Asenapine 50 Iloperidone 51 Sertindole 52

The pharmacological mechanisms underlying the 'atypical' clinical properties of clozapine as well as the other newer antipsychotic agents have been richly debated. Since the major recognized benefit of these 'atypical' drugs appears to be a reduction in EPS liability and hyperprolactinemia, it was proposed that the differences in EPS liability of the older and newer antipsychotic drugs lie in the degree of DA receptor occupancy. According to this view, the older antipsychotic drugs are thought to more completely and persistently occupy the D2 receptor at efficacious concentrations than do atypical antipsychotic drugs. If so, a simple reduction in drug concentrations/dosage of these older drugs should, therefore, lead to emergence of the atypical profile. Thus drugs like haloperidol, thioridazine, or perphenazine should have atypical clinical profiles at low doses and typical clinical profiles at higher doses. However, this is not the case. Even at very low doses, drugs like haloperidol induce very different neurochemical effects in rodent, primate, and human brain than do drugs like clozapine. Further, in the patients with Parkinson's disease who experience psychotic episodes, and who have an already compromised DA system, even very low doses of thioridazine, the first-generation drug with the fewest motor side effects in schizophrenia, induces EPS. In addition, most atypical antipsychotics other than clozapine and quetiapine may cause EPS in Parkinson's patients at low doses and in non-Parkinson's patients in a dose-dependent manner. Rarely, cases of neuroleptic malignant syndrome and tardive dyskinesia have also been reported with these agents, suggesting that even agents like olanzapine and risperidone may cause too much and persistent D2 receptor occupancy in vulnerable individuals, e.g., those with inherently weak dopaminergic function. Clozapine and quetiapine, because of their low binding affinity, dissociate rapidly from the D2 receptor, which may account for their tolerability in Parkinson's disease patients. This property appears to occur independent of dose, and may thus preserve clinically 'atypical' properties of clozapine, quetiapine, and other atypical agents, even at high doses. However, under the 'fast dissociation' model, risperidone would be reclassified as not being atypical, and some first-generation agents (loxapine, molindone) would be considered pharmacologically atypical. The uniqueness of the atypical antipsychotic drugs must be driven by biological processes that add to or counteract some of the influences of strong D2 receptor blockade of the typical antipsychotic drugs. Higher antagonist affinity at the 5HT2A receptor relative to the D2 receptor has been proposed to distinguish atypical from typical antipsychotic drugs.12 More recently, nearly all compounds with antipsychotic activity have been characterized as potent and efficacious 5HT2A inverse agonists (i.e., they turn off the intrinsic basal activity of the receptor). Furthermore, 'atypical' antipsychotic drugs that can occupy D2 receptors (e.g., clozapine, olanzapine, risperidone, and ziprasidone) are unique in having higher potency as 5HT2A inverse agonists than as DA antagonists. This correlation strongly indicates that 5HT2A inverse agonism can predict the 'atypical' nature of these kinds of antipsychotic drugs. These antipsychotic drugs occupy > 70-80% of cortical 5HT2A receptors, while occupancy of the striatal D2 receptors is much less. There also may be important differences between typical and atypical drugs in striatal D2 receptor occupancy relative to extrastriatal D2 receptor occupancy. Recent PET studies56 have shown that these compounds also occupy fewer D2 receptors in the ventral tegmental/substantia nigra, thalamic and limbic areas of the brain that contain the cell bodies of the DA neurons which project to the limbic system and cortex, and caudate-putamen, respectively.

Typical antipsychotic drugs appear to preferentially interact with striatal D2 receptors while atypical antipsychotic drugs have a complex pattern of effects on extrastriatal D2 receptors, as noted above. Consistent with the above receptor binding interactions, atypical antipsychotic drugs appear to preferentially increase DA release in rat prefrontal cortex relative to the nucleus accumbens. The reverse is true for typical antipsychotic drugs. This differential neurochemistry largely is attributable to 5HT2A antagonism, 5HT1A agonism, and weak D2 antagonism. In the striatum, antagonism of 5HT2A receptors located on dopaminergic neurons may release these cells from serotonergically mediated inhibition. The end result may be preservation of striatal dopaminergic tone and a reduction in EPS liability.

Thus, 5HT2A and D2 receptor interactions are shared by all atypical antipsychotics and the combined interaction with these two receptors is sufficient to drive the antipsychotic efficacy against positive symptoms while maintaining a low risk for inducing EPS and hyperprolactinemia. Recent meta-analyses of randomized controlled trials have suggested that atypical antipsychotics are also superior to typical antipsychotics in improving negative symptoms, although the difference is slight. The superiority for improving cognitive deficits is larger and more robust. As alluded to earlier, animal studies have shown that 5HT2A antagonism may increase DA efflux in the prefrontal cortex and hippocampus, key brain regions associated with cognitive functioning. They have lesser effect on DA efflux in the limbic system. Thus, 5HT-DA interactions may contribute to the relative success of atypical agents for improving cognitive and deficit symptoms that were beyond the reach of first-generation medications. Some thought leaders, however, believe this advantage does not reflect an absolute improvement in cognitive or negative symptoms as much as a lack of impairment in these symptoms due to treatment with first-generation antipsychotic drugs. What is certain is that most of these atypical agents do not normalize function in these domains and patients still have residual deficits that call for a more effective treatment.

It also is important to note that while atypical antipsychotic drugs are relatively free of EPS liability and hyperprolactinemia, treatment with this class of drugs results in other serious side effects associated with their use. These adverse events are thought to be unrelated to the interactions with the 5HT2A and D2 receptors but more to the polypharmic or 'dirty' nature of these compounds22 and their propensity to interact with many off-target receptors, including but not limited to the H1 (sedation, obesity), 5HT2C (obesity), muscarinic M1 (blurry vision, dry mouth, constipation, urinary retention, cognitive dulling, and other mental status changes in susceptible individuals), muscarinic M2 and M3 (modulation of parasympathetic tone), and a1A (orthostasis, reflex tachycardia) receptors. Adverse events observed in association with the use of atypical agents in clinical trials include, in addition to the above effects, hypersalivation (clozapine only), sweating, hypotension, myocarditis (clozapine), syncope, gastrointestinal complaints including constipation and nausea, and drug-induced fever. Olanzapine and clozapine are associated with increased weight gain, changes in adiposity, dyslipidemia, induction of insulin resistance (potentially progressing to type 2 diabetes mellitus), and, rarely, pancreatitis. Quetiapine and risperidone are considered to be more intermediate with regard to dysmetabolic risk, while ziprasidone and aripiperazole appear to be relatively free of these side effects. The most significant safety concerns with clozapine are the occurrence of seizures and agranulocytosis in some patients. Currently, the occurrence of clozapine-induced agranulocytosis is estimated to be 0.8% at 1 year and 0.91% at 18 months. While potentially fatal, morbidity and mortality due to agranulocytosis resulting from clozapine administration have been dramatically reduced by careful blood monitoring and the use of colony cell stimulating factors. Unlike the idiosyncratic occurrence of clozapine-associated blood dyscrasias, seizure risk appears to be dose related. Certain antipsychotic medications appear to affect other excitable tissues. For instance, the atyipal antipsychotics ziprasidone, iloperidone, and sertindole prolong the corrected QT interval (QTc); however, there is as yet no evidence that routine clinical use of ziprasidone is associated with the development of potentially fatal arrhythmias such as torsade de pointes. Several first-generation antipsychotic agents are also known to prolong the QTc interval, including thioridazine, mesoridazine, droperidol, pimozide, and haloperidol (in large intravenous doses).

What is the clinical impact of having 5HT2A inverse agonism/antagonism in addition to D2 antagonism? Does this combination merely reduce the consequences of high D2 receptor occupancy or does this combination expand the therapeutic domains available to treatment? These questions can be answered by the use of combination strategies wherein relatively pure D2 antagonists are combined in various proportions with relative pure 5HT2A antagonists. A low dose of mirtazapine, a 5HT2A antagonist, significantly reduced the acute akathisia produced by high doses of typical antipsychotics.57 Additionally, in normal healthy volunteers and rodents, 5HT2A inverse agonists/antagonists have been shown to reduce high dose haloperidol-induced increases in prolactin secretion. The addition of mianserin, a combined 5HT2A/2C and a2-adrenoceptor antagonist, to first-generation antipsychotic treatment in stabilized schizophrenic patients was associated with improvements in neurocognitive performance. What remains to be determined is whether 5HT2A inverse agonism/antagonism can expand the treatment domains of low dose treatment with typical antipsychotics and atypical antipsychotics with 'too much' D2 antagonist activity. A number of hurdles face this combination approach, including determining the correct ratio of 5HT2A to D2 receptor occupancy, pharmacokinetic and metabolism issues, etc. Solving these problems could provide a new approach to treating psychosis and a means to avoid the side effects caused by off-target activities of existing atypical antipsychotics. Flexibility in selecting the optimal 5HT2A to D2 ratio would be an advantage of a combination approach that could not be achieved with a single molecule having a fixed intrinsic ratio.

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