Mood Stabilizers + Other Drugs used in Bipolar Flashcards
1
Q
Timeline for medication response to mania is about ____ weeks.
A
1-2 weeks, to see decrease in symptoms
2
Q
Main goals of therapy with bipolar treatment include…
There are 2 main ones, and then a few other ones that may be important
A
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
3
Q
Timeline for a full clinical benefit from medications for mania symptoms is about ____ weeks.
A
3-4 weeks
4
Q
Timeline for medication response to bipolar depression is about ____ weeks.
A
2-6 weeks
5
Q
Timeline for a full clinical benefit from medication, for bipolar depressive symptoms is about ____ weeks.
A
6-12 weeks
Usually longer than unipolar depression
6
Q
Some key non-pharmacological therapies that may help with bipolar treatment include…
A
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
7
Q
A relapse prevention plan is important in bipolar treatment, since…
A
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
8
Q
Our most commonly used mood stabilizers for bipolar include these 3…
A
Lithium
Valproic acid
Lamotrigene
9
Q
MOA of lithium is…
A
Exact mechanism not fully understood
Interaction with downstream signalling cascades
Enhancement of GABA activity (inhibitory)
Decreased CNS adrenergic activity
10
Q
Lithium distributes evenly in the total body water space. This is an important factor to consider in elderly patients because…
A
There will be decreases in Vd in elderly, due to decreased % of total body water and lean body mass
Results in increased lithium concentrations
11
Q
Elimination of lithium is mainly via…
A
Renal excretion
Freely filtered by glomerulus, like sodium and potassium
Also 80% reabsorbed in proximal tubules, with sodium
12
Q
When considering lithium PK, we can think of lithium like…
A
A salt, similar to sodium
13
Q
If the amount of filtered sodium decreases, this results in an increase in sodium reabsorption, which would affect lithium via…
A
Increases in lithium reabsorption and potential lithium toxicity
Hence hyponatremia decreases clearance
14
Q
Factors that may decrease clearance of lithium include…
KIDNEY related - why?
A
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
15
Q
What is the therapeutic range of lithium for acute mania?
A
0.8 to 1.2 mmol/L
Narrow TR; so possibility for toxicity with even 1.2…
16
Q
The therapeutic range of lithium for maintenance therapy is…
A
0.6 to 1.0 mmol/L
17
Q
The therapeutic range of lithium for maintenance in elderly patients is…
A
0.6 to 0.8 mmol/L
18
Q
When should lithium levels be sampled?
A
12 hours post dose, OR stat if toxicity/non-adherence is suspected
12 hours - complete absorption/distribution
19
Q
How often should lithium levels be taken?
Starting dose/changes; physiological conditions?
A
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
20
Q
Lithium doses are titrated and started BID because of…
A
Increase likelihood of GI side effects
21
Q
Initial dosing of lithium for acute mania is usually started at…
What about the elderly?
A
600-900mg per day, in 1-2 divided doses
300mg/day for elderly
22
Q
Subsequent doses of lithium for acute mania are guided by…
A
Plasma levels and clinical response
23
Q
Usual doses of lithium for acute mania is…
What about elderly?
A
900-2100 mg/day, in two divided doses
300-1200mg/day for elderly
24
Q
Lithium dosing for maintenance therapy is usually…
Whats the target plasma level?
A
900mg in divided doses (600-1800mg/day)
Target plasma level of 0.6 to 1 mmol/L
25
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
26
A potential benefit of switching to once daily dosing of lithium is...
Decrease in urine volume, and decreased renal toxicity/dysfunction
27
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
28
Lithium dosing in renal impairment...
Needs to be reduced; is CI in acute renal failure
## Footnote
CrCl 10-50 mL/min: 50-75% of normal dose
CrCl below 10mL/min: 25-50% of normal dose
29
If a toxic plasma level of lithium is obtained, we should...
**HOLD DOSE**
Repeat plasma level next day
Restart therapy when within target range
30
Pregnancy will ____ lithium concentrations, because...
Decrease; increase in blood volume and renal clearance
31
Sodium supplementation will ____ lithium concentrations, because...
Decrease; will result in increased secretion of sodium, and lithium follows
32
Dialysis will ____ lithium concentrations, because...
Decreased; removal of drug from blood
33
Caffeine will ____ lithium concentrations because...
Decreased; likely due to increased renal clearance
34
Dehydration will ____ lithium concentrations, because...
Increased; less fluid volume (total body water) means increased concentration of lithium
35
Renal impairment will ____ lithium concentrations, because...
Increase; lithium is primarily renally excreted
| Distributed in total body water; impaired fluid excretion in CKD
36
Sodium loss will ____ lithium concentrations, because...
Increase; retention of sodium will occur, lithium will follow
37
Increased age will ____ lithium concentrations, because...
Increased; decreased total body water as well as decreased kidney function
38
Strenuous exercise will ____ lithium concentrations, because...
Increase; sweat and dehydration lower fluid volume, leading to increased lithium concentrations
39
Cirrhosis will ____ lithium concentrations, because...
Increase; connection to hepatorenal syndrome
40
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
41
Thiazide diuretics will ____ lithium concentrations, because...
Increase; decrease in blood volume
42
ACEI's and ARB's will ____ lithium concentrations, because...
Increase; dilate the efferent arteriole and reduce kidney pressure for filtration
43
SSRI's and SNRI's have a potential drug interaction with lithium, which is...
Theoretical risk of serotonin syndrome
44
Usage of antipsychotics with lithium may increase risk of...
Neurotoxicity
45
Loop diuretics and CCB's will ____ lithium concentrations, because...
Increase or decrease - impact it has on fluid volumes
46
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
47
Lithium causes weight gain, of about ____ kg.
4-6kg in the first 2 years
48
One of the first signs of lithium toxicity is...
GI upset - nausea, diarrhea
49
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
50
What is nephrogenic diabetes insipidus? Why can it occur with lithium usage?
Inability to concentration urine; lithium may be interfering with antidiuretic hormone
51
Nephrogenic diabetes insipidus with lithium usage will result insymptoms such as...
Severely increased thirst + urination; leads to volume depletion and lithium reabsorption, toxicity
52
This is the drug of choice for lithium-induced nephrogenic diabetes inspidius...
Amiloride - potassium sparing diuretic
53
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
54
Moderate lithium toxicity symptoms may manifest as...
| (6)
Sedation, lethargy, ataxia + involuntary muscle movements, impaired senses, hyperthermia, coarse tremors
55
Severe lithium toxicity may manifest as...
| CV, CNS based
Coarse tremors, delirium, seizures, coma, respiratory complications, AKI
ECG changes, pulse irregularities
Death
56
What should be monitored with lithium usage?
Symptoms of mania/depression
Labs
Adherence/side effects of lithium usage
57
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.
58
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
59
A woman should consider ____ on lithium, due to...
Contraception - potential heart anomoly may develop in children
60
Valproic acid indications include...
Seizures
Bipolar disorder (acute mania treatment + maintenance)
61
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
62
Valproic acid relationship to protein binding is...
85-90% bound to serum albumin
| Important when considering drug interactions
63
Valproic acid is primarily eliminated via...
Hepatic metabolism, via glucoronidation, beta-oxidation, and alpha-hydroxylation
64
Therapeutic range of valproic acid is...
350-700 micromol/L of total valproic acid; **guideline only and needs to be individualized**
65
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
## Footnote
For seizures... needs to be measured at time of serizure to determine seizure threshold
66
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
67
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
68
Dosing frequency of valproic acid is...
Usually BID/TID
69
Therapeutic doses of valproic acid is usually...
1500-2500 mg/day
70
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
71
Valproic acid PK changes in elderly, because...
| How does this affect dosing?
Protein binding and clearance is decreased; use lower initial doses
72
Does renal impairment affect valproic acid dosing?
No dosage adjustment necssary, but may decrease protein binding (resulting in increased unbound drug concentration)
73
Common drugs that may increase valproate levels include...
Antibiotics - macrolides
ASA/salicylates
74
Common drugs that may decrease valproic acid levels include...
Antibiotics - carbapenems
ASM's - carbamazepine, phenytoin
| Carbapenem interaction is very relevant
75
Common drugs that are increased by valproic acid include...
Anticonvulsants: carbamazepine, phenytoin, phenobarb
**Lamotrigine**
76
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%
77
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
78
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)
79
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...
80
Contraception is warranted with valproic acid use, because...
Valproic acid is teratogenic; will cause neural tube deficits
81
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
82
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
83
Indications for lamotrigine include...
Seizures
Acute + maintenance therapy for bipolar depression
84
Lamotrigene is not recommended in...
Acute mania
85
Lamotrigine MOA is...
Blockage of sodium channels + reducing glutamate release
Weak serotonin receptor inhibitory effect
86
Lamotrigine is metabolized via...
Both hepatic and renal metabolism
87
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
88
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
89
Usual dosing for lamotrigine is...
225-375 mg/day, divided BID
90
Common AE's that occur with lamotrigine include...
Sedation/insomnia, headaches, nausea, dizziness
| Overall quite well tolerated
91
Serious but rare AE that we must monitor in lamotrigene usage includes...
**Life-threatening SJS/TENS**
Blood dyscrasias
92
85% patients on lamotrigene who experience SJS rash have prodromal symptoms, which involve...
Flu-like symptoms
93
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
94
Does lamotrigine need serum level monitoring?
No - relationship between clinical efficacy and plasma concentration is not clearly established
| Will only indicate adherence
95
Lamotrigine titration needs to be restarted if ____ days are missed, to avoid...
5 days - avoid increased risk of skin rash
96
Lamotrigine DI's that are important to note include...
Other ASM's - VPA, other enzyme-inducing ASM's
Estrogen products
| Both decrease lamotrigine levels
## Footnote
**Always check for DI's**
97
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
98
Lamotrigine onset of effect is usually...
Several weeks, especially due to slow titration
99
Carbamazepine MOA is...
Signal transduction modulation (blockage of sodium channels; NMDA glutamate, modulate aspartate + glutamate release)
Stimulates release of ADH, promoting reabsorption of water
100
Indications for carbamazepine include...
Seizures
BD - acute mania treatment + maintenance
Trigeminal neuralgia
| Neuropathic pain (off-label)
101
Carbamazepine is primarily metabolized via...
| Also which enzyme?????
Hepatically - CYP3A4
| Therefore, not recommended in decompensated liver disease
102
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
## Footnote
Makes it difficult to reach target levels
103
Clearance and half-life of carbamazepine are variable, due to...
Autoinduction
104
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)
105
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
106
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
107
Empiric, initial dosing of carbamazepine for BD is...
100-200mg PO BID, increase by 100-200mg/day q1w to target
108
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
109
Carbamazepine dosing is usually given in ____, and is best given at...
Divided doses in BID or TID, and is best given at mealtime
110
Carbamazepine formulations are available in...
Oral suspension
IR tablets
CR tablets
Chewable tablets
111
Everytime carbamazepine is started or stopped, this should be done...
Drug interaction check
112
Notable drugs that will increase carbamazepine levels include...
Macrolides
Antifungals
CCB's
Other ASM's - valproic acid + lamotrigine
113
Notable drugs that may decrease carbamazepine levels include...
Other ASM's - phenytoin, phenobarbital, primidone
114
Notable drugs that have their serum levels decreased by carbamazepine include...
Anticoagulants
Antipsychotics
Antidepressants
Estrogen/progesterone
115
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
116
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
117
These lab values should be monitored with carbamazepine usage...
LFT's + Thyroid
Renal fx
CBC with diff + platelets
Electroytes
ECG
Bone mineral density
118
These patients have increased risk of rash + hypersensitivity reactions with carbamazepine:
Asian ancestry + HLA-B1502
Caucasian + HLA-A3101
119
Chronic usage of carbamazepine may lead to...
Osteomalacia
Vitamin D deficiency
120
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
121
While on carbamazepine, a patient should monitor themselves for...
Sedation, tremor, cognitive changes
Rashes/hypersensitvity rxns
122
Carbamazepine will decrease efficacy of estrogen/progestin, therefore...
Need to recommend alternative methods of birth control
123
Atypical antipsychotics include the 6 following drugs...
Risperidone
Quetiapine
Olanzapine
Aripiprazole
Lurasidone
Asenapine
124
Antipsychotics primary MOA is...
Dopamine blockade
| And other receptors
125
Atypical antipsychotics are preferred for BD because...
Lower risk of EPS and hyperprolactinemia
126
EPS with antipsychotics refers to...
Involuntary movement that individual cannot control
127
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
## Footnote
Also patients on typical antipsychotic is more likely to switch into depression, compared to lithium/VPA
128
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
129
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
130
Antidepressants in BD should be...
Avoided as monotherapy, without an antimanic agent
| Cautioned in history of AD-induced mania, mixed features, or cycling
131
Antidepressant usage in BD should be discontinued during...
An acute manic episode - preferably taper, or abrupt discontinuation if severe mania
132
Once depression symptoms are eliminated in an individual using antidepressants, we should...
Consider tapering off once asymptomatic for 6-12 weeks
133
If we are going to use an antidepressant in bipolar, we should avoid...
TCA's > SNRI's > SSRI's
134
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
135
In BD, using short courses of antidepressant for ____ is recommended, because...
3-4 months; prolonged use beyond 1 year may increase mania risk
