The atypical antipsychotics (AAP) (also known as second generation antipsychotics) are a group of antipsychotic tranquilizing drugs 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 depression, psychotic agitation, bipolar maintenance, and other indications. Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal motor control disabilities in patients, which include unsteady Parkinson's disease-type movements, body rigidity and involuntary tremors. More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction." 
During the course of treatment atypical antipsychotics are associated with the following benefits: higher rate of responders, efficiency in patients with refractory disease, lower risk of suicides, better functional capacity and an improved quality of life. However, there has been considerable debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia, a serious movement disorder, neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Significant weight gain may also occur.
Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used for agitation associated with dementia, anxiety disorder, and obsessive-compulsive disorder. Some agents showing some benefits for these uses but are associated with significant rates of adverse events. In dementia they should only be considered after other treatments have failed and if the person in question is at either risk to themselves or others.
The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of psychosis in about 8–15 days. Antipsychotics, however, fail to significantly improve the negative symptoms and cognitive dysfunction.
The choice of which antipsychotic to use is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in 20% of people. Clozapine is an effective treatment for those who respond poorly to other drugs, but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in 1–4%.
There has been considerable debate about whether second-generation antipsychotic drugs are more effective than first-generation antipsychotic drugs. It has been suggested that there is no validity to the term "second-generation antipsychotic drugs" and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles:
...the second-generation drugs have no special atypical characteristics that separate them from the typical, or first-generation, antipsychotics. As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective. The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed.
Robert Whitaker suggests that the "wonder drug" glow around the second generation psychotropics has long since disappeared. He views the "hyping" of the top-selling atypicals as "one of the more embarrassing episodes in psychiatry's history, as one government study after another failed to find that they were any better than the first-generation anti-psychotics".
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 than 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) had been approved for children, and there was 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). Since the article's publication several of the atypicals now carry limited FDA approval for pediatric indications.
Some of the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. The research that Kabinoff et al. evaluated found that the increase in cardiovascular disease is seen regardless of the treatment they receive, instead it is caused by many different factors such as lifestyle or diet. Metabolic syndrome is a leading cause of morbidity and mortality in patients with schizophrenia, with a prevalence rate more than triple that of nonpsychiatric populations. Given the amount of evidence suggesting a link between antipsychotic medications and metabolic syndrome, several agencies have recommended regular clinical monitoring of weight, symptoms of hyperglycemia,glucose, hypertension and signs and symptoms of cardiovascular disease in chronically medicated patients with schizophrenia. Atypical antispychotics may have favourable risk benefit profile, however epecially some older atypicals like clozapine and olanzapine may increase the risk for developing metabolic syndrome. Longterm cardiovascular or diabetic complications may be the result. Newer atypicals with low risk for metabolic complications, but not classic antipsychotics should be prescribed. Sexual side effects have also been reported when taking atypical antipsychotics. In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. In females there may be abnormal menstrual cycles and infertility. In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. Sexual adverse effects caused by some anti-psychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride and in less extense Risperdone and paliperidone cause a high increase of prolactin.
In April 2005, the US Food and Drug Administration (FDA) issued an advisory and subsequent black box warning regarding the risks of atypical anti psychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with dementia include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. Conventional antipsychotics may pose an even greater safety risks. Moreover high potential conventional antipsychotics like haloperidol may be associated with the highest risk followed by low potential neuroleptics thereafter risperidone and olanzapine. Quetiapine seemed to have a lower risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants)
All of 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. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.
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 atypicals are not equal in their effects on 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.
A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics.
The most common route of administration of AAP is oral. Antipsychotics can also be injected, but this method is not as common. Once the antipsychotics are in the body they are lipid soluble and are readily absorbed from the digestive tract and can easily pass the blood brain barrier and placental barriers. Once in the brain the antipsychotics make their way to the synapse and work at the synapse by binding to the receptor (Culpepper, 2007). Antipsychotics are entirely destroyed by the body's metabolism and the metabolites are excreted in the urine (McKim, 2007). These drugs have relatively long half lives. Each drug has a different half life but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare, therefore withdrawal symptoms are rarely seen. Sometimes if AAP are abruptly stopped psychotic symptoms, movement disorders and difficulty in sleep are seen. It is possible that withdrawal is rarely seen because the AAP are stored in the fat tissues in the body and slowly released.
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. The mechanisms behind atypical antipsychotic action are not clear. All antipsychotics work on the dopamine system but all vary in regards to the affinity to the dopamine receptors. There are 5 types of dopamine receptors in humans. There are the “D1-like” group which are types 1 and 5 which are similar in structure and drug sensitivity. The “D2-like” group includes dopamine receptors 2, 3 and 4 and have a very similar structure but very different sensitivities to antipsychotic drugs.
The “D1-like” receptors have been found to not be clinically relevant in therapeutic action. If D1 receptors were a critical component of the mechanism of AAP blocking just the D1 receptor would improve the psychiatric symptoms that are exhibited. If D1 receptor binding was a critical component of the action of antipsychotics they would need to be present in maintenance dosages. This is not seen. They are not present or present in low or negligible levels which would not even maintain the elimination of the symptoms that are seen.
The “D2-like” group of dopamine receptors are classified together based on structure but not drug sensitivity. It has been shown that D2 receptor blockade is necessary for action. All antipsychotics block D2 receptors to some degree, but the affinity of the antipsychotics vary from drug to drug and it has been hypothesized that it is the varying in affinities that causes a change in effectiveness (Horacek et al., 2002).
One theory for how atypicals work is the “fast-off” theory. This theory of antipsychotic action is that AAP have low affinities for the D2 receptor and only bind loosely to the receptor and are rapidly released. In fact, the AAP bind more loosely to the D2 receptor than dopamine itself. The AAP effectively interfere with the phasic release of endogenous dopamine. The AAP transiently bind and rapidly dissociate from the D2 receptor to allow normal dopamine transmission. It is this transient binding that that keeps prolactin levels normal, spares cognition and obviates EPS.
From a historical point of view there has been interest in the role of serotonin and treatment with the use antipsychotics. Experience with LSD suggests that 5-HT2A receptor blockade may be a promising method of treating schizophrenia; see also LSD and schizophrenia. One problem with this is the fact that psychotic symptoms caused by 5-HT2 receptor agonists differs substantially from the symptoms of schizophrenic psychoses. One promising factor of this is where the 5-HT2A receptors are located in the brain. They are localized on hippocampal and cortical pyramidal cells and have a high density in the fifth neocortex layer where the inputs of various cortical and subcortical brain areas are integrated. This makes the blocking of this receptor an interesting area considering these areas in the brain are of interest in the development of schizophrenia. This is an area of research that could prove convincing but has not yielded any convincing results. Evidence points to the fact that serotonin is not sufficient to produce an antipsychotic effect but serotonergic activity in combination with D2 receptor blockade may be responsible. Regardless of the neurotransmitters these AAP have an effect on antipsychotic drugs appear to work by inducing restructuring of neuronal networks. They are able to induce these structural changes.
List of atypical antipsychotics
The following are approved and marketed in various parts of the world:
And these are currently under development but are not yet licensed:
- Bitopertin (RG1678)
- Brexpiprazole (OPC-34712)
- Cariprazine (RGH-188)
- Pimavanserin (ACP-103)
- Vabicaserin (SCA-136)
- Zicronapine (Lu 31-130)
The first major tranquiliser or anti-psychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly after. Clozapine, a.k.a. Clozaril,an atypical antipsychotic, 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. According to Barker (2003) the three most accepted atypical drugs are; clozapine, risperidone and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (which is decreased number of white blood cells), Barker (2003) explains that a person on clozapine will have to go through rigorous blood monitoring. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favourable 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 anti-psychotic paliperidone was approved by the FDA in late 2006.
The atypical anti-psychotics have found favour 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 extrapyramidal side effects (EPS) and an absence of sustained prolactin elevation.
The terminology can still 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.) Recent literature focuses more upon specific pharmacological actions, and less upon categorization of an agent as "typical" or "atypical". There is no clear dividing line between the typical and atypical antipsychotics therefore categorization based on the action is difficult.
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, Manchester University researchers found that typical anti-psychotics were no worse than atypical anti-psychotics. The research was funded by the National Health Service (NHS) of the UK. Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older ("typical" or 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.
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