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Psych/Neuro EXAM 1
Psych/Neuro EXAM 1 Gable Bipolar Disorders
57
Pharmacology
Graduate
08/18/2011

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Term
clinical features of bipolar disorder
Definition
age of onset: 15-24 yo

misdiagnosis is common (people will get diagnosed with depression; if bipolar disorder is treated with anti-depressants, it causes mania)

75% of patients report experiencing depression

chronic and recurrent condition

life-long treatment necessary

new-onset bipolar disorder is rare > 60 yo (usually secondary to medication or medical/neurological condition)
Term
etiology of bipolar disorder
Definition
NEUROBIOLOGICAL:
disruption of monoamine signaling (DA, NE, serotonin) and the hypothalamic-pituitary-adrenal axis

GENETICS:
multiple genes likely contribute to the risk of developing bipolar disorder
80-90% of patients with bipolar disorder have biological relatives with mood disorders
monozygotic twins - 75% concordance rate

ENVIRONMENT:
obstretric complications, intrauterine viral infections, neurodevlopmental abnormalities in childhood, use of hallucinogenic drugs, psychosocial trauma, change in sleep-wake cycle

PSYCHOSOCIAL STRESSORS:
serve as triggers for initial mood episode
Term
medical conditions that can cause mania
Definition
CNS trauma:
brain tumor, stroke, head injury, seizure disorder

endocrine abnormalities:
hyperthyroidism, menstrual related, pregnancy related

infections:
encephalitis, HIV, neurosyphiis

vitamine and nutritional deficiencies (B12)

sleep deprivation
Term
medications that can cause mania
Definition
stimulants - amphetamines, cocaine

hallucinogens - LSC, PCP

antidepressants - SSRIs, TCAs

steroids - anabolic, corticosteroids

thyroid hormone - levothyroxine

xanthines - caffeine, theophylline

OTC products - pseudoephedrine, SAM-e, St. John's Wort
Term
symptoms of mania
Definition
GIDDINESS

Grandiosity
increased activity
decreased judgment (risky activities)
distractibility
irritability
need for sleep decreased (USUALLY ONE OF THE 1ST SYMPTOMS)
elevated mood
speedy thoughts
speedy speech
Term
DMS-IV criteria for a manic episode
Definition
A.
> or equal to 1 week of elevated, expansive, or irritable mood

B.
mood disturbances: > or equal to 3 of the following symptoms (decreased need for sleep, hyperverbal, flight of ideas, distractibility, excessive involvement in pleasurable activities, increase in goal-directed activity

C.
symptoms must NOT meet criteria for mixed episode

D.
mood disturbances severe enought to cause marked impairment, need for hospitalization, or psychosis is present

E.
symptoms not due to substance abuse or general medical condition (hyperthyroidism)
Term
classification of hypomania
Definition
less severe form of mania

at least 4 days of persistently elevated mood and associated with > or equal to 3 of the following symptoms:
inflated self-esteem
decreased need for sleep
distractibility
irritability
pressured speech
increased activity or excessive involvement in pleasurable activities
racing thoughts (flight of ideas)

hospitalization NOT required

NO psychotic features
Term
symptoms of depression
Definition
D SIGECAPS

depressed mood or anhedonia
sleep (insomnia or hypersomnia)
interest (loss of)
guilt or worthlessness
energy loss
concentration loss
appetite changes (weight loss or gain)
psychomotor agitation or retardation
suicidal ideation
Term
bipolar disorder: type I
Definition
males = females

presence of only 1 manic episode (necessary)

episode of depression is not necessary for this diagnosis

the manic episode is not better accounted for by schizoaffective disorder
Term
bipolar disorder: type II
Definition
females > males

diagnostic criteria:
presence (or history) of 1 or more major depressive episodes
presence (or history) of at least 1 hypomanic episode
there has never been a manic episode or a mixed episode
the mood symptoms are not better accounted for by schizoaffective disorder
the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
Term
bipolar disorder specifiers: mixed episode
Definition
characteristics of both MANIA AND DEPRESSION exist at the same time

ex) suicidal with increased agitation/psychomotor movements
Term
bipolar disorder specifiers: rapid cycling
Definition
> or equal to 4 mood episodes (mania, depression, mixed episode, hypomania) in 1 year

> women

more difficult to treat
Term
clinical signs and symptoms of bipolar disorder
Definition
stage 1 (hypomania):
euphoria, labile mood, grandiosity, overconfidence, racing thoughts, hyperverbal

stage 2 (mania):
irritability, dysphoria, hostility, anger, delusions, cognitive, disorganization

stage 3 (psychosis)
terror, panic, bizarre behavior, hallucinations, disorientation
Term
what is a mood stabilizer?
Definition
commonly defined as an agent which treats a phase of bipolar disorder (depression and/or mania) without causing either

in addition, must prevent episodes from occurring (maintenance or prophylaxis)

antidepressants are not mood stabilizers

lithium treats mania and depression and prevents both from occurring
Term
uses of mood stabilizers
Definition
acute manic, mixed and hypomanic episodes

acute major depressive episodes in bipolar disorder

maintenance treatment of bipolar disorder

schizoaffective disorder

refractory schizophrenia

refractory depression

assaultive, aggressive, impulsive behavior
Term
what drugs have the strongest evidence for efficacy as mood stabilizers?
Definition
lithium
valproate
carbamazepine
lamotrigine
atypical antipsychotics

possibly effective:
oxcarbazepine
topiramate
NDP CCBs (diltiazem)

NOT effective: gabapentin
Term
indications for lithium
Definition
bipolar disorder

approved for acute and maintenance treatment of bipolar disorder

efficacy for:
bipolar mania and depression
bipolar relapse prevention
unipolar depression augmentation
suicidality prevention

MOST EFFECTIVE FOR BIPOLAR DISORDER TYPE I (mania)

less effective for: rapid cyclers and mixed episodes
Term
lithium pharmacokinetics
Definition
absorption: almost 100%

METABOLISM: NO HEPATIC CYP450 METABOLISM

elimination:
steady state reached in 5 days
t1/2 = 24 hours
blood levels should be drawn 5 days after a dosage change

excretion:
90-95% excreted unchanged by kidneys
interactions are possible with other drugs excreted by the kidneys
Term
lithium plasma level monitoring
Definition
NARROW THERAPEUTIC WINDOW

therapeutic plasma levels:
0.8-1.5 mEq/L (acute mania)
0.6-1.2 mEq/L (maintenance)

toxicity may occur if > 1.5 mEq/L

every 300 mg increase in dose will increase lithium plasma levels by 0.15 - 0.35 mEq/L

draw plasma levels 12 hours post dose

obtain plasma level ~5 days after initiating therapy or after dose change

check plasma levels every 1-2 weeks until patient is stable

maintenance plasma levels may be measured every 3-6 months
Term
lithium onset
Definition
once you reach steady state at a therapeutic plasma level, it takes 3-10 more days to see initial response

it may take 2-4 weeks (~21 days) to see full therapeutic effects

patients may be given a benzodiazepine until the lithium begins working
Term
lithium dosing
Definition
BASED ON PHARMACOKINETICS:
dose based on plasma level and symptom control

initial: 300-1200 mg/day bid

increase by 300-600 mg q5d depending on lithium plasma level
Term
lithium early onset ADRs
Definition
nausea/vomiting

diarrhea

fine hand tremor

muscle weakness

fatigue

lethargy

headache

polydpsia and polyuria

impaired cognitive functioning

"mental clouding or loss of creativity"
Term
managing lithium ADRs: GI upset
Definition
take lithium with food

change to ER product
Term
managing lithium ADRs: polyuria/polydipsia
Definition
give total dose q HS to decrease urine volume

ADD HZTZ 25-50 MG/DAY AND DECREASE LITHIUM DOSE
adding HCTZ has a paradoxical effect
HCTZ is the treatment of choice for polyuria with lithium
there is an interaction between HCTZ and lithium (competition between Li and Na for renal excretion) and the patient will become toxic if the lithium dose is not decreased
Term
managing lithium ADRs: intentional hand tremor
Definition
check for toxicity and consider decreag lithium dose

change to ER product

add propranolol 20-120 mg/d
Term
lithium late onset ADRs
Definition
CARDIOVASCULAR:
prolonged QT interval, T-wave flattening or inversion, AV block, bradycardia

DERMATOLOGICAL:
worsen acne, alopecia

ENDOCRINE:
hypothyroidism - have to treat and continue lithium

METABOLIC:
weight gain

HEMATOLOGIC:
BENIGN REVERSIBLE leukocytosis

NEPHROLOGY:
decreased GFR, diabetes insipidus (polyuria, polydipsia)
Term
lithium baseline monitoring
Definition
thyroid (TSH) q6 months
renal function (SCr and BUN) q3 months
CBC with diff
electrolytes (hyponatremia)
ECG (patient > 40 yo or preexisting heart condition)
urinalysis (with specific gravity)
pregnancy test (Ebstein's anomaly - pregnancy category D) - most risk in the 1st trimester, clinically used in the 2nd and 3rd trimester
Term
signs and symptoms of acute lithium toxicity
Definition
moderate (>1.5 mEq/L):
confusion, sedation, lethargy, muscle weakness, ataxia, dysarthria, nausea/vomiting, slurred speech, fine to coarse hand tremor

severe (>3 mEq/L):
hyperreflexia, delirium, seizures, coma, renal failure, death

patient should be taken to the ER and lithium should be discontinued
Term
what patients are at an increased risk for lithium toxicity?
Definition
elderly patients

drug interactions

sodium restricted diets (< 2 g/day)

dehydration, heavy exercise, hot weather

vomiting and severe diarrhea
Term
pharmacokinetic drug interactions with lithium
Definition
INCREASE LITHIUM CONCENTRATIONS:

NSAIDS (including COX2 inhibitors) - MOA-enhance reabsorption of Li secondary to inhibition of PG synthesis

diuretics (thiazide diuretics) - MOA-cause Na depletion which causes an increase in proximal tubular reabsorption of Li

ACE inhibitors, ARBs - MOA-volume depletion = decrease in glomerular filtration rate causing decreased Li excretion and increased Li levels

DECREASE LITHIUM CONCENTRATION:

theophylline and caffeine - increase the renal clearance of lithium

OTHER:

alcohol: results in small increase or decreases in Li concentrations
Term
pharmacodynamic drug interactions with lithium and neurotoxicity
Definition
No blood level changes, but can result in neurotoxicity!

methyldopa

carbamazepine

CCB (diltiazem, verapamil)

phenytoin

SSRIs (fluoxetine)
Term
indications for valproate for bipolar disorder, advantages and disadvantages
Definition
valproate is good to use for rapid cycling or mixed mania

advantages:
lower risk of toxicity
safer in renal disease
less drug interactions (compared to lithium)

disadvantages:
less evidence for relapse prevention
hepatotoxicity
no IM dosage form available
Term
valproate dosing
Definition
initial loading dose (give in divided doses): add "0" to weight in lbs (i.e. 150 lbs + 0 = 1500 mg/day)

more of the dose should be given at HS (sedating drug)
Term
ADRs of valproate
Definition
dose-related ADRs:

GI upset (nausea, diarrhea, dyspepsia)
sedation, ataxia
intentional hand tremor
transient elevated LFTs
thrombocytopenia (<100,000 caution; <50,000 DC)
weight gain
amenorrhea - PCOS

other ADRs:
alopecia - zinc and selenium can treat
hyperammonemia = changes in mantal status
rash
pancreatitis
Term
valproate black box warnings
Definition
teratogenicity:
fetal neural tube defects - pregnancy category D
should NOT be used in pregnancy (lithium can be used in pregnancy)

hepatotoxicity:
hepatic failure

pancreatitis
Term
monitoring of valproate plasma levels
Definition
obtain plasma level 2-3 days after initiating treatment or after dose change
draw plasma levels 12 hours post dose

obtain plasma levels monthly until stable then q3 months

THERAPEUTIC PLASMA LEVEL: 50-125 mcg/mL
Term
other valproate monitoring parameters
Definition
LFTs - elevated transaminases, hepatotoxicity

CBC with diff - thrombocytopenia

measure weight - weight gain

check ammonia level - hyperammonemia (unexpected lethargy, vomiting, changes in mental status)

OB/GYN exam - PCOS

pregnancy test - neural tube defects; pregnancy category D
Term
drug interactions with valproate
Definition
aspirin and anticoagulants (warfarin):
displacement from protein binding sites
effect: increased risk of bleeding

lamotrigine, lorazepam:
valproate inhibits glucuronidation
effects: increased blood levels of lamotrigine and lorazepam

alcohol and CNS depressants:
augmented CNS depression
effect: increased toxicity of CNS depressants
Term
indications for lamotrigine for bipolar disorder
Definition
controlled trials show efficacy for depressed phase of bipolar I and II

FDA indicated for maintenance phase of bipolar I disorder

no anti-manic efficacy

CLINICALLY, MOST USED FOR BIPOLAR TYPE II, DEPRESSIVE EPISODE
Term
lamotrigine dosing: not taking carbamazepine or valproate; taking valproate; taking carbamazepine, phenytoin, phenobarbitol, primidone, rifampin (enzyme inducing drugs)
Definition
PATIENTS NOT TAKING CARBAMAZEPINE:

initiate with 25 mg da
max 200 mg da

PATIENTS TAKING VALPROATE:

initiate 25 mg every other day
max 100 mg da

PATIENTS TAKING CARBAMAZEPINE, PHENYTOIN, PHENOBARBITOL, PRIMIDONE, RIFAMPIN (enzyme inducing drugs):

initiate with 50 mg da
max: > 200 mg bid
Term
lamotrigine ADRs and monitoring
Definition
ADRs:
dizziness, somnolence, ataxia, N/V, blurred vision, HA

BBW: serious rashes (SJS)

monitoring parameters:
skin for rash
LFTs annually
no plasma blood monitoring necessary
Term
indications for carbamazepine for bipolar disorder
Definition
2nd line for bipolar disorder in patients unresponsive to lithium or valproate

treatment of bipolar disorder (mania or major depression) alone or in combo with lithium

less weight gain than lithium or valproate
Term
ADRs of carbamazepine
Definition
CNS:
sedation, slurred speech, dizziness, ataxia, diplopia

HYPONATREMIA

TRANSIENT LFT INCREASES; cholestatic jaundice

severe rash: rare

BBW:
agranulocytosis (contraindicated to use clozapine and carbamazepine together b/c of agranulocytosis risk)
aplastic anemia
Term
carbamazepine plasma monitoring
Definition
obtain plasma level 7 days after initiating therapy or after dose change

draw plasma levels 12 hours post dose

monitoring for toxicity

obtain level weekly during titration; every 3 months or as clinically necessary thereafter
Term
carbamazepine monitoring parameters
Definition
liver (ALT/AST) - elevated LFTs, liver damage, hepatitis

CBC - aplastic anemia, agranulocytosis, pancytopenia, bone marrow suppression, thrombocytopenia, leukopenia, eosinophilia

urinalysis and BUN - renal dysfuunction

metabolic panel (electrolytes) - hyponatremia

ECG - aggravation of CHF and arrhythmias

pregnancy test - teratogenicity (pregnancy category D)
Term
drug interactions with carbamazepine
Definition
ANTICONVULSANTS: PHENYTOIN, BARBITURATES
induction of AED metabolism, induction of CBZ metabolism
decreased levels of AEDs
decreased CBZ clearance

CYP450 INHIBITORS: DILTIAZEM, ERYTHROMYCIN, ISONIAZID, CIMETIDINE, AZOLE ANTIFUNGALS, FLUOXETINE, FLUVOXAMINE, NEFAZODONE
inhibition of metabolism of CBZ
increased toxicity of CBZ

CYP450 SUBSTRATES: WARFARIN, CYCLOSPORINE, THEOPHYLLINE, VPA, ORAL CONTRACEPTION
induction of metabolism of substrates
reduced effects of concomitant drug therapy

carbamazepine is a potent enzyme inducer (CYP3A4) and autoinducer

onset of enzyme induction ~1 week and max effect at 5 weeks
Term
oxcarbazepine dosing
Definition
treatment of bipolar disorder, including mania

initiate at 300 mg bid
maintenance dose 1200-2400 mg da given in divided doses
Term
oxcarbazepine ADRs
Definition
better tolerated than CBZ

CNS:
sedation, dizziness, ataxia, HA

HYPONATREMIA: twice as common than with CBZ

rash

nausea
Term
oxcarbazepine monitoring parameters
Definition
therapeutic plasma concentration monitoring generally not necessary

metabolic panel (Na): significant hyponatremia may develop
Term
indication of topiramate in bipolar disorder
Definition
no established efficacy as monotherapy

may help as an add-on for bipolar I mania/mixed episode with partial response to lithium or VPA

patients ask for this because it causes weight loss (all others can cause weight gain)
Term
ADRs of topiramate
Definition
weight loss (nausea, dyspepsia)

kidney stones

narrow angle glaucoma

oligohydrosis - decreased ability to sweat

metabolic acidosis

COGNITIVE DYSFUNCTION
Term
atypical antipsychotics in bipolar disorder
Definition
usually used to help stabilize patients who are acutely manic or agitated

generally not accepted as monotherapy for maintenance, although OLANZAPINE, QUETIAPINE, RISPERIDONE, ARIPIPRAZOLE are indicated for maintenance treatment

PATIENTS WITH MOOD DISORDERS MAY BE MORE SENSITIVE TO EPS, which is a possibility with the atypical antipsychotics
Term
mood stabilizer benefits
Definition
feeling more relaxed
improved sleep habits
improved appetite
getting along better with others
improved concentration
feeling less irritable or upset
prevention of relapse of depression or mania
decreased risky behavior (IV drug use, sexually promiscuous behavior)
Term
APA guidelines for bipolar disorder: bipolar type I (mania)
Definition
1st line: lithium, VPA, or olanzapine

2nd line: carbamazepine or oxcarbazepine
Term
APA guidelines for bipolar disorder: bipolar type II (depressed)
Definition
1st line: lithium or lamotrigine or quetiapine (may add on anti-depressant in more severely ill patients)

other: fluoxetine + olanzapine combination

psychosis or high suicide rate: add olanzapine or electro-convulsive therapy
Term
APA guidelines for bipolar disorder: bipolar mixed or rapid cycling
Definition
1st line: combination therapy (rapid cycling DC all antidepressants); VPA may be more effective than lithium
Term
antidepressants and mania
Definition
AVOID ANTIDEPRESSANT MONOTHERAPY FOR BIPOLAR DEPRESSION
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