Schizophrenia caused by increased dopamine transmission in the brain (based on fact that effectiveness of typicals correlates with blocking dopamine receptors) 

Hallucinations are also a side effect of L-DOPA therapy in Parkinsons

DA levels in subcortical areas of the brain were found to be twice as high in schizophrenic patients compared to controls 

Nigrostriatal Pathway (extrapyramidal nervous and controls nervous and controls motor function)

Mesolimbic (midbrain VTA --> nucleus accumbens); thought to be overactive

Mesocortical (midbrain VTA --> cortex); though to be underactive --> apathy, withdrawal, lack of motivation, and pleasure

Tuberoinfundibular pathway: hypothalamus --> anterior pituitary (decreases prolactin secretion) 

Haloperidol, Fluphenazine

EPS - high

Anticholinergic - low non neurologic side effects

Perphenazine 

Medium EPS and anti-cholinergic effects

Chlorpromazine and Thioridizine

Low EPS, High anti-cholinergic effects

High extrapyramidal symptoms compared to atypicals

Enhancement of negative symptoms by blocking reward symptoms of mesolimbic system 

Ability to cause effective and long lasting blockade of dopamine D2 receptors in all dopaminergic pathways, leading to undesirable effects

Involuntary contractions of face, neck, tongue, and extraocular muscles 

Will respond to anticholinergics or diphenhydramine (Benadryl has anti-muscarinic properties)

Low potency antipsychotics with significant anticholinergic effects are LESS likely to cause acute dystonia 

Akinesia, muscle rigidity, tremor, shuffling gate (due to blockade of nigrostriatal pathway)

Must be treated with anticholinergics or amantadine

Motor restlessness and urge to move

Reduce dose, treat with propranolol

May be treated with benzodiazepines (increase GABA) **Gaba B receptor agonist; baclophen to reduce muscle spasticity**

Late onset and sometimes irreversible

exposed to antipsychotics 3 months or longer 

Involuntary movements of lips, face, tongue, and limbs

Due to supersensitivity of dopamine receptors in caudate

Treated by reducing dose, discontinuing drug, or switching to an atypical

Patients with dystonia are more likely to develop tardive dyskinesia 

Blockade of alpha -- orthostatic hypotension, male sexual dysfunction

Blockade of muscarinic - constipation, dry mouth, urinary retention, and visual problems 

Blockade of histamine and muscarinic receptors - sedation

Blockade of dopamine D2 in pituitary - increased prolactin --> galactorrhea and amenorrhea 

Weight gain (atypicals more)

Decreased seizure threshold

Thioridazine retinal deposits and arrhythmias

Neuroleptic malignant syndrome - similar to malignant hyperthermia, extreme muscle rigidity, dystonia, akinesia, agitation, hyperthermia, and autonomic instability 

Increased WBC count and creatinine phosphokinase

Rx: Dantrolene and dopamine agonists like bromocriptine 

Comparatively low extrapyramidal symptoms

Effective for both positive and negative symptoms relative to typicals which mostly only treat positive 

Serotonin antagonist at 5HT2A receptors

D2 antagonists with rapid dissociation

Dopamine D2 partial agonist (only aripiprazole)

1) Reduction of EPS symptoms

2) Reduction of negative symptoms

3) Reduction of positive symptoms

4) Inhibiton of prolactin release 

Stimulation of 5HT2A normally inhibits dopamine release (directly or through GABA release) 

Inhibition of 5HT2A will enhance dopamine release which will compete with atypical at D2 receptor

Since there is competition, there are less extrapyramidal effects 

Still a substantial block of D2 receptors in mesolimbic system, but is somewhat attenuated due to this effect 

Schizophrenics have decreased dopaminergic activity in prefrontal cortex (responsible for some negative symptoms)

Blockade of 5HT2A will increase dopamine from mesocortical (originating in VTA) neurons terminating in prefrontal cortex

Density of dopamine D2 receptors in the prefrontal cortex is low relative to the striatum so the ratio of 5HT2A to D2 blockade is large and the serotonin effect predominates 

Pyramidal cells in cortex have glutamate and project back to dopaminergic cell bodies in mesolimbic pathway in mesolimbic pathway 

Blocking 5HT2A blocks gluatmate which indirectly inhibits mesolimbic system which reduces positive symptoms 

May be possible to attenuate overactivity in mesolimbic pathway while minimizing side effects of dopamine blockade 

Aripiprazole

Causes signal transduction to be intermediate between full output and zero output 

Maybe could attneuate signal transduction at DA D2 mesolimbic pathway and simulate in nigrostriatal pathway 

Generally decreased APS and decreased anti-cholinergic effects

Cardiometabolic risk

Sedation 

Blockade of both histamine and 5HT2C receptors in hypothalamus will cause an increased appetite - increased intake - increased triglycerides, insulin resistance, diabetes, and CV events 

Some atypicals will elevate these without any relation to increased weight gain

Monitor weight, waist circumference, glucose, lipids, and triglycerides 

Olanzapine, Clozapine

Quetiapine second 

All of them cause weight gain doe 

Many antipsychotics will block muscarinic, histamine, and alpha adrenergic receptors 

Blockade of these receptors will cause sedation and somnolence 

May be preferrable early on but later on can cause cognitive impairment 

Atypical

Can be effective in patients who don't respond to other treatment

Big side effect is agranulocytosis - WBC need to be monitored, therefore only reserved for patients who really don't respond to anything else

Also causes a large increase in salivation and seizures 

Cardiac arrhythmia and has risk of death

Rare side effect due to prolongation of QT interval by inactivation of fast acting delayed rectifier channels 

May lead to torsades arrhythmia 

Problem in higher doses and older patients 

Only one to cause hyperprolactinemia

Also will cause EPS at higher doses 

Newer atypical drugs like quetiapine (decreased EPS) 

Generally patients that suffer from acute dystonia with typical antipsychotics will be more likely to get tardive dyskinesia 

Typicals: Fluphenazine, halperidol

Atypicals: Risperidonze, Ziprasidone