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The atypical antipsychotics (also known as second generation antipsychotics) are a class of prescription
medications used to treat psychiatric conditions. All atypical antipsychotics are FDA approved for use in the treatment of
schizophrenia. Some carry FDA approved indications for acute mania, bipolar mania, psychotic aggitation, bipolar
maintenance, and other indications.
History
The first atypical antipsychotic medication, clozapine, was discovered in the
1950's, and introduced in clinical practise in the 1970's. Clozapine fell out of popularity due to concerns over drug induced
agranulocytosis. With research indicating its effectiveness in treatment-resistant schizophrenia and the development of an
adverse event monitoring system, clozapine reemerged as a viable antipsychotic. Despite the effectiveness of clozapine for
treatment resistant schizophrenia, agents with a more favorable side effect profile were sought after for widespread use. During
the 1990s, olanzapine, risperidone, and quetiapine were
introduced, with ziprasidone and aripiprazole following in the early 2000's.
The atypical antipsychotics have found favor among clinicians and are now considered to be first line treatments for
schizophrenia and are gradually replacing the typical
antipsychotics. Most researchers agree that the defining characteristic
of an atypical antipsychotic is the decreased propensity of these agents to cause extrapyramindal side effects and an absence of
sustained prolactin elevation.
Pharmacology of the Atypicals
The mechanism of action of these agents is unknown, and likely differs to some extent among the various drugs within the
class. Indeed, the receptor binding profile of the atypical antipsychotics varies quiet substantiably, and this variability may
be responsible for clinical differences, such as patient response and side effect profile. While modulation of the dopamine
neurotransmitter system is necessary for antipsychotic activity, the role of the serotonergic activity of the atypicals is
debated. Some researchers believe that D2 receptor antagonism, coupled with 5-HT2A receptor antagonism, is responsible for the
"atypicality" of atypical antipsychotics. Others believe that fast dissociation (a fast Koff) from the D2 receptor, allowing for
better transmission of normal physiological dopamine surges, better explains the pharmacological evidence.
Side Effects
The side effects reportedly associated with the various atypical antipsychotics vary and are medication specific. Generally
speaking, atypical antipsychotics are associated with less extrapyramidal side effects and less propensity for the development of
tardive dyskinesia than the typical antipsychotics.
Metabolic Side Effects with Atypical Antipsychotics
Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the FDA required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the
risks of hyperglycemia and diabetes with atypical antipsychotics. It must also be pointed out that all though all atypicals must
carry the warning on their labeling, some evidence shows that all atypicals are not equal in their effects of weight and insulin
sensitivity.
The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased
insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest
effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the
older agents.
The issue of metabolic side effects such as hyperglycemia with these medicaitons is somewhat clouded by the fact that
drug-naive schizophrenics also appear to have an increased incidence of impaired glucose metabolism. The question is whether the
increased risk for diabetes and hyperglycemia a function of the disease state of schizophrenia, or whether these metabolic
effects are the result of adverse medication side effects. It is probably an interaction involving both of these factors that is
responsible for the observations of increased adverse metabolic events in patients taking atypical antipsychotics.
Atypical medications
- Clozapine (Clozaril®) Available only in oral tablets
- Olanzapine (Zyprexa®) Available in oral tablets, dissolving
tablets, and intramuscular injection.
- Quetiapine (Seroquel®) Available only in oral tablets.
- Risperidone (Risperdal®) Available in oral tablets, dissolving
tablets, and extended release intramusclar injection.
- Ziprasidone (Geodon®) Available in oral capsules and
intramuscular injection.
- Aripiprazole (Abilify®) Available only in oral tablets.
- Sertindole (Serlect®, Serdolect®) (Not approved by
the FDA for use in the USA)
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