Atypical antipsychotic

The atypical antipsychotics (AAP; also known as second generation antipsychotics (SGAs)) are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilisers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval (e.g. by the FDA of the US, the TGA of Australia, the MHRA of the UK) for schizophrenia, bipolar disorder, autism and as an adjunct in major depressive disorder.

Both generations of medication tend to block receptors in the brain's dopamine pathways. Atypicals are less likely than the most widely used typical antipsychotic haloperidol to cause extrapyramidal motor control disabilities in patients, which include unsteady Parkinson's disease-type movements, body rigidity and involuntary tremors, but only a few have been demonstrated to be superior to lesser used, low potency first generation antipsychotics in this regard.

As experience with these agents has grown, several studies have questioned the utility of broadly characterizing antipsychotic drugs as “atypical” vs “first generation”, noting that each agent has its own efficacy and side effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. 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. Critics have argued that "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction."

Medical uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used for agitation associated with dementia, anxiety disorder, Autism Spectrum Disorder, and off-label uses in the obsessive-compulsive disorder. 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.

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of psychosis in about 8â€"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 40â€"50%, a partial response in 30â€"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 1â€"4%.

Efficacy in the treatment of schizophrenia

The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. In 2005 the US government body NIMH published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides. No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Leucht et al. published in The Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. Compliance has not been shown to be different between the two types. Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.

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, in his book Anatomy of an Epidemic, 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".

Bipolar disorder

In bipolar disorder SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilisers (which tend to have a delayed onset of action in mania and mixed episodes) such as lithium and valproate and benzodiazepines (to alleviate agitation), although in milder cases of mania and mixed episodes mood stabiliser monotherapy may be attempted first. SGAs may also be used to treat other aspects of the condition (e.g. acute bipolar depression and as a prophylactic treatment) as adjuncts and, according to the antipsychotic in question, even as a monotherapy. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone has demonstrated some efficacy in the acute depressive phase of bipolar disorder.

Major depressive disorder

In non-psychotic major depressive disorder (MDD) several SGAs have demonstrated significant efficacy as adjunctive agents, such agents include:

• Aripiprazole
• Olanzapine
• Quetiapine
• Risperidone
• Ziprasidone â€" which has only demonstrated adjunctive benefit in an open-label study.

whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.

Autism

Both risperidone and aripiprazole have received FDA labelling for autism.

Adverse effects

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed 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.

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.

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).

Tardive dyskinesia

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.

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.

Metabolism

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. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H₁ and 5-HT_2C receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the M₃receptor. Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone have clinically-insignificant effects on the M₃ receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M₃ receptor at therapeutic-relevant concentrations.

Recent evidence suggests a role of the α₁ adrenoceptor and 5-HT_2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT_2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.

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.

Pharmacodynamics

The exact mechanism of action of antipsychotic drugs remains unknown but it is known that all clinically-utilised antipsychotics work by antagonising (blocking) the dopamine D₂ receptor. This action is common to both typical and atypical antipsychotics.

It is not entirely known what pharmacologically distinguishes the typical from the atypical antipsychotics, but it is known that in addition to this dopamine-blocking action all atypical antipsychotics with the only notable exceptions being the benzamide antipsychotics such as amisulpride and remoxipride (an agent that was withdrawn from the market in the 90s due to adverse effects) antagonise the 5-HT_2A receptor with at least equal (or near equal) affinity to their blockade of the D₂receptor. The 5-HT_2A receptor has historically gained some interest as a therapeutic target in the treatment of psychoses like schizophrenia is the fact that 5-HT_2A partial agonists like lysergic acid diethylamide (LSD) and psilocybin. This interest is further supported by the finding that the 5-HT_2A receptors are densely expressed in the pyramidal cells of the fifth layer of the neocortex where inputs from the subcortical and cortical layers of the brain are integrated. This area is implicated in psychosis and despite this finding selective 5-HT_2A antagonists have failed to demonstrate clear antipsychotic activity on their own. The 5-HT_2A receptor regulates the release of dopamine in striatal structures including the basal ganglia which is responsible for the control of voluntary movement. By blocking this receptor the atypical agents may increase dopamine release in the basal ganglia (especially the substantia nigra), hence potentially attenuating the high D₂ receptor occupancy (by displacing the drug from the receptor with the increase in dopamine levels) seen in subjects being treated with antipsychotic agents. This theory, however, fails to account for the finding that the first typical antipsychotic, chlorpromazine, is a potent 5-HT_2A antagonist occupying 65% of receptors at a 500 mg daily dose. It also fails to account for the fact that the selective 5-HT_2A inverse agonist, M-100,907, enhances catalepsy (an animal correlate of extrapyramidal symptoms) induced by the D₂ antagonist, raclopride.

Another theory as to how atypicals achieve such a low rate of adverse effects associated with excessive dopamine receptor blockade (such as extrapyramidal side effects and prolactin elevation) is the so-called "fast-off" theory. It proposes that SGAs achieve such a low incidence of these adverse effects by binding more loosely to the D₂ receptor than the previous generation of antipsychotics (that is, the first-generation antipsychotics (FGAs)) and even dopamine itself. By so doing they only bind to the D₂receptor for long enough to produce their therapeutic effects but not long enough to produce extrapyramidal side effects or prolactin elevation. There is one antipsychotic agent that does not quite satisfy this requirement of looser binding than dopamine, namely, risperidone is considered weakly atypical due to its high incidence of hyperprolactinaemia and, at higher doses, extrapyramidal side effects. Supporting this theory are the findings that the antipsychotic agents that bind the most loosely to the D₂ receptor namely clozapine, melperone, quetiapine and remoxipride are associated with the lowest incidence of these adverse effects.

Binding profile

Note: Unless otherwise specified the drugs below serve as antagonists/inverse agonists at the receptors listed.

Legend:

Pharmacokinetics

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. Antipsychotics are entirely destroyed by the body's metabolism and the metabolites are excreted in the urine. 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.

Comparison of atypical antipsychotics

Data sources for table:

And these are currently under development but are not yet licensed:

• Bitopertin (RG1678)
• Brexpiprazole (OPC-34712)
• Cariprazine (RGH-188)
• LY2140023
• Pimavanserin (ACP-103)
• Vabicaserin (SCA-136)
• Zicronapine (Lu 31-130)

History

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 (a 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.

See also

• Antipsychotic
• Typical antipsychotic
• List of antipsychotics

Notes

References

External links

• New antipsychotic drugs carry risks for children (USA Today 2006)
• Simpson, GM (2005). "Atypical antipsychotics and the burden of disease". The American Journal of Managed Care 11 (8 Suppl): S235â€"41. PMID 16180961. 
• "NIMH Study to Guide Treatment Choices for Schizophrenia" (Press release). National Institute of Mental Health. September 19, 2005. Retrieved August 18, 2013.