Atypical Antipsychotics & Schizophrenia

These are second generation antipsychotics. The first atypical antipsychotic, clozapine (Clozaril®, Novartis), was approved by the FDA in 1990 and is now considered to be the most effective therapy for treatment-resistant (refractory) schizophrenia. Currently, four other atypical antipsychotics are also available in the United States. Atypical antipsychotics can be generally defined as a class because they block both serotonin and dopamine receptors. The dual action of atypical antipsychotics enables them to retain their antipsychotic benefits while reducing some of the side effects seen with pure D2 antagonists (i.e., typical antipsychotics).

Three key features of atypical antipsychotics are that they:

• block serotonin 2A (5-HT2A ) receptors and D2 receptors
• cause fewer EPS than typical antipsychotics
• are as effective as typical antipsychotics for treating positive symptoms and may be more effective for treating negative and cognitive symptoms

One theory as to how atypical antipsychotics work is that they simultaneously exert two opposing effects on dopamine neurons:

• Like typical antipsychotics, atypical antipsychotics block D2 receptors on dopamine neurons.
• Atypical antipsychotics also block 5-HT2A receptors on dopamine neurons.

Normally, when serotonin binds with 5-HT2A receptors it acts like a brake and inhibits dopamine release. Thus, when atypical antipsychotics block 5-HT2A receptors, they remove this brake and cause increased dopamine release. This increased release of dopamine partly counteracts the D2-blocking properties of atypical antipsychotics. All atypical antipsychotics work in this way, playing a kind of tug-of-war — blocking dopamine receptors while increasing dopamine release. And, depending on the particular dopaminergic pathway in the brain on which they are acting, atypical antipsychotics consequently avoid some of the adverse effects associated with pure D2 receptor antagonism. In the mesocortical pathway, the ability of atypical antipsychotics to block 5-HT2A receptors and increase dopamine levels may help explain why these agents improve negative symptoms better than some typical antipsychotics. As atypical antipsychotics block 5-HT2A receptors and increase dopamine levels in the nigrostriatal pathway, the partial reversal of their antagonism of D2 receptors may be why atypical antipsychotics have a reduced incidence of EPS compared with typical antipsychotics. Atypical antipsychotics are not completely devoid of the ability to cause EPS, as is seen with risperidone when used at higher doses. In fact, while typical antipsychotics block about 90% of D2 receptors and cause EPS, atypical antipsychotics block less than 70% to 80% of D2 receptors, a level that is high enough to relieve psychotic symptoms but low enough to avoid EPS in many patients. Similarly, atypical antipsychotic blockade of 5-HT2A receptors in the tuberoinfundibular pathway may reverse D2 antagonism enough to prevent the release of prolactin. As a result, some atypical antipsychotics do not cause hyperprolactinemia, thereby avoiding side effects such as sexual dysfunction.

What are the Atypical Antipsychotics available in the US?

• Abilify (aripiprazole, BMS)
• Risperdal (Risperidone, Janssen-Cilag)
• Clorazil (Clozapine, Novartis)
• Serequel ( quentiapine, AstraZeneca)
• Zyprexa (olanzapine, Eli Lilly)
• Geodon (ziprasidone, Pfizer)

What are the adverse Effects Associated with Atypical Antipsychotics?

Despite these basic principles, many other factors affect the pharmacology of atypical antipsychotics, making them different from one another in efficacy and adverse effects. For example, some atypical antipsychotics (e.g., risperidone) begin to lose their atypical properties at higher doses and may therefore cause EPS. In addition, the five approved atypical antipsychotics vary in their effects not only on various dopamine and serotonin receptor subtypes, but on other receptors (including alpha1 and alpha2 noradrenergic, cholinergic, and histaminergic receptors). These varying actions can cause adverse effects similar to those seen with typical antipsychotics. In addition to the potential adverse effects mentioned above (e.g., hyperprolactinemia), some atypical agents may also cause:

• weight gain
• sedatio
• anticholinergic side effects
• orthostatic hypotension
• tachycardia (increased heart rate)
• QTC prolongation
• seizures

In addition, recent evidence suggests that some atypical antipsychotics may raise triglyceride and total cholesterol levels. Atypical antipsychotics may also increase the risk of glucose intolerance and new-onset diabetes mellitus. As a result, some researchers now recommend that patients receiving atypical antipsychotics particularly clozapine, olanzapine, and possibly quetiapine be monitored for changes in glucose metabolism and lipid profiles every 3 months.