Therapeutics Neuro/psych Exam 1- Bipolar

Front 1

gender for bipolar I vs. II

Back 1

 Women = Men for Bipolar I
 Women > Men for Bipolar II

Front 2

age of onset (2)

Back 2

Mean age at onset is early 20s
 Rare to have first episode after age 40

Front 3

incidence in relatives

Back 3

Increased rate among first-degree relatives (5-10%)
 Monozygotic twins 65% concordance rate

Front 4

substance abuse in bipolar

Back 4

Comorbid alcohol and other substance
abuse in ~40% of patients with bipolar
disorder

Front 5

suicide attempts in bipolar (3)

Back 5

Suicide attempts in up to 50% of
patients with bipolar disorder
 Bipolar II > Bipolar I
 More attempts in depressive or mixed
episodes

Front 6

Bipolar Disorder Pathophysiology:
Multiple Theories (4)

Back 6

Kindling hypotehesis
Monoamine hypothesis
Glutamate dysregulation
Alterations in signal transduction pathways

Front 7

Kindling hypothesis (2)

Back 7

 Initial manic episodes brought on by trigger
 Recurrent episodes quicker and occur
spontaneously due to kindling effect

Front 8

monoamine hypothesis (2)

Back 8

 Mania: excess NE, DA
 Depression: deficit of 5-HT, NE, DA

Front 9

DSM-IV: Manic Episode (3 parameters)

Back 9

1+ week of abnormally and persistently
elevated, expansive, or irritable mood
 PLUS three of the following (four if mood only
irritable):
 Inflated self-esteem or grandiosity
 Decreased need for sleep
 Pressured speech
 Flight of ideas
 Distractibility
 Increased goal-directed activity (though tend to not finish)
 Excessive involvement in risky behavior

Associated with marked impairment in function

Front 10

Bipolar dx: mnemonic

Back 10

DIGFAST

 Distractibility
 Indiscretion
 Grandiosity
 Flight of ideas
 Activity increase
 Sleep (decreased need)
 Talkativeness

Front 11

medical conditions that induce mania

Back 11

 Hyperthyroidism
 Cushing’s disease
 Carcinoid tumors
 Vit B12 deficiency
 AIDS
 CNS Infections
 Epilepsy
 CVA
 Head trauma
 Huntington’s Disease
 Multiple sclerosis

Front 12

meds that induce mania

Back 12

 Alcohol
 Antidepressants
 Stimulants
 Decongestants
 Dopamine Agonists
 Xanthines (caffeine,
theophylline)
 Anabolic steroids
 Corticosteroids
 Hallucinogens (LSD,
PCP)
 Bronchodilators

Front 13

DSM-IV: Major Depressive
Episode (3 parameters)- same as before

Back 13

 ≥ 2 weeks of one of the following:
 Depressed mood
 Decreased interest/pleasure in nearly all activities
 PLUS 4 of the 7 following:
 Weight or appetite change (up or down)
 Sleep disorder on most days
 Psychomotor up or down
 Fatigue or decreased energy
 Feelings of guilt/worthlessness
 decreased concentration/decisiveness
 Suicidal ideation or attempt
 Associated with marked impairment in function

Front 14

Mixed Episode definition DSM-IV

Back 14

Meets criteria for both a manic episode and
a major depressive episode nearly every
day for 1+ week (increased risk for completing suicide- hospitalize)

Front 15

hypomanic episode definition (3

Back 15

Same as criteria for manic episode except:
 Duration of ≥ 4 days (doesn't have to last as long)
 No psychotic symptoms (like grandiosity)
 NOT severe enough to cause marked
impairment in function (****)

Front 16

spectrum of manic states (4)

Back 16

normal- happiness, pleasure joy
hypomania- little bit heightened self esteem, increased creativity, work ability, decreased need for sleep
mania
psychotic mania

(see slide for properties of each)

Front 17

3 types of bipolar disorders

Back 17

 Bipolar I Disorder
 Bipolar II Disorder
 Cyclothymic Disorder

Front 18

Bipolar I Disorder definition

Back 18

1+ manic or mixed episodes (don't need depression)

Front 19

Bipolar disorder II definition

Back 19

1+ major depressive episode with 1+ hypomanic episode

NO manic or mixed- if you have those you are auto-bipolar I

Front 20

Cyclothymic disorder- similar to dysthymia (4)

Back 20

Numerous periods of hypomanic and
numerous periods of depressive
symptoms for2+ years with no
symptom-free period lasting for greater than 2 months
 Depressive symptoms do not meet criteria
for Major Depressive Episode
 Hypomanic symptoms may but do not have
to meet criteria for Hypomanic Episode
 Symptoms lead to significant impairment in
function

Front 21

Course of illness- % of pt that will have 1+ episode (manic)
avg episodes in 10 years if not treated

if not managed, how long can mania last

Back 21

 90% of patients will have > 1 episode
 Average of 4 episodes in 10 yrs without
treatment
 Untreated mania may last for months

Front 22

if mania is treated- how fast is onset of tx

Back 22

Reduction in symptoms may be evident in a
few days to 2 weeks with treatment

Front 23

% of patients with rapid cycling
what is rapid cycling, gender, ease of tx

Back 23

10-20%

4+ mood episodes (any type) per year
 Women > men
 Difficult to treat, usually requires
combination of mood stabilizers

Front 24

% of bipolars that commit suicide

Back 24

15-20%

Front 25

bipolar symptoms are predominantly of what sort

Back 25

depressive

Front 26

4 tx goals of bipolar

Back 26

 Complete symptomatic REMISSION
 Prevention of further episodes
 Maximize adherence to medication
regimen
 Maintain optimal quality of life

Front 27

5 drugs to treat bipolar

Back 27

 Lithium
 Anticonvulsants
Antidepressants (controversial- only in combo with mood stabilizer)
first gen antipsychotics
second gen antipsychotics

Front 28

4 anticonvulsants used

Back 28

 Valproate
 Carbamazepine
 Oxcarbazepine
 Lamotrigine

Front 29

7 second gen antipsychotics

Back 29

 Risperidone
 Olanzapine/OFC
 Quetiapine
 Ziprasidone
 Aripiprazole
 Asenapine
 Clozapine

Front 30

FDA approved indications for bipolar

Back 30

for reference

Front 31

most bipolar drugs are FDA approved for what part of bioplar? (what type of episodes)

Back 31

mostly acute mania and maintenance

Front 32

2 antipsychotics used for depressive episodes

Back 32

olanzapine + fluoxetine
Quetiapine

Front 33

Summary of 15 Acute Mania monotherapy studies (% responders) (2)

Back 33

similar efficacy in antipsychotic monotherapy vs. traditional MS

Combo therapy is a little better

Front 34

combining therapies for acute mania

Back 34

--look better

Front 35

4 acute bipolar depression studies showed what? (most effective drug)

Back 35

QTP most effective

LTG also ok

but everything kind of sucks- most difficult to treat and pt at higher risks- need to be aggressive

Front 36

Lithium beginnings (2)

Back 36

 First noted to have mood stabilizing
properties in the late 1800’s when
physicians were using it to treat gout
 John Cade published the first paper in
1949 on the use of lithium to treat acute
mania

Front 37

when was lithium approved for mania

Back 37

FDA approved for the treatment of mania in 1970

Front 38

Li line of therapy

Back 38

considered by most treatment guidelines
to be a first-line agent for the treatment of
bipolar disorder

Front 39

lithium dosing slide

Back 39

--

Front 40

Efficacy of Lithium in the
Treatment of Bipolar Disorder in acute mania in acute mania

levels required for efficacy

Back 40

response rate of 70%
need levels of 0.8-1.2 mEq/L (higher lvls)

Front 41

lithium may be less effective for what types of bipolar (2)

Back 41

severe mania with psychotic features

less effective than valproate for depressive sx in mixed episodes (usually require combo therapy anyways)

Front 42

Li in depressive episodes (2)
levels

Back 42

Li alone if at high enough levels (0.8+ mEq/L) is as effective as Li + antidepressant
may have added benefit of reducing suicidal behavior

Front 43

Li in maintenance therapy
levels

Back 43

several trials supporting efficacy
Li levels generally are lower- 0.6-1 mEQ/L (to avoid AE like diabetes insipidus/nephrotoxicity)

Front 44

Li PK- protein binding, elimination
kinetics, half life

Back 44

no protein binding
renally eliminated- CL completely depends on GFR/kidney perfusion
linear kinetics

half life- 14-24h

Front 45

Time to Peak Concentration for Li : IR vs. SR

Back 45

 Immediate release = 0.5-2 hours
 Sustained release = 4-12 hours

Front 46

other factors affecting Li serum conc (2)

Back 46

sodium levels
fluid balance

Front 47

Li and sodium effects (3) what pt needs to keep in mind

Back 47

 Li+ and Na+ are monovalent cations
 Both reabsorbed in proximal tubule (Li+ > Na+)
 Avoid starting low-salt diet without consulting
physician

Front 48

Li and fluid balance- what must be noted and what must patient do

Back 48

 Dehydration leads to decreased kidney perfusion &
promotes Li+/Na+ retention
 Maintain adequate hydration during
exercise/exposure to heat

Front 49

Li metabolic interactions

Back 49

 No metabolic interactions

Front 50

drugs that can cause increase in Li levels (not sure why) (3)

Back 50

 Diuretics: Thiazide > Loop Diuretics
 NSAIDs (no OTC without checking), including selective COX-2 inhibitors (decrease renal BF)
 ACE inhibitors and ARBs- decrease renal BF (usually takes 3-5 weeks to see increased Li levels- delayed response)

Front 51

2 drugs types that cause decrease in Li levels

Back 51

 Methylxanthines (caffeine and theophylline)
 Sodium bicarbonate

Front 52

Li AE (5)

Back 52

GI side effects
positional tremor
renal dysfunction
Li induced nephrogenic diabetes insipidus
sex dysfunction

Front 53

GI side effects of Li- tolerance? how to tell if it's toxicity related

Back 53

Tolerance usually develops within 1-2 weeks
 Severe nausea and vomiting may be a sign of
toxicity

Front 54

Li signs of toxicity (2)

Back 54

severe n/v
severe tremor

Front 55

4 ways to circumvent positional tremor AE of Li

Back 55

 May lower dose, divide the dose, switching to ER,
add a beta-blocker

Front 56

More Li side effects... (6)

Back 56

interferes with iodine- hypothyroidism
leukocytosis
acne/psoriasis/thinning hair
weight gain!
impaired memory/conc.
CV issues

Front 57

hypothyroidism- reversible? how to deal with it

Back 57

 Usually reversible upon discontinuation
 May continue lithium and add thyroid
supplementation

Front 58

CV abnormalities of Li (2)

Back 58

AV block or other cardiac conduction abnormalities- usually benign
ventricular arrhythmias (rare)

Front 59

do not use Li in pt with what comorbidity

Back 59

severe CV disease

Front 60

Lithium monitoring (6)

Back 60

 ECG
 CBC- leukocytosis
 Thyroid studies
 BUN, SCr, glucose, and electrolytes
 UA- to rule out UTI- why?
 Pregnancy test- Li is teratogenic
Lithium trough

Front 61

when to take lithium trough
how often

Back 61

12 hours post dose (even if dosing once a day) usually 4-7 days after initiation (for SS), then periodically as indicated (usually 3-6 mo, but at least annually)

Front 62

Association Between Lithium
Plasma Level and Toxicity chart

Back 62

1.0-1.5 Fine tremor, nausea, fatigue
1.5-2.0 Pronounced tremor, N/V/D, somnolence
2.0-2.5 Ataxia, confusion
2.5-3.0 Dysarthria, gross tremor
> 3.0 Delirium, seizures, coma, death

Front 63

Valproate (VPA) Oral Dosage
Forms (6)

Back 63

caps, syrup, sprinkles, DR tabs, DR soft gel caps, ER tabs

Front 64

Efficacy of VPA in the Treatment
of Bipolar Disorder: acute mania levels

Back 64

several RCTs reporting efficacy in acute mania if lvls between 85-125 mcg/mL

Front 65

onset of VPA for acute mania
what if you use loading dose

Back 65

rapid- 1 week
4-5 days if “loading dose” started on day 1

Front 66

mixed episodes efficacy

Back 66

effective- may be better than Li

Front 67

VPA efficacy in acute mania, mixed, depressive and maintenance

Back 67

efficacious in acute/mixed mania

depressive- limited evidence but still used

compareable to lithium/SGAs in maintenance efficacy

Front 68

VPA oral BA
in ER vs. DR (enteric coated)

Back 68

100%- convert 1:1

ER is 15% less

Front 69

protein binding of VPA

Back 69

80-90% (saturable)

Front 70

VPA PK- protein binding (y/n?)

metabolism

Back 70

 Protein Binding 80-90% (saturable)
 Extensive hepatic metabolism
 Primarily via glucuronide conjugation and
mitochondrial beta-oxidation- no CYP i guess

Front 71

AE of VPA

Back 71

GI side effects (e.g. nausea, vomiting)
CNS side effects (smonolence/dizzy)
termor
alopecia
weight gain
PCOS
thrombocytopenia- dose dependent
rash (rare)
hyperammoniemia
hepatic failure
pancreatitis

Front 72

2 AE of VPA that pt can gain tolerance to

Back 72

GI and CNS (within 1-2 weeks)

Front 73

how to deal with postural tremor in VPA - 3

Back 73

same as Li- lower dose, divide dose, switch to ER

pronounced tremor can be sign of toxicity

Front 74

hepatic failure in VPA risk factors (2)

Back 74

younger than 2 years
AED polytherapy

Front 75

why does VPA cause hyperammonemia

Back 75

VPA interferes with urea cycle

Front 76

BBW for VPA (2)

Back 76

acute hepatic failure- very rare in adults, can also see transient benign LFT increases
acute pancreatitis

Front 77

when to d/c VPA due to LFTs

Back 77

d/c if LFTs > 3x ULN

Front 78

VPA DDIs- enzymes (4)

3 other DDIs (none metabolism related)

Back 78

weak inhibitor of CYP2C9, 2C19, 2D6, 3A4

usually issue with ASA only if pt using a lot for pain- ASA can maybe increase VPA free fraction

VPA can displace phenytoin from protein

increased risk of hyperammonia with topiramate

Front 79

VPA monitoring (4)

Back 79

 LFTs at baseline and frequently during
first 6 months of therapy
 CBC w/platelets at baseline then 1-2
weeks after initiation and dose changes
 Pregnancy test
 Ammonia level in pts with altered mental
status

Front 80

VPA therapeutic drug monitoring- target serum conc.
SS levels
when to draw

Back 80

50-125 mcg/mL unless acute mania (higher- 85-125)

SS levels in 3-4 days
draw trough immediately prior to next dose

Front 81

when to consider getting a "free" VPA level (unbound) if...(2)

Back 81

hypoalbuminemia
or high conc??? (6-22???)

Front 82

VPA toxicity- what level

Back 82

>125
similar to Li tox

Front 83

sx of VPA tox

Back 83

severe nausea/vomiting,
lethargy, ataxia, course tremor, mental status
changes, seizure

Front 84

CBZ dosage forms

Back 84

--

Front 85

efficacy of CBZ in acute mania and onset

Back 85

effective
rapid onset (1 week)

Front 86

CBZ in mixed episodes- efficacy

Back 86

limited data though Equetro approved for mixed

Front 87

usage of CBZ in combo for mixed episodes issues

Back 87

Patients may require combination mood
stabilizers for symptom remission and CBZ
interacts with many other mood stabilizers

Front 88

CBZ depressive episodes and maintenance efficacy

Back 88

Little evidence regarding efficacy in acute
depressive episodes

maintenance- not FDA approved by evidence shows it is similar to Li

Front 89

CBZ PK- protein binding

Back 89

75-90%

Front 90

CBZ metabolism- which enzyme, weird thing about it's metabolism, protein binding

Back 90

protein bound

3A4

takes a month to get to steady state due to self induction

Front 91

CBZ ADEs (3)

Back 91

CNS side effects and GI
hyponatremia (SIADH)

Front 92

how to assuage GI effects of CBZ (3)

Back 92

take with food, reduce daily dose, switch to ER

Front 93

BBW for CBZ (2)
when would you d/c
avoid use with what drug?

Back 93

 Agranulocytosis and aplastic anemia (rare)- ANC less than 1000 cells/mm3 warrants medication
discontinuation. Avoid using in combination with clozapine
 Rash – can progress to SJS, particularly in
Asians

Front 94

CBZ DIs slides

more importantly know what meds CBZ can reduce levels of (3 main ones)

Back 94

know if you use with strong inducers you can get a decrease in CBZ level (like clarithromycin, cimetidine)


induces metabolism of...

antipsychotics, oral contraceptives, antiepileptics, shit ton of other stuff

Front 95

CBZ monitoring at baseline (5)

Back 95

 CBC (repeat periodically)
 Electrolytes
 Hepatic function panel
 Pregnancy test
 HLA-B 1502* before initiation for those of Asian
descent (for rash/SJS)

Front 96

CBZ monitoring general (2)

Back 96

CBC periodically
CBZ trough level- often do to check for tox

Front 97

when to take CBZ levels (2)

Back 97

 1-2 weeks after initiation and dose change, then
periodically as clinically indicated
however, Steady state levels will typically not be reached
for 3-4 weeks due to autoinduction so need to get another level then

Front 98

CBZ levels correlation with response

general level

Back 98

not clearly correlated with response in mania

generally target 4-12 mcg/mL

Front 99

when to draw trough of CBZ

Back 99

immediately prior to next dose