Pharmacotherapy of Schizophrenia

Question 1

What are antipsychotics?

Answer 1

chlorpromazine (CPZ) was the first “neuroleptic” drug

drugs affecting pathological behavior

contributed directly to medicalization of mental illness

recognition of mental illness as a consequence of an underlying biological deficit

Question 2

What are the anti-cholinergic side effects of CPZ?

Answer 2

acetylcholine is the major neurotransmitter of the parasympathetic nervous system

dry-mouth, blurred vision, constipation, weight gain

Question 3

What are the anti-histaminergic side effects of CPZ?

Answer 3

sedative and anti-emetic effects

Question 4

What are the anti-adrenergic side effects of CPZ?

Answer 4

lowered blood pressure, tachycardia, vertigo, incontinence, sexual dysfunction

Question 5

What are the anti-dopaminergic side effects of CPZ?

Answer 5

antipsychotic effects (positive symptoms)

extrapyramidal side effects

Question 6

What is the first versions of dopamine hypothesis of schizophrenia?

Answer 6

schizophrenia results from excessive dopaminergic activity specifically in the mesolimbic pathway

Question 7

What are the dopaminergic pathways?

Answer 7

nigrostriatal system: projects from substantia nigra and ventral tegmental area to striatum (caudate and putamen)

tuberoinfundibular system: projects from the medial eminence to the pituitary

mesolimbic/mesocortical system: projects from the ventral tegmental area to the limbic system, nucleus accumbens, mesial frontal, anterior cingulate, and entorhinal cortex

Question 8

What are the mesolimbic dopaminergic pathways?

Answer 8

primary target of antipsychotics

targets enriched in D1/D5, D2/D3 receptors

corticolimbic connections are proposed to mediate memory, learning, and affect (and corresponding deficits in SCZ)

the nucleus accumbens is proposed to act as a gating mechanism to protect consciousness from excess stimuli (internal and external)

Question 9

What are the D1 and D2 family receptors?

Answer 9

D1 and D2 family receptors are G-protein coupled receptors

D1 and D2 receptors oppose each other

dopamine plays a role in modulating information in the brain, with the balance between D1 and D2 acting as a gating mechanism

Question 10

How does the nucleus accumbens interact with schizophrenia?

Answer 10

mesolimbic dopamine is proposed to mediate salience

motivational salience: addictions
sensory salience: sensory gating

excess dopamine activity leads the patient to perceive voices, sounds, and imagery as inappropriately salient

false significance assigned to internal and external stimuli are interpreted as delusions and hallucinations

Question 11

What is the activity of dopamine in schizophrenia?

Answer 11

dopamine levels in post-mortem SCZ brains are elevated in the striatum

PET and SPECT imaging of dopamine receptors show increased basal levels of dopamine

basal dopamine levels are predictive of responsiveness to antipsychotic therapy

BUT hypoactivity of dopamine seen in cortex

dopamine hypothesis version 1 and therapy only address positive symptoms

Question 12

What are the extrapyramidal side effects of decreased dopamine?

Answer 12

akinesia: inability to initiate movement

akathisia: inability to remain motionless

acute dystonia: sustained muscle contraction, twisting and repetitive movements

pseudo parkinsonism: fixed (non-progressive) Parkinsonism without degeneration of dopaminergic neurons

tardive dyskinesia: involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy

Question 13

How do dopaminergic pathways cause extrapyramidal side effects?

Answer 13

degeneration of dopaminergic neurons in the nigrostriatal system central to the pathophysiology of Parkinson’s disease: tremors, rigidity, forward-flexed posture and shuffling steps, bradykinesia (slowed movement)

antipsychotic blockade of D2 receptors in striatum is responsible for extrapyramidal side-effects

dopamine in the tuberoinfundibular pathway suppresses the release of prolactin from the pituitary

hyperprolactinemia can result from antipsychotic treatment

Question 14

What is the second version of the dopamine hypothesis?

Answer 14

schizophrenia results from a combination of subcortical dopaminergic hyperactivity and cortical dopamine hypoactivity

Question 15

What are the revisions to the dopamine hypothesis?

Answer 15

many studies conflate psychosis with schizophrenia: psychosis is certainly associated with dopamine dysregulation, but is only one feature of schizophrenia

dopamine dysregulation and psychosis represent the cumulative result of genetic and environmental changes to neurobiology and neurochemistry: other neurotransmitters implicated in circuit changes upstream to mesolimbic dopamine

current antipsychotic treatment focus on the downstream changes in dopamine and fail to address the primary abnormality

antipsychotics target postsynaptic dopamine signaling while dopamine dysfunction likely emerges due to aberrant presynaptic regulation

presynaptic dopamine also likely lies downstream of other neurotransmitter and circuit changes

Question 16

What is the third version of the dopamine hypothesis?

Answer 16

schizophrenia results from combined genetic and environmental insult resulting in altered neurodevelopment, including subcortical dopaminergic hyperactivity and psychosis

Question 17

What are atypical antipsychotics?

Answer 17

atypical antipsychotics (e.g., clozapine, risperidone, quetiapine) are those having activity at sites other than D2 receptors

common binding sites include 5-HT2A receptors

atypical antipsychotics often have reduced extrapyramidal side-effects and are more effective against negative symptoms (than typical antipsychotics)

aripiprazole is a partial agonist at D2 receptors: increase signaling at D2 receptor system with low dopaminergic tone, reduce signaling at D2 receptor system with high dopaminergic tone

Question 18

What is the glutamate (NMDA receptor) hypothesis in schizophrenia?

Answer 18

antagonists (ketamine, phencyclidine) of the NMDA receptor produce positive and negative symptoms and frontal cognitive deficits

haloperidol increases NMDA receptor density and extracellular glutamate concentrations

elevated glutamate levels are reported in patients taking antipsychotics

multiple genetic risks associated with excitatory synaptic function

oral administration of glycine (NMDA receptor co-agonist) reported to improve negative symptoms in patients

Question 19

How is NMDA involved in schizophrenia in animal studies?

Answer 19

NMDA receptor-1 partial deletion causes behavioral abnormalities in mice

consistent phenotypes to PCP treatment

NMDAR-1 mice respond to typical (haloperidol) and atypical (clozapine) antipsychotics

haloperidol treatment ameliorates hyperactivity (proxy for positive symptoms)

clozapine treatment ameliorates hyperactivity and social deficits (proxy for negative symptoms)

Question 20

What is the postmortem evidence for the glutamate hypothesis?

Answer 20

postmortem analysis from chronic SCZ patients has shown decreased glutamate (relative to control tissues) in hippocampus and prefrontal cortex

increased activity of glial glutamate transporters has been observed in post-mortem tissue from SCZ patients

Question 21

What are GABA deficits in schizophrenia?

Answer 21

GABA is the primary inhibitory neurotransmitter in the CNS

GABA receptors are ligand gated Cl- channels that hyperpolarize the target membrane on activation

deficits in glutamic acid decarboxylase (GAD) have been identified in the prefrontal cortex in SCZ patients