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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 agitation, bipolar maintenance, and other indications.
The first atypical antipsychotic medication, clozapine, was discovered in the 1950s, and introduced in clinical practice in the 1970s. 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 2000s.
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 extrapyramidal 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 quite 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.
There is extensive evidence that atypical antipsychotics have less of an affinity for D2 receptors and more of an affinity for the D4 receptors. This is primarily because atypical antipsychotics are somewhat less likely to cause tardive dyskinesia. The idea is that D2 receptors are dopaminergically ubiquitous and affect the motor system as much as the motivational aspect of the dopamine system. On the other hand, D4 is a more accurate dopamine receptor subtype. Atypical antipsychotics also affect the norepinephrine, acetylcholine, and histamine receptors of various subtypes. 
All of the atypical antipsychotics warn about the possiblity of tardive dyskinesia. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time.
Still, it is safe to say that the atypicals will probably not cause tardive dyskinesia as often as older anti-psychotics do. However, the atypicals "may cause serious metabolic disorders, e.g., diabetes, frequently enough to make them equally dangerous" as the older anti-psychotic drugs.
The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are associated with fewer extrapyramidal side effects and less propensity for the development of tardive dyskinesia than the typical antipsychotics. In 2004, the Committee for the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone should not be given to elderly patients with dementia, because of an increased risk of stroke.
The main advantage to taking atypical antipsychotics over older anti-psychotics such as Haldol is the decreased rise of developing tardive dyskinesia. However, all of the atypical antipsychotics warn about the possiblity of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks.
Still, it is safe to say that the atypicals will probably not cause tardive dyskinesia as often as older anti-psychotics do. However, the atypicals may cause serious metabolic disorders to make them equally dangerous as the older anti-psychotic drugs.
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 although 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 medications is somewhat clouded by the fact that drug-naïve schizophrenics also appear to have an increased incidence of impaired glucose metabolism. The question is whether the increased risk for diabetes and hyperglycemia is 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 antipsychotic medications
- Clozapine (Clozaril®) (FDA-approval: 1990) Available only in oral tablets.
- Risperidone (Risperdal®) (FDA-approval: 1993) Available in oral tablets, dissolving tablets, liquid form, and extended release intramusclar injection.
- Olanzapine (Zyprexa®) (FDA-approval: 1996) Available in oral tablets, dissolving tablets, and intramuscular injection.
- Quetiapine (Seroquel®) (FDA-approval: 1997) Available only in oral tablets.
- Ziprasidone (Geodon®) (FDA-approval: 2001) Available in oral capsules and intramuscular injection.
- Aripiprazole (Abilify®) (FDA-approval: 2002) Available only in oral tablets.
- Sertindole (Serlect®, Serdolect®) (Not approved by the FDA for use in the USA).
- Zotepine (Not approved by the FDA for use in the USA).
- Amisulpride (Not approved by the FDA for use in the USA).
Psycholeptics: antipsychotics (N05A)
|Phenothiazine typical antipsychotics||Chlorpromazine • Fluphenazine • Mesoridazine • Perphenazine • Prochlorperazine • Promazine • Thioridazine/Sulforidazine • Trifluoperazine|
|Other typical antipsychotics||Indoles (Molindone) • Butyrophenones (Azaperone, Benperidol, Droperidol, Haloperidol) • Thioxanthenes (Flupentixol, Chlorprothixene, Thiothixene, Zuclopenthixol) • diphenylbutylpiperidines (Fluspirilene, Penfluridol, Pimozide) • other (Loxapine)|
|Atypical antipsychotics||Butyrophenones (Melperone) • Indoles (Sertindole, Ziprasidone) • Benzamides (Sulpiride, Remoxipride, Amisulpride) • diazepines/oxazepines/thiazepines (Clozapine, Olanzapine, Quetiapine) • other (Aripiprazole, Risperidone, Paliperidone, Zotepine)|
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