The atypical antipsychotics (also known as second generation antipsychotics) are a group of
antipsychoticdrugs used to treat psychiatric conditions. Some 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.
Atypicals are a group of unrelated drugs united by the fact that they work differently from
typical antipsychotics. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. One drug, amisulpride, does not have serotonergic activity, instead it has some partial dopamine agonism. Another drug, aripiprazole, also displays some partial dopamine agonism, 5-HT1A partial agonism and 5-HT2A antagonism. [Abilify package insert at [http://packageinserts.bms.com/pi/pi_abilify.pdf http://packageinserts.bms.com/pi/pi_abilify.pdf] ]
The first atypical anti-psychotic medication,
clozapine, was discovered in the 1950s, and introduced in clinical practice in the 1970s. Clozapine fell out of favor 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 quetiapinewere introduced, with ziprasidoneand aripiprazolefollowing in the early 2000s. The newest atypical anti-psychotic, paliperidone, was approved by the FDA in late 2006.
The atypical anti-psychotics have found favor among clinicians and are now considered to be first line treatments for schizophrenia and are gradually replacing the typical
antipsychotics. In the past, most researchers have agreed that the defining characteristic of an atypical antipsychotic is the decreased propensity of these agents to cause ExtrapyramidalSide Effects [EPS] cite journal |author=Farah A |title=Atypicality of atypical antipsychotics |journal=Prim Care Companion J Clin Psychiatry |volume=7 |issue=6 |pages=268–74 |year=2005 |pmid=16498489 |pmc=1324958 |doi= |url=http://www.psychiatrist.com/pcc/redirect/v07n06p268.htm] and an absence of sustained prolactinelevation.cite journal |author=Seeman P |title=Atypical antipsychotics: mechanism of action |journal=Can J Psychiatry |volume=47 |issue=1 |pages=27–38 |year=2002 |month=February |pmid=11873706 |doi= |url=]
The terminology can be imprecise. The definition of "atypicality" was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics.)cite journal |author=Weiden PJ |title=EPS profiles: the atypical antipsychotics are not all the same |journal=J Psychiatr Pract |volume=13 |issue=1 |pages=13–24 |year=2007 |month=January |pmid=17242588 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00131746-200701000-00003] Recent literature focuses more upon specific pharmacological actions, and less upon categorization of an agent as "typical" or "atypical".
More recent research is questioning the notion that second generation anti-psychotics are superior to first generation typical anti-psychotics. Using a number of parameters to assess quality of life,
University of Manchesterresearchers found that typical anti-psychotics were no worse than atypical anti-psychotics. The research was funded by the National Health Service of the UK.cite journal |author=Jones PB, Barnes TR, Davies L, "et al" |title=Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) |journal=Arch. Gen. Psychiatry |volume=63 |issue=10 |pages=1079–87 |year=2006 |pmid=17015810 |doi=10.1001/archpsyc.63.10.1079] Because each medication (whether first or second generation) has its own profile of desirable and andverse effects, a neuropsychopharmacologist may recommend one of the older (first generation) or newer (atypical or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.
The mechanism of action of these agents is unknown, and differs greatly from drug to drug.The variation in the receptor binding profile is such that the only effect all have in common is an anti-psychotic effect; the side effect profiles vary tremendously. While modulation of the dopamine neurotransmitter system is the most important mechanism by which anti-psychotics exert their benefits, 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 anti-psychotics. 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 anti-psychotics have less of an affinity for D2 receptors and more of an affinity for the D4 receptors.Fact|date=October 2007 This is primarily because atypical anti-psychotics are somewhat less likely to cause
tardive dyskinesia.Fact|date=March 2007 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 anti-psychotics also affect the norepinephrine, acetylcholine, and histamine receptors of various subtypes. [cite journal |author=Sharafi M |title=Comparison of Classical and Clozapine Treatment on Schizophrenia Using Positive and Negative Syndrome Scale of Schizophrenia (PANSS) and SPECT Imaging |journal=Int J Med Sci |volume=2 |issue=2 |pages=79–86 |year=2005 |pmid=15968344 |doi= |url=http://www.medsci.org/v2p79.htm] However, studies have shown that D4 selective antagonism has no anti-psychotic effect. Fact|date=June 2007
The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are hoped to have a lower likelihood for the development of
tardive dyskinesiathan the typical antipsychotics. However, tardive dyskinesia typically develops after long term (possibly decades) use of antipsychotics. It is not clear, then, if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia. Akathisiais more likely to be less intense with these drugs then the typical antipsychotics Fact|date=June 2007 although many patients would dispute this claim. 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. Sometimes atypical antipsychotics can cause abnormal shifts in sleep patterns, and extreme tiredness and weakness.
In 2006, USA Today published an article about the effects of antipsychotic medication in children. None of the atypicals (Clozaril, Risperdal, Zyprexa, Seroquel, Abilify and Geodon) have been approved for children, and there is little research on their effects on children. From 2000–2004, there were 45 reported deaths in which an atypical antipsychotic was listed as the "primary suspect." There were also 1328 reports of serious, and sometimes life threatening, side effects. These include tardive dyskinesia (involuntary jerking and facial grimacing) and dystonia (involuntary muscle contractions that can interfere with talking and eating).
All the atypical antipsychotics warn about the possibility of
tardive dyskinesiain 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.
Metabolic side effects with atypical antipsychotics
Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the
Food and Drug Administration(FDA) required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the risks of hyperglycemiaand diabeteswith 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. Fact|date=July 2007The 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. Fact|date=July 2007 Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, Fact|date=July 2007 but clinical experience with these newer agents is not as developed as that with the older agents.
Atypical antipsychotic medications
Clozapine(Clozaril) (FDA-approval: 1990) Available in oral tablets and dissolving tablets (FazaClo).
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 in oral tablets and dissolving tablets.
Paliperidone(Invega) (FDA)-approval: 2006) Available in extended-release oral tablets.
AsenapineFDA has accepted NDA as of November 26, 2007. [cite press release
title = Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA
publisher = Schering-Plough
url = http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1080771
accessdate = 2007-11-26 )]
Iloperidone(Fanapta or Zomaril) FDA has accepted NDA as of November 27, 2007. [cite press release
title=Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application
accessdate= 2007-11-27 ]
Sertindole(Serlect) (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).
Bifeprunox(Not approved by the FDA for use in the USA).
MelperoneApproved in Europe. Currently in clinical trial in the USA.
* [http://www.usatoday.com/news/health/2006-05-01-atypical-drugs_x.htm New antipsychotic drugs carry risks for children (USA Today 2006)]
* [http://www.ajmc.com/Article.cfm?ID=2953&CFID=1242844&CFTOKEN=84638270 Atypical Antipsychotics and the Burden of Disease (Am J Manag Care. 2005;11:S235-S241)]
* [http://www.nih.gov/news/pr/sep2005/nimh-19.htm NIMH Study to Guide Treatment Choices for Schizophrenia (September 2005)]
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