Schizophrenia

Diagnostic criteria for Schizophrenia

- at least 2 sx present for significant % of time during 1 month period, less if treated (other sx included grossly disorganized or catatonic behavior or negative sx)
- at least one of sx must be: delusions, hallucinations, disorganized speech
- one or more areas of function (work, intrepersonal, relations, self care) markedly below prev level for significant portion of time (social isolation, cant keep job, impaired self care, dimished family or social relationships)
- Duration of at least 6 months, including at least 1 month of sx
- not a mood disorder
- origin of sx not soley due to substance or general medical condition

List of Positive Sx Schizophrenia

- Delusions
- Hallucinations
- Disorganized Speech
- Grossly disorganized/Catatonic Behavior

What is a Delusion and what type of Schiz Sx, pos or neg?

Positive symptom
- fixed false belief generally outside of cultural or societal norms

What is a Hallucination and what type of Schiz Sx, pos or neg?

Positive symptom
- Sensory perception w/ no basis in external stimuli
- Not illusion (sees shadow and thinks its out to get them) bc that has sensory input

What is Disorganized Speech and what type of Schiz Sx, pos or neg?

Positive Sx
- Cant find the thought process
- frequent derailment or loose associations (Constantly moving from one topic to another), tangentiality, incoherence, repetition of words

What is Grossly Disorgaized/Catatonic behavior and what type of Schiz Sx, pos or neg?

Positive Sx
- Ranges from silliness to catatonia to purposeless movement to agitation
- Catatonic Behavior: sitting in corner and not responding to any external stimuli

List and Definition of Negative Sx Schizophrenia (Hint 4 As)

Negative Sx: an absence or reduction in function in certain areas
- Blunted Affect
- Alogia
- Avolition
- Anhedonia
- Asociality
- Mood Sx
- Social and Occupational Dysfunction

What is Blunted Affect and what type of Schiz Sx, pos or neg?

Negative Sx
- Emotional blunting or difficulty expressing emotion
- Either dont react to whats happening around them or dull to respond

What is Alogia and what type of Schiz Sx, pos or neg?

Negative Sx
- Inability to speak
- Poverty of speech
- Not always mute but not long sentences, or only speak when spoken to

What is Avolition and what type of Schiz Sx, pos or neg?

Negative Sx
- Lack of desire or motivation to pursue self initiated goals

What is Anhedonia and what type of Schiz Sx, pos or neg?

Negative Sx
- Inability to experience pleasurable emotions

What is Asociality and what type of Schiz Sx, pos or neg?

Negative Sx
- Extreme inability or unwillingness to participate in normal social situations

What are cognitive sx associated with Schiz and what type of Schiz Sx, pos or neg?

Negative sx
- Difficulty maintaining or shifting attention
- deficiits in working/long term declarative memory
- deficits in executive function
- deficits in skill acquisition
- deficits in social cognition

What are mood sx associated with Schiz and what type of Schiz Sx, pos or neg?

Negative sx
- Depression
- Dysphoria
- Hopelessness
- Demoralization

What social and occupational sx and what type of Schiz Sx, pos or neg?

Negative Sx
- unable to maintain employment
- homelessness
- lack of close friendship

What are some primary or secondary causes of Negative sx associated with Schiz?

Primary sx: disease (schiz) related
Secondary:
- antipsychotic induced,
- depression,
- EPS,
- Stop taking meds due to percieved resolution of pos sx or not tolerating drug and have negative withdrawal sx

What is the law of thirds in Schiz?

⅓ Significant tx effects! this is the goal! (Sx under control/functioning with disease)

⅓ Significant improvement but relapses, hospitalizations, difficulty with employment/social (periods doing well then hospitalization/relapse and repeating cycle)

⅓ Significant sx w/ mild response to tx. need assistance or group homes
- 10% of that ⅓ are treatment resistant! Institutionalization state hospital situation

Which Dopamine pathways are we affecting in Pathophis of Schiz?

Main ones
- Limbic system has too much dopamine (Mesolimbic)
- Pre-Frontal Cortex has not enough dopamine (Mesocortical)

Other possible ones:
- Temporal lobe atrophy, so emotions out of wack
- Changes in Hippocampus and white/grey matter

Limbic system and Schiz pathophis (Mesolimbic)

- Hyperstimulated/too much dopamine
- D2 activation in Nucleus Accumbens projected from VTA (Ventral Tegmental Area)
- See lots of Pos sx with overstim limbic system "happy" and agitation, messed up speech

Pre Frontal Cortex and Schiz pathophis (Mesocortical)

- Low dopamine/hypodopaminergic
- Dec activity from VTA (Ventral Tegmental Area) to dorsolateral pre frontal cortex
- See lots of the negative sx and cognitive sx

Which brain pathways are being affected with dopamine modifying drugs that are not desired?

- Nigrostriatal
- Tuberoinfundibular (Prolactin)

Nigrostriatal pathway is associated with what AE of Schiz tx

Usually see problems in movement when blocking dopamine here (bc mvnt coordination blocked)
- EPS
- Tartative dyskenesia
- Parkansonism like sx

Tuberoinfundibular pathway is associated with what AE of Schiz tx?

- Problems with prolactin release from pituitary gland/endocrin problems
- gyencomastia
- galactorea
- breast secretions

What changes with glutamate do you see in schiz pts and w/ which receptor?

- Low glutamate state, leading to inc in Pos and Neg sx!
- involved in neuronal dev and regulating dopamine signal
- the NMDA receptor is involved

What effects are seen in a pt in a hyperglutamic state (from taking PCP)

- Cells are excitotoxic
- develop psychosis

What changes with Serotonin do you see for the hypothetical treatment of schiz pts in what SPECIFIC areas of the brain and which receptor is involved?

- 5HT 2A Receptor is Inhibited leads to inc dopamine release in certain parts of the brain (Mesocortical and Nigrostriatal)

What effect is seen with inc in serotonin seen in the Mesocortical pathway (inhibiting what receptor also)?

- inhibit 5HT2A receptor = inc serotonin
- Improved cognitive function
- Dec in (-) sx

What effect is seen with inc in serotonin seen in the Nigrostriatal pathway (inhibiting what receptor also)?

- Inhibit 5HT2A receptor = inc serotonin
- Dec EPS side effects! (Extrapyramidal)

What are the two classes of antipsychotics that are used in schiz and what schiz sx do they effect via what general MOA?

First Gen/Typical Antipsychotics (Dop only)
- Dec Positive sx: Block D2 receptors in LIMBIC pathway

Second Gen/Atypical Antipsychotics (Serotonin and Dop)
- Dec Positive Sx: Block D2 in LIMBIC pathway
- Blocking 5HT2 receptors: Improvement in Neg/affective/cognitive sx

List of First Generation/Typical Antipsychotics (W/ specific suffix) (10)

Most have -azine suffix bc they are in Phenothiazine drug class
- Chlorpromazine (Thorazine)
- Perphenazine (Trilafon)
- Fluphenazine (Prolixin)
- Haloperidol (Haldol)
- Thioridazine (Mellaril)
- Trifluoperazine (Stelazine)
- Thithixene (Navane)
- Meseoidazine (Serentil)
- Loxapine (Loxitane)
- Molindone (Moban)

What are the list of the Second Generation/Atypical Antipsychotics (11, technically 12)

- Clozapine (Clozaril)

- Risperidone (Risperdal)
- Olanzapine (Zyprexa)
- Quetiapine (Seroquel)
- Ziprasidone (Geodon)
- Aripiprazole (Abilify)
- Paliperidone (Invega)
- iLLoperidone (Fanapat)
- Asenapine (Saphris)
- Lurasidone (Latuda)
- Brexpiprazole (Rexulti)
- Cariprazine (Vraylar)

When the patient is being treated for schiz, what sx are relieved in 1-2 days?

- Agitation, Hyperactivity, combativeness, hostility
(basically not afraid for staff safety, still scared for pt safety, they can at least communicate now)

When the patient is being treated for schiz, what sx are relieved in 1-2 weeks?

- Hallucinations, sleep, appetite, hygeine, social skills, some delusions
- not full relief but more like not as preoccupied with them that it affects/controls their actions)

When the patient is being treated for schiz, what sx are relieved in 1-2 Months?

- Delusions
- Gain judgement, insight and abstract thinking aka better view on themselves and their disease

**What is the definition of a Response in Schiz tx**

- 20 to 50% dec in pos or neg sx over 4 weeks
- Evident by BPRS or PANNS (lower # = better) scores
- PANNS score for refactory vs acute, sx pts
- dec 25% = refractory response
- dec 50% = acute, sx pts response

what is the definition of a partial response in schiz tx

- partial dec in pos or neg sx over 12 weeks (3 months)

What is the definition of no response in schiz tx

- no dec in pos or neg sx in 3 to 4 weeks

Which Schiz drugs Antagonize the D2 receptor for their MOA?

Trick question, Basically all of them do!

What schiz drugs Antagonize the 5HT2C receptor for their MOA?

- Clozapine (Clozaril)
- Olanzapine (Zyprexa) 2nd gen
- Norquetiapine
- Ziprazidone (Geodun) 2nd gen
- Asenapine (Saphris) 2nd gen

Which schiz drugs Antagonize 5HT2A receptor for their MOA?

All the second generation ones
Loxapine (Moban)

List the High Potency Typical Antipsycotics

- Fluphenazine (Prolixin)
- 2 mg Haloperidol (Haldol)

What characteristics do the High Potency Typical Antipsychotics have?

The effective dose = mosttimes the EPS causing dose so expect it
- Exclusively bind to the D2 Receptor
- INC risk of EPS
- Inc risk of Akathisia too

List the low potency typical antipsychotics

- Mesoridazine (Serentil) 50 mg
- Thioridazine (Mellaril)
- Chlorpromazine (Thorazine) 100 mg

What characteristics do the Low Potency Typical antipsycotics have?

- Dec risk of EPS (compared to high potency)
- We use higher doses more often and see * inc in alpha 1 (orthostasis), Muscarinic 1 (Constipation) and Histamine 1 (Confusion) receptor* so get other AEs

List the mid potency Typical Antipsychotics

- Thioxthixene (Navane) 4 mg
- Trifluoperazine (Stelazine) 5 mg
- Pherphenazine (Trilafon) 8 mg
- Loxapine (Loxitane)
- Molindrone (Moban) 10 mg

Chlorpromazine (Thorazine) Initial Dosing

10 to 25 mg TID

Chlorpromazine (Thorazine) Usual Range

100 to 800 mg

Thioridazine (Mellaril) initial dose

50 to 100 mg TID

Thioridazine (Mellaril) Usual range

100 to 800 mg

Mesoridazine (Serentil) initial dose

50 mg TID

Mesoridazine (Serentil) usual range

100 to 400 mg

Loxapine (Loxitane) initial dose

10 mg BID

Loxapine (Loxitane) usual range

60 to 100 mg

Molindone (Moban) initial dose

50 to 75 mg day

Molindone (Moban) usual range

40 to 100 mg

Perphenazine (Trilafon) initial dose

4 to 8 mg TID

Perphenazine (Trilafon) usual range

12 to 64 mg

Trifluoperazine (Stelazine) Initial dose

2 to 5 mg BID

Trifluoperazine (Stelazine) usual range

- 15 to 20 mg

Thiothixene (Navane) initial dose

5 to 10 mg/day

Thiothixene (Navane) usual dosing

15 to 20 mg

Fluphenazine (Prolixin) initial dose

0.5 to 10 mg/day

Fluphenazine (Prolixin) usual range

2 to 20 mg

Haloperidol (Haldol) initial dose

1 to 15 mg/day

Haloperidol (Haldol) usual range

2 to 20 mg

Which antipsychotics would you avoid in a patient with an already long QT interval?

- Ziprasidone (Geodon), 2nd gen
- Haloperidol (Haldol), 1st gen
- Thioridazine (Mellaril) 1st gen, BBW
- Chlorpromazine (Thorazine) 1st gen

Which antipsychotics would you avoid in patient with a movemnet disorder (parkinsons)

High risk of EPS drugs:
- Risperidone (risperidal)
- Paliperidone (Invega)

All first generations, high binding are the worst
- Haloperidol (Haldol)
- Fluphenazine (Prolixin)

Which antipsychotics would you avoid in Overweight patients?

- Olanzapine
- Clozapine (Clozaril)
- Quetiapine (Seroquel)

All the AEs for First Generation Antipsychotics

EPS (Extrapyramidal Sx)
- Dystonia, Akathisia, Pseudoparkinsonism, Tardive Dyskinesia, Neuroleptic Malignant Syndrome

Cardiovascular:
- Inc QT interval
- Orthostatic Hypotension (mostly low potency)

Endocrine/metabolic:
- High prolactin

CNS/ANS:
- Seizures
- Antihistamine effects
- Anticholinergic effects
- Antimuscarinic effect: Hard to regulate body temperature

Blood dyscrasia

AEs specific to/much worse in Chlorpromazine

- Photosensitivity: sun exposure = blue/grey tint, may be reversible
- Cornea Deposits/Change in pigmentation (reversible)
- Choleostatic Jaundice
- Super Inc Risk Seizures
- Higher risk of orthostatic hypotension (Alpha 1 blocker)

AE specific to Thiordazine

- Pigmentary Retinopathy: dose dependent and NOT reversible

Which first gen Antipsychotic has a BBW for prolonging the QT interval?

-** Thioridazine (Mellaril) **
- Mesoridazine (Serentil)
- Haloperidol (Haldol) IV specifically

What is EPS?

Extrapyramidal Symptoms: Drug induced movements that are from blocking dopamine in an unintended area

What are the acute s/sx of Acute EPS?

- Dystonia
- Akathisia
- Pseudoparkinsonism

What are the chronic s/sx of EPS?

- Tardive Dyskinesia

What s/sx is an EPS Emergency?

- Neuroleptic Malignant Syndrome
- Loringal dystonia (close off throat)

What is Dystonia, what is the onset and who is at risk?

Sustained uncontrollable muscular contractions in any part of the body:
- like a charlie horse in leg
- really rigid and cant move in the direction you want

Fast: 24 to 96 hrs after initial dose or dose change

Risk:
- younger males
- High potency D2 blockers, esp at high doses (Haloperidol (Haldol) and Fluphenazine (Prolixin))

What are the treatments for Dystonia?

1st: Anticholinergics IM/IV
- Diphenhydramine 50 mg
- Benztropine 2 mg

2nd Line: Benzos (Muscle relaxant)
- Lorazepam 2 mg IM
- Diazepam 5-10 mg IV push

Why are anticholinergics first line treatment for Dystonia?

- because there is an imbalance btwn dopamine and ACh (too much)
- Block the excess ACh to restore the balance

What are the 4 cardinal s/sx of Parkinson’s that would be seen in Pseudoparkinsonism, when dos it appear in schiz tx and who is at inc risk?

- Hypertonia (too much muscle tone)
- Shuffling gait w/ no arm movement (abnormal gait)
- Bradykinesia/Akinesia (slow purposeful movements, not much emotion in face (bc cant get muscles to move in face))
- *Slow resting tremor*

seen first 1-3 months of treatment

at risk:
- inc age
- high doses of first generation
- hx parkinsons
- hx basal ganglia injury

Why does Pseudoparkinsonism sx happen in patients using antipsychotics?

- bc block overactive dopamine in nigral stratal system (when trying to block the overactive in limbic pathway with first generation drugs)

What is the treatment of Pseudoparkinsonism and when do sx resolve once tx starts

Decrease dose or switch drug
Use Benzotropine (Cogentin) a highly anticholinergic drug
or one of the following drugs:
- Biperiden
- Procyclidine
- Trihexyphenidyl
- Diphenhydramine
- Amantadine LAST LINE (compete w/ antipsychotic and make psychosis worse)

sx resolve 3-4 days after tx

What is Akathisia and who is at inc risk

- patient has creepy crawly feeling and cant sit still (internal and motor restlessness)

Inc risk:
- high potency typicals (Haloperidol (Haldol) and Fluphenazine (Prolixin))
- Using ssris Esp Fluoxetine bc stimulating

What is the treatment for Akathisia?

Dec Dose
Switch Drug

Use Non specific Beta Blocker:
- *Propranalol (Inderal)* Great bc get into CNS
- Metoprolol (Lopressor)

Use Benzo if BP too low for Beta Blocker:
- Lorazepam (Ativan)
- Clonazepam (Klonopin)

Use anticholinergic drug ONLY if concomitant parkinsonism present

What is Tardive Dyskinesia, when is the onset?

- Combo of tongue twisting/protrusion, lip smacking, puckering and lateral jaw movements in a stereotypical manner (rhythmic manner)

Long Term use SE (many months to years)
- 20% year rate if taking typical
- inc 5% risk w/ each year using typical (1% w/ atypical)
- 5% chance in newly diagnosed
- 8% cases irreversible

Pathophis of Tardive Dyskinesia

1. D2 receptors are constantly being blocked in the nigrostriatal pathway (off site effect)
2. The receptors are upregulated
3. Cells are hypersensitive to dopamine effects

Who is at risk for tardive dyskinesia

- inc age
- Female gender
- Chronic Antipsychotic use: Duration of therapy and cumulative/lifetime dose!

Prevention of Tardive Dyskinesia

Any signs of TD switch drug!
- 1st gen to 2nd gen
- 2nd gen to low risk 2nd gen (Clozapine, Quetiapine (Seroquel))

Which drugs do you use if want to avoid TD or have parkinsons?

- clozapine
- Quetiapine (Seroquel)

Treating Tardive Dyskinesia drug list

- Reserpine
- Tetrabenazine (Xenazine) VMAT2 inhibitor
- Vitamin E

List of VMAT2 Inhibitors

- Tetrabenzine
- Duetetrabenazine
- Valbenazine

MOA of VMAT2 Inhinitors

Inhibits VMAT 2 (Vesicular monoamine transporter 2)
- So inhibit breakdown of the vesicles.
- This decreases the release of dopamine and monoamine oxidase breakdown of dopamine
- Non specific inhibtion of VMAT2

NORMAL function of VMAT2

- Depletes storage of dopamine (prevent go into vesicle)
- Then allows continual degredation of NT within the synapse so less dopamine

What are the AEs of VMAT2 inhibitors?

- Parkinsonism (bc effects dopamine)
- Depression (bc effects serotonin)

What is NMS?

Neuroleptic Malignant Syndrome
- Severely rigid muscles and inc temperature

S/Sx associated with NMS (need at least 2 for dx)

- LEAD PIPE rigidity
- Cant regulate temperature (high fever and sweating)
- Diaphoresis
- Dysphagia
- Tremor
- Incontinence
- Change in consciousness
- Mutism
- Inc or dec in BP
- Leucocytosis
- Inc CPK/Urinary Myoglobin (muscle breakdown) could lead to AKI!

Clinical presentation of moderate NMS

- Moderate rigidity confusion or catatonia
- inc temp at least 38 to 40 C
- HR 100 to 120 BPM

Treatment for Moderate NMS

1st Line Treatment:
- *Benzos (Lorazepam)*
- Bromocriptine (Dopamine agonist)
- Amantadine

can use these drugs as a combo too

Clinical presentation of Severe NMS

- Severe rigidity
- Catatonia or coma
- Temp at least 40 C
- HR at least 120

Supportive care for moderate to severe NMS

- dec offending drug
- fluids
- cooling measures
- put into ICU
- correct risk factors