission and alteration of VOLTAGE GATED ION CHANNELS or intracellular signalling pathways
what is the mechanism of action of lithium
“unknown and complex”
alters SODIUM TRANSPORT across cell membranes in nerve and muscle cells
alters metabolism of neurotransmitters including catecholamines and serotonin –> may alter intracellular signalling through actions on second messenger systems
specifically–> INHIBITS INOSITOL MONOPHOSPHATASE–> possibly affecting neurotransmission via phasphatidyl inositol second messenger system
also REDUCED PROTEIN KINASE C activity–> possibly affecting genomic expression associated with neurotransmission
how might lithium provide neuroprotective effects (what mechanism of action)
–increasing glutamate clearance
–inhibiting apoptotic glycogen synthase kinase activity
–increasing levels of antiapoptotic protein Bcl-2
–enhancing the expression of neurotropic factors (including brain derived neurotropic factor)
how might lithium affect genomic expression associated with neurotransmission
possibly by reducing protein kinase C activity
indications for lithium therapy
manic episodes in bipolar illness
maintenance patients with bipolar disorder
bipolar depression
MDD (adjunctive)
onset of action of lithium
1-3 weeks
how do you titrate lithium in the acute setting
start 300mg 2-3x/day
rapidly increase to 900-1200mg per day
(“dr lam slams it in after one day of 600mg)
THEN DO LEVELS
how do you titrate lithium in the outpatient setting
for low mood–> 150mg po daily for 1 week, then increase to 300mg po daily
then measure levels
what are the benefits to converting lithium from split dosing to once daily dosing
ideally daily at HS
less kidney exposure to lithium, possibly less CKD and side effects overall
how do you change the dose of lithium if going from divided doses to once daily dose
once daily dose is 20% LOWER than in divided doses–> this is because kidneys filter lithium more slowly while u are sleeping
i.e if was on 1500mg total daily dose in divided doses, then nighttime dose would be 1200mg
what is the typical adult target range dose for lithium
300-2400mg per day
what is the typical adolescent dose range for lithium
300-1800mg per day
in what forms does lithium come
capsules (carbonate)
liquid (citrate)
what baseline monitoring needs to be done for lithium
CBC/diff
electrolytes
creatinine/BUN
TSH, Ca, consider PTH
weight
beta-hcg in all women
ECG if over 40 or cardiac hx
what investigations should be ordered during maintenance phase of lithium therapy for monitoring
CBC.diff
electrolytes
creatinine, BUN
TSH
lithium level (minimum 5 days after dose change)
weight q6 months
calcium
PTH
how frequently should you measure calcium and PTH in lithium maintenance monitoring
calcium q2years
PTH ?q5 years and if indicated
when should you draw lithium levels
12 hours post dose so a “trough” level
what is the lithium level range in acute treatment
0.8-1.2 mmol/L
what is the lithium level range in maintenance therapy
0.6-0.8 mmol/L
(psych DB says 0.6-1.0 mmol/L)
what is the lithium level target range generally in peds and geri populations
0.3-0.7 mmol/L
(other sources say 0.4-0.8 in acute bipolar mania/depression in those above 65 years old)
how does one daily dosing affect lithium levels compared to divided doses
a 10-26% INCREASE of a 12 hour level can be expected with ONCE DAILY dosing compared to a 12 hour level checked of an EQUAL dose if given twice a day–> hence why you would usually decrease the total daily dose if going from BID to OD dosing for same blood level
list possible CNS side effects/adverse events associated with lithium
sedation
FINE tremor
ataxia
lethargy
pseudotumor cerebri/seizures (rare)
serotonin syndrome
cognitive dulling
how do we understand the cognitive dulling some patients complain of on lithium
likely the subjective loss of highly creative/brilliant thinking of manic state or being in mildly depressed phase
list possible endocrine side effects/adverse events associated with lithium
hypothyroidism
hyperparathyroidism
weight gain/loss
polydipsia
why is hypothyroidism a complication of lithium therapy
lithium interferes with iodine uptake
if someone it going to develop hypothyroidism on lithium, when will it usually happen
within 6-18 months of initiating treatment
women may be at higher risk–> 14% vs 5% in men
how do you manage hypothyroidism developing while on lithium? what is the target TSH?
synthroid–> target TSH of 1.0
what is a sign of hyperparathyroidism (seen in lithium therapy)
hyper calcemia
list possible cardiovascular side effects/adverse events associated with lithium
bradycardia
arrhythmias
heart failure (reversible on discontinuation of lithium)
what might you see on ECG in someone on lithium
diffuse slowing
flattening
t wave changes
list possible GI side effects of lithium
nausea
vomiting
diarrhea
list possible genitourinary side effects/adverse events associated with lithium
nephrogenic diabetes insipidus
CKD
polyuria
non-specific chronic tubulointerstitial nephropathy
sexual dyfunction
what can you do if someone develops polyuria on lithium
consolidate to once daily dosing which may decrease urine output
list possible hematological side effects/adverse events associated with lithium
REVERSIBLE agranulocytosis
BENIGN leukocytosis
list possible derm side effects/adverse events associated with lithium
alopecia
new or worsening acne and psoriasis
what % of people develop new or worsening acne or psoriasis on lithium? why?
about 45%
due to increase in neutrophils
what fetal abnormality are you concerned about in pregnant women on lithium
ebsteins anomaly
what is the baseline population risk of ebsteins anomaly
1/40 000 births
what is the risk of ebsteins anomaly in pregnant women on lithium
1/10 000 (0.1%)
(vs 1/40 000 at baseline)
what factors affect risk of ebsteins anomaly in pregnant women on lithium
dose dependent
higher risk with doses of lithium above 900mg/day
what can lithium toxicity/overdose look like?
can look like EtOH intoxication
what serum lithium level suggests mild toxicity
1.5-2.0 mmol/L
(occasionally can have signs of mild toxicity even when blood levels are in normal range)
what serum lithium level would suggest severe toxicity
above 2 mmol/L
list symptoms of mild lithium toxicity
N/V/D
COARSE (vs fine) tremor–> this will be much worse than normal tremor
HYPERreflexia
agitation
dysarthria/slurred speech
impaired vision
muscle weakness and ataxia
list symptoms of moderate lithium toxicity
stupor
rigidity
hypertonia
HYPOtension
list symptoms/signs of severe lithium toxicity
coma
seizures
myoclonus
list four other meds/conditions that can increase levels of lithium
NSAIDs
diuretics
ACEi/ARBs
dehydration
list four meds/conditions that can decrease lithium levels
caffeine
high salt diets
manic episodes
pregnancy (later in pregnancy, higher circulating blood volume)
must you make changes to lithium dosing in liver impairment
no
what is the half life of lithium
18-30 hours
how must you adjust lithium dosing in renal impairment
based on eGFR
reduce dose
if 10-50ml/min use 50-75% of standard dose
if less than 10ml/min use 25-50% of standard dose
what % of people achieve adequate relief with lithium monotherapy
only about 1/3
list 7 predictors of poor efficacy related to lithium therapy
dysphoric/psychotic mania
mixed states
rapid cycling
multiple prior episodes
comorbid medical conditions
substance abuse
high anxiety
list 6 predictors of positive response to lithium therapy
prior response to lithium
history of response in 1st degree relative–> 67% likelihood of also being responsive (vs 35% baseline likelihood)
family history of BD
classic euphoric/grandiose mania
few prior mood episodes and complete recovery between episodes
how long should you continue treatment with lithium in the case of mania
continue treatment until all symptoms are gone or until improvement is stable and then continue treating INDEFINITELY as long as improvement persists
continue treatment indefinitely to avoid recurrence of mania or depression
is there a significant withdrawal syndrome associated with lithiuim
no significant withdrawal
what are risks associated with stopping lithium
risk of recurrence within MONTHS
increased risk of suicide within the first year
risk of this is increased with rapid withdrawal of lithium (ie within 2 weeks)
some patients reported to become refractory to lithium if discontinued –> this is controversial but Dr. Shabbits quotes this study to reinforce adherence
does lithium reduce suicide risk
yes
what meds/substance should be counselled about when starting lithium
ACEi/ARB
NSAIDs
diuretics
caffeine
what can you do to help deal with nausea associated with taking lithium
take with food
in addition to ebsteins anomaly, what other abnormality might be noted in infants born to mothers on lithium
hypotonia
how do you counsel women RE breastfeeding and lithium
lithium is found in breast milk, possibly at full therapeutic levels–> either stay off lithium or bottle feed
however, if has done well on lithium before may be best to restart lithium and bottle feed ideally
list factors that can cause or contribute to lithium toxicity
overdose
volume depletion/dehydration
reduced GFR
drug interactions (thiazide diuretics, NSAIDs–> not aspirin, ACEi
how do you manage lithium toxicity
lithium levels q2-4 hours
IV hydration
bowel irrigation (asymptomatic acute overdose)–> to reduce absorption
consider hemodialysis
when should you consider pursuing hemodialysis in the case of lithium toxicity
lithium level above 4mmol/L empirically/with ANY symptoms
lithium level above 2.5 mmol/L + serious symptoms or renal failure
if theres an increasing lithium level despite IV fluids
what would you counsel someone if theyre home and doing okay but worried about possible signs of lithiuim toxicity
tell them to drink a bunch of fluid
when do you restart lithium after an overdose/toxicity
since it accumulates in the CNS, the serum level will fall faster than in the tissue
restart based on CLINICAL PICTURE i.e when coarse motor tremor resolves
what type of compound is lithium
alkali metal
is lithium absorbed rapidly?
yes–> rapidly absorbed from the GI tract
Tmax = 1-3 hours
do food or antacids affect lithium absorption
no dont appear to
is lithium protein bound
no–> distributes freely in the body water both intra and extracellularly
how is lithium metabolized and excreted
not metabolized, almost entirely excreted by kidneys
what types of neurotransmission are thought to be modulated by lithium
glutamatergic
dopaminergic
GABAergic
via alteration of sodium transport across cell membranes of muscle and nerve cells
how does lithium increase synthesis of serotonin
by increasing tryptophan reuptake in synaptic terminals
what effect does lithium have on 5HT receptors
downregulation of 5HT1A, 5HTB and 5HT2 receptors
changes in what electrolyte is closely related to risk factors for developing lithium toxicity
changes in sodium levels or the way the body handles sodium
what types of diuretics would worsen or risk lithium toxicity
thiazide and loop diuretics
what types of diuresis could be used to help treat mild to moderate lithium toxicity
osmotic or alkaline diuresis
above what lithium level is lithium toxic
above 1.5mmol/L (though can have sx toxicity below this so be aware)
what is one way to figure out what dose your patient would need of lithium if their current lithium level is subtherapeutic
divide current dose over current lithium level, then multiple by target level
ie if dose is 600mg/day and current level is subtherapeutic at 0.5, and your target level is 0.8 then do
(600mg/0.5) x 0.8 = 960mg po daily
do we know why there is a “rebound affect” of mood episodes associated with abrupt discontinuation of lithium
no–> but risk of mood episodes with abrupt stop can actually be above risk of untreated bipolar disorder
is intermittent treatment with lithium recommended in bipolar disorder
no–> intermittent treatment may worsen the natural course of bipolar disorder –> some recommendations that lithium should not be started unless there is a clear intention to continue it for at least 3 years
how does sodium depletion affect lithium uptake
lithium undergoes higher reabsorption in the kidneys if there is low sodium resulting in higher lithium levels
when there is high sodium intake, there is less lithium reabsorption, leading to lower levels
what pathways are associated with lithium’s hypothesized neuroprotective effects
NMDA pathways
some mild evidence for lower risk of dementia in those with mood disorders treated on lithium
which has better anti-suicidal evidence, lithium or clozapine
lithium
what is the hypothesis behind why lithium protects against suicide
?lithium leads to a decrease in impulsivity and aggression via several influences within the nerve cell
however one recent study of lithium as an AUGMENTATION agent at SUBTHERAPEUTIC doses did NOT reduce the overall incidence of suicide related events compared to placebo
contraindications to lithium therapy
first trimester of pregnancy (teratogen)
severe renal impairment
CV disease with arrhythmias (can cause reversible T waves changes or unmask Brugada syndrome)
addisons disease
untreated hypothyroidism of thyroid disorder
list the most common side effects of lithium
metallic taste in the mouth
GI upset
fine tremors
polyuria and polydipsia
ankle edema
weight gain
how is the tremor associated with lithium categorized
postural tremor–> produced by voluntary maintenance of a particular posture held against gravity
what is the typical frequency of the tremor (postural) associate with lithium
8-12 Hz
what is the average rate of tremor associated with lithium
ranges depending on study
around 27% average
does lithium tremor (postural) improve
yes often improves over time
is often tolerable
how might you manage lithium tremors
beta blockers (propanolol)
primidone
gabapentin
topiramate
*benzos generally not recommened
what is nephrogenic diabetes insipidus
can be due to lithium
characterized by intense thirst and polyuria with inability to concentrate urine due to reduction of ADH
chronic lithium use can cause ADH RESISTANCE in the kidneys
usually REVERSIBLE in the short term but may be irreversible after long term treatment with lithium ie over 15 years
lithium levels over 0.8 assoc with higher risk of nephrotoxicity
how do you diagnose nephrogenic diabetes insipidus
water restriction test
+ when theres no change in urine osmolality despite water restriction
what is the management of nephrogenic diabetes insipidus
d/c lithium or reduce dailty dose or dosing schedule
diuretics can be used to treat NDI but require close monitoring of Li and K levels
what are consequences of long term hypercalcemia (i.e due to long term lithium therapy)
renal stones, osteoporosis, dyspepsia, hypertension and renal impairment.
can lithium prolong QTc
yes
what is the risk of developing CKD and progressing to ESRD in patients on lithium
about 1.5% in long term Li users
most people on long term Li do NOT appear to develop impaired renal function
how does drinking caffeine reduce lithium levels
?increasing renal Li clearance
should lithium be held in delivery (of a baby)
yes–> 24 hours before
due to risks of massive fluid shifts from delivery causing lithium toxicity
what lithium levels and doses are recommened in geriatric patients
For geriatric patients, lithium levels should be <0.8 mmol/L where possible (0.4 to 0.6 for depression, and 0.4 to 0.8 for mania/hypomania). Once daily dosing is best, and it is best to start at a lower dose of 150 mg per day.
Typically, 450 mg per day is enough to reach a therapeutic level for geriatric patients. In some cases, a therapeutic effect is achieved between 0.2 to 0.6 mmol/L, this is because there is a lower correlation between serum lithium levels and cerebrospinal levels in older age (due to a leakier blood brain barrier).
what are the big possible adverse events you should know about:
lithium
renal impairment
nephrotoxicity
what are the big possible adverse events you should know about:
valproic acid
pancreatitis
hepatotoxicity
what are the big possible adverse events you should know about:
cabamazepine
agranulocytosis
asplastic anemia
hepatotoxicity
SJS
TEN
what are the big possible adverse events you should know about:
oxcarbazapine
agranulocytosis
asplastic anemia
hepatotoxicity
SJS
TEN
what are the big possible adverse events you should know about:
lamotrigine
SJS
TEN
is there any blood work monitoring with lamotrigine specifically
no–> but monitor for rashes
what teratogenic effects are associated with:
lithium
ebsteines anomaly
what teratogenic effects are associated with:
valproic acid
neural tube defects
what teratogenic effects are associated with:
carbamazepine
neural tube defects
cleft lip
what teratogenic effects are associated with:
oxcarbazepine
neural tube defects
cleft lip
what teratogenic effects are associated with:
lamotrigine
safe in pregnancy
what is a particular drug-drug interaction to know amongst the mood stabilizers/anticonvulsants
combo of valproic acid with LAMOTRIGINE can cause significant and dangerous increases of lamotrigine –> due to inhibition of GLUCURONIDATION
what mood stabilizer should you consider in those with hx of comorbid substance use or TBI
VPA
what is the benefit of oxcarbazepine vs carbamazepine
similar to carbamazepine but NO autoinduction and much fewer CYP 450 enzyme interactions
what is the mechanism of action of VPA
blocks voltage-sensitive sodium channels by unknown mechanism
acute effects–> mediated by ENHANCEMENT OF GABA-MEDIATED neurotransmission via interference with GABA metabolism and effects on signalling pathways
long term effects–> alteration in multiple gene expression–> at least partly mediated through direct inhibition of HISTONE DEACETYLASE (leads to increase acetylation of lysine residues and thus enhanced transcriptional activity)
list 5 indications for treatment with VPA
manic episodes
maintenance treatment of bipolar I
bipolar depression
seizures (complex partial, simple/complex absence)
migraine prophylaxis
how long is the onset of action of VPA for acute mania? for mood stabilization?
acute mania–> a few days
mood stabilization–> a few weeks
how would you titrate VPA in the acute setting
start at 500-750mg /day then increase by 250-500mg q1-3 days until reach clinical effect
how would you titrate VPA in outpatient settings
start at 250-500mg qHS, increase weekly, to clinical effect
what is the target dosing range for VPA
1200-1500mg/day for mania–> extended release formulation with HS dosing once daily
what is the benefit of divalproex vs valproic acid
less GI side effects with divalproex
what baseline monitoring is needed before starting VPA
CBC/diff (platelets)
LFTs
weight
blood glucose
lipid panel
beta HCG in all women
consider serum testosterone in young females
what is the maintenance monitoring required for VPA
cbc/diff (platelets)
LFTs
serum ammonia (with symptoms of lethargy, mental status change)
metabolic monitoring annually
serum testosterone if sx of hyperandrogenization/irregular menses
menstrual hx
why do you do a menstrual hx for women on VPA
can cause PCOS
do it as q3-6 month intervals for first year, then annually
when should you do a serum ammonia for someone on VPA
with symptoms of lethargy, mental status change
how soon after a dose change should you do a VPA level
3-4 days after initiation and dose changes
draw 12 hours post dose as a trough
what is the target VPA level
350-700umol/L (aim for around 500)–> this is for safety not efficacy
is VPA dosing linear
no–> due to saturable protein binding
doubling the dose will double the level minus 10-20% ish
list CNS side effects/adverse events associated with VPA
COGNITIVE BLUNTING
headache (30%)
sedations (up to 30%)
dizziness (up to 25%)
insomnia (15%)
tremor
encephalopathy
list endo side effects/adverse events associated with VPA
hyperammonemia
metabolic acidosis
hyperosmolality
hypernatremia
hypocalcemia
WEIGHT GAIN
list GI side effects/adverse events associated with VPA
N/V/D
pancreatitis
hepatotoxicity
list heme side effects/adverse events associated with VPA
anemia
thrombocytopenia (dose related, up to 25%)
rare pancytopenia
what % of people develop thrombocytopenia on VPA
up to 25%–> dose related
list derm side effects/adverse events associated with VPA
alopecia
hypersensivitity (SJS, TEN)
list sexual side effects/adverse events associated with VPA
PCOS
hyperandrogenism
1-2% risk of neural tube defects (i.e spina bifida)
how should you adjust dose of lamotrigine if paired with VPA
reduce lamotrigine by 50%
is there any adjustment in dosing needed for VPA in cases of renal impairment
no
what is the half life of VPA
9-16 hours
is there any dose adjustment required for VPA in cases if liver impairment
since metabolized primarily by liver, use with caution–> not recommended in mild/mod disease and contraindicated in severe liver disease
what could you pair with VPA to possibly help reduce risk of alopecia
multivitamin with zinc and selenium
is VPA generally recommended in kids
not generally recommended under age 10 except by experts and when other options have been considered
how should you handle a pregnant patient on VPA
ideally, stop VPA before pregnancy to reduce risk of NTDs and other abnormalities
atypical antipsychotics are generally preferred to mood stabilizers like lithium and VPA during pregnancy
is it generally considered safe to breastfeed on VPA
yes generally
may be safer than lithium during the post partum period when breast feeding
what is the mechanism of action of lamotrigine
blocks the alpha subunit of voltage sensitive sodium channels which INHIBITS release of GLUTAMATE
this may modulate reuptake of serotonin and may block reuptake of dopamine
also thought to stabilize neuronal membranes and inhibit the release o excitatory amino acid neurotransmitters i.e glutamate and aspartate that are thought to play a role in the generation and spread of epileptic seizures
how do you titrate lamotrigine
25mg po daily x 2 weeks
increase by 25mg every 2 weeks
what is the target dose of lamotrigine
“at least” 200mg po daily
what increases the risk of developing SJS on lamotrigine
also on VPA
age below 16 years
what is the risk of SJS in lamotrigine start
0.8 in 1000
what is the half life of lamotrigine
about 25 hours
does lamotrigine affect contraceptive efficacy (OCP)
while studies have shown that lamotrigine decreases progestin levels by about 20% it is NOT thought to have an overall impact on contraception efficacy
lamotrigine has been observed to cause false positive of what drug on urine drug screen
phencyclidine
is lamotrigine safe in pregnancy
yes
how do you titrate lithium
150mg po BID
can increase by 300mg every 1-5 days
what is the usual dose of lithium
900-1800mg /day
is lithium first line for MDD
no–> second line adjunct
do you hold lithium before ECT
yes–> risk of delirium
hold for 24 hours prior
VPA is particularly well suited to treated bipolar patients with what diagnostic specifier
rapid cycling
can you use VPA in liver failure
no–> health canada warning
what is the max dose of lamotrigine
400mg/day
what % of people get a benign rash with lamotrigine
8-10%
can you add epival to lamotrigine?
no, only add lamotrigine to epival (at reduced dose)
does carbamazepine cause weight gain
no
in which patients should you avoid using carbamazepine
pregnant (risk of cleft palate, NTDs, microcephaly)
EtOH abuse
what impact does carmabazepine have on the effect of lithium
increases neurotixicity of lithium
what is the starting dose of topiramate
50mg /day
what is the usual dose of topiramate
200mg / day (max is 400mg/day)
what are indications for use of topiramate
SECOND line for AUD
binge eating
bulimia
antipsychotic induced weight gain
side effects of topiramate
weight loss
dizziness
sedation
paresthesias
cognitive dulling
rare metabolic acidosis
NEPHROLITHIASIS
glaucoma
is topiramate recommended for PTSD
NO not recommended
what is the starting dose of gabapentin
300mg/day
usual dose is 300-600mg / day
what is the max dose of gabapentin
3600mg/day
list indications for gabapentin
second line for AUD
used for neuropathic pain, EtOH withdrawal
side effects of gabapentin
sedation
ataxia
fatigue
should you use gabapentin/pregabalin in pregnancy or breastfeeding
no, avoid
what effect does gabapentin/pregabalin have on other sedatives
potentiates them
starting dose of pregabalin
150mg/day
usual dose is 150mg BID
max dose of pregabalin
600mg/day
indications for pregabalin
FIRST line for GAD, SAD, restless legs
used for neuropathic pain
why is divalproex better for GI side effects
its enteric coated
half life of VPA
10-16 hours
is VPA approved for any psychiatric conditions in canada in kids/teens
no
often used off label for bipolar or for symptoms of impulsivity, rage, aggression
maximum dose of VPA
3000mg po daily
or 60mg/kg/day
what is the risk of NTDs in women on VPA
5%
what should women taking VPA also be taking
OCP
what % of people develop a tremor within 1 year of taking VPA
25%
dose response relationship
reducing dose or changing to slow release can help
when is VPA induced pancreatitis most likely to occur
it does NOT depend on the serum level and can occur ANYTIME after the onset of therapy
what % of people will experience hair loss/alopecia with VPA therapy? does this happen at any particular time in therapy?
up to 25% of people
more common in women than men
temporary
most common with long term VPA treatment
appears to be dose related
what should you do if you see a patient who is on VPA and develops decreased LOD, focal neuro signs, cognitive slowing, vomiting, drowsiness, lethargy
draw ammonia level–> ?hyperammonenia encephalopathy
