Typical Antipsychotics

What do they act on in the CNS? (Give neuron, and 4 specific neuronal pathways)

They are dopamine D2 receptor blockers

Affected Dopaminergic Pathways:

1. Nigra-striatal

2. Mesolimbic

3. Mesocortical

4. Tubero-infundibular

A. Nigro-Striatal Track

Function(s)?

Effects of low DA in this track?

Activity in schizophrenics?

Effect of typical antipsychotic on this track?

Track regulates movement

Low DA here = Parkinsonism

Nigrostriatal pathway functions normally in schizophrenics

Typical antipsychotic (D2 antagonist) acts on nigro-striatal path to cause Extra-pyramidal symptoms:

Parkinsonism

Akathisia

Dystonic reactions

Tardive dyskinesia is possible

Neuroleptic Malignant Syndrome

Involved in pleasure sensations, drugs of abuse

Mesolimbic activity is HIGH in Schizophrenics:

Thought to mediate the positive symptoms of Schizophrenia (hallucinations)

D2 Antagonists (Typical Antipsychotics) cause a reduction in positive symptoms, but also unpleasant/uncomfortable mood (dysphoria) and lack of reward/pleasure response

C. Mesocortical Pathway

Function(s)?

Activity in schizophrenics?

Effect of typical antipsychotic on this track?

Involved in emotional response and motivation

Mesocortical activity is low in untreated schizophrenics, responsible for the negative emotional/social/cognitive symptoms

Typical antipsychotics decrease DA, so they further lower mesocortical activity, making negative symptoms worse!

D. Tuberoinfundibular pathway

Function(s)?

Activity in schizophrenics?

Effect of typical antipsychotic on this track?

Normal function is to inhibit the release of prolactin

Pathway is normal/unaffected in schizophrenics

typical antipsychotics results in hyperprolactinemia, w/ assoc. side effects:

galactorrhea

amenorrhea

sexual dysfunction

Antipsychotics/Neuroleptics

Extra-pyramidal symptoms

Cause/pathway affected

3 acute levels of symptoms

1 late-onset symptom

Caused by antipsychotics blocking DA nigro-striatal pathway

Acute:

Dystonia within 4 hours (muscle spasm, stiffness, oculogyric crisis)

Parkinsonism within 4 days (parkinsonian symptoms)

Akathisia within 4 weeks (restlessness)

Late Onset:

Tardive Dyskinesia:

usually after 4 months

Involuntary repetitive movements,

generally irreversible

Dystonia - give anticholinergics

Akathisia - give anticholinergics or beta blockers

Parkinsonism - anticholinergics, or

amantadine (a DA agonist) - because Dopamine suppresses Ach effects

Antipsychotics

Anticholinergic side effects (5)

Constipation

Dry mouth

Blurred vision

Drowsiness

Confusion/Impaired cognition

Weight gain

Drowsiness

Decreased BP

dizziness

drowsiness

Low potency, have to increase the dose to get effective anti-dopamine effect, results in non-specific neuro side effects (Anticholinergic/histaminergic/alpha-adrenergic)

High potency will result in EPS side effects and Prolactin elevation (both directly due to low dopamine)

High = Haloperidol

Mid = Perphenazine (like Purgatory)

Low = Chlorpromazine (like chlorine that's down in the pool)

Atypical Antipsychotics

Closapine:

3 indications for use

How is it therapeutic?

Significant side effect(s)?

Indications:

1. treatment-resistant schizophrenia

2. schizophrenia w/ tardive dyskinesia

3. schizophrenia or schizoaffective disorder w/ recurrent suicidal behavior

Therapeutic value:

Treats positive symptoms, and improves negative/cognitive symptoms as well

Also, much lower incidence of EPS and TD

Side effect: Agranulocytosis, a life-threatening drop in WBC count

Dont use if you have a pre-existing blood disorder, and blood monitoring the entire time patient is on the drug

Serotonin inhibits the effects of dopamine in some places (i.e. the Nigro-striatal tract)

...so 5HT inhibition by atypical antipsychotics will increase dopamine in the nigrostriatal, resulting in a decrease in EPS symptoms

(and Serotonin doesn't act in the mesocortical and mesolimbic pathways, so the anti-DA effects still occur here as in treatment with typical neuroleptics)

Abilify

Its a D2 partial agonist (its also a 5HT antagonist)

As a partial agonist, arapiprazole reduces the stimulation of the mesolimbic pathway (reducing pos symptoms), provides some stim to the mesocortical pathway (reduce neg symptoms), and does not overstimulate the nigrostriatal pathway (so no EPS)

Side effects are Metabolic:

Weight gain

Hyperlipidemia

Hyperglycemia, diabetes, ketoacidosis

araprazole treatment results in less metabolic side effects than clozapine or olanzapine, but may also be less efficacious

(olanzapine is most effective and worst for wt gain)