Psychopharmacology: Schizophrenia

What is the annual incidience of schizophrenia?

0.5 to 5 per 10,000 people

what is the incidence of NMS?

1%

what is the long term management of drugs if patient just had their first episode?

1) 80% relapse within one year, 98% relapse two years of being medication free 2) May reduce and potentially discontinue after one year if suspected misdiagnosis

what is the presentation like for acute dystonia?

1) Acute, severe, painful muscle contraction 2) Usually high potency antipsychotics at high doses 3) Risk factors: young, male, antipsychotic naïve

What are some condierations when you initiate LAIAs?

1) Assess patient's willingness to use LAIA 2) Must establish oral antipsychotic tolerability 3) Must convert PO dose to equivalent LAIA dose 4) Confirm insurance coverage/ affordability 5) Determine outpatient follow up plan

what can you give for the drooling?

1) Atropine eye drops: SL 2) Ipratropium spray: SL 3) Glycopyrrolate 4) Benztropine 5) Clonidine 6) Sialorrhea - non pharmacologic - towel on pillow, chew gum during the day

what anticholinergics are ok to give for acute agitation treatment?

1) Benztropine (PO/IM) 2) Diphenhydramine (PO/IM)

What are the low potency FGAs? they bind to the receptors less

1) Chlorpromazine (100mg) 2) Thioridazine (100mg) ~100mg

what are the things when you are selecting an antipsychotic agent?

1) Clinical treatment guidelines 2) First episode of psychosis versus several prior episodes 3) Prior medication trials 4) Family history of medication response 5) Comorbidities (cardiovascular, endocrine, etc.) 6) Special populations -Geriatric -Pediatric -Pregnancy/lactation 7) Adherence 8) Monitoring parameters 9) Drug interactions 10) Cost 11) Duration of treatment (maximum response: 4-6 weeks)

what are the risk factors for seisure when on clozapine?

1) Clozapine level ≥500 μg/L - 300-500 is where you see effectiveness and anything above that is a risk usually from rapid dose increases

What are some condierations when you continue LAIAs?

1) Confirm most recent LAIA administration date 2) Continue to assess patient's willingness to use LAIA 3) Assess insurance coverage/ affordability at least yearly

what is the treatment for aciuet dystonia

1) Diphenhydramine (Benadryl®) 25-50 mg IM - esp if in the neck 2) Benztropine (Cogentin®) 1-2 mg IM

what is the treatment for pesudoparkinsonism?

1) Diphenhydramine (Benadryl®) 50-200 mg PO 2) Benztropine (Cogentin®) 4-10 mg PO 3) Trihexyphenidyl (Artane®) 4-20 mg PO 4) Amantadine (Symmetrel®) 100-200 mg BID 5) Change to a different antipsychotic, decrease dose

what is the treatment for NMS?

1) Discontinue all psychotropics (except benzodiazepines) for at least two weeks 2) Bromocriptine (Cycloset®) and dantrolene (Dantrium®)

MOA: what receptors do FGAs antagonize?

1) Dopamine (D2) 2) Muscurinic (M1) 3) Histaminnc (H1) 4) Alpha (alpha1)

what receptors do SGAs antagoize?

1) Dopamine (D2) 2) Serotonin (5-HT2A) not much effect on histamine (H1), Alpha - 1, and muscurinic receptors (M1)

what is the presentation for pseudoparkinsonism?

1) Gait disturbance, cogwheel rigidity, bradykinesia 2) Usually high-potency antipsychotics at high doses

what are oral treatments for acute agitation treatment?

1) Haloperidol 2) Fluphenazine 3) Chlorpromazine 4) Olanzapine 5) ziprasidone 6) Risperidone 7) Aripiprazole

what are IM treatments for acute agitation treatment?

1) Haloperidol 2) Fluphenazine 3) Chlorpromazine 4) Olanzapine* 5) Ziprasidone

What are the high potency FGAs? they bind to the receptors more

1) Haloperidol (2mg) 2) Fluphenazine (2mg) 3) Thiothixene (4mg) 4) Trifluoperazine (5mg) ~2mg

What is the presentation of NMS?

1) Hyperthermia 2) Muscle rigidity 3) Altered mental status 4) Leukocytosis, elevated creatine kinase and AST/ALT

what is the presentation of myocarditis when on clozapine?

1) Hypotension 2) Flu-like symptoms 3) Dyspnea 4) Chest pain 5) EKG changes (ST depression), eosinophilia, enlarged heart on imaging

How can long acting injectable antipsychotics (LAIAs) help with adherence?

1) Improve adherence rates 2) Effects last two weeks to three months 3) Require clinician administration 4) Require follow up plan 5) May be costly

What are some consequences of poor adherrence?

1) Increased relapse rates 2) Increased healthcare costs 3) Increased risk of illness/death

how do you manage the seizures from clozapine?

1) Initiate anticonvulsant (levetiracetam or valproic acid) 2) Hold dose for one day, decrease total daily dose 3) Re-check clozapine level

what benzos are ok to give for acute agitation treatment?

1) Lorazepam (PO/IM) 2) Diazepam (PO only, IM erratic absorption)

What are the intermediate potency FGAs?

1) Loxapine (8mg) 2) Perphenazine (10mg) ~8-10mg

what is the long term management of drugs if patient has multiple episode?

1) Maintenance treatment needed 2) May try up to a 30% dose decrease - slow taper

For diagnosis, Schizoaffective/mood disorder exclusion includes:

1) Must not have major depressive disorder, manic or mixed episodes coinciding with active-phase symptoms 2) If present, must last for minor portion of duration

how do you manage severe neutropenia for clozapine?

1) Obtain baseline absolute neutrophil count (ANC) 2) Continually monitor ANC via Clozapine REMS 3) Hold and/or discontinue clozapine

what is the treatment for Akathisia?

1) Propranolol (Inderal®) 30-120 mg PO daily 2) Lorazepam (Ativan®) 0.5-10 mg 3) Decrease dose, change agent

what effects does SGAs have on serotonin receptors (5-HT2A)?

1) Reduce EPS 2) Possibly improve cognition

what is the treatment for tardive dyskinesia?

1) Remove anticholinergics - can worsen 2) Give lowest effective dose - 3) Switch to an atypical antipsychotic (clozapine, quetiapine) 4) FDA approved VMAT2 inhibitors- valbenazine, deutetrabenazine ($$$)

what is the presentation for tardive dyskinesia?

1) Repetitive involuntary movements (typically mouth/face) 2) May be irreversible 3) Seen more often in elderly females

what effects does FGAs have on histamine receptors (H1)?

1) Sedation 2) Weight gain

Strategies to Improve Adherence?

1) Side effects - Attempt to select most tolerable medication 2) Assess and treat side effects - Lack of medication counseling - Ensure proper medication counseling 3) Lack of follow up - Ensure proper transitions of care 4) Simplify medication regimen - Consider once daily dosing - Use as few agents as possible - Consider using long-acting injectable antipsychotics

What are some reasons for poor adherrence?

1) Side effects 2) Lack of patient medication counseling 3) Poor insight 4) Lack of follow up 5) Lack of social support 6) Complicated medication regimen 7) Stigma

what is the presentation for akathisia?

1) Subjective restlessness, jitteriness, fidgeting, pacing 2) Usually high-potency antipsychotics at high doses, fast titration

what effects does FGAs have on alpha 1 receptors?

1) Syncope 2) Orthostatic Hypotension 3) Reflex tachycardia

what effects does SGAs have on dopamine receptors (D2)?

1) Therapeutic effect 2) Extrapyramidal symptoms 3) Hyperprolactinemia

Why is medication formulation particularly important in psychiatry? (5)

1) Unable to take oral medication - give them liquid medication 2) "Cheeking" medications - not swallowing medications, ODT formulation 3) Medication over objection protocol - they are deemed not able to make the decision to not take their medications, they need multiple doctors to say they can't take the medications and so they the IM formulation or something 4) Onset of action for acute agitation - IM over oral medication in emergent situations 5) Long-term adherence

what are the 4 components to EPS?

1) acute dystonia 2) Pseudoparkinsonism 3) Tardive Dyskinesia 4) Akathisia

what other receptors does aripiprazole target?

1) also antagonist at 5HT7 2) partial agonist at D3, D4, and 5HT1A 3) no affinity for muscarinic receptors

what other receptors does brexipiprazole target?

1) also antagonist at 5HT7 and M1 2) partial agonist at D2, D3, and 5HT1A

So normally you see antagonism of D2 and 5-HT2A receptors for SGAs, what SGAs are exceptions to this?

1) aripiprazole 2) brexipiprazole 3) cariprazine

what are the different second generation LAIAs?

1) aripiprozole 2) olanzapine 3) risperidone 4) Paliperidone

what are the verious SGAs?

1) aripiprozole (Abilify) 2) cariprazine (Vraylar) 3) lurasidone (Latuda) 4) pimvanserin (Nuplazid) 5) asenapine (Saphris) 6) clozapine (Clozaril) 7) olanzapine (Zyprexa) 8) ziprasadone (Geodon) 9) brexipiprazole (Rexulti 10) iloperidone (Fanapt) 11) paliperidon (Invega) 12) risperidone (Risperdal) 13) Quetiapine (Seroquel)

what are the rating scales for each of the EPS categories?

1) dystonia - none 2) Pesudoparkinsonism - Simpson-Angus EPS Rating Scale 3) Akathisia - Barnes Akathisia Rating Scale (BARS) 4) Tardive Dyskinesia (abnormal involuntary movement scale (AIMS)

what are examples of environmental fatcors?

1) early cannibas use 2) advanced paternal age 3) perineal complication (hypoxia) 4) famine

what are to two catgegories of risk factors?

1) genetic 2) environment

what are the different hypotheses for pathophysiology for schizophrenia?

1) glutamate hypotheiss 2) dopamine hypothesis 3) neurodegenerative hypothesis

what are examples of positive symptoms?

1) hallucincations 2) hostility 3) Grandiosity 4) Delusions 5) Excitabilty 6) Suspiciousness

what are the different first generation antipsychotics?

1) halperidol (haldol) 2) fluphenazine (prolixin) 3) trifluoperazine (stelazine) 4) thiothixene (navane) 5) loxapine (loxitane) 6) perphenazine (trilafon) 7) thiordazine (mellaril) 8) chlorpromozine (thorazine)

what is the presentation of severe neutropenia?

1) infection 2) fever or chills 3) abdominal pain 4) fatigue

What are examples of cognitive symptoms?

1) memory 2) speech 3) attention 4) executive function

what are the 4 tracts that are affected by dopamine blockade?

1) mesolimbic 2) mesocortical 3) tuberoinfundibular 4) nigrostriatal

what other receptors does cariprazine target?

1) no affinity muscarinic receptor 2) partial agonist at D3 and 5HT1A

what are other dose dependent effect of clozapine?

1) orthostasis 2) tachycardia 3) Seizures 4) Sedation 5) sialorrhea - drooling 6) Seizures 7) constipation

what kind of symptoms make up schizophrenia?

1) positive symptoms 2) negative symptoms 3) cognitive symptoms

what is the clinical course of Schizophrenia?

1) premorbid phase - cognitive motor or social decificts 2) Prodromal phase - brief/attentuated positive symptoms and/or functinal decline. first psychotic episode. adolescence/young adulthood 3) psychotic phase - florid positive symptoms. adolescence/young adulthood 4) Stable phase - negative symptoms, cognitive/social deficits, functional decline. adolescence/young adulthood

what are some of the metabolic side effects we see with SGAs?

1) weigth gains - olanzapine and clozapine are the worst 2) hypetension 3) hyperglycemia 4) hyperlipidemia

what are agnets you can give fot seizures?

1)Valproic acid 2) Levetiracetam

how many calories should you be eating with latuda?

350 If you don't take food, may not reach the max benefit of med form BA

what is the corcordance for genetics for schizophrenia?

40-50%

What is the usual dose of FGAs for Schizophrenia?

400-600 mg chlorpromazine equivalents

ziprasidone is take with how many calories?

500 to maximize the BA

In selecting an anti-psychotic agent, there are?

6 stages

when is the onset of mycarditis?

6-8 weeks (great incidence in this time)

what do you monitor?

ANC

what should you avoid withing 2 hours when giving olanzasine

AVOID IM benzodiazepines within two hours

what is an adequate dose according to the Kane Criteria?

Adequate dose At least 1000 mg of chlorpromazine equivalents

for paliperidone (Invega Sustenna) what do you have to adjust for?

Adjust dose for renal impairment

First monthly dose of Arisrada?

Administer aripiprazole 30 mg PO once + aripiprazole lauroxil (Aristada Initio®) 675 mg IM once + first monthly dose of Aristada®

what is a common side effect of abilify?

Akathisia - uncomfortable rest Can be a good thing because if they feel more withdrawn, you can give them more energy that way

Which of the following is FALSE? ALL 1) Metabolic effects are the primary concern with FGAs 2) Tardive dyskinesia occurs within hours to weeks 3) Elderly females are at greatest risk for acute dystonia 4) Benztropine is an appropriate agent for akathisia

All are false

what effects does FGAs have on muscurinc receptors (M1)?

Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion)

Pimavanserin is approved for

Approved for Parkinson's psychosis

what should you monitor to prevent QT prolongation?

Baseline and annual EKG, K+, and Mg2+

what are agents you can give for the constipation?

Bulk-forming laxative --> osmotic --> stimulant

what is stage 4?

Clozapine with SGA or FGA or ECT

What is stage 6?

Combination therapy: SGA + FGA SGA or FGA + ECT SGA or FGA + mood stabilizer)

These drugs also have what kind of effectson of what receptors?

D2 - partial agonists at the following receptor (helps with the EPS symptoms): 5-HT2A, H1, and Alpha 1 - antagonists at the following receptors

In general, FGAs cause mainly?

EPS

quetiapine has low risk of?

EPS

what exactly is executive function?

Executive functioning - Self-care, social, interpersonal, community, and occupational functions are all associated with executive functioning in schizophrenia Executive functions (EFs) make possible mentally playing with ideas; taking the time to think before acting; meeting novel, unanticipated challenges; resisting temptations; and staying focused. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances).

what is the effect of dopamine receptor antagonism on the nigrostriatal pathway?

Extrapyramidal symptoms (EPS) (dystonia, pseudoparkinsonism, akathisia, tardive dyskinesia) if you block, see EPS EPS - umbrella term of 4 other things

What is pimavanserin approved for?

FDA approved for Parkinson's Disease Psychosis, but not for any other indication

risperidone has a similar potency to a?

FGAs

what is the glutamate hypothesis?

Glutamate excessively excites dopamine neurons People who are at risk for developing schizophrenia may have too much glutamate activity in certain areas of the brain at first. As the disease progresses, those brain areas may have too little glutamate activity.

what is the relative portency of the SGAs in comparison to haloperidol? NOT black and white, general guide

Haloperidol - 1mg 1) aripiprozole (Abilify) - 5mg 2) clozapine (Clozaril) - 75mg 3) olanzapine (Zyprexa) - 2.5mg 4) quetioapine (Seroquel) - 100mg 5) risperidone (Risperdal) - 1mg 6) ziprasidone (Geodon) - 40mg

what is the effect of dopamine receptor antagonism on the tuberoinfundibular pathway?

Hyperprolactinemia (galactorrhea, amenorrhea, decreased libido) if you have excess prolactin in the blood from the blood, can cause the following

Effects of dopamine blockade based on the dose given

If you give a patient a low dose and you see 40% of DA receptors in brain being blocked - that is a subtherapeutic dose. If you give them a higher dose that resulted in 60% blockage, you see more of a response 70% blockage - more response - theraputic dose 80% - you start to see EPS (supratherpeutic effects) So really you want to see 60-80% receptor blockage

with risperidone IM, what is significant about the overlap?

If you only give it for 3 weeks, you may see relapse because the med is in microspheres and there may come out and the risperidone is not enough in their system so you see more over 4-6 weeks of an overlap

What is the critateria for clozapine initiation?

Kane Criteria

These drugs are given when?

Meds are more $ and not as effective with pt who have a long standing illness - so usually given at first episode

what is the dopamine hypothesis?

Mesolimbic dopamine hyperactivity leads to psychosis Schizophrenia manifests due to excess of dopamine activity

What is the minimum effective dose of FGAs for Schizophrenia?

Minimum effective dose: 300 mg chlorpromazine equivalents

what do you have to monitor for IV aripiprozole?

Monitor for interactions with strong CYP3A4 or CYP2D6 inhibitors/inducers

what is the onset of tardive dyskinesia?

Months to years - esp when using the FGA high potency anti-psychotics (increases 3%/year)

Clozapine is the most effective?

Most effective anti-psychotic (but may not be effective if it is the first episode of psychosis )

for paliperidone (Invega Trinza) what do you have to do?

Must use ≥4 months of Sustenna® with last two doses of same strength

FGAs and SGAs can cause?

NMS Neuroleptic Malignant Syndrome

what is normal ANC for BEN population?

Normal ≥1000/μL

You may need oral overlap depending on the drug you choose, what is that?

Oral overlap, you don't give a loding dose but you keep the oral drug until steady state at the same time

what is the BBW with IM olanzapine?

Patient must be monitored for three hours after administration for post-injection delirium sedation syndrome (PDSS): orthostasis, sedation, coma [incidence <1%] no loading dose is needed here

How can positive, negative, and cognitive symptoms be a barrier to medication adherence?

Positive - you may have a delusion that someone is trying to poison you with the medication Negative - if you don't have the desire or motivation to take meds, you just wont take them Cognitive - they can just forget to take the medication

FGAs and SGAs both can cause increased in QT interval in?

Pre-existing abnormalities, other QTc prolonging medications, and QTc near 500 msec

what is the neurodegenerative hypothesis?

Progressive loss of neuronal function (apoptosis, fetal insults, excitotoxicity)

what is the treatment for myocarditis while on clozapine?

Re-challenge possible, but carries risk - must monitor CRP and troponin closely

What is stage 5

SGA or FGA

What is satge 2?

SGA or FGA or clozapine

For diagnosis, Relationship to a Pervasive Developmental Disorder:

Schizophrenia diagnosis only made if prominent delusions/hallucinations are present for one month

what are some side effects seen in both FGAs and SGAs?

Sedation Orthostatic hypotension Anticholinergic effects -Dry mouth - Constipation - Urinary retention - Confusion

what are effects of smoking on clozapine?

Smoking increases drug metabolism (20-50%) - this is important because people on this have long standing illness (CYP1A2 interaction)

what are examples of negative symptoms?

The Five As: 1) Avolition - lack of goal-directed behavior 2) Alogia - poverty of speech 3) Affect - outward expression of mood 4) Asociality 5) Anhedonia

what are the different first generation LAIAs?

These are high potency 1) Haloperisone Decanoate (Haldol) 2) Fluphenazone Decanoate (Prolixin)

what are the drugs that cause the most prolongation?

Thioridazine 30.1 (24.8-35.5)* Ziprasidone 15.9 (10.6-21.2)* Haloperidol 7.1 (1.8-12.4) Quetiapine 5.7 (1.8-9.7) Risperidone 3.9 (0.3-7.5) Olanzapine 1.7 (-3.8-7.1

what is adequate trial according to the Kane Criteria?

Two antipsychotics from different chemical classes Adequate duration At least six weeks

what is the mesolimbic pathway?

VTA --> Nucleus accumbens

how often should you monitor ANC?

Weekly x 6 months, then every 2 weeks x 6 months, then monthly after 12 months

what is the onset of sever neutropenis with clozapine?

Within 18 weeks to one year is the time frame where you have the highest risk of this occurring

what is the effect of dopamine receptor antagonism on the mesocortical pathway?

Worsened negative symptoms and cognition

what method so you use when you adminster LAIAs?

Z-track method - why?? Sesame oil - need a different type of administration

Which of the following is TRUE? a-PDSS is a black box warning associated with olanzapine b - Invega Trinza® requires four months of oral overlap c - Carbamazepine increases levels of Abilify Maintena® d - Aristada® can be given up to every three months

a

what risk doe clozapine impose?

a weight gain risk

what makes up the diagnosis of schiziphrenia according to the DSM-5 Criteria?

at least 2 symtposm for the following five for at leas 1 months AND continuous signs for at least 6 months: 1) grossly disorganized or caatonic behavior 2) negative symptoms 3) delusions* 4) hallucinations* 5) disorganized speech* * at least one is required for diagnosis

what is adequate duration according to the kane criteria?

at least 6 weeks

what entails someone being diagnoses with metabolic syndrome?

at least three of the following: 1) ↓High-Density Lipoprotein women: ≤50 mg/dL men: ≤40 mg/dL 2) High Triglycerides ≥150 mg/dL 3) High Fasting Blood Glucose ≥100 mg/dL 4) Large Waist Circumference women: ≥35 in men: ≥40 in 5) Hypertension ≥130/85 mmHg

Which is the most correct statement? a -Smoking is expected to significantly increase clozapine level b - A patient with ANC of at least 1500/μL considered "normal" c- Seizures are associated with clozapine level ≥1000 μg/L d - Myocarditis risk is highest 4-6 weeks after starting clozapine

b

for diagnosis, the symptom must include social, occupational dysfunction below

baseline

what receptors do low potent FGAs bind to?

bind to alpha 1, M1, and H1 more (antagonism)

what receptors do highly potent FGAs bind to?

binds to D2 receptors more (antagonism)

What is stage 3?

clozapine

what is the onset for pseudoparkinsonism?

days to weeks

risperidone is renally?

eliminated

The intermediate potency has an?

equal proportion of EPS symptoms as to the M1, H1, and alpha 1

What is stage 1?

first episode of psychosis SGA or FGA

what is the onset fort akathisia?

hours to weeks

what is the effect of dopamine receptor antagonism on the mesolimbic pathway?

improved positve symptoms improvement in positive symptoms - hallucination, hostility

what is the age where you start to see an onset?

late teens to early thirties

abilify is activating at?

low doses

clozapine exerts?

low/no EPS which is a fgood thing

in general, SGAs cause mainly?

metabolic side effects

when is the onset for acute dystonia?

minutes to hours

Clozapine can also cause?

myocarditis

for diagnosis, residual signs include:

negative symptoms, odd beliefs

when is the onset of seizures for clozapine?

no specific onset

what AE should we worry about with iloperdone?

orthostasis

you must avoid the FGA IM in?

patients who have a sesame allergy

abilify is known to cause weight gain in?

pediatrics more than adults BUT there is a low risk of weight gain

So normally you see antagonism of D2 and 5-HT2A receptors for SGAs, what SGAs are exceptions to this?

pimavanserin

what other receptors does pimavanserin target?

pimavanserin is an inverse agonist and antagonist at 5-HT2A receptors (and 5-HT2C with less affinity). It has little to no affinity for dopaminergic, muscarinic, histaminergic, or adrenergic receptors.

what can ziprasidoen cause?

prolonged Qt interva

what are your other options for parkinson's disease?

quetiapine or clozapine

what should you be cognicent of with Cariprazine?

renal elimination

what should you be cognicent of with brexipiprazole?

renal elimination

Paliperidone is?

renally eliminated really expensive without too much benefit from ripseridone and is the active metabolite of reisperidone

quetiapine is very?

sedating - don't use too much from acute psychosis because it has a lot of potency anti-psychotic

clozapine can also cause?

seizures

what can you experience when you are taking clozapine?

severe neutropenia

what effects does FGAs have on dopamine receptors (D2)?

should block 60-80% of receptors to see therpeutic effects 1)Therapeutic effect 2) Extrapyramidal symptoms 3) Hyperprolactinemia

what are the increments you should titrate clozapine at?

slow titration in 25-50mg increments because too many adverse effects can occur otherwise

how should asenaprine be used?

sublingually and the patint cannot have food or drink within 10 minutes of use

for diagnosis, symptoms must no be due to effects of?

substance or medical condition

Who is the REMS for ANC on Clozapine directed towards?

the general population and Benign Ethnic Neutropenia Population (BEN)

what is he ratio of males to females affected?

they are the same

what is the metabolic risk with olanzapine?

weight gain

avoid IM olanzasine within?

within 2 h of IM lorazepam can cause very severe sedation

if the patient is not adherent for more than 48 hours, then?

you must retritrate them again

what is the lifetume prevalence of schizophrenia?

~1%

What is normal ANC for the normal population?

≥1500/μL