CANMAT Guidelines: Bipolar Disorder Part 2 Flashcards
which is often more debilitating for patients with BD, the depressive or manic states
the depressive
*depressed mood accounts for estimate 2/3 of the time spent unwell, even with treatment
what % of suicide deaths and suicide attempts in those with BD occur during the depressive phase
over 70%
*depressive episodes with mixed features are particularly risky with even higher short term risks of suicide and death
what are the most common medication classes ingested at lethal levels in suicide attempts in BD
opioids and benzos
*there were fewer deaths due to lethal lithium levels than lethal carbamazepine levels
are there any first line psychosocial treatment options for acute bipolar depression
no
what is a mnemonic for remembering first line treatments for acute bipolar depression
Quivering Ladies Languish Losing Loud Laughter
Quietiapine
Lurasidone + Li/DVP
Lithium
Lamotrigine
Lurasidone
Lamotrigine (Adj)
Name the two agents that are first line for acute bipolar depression that treat all of the following: acute depression, acute mania, prevent both mania and depression
quetiapine + lithium
does lamotrigine treat acute mania
no–we have evidence it does NOT
does lurasidone + Li/DVP or lurasidone alone treat acute mania?
we dont have the data
which first line agent for acute bipolar depression have the most safety concerns in the acute period
lamotrigine
which two first line agents for acute bipolar depression have the most tolerability concerns in the acute phase
quetiapine and lurasidone + Li/DVP
list second line agents for acute bipolar depression in order
Divalropex
SSRIs/buprioprion (adjuvant)
ECT
Cariprazine
olanzapine-fluoxetine
what is a mnemonic to remember second line treatment for acute bipolar depression
Deep Sleep Eludes Crying Octopi
Divalproex
SSRIs/buproprion
ECT
Cariprazine
Olanzapine-Fluoxetine
list the 4 mnemonics for 1st and 2nd line treatments for acute mania and acute bipolar depression
Acute Mania:
1st mono: Love Quiet Days At A Placid Rustic Cabin
(lithium, quetiapine, Divalproex, Asenapine, Aripiprazole, Paliperidone, Risperidone, Cariprazine)
1st combo: Quietly Arguing with Righteous Assholes (QARA)
Quetiapine, Aripiprazole, Risperidone, Asenapine + Li/DVP)
2nd: Only Cows on LSD Zipline Happily Evermore
(olanzapine, carmabazepine, olanzapine + lithium/divalproex, lithium + divalproex, ziprasidone, haloperidol, ECT)
Acute bipolar depression:
1st: Quivering Ladies Languish Losing Loud Laughter
(Quetiapine, Lurasidone + Li/DVP, Lamotrigine, Lurasidone, Lamotrigine (adj))
2nd: Deep Sleep Eludes Crying Octopi
(Divalproex, SSRIs/buproprion, ECT, Cariprazine, Olanzapine + fluoxetine)
which second line med for acute bipolar depression has the most safety concerns in maintenance phase
olanzapine + fluoxeitne
which 1st or second line meds for acute bipolar depression have the greatest risk for manic switch
SSRIs/buproprion (adj) and olanzapine + fluoxetine
which first line treatment for acute bipolar depression has level 1 evidence
quetiapine
(lurasidone has level 1 as an adjuvant but level 2 as monotherapy)
what trough serum level of lithium is recommended by the guidelines for clinical effectiveness in treating acute bipolar depression
0.8-1.2 mEq/L
what medication should you consider adding in management of BD in lithium nonresponders
lurasidone or lamotrigine
what dose of quetiapine does the guidelines reocmmend
quetiapine 300mg daily
*clinical trials have shown that there is “no difference” in efficacy between quetiapine 300mg and 600mg daily doses (lower doses have not been studied)
what is the minimum target dose of lamotrigine
minimum 200mg/day
is there good data for efficacy of adding antidepressant to a mood stabilizer or AP in treatment of acute bipolar depression?
no, actually relatively weak efficacy data (which is why downgraded to second line from first line)
in which patients with acute bipolar depression should antidepressants be ideally avoided or used cautiously if necessary
- those with history of antidepressant induced mania or hypomania
- those with current or predominant mixed features
- recent rapid cycling
should antidepressant monotherapy be used for treatment of bipolar I depression
NO
in which patients might you consider doing ECT for acute bipolar depression
treatment refractory patients
those for whom rapid response is needed ( i.e severe depression with imminent suicide risk, catatonia or psychotic depression)
when rapid response needed for medical stabilization
is aripiprazole monotherapy recommended for treatment of acute bipolar depression
no (negative evidence)
what type of light therapy is recommended as a third line tx for acute bipolar depression
bright light delivered midday
list some other third line or ancillary treatments for acute bipolar depression (adjunctive)
eicosapentaenoic acid (EPA)
N-acetylcysteine
light therapy
ketamine IV
aripiprazole
asenapine
levothyroxine
modafinil
armodafinil
what treatment options may be preferentially used in treatment of acute bipolar depression if a rapid response is needed
quetiapine
lurasidone
ECT
cariprazine
olanzapine-fluoxetine
(start to separate from placebo within/by one week)
what agent might be avoided in the treatment of acute bipolar depression if rapid response is required
lamotrigine (due to need for slow titration)
what are the risks associated with an overly rapid titration of lamotrigine
skin rashes
stevens-johnson syndrome
toxic epidermal necrolysis
once the titration is completed, is lamotrigine well tolerated
yes–> and effectiveness may be even more pronounced in those with depressive cognitions and psychomotor slowing
which agents may be preferentially used in the treatment of acute bipolar depression if anxious distress is prominent
quetiapine
olanzapine-fluoxetine
lurasidone
which agents used in the treatment of acute bipolar depression seem to have limited efficacy on anxious distress
divalproex
risperidone
lamotrigine
what type of med has been shown to alleviated mixed features in bipolar depression
atypical antipsychotic have a class effect
ECT is very effective (according to clinical experience) in what type of patient with acute bipolar depression
those with melancholic features
what % of inpatients experience psychosis in the context of an acute bipolar depression
up to 20%
is lamotrigine recommended for those with rapid cycling BD
no
why is it important that comprehensive treatment for BD be initiated even after a first episode
in a subset of patient BD may be a NEUROPROGRESSIVE disease
–recurrences associated with reductions in brain grey and white matter volumes
–worsening cognitive impairment
–decrease in inter-episodic recovery and functioning
–higher rate and severity of relapse
–reduced rate of treatment response to both pharmacological and psychotherapeutic strategies
what effect does effective early treatment have on the brain of someone with BD
reverses cognitive impairment
preserves brain plasticity
*particularly in those who remain episode free
*may lead to improved prognosis and minimization of disease progression
between lithium and quetiapine, which seems to be superior in both volumetric and cognitive outcomes after a first BD episode
lithium
what % of the following populations will experience a recurrence every year:
- with treatment
- without treatment
- with treatment–> 19-25%
- without treatment–> 23-40% (of those on placebo)
list risk factors for recurrence of a mood episode in BD
younger age at onset
psychotic features
rapid cycling
more/more frequent previous episodes
comorbid anxiety
comorbid SUD
how quickly do patients with BD discontinuing lithium experience a recurrent mood episode
50-90% experience a recurrence within 3-5 months
list some risk factors for partial or nonadherence to medications in BD
what is a mnemonic for the first line maintenance treatments for BD
Lengthy Questions Distress Ladies Awaiting Quiet And Appropriate Activities
Lithium
Quetiapine
Divalproex
Lamotrigine
Asenapine
Quetiapine + Li/DVP
Aripiprazole + Li/DVP
Aripiprazole
Aripiprazole OM
What is a mnemonic for second line agents for maintenance treatment of BD
Only Really Ragged Children Pet Little Zebras
(Olanzapine, Rispridone LAI, Risperidone LAI (adj), Carbamazepine, Paliperidone, Lurasidone + Li/DVP, + Ziprasidone Li/DVP)
is long term antidepressant use recommended?
no–> only included in recommendations for acute treatment of bipolar depression HOWEVER if someone is stable on combo that includes antidepressant, withdrawing them may contribute to destabilization
how might dose be adjusted once the acute episode resolves and the patient enters maintenance treatment
may be necessary to lower the dose
patients often experience greater side effects once out of the acute episode
does combo treatment of AP + Li/DVP reduce risk of recurrence?
yes there is evidence for this –> continuing the AP for the first 6 months following response offers clear benefit in reducing risk of mood episode recurrence
reevaluate AP use after 6 months
which is more effective at preventing any mood or manic episode, paliperidone or olanzapine
olanzapine
but olanzapine does have more safety concerns
why is cariprazine not included in the maintenance recommendations
only currently have evidence for efficacy in acute mania and depression
why are TCAs not recommended as adjunctive therapy in BD
increased risk of manic switch
why is perphenazine not recommended for maintenance treatment of BD
those on perphenazine + mood stabilizer more likely to have emergent depressive sx and intolerable side effects
list factors associated with overall good prognosis with BD
good treatment adherence
lack of early adversity
intermediate age at onset
good social support
absence of spontaneous rapid cycling
absence of features of a personality disorder
what is the gold standard of maintenance treatment of BD? why?
lithium
b/c effective at preventing both manic and depressive episodes and appears to have anti suicidal effects
how heritable is lithium-responsiveness in BD
you are about twice as likely to respond to lithium if you have a lithium responding parents vs if you dont
patients who have a lithium responding relative have a 67% likelihood of also being lithium responsive
(vs 35% of those without a responsive relative)
(“The neurons from people with BD were hyperexcitable and their activity was selectively modified by in vitro lithium in accordance with clinical response”)
who tends to respond to lamotrigine
predominantely depressive polarity + comorbid anxiety
who is more likely to respond to carbamazepine
atypical illness
BDII
schizoaffective disorder
in which type of patients might you consider genotyping for CYP450 enzyme like 2D6 and 3A4
patients with refactory BD who have not responded to high doses of various first, second and third line agents or their combos
goal to exclude possibility of ultra rapid metabolizers
what is the prevalence of BDI in canada
0.87%
what is the prevalence of BDII in canada
0.67%
how does the disability and economic burden of BDII compare to that of BDI
disability is comparable
economic burden is up to 4x higher for BDII
–> patients with BDII spend as much time symptomatic as those with BDI with mood symptoms mostly in depressive phase
how do rates of suicide in people with BDII vs BDI compare
similar for both attempts and completed suicides
what % of those with BDII attempt suicide over the course of their illness? complete?
attempt–> 30%
complete–> 1/25
why is it harder to generate recommendations for treatment of BDII
because there is a relative paucity of large, methodologically sound clinical trials in BDII
has lithium been studied in acute hypomania
no
what four medications have been studied in placebo controlled trials for acute hypomania
divalproex
N-acetylcysteine
quetiapine
risperidone (open label)
*all generally suggested efficacy but had significant weaknesses
what does clinical practice suggest in terms of the management of acute hypomania
when its frequent, severe or impairing enough to require treatment–> consider mood stabilizers like lithium or divalproex and/or atypicals
N-acetylcysteine may also be of benefit but needs more studies
what is the only first line agent for BDII depression listed in the guidelines
quetiapine
list the second line agents for BDII depression
Lithium
Lamotrigine
Buproprion (adj)
ECT
Sertraline
Venlafaxine
list some of the third line agents for bipolar II depression
agomelatine (adj)
divlaproex
EPA (adj)
N-acetylcysteine (adj)
T3/T4 thyroid hormones
ziprasidone
ketamine (adj)
fluoxetine
what SSRI is NOT recommended in BDII depression
paroxetine
which antidepressants are associate with manic switch in BDI in particular
venlafaxine
TCAs
how do the rates of manic switch compare between BDI and BDII
lower rates of switch in BDII–> even when on antidepressant monotherapy and with agents known to be higher risk for switch in BDI
*risk benefit ratio of antidepressants is more favorable in BDII depression than BDI depression
how does the efficacy of sertraline compare to lithium in treatment of BDII depression
as effective as both lithium monotherapy and lithium + sertraline therapy
how does the efficacy of venlafaxine compare to lithium in treatment of BDII depression
venlafaxine monotherapy was shown to be more effective than lithium
theres also maintenance data for venlafaxine in preventing relapses
*also–> buproprion was shown to be as effective as sertraline and venlafaxine
can findings about, say, sertraline be generalized to other antidepressants in treatment of BDII depression
no–> and in fact safety issues have not been well studied
list the 3 agents recommended for first line maintenance of BDII
quetiapine
lithium
lamotrigine
what agent is recommended second line for BDII maintenance
venlafaxine
list agents recommended third line for BDII maintenance
carbamazepine
divalproex
escitalopram
fluoxetine
other antidepressants
risperidone
how much does ongoing maintenance therapy with quetiapine monotherapy reduce the risk of relapse in BDII patients if used for maintenance
67% reduction in risk of relapse into any mood episode
72% reduction in risk of relapse into depression
(less robust risk reduction for relapse into hypomania)
how might atypical antipsychotics interfere with fertility
may increase serum prolactin levels and thus interfere with ovulation and decrease fertility
in which BD patients might you consider tapering psychotropic medications before pregnancy
clinically stable x 4-6 months prior and considered at low risk of relapse
which anticonvulsants have been known to affect the pharmacokinetics of oral contraceptives
carbamazepine
topiramate
lamotrigine
according to health canada, in which populations should valproate products not be used
should not be used in:
–female children
–female adolescents
–women of childbearing potential
–pregnant women
UNLESS alternative treatments are ineffective or not tolerated
why should valproate products be avoided in women of childbearing potential etc…
high teratogenic potential
risk of developmental disorders to exposed infants
what % of pregnant women with BD had a recurrence of a mood episode:
- when they discontinued their mood stabilizer during pregnancy
- when they continued their mood stabilizer during pregnancy
in a tertiary center:
- when discontinued–> 85% recurrence during pregnancy
- when continued–> 37% recurrence during pregnancy
*usually depressive or mixed episodes
*50% of recurrences happened in 1st trimester
*lower rates in community
are there any medications used for tx of BD for which we have evidence of controlled studies showing no risk in pregnancy
no
name two medications used to treat BD (I or II) with evidence level B (no evidence of risk in humans) during pregnancy
clozapine
buproprion
what level of evidence do we have for safety of most agents used in the tx of BD during pregnancy
C or D–> either risk cannot be ruled out or positive evidence of risk (benefit may outweigh risk)
lithium has what risk category in pregnancy
D
lamotrigine has what risk category in pregnancy
C
aripiprazole has what risk category in pregnancy
D
valproate has what risk category in pregnancy
D
olanzapine has what risk category in pregnancy
C
quetiapine has what risk category in pregnancy
C
sertraline has what risk category in pregnancy
C
what risks are there to the fetus of using divalproex/valproate in pregnancy
neural tube defects
+ other abnormalities
evidence of “striking degrees” of neurodevelopmental delay in children at 3 years of age
loss of avg. 9 IQ points
what is the risk of neural tube defects in infants exposed to valproate products in utero
up to 5%
are pregnant women more likely to require higher medication doses in the first, or in the second + third trimesters
second + third due to increased plasma volume, hepatic activity, renal clearance
what dose of folic acid should women with BD take during pregnancy
5mg/day
prenatal vitamins containing what compound have been recently recommended as possibly preventive of the later development of schizophrenia
prenatal vitamines containing CHOLINE
what is the concern about very high materal folate levels
?risk of autism spectrum disorders
what % of women with BD who were medication free experience a recurrence inthe post partum period
66%
(compared to 23% who were maintained on medication)
risk or recurrence is highest in which women in the post partum period
highest in those who experiened a recurrence of their BD during pregnancy
+
those who were not on prophylactic tx
for which agents do we have evidence for efficacy in tx of postpartum bipolar depression
quetiapine
for which agents do we have evidence for efficacy in tx of postpartum bipolar mania
benzos
antipsychotics
lithium
what website may be useful for choosing which medications to use for BD in pregnancy and lactation
the FDA PLLR
“pregnancy and lactation last rule”
what two medications used in the treatment of BD may be preferred choices for lactating mothers
quetiapine
olanzapine
*due to relatively lower infant dosages
how does comorbidity with PMDD (premenstrual dysphoric disorder) affect course of BD
earlier illness onset of BD
more comorbid axis I disorders
higher number of manic/hypomanic + depressive episodes
higher rates of rapid cycling
do PMS and PMDD occur more or less frequently in people with BD
more frequently
how does menopause affect the course of BD
increased rates of depressive, but not manic, episodes during menopause transition
*more data needed
what % of people with BD experience their first mood episode during childhood or adolescence
between 1/3 (community) to 2/3 (clinical samples)
*earlier age of onset characterized by increased symptom burden and comorbidity
should the same set of symptoms be used to diagnose BD in kids and adults
yes
what other conditions are often confused for BD in kids and adolescents
ADHD
DMDD
ODD
substance use
personality disorders
GAD
what is one way to distinguish ADHD from BD
ADHD is ongoing whereas BD is episodic
decreased sleep, hypersexuality, hallucinations, delusions, HI and SI are rare or absent in uncomplicated ADHD
what is the relationship between DMDD and BD
The recent DSM‐5 diagnosis DMDD—which includes chronic irritability as a defining feature—lists BD as an exclusion criterion. However, the DMDD phenotype is evident in about 25% of adolescents with episodic BD, and is associated with factors such as greater family conflict and ADHD comorbidity.571 Classical BD and chronic irritability are therefore not mutually exclusive, the nonspecific nature of the latter notwithstanding.
what % of children or youth with MDD will go on to develop BD
28%
(about a third)
list risk factors for switch to mania in child with MDD
family history of mood disorders
emotional and behavioural dysregulation
subthreshold manic symptoms
cyclothymia
atypical depression
psychosis
what were the three most potent predictors of switch to mania in youth with MDD
family history
earlier age of onset
presence of psychotic symptoms
are kids and teens more or less susceptible or the metabolic side effects of psychiatric medications
more susceptible
(especially atypical APs)
risperidone may be preferable to lithium for treatment of BD in what type of kids/teens
non obese youth
youth with ADHD
list first line treatment for mania in kids/teens
lithium
risperidone
aripiprazole
asenapine
quetiapine
second line treatments for mania in kids/
olanzapine
ziprasidone
quetiapine adj.
first line for tx of bipolar depression in kids/teens
lurasidone (has RCT data)
second line for tx of bipolar depression in kids/teens
lithium
lamotrigine
(no data in kids but ++ in adults)
third line for tx of bipolar depression in kids/teens
olanzapine-fluoxetine combo (has RCT data but ++ metabolic concerns + limited clinical experience in youth)
quetiapine
first line for BD maintenance in kids/teens
aripiprazole
lithium
divalproex
can stimulants be used to treat comorbid ADHD in kids/teens
yes–> in stable/euthymic youth taking optimal doses of antimanic medications
what is the lifetime prevalence of late life BD
1-2%
*though 90-95% of older adults with BD will have their initial episode before age 50
what are the most often comorbid conditions with late life BD
anxiety and SUDs
what is the reduction in life expectancy in older adults with BD compared to non-psychiatric populations
reduction in life expectancy of 10-15 years
older adults with BD have an average of how many medical comorbidities
3-4
what are the most common medical comorbidities of older adults with BD
metabolic syndrome
HTN
diabetes
CV disease
arthritis
endocrine abnormalities
what side effects can be seen with LITHIUM in particular for older adults with BD
adverse neurological effects
renal disease
what side effects can be seen with DIVALPROEX in particular for older adults with BD
motor side effects
metabolic effects (weight gain and DM)
what side effects can be seen with CARBAMAZEPINE in particular for older adults with BD
induces CYP450
what medications should be monitored closely in older adults when also prescribed lithium
NSAIDs
ARBs
ACEIs
thiazide diuretics
how often should you do lithium levels and renal monitoring in older adult populations with BD
Li level and renal monitoring:
q3-6 months
+
5-7 days after lithium dose adjustment or adjustment of NSAID/ARB/ACEI/ thiazide diuretic
what two medications are listed as first line for acute mania in older adults
lithium
divalproex
