Mood Stabilizers + Other Drugs used in Bipolar Flashcards
Timeline for medication response to mania is about ____ weeks.
1-2 weeks, to see decrease in symptoms
Main goals of therapy with bipolar treatment include…
There are 2 main ones, and then a few other ones that may be important
Eliminated mood episode with complete remission of symptoms, ongoing; acute treatment
Prevent recurrences or relapses of mood episodes, ongoing; maintenance treatment
May also improve QoL and optimize psychosocial functioning
Minimizing harm to self + others
Maximizing adherence and minimizing adverse effects
Minimizing risk factors for mood episodes
Providing care for comorbid conditions
Timeline for a full clinical benefit from medications for mania symptoms is about ____ weeks.
3-4 weeks
Timeline for medication response to bipolar depression is about ____ weeks.
2-6 weeks
Timeline for a full clinical benefit from medication, for bipolar depressive symptoms is about ____ weeks.
6-12 weeks
Usually longer than unipolar depression
Some key non-pharmacological therapies that may help with bipolar treatment include…
Exercise
Adequate sleep
Healthy diet
Decreased substance use
Decreased caffeine, nicotine, alcohol
May also involve psychoeducation, supportive counselling, psychotherapy…
ECT for extremes of mania or psychotic depression
A relapse prevention plan is important in bipolar treatment, since…
It outlines early warning symptoms and tools they can use when threat of a crisis starts to come on; and what they will do/who to entrust when they are in crisis
Also references what they have to do to stay well, and their responsibilities
Our most commonly used mood stabilizers for bipolar include these 3…
Lithium
Valproic acid
Lamotrigene
MOA of lithium is…
Exact mechanism not fully understood
Interaction with downstream signalling cascades
Enhancement of GABA activity (inhibitory)
Decreased CNS adrenergic activity
Lithium distributes evenly in the total body water space. This is an important factor to consider in elderly patients because…
There will be decreases in Vd in elderly, due to decreased % of total body water and lean body mass
Results in increased lithium concentrations
Elimination of lithium is mainly via…
Renal excretion
Freely filtered by glomerulus, like sodium and potassium
Also 80% reabsorbed in proximal tubules, with sodium
When considering lithium PK, we can think of lithium like…
A salt, similar to sodium
If the amount of filtered sodium decreases, this results in an increase in sodium reabsorption, which would affect lithium via…
Increases in lithium reabsorption and potential lithium toxicity
Hence hyponatremia decreases clearance
Factors that may decrease clearance of lithium include…
KIDNEY related - why?
Hyponatremia
Dehydration
Renal failure/dysfunction
Decreasd renal blood flow
Lithium relies on total body water/fluid status
Therefore, lower body water = higher concentration of lithium
What is the therapeutic range of lithium for acute mania?
0.8 to 1.2 mmol/L
Narrow TR; so possibility for toxicity with even 1.2…
The therapeutic range of lithium for maintenance therapy is…
0.6 to 1.0 mmol/L
The therapeutic range of lithium for maintenance in elderly patients is…
0.6 to 0.8 mmol/L
When should lithium levels be sampled?
12 hours post dose, OR stat if toxicity/non-adherence is suspected
12 hours - complete absorption/distribution
How often should lithium levels be taken?
Starting dose/changes; physiological conditions?
5-7 days after starting therapy/changing dose, then once weekly until at stable dose for 2 weeks.
Then monthly for up to 3 months, then at least every 6 months
More frequent during times of infection, debiliation, diet changes, symptoms recurrence, noncompliance, signs of toxicity
Lithium doses are titrated and started BID because of…
Increase likelihood of GI side effects
Initial dosing of lithium for acute mania is usually started at…
What about the elderly?
600-900mg per day, in 1-2 divided doses
300mg/day for elderly
Subsequent doses of lithium for acute mania are guided by…
Plasma levels and clinical response
Usual doses of lithium for acute mania is…
What about elderly?
900-2100 mg/day, in two divided doses
300-1200mg/day for elderly
Lithium dosing for maintenance therapy is usually…
Whats the target plasma level?
900mg in divided doses (600-1800mg/day)
Target plasma level of 0.6 to 1 mmol/L
Once a patient is stabilized on their maintenance dose of lithium, this could be done to the regimen…
Switch to once daily at bedtime, if able to tolerate
A potential benefit of switching to once daily dosing of lithium is…
Decrease in urine volume, and decreased renal toxicity/dysfunction
Patients who are sensitive to peak related side effects such as tremors or urinary frequency from lithium may benefit from…
Switching to the extended release formulation
Lithium dosing in renal impairment…
Needs to be reduced; is CI in acute renal failure
CrCl 10-50 mL/min: 50-75% of normal dose
CrCl below 10mL/min: 25-50% of normal dose
If a toxic plasma level of lithium is obtained, we should…
HOLD DOSE
Repeat plasma level next day
Restart therapy when within target range
Pregnancy will ____ lithium concentrations, because…
Decrease; increase in blood volume and renal clearance
Sodium supplementation will ____ lithium concentrations, because…
Decrease; will result in increased secretion of sodium, and lithium follows
Dialysis will ____ lithium concentrations, because…
Decreased; removal of drug from blood
Caffeine will ____ lithium concentrations because…
Decreased; likely due to increased renal clearance
Dehydration will ____ lithium concentrations, because…
Increased; less fluid volume (total body water) means increased concentration of lithium
Renal impairment will ____ lithium concentrations, because…
Increase; lithium is primarily renally excreted
Distributed in total body water; impaired fluid excretion in CKD
Sodium loss will ____ lithium concentrations, because…
Increase; retention of sodium will occur, lithium will follow
Increased age will ____ lithium concentrations, because…
Increased; decreased total body water as well as decreased kidney function
Strenuous exercise will ____ lithium concentrations, because…
Increase; sweat and dehydration lower fluid volume, leading to increased lithium concentrations
Cirrhosis will ____ lithium concentrations, because…
Increase; connection to hepatorenal syndrome
NSAID’s will ____ lithium concentrations, because…
Increase; affects the kidney via vasoconstriction of the afferent arteriole, leading to decreased pressure, decreased blood flow to kidney
Decreased excretion
Thiazide diuretics will ____ lithium concentrations, because…
Increase; decrease in blood volume
ACEI’s and ARB’s will ____ lithium concentrations, because…
Increase; dilate the efferent arteriole and reduce kidney pressure for filtration
SSRI’s and SNRI’s have a potential drug interaction with lithium, which is…
Theoretical risk of serotonin syndrome
Usage of antipsychotics with lithium may increase risk of…
Neurotoxicity
Loop diuretics and CCB’s will ____ lithium concentrations, because…
Increase or decrease - impact it has on fluid volumes
Common adverse effects of lithium that are DOSE-RELATED include…
Increased thirst + urinary frequency
Fine tremors to hands/arms
Headache, sedation, weakness
GI upset
Skin changes (acne, psioriasis), alopecia
Lithium causes weight gain, of about ____ kg.
4-6kg in the first 2 years
One of the first signs of lithium toxicity is…
GI upset - nausea, diarrhea
Some serious adverse effects that may result from lithium include…
Affects variety of body systems
Hypothyroidism
Renal injury
Blood dyscrasias
Bradycardias/conduction abnormalities
Nephrogenic diabetes insipdus
What is nephrogenic diabetes insipidus? Why can it occur with lithium usage?
Inability to concentration urine; lithium may be interfering with antidiuretic hormone
Nephrogenic diabetes insipidus with lithium usage will result insymptoms such as…
Severely increased thirst + urination; leads to volume depletion and lithium reabsorption, toxicity
This is the drug of choice for lithium-induced nephrogenic diabetes inspidius…
Amiloride - potassium sparing diuretic
Mild lithium toxicity symptoms may manifest as…
Think of the dose-related side effects that may be common
Ataxia, fine tremors, GI issues, muscle weakness, fatigue
Moderate lithium toxicity symptoms may manifest as…
(6)
Sedation, lethargy, ataxia + involuntary muscle movements, impaired senses, hyperthermia, coarse tremors
Severe lithium toxicity may manifest as…
CV, CNS based
Coarse tremors, delirium, seizures, coma, respiratory complications, AKI
ECG changes, pulse irregularities
Death
What should be monitored with lithium usage?
Symptoms of mania/depression
Labs
Adherence/side effects of lithium usage
Lab values that should be monitored lithium usage include…
Think about what affects lithium concentrations/side effects
CBC with differential
Electrolytes (sodium)
Thyroid function
Renal function
ECG
Weight
Plasma lithium conc.
In order to maintain adequate lithium concentrations, patients should…
Maintain adequate/consistent hydration, sodium, and caffeine intake
No drastic changes, or else lithium concentrations will change
A woman should consider ____ on lithium, due to…
Contraception - potential heart anomoly may develop in children
Valproic acid indications include…
Seizures
Bipolar disorder (acute mania treatment + maintenance)
The MOA of valproic acid includes…
Exact MOA is unknown
Inhibition of voltage-gated sodium channels
Increasing action of GABA
Modulation of signal transduction cascades + gene expression
May affect neuronal excitation
Also affects other neurotransmitters
Valproic acid relationship to protein binding is…
85-90% bound to serum albumin
Important when considering drug interactions
Valproic acid is primarily eliminated via…
Hepatic metabolism, via glucoronidation, beta-oxidation, and alpha-hydroxylation
Therapeutic range of valproic acid is…
350-700 micromol/L of total valproic acid; guideline only and needs to be individualized
Valproic acid levels should be taken…
At a steady state trough level; 3-4 days after initial therapy
Or at suspected s/sx’s of valproic acid toxicity
For seizures… needs to be measured at time of serizure to determine seizure threshold
If valproic acid needs to be used for acute mania treatment,this is what needs to be given as a loading dose…
20-30 mg/kg/day
Empiric doses of valproic acid should start at…
10-15 mg/kg/day
or
500-750 mg/day; increase by 5-10mg/kg/day (250-500 mg/day) using response, levels, and tolerance
MAX = 60 mg/kg/day
Dosing frequency of valproic acid is…
Usually BID/TID
Therapeutic doses of valproic acid is usually…
1500-2500 mg/day
Hepatic disease affects valproic acid dosing via…
Decreased protein binding + clearance; may result in increased unbound drug while total concentrations may remain unchanged
AVOID in hepatic disease
Valproic acid PK changes in elderly, because…
How does this affect dosing?
Protein binding and clearance is decreased; use lower initial doses
Does renal impairment affect valproic acid dosing?
No dosage adjustment necssary, but may decrease protein binding (resulting in increased unbound drug concentration)
Common drugs that may increase valproate levels include…
Antibiotics - macrolides
ASA/salicylates
Common drugs that may decrease valproic acid levels include…
Antibiotics - carbapenems
ASM’s - carbamazepine, phenytoin
Carbapenem interaction is very relevant
Common drugs that are increased by valproic acid include…
Anticonvulsants: carbamazepine, phenytoin, phenobarb
Lamotrigine
Lamotrigine and valproic acid have a key drug interaction in that…
And what do we have to do about it?
Lamotrigine concentrations are increased by ~50%, so we have to decrease lamotrigene dose by 50%
Notable side effects of valproic acid include…
Two systems are involved
GI: N/V/D, constipation, anorexia
CNS: Tremor, sedation, ataxia, dizziness
Thrombocytopenia
Hair loss/thinning, weight gain, amenorrhea
Lots, so important to find lowest effective dose + continuously monitor
Some serious adverse effects of valproic acid include…
Lots are hepatically related
Increased transanimases, LDH; hepatotoxicity
Pancreatitis
Hyperammonemia
Leukopenia
Skin rash (increased with lamotrigene usage)
With chronic usage of valproic acid, the following may occur…
Weight gain (up to 8-14kg)
Menstrual disturbances; PCOS
Alopecia
Menstrual disturbances could mean spotting, amenorrhea, more bleeding…
Contraception is warranted with valproic acid use, because…
Valproic acid is teratogenic; will cause neural tube deficits
The following should be monitored with valproic acid usage…
Both AE’s and labs
Sedation
Rash
CBC, platelets, and LFT’s
Ammonia levels (unexplained lethargy, confusion, vomiting)
Valproate levels
How often should valproate levels be tested?
2-4 days after a dose change or an interacting drug is started, then in 1-2 weeks to ensure stability
Then PRN
Indications for lamotrigine include…
Seizures
Acute + maintenance therapy for bipolar depression
Lamotrigene is not recommended in…
Acute mania
Lamotrigine MOA is…
Blockage of sodium channels + reducing glutamate release
Weak serotonin receptor inhibitory effect
Lamotrigine is metabolized via…
Both hepatic and renal metabolism
A key aspect of lamotrigine dosing is…
And what happens if we miss dose for long time?
SLOW titration
If dose is missed for 5+ days, need to restart titration
Lamotrigine titration is usually as follows…
Week 1-2: 25mg once daily
Week 3-4: 50mg once daily
Week 5: 100mg once daily
Then increase dose by 50mg-200mg every 1-2 weeks
Usual dosing for lamotrigine is…
225-375 mg/day, divided BID
Common AE’s that occur with lamotrigine include…
Sedation/insomnia, headaches, nausea, dizziness
Overall quite well tolerated
Serious but rare AE that we must monitor in lamotrigene usage includes…
Life-threatening SJS/TENS
Blood dyscrasias
85% patients on lamotrigene who experience SJS rash have prodromal symptoms, which involve…
Flu-like symptoms
The following needs to be monitored while on lamotrigine…
Obtain baseline hepatic + renal function
Monitor for rash
CBC, LFT, SCr
Avoid new soaps/detergent that may cause skin reaction in 1st month
Does lamotrigine need serum level monitoring?
No - relationship between clinical efficacy and plasma concentration is not clearly established
Will only indicate adherence
Lamotrigine titration needs to be restarted if ____ days are missed, to avoid…
5 days - avoid increased risk of skin rash
Lamotrigine DI’s that are important to note include…
Other ASM’s - VPA, other enzyme-inducing ASM’s
Estrogen products
Both decrease lamotrigine levels
Always check for DI’s
With medications that have indication for seizure, we want to ____, because…
EVEN if its not being used for seizures
Taper off; because we want to prevent seizure occurrence
Threshold of seizure protection, to no protection at all
Lamotrigine onset of effect is usually…
Several weeks, especially due to slow titration
Carbamazepine MOA is…
Signal transduction modulation (blockage of sodium channels; NMDA glutamate, modulate aspartate + glutamate release)
Stimulates release of ADH, promoting reabsorption of water
Indications for carbamazepine include…
Seizures
BD - acute mania treatment + maintenance
Trigeminal neuralgia
Neuropathic pain (off-label)
Carbamazepine is primarily metabolized via…
Also which enzyme?????
Hepatically - CYP3A4
Therefore, not recommended in decompensated liver disease
Carbamazepine is uniquely metabolized, in that…
Onset? Duration?
It can induce its own metabolism, resulting in increased clearance + decreased half-life with continued dosing
Onset is within 1-5 days; time to completion in 1-5 weeks
Makes it difficult to reach target levels
Clearance and half-life of carbamazepine are variable, due to…
Autoinduction
Therapeutic range of carbamazepine is ____, however…
17-51 micromol/L - is a guideline extrapolated from seizure guidelines and does not correlate well with efficacy in BD (look for clinical response)
If we are obtaining carbamazepine serum concentrations, this is when we need to sample, and how often.
Trough, within 1 hour prior to dose.
Every 1-2 weeks during auto-induction to prevent toxicity, and steady state trough after 5 weeks
Routine monitoring of serum levels isn’t necessary for carbamazepine; it is usually done when…
Non-adherence suspected, or signs/symptoms of toxicity
Potential DI’s, or altered PK
Conversion between dosage forms
Establish drug concentration that resulted in mood stability
Empiric, initial dosing of carbamazepine for BD is…
100-200mg PO BID, increase by 100-200mg/day q1w to target
Maintenance dosing range for carbamazepine is ____, and a common target is…
300-1600 mg/day, absolute max of 1800mg/day
Common target is 400-600mg BID
Carbamazepine dosing is usually given in ____, and is best given at…
Divided doses in BID or TID, and is best given at mealtime
Carbamazepine formulations are available in…
Oral suspension
IR tablets
CR tablets
Chewable tablets
Everytime carbamazepine is started or stopped, this should be done…
Drug interaction check
Notable drugs that will increase carbamazepine levels include…
Macrolides
Antifungals
CCB’s
Other ASM’s - valproic acid + lamotrigine
Notable drugs that may decrease carbamazepine levels include…
Other ASM’s - phenytoin, phenobarbital, primidone
Notable drugs that have their serum levels decreased by carbamazepine include…
Anticoagulants
Antipsychotics
Antidepressants
Estrogen/progesterone
Dose related AE’s with carbamazepine include…
3 related systems
GI - N/V, constipation, dry mouth
CNS - lethargy, sedation, dizziness, blurred vision, ataxia
CV - tachycardia, hypotension, conduction abnormalities
Some idiosyncratic AE’s with carbamazepine include…
A lot of these require lab monitoring
Hyponatremia
Blood dyscrasias
Rash + hypersensitivity rxns
Weight gain
Hepatic and thyroid issues
Menstrual disturbances
These lab values should be monitored with carbamazepine usage…
LFT’s + Thyroid
Renal fx
CBC with diff + platelets
Electroytes
ECG
Bone mineral density
These patients have increased risk of rash + hypersensitivity reactions with carbamazepine:
Asian ancestry + HLA-B1502
Caucasian + HLA-A3101
Chronic usage of carbamazepine may lead to…
Osteomalacia
Vitamin D deficiency
CI’s for carbamazepine include…
Think of some of the idiosyncratic AE’s and lab monitoring needed
Hx of hepatic disease, CVD, blood dyscrasias, and bone-marrow depression
CANNOT be used with clozapine
While on carbamazepine, a patient should monitor themselves for…
Sedation, tremor, cognitive changes
Rashes/hypersensitvity rxns
Carbamazepine will decrease efficacy of estrogen/progestin, therefore…
Need to recommend alternative methods of birth control
Atypical antipsychotics include the 6 following drugs…
Risperidone
Quetiapine
Olanzapine
Aripiprazole
Lurasidone
Asenapine
Antipsychotics primary MOA is…
Dopamine blockade
And other receptors
Atypical antipsychotics are preferred for BD because…
Lower risk of EPS and hyperprolactinemia
EPS with antipsychotics refers to…
Involuntary movement that individual cannot control
Doses of atypical antipsychotics are lower for bipolar compared to patients with psychosis, because…
BD patients are more likely to show EPS when treated with comparable doses of antipsychotics
Also patients on typical antipsychotic is more likely to switch into depression, compared to lithium/VPA
General AE’s of atypical antipsychotics include…
Lots of different AE’s
Anticholinergic, antihistaminergic, alpha1 blockade; Sedation
Metabolic disturbances
EPS
Sexual dysfxn, QT prolongation, seizures
The following should be monitored with atypical antipsychotics:
Think of some of the general AE’s
BMI, vitals
A1C and lipids
ECG
Liver + renal fxn, electrolytes, and CBC
Prolactin
Antidepressants in BD should be…
Avoided as monotherapy, without an antimanic agent
Cautioned in history of AD-induced mania, mixed features, or cycling
Antidepressant usage in BD should be discontinued during…
An acute manic episode - preferably taper, or abrupt discontinuation if severe mania
Once depression symptoms are eliminated in an individual using antidepressants, we should…
Consider tapering off once asymptomatic for 6-12 weeks
If we are going to use an antidepressant in bipolar, we should avoid…
TCA’s > SNRI’s > SSRI’s
Antidepressants are safest in this type of BD; and these are the best ones to use
BD2; bupropion > sertraline, then fluoxetine/other SSRI’s
PAROXETINE NOT recommended
In BD, using short courses of antidepressant for ____ is recommended, because…
3-4 months; prolonged use beyond 1 year may increase mania risk
