Atypical antipsychotics

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


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.

Atypicals are a heterogeneous group of otherwise unrelated drugs united by the fact 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.


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.

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.

Pharmacology of the atypicals

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. This is primarily because atypical anti-psychotics 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 anti-psychotics also affect the norepinephrine, acetylcholine, and histamine receptors of various subtypes. [2] However, studies have shown that D4 selective antagonism has no anti-psychotic effect.

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.

Akathisia is more likely to be less intense with these drugs then the typical antipsychotics 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).

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.

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 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. 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.

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 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. [1]
  • Iloperidone (Zomaril®) FDA has accepted NDA as of November 27, 2007. [2]
  • 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.

See also


  1. "Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA" (Press release). Schering-Plough. 2007-11-26. Retrieved 2007-11-26. Check date values in: |date= (help))
  2. "Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application" (Press release). Vanda Pharmaceuticals. 2007-11-27. Retrieved 2007-11-27. Check date values in: |date= (help)

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