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What are the Characteristic symptoms of a schizophrenic?
- Hallucinations
- Delusions
- Disorganized Speech
- Grossly disorganized or catatonic behavior
- Negative symptoms
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What is the fx of the Nigrostriatal tract in schizophrenia?
- Route:
- Substantia nigra to Caudate nucleus and Putamen
- Function:
- Extrapyramidal system
- Movement
- DA Antagonist Effect:
- Movement disorders
- Tardive dyskinesia
- Pseudo-Parkinsonism
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What is the fx of the Mesolimbic tract in schizophrenia?
Excess DA = positive Schiz symptoms
- Midbrain ventral tegmentum (A10 area) to Limbic areas
- Function:
- Arousal, memory, stimulus processing, motivation, emotional content
- DA Antagonist Effect:
- Relief of psychosis
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What is the fx of the Mesocortical tract in schizophrenia?
Insuffient DA = negative Schiz symptoms
- Route:
- Midbrain ventral tegmentum (A10 area) to Frontal and Prefrontal Cortex
- Function:
- Cognition, communication, social function, response to stress
- DA Antagonist Effects:
- Relief of psychosis
- Akathisia
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What is the fx of the Tuberoinfundibular tract in schizophrenia?
- Route:
- Hypothalamus to Pituitary
- Function:
- Regulate prolactin release
- DA Antagonist Effect:
- Increased prolactin concentrations
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What drugs are used to treat schizophrenia?
- 1st generation antipsychotics (FGAs or neuroleptics)
- 2nd generation antipsychotics (SGAs or atypicals)
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Which FGAs (neuroleptics)are used to treat schizophrenia?
- chlorpromazine (Thorazine)
- thioridazine (Mellaril)
- mesoridazine (Serentil)
- haloperidol (Haldol)
- perphenazine (Trilafon)
- fluphenazine (Prolixin)
- loxapine (Loxitane)
- trifluoperazine (Stelazine)
- thiothixene (Navane)
- molindone (Moban)
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What are the advantages of FGAs (neuroleptics)?
- cheap
- effective for positive sx (perphenazine was 2nd best in CATIE trial)
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What are the disadvantages of FGAs (neuroleptics)?
- MANY SE!
- failure to change insight or judgment
- lack of efficacy in 20-30% of pts
- may worsen negative sx
- DI with drugs that affect gastric pH
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What are the side effects of FGAs (neuroleptics)?
- EPSE
- prolactin elevation
- sexual dysfx
- anticholinergic effects
- sedation
- wt gain
- dizziness
- OH
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Which SGAs (atypicals) are used to treat schizophrenia?
- clozapine (Clozaril)
- risperidone (Risperdal)
- paliperidone (Invega)
- olanzapine (Zyprexa)
- quetiapine (Seroquel)
- ziprasidone (Geodon)
- iloperidone (Fanapt)
- asenapine (Saphris)
- aripiprazole (Abilify)
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How do most of the SGAs (atypicals) work?
- serotonin-dopamine antagonism (SDA
- more 5-HT2 than D2
- increased DA release:
- improved neg sx (MC tract)
- less EPSE (NS tract)
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What is the only drug succussfully used to treat pts refractory to FGAs?
clozapine (Clozaril)
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Which SGAs are better than FGAs for depressive-type sx seen in schizophrenia?
- aripiprazole (Abilify)
- quetiapine (seroquel)
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Which antipsychotic is cheapest of all APs (FGA and SGA)?
resperidone (Risperdal) (generic)
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Which SGA is the only one that may not need to be titrated to an effective dose?
asenapine (Saphris)
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How are the SGAs associated with metabolic problems (ranking)?
- up to 100lbs/y
- 10-20lbs in a few months
- clz, olz > risp, quet >ase > zip, ari
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What are the advantages of clozapine (Clozaril)?
- the only AP effective for tx refractory Schizophrenics
- the only AP FDA approved to reduce risk of recurrent suicidal behavior
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What are the disadvantages of clozapine (Clozaril)?
- Agranulocytosis (reason to d/c)
- Seizures (if cont'd tx needed, add VPA and keep < 900 mg/d)
- Most metabolic problems (wt gain)
- 2D6 substrate (Fluoxetine, Paroxetine)
- sialorrhea
- sedation
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What are the advantages of risperidone (Risperdal, Risperdal Consta, Risperdal M-TAB)?
- First-line agent
- many dosage forms
- most potent D2 blocker SGA (good for very psychotic pt)
- FDA approved for schiz and bi-polar in children and adolescents
- cheapest AP available
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What are the disadvantages of risperidone (Risperdal, Risperdal Consta, Risperdal M-TAB)?
- Most potent D2 blockade SGA (more EPSE, dose dependent)
- Most Prolactin elevation
- 2D6 substrate
(Fluoxetine, Paroxetine)
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Paliperidone (Invega, Invega Sustenna)
9-OH metabolite of Risperidone
- Same SE as Risperidone, maybe more Prolactin elevation
- OROS extended-release (Invega)
Extended release injectable = 1/mo dosing (Invega Sustenna)
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What are the advantages of Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis)?
- Relatively free of drug interactions (best in CATIE trial)
- long-acting injectable dosing q 2-4wks (Zyprexa Relprevv)
- oral disentegrating tablet (Zyprexa Zydis)
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What are the disadvantages of Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis)?
- Most expensive of any AP $$$$
- Most metabolic problems
- Most wt gain
- Dose-dependent EPSE above 20mg
- 3h observation req'd after Relprevv injection for delirium/sedation or coma
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What are the advantages of Quetiapine (Seroquel)?
- Very low risk of EPSE Very good....if it works
- well tolerated by many pts
- seems to help depressive sx
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What are the disadvantages of Quetipine (Seroquel)?
- Second most expensive $$$$
- Some don't think it works (CATIE trial)
- Must titrate slowly
- Somnolence
- 3A4 substrate
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What are the advantages of Ziprasidone (Geodon)?
- LITTLE TO NO WT GAIN OR METABOLIC EFFECTS@!
- somewhat novel MOA - SDA, but also modest reuptake inhibition of 5-HT and NE
- available as a short-acting injection
- giving w/ food doubles bioavailability
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What are the disadvantages of Ziprasidone (Geodon)?
- Most QTc prolongation - no Antiarrhythmics, Antihistamines, Moxifloxacin, Sparfloxacin Erythromycin Ketoconazole, Thioridazine, Pimozide, Methadone, possibly TCA's
- w/ or w/o food needs to be consistent
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What are the risk factors for QT prolongation?
- Known heart disease
- History of Syncope
- Family hx of sudden death at < 40yo
- Congenital long QT syndrome
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What are the advantages of Iloperidone (Fanapt)?
- low EPSE
- little effect on lipids
- little effect on prolactin
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What are the disadvantages of Iloperidone (Fanapt)?
- Most potent Alpha blocker - slow dose titration required to dec.
- risk of OH
- Numerically, if not statistically, least effective in studies
- QTc prolongation
- 2D6 and 3A4 interactions
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What are the advantages of Asenapine (Saphris)?
- Novel MOA - Blocks 5-HT2A, 5-HT2C, and D2 receptors
- no titration required (maybe)
- First drug approved for Schiz and Bipolar simultaneously
- Sublingual tablets only - no food or liquids for 10 min after dose; DON'T swallow tablet
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What are the advantages of Asenipine (Saphris)?
- 2D6 substrate and inhibitor
- Insomnia
- Oral hypoesthesia
- no food or liquids for 10min after dose
- little research completed
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What are the advantages of Aripiprazole (Abilify)?
- Unique pharmacology - D2 and 5-HT1A partial agonist (D2 partial is unique)
- 5-HT2A antagonist
- little effect on wt or metabolism
- may DECREASE prolactin (d/t partial agonism of DA)
- Less sedating
- Approved for adjunct tx of tx-resistant depression
approved for adolescents
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What are the disadvantages of Aripiprazole (Abilify)?
- Akathisia
- Nausea
- Dizziness
- OH
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Which SGAs cause agranulocytosis?
clozapine (Clozaril)
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Which SGAs cause the most EPSE?
- risperidone (Risperdal)
- olanzapine (Zyprexa)
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Which SGA causes the most prolactin increase?
risperidone (Risperdal)
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What SGAs causes the most wt gain?
- Olanzapine (Zyprexa)
- Clozapine (Clozaril)
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Which SGAs cause the most metabolic problems?
- Clozapine (Clozaril)
- Olanzapine (Zyprexa)
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Which SGA causes the most nausea?
Aripiprazole (Abilify)
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Which SGA causes akathisia?
Aripiprazole (Abilify)
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Which SGA causes the most dizziness?
Aripiprazole (Abilify)
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Which SGA causes the most OH?
Aripiprazole (Abilify)
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Which SGA causes the most somnolence?
Quetiapine (Seroquel)
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What are the optimal doses of SGAs?
- risperidone (Risperdal) - 3-6mg/d
- asenipine (Saphris) - 5mg/d
- olanzapine (Zyprexa) - 10-20mg/d qd
- iloperidone (Fanapt) - 12-24mg/d
- aripiprazole (Abilify) - 15mg/d
- ziprasidone (Geodon) - 120-160mg/d
- clozapine (Clozaril) - 300-60 mg/d
- quetiapine (Seroquel) - 300-600mg/d
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Schizophrenia Symptom clusters
- Positive:
- Bizarre behavior, Delusions, Loose associations, Hallucinations, Disorganized thinking, Conceptual disorganization
- Negative:
- Blunted affect, Alogia, Poverty of speech, Anhedonia, Withdrawal, Avolition
- Cognitive:
- Impaired attention, working memory and/or executive function
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What are the symptoms of Neuroleptic Malignant Syndrome (NMS)?
- Autonomic dysfunction:
- tachycardia, HTN, tachypnea, diaphoresis, dysrrhythmias, sialorrhea, incontinence, normal or decreased bowel sounds
- Altered mental status:
- confusion, delirium, lethargy, stupor, coma, fluctuating levels of consciousness (LOC)
- Muscular Rigidity:
- lead pipe rigidity, akinesia, bradykinesia, bradyreflexia, tremor, myoclonus, chorea, opisthotones, cogwheeling
- Hyperthermia:
- T >38.5 (often higher than 41.1
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NMS lab findings
- leukocytosis
- increased transaminases
- increased CK
- metabolic acidosis
- hyper/hyponatremia
- myoglobinuria
- mild coagulopathies
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NMS complications
- rhabdomyolysis
- renal failure
- aspiration pneumonia
- pulmonary embolism
- adult respiratory distress syndrome (ARDS)
- disseminated intravasular coagulation (DIC)
- seizures
- MI
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Symptoms of Serotonin Syndrome
- Mental status changes:
- agitation, delilrium, hypervigilance, pressured speech, exaggerated startle response
- Autonomic hyperactivity:
- tachycardia, shivering, diaphoresis, mydriasis, diarrhea, HTN
- Neuromuscular abnormalities:
- hyper-reflexia, myoclonus, peripheral hypertonicity, repetetive head rotation, tremor, rigidity
- Other:
- hyperthermia, hyperactive bowel sounds
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Serotonin Syndrome lab findings
- metabolic acidosis
- rhabdomyolysis
- increased transaminases
- increased creatinine
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Complications of Serotonin Syndrome
- seizures
- renal failure
- disseminated intravascular coagulation (DIC)
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What symptoms are unique between NMS and Serotonin Syndrome?
- NMS:
- lead-pipe rigidity in all muscle groups, bradyreflexia, stupor, time to develop = 1-3 days
- SS:
- rigidity predominantly in lower extremities, hyperreflexia, agitation, mydriasis, hyperactive bowel sounds, clonus, time to develop = <12h
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Define serotonin syndrome
a predictable consequence of excess serotonergic agonism of central and peripheral serotonergic receptors
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What is the most favored hypothesis for NMS?
sudden and profound central dopaminergic blockade
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How is NMS managed?
- d/c APs
- d/c any anticholinergics
- dopamine agonists (bromocriptine, amantadine)
- dantrolene (direct-acting skeletal muscle relaxant)
- benzodiazepines
- aggessive cooling
- antipyretics
- fluid and electrolyte repletion
- appropriate tx of potential complications
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How is serotonin syndrome managed?
- d/c serotonergic drugs
- supportive care
- benzodiazepines to control agitation
- 5-HT2A antagonists – cyproheptadine, atypical antipsychotics, chlorpromazine pressors for BP control
- vecuronium to decrease muscle activity
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What role do the following drugs play in NMS?
- BZD - decrease muscular rigidity = decrease heat
- Chlorpromazine - can be the cause
- Anticholinergics - DO NOT USE!!!!
- antipyretics - decrease temp
- Bromocriptine - DA agonist = decrease temp by increase DA production
- Dantrolene - muscle relaxant = decrease temp
- Amantadine - DA agonist = decrease temp by increase DA production
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What role do the following drugs play in serotonin syndrome?
- BZD - control agitation = decrease heat
- Cyproheptadine - 5-HT2a antagonism
- SGAs - 5-HT2a antagonism
- Chlorpromazine - 5-HT antagonism
- Anticholinergics - DO NOT USE !!!!
- Vecuronium - paralysis to decrease excessive muscle movement = decrease temp
- Succinylcholine - DO NOT USE!!!!
- antipyretics - NONE
- Propranolol - DO NOT USE could cause hypotension and mask tachycardia
- Bromocriptine - DO NOT USE/ could cause ss
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How should AP tx be reinstituted after a case of NMS?
- 2 week minimum washout after full resolution of NMS
- reduction of risk factors
- resume with informed consent
- close observation
- low dose, low potency agent
- slow, cautious titration to full effectiveness
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What are the risk factors for NMS?
- high initial dose of AP
- rapid upward titration
- change to higher potency
- use of long-acting depot injectable neuroleptics
- high ambiet temps
- dehydration
- concommittant illness
- AIDS-related dementia
- head trauma
- general debilitation
- organic brain disease
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What are the risk factors for serotonin syndrome?
- Use of serotonergic drugs
- Use of combinations of drugs that lead to increased serotonin
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