98/99. Schizophrenia, Antipsychotics

Question 1

What is the difference between:
Psychosis
Delusion
Hallucination
Thought Disorder

Answer 1

Psychosis: disturbance in perception/understanding of reality; not a dx but a SIGN (like pain/fever)

Delusion: firmly held, “fixed” false believe, bizarre (violates laws of physics) or non-bizarre (plausible in reality)

Hallucination: any modality (auditory, visual, tactile, olfactory, gustatory, propioceptory)

Thought Disorder: disorder in FORMATION of thought - evident in speech/behavior

Question 2

What is the DSM 5 Dx Criteria for Schizophrenia?

Answer 2

2+ symptoms w/ marked impairment in functioning, for >6mo

Sx:
Positive: Delusions, Hallucinations, Disorganized Speech, Disorganized/Catatonic Behavior
Negative: Apathy, Flat affect, Alogia, Anhedonia

Question 3

What are signs of schizophrenia on imaging (MRI, DTI) and pathology?

Answer 3

Imaging: enlargement of ventricles (size correlates to poorer outcome)
MRI: volume/shape changes to interior brain (thalamus, hippocampus)
DTI: loss of integrity to white matter tracts in frontotemporal regions (network dysfx)

Path: volume loss w/o reduced #neurons, may have impaired neuronal migration, changes in interneurons, dendritic spines, neuronal support structures

Question 4

What are the genetics of schizophrenia? What is the epidemiology?

Answer 4

Genetics: 16p11.2: 25 genes for neuron differentiation, migration, plasticity - involved in schizophrenia
1/3 cases are genetic

Epidemiology
biggest RF: genetics
Enviro RF: fetal hypoxia/birth trauma, maternal infections, winter birth month, low SES, stress, smoking cannabis(?)

Question 5

What are the four pathways of DA in the CNS and which is clinically useful in schizophrenia tx? What happens when these are blocked?

Answer 5

1. Mesolimbic pathway: from VTA to limbic system (Emotion, Motivation, Goals) - blocking this causes increased indifference to tx shizophrenia
2. Nigrostriatal pathway: from VTA to BG (fine movement) - blocking causes tardive dyskinesia (involuntary movment of fingers/tongue) and parkinsonism
3. Mesocortical pathway: from VTA to Frontal Cortex (Cognition) - blocking could WORSEN cognitive sx (poor SE)
4. Tuberoinfundibular Pathway: hypothalamus to ant pituitary (inhibits prolactin) - blocking causes more prolactin release = galactorrhea, gynecomastia, sex dysfx, amenorrhea

Question 6

What is the common antipsychotic mechanism of action?

What is the difference between efficacy and potency?

What does it mean for an antipsychotic to be highly potent? Which antipsychotic has the best efficacy?

Answer 6

Mechanism: Mesolimbic D2 Block (block DA signaling)

Efficacy: ability to achieve desired clinical effect
Potency: measure of how much med is needed to achieve clinical effect

High mesolimbic D2 affinity = high potency = less med needed to achieve desired efficacy

Clozapine BEST efficacy

Question 7

Chlorpromazine

• mechanism
• effects
• SE

Answer 7

Mech

• blocks alpha1: reverses EPI
• blocks DA: antiemetic, more catalepsy, MORE INDIFFERENCE (KEY)
• blocks AChR: atropine-like
• blocks Histamine: prevented bronchospasm

Effects: less agitation, emotional intensity, interest to enviro. (more indifference)
Delayed: less hallucinations, delusions, disordered thinking

SE: Less cognition (block DA in mesocortical path)
Hypotension, Dizziness, Sedation (a1 block)
Sedation Weight Gain (histamine block)
Memory/Cognitive Deficits, dry mouth, urine retention, tachycardia, blurred vision, hyperthermia (antimuscarinic block)

Question 8

Haloperidol

• mech
• SE

Answer 8

mech: ONLY blocks DA (selective for D2R) = high potency = greater affinity for D2R

SE: parkinsonism, less cognition, more prolactin (galactorrhea), akathesia (sensation of inner restlessness)

Question 9

Clozapine

• mechanism
• SE
• use

Answer 9

Mechanism

• A1 block (reverse EPI)
• DA block (anti-emetic, MORE INDIFFERENCE)
• ACh block (anti-muscarinic)
• Histamine block (prevent bronchospasm)

SE: NO CATALEPSY (blocks 5HT and DA receptors - “atypical” by removing movement SEs
Agranulocytosis (fatal neutropenia)

Use: 3rd line agent for schizophrenia, decreases suicidal behavior

Question 10

Risperidone

• mechanism
• type
• SE

Answer 10

Mechanism: combo of pure 5HT and pure DA block = lacks movement SE (blocks 5HT&raquo_space; DA)
Type: Atypical Antipsychotic (2nd gen)
SE: related to relative receptor affinity

Question 11

What are the SE of the following atypical antipsychotics?

• Olanzapine and Quetiapine
• Ziprasidone
• Aripiprazole
• Lurasidole
• Paliperidone

Answer 11

Olanzapine/Quetiapine: weight gain, sedation, metabolic dysfx
Ziprasidone: QT prolongation
Aripiprazole: (3rd gen) partial DA agonist
Lurasidole: tolerable
Paliperidone: active Risperidone metabolite

Question 12

Ketamine and Phencyclidine (PCP)

• effects
• mechanism
• potential new schizo tx?

Answer 12

Effects: induce schizo-like effects
Mech: NMDA Antagonists; reversed by NMDA agonists

Glutamate Hypothesis

• NMDA involved in neuronal development and plasticity
• NMDA antagonists cause psychosis, reversed by NMDA agonists
• NMDA must modulate DA release (possible tx avoids cognitive SE of DA blockers)

Question 13

Non-Pharm tx of Schizo

What is schizoaffective disorder and schizophreniform disorder?

Answer 13

• ECT
• Community Management
• CBT
• Supported Employment
• Family/Caregiver Education
• Substance Abuse Tx

Schizoaffective Disorder: psychosis with prominent mood sx (mood sx come and go while psychosis persists)

Shizophreniform Disorder: <6mo (shorter state)