Skeletal formula of clozapine, the first atypical antipsychotic

The atypical antipsychotics (also known as second generation antipsychotics) are a class of prescription medications 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. Skeletal structure redirects here. ... Clozapine (sold as Clozaril®, Leponex®, Fazaclo®) was the first of the atypical antipsychotics to be developed. ... FDA redirects here. ... This article is an expansion of a section entitled Mania from within the main article Bipolar disorder. ... For other uses, see Bipolar. ...

Atypicals are a heterogeneous group of otherwise 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-HT_1A partial agonism and 5-HT_2A antagonism.^[1] Typical antipsychotics (sometimes referred to as conventional antipsychotics or conventional neuroleptics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia), and are generally being replaced by atypical antipsychotic drugs. ... Amisulpride (brand name Solian®) is an antipsychotic drug sold by Sanofi laboratories. ... Aripiprazole (produced by Otsuka Pharmaceutical Co,. Ltd. ...

History

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 quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The newest atypical anti-psychotic, paliperidone, was approved by the FDA in late 2006. Clozapine (sold as Clozaril®, Leponex®, Fazaclo®) was the first of the atypical antipsychotics to be developed. ... Olanzapine (oh-LAN-za-peen, sold as Zyprexa®, Zyprexa Zydis®, or in combination with fluoxetine, as Symbyax®) was the third atypical antipsychotic to gain approval by the Food and Drug Administration (FDA) and has become one of the most commonly used atypical antipsychotics. ... Risperdal tablets Risperidone (pronounced Ris-PER-ǐ-dōn and sold under the trade name Risperdal in the United States, Canada, the United Kingdom, Portugal and several other countries, Risperdal or Ridal in New Zealand, Rispolept in Eastern Europe, and Belivon, or Rispen elsewhere) is an atypical antipsychotic medication developed by... Quetiapine (IPA: , kwe-TYE-a-peen), marketed by AstraZeneca with the brand name Seroquel, belongs to a series of neuroleptics known as atypical antipsychotics, which have, over the last two decades, become increasingly popular alternatives to typical antipsychotics, such as haloperidol. ... Ziprasidone (marketed as Geodon, Zeldox) was the fifth atypical antipsychotic to gain FDA approval (February 2001). ... Aripiprazole (produced by Otsuka Pharmaceutical Co,. Ltd. ... Paliperidone is an atypical antipsychotic being developed by Janssen. ...

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. 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. Typical antipsychotics (sometimes referred to as conventional antipsychotics or conventional neuroleptics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia), and are generally being replaced by atypical antipsychotic drugs. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ... Prolactin (PRL) is a peptide hormone primarily associated with lactation. ...

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 Manchester researchers found that typical anti-psychotics were no worse than atypical anti-psychotics. The research was funded by the National Health Scheme of the UK^[2] Affiliations: Russell Group, EUA, N8 Group, NWUA, Worldwide Universities Network (WUN), Association of Commonwealth Universities Website: http://www. ...

Pharmacology

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.^{[citation needed]} This is primarily because atypical anti-psychotics are somewhat less likely to cause tardive dyskinesia.^{[citation needed]} 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.^[3] However, studies have shown that D4 selective antagonism has no anti-psychotic effect.^{[citation needed]} Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ...

Side effects

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 dyskinesia than 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. Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ...

Akathisia is more likely to be less intense with these drugs then the typical antipsychotics^{[citation needed]} 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. Akathisia (or acathisia) is an often extremely unpleasant subjective sensation of inner restlessness that manifests itself with an inability to sit still or remain motionless, hence the origin of its name: Greek a (without) + kathesis (sitting). ... For other uses, see Dementia (disambiguation). ... For other uses, see Stroke (disambiguation). ...

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).

Tardive Dyskinesia

All the atypical antipsychotics warn about the possibility 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. Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ... Pdr or PDR may refer to: Packet Delivery Ratio Paintless Dent Repair Peripheral Distribution Road (Cardiff) Photon-Dominated Regions Physicians Desk Reference Population and Development Review Pounder referring to Pound (mass) used as measure of calibre Preliminary Design Review Professional Disk Recorder a Hard disk recorder from Grass Valley (company...

However, the atypicals may cause serious metabolic disorders to make them equally dangerous as the older anti-psychotic drugs.^{[citation needed]}

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 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.^{[citation needed]} 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.^{[citation needed]} Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance,^{[citation needed]} but clinical experience with these newer agents is not as developed as that with the older agents. FDA redirects here. ... Hyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. ... This article is about the disease that features high blood sugar. ... Insulin sensitivity is the opposite of insulin resistance. ... Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. ...

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.
• Asenapine FDA has accepted NDA as of November 26, 2007. ^[4]
• Iloperidone (Zomaril) FDA has accepted NDA as of November 27, 2007. ^[5]
• 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).
• Melperone Approved in Europe. Currently in clinical trial in the USA.

accoring to goodman gillman's 11 th edition, low dose olanzepine and low dose risperidone are considerd as atypical antipsychotics( only in low dose they have less extra pyramidal side effects ) Clozapine (sold as Clozaril®, Leponex®, Fazaclo®) was the first of the atypical antipsychotics to be developed. ... Risperdal tablets Risperidone (pronounced Ris-PER-ǐ-dōn and sold under the trade name Risperdal in the United States, Canada, the United Kingdom, Portugal and several other countries, Risperdal or Ridal in New Zealand, Rispolept in Eastern Europe, and Belivon, or Rispen elsewhere) is an atypical antipsychotic medication developed by... Olanzapine (oh-LAN-za-peen, sold as Zyprexa®, Zyprexa Zydis®, or in combination with fluoxetine, as Symbyax®) was the third atypical antipsychotic to gain approval by the Food and Drug Administration (FDA) and has become one of the most commonly used atypical antipsychotics. ... Quetiapine (IPA: , kwe-TYE-a-peen), marketed by AstraZeneca with the brand name Seroquel, belongs to a series of neuroleptics known as atypical antipsychotics, which have, over the last two decades, become increasingly popular alternatives to typical antipsychotics, such as haloperidol. ... Ziprasidone (marketed as Geodon, Zeldox) was the fifth atypical antipsychotic to gain FDA approval (February 2001). ... Aripiprazole (produced by Otsuka Pharmaceutical Co,. Ltd. ... Paliperidone is an atypical antipsychotic being developed by Janssen. ... The New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following: Is the drug... is the 330th day of the year (331st in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 331st day of the year (332nd in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... Sertindole (brand names: Serlect®, Serdolect®) is one of the newer antipsychotic medications to hit the market. ... Zotepine (Nipolept) is an atypical antipsychotic indicated for acute and chronic schizophrenia. ... Amisulpride (brand name Solian®) is an antipsychotic drug sold by Sanofi laboratories. ... Melperone is sold under the tradenames Buronil, Burnil, and Eunerpan and is a conventional butyrophenone antipsychotic drug. ...

See also

• Typical antipsychotics

Typical antipsychotics (sometimes referred to as conventional antipsychotics or conventional neuroleptics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia), and are generally being replaced by atypical antipsychotic drugs. ...

References

1. ^ Abilify package insert at http://packageinserts.bms.com/pi/pi_abilify.pdf
2. ^ Jones PB, Barnes TR, Davies L, et al (2006). "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)". Arch. Gen. Psychiatry 63 (10): 1079–87. doi:10.1001/archpsyc.63.10.1079. PMID 17015810. 
3. ^ Sharafi M (2005). "Comparison of Classical and Clozapine Treatment on Schizophrenia Using Positive and Negative Syndrome Scale of Schizophrenia (PANSS) and SPECT Imaging". Int J Med Sci 2 (2): 79–86. PMID 15968344. 
4. ^ Schering-Plough (2007-11-26). "Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA". Press release. Retrieved on 2007-11-26.)
5. ^ Vanda Pharmaceuticals (2007-11-27). "Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application". Press release. Retrieved on 2007-11-27.

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 330th day of the year (331st in leap years) in the Gregorian calendar. ... For information on Wikipedia press releases, see Wikipedia:Press releases. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 330th day of the year (331st in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 331st day of the year (332nd in leap years) in the Gregorian calendar. ... For information on Wikipedia press releases, see Wikipedia:Press releases. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 331st day of the year (332nd in leap years) in the Gregorian calendar. ...

External links

• New antipsychotic drugs carry risks for children (USA Today 2006)
• Atypical Antipsychotics and the Burden of Disease (Am J Manag Care. 2005;11:S235-S241)
• NIMH Study to Guide Treatment Choices for Schizophrenia (September 2005)