Atypical antipsychotic drugs: Part 1.

This is the second of two columns on atypical antipsychotic drugs. Part II discusses olanzapine, quetiapine, and ziprasidone. Olanzapine (Zyprexa) Since evidence continues to accrue implicating numerous neurotransmitter pathways, antipsychotics with broader effects are sought. Olanzapine appears to affect the glutamate system and can prevent the schizophrenic signs and symptoms typically induced by N-methyl-D-aspartate (NMDA) receptor antagonists PCP or ketamine (Tollefson, 1997). Olanzapine is similar to clozapine in receptor affinity, antagonizing 5[HT.sub.2], [D.sub.2], [D.sub.1], and [D.sub.4] receptors significantly. It is thought to target mesolimbic and mesocortical systems over the nigrostriatal system (Allan, Sison, Alpert, Connolly, & Crichton, 1998). Olanzapine has affinity for muscarinic, [H.sub.1] and alpha-1 receptors, accounting for moderate anticholinergic effects, significant sedation, and weight gain (Ganguli, 1999; Sussman & Ginsberg, 1999; Wirshing et al., 1999), and mild levels of orthostasis. Other side effects include nausea, lightheadedness, dizziness, headache, and akathisia (Bever & Perry, 1998; Tran et al., 1997). It causes few extrapyramidal side effects (EPSEs) and is not thought to produce tardive dyskinesia. Though transient increased levels of prolactin have been reported, those levels are not long lasting (Jibson & Tandon, 1998). Unlike clozapine, olanzapine is not a significant risk for agranulocytosis, though anecdotal reports confirm some instances of this disorder. A number of studies support the overall effectiveness of olanzapine in treating schizophrenia, and it often is the drug used when patients have treatment-ending reductions in WBCs related to clozapine (Breier & Hamilton, 1999; Conley et al., 1998; Tollefson et al., 1997). Further, olanzapine has proven effective for treating acute mania (Tohen et al., 1999) and is the only atypical drug FDA approved for monotherapy for bipolar disorder. In a large study (N = 1,996) at multiple sites, when compared to haloperidol, olanzapine was significantly more effective for negative symptoms, had fewer EPSEs and other side effects, was safer, and did not cause significant elevations of prolactin (Tollefson et al.). Further, these individuals continued to manifest a positive clinical effect during a 1-year study extension. These patients demonstrated a statistically higher score on a quality-of-life scale than did patients treated with haloperidol. Pharmacokinetically, olanzapine is conducive to compliance due to its relatively long half-life of 21-54 hours and is suitable for one-per-day dosing. It can be used across gender, ethnicity, and age groups (Tollefson, 1997). Though metabolized by the CYP-450 isoenzymes 1A, 2D6, and 2C, olanzapine has few significant interactions. Typical dosage is 5-40 mg/day, and an intramuscular formulation is anticipated. Quetiapine (Seroquel) Quetiapine was developed as an answer to the clozapine dilemma (i.e., clozapine is an effective drug with a life-threatening side effect). Quetiapine is similar to clozapine pharmacodynamically but does not cause agranulocytosis (Green, 1999; Hustey, 1999; Peuskens & Link, 1997). Several studies indicate quetiapine has a greater affinity for 5[HT.sub.2] receptors (58%-72% occupancy) than for dopamine [D.sub.2] receptors (27%-44% occupancy), at about the same occupancy ratio as clozapine (Borison et al., 1996; Green, 1999; McManus et al., 1999; Parsa & Bastani, 1998; Small et al., 1997). As with other atypicals, this occupancy ratio is thought to be instrumental in the low incidence of EPSEs for quetiapine. For example, Green found a 44% occupancy of striatal [D.sub.2] receptors (threshold occupancy for EPSEs ~80%). These and other studies have shown quetiapine to significantly antagonize alpha-1 adrenoreceptors with a less significant blockade of alpha-2 and muscarinic receptors (Hustey, 1999; Peuskens & Link, 1997, Saller & Salama, 1993). …