Anticonvulsants

(lamotrigine, carbamazepine, oxcarbazepine)

Atypical antipsychotics

(aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone)

antidepressants

additional mood stabilizers

antipsychotics

benzodiazepines

Bipolar I - one or more manic or mixed episode

lifetime prevalence is 0.4-1.6%

Bipolar II - recurrent major depressive episodes with hypomanic episodes

lifetime prevalence is ~0.5%

Is bipolar I more common in men or women?

Is bipolar II more common in men or women?

men = women

women>men

What % of pt with bipolar disorder have a relative with a mood disorder (bp, major depress, cyclothymia, dysthymia)?

What is the lifetime risk of developing a mood disorder or bpd if a first-degree relative has bpd?

80-90%

15-35% for mood disorder

5-10% for bpd

1. perinatal insult

2. head trauma

3. environmental factors

4. psychosocial or physical stressors

5. nutritional factors

6. neurotransmitter/neuroendocrine/hormonal theories

7. monoamine hypothesis

8. dysregulation of amino acid neurotransmitters

9. cholinergic hypothesis

10. secondary messenger system dysregulation

11. hypothalamic-pituitary-thyroid axis dysregulation

12. membrane and cation theories

13. sensitization and kindling theories

1. desynchronization of circadian or seasonal rhythms

2. changes in the sleep-wake cycle or light-dark cycle

1. deficiency of essential amino acid precursors that can lead to dysregulation of NT activity (L-tryptophan deficiency causes a decrease in 5-HT and melatonin synth and activity)

2. deficiency in essential fatty acids (omega-3-fatty acids) leading to dysregulation of NT

Excitatory: NE, DA, glutamate, aspartate

Inhibitory: 5-HT, GABA

According to the monoamine hypothesis:

1. an excess of these catecholamines cause mania?

2. a deficit of these NT cause depression?

1. NE, DA (so treat with DA antag or a2-agonists)

2. NE, DA, 5-HT (so treat with 5-HT inh, NE/DA inh, and MAOIs)

According to the cholinergic hypothesis:

1. (increased/decreased) acetylcholine can increase the risk of a manic episode

2. (increased/decreased) acetylcholine levels can increase the risk for a depressive episode

3. What are the treatment strategies that go along with this hypothesis? 

1. decreased = manic

2. increased = depressive

3. Mania -

agents that increased ACh activity: cholinesterase inhibitors 

   Depressive Episode -

agents that decrease ACh activity:

anticholinergics

1. abnormal G protein functioning

2. abnormal cyclic adenosine monophosphate and phosphoinositide secondary messenger system activity

3. abnormal protein kinase C activity and signaling pathways

Hypothyroidism can precipitate depression and can be a risk factor for what? 

When is thyroid supplementation useful in pts?

rapid cycling

when treatment for rapid cycling is refractory or as augmentation to antidepressants in unipolar depression

According to the membrane and cation theories:

1. (Hypo/Hyper)calcemia is associated with anxiety, irritability, mania, psychosis, and delirium

2. (Hypo/Hyper)calcemia is associated with depression, stupor, and coma. 

3. Ca concentrations may affect the excitability of neuronal firing and the synthesis and release of what 3 NT? 

Hypo

Hyper

NE, DA, 5-HT

1. CNS disorders 

brain tumor, stroke, subdural hematoma, MS, lupus, seizures, Huntington's

2. Infections

encephalitis, neurosyphilis, sepsis, HIV

3. Electrolyte or Metabolic abnormalities

Ca or Na flux, hyper or hypoglycemia

4. Endocrine or hormonal dysregulation

Addison's, Cushing's, hyper or hypothy, menstrual, pregnancy, perimenopausal

Alcohol intoxication

Drug withdrawals

Antidepressants

DA-augmenting agents (CNS stim, amphetamines)

Hallucinogens

Marijuana

NE-augmenting agents (A2antag, Bag, SNRI)

Steroids

Thyroid preparations

Xanthines (caffeine, theophylline)

OTC weight loss and decongestants

Herbals (St.John's Wort)

1. bipolar I

2. bipolar II

3. cyclothymic disorder

4. bipolar disorder not otherwise specified

1. major depressive

2. manic

3. hypomanic

4. mixed

1. mood lability

2. hypersomnia

3. low energy

4. psychomotor retardation

5. cognitive impairment

6. anhedonia

7. decreased sexual activity

8. slowed speech

9. carb craving

10. weight gain

1. To diagnose mania how long do symptoms need to be present?

2. What are the common symptoms of mania?

1. 1 week with impairment in functioning

2. grandiosity, decreased need for sleep or food, pressured speech, flight of ideas (racing thoughts), distractibility, increased activity, poor judgment, and involvement in pleasurable activities with potentially negative consequences

1. less severe

2. does not cause marked impairment in social or occupational functioning

3. no delusions or hallucinations

What is a mixed episode?

In what population are they more common?

How does a mixed episode affect the suicide rate? prognosis? 

When is BPD usually diagnosed?

What is the avg. age of onset for a first manic episode?

Which type of episode typically presents first in females? males?

15-30 years old

21

major depressive episode in females

manic episode in males

More than __ mood episodes per year = rapid cycling

Frequent and severe ____ episodes are the most common hallmark of rapid cycling.

What factors contribute to rapid cyclining?

4

depression

alcohol, stimulants, antidepressants, sleep deprevation, hypothyroidism, seasonal changes

How does BPD affect mortality rate?

What % of BPD pt attempt to commit suicide?

Are suicide attempts more likely with BP1 or BP2?

Increased: 2.3x higher

50% attempt

BP2

adherence to medical treatment

50% of pt DC meds because of SE

How long must symptoms be present to be diagnosed as:

1. Major Depressive?

2. Manic?

3. Hypomanic?

4. Mixed?

5. Rapid Cycling? 

1. >2 weeks

2. >1 week

3. at least 4 days

4. nearly every day for at least 1-week

5. >4 major depressive or manic episodes in 12 months

Diagnostic criteria for a major depressive episode includes

>2wk period of depressed mood or loss of interest or pleasure in nl activities associated with at least 5 of the following:

1. depressed, sad mood (adults) irritable (children)

2. decreased interest and pleasure in nl activities

3. decreased appetite, weight loss

4. insomnia or hypersomnia

5. psychomotor retardation or agitation

6. decreased energy or fatigue

7. feelings of guilt or worthlessness

8. impaired concentration and decision making

9. suicidal thoughts or attempts

Diagnostic criteria for a manic episode includes

>1 week period of abnormal and persistent elevated mood (expansive or irritable), associated with at least 3 of the following (or 4 if irritable):

1. inflated self-esteem (grandiosity)

2. decreased need for sleep

3. increased talking (pressure of speech)

4. racing thoughts (FOI)

5. distractible (poor attention)

6. increased activity (social, work, sexual) or increased motor activity or agitation

7. excessive involvement in activities that are pleasurable but have a high risk for serious consequences

How often should a patient be seen who is:

1. severely ill

2. less ill but symptomatic

3. starting or switching meds

4. continuation phase

1. q week

2. q2 weeks

3. q2 weeks

4. qmonth for 3 months then q2-3m

What drugs have A+ ratings as monotherapy for acute mania or mixed states?

A+ as adjunctive?

Monotherapy:

1. Lithium

2. Divalproex

3. Aripiprazole

4. Olanzapine

5. Risperidone

6. Quetiapine

7. Ziprasidone

Adjunctive:

1. Olanzapine

2. Risperidone

3. Quetiapine

1. Carbamazepine

2. Clozapine - monotherapy for treatment-resistant pts

3. Haloperidol - monotherapy or adjunctive

Gabapentin - X for monotherapy and adjunctive

Tiagabine - for monotherapy

A+: Quetiapine

A: Lithium + Lamotrigine

1. Carbamazepine

2. Olanzapine - adjunctive with fluoxetine

3. Risperidone - adjunctive

A+:

1. Lithium carbonate

2. Lamotrigine (Lamictal)

3. Olanzapine (Zyprexa)

A: Divalproex (Depakote)

What are the efficacy ratings for lithium carbonate in:

1. acute mania or mixed states

2. acute bipolar depression

3. continuation or maintenance therapy

1. A+

2. A

3. A+

What are the efficacy ratings for olanzapine in:

1. acute mania or mixed states

2. acute bipolar depression

3. continuation or maintenance therapy

1. A+ monotherapy or adjunctive

2. B adjunctive with fluoxetine

3. A+

Lamotrigine - A

Carbamazepine - B

What are the efficacy ratings for quetiapine in:

1. acute mania or mixed state

2. acute bipolar depression

3. continuation or maintenance

1. A+ monotherapy or adjunctive

2. A+

3. D

1. lithium

2. valproate (or divalproex sodium) (Depakote)

3. aripiprazole (Abilify)

4. olanzapine (Zyprexa)

5. quetiapine (Seroquel)

6. risperidone (Risperdal)

7. ziprasidone (Geodon)

1. Lithium

2. Olanzapine (Zyprexa)

3. Lamotrigine (Lamictal)

1. patient-specific characteristics

2. comorbid psychiatric and medical conditions

3. avoidance of drug interactions and adverse effects

What drugs are recommended for short-term adjunctive treatment of agitation or insomnia if needed?

Which is preferred for catatonia?

benzodiazepines:

lorazepam (Ativan) or

clonazepam (Klonopin)

lorazepam (Ativan)

1. Lithium or Valproate PLUS

2. benzodiazepine (lorazepam or clonazepam) PLUS

3. atypical antipsychotic if psychosis is present

When is valproate preferred over lithium?

Which drugs are preferred for bipolar depression?

mixed episodes and rapid cycling

lithium and lamotrigine are preferred over valproate for depression

1. renal function

2. thyroid function

3. blood level monitoring

paroxetine (Paxil)

venlafaxine (Effexor)

fluoxetine (Prozac)

fluvoxamine (Luvox)

nefazodone (Serzone)

paroxetine (Paxil)

extrapyramidal reactions

sedation

emotional blunting

sexual dysfunction

metabolic syndrome

orthostatic hypotension

obesity

T2DM

hyperlipidemia

hyperprolactinemia

cardiac disease

tardive dyskinesia

clonazepam

lorazepam

1. CNS depression

2. sedation

3. cognitive and motor impairment

4. dependence

5. withdrawal reactions

Although they are rarely used, calcium channel blockers inactivate voltage-sensitive calcium channels, thus inhibiting NT synthesis and release and neuronal signal transmission. 

Which nondihydropyridine may have mood-stabilizing properties?

Which dihydropyridine?

Verapamil (Isoptin)

Nimodipine (Nimotop)

What are the ADEs associated with CCBs?

When can they be used?

bradycardia and hypotension

preferred over lithium or anticonvulsants during pregnancy and breast feeding

nimodipine can be more effective than verapamil for rapid-cycling bc it has anticonvulsant properties, is highly lipid soluble, and can penetrate the brain

Are gabapentin and topiramate effective for acute mania?

When is topiramate sometimes used?

Levetiracetam and zonisamide may have efficacy in what 2 situations?

probably not

as an add on weight-reduction med (but no evidence)

mania and for treatment-refractory rapid cycling

What are the risks associated with lithium use during the first trimester of pregnancy?

Should you breast feed on lithium?

1.Epstein's anomaly (1:1000-2000)

2."floppy" infant syndrome (low Apgar score, lethargy, hypotonia, bradycardia, cyanosis, shallow respiration, and poor sucking)

3.hypothyroidism

4.nontoxic goiters

discouraged

1. neural tube defects - 1st trimester

(carbamazepine 0.5-1%, valproate 5-9%)

valproate - spina bifida

2. craniofacial abnormalities

3. developmental delays

4. microcephaly

How can you reduce the risk of neural tube defects while taking an anticonvusant like valproate?

Can you breast feed while taking valproate?

folate

Yes, valproic acid is excreted in low concentrations

What drugs are used to treat catatonia?

Why should you minimize the use of antipsychotics in catatonia?

What is the preferred treatment in this population?

Increased risk of neuroleptic malignant syndrome

ECT

MOA:

Typical Antipsychotics

Atypical Antipsychotics

block DA2 receptors

block DA2 and 5-HT2A receptors

haloperidol decanoate

fluphenazine decanoate

risperidone LA injection

not first line

reserved for lithium-refractory patients, rapid cyclers, or mixed states

What is carbamazepine's ddi with antidepressants, anticonvulsants, and antipsychotics?

What drugs increase carbamazepine levels?

it increases the hepatic metabolism and dosage increases may be necessary

calcium channel blockers (verapamil and diltiazem)

What carbamazepine serum level is associated with ataxia, choreiform movements, diplopia, nystagmus, cardiac conduction changes, seizures, and coma?

Which hepatic enzymes are induced?

What should be done for carbamazepine toxicity?

15mcg/mL

3A4 (mainly), 1A2, 2C9/10 and 2D6

gastric lavage, hemoprerfusion, symptomatic treatment - for carbamazepine (Tegretol) toxicity

What is carbamazepine's active metabolite?

What 3A4 inhibitors can lead to toxicity?

What is the interaction between valproate and carbamazepine?

What is the potential risk of combining carbamazepine with clozapine?

10,11-epoxide metabolite

cimetidine, diltiazem, erythromycin, fluoxetin, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoyphene, verapamil

Valproate displaces carbamazepine from protein binding sites and increases free levels, reduce the carbamazepine dose

possibility of bone marrow suppression

6-10mcg/mL 

12-14mcg/mL in some treatment resistant pts

blocks voltage-sensitive sodium channels

modulates or decreases glutamate and aspartate release

and has antikindling properties

HA, nausea, dizziness, ataxia, diplopia, drowsiness, tremor, rash, pruritis

~10% developed maculopapular rash - DC

SJS- greatest risk with coadmin of valproate (Valproate decreases the clearance of lamotrigine)

DC if diffuse, involves mucosal membranes, with fever or sore throat

Lithium kinetics:

A?

D?

M?

E?

Absorption - rapidly

Distribution - widely, no protein binding

Metabolism - no metabolism

Excretion - unchanged in urine

it is a monovalent cation

What are the risks of using lithium with CCBs?

Lithium with ECT?

neurotoxicity

severe bradycardia with verapamil and diltiazem

acute neurotoxicity and delerium, WD lithium at least 2 days before and resume 2-3 days after the last treatment

Toxicity (tremor, n/v, diarrhea, drowsiness, muscular weakness)

can occur within therapeutic range

2mEq/L

1. gastrointestinal (v, diarrhea, incontinence)

2. coordination (fine to coarse hand tremor, unstable gait, slurred speech, twitching)

3. cognition (poor concentration, drowsiness, disorientation, apathy, coma)

Lithium DDIs:

1. drugs that elevate lithium concentrations

2. increase neurotoxicity risk

3. enhance renal elimination

1. thiazides, NSAIDs, COX-2I, ACEI, NaCl-restricted diets

2. carbamazepine, diltiazem, losartan, methyldopa, metronidazole, phenytoin, and verapamil

3. caffeine and theophylline

What concentration is recommended for bipolar prophylaxis in the elderly?

Acute mania concentrations?

0.4-0.6mEq/L

1-1.5mEq/L

1. Oxcarbazepine is the 10-keto analog of carbamazepine

2. milder ADE

3. no autoinduction of liver enzymes (3A4)

4. potentially fewer drug interactions (controversial)

dose-related:

dizziness, sedation, HA, ataxia, fatigue, vertigo, abnl vision, diplopia, n/v, abp

possibly higher rates of hyponatremia

2C19 inhibitor

3A3/4 inducer

induces metabolism of oral contraceptives

What should you do to alleviate the following frequent dose-related ADE with valproate:

1. GI complaints

2. Tremors

3. Sedation

1. with food, switch to divalproex sodium ER, adding a H2antag like famotidine or ranitidine

2. dose reduction or addition of a BB

3. give total daily dose at bedtime

1. Thrombocytopenia

2. fatal necrotizing hepatitis in children with epilepsy receiving multiple antiepileptics (idosyncratic, not dose-related)

3. life-threatening hemorrhagic pancreatitis

What is the maximum recommended dose of valproate?

Which valproate formulation has a higher BA? How do you adjust the dose to compensate?

60mg/kg/day

the immediate release has a higher BA by ~15%, if using the XR you will need slightly higher doses

What is the goal trough after the first week of therapy on valproate for acute mania?

What do most use for the therapeutic range?

>45mcg/mL

50-125mcg/mL taken 12h after last dose

What are the 4 rating scales used in bipolar disorder?

What are some recommended QOL scales?

1. Young Mania Rating Scale

2. Brief Bipolar Disorder Symptoms Scale

3. Hamilton Rating Scale for Depression

4. Montgomery-Asberg Depression Rating Scale

Short Form (SF)-36

Psychological General Well Being Scale

Lithium carbonate:

Eskalith - 300mg capsule

Eskalith CR - 450 mg ER tab

Lithobid - 300mg ER tab

Lithium citrate:

Cibalith-S - 8mEq/5mL 

What is the therapeutic trough of serum lithium concentration:

1. during acute episodes

2. as maintenance therapy

1.) 1-1.5mEq/L

2.) 0.6-1.2mEq/L

1. nomalizes or inh 2nd messenger systems

2. dec. 5-HT reuptake and increases synaptic sensitivity

3. inh synthesis of DA, decreases B receptors and inh DA2 and B receptor supersensitivity

4. Enhances GABAergic activity and nl GABA levels

5. reduces glutaminergic activity (increases glutamate)

6. Decreases Ca transport into cells, interferes with Ca-Na active transport, increases renal tubular reabsorption of Ca and increases serum Ca and parathyroid concentrations

7. Increases choline in RBCs and potentiates the cholinergic 2nd messenger system

What are the brands for divalproex sodium?

What serum concentration should divalproex be titrated to?

What is divalproex sodium's MOA?

Depakote - 125, 250, 500mg EC, DR t; 125mg sprinkle cap

Depakote ER - 250, 500mg EC, ER tab

50-125mcg/mL

1.increases GABA levels in plasma and CNS, inh GABA catabolism, increases synth and release, can prevent reuptake, enhances action of GABA at GABAa receptor

2.normalizes Na and Ca channels

3. reduces intracellular inositol and protein kinase C isoenzymes

4. can modulate gene expression

5. antikindling properties can decrease in rapid cycling and mixed states

How is valproic acid or valproate available commercially? brands?

Depakene 250mg capsule (valproic acid)

Depakene 250mg/5mL syrup (valproate sodium)

What is the brand name for lamotrigine?

MOA?

Lamictal 25,100,150,200mg tablets; 2,5,25mg CT

1. blocks voltage-sensitive Na and Ca channels

2. modulates or decreases presynaptic aspartate and glutamate release

3. antikindling properties

Tegretol, Epitol 200mg tablet

Tegretol 100mg CT, 100mg/5mL suspension

Tegretol-XR 100,200,400mg ER tab

Carbatrol 200,300mg ER cap

Equetro 100,200,300mg ER cap

1. blocks voltage-sensitive Na channels

2. stimulates the release of ADH and decreases Na serum concentrations

3. blocks Ca influx through NMDA glutamate receptor and decreases Ca serum concentrations

4. Modulates presynaptic aspartate and glutamate release

5. Antikindling properties may decrease rapid cycling and mixed states

How is oxcarbazepine available?

MOA?

Trileptal 150,300,600mg t; 300mg/5mL susp

Oxcarbazepine and it's active monohydroxy metabolite increase K conductance and modulate the activity of high-voltage activated Ca channels and block Na channels

Benzodiazepine MOA?

Which are used in BPD? Availability?

binds to BZD site and augments action of GABAa by increasing the frequency of Cl channel opening (causing hyperpolarization - a less excitable state) and inh neuronal firing

Clonazepam (Klonopin) 0.5,1,2mg t - 0.5-20mg/day 

Lorazepam (Ativan) 0.5,1,2mg t;     2-40mg/day

2mg/mL sol;

2mg/mL + 4mg/mL inj

Aripiprazole (Abilify) 5,10,15,20,30mg t

Olanzapine (Zyprexa) 2.5,5,7.5,10,15,20mg t

(Zyprexa Zydis) 5,10,15,20mg ODT

Quetiapine (Seroquel) 25,50, (1/2/3)00 t

Risperidone (Risperdal) 0.25,0.5,1,2,3,4mg t

1mg/mL solution

(Risperdal M-Tab) 0.5,1,2,3,4mg 

Ziprasidone (Geodon) 20,40,60,80mg cap

What CCB are used as third-line agents in combination with other drugs (carbamazepine, valproate, antipsychotics)?

MOA?

Nimodipine (Nimotop) 30mg capsule - 30-120mg/day

Verapamil (Verelan) 120,180,240,360mg cap -80-480/day

(Calan, Isoptin) 40,80,120mg film-coated t

120,180,240 mg ER t

Blocks Ca influx through L-type Ca channels

Alters Ca-Na exchange

Decreases 5-HT, DA, and endorphin activity

1. Carbamazepine: DC- plt<100th/mm3; WBC<3th/mm3

2. Lithium 

3. Valproate: DC if plt<100th/mm3 or prolonged bleeding time

1. Atypical antipsychotics (increased app w weight gain (initial low or normal BMI), rapid or signif gain during early therapy, hyperlipidemia, diabetes)

2. Lithium 

3. Valproate 

Carbamazepine -DC if liver dysfunction

Valproate

Carbamazepine + Lithium

Lithium (q2-3m during first 6 then q6-12; if impaired monitor 24-h urine volume and creatinine q3m; if urine volume>3L/day, monitor urinalysis, osmolal, and spgrav q3months)

Lithium

Carbamazepine

Oxcarbazepine

Carbamazepine

Lamotrigine - serious dermatologic rxn, SJS, within 2-3mo

Lithium - alopecia

Valproate

Valproate

Which drug was recently approved for maintenance treatment?

Efficacy?

Aripiprazole (Abilify)

Showed efficacy in preventing relapse into mania (did not show efficacy at preventing depression)

Duration - no systemic data to support use beyond 6 weeks

Which drug is now FDA approved for maintenance therapy of BPD when given in combination with lithium or divalproex?

Efficacy?

Quetiapine

showed efficacy for preventing manic and depressive relapse

Which ADE is more frequently associated with oxcarbazepine than carbamazepine?

A. Ataxia

B. N/V

C. SJS

D. Hyponatremia

Which of the following lab tests is needed before initiating therapy with valproic acid?

A. K level

B. LFT

C. Thyroid FT

D. Mg level

Antidepressants can be used when treating a patient with BPD who is currently:

A. depressed and taking a mood stabilizer

B. not depressed but hx of severe depression before each manic episode

C. hypomanic but hx of severe depression

D. Manic but hx of severe depression after manic episode

E. A+B

F. All of the above

Antipsychotics could be used in a pt displaying which of the following symptoms:

A. Mania with psychotic features

B. Mania without psychotic features

C. Depression with psychotic features

D. A and B

E. All of the above

A diagnosis of BPD comes only after a pt has a:

A. manic episode

B. hypomanic episode

C. depressed episode

D. A or B

E. All of the above

Which medication is FDA approved as monotherapy or adjunctive therapy for BPD maintenance?

A. olanzapine

B. quetiapine

C. risperidone

D. ziprasidone

E. A and B

E. Olanzapine (Zyprexa) - mono or adjunctive

+ Quetiapine (Seroquel) - adjunctive with lithium or valproate

Which statement concerning the use of lithium in the treatment of bipolar affective disorder is accurate?

A. excessive NaCl intake enhances the toxicity

B. it aleviates the manic phase within 12h

C. dosage may need to be decreased in pts on thiazides

D. it doesn't cross the placental barrier and is quite safe in pregnancy

E. elimination rate is equivalent to that of creatinine

C. Correct

*high urinary levels of Na inh renal tubular reabsorption of lithium = decreased plasma levels

*lithium clearance is decreased by distal tubule diuretics (thiazides) because natriuresis stimulates a reflex increase in the proximal tubule reabsorption of Li and Na

*any drug that can cross the BBB can cross the PB. teratogenic risk is low, but use during prego may contribute to low Apgar score in neonate; Ebstein's anomaly - tricuspid

*elimination rate of lithium is equivalent to 1/5th that of creatinine

A 30-year-old male is on drug therapy for a psychiatric problem. He complains that he feels "flat" and that he gets confused at times. He has been gaining weight and has lost his sex drive. As he moves his hands, you notice a slight tremor. He tells you that since he has been on medication, he is always thirsty and frequently has to urinate. The drug he is most likely to be taking is:

A. carbamazepin           D. risperidone

B. haloperidol               E. valproic acid

C. lithium

C. lithium:

confusion, mood changes, decreased libido, weight gain are all symptoms that may be unrelated to drug admin; on the other hand, psychiatric drugs are often responsible for such symptoms. Tremor and symptoms of nephrogenic diabetes insipidus are characteristic adverse effects of lithium that may occur at blood levels within the therapeutic range

Which of the following drugs is established to be both effective and safe to use in a pregnant patient suffering from bipolar disorder?

A. carbamazepine

B. chlorpromazine

C. lithium

D. olanzapine

E. valproic acid

D. olanzapine;

carbamazepine and valproic acid are effective in BPD but CI in prego because of effects on fetal development. although the potential for dysmorphogenesis due to lithiumm is probably low, the most conservative approach would be to treat the pt with olanzapine. chlorpromazine has no proven efficacy in BPD

The effective treatment of a bipolar pt has necessitated doses of lithium that result in plasma levels of 1.4-1.6mEq/L. Lately he has begun to suffer from increased motor activity, aphasia, mental confusion, and social withdrawal. The best course of action would be to:

A. add amitriptyline to the drug regimen

B. continue lithium and add haloperidol

C. DC lithium and start valproic acid

D. DC lithium and start clozapine

E. increase the dose of lithium

C. DC lithium and start valproic acid;

these are symptoms of lithium toxicity. it is appropriate to try an alternative drug (olanzapine, carbamazepine, valproic acid) Clozapine as a single agent has minimal efficacy in BPD.

A young pt treated with an antipsychotic for a few weeks becomes easily fatigued and experiences periodic fevers. Petechiae are apparent on PE, and lab studies revel leukopenia and thrombocytopenia. If a diagnosis is made that the patient is suffering from drug-induced agranulocytosis, he is most likely being treated with:

A. aripiprazole

B. clozapine

C. haloperidol

D. olanzapine

E. risperidone

B. clozapine; 

Within days of starting haloperidol treatment, a young male developed generalized muscle rigidity and a high temp. In the ER he was incoherent, with increased HR, hypotension, and diaphoresis. Labs indicated acidosis, leukocytosis, and increased creatine kinase. What is the most likely reason for his symptoms?

A. agranulocytosis

B. bacterial inf

C. NMS

D. spastic retrocollis

E. TD

C. Neuroleptic Malignant Syndrome (NMS);

result of an extremely rapid block of dopamine receptors in pt who are highly sensitive to EPS of antipsychotics. Management involves fever control, muscle relaxants (dantrolene or diazepam) and possibly admin of dopamine receptor ag (bromocriptine). 

Which of the following drugs has a high affinity for 5HT2 receptors in the brain, does not cause EPS or hematotoxicity, and is reported to increase the significant QT prolongation?

A. chlorpromazine

B. clozapine

C. fluphenazine

D. olanzapine

E. ziprasidone

E. ziprasidone (Geodon)

the newer antipsychotics have greater affinity for 5HT2 than DA receptors. Clozapine is hematotoxic. Ziprasidone carries a greater risk of QT prolongation than olanzapine.

How do you reduce polyuria when taking lithium?

What is a treatment available to control the lithium-associated tremor?

change to once daily dosing

bb- propranolol 10mg po TID

Which comes first, polyuria or polydepsia?

Nephrogenic diabetes insipidus is diagnosed with a urine output >__ L/day

Treatment?

Polyuria

3L/day

diuretic: loop, thiazides, triamterene

1. Ebstien's anomaly in ~0.1% (1-8x increase)

2. increased neonatal goiter

3. "floppy baby syndrome" - hypotonia, low Apgar score, lethargy, bradycardia, cyanosis, premature delivery, thyroid abnormalities

4. lithium clearance is increased 50-100% during prego

What is the serum lithium level for acute toxicity?

maintenance toxicity?

Acute >6-8mEq/L

Maintenance >4mEq/L

Divalproex peak = 3-5h

Valproic acid peal = 1-4h

metabolism?

ddi?

CYP2C9, 2C19, UGT

inh 2C9 + UGT

Valproate ADEs:

BBW?

alopecia, tremor, ataxia, pancreatitis, TCP, hepatotox, hyperammonemia, POS, insulin resis, hyperandrogenism, bone demineralization

Hepatotoxicity: fatal; occurs within first 6 months of therapy

Pancreatitis: abp, n/v, anorexia

neural tube defects 5-9%

use folic acid supplementation in women of child-bearing age

CYP3A4 substrate

metabolized by autoinduction 

Induces CYP3A4, 1A2, 2C9, 2D6 (may decrease levels of BC)

Carbamazepine ADEs:

BBW:

hyponatremia, thrombocytopenia, leukopenia, agranulocytosis, hepatotoxicity, diplopia, dry mouth, blurry vision, constipation, SJS 5-10%, confusion, arrhythmias, alopecia, lupus-like symptoms

aplastic anemia, agranulocytosis (monitor blood levels q2weeks for first 2 months then q3 months)

S/S: oral ulcers, sore throat, easy bruising, bleeding, fever

What are the risks of carbamazepine and pregnancy?

What is the maximum daily dose of oxcarbazepine?

What is the MOA?

2400mg/day

10-keto analog of carbamazepine, blocks voltage-sensitive Na channels, modulates voltage-activated Ca currents, and increases K conductance

What is the active metabolite of oxcarbazepine?

Inh? Induces?

10-monohydroxy-carbazepine

Inh: 2C19

Inducer: 3A4 (induced metabolism of OC)

Lamotrigine

MOA?

Lamictal

may stabilize neuronal membranes by acting on voltage-sensitive sodium channels; decrease release of presynaptic glutamate and asparte

What are the ADE of lamotrigine?

Toxicity?

TEN, SJS?, 10% have some rash; ataxia, blurred vision, sedation

Rash >> with valproate+lamotrigine

Tox: stupor, coma, death

What are the ddi of lamotrigine?

Aseptic meningitis?

Lamotrigine increases the serum concentration of valproic acid.

Lamotrigine decreases the serum concentration of cabazepine, phenytoin, and phenobarbital

1. possible increase in rate of major congenital malformations

2. increased risk of cleft-lip, cleft-palate

3. greater risks at doses >200mg

Clozaril (clozapine) - agranulocytosis

Zyprexa Relprevv (olanzapine extended-release injectable suspension) - post-inj delirium/sedation

Symbyax

1. Dose?

2. Indications?

3. CI?

4. Warnings/Precautions?

olanzapine (zyprexa) + fluoxetine (paxil)

1. capsule

2. Depressive episodes associated with BP1, treatment resistant depression (in MDD)

3. no use with MAOI or within 12d of DC, wait 5 weeks to start MAOI, pimozide or thioridazine - QT prolongation, do not use thioridazine within 5 weeks of DC symbyax

4. worsening/suicide risk, elderly with dementia, NMS, hyperglycemia, hyperlipidemia, weight gain, SS and NMS-like reactions, allergic reaction/rash, activation of mania/hypomania, TD, orthostatic hypo, leukopenia, neutropenia, agranulocytosis, seizures, abnormal bleeding, hyponatremia (SIADH), potential for cog and motor impairment, hyperprolactinemia, long elimination half-life of fluoxetine, lab test (FBG, lipids)

Olanzapine/Fluoxetine:

3/25

6/25

6/50

12/25

12/50

Symbyax metabolism?

What factors affect metabolism?

Fluoxetine - metabolized by 2D6

Olanzapine - metabolized by 1A2, 2D6

smoking status, gender, and age

Mono:

Aripiprazole

Olanzapine

Adj:

Quetiapine 

Ziprasidone 

Quetiapine 

Olanzapine (adjunctive with fluoxetine)

aripiprazole (Abilify)

asenapine (Saphris)

olanzapine (Zyprexa)

ziprasidone (Geodon)

risperidone (Risperdal)

quetiapine (Seroquel)

Which atypical antipsychotics:

1. is available as SL

2. is available as ODT

3. inj for acute agitation

4. long acting or extended release inj

1. asenapine (Saphris)

2. aripiprazole, olanzapine, risperidone

3. aripiprazole, olanzapine, ziprasidone*

4. paliperidone, risperidone

*indicated for acute agitation with schizo not BPD

1. Which atypicals have the worst metabolic profiles?

2. Which has no QT-prolongation?

3. Which has the least EPS?

4. Most EPS?

5. Most hyperprolactinemia (sexual dysfunction, gynecomastia, irregular periods)?

6. no CYP3A4 metabolism?

7. Most sedation? 

8. least sedation?

1. olanzapine and clozapine

2. olanzapine

3. iloperidone and quetiapine

4. paliperidone and risperidone

5. paliperidone and risperidone

6. risperidone and olanzapine

7. clozapine

8. aripiprazole, iloperidone, paliperidone, risperidone, ziprasidone