The Atypical Surrealist Second Generation Antipsychotics

5.2 – “The Atypical surrealist”: Second generati generation on ant antipsychotics ipsychotics (o (olanzapine, lanzapine, quetiapine, ari aripiprazole, piprazole, ziprasid ziprasidone, one, risperidone, cl clozapine) ozapine) Historical note: surrealism was a cultural movement developed in the aftermath of World War I, best known for juxtaposing uncommon imagery to create scenes to unnerving or illogical effect. These works drew on dreams and the unconscious as means of expressing a surrealist philosophy. Salvador Dalí was a Spanish Surrealist renowned for technical skill, precision, and striking and bizarre imagery in a variety of visual art forms. Themes prevalent in his work include dreams, the subconscious, sexuality, religion, science, and his personal relationships. Now on to the medical stuff. Atypical an antipsychotics tipsychotics • Clozapine is the prototype (closet). Quetiapine, olanzapine, risperidone, aripiprazole, ziprasidone (“Quiet please, only whispering appropriate”; zippered dress). • MOA o SGAs block 5HT-2A receptors, which are key in modulating release of both excitatory and inhibitory NTs including dopamine, glutamate, GABA, NE, ACh release in the CNS (block cut out of serotonin cake). Serotonin signaling is also often involved in psychoactive substance use, e.g. LSD – a serotonin agonist (these paintings are pretty trippy) o Like FGA, block postsynaptic D2 receptors in the mesolimbic & striatofrontal system, although effect is less than in the FGAs (snapping double rope with D-rings). MOA is not completely understood; the degree of blockade of D2 receptors does not necessarily correlate to effects at other receptors throughout the body. • Indications o As with FGAs, primary indication is schizophrenia. SGAs are more effective in treating negative symptoms (devil and angel can both be heard; and that mustache – no flat affect here). o Adjunctive treatment for treatment resistant depression (difficulty opening wine bottle with masks) o risperidone can be combined with SSRIs for refractory OCD (person fixing crooked panel of Millet’s The Angelus; Dali was obsessed with this painting) o Motor tics of Tourette’s (funky marionette). • Adverse effects o Cause fewer of the “typical” extrapyramidal effects seen with FGAs, hence “atypicals” (newspaper hat patron). Of the SGAs, risperidone highest risk (person whispering, asking disruptive patron to leave) ▪ Elevated prolactin d/t Tuberoinfundibular D2 blockade (laughing milk out nose). Much more of a problem than with FGAs. Downstream effects include inhibition of GnRH release, resulting in central hypogonadism (galactorrhea, amenorrhea, impotence, ↓libido) ▪ Neuroleptic malignant syndrome (“Now More Spicy” chicken). More common FGAs but can be seen with any antipsychotic meds. • Lead pipe rigidity • Altered mental status, fever, autonomic instability (patron being intrusive, may have altered mental state) • Rhabdomyolysis (eating chicken). Watched for elevated CK. • Treatment: Dantrolene (mm relaxant). Blocks RyR and prevents further release of calcium into muscle fibers o H1 antagonists → sedation (bee swatter); especially clozapine & quetiapine o Orthostatic hypotension d/t α 1 antagonism (extinguished α candle); accompanied by tachycardia, especially in the first days of treatment or with increased doses. May be severe enough to warrant changing medication. o Antimuscarinic action (tea party painting): dry mouth, constipation common; blurred vision, urinary retention less common. Result from inhibition of central and peripheral muscarinic receptors. Clozapine has highest affinity (painting behind closet). Less antimuscarinic affinity than FGAs (partly obscured painting) o Unlike FGAs, can have significant metabolic syndrome: ▪ Weight gain (fat face). Mechanism not totally clear; evidence for ↑appetite & altered metabolism ▪ Dyslipidemia (elevated melting butter) ▪ Hyperglycemia (candy filled landscape) ▪ All SGAs cause to varying degrees (clozapine & olanzapine most, ziprasidone) (gal in zippered dress looking pretty slim) o QT prolongation, increasing risk for torsades des pointes (twisted streamers). Hypothesized to be d/t direct inhibition of cardiac potassium channels. o Clozapine specifically is infamous for the following, although others may cause as well (The Persistence of Memory inspired painting on closet) ▪ Agranulocytosis (hourglass). Absolute neutrophil counts must be routinely monitored. If ANC < 1500, change agents (has been reported in other SGAs as well) ▪ Fatal myocarditis or cardiomyopathy (surrealist heart) ▪ Lowered seizure threshold (shaking alarm clock). Also seen to lesser degree with other SGAs.