Schizophrenia

Question 1

List the cognitive functions of the prefrontal cortex, including working memory, integration of sensory data, and development and execution of action plans.

Answer 1

Interconnected with cortical and subcortical regions processing sensory information

Prioritizes and integrates highly processed and complex info
o Regulates executive function
o Classic example = Phineas Gage

Components:
1) Dorsolateral: (purple →)
• Working/short-term memory
• Planning/prioritizing/multi-tasking
• Behavioral flexibility/shifting responses
2) Orbitofrontal (medial prefrontal) (green →)
• Affective/emotional regulation

Question 2

List the emotional and social functions of the prefrontal cortex.

Answer 2

• Modulates emotions

* Put “brakes” on feelings/ apply reason to emotion

Question 3

Describe the cognitive dysmetria hypothesis

Answer 3

Schizophrenia symptoms come from disruption of neural network involving PFC, anterior cingulate gyrus, thalamus, temporal cortex, and cerebellum

Question 4

Describe the roles of the temporal lobe, prefrontal cortex, and dopaminergic systems in the etiology of schizophrenia

Answer 4

Schizophrenia has dysfunction in 3 systems:
Prefrontal cortex
• Dysfunction of dorsolateral PFC → thought disorder (disorganization, preservation, can’t formulate/sustain plans)
• Dysfunction of orbitofrontal PFC → emotional blunting and/or lability

Temporal lobe (lateral surface of temporal cortex, amygdala, hippocampus)
• Merges all sensory input
• Regulates info-processing, sensory perception, memory & emotion
• Involved in complex perceptual processes
• Important for regulating emotionally laden info
• Activated during hallucinations
• Electrical stimulation → vivid memories, auditory hallucinations
• Dysfunction → psychosis (hallucinations, paranoia, delusion, perceptual abnormalities

Dopamine Systems:
1) Mesocorticolimbic Pathway = Ventral Tegmental Area → PFC, accumbens, temporal lobe, subcortical limbic structures
• Widespread distribution
• Regulates thought and perception:
o DA agonists → psychosis (hallucinations, paranoia, attention abnormalities)
o DA (D2 receptors) antagonists → anti-psychotics (reverse symptoms); normalize schizophrenia
• Need optimal levels for cognitive function
• Dysfunction (excess DA) → psychosis (hallucinations, paranoia, delusion, perceptual abnormalities
2) Nigrostriatal Pathway = substantial nigra → forebrain
• Involved in motor movement

Question 5

Explain the role of genetic and neurodevelopmental factors in schizophrenia.

Answer 5

Strong genetic component:
o	Neuregulin 1
o	Dysbindin
o	COMT
o	BDNF

Neurodevelopmental 
Intrauterine (especially in 2nd trimester)
•	Maternal influenza
•	Maternal starvation 
Cannabis use during adolescence 

Brain abnormalities:
• Ventricular enlargement (Shows atrophy; Not specific)
• Temporal lobe reduction (Not enough for severity of symptoms)
• Cytoarchitectural changes in temporal and frontal regions = Crucial part (Morphology, location and orientation of neurons disorganized)

Psychosocial factors:
o Low SES
o Higher relapse in families with high expressed emotions

Question 6

Differentiate among the positive, negative and cognitive symptoms of schizophrenia.

Answer 6

Positive:
o	Delusions (persecutory; thought broadcasting, insertion or withdrawal; delusion of passivity)
o	Hallucinations (especially auditory)

Negative:
o Flat affect
o Diminution of thought and speech (alogia)
o Difficulty initiating and persisting in goal-directed activities (avolition)

Cognitive:
o Disorganized speech and behavior
o Decreases in overall cognitive function (IQ)

Question 7

Recognize the substance­ and medication- induced and other medical etiologies of psychosis.

Answer 7

Medical conditions:
o Neurological disorders: temporal lobe epilepsy
o Neurodegenerative disorders: Wilson’s disease, Huntington’s disease
o Neoplasia: brain tumor
o Nutritional disorder: B12 deficiency
o Infection: neurosyphilis
o Autoimmune: SLE
o Toxicity: heavy metal poisoning
o DiGeorge syndrome = deletion in chromosome 22q

Substance-induced:
o	Stimulants: amphetamine, cocaine
o	Hallucinogens
o	Antiparkinsonian meds
o	Anticholinergics 
o	Withdrawal from alcohol, benzodiazepine, barbiturates

Question 8

Schizophrenia: Epidemiology

Answer 8

o Mean age onset: 21
o High risk of suicide: 10-15%
o Higher rates of violence
o Account for 1% of population, but smoke 25% of cigarettes in U.S.

Question 9

Schizophrenia: pathophysiology

Answer 9

Cognitive dysmetria hypothesis

Loss of inhibition of DA neurons:
• Hyperactivity of PFC → disinhibition of VTA → hyperactivity of DA in mesocorticolimbic pathway
• A feed-forward cycle

Question 10

Schizophrenia: prognosis

Answer 10

Prodrome phase
• Lasts months to years
• Subtle symptoms of psychosis: social withdrawal, loss of interest in school/work, deterioration in hygiene or grooming, unusual behavior, outbursts of anger

Active phase
• Develops over weeks to months
• Requires medication intervention

Later course = highly variable:
• Residual phase: minimal symptoms, mildly impaired functioning
• Chronic, severe course
• Intermediate outcomes

Predictors of poor outcomes:
• Lower pre-morbid intelligence
• Male gender
• Earlier age of onset
• Presence of negative and cognitive symptoms
• Presence of structural brain abnormalities
• Long prodrome
• Absence of mood symptoms
• Presence of obsessions/compulsion
• Presence of neurological soft signs (poor coordination, right/left confusion, gait impairment)
• Family history of schizophrenia
• Individuals in industrialized nations (vs. developing nations)

Question 11

Schizophrenia: psychotropic medications

Answer 11

Antipsychotics:
o Treat psychosis, especially positive symptoms
o 1st line: atypical antipsychotic
o Typical antipsychotics = used less often because more side effects
o Clozapine = If severe or refractory

Side effects:
• Metabolic
• Extrapyramidal (dystonia, tremor, akathisia, dyskinesia)
• QT prolongation, sudden cardiac death
• Neuroleptic malignant syndrome: mental status changes, rigidity, fever, autonomic instability

Question 12

Schizophrenia: psychotherapy

Answer 12

Cognitive therapy
o Address psychosis
o Focuses on changing delusional thoughts or response to them

Psychosocial rehabilitation
o Address functional consequences of psychosis
o Combines medical treatment with teaching basic living skills
o Reintegrates into society

Family psychoeducation
o Improve family support and communication
o Reduces relapses

Treat comorbid conditions
o Ex: substance use disorder, mood disorders

Question 13

List the typical antipsychotics

Answer 13

Chlorpromazine

Haloperidol

Question 14

List the Atypical Antipsychotics

Answer 14

Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone

Question 15

Describe the theories and evidence supporting the use of different antipsychotics

Answer 15

Dopamine hypothesis:
o Disorder is result of excess DA activity
Evidence:
• D2 receptor blockade correlates with therapeutic potency
• Drugs that increase DA activity aggravate psychotic symptoms
• Ex: cocaine, amphetamine
• PET scans and brain analysis show increased DA receptor density
• Successful treatment decreases levels of DA metabolites in CSF, plasma, and urine

5-HT hypothesis:
o Disorder is result of excess 5-HT activity
Evidence:
• 5-HT2A partial agonists = hallucinogens, produce perceptual and cognitive changes
• Atypical antipsychotic agonists are inverse agonists at 5-HT2A receptors
• 5-HT2A receptors modulate DA release in cortex, limbic areas, and striatum

Glutamate hypothesis
o Disorder from glutamate hypofunction
Evidence:
• Noncompetitive NMDA antagonists induce positive, negative, and cognitive symptoms in healthy patients & exacerbate symptoms in patients
• Increased glycine (promotes glutamate binding to NMDA receptors) improves negative and cognitive symptoms
• 5-HT2A partial agonists inhibit NMDA mediated transmission in cortex

Question 16

Describe the mechanisms of action of typical and atypical antipsychotic drugs

Answer 16

o Typical: D2 receptor antagonist

o Atypical: more potent 5-HT2A receptor antagonists, but still have D2 affinity

Question 17

Summarize the pharmacokinetics of oral and parenteral (including depot) administration of antipsychotic drugs and state when parenteral or depot formulations might be used.

Answer 17

• Well-absorbed orally
• Lipid soluble
• Require liver metabolism before elimination
• Long plasma half-lives = once daily dosing (P450 inhibitors prolong the half-life)

Parenteral forms:
o Rapid initiation of therapy
o Depot treatment = improve compliance

Question 18

List the major side effects of the typical and atypical antipsychotic drugs and the mechanisms underlying those side effects

Answer 18

Extrapyramidal symptoms (EPS)
o Acute dystonia: spasms of tongue, face, neck, back muscles; onset hours-to-days; TX with anticholinergic drugs for 4-7 days
o Parkinsonism: bradykinesia, tremors, shuffling gait; onset 5-30 days; TX with anticholinergic drugs, usually resolves after a few months
o Akathisia: uncontrollable urge to be in motion; pacing, restlessness; onset 5-60 days; TX with anticholinergics, benzodiazepines, beta blockers
o Tardive dyskinesia: worm-like twisting movements of tongue, mouth, and face; onset months-to-years, no reliable TX, often irreversible

Neuroleptic malignant syndrome (~ 0.2%; onset weeks-to-months)
o Mental changes: Agitated delirium, progressing to lethargy, stupor, coma; patient appears dazed and disoriented
• Incoherent speech, becomes mute
o “Lead-pipe” rigidity, tremor
o Hyperthermia > 38 °C
o Autonomic instability: Tachycardia, labile blood pressure, diaphoresis

Anticholinergic effects
Orthostatic hypotension
Sedation
Hyperprolactinemia via D2 receptor blockade in pituitary
o	Can lead to sexual dysfunction 
Seizures (< 1%, but clozapine 3-5%)
Sexual dysfunction
Dermatoses, photosensitivity
Cardiac dysrhythmias (QT prolongation)
Metabolic effects
o	Weight gain
o	Hyperlipidemia
o	Insulin insensitivity, elevated blood glucose
Agranulocytosis: clozapine

Question 19

List conditions other than schizophrenia for which antipsychotic drugs are also useful

Answer 19

• Delirium and dementia with psychotic features
• Disruptive behaviors associated with autism or mental retardation
• Emesis
• Acute mania
• Intractable hiccups
• Tourette’s syndrome, tics
• As adjuncts to uptake inhibitors for anxiety disorders
• As adjuncts to uptake inhibitors for major depression

Question 20

Describe the clinical presentation, course and risks of neuroleptic malignant syndrome, and contrast it with serotonin syndrome

Answer 20

• ~ 0.2%; onset weeks-to-months (differentiates from Serotonin syndrome)

Mental changes
o Agitated delirium, progressing to lethargy, stupor, coma; patient appears dazed and disoriented
o Incoherent speech, becomes mute

• “Lead-pipe” rigidity, tremor
• Hyperthermia > 38 °C
• Autonomic instability: Tachycardia, labile blood pressure, diaphoresis

Treatment:
o	Stop drug
o	Give dopamine agonists
o	Benzodiazaphine
o	Dantrolene: block Ca2+ channels in skeletal muscle

Question 21

Describe the unique adverse effect of clozapine that has limited its use

Answer 21

• Agranulocytosis (bone marrow not make WBCs)

* Seizures at high doses