Atypical antipsychotic: Difference between revisions

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==Pharmacokinetics==
==Pharmacokinetics==
The most common route of administration of AAP is oral.<ref name="McKim, W. 2007 pp.241-260">{{cite book |last=McKim |first=W. |year=2007 |title=Antipsychotics in Drugs and Behavior: An Introduction to Behavioral Pharmacology |pages=241–60 |location=Upper Saddle River, NJ. |publisher=Pearson Prentice Hall}}</ref> Antipsychotics can also be injected, but this method is not as common.<ref name="McKim, W. 2007 pp.241-260"/> 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.<ref name="McKim, W. 2007 pp.241-260"/> Once in the brain the antipsychotics make their way to the synapse and work at the synapse by binding to the receptor.<ref>Culpepper, 2007{{vs|date=August 2013}}</ref> Antipsychotics are entirely destroyed by the body's metabolism and the metabolites are excreted in the urine.<ref>McKim, 2007{{vs|date=August 2013}}</ref> These drugs have relatively long half lives.<ref name="McKim, W. 2007 pp.241-260"/> 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.<ref name="Seeman 2002"/> 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.<ref name="Seeman 2002"/> Physical dependence with these drugs is very rare, therefore withdrawal symptoms are rarely seen.<ref name="McKim, W. 2007 pp.241-260"/> Sometimes if AAP are abruptly stopped psychotic symptoms, movement disorders and difficulty in sleep are seen.<ref name="McKim, W. 2007 pp.241-260"/> It is possible that withdrawal is rarely seen because the AAP are stored in the fat tissues in the body and slowly released.<ref name="McKim, W. 2007 pp.241-260"/>
The most common route of administration of AAP is oral.<ref name="McKim, W. 2007 pp.241-260">{{cite book |last=McKim |first=W. |year=2007 |title=Antipsychotics in Drugs and Behavior: An Introduction to Behavioral Pharmacology |pages=241–60 |location=Upper Saddle River, NJ. |publisher=Pearson Prentice Hall}}</ref> Antipsychotics can also be injected, but this method is not as common.<ref name="McKim, W. 2007 pp.241-260"/> 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.<ref name="McKim, W. 2007 pp.241-260"/> Once in the brain the antipsychotics make their way to the synapse and work at the synapse by binding to the receptor.<ref>Culpepper, 2007{{vs|date=August 2013}}</ref> Antipsychotics are entirely destroyed by the body's metabolism and the metabolites are excreted in the urine.<ref>McKim, 2007{{vs|date=August 2013}}</ref> These drugs have relatively long half lives.<ref name="McKim, W. 2007 pp.241-260"/> 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.<ref name="Seeman 2002"/> 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.<ref name="Seeman 2002"/> Physical dependence with these drugs is very rare, therefore withdrawal symptoms are rarely seen.<ref name="McKim, W. 2007 pp.241-260"/> Sometimes if AAP are abruptly stopped psychotic symptoms, movement disorders and difficulty in sleep are seen.<ref name="McKim, W. 2007 pp.241-260"/> It is possible that withdrawal is rarely seen because the AAP are stored in the fat tissues in the body and slowly released.<ref name="McKim, W. 2007 pp.241-260"/>

'''<big>Pharmacokinetic parameters of available atypical antipsychotics</big>'''<ref>{{cite web|title=[Drug Name]|work=DailyMed|publisher=[Drug sponsor]|accessdate=26 November 2013|url=http://dailymed.nlm.nih.gov/dailymed/about.cfm?}}</ref><ref>{{cite web|title=[Drug Name]|work=Medscape Reference|publisher=WebMD|accessdate=26 November 2013|url=http://reference.medscape.com/medscapetoday}}</ref><ref>{{cite web|title=[Drug Name]|work=TGA eBusiness Services|publisher=[Drug Sponsor]|accessdate=26 November 2013|url=https://www.ebs.tga.gov.au/}}</ref>

{| class="wikitable"
! Drug !! Half-life (t<sub>1/2</sub> in hours) !! Volume of distribution (V<sub>d</sub> in L/kg) !! Protein binding !! Excretion !! Enzymes involved in metabolism !! Bioavailability !! Peak plasma time (h) !! C<sub>max</sub> (ng/mL)

|-
| [[Aripiprazole]] || 75 (94 for active metabolite) || 4.9 || 99% || Faeces (55%), urine (25%) || [[CYP2D6]] & [[CYP3A4]] || 87% (Oral), 100% ([[Intramuscular|IM]]) || 3-5 || ?
|-
| [[Asenapine]] || 24 || 20-25 || 95% || Urine (50%), faeces (40%) || [[CYP1A2]] & [[UGT1A4]] || 35% (sublingual), <2% (Oral) || 0.5-1.5 || 4
|-
| [[Blonanserin]]<ref name = "CNS Drugs">{{cite journal|title=Blonanserin A Review of its Use in the Management of Schizophrenia|journal=CNS Drugs|date=January 2010|author=Deeks, ED; Keating, GM|volume=24|issue=1|pages=65-84|pmid=20030420|doi=10.2165/11202620-000000000-00000}}</ref> || 10.7 (single 4 mg dose), 12 (single 8 mg dose), 16.2 (single 12 mg dose), 67.9 (repeated bid dosing) || ? || >99.7% || Urine (59%), faeces (30%) || [[CYP3A4]] || 84% (Oral) || <2 || 0.14 (single 4 mg dose), 0.45 (single 8 mg dose), 0.76 (single 12 mg dose), 0.57 (bid dosing)
|-
| [[Clozapine]] || 8 hours (single dosing), 12 (twice daily dosing) || 4.67 || 97% || Urine (50%), faeces (30%) || [[CYP1A2]], [[CYP3A4]], [[CYP2D6]] || 50-60% || 1.5-2.5 || 102-771

|-
| [[Iloperidone]] || ? || 1340-2800 || 95% || Urine (45-58%), faeces (20-22%) || [[CYP2D6]] & [[CYP3A4]] || 96% || 2-4 || ?
|-
| [[Lurasidone]] || 18 || 6173 || 99% || Faeces (80%), urine (9%) || [[CYP3A4]] || 9-19% || 1-3 || ?
|-
| [[Melperone]]<ref>Product Information: Eunerpan(R), Melperonhydrochlorid. Knoll Deutschland GmbH, Ludwigshafen, 1995.</ref><ref>{{cite journal|last=Borgström|first=L|coauthors=Larsson, H; Molander, L|title=Pharmacokinetics of parenteral and oral melperone in man|journal=European Journal of Clinical Pharmacology|year=1982|volume=23|issue=2|pages=173–176|pmid=7140807|url=http://link.springer.com/article/10.1007/BF00545974|doi=10.1007/BF00545974}}</ref>|| 3-4 (Oral), 6 (IM) || 7-9.9 || 50% || Urine (70% as metabolites; 5-10.4% unchanged drug) || ? || 65% (tablet), 87% (IM), 54% (oral syrup) || 0.5-3 || 75-324 (repeated dosing)
|-
| [[Olanzapine]] || 30 || 1000 || 93% || Urine (57%), faeces (30%) || [[CYP1A2]], [[CYP2D6]] || >60% || 6 (Oral) || ?
|-
| [[Paliperidone]] || 23 (Oral) || 390-487 || 74% || Urine (80%), faeces (11%) || [[CYP2D6]], [[CYP3A4]] || 28% || 24 (Oral) || ?
|-
| [[Perospirone]]<ref>{{cite journal |author = Onrust, SV; McClellan, K | title = Perospirone | journal = CNS Drugs | volume = 15 | issue = 4 | pages = 329–37; discussion 338| year = 2001 | pmid = 11463136 | doi = 10.2165/00023210-200115040-00006 | url = http://link.springer.com/article/10.2165%2F00023210-200115040-00006}}</ref> || ? || ? || 92% || Urine (0.4% as unchanged drug) || ? || ? || 1.5 || 1.9-5.7
|-
| [[Quetiapine]] || 6 (IR), 7 (XR) || 6-14 || 83% || Urine (73%), faeces (20%) || [[CYP3A4]] || 100% || 1.5 (IR), 6 (XR) || ?
|-
| [[Risperidone]] || 3 (EM), 20 (PM) || 1-2 || 90%, 77% (metabolite) || Urine (70%), faeces (14%) || [[CYP2D6]] || 70% || 3 (EM), 17 (PM)
|-
| [[Sertindole]] || 72 (55-90) || 20 || 99.5% || Urine (4%), faeces (46-56%) || [[CYP2D6]] || 74% || 10 || ?
|-
| [[Ziprasidone]] || 7 (oral) || 1.5 || 99% || Faeces (66%), urine (20%) || [[CYP3A4]] & [[CYP1A2]] || 60% (Oral), 100% (IM) || 6-8 || ?
|-
| [[Zotepine]]<ref>Product Information: Nipolept(R), zotepine. Klinge Pharma GmbH, Munich, 1996.</ref><ref>{{cite journal|title=Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects|date=February 1998|volume=20|issue=1|pages=117-119|author=Tanaka, O; Kondo, T; Otani, K; Yasui, N; Tokinaga, N; Kaneko, S|journal=Therapeutic Drug Monitoring|pmid=9485566}}</ref> || 13.7-15.9 || 10-109 || 97% || Urine (17%) || ? || 7-13% || ? || ?

|}

Acronyms used:<br>
IR - Immediate release formulation.<br>
XR - Extended release formulation.<br>
EM - Extensive metabolisers.<br>
PM - Poor metabolisers.
C<sub>max</sub> - maximum plasma concentrations of the drug.


== Comparison of atypical antipsychotics ==
== Comparison of atypical antipsychotics ==

Revision as of 08:14, 26 November 2013

Skeletal formula of clozapine, the first 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, etc.) 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, 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.[1] 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."[2]

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.[3] However, there has been considerable debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs.[4] 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.

Medical uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder.[5] They are also frequently used for agitation associated with dementia, anxiety disorder, Autism Spectrum Disorder, and obsessive-compulsive disorder.[6] Some agents showing some benefits for these uses but are associated with significant rates of adverse events.[6] 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.[7]

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication,[8] 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.[9][10]

The choice of which antipsychotic to use is based on benefits, risks, and costs.[11] It is debatable whether, as a class, typical or atypical antipsychotics are better.[12] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[13] 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.[9] 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%.[11][14][15]

Efficacy in the treatment of Schizophrenia

There has been considerable debate about whether second-generation antipsychotic drugs are more effective than first-generation antipsychotic drugs.[4] 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.[16][17] 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).[18] This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 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 44 pounds (20 kg) 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[4] by Dr. Leucht published in 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.[19] Compliance has not been shown to be different between the two types.[20] 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.[21][22][23]

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.[24]

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".[25]

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.[26] 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.[26][27][28]

Major Depressive Disorder

In non-psychotic major depressive disorder (MDD) several SGAs have demonstrated significant efficacy as adjunctive agents, such agents include:[29][30][31]

whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD.[33] Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.[34][35]

Autism

Both risperidone and aripiprazole have received FDA labelling for autism.[34]

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.[26][36]

Some of the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease.[37] 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.[37]

Sexual side effects have also been reported when taking atypical antipsychotics.[38] In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate.[39] In females there may be abnormal menstrual cycles and infertility.[40] In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples.[39] 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.[41] 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).[citation needed]

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.[42] The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.[42]

Both typical and atypical antipsychotics can cause tardive dyskinesia.[43] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.[43]

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.[44] 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.[44] 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.[44] 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-HT2C 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 M3 receptor. 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.[45]

Recent evidence suggests a role of the α1 adrenoceptor and 5-HT2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.[46]

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.[37] The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association.[37] 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.[37]

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. 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.[3] There are 5 types of dopamine receptors in humans.[42] There are the “D1-like” group which are types 1 and 5 which are similar in structure and drug sensitivity.[42] The “D2-like” group includes dopamine receptors 2, 3 and 4 and have a very similar structure but very different sensitivities to antipsychotic drugs.[42]

The “D1-like” receptors have been found to not be clinically relevant in therapeutic action.[42] 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.[42] If D1 receptor binding was a critical component of the action of antipsychotics they would need to be present in maintenance dosages.[42] 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.[42]

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.[3] 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.[47]

One theory for how atypicals work is the “fast-off” theory.[42] 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.[42] In fact, the AAP bind more loosely to the D2 receptor than dopamine itself.[42] The AAP effectively interfere with the phasic release of endogenous dopamine.[3] The AAP transiently bind and rapidly dissociate from the D2 receptor to allow normal dopamine transmission.[42] It is this transient binding that that keeps prolactin levels normal, spares cognition and obviates EPS.[42]

From a historical point of view there has been interest in the role of serotonin and treatment with the use antipsychotics.[42] Experience with LSD suggests that 5-HT2A receptor blockade may be a promising method of treating schizophrenia;[42] 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.[42] 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.[42] This makes the blocking of this receptor an interesting area considering these areas in the brain are of interest in the development of schizophrenia.[42] This is an area of research that could prove convincing but has not yielded any convincing results.[42] 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.[42] Regardless of the neurotransmitters these AAP have an effect on antipsychotic drugs appear to work by inducing restructuring of neuronal networks.[42] They are able to induce these structural changes.

Binding Profile

Generic Name[48] D1 D2 D3 D4 5-HT1A 5-HT1B 5-HT2A 5-HT2C 5-HT6 5-HT7 α1 α2 M1 M3 H1
Amisulpride - ++++ ++++ - - - - - - ++/+ - +/- - - -
Aripiprazole + ++++ (PA) +++ (PA) + (PA) +++ (PA) + +++ ++ (PA) + +++ (PA) ++/+ + - - ++/+
Asenapine ++ ++ +++ ++ + (PA) + ++++ ++++ +++ +++ ++ ++ - - ++
Blonanserin - ++++ ++++ + - ? +++ + + +/- + (RC) + (RC) + ? -
Clozapine ++ ++ ++ +++ ++ (PA) ++/+ ++++ ++++ (IA) +++ +++ ++++ +++ ++++ +++ ++++
Iloperidone + +++ +++ ++ + (PA) + +++ + ++ + ++++ +++/++ - - +++
Lurasidone ? +++ ? ++++ +++ (PA) ? ++++ +/- ? ++++ - +++/++ - - -
Melperone ? ++ ++++ ++ + (PA) ? ++ + - ++ ++ ++ - - ++
Olanzapine +++ +++ +++ +++ + (PA) ++ ++++ +++ +++ ++ ++ ++ ++++ ++++ ++++
Paliperidone ++ +++ +++ ++ + (PA) +++/++ ++++ + - ++++/+++ +++ +++ - - +++/++
Quetiapine + ++/+ ++/+ + ++/+ (PA) + + + ++ +++/++ ++++ +++/++ ++ +++ ++++
Risperidone + +++ ++ +++ + (PA) ++ ++++ ++ - +++/++ +++/++ ++ - - ++
Sertindole ? +++ +++ +++ ++/+ (PA) ++ ++++ ++++ +++ ++ ++++/+++ + - - ++/+
Sulpiride ? ++++ ++++ +++ - - - - - - - - - - -
Ziprasidone +++/++ +++ +++ +++/++ +++ (PA) +++ ++++ +++ ++ +++ +++/++ ++ - - ++
Zotepine +++/++ +++ ++++/+++ +++ ++ (PA) +++ ++++ ++++ (RC) ++++ ++++/+++ +++ +++/++ ++ (RC) ++ (RC) ++++

Legend: (Antagonistic unless otherwise specified; binding to cloned human receptors unless otherwise specified)

- clinically insignificant
+ low
++ moderate
+++ high
++++ very high
PA Partial agonist
IA Inverse agonist
RC Cloned rat receptor

Pharmacokinetics

The most common route of administration of AAP is oral.[39] Antipsychotics can also be injected, but this method is not as common.[39] 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.[39] Once in the brain the antipsychotics make their way to the synapse and work at the synapse by binding to the receptor.[49] Antipsychotics are entirely destroyed by the body's metabolism and the metabolites are excreted in the urine.[50] These drugs have relatively long half lives.[39] 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.[42] 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.[42] Physical dependence with these drugs is very rare, therefore withdrawal symptoms are rarely seen.[39] Sometimes if AAP are abruptly stopped psychotic symptoms, movement disorders and difficulty in sleep are seen.[39] It is possible that withdrawal is rarely seen because the AAP are stored in the fat tissues in the body and slowly released.[39]

Pharmacokinetic parameters of available atypical antipsychotics[51][52][53]

Drug Half-life (t1/2 in hours) Volume of distribution (Vd in L/kg) Protein binding Excretion Enzymes involved in metabolism Bioavailability Peak plasma time (h) Cmax (ng/mL)
Aripiprazole 75 (94 for active metabolite) 4.9 99% Faeces (55%), urine (25%) CYP2D6 & CYP3A4 87% (Oral), 100% (IM) 3-5 ?
Asenapine 24 20-25 95% Urine (50%), faeces (40%) CYP1A2 & UGT1A4 35% (sublingual), <2% (Oral) 0.5-1.5 4
Blonanserin[54] 10.7 (single 4 mg dose), 12 (single 8 mg dose), 16.2 (single 12 mg dose), 67.9 (repeated bid dosing) ? >99.7% Urine (59%), faeces (30%) CYP3A4 84% (Oral) <2 0.14 (single 4 mg dose), 0.45 (single 8 mg dose), 0.76 (single 12 mg dose), 0.57 (bid dosing)
Clozapine 8 hours (single dosing), 12 (twice daily dosing) 4.67 97% Urine (50%), faeces (30%) CYP1A2, CYP3A4, CYP2D6 50-60% 1.5-2.5 102-771
Iloperidone ? 1340-2800 95% Urine (45-58%), faeces (20-22%) CYP2D6 & CYP3A4 96% 2-4 ?
Lurasidone 18 6173 99% Faeces (80%), urine (9%) CYP3A4 9-19% 1-3 ?
Melperone[55][56] 3-4 (Oral), 6 (IM) 7-9.9 50% Urine (70% as metabolites; 5-10.4% unchanged drug) ? 65% (tablet), 87% (IM), 54% (oral syrup) 0.5-3 75-324 (repeated dosing)
Olanzapine 30 1000 93% Urine (57%), faeces (30%) CYP1A2, CYP2D6 >60% 6 (Oral) ?
Paliperidone 23 (Oral) 390-487 74% Urine (80%), faeces (11%) CYP2D6, CYP3A4 28% 24 (Oral) ?
Perospirone[57] ? ? 92% Urine (0.4% as unchanged drug) ? ? 1.5 1.9-5.7
Quetiapine 6 (IR), 7 (XR) 6-14 83% Urine (73%), faeces (20%) CYP3A4 100% 1.5 (IR), 6 (XR) ?
Risperidone 3 (EM), 20 (PM) 1-2 90%, 77% (metabolite) Urine (70%), faeces (14%) CYP2D6 70% 3 (EM), 17 (PM)
Sertindole 72 (55-90) 20 99.5% Urine (4%), faeces (46-56%) CYP2D6 74% 10 ?
Ziprasidone 7 (oral) 1.5 99% Faeces (66%), urine (20%) CYP3A4 & CYP1A2 60% (Oral), 100% (IM) 6-8 ?
Zotepine[58][59] 13.7-15.9 10-109 97% Urine (17%) ? 7-13% ? ?

Acronyms used:
IR - Immediate release formulation.
XR - Extended release formulation.
EM - Extensive metabolisers.
PM - Poor metabolisers. Cmax - maximum plasma concentrations of the drug.

Comparison of atypical antipsychotics

Data sources for table:[4][26][29][45][60][61][62][63][64]

Generic Name Trade Name FDA
approved		 TGA
approved		 EMA
approved		 PMDA
approved		 MHRA
approved		 Weight gain Metabolic Effects EPS Prolactin Sedation Hypotension QTc prolongation Anti-ACh effects Other Adverse Effects* & Notes
Amisulpride Solian No Yes No No Yes + + + ++ - - +++ - Seizures, suicidal ideation
Aripiprazole Abilify Yes Yes Yes Yes Yes +/- - +/- - + - - - Seizures (0.1-0.3%), anxiety, rhabdomyolysis, pancreatitis (<0.1%), agranulocytosis (<1%), leukopenia, neutropenia, suicidal ideation, angioedema (0.1-1%)
Asenapine Saphris Yes Yes Yes No Yes + - + +/- ++ +/- + - Immune hypersensitivity reaction, angioedema, suicidal ideation
Blonanserin Lonasen No No No Yes No +/- - ++ + +/- - + +/- Was significantly more effective than haloperidol in treating negative symptoms in one clinical trial.[65]
Carpipramine Prazinil No No No Yes No ? ? ? ? ? ? ? ? ?
Clocapramine Clofekton No No No Yes No ? ? ? ? ? ? ? ? Often classed with typical antipsychotics.
Clozapine Clozaril Yes Yes Yes Yes Yes +++ +++ - - +++ +++ + +++ Seizures (3-5%), agranulocytosis (1.3%), leukopenia, pneumonia, respiratory arrest, angle-closure glaucoma, eosinophilia (1%), thrombocytopenia, Stevens-Johnson syndrome, myocarditis, erythema multiforme and abnormal paristalsis
Iloperidone Fanapt Yes No No No No ++ + + ++/+ - +/- ++ - Suicidal ideation (0.4-1.1%), syncope (0.4%)
Lurasidone Latuda Yes No No No No +/- - ++ ++ + + + + Agranulocytosis, seizures (<1%), elevated serum creatinine (2-4%)
Melperone Buronil No No No No No + + +/- - +/++ +/++ ++ - Agranulocytosis, neutropenia and leukopenia appears to be effective in treatment-resistant cases of schizophrenia.
Mosapramine Cremin No No No Yes No ? ? ? ? ? ? ? ? Often classed with the typical antipsychotics.
Olanzapine Zyprexa Yes Yes Yes Yes Yes +++ +++ - + ++ + + + Acute haemorrhagic pancreatitis, immune hypersensitivity reaction, seizures (0.9%), status epilepticus, suicidal ideation (0.1-1%)
Paliperidone Invega Yes Yes Yes ? Yes ++ + ++ +++ - ++ +/- (7%) - Agranulocytosis, leukopenia, priapism, dysphagia
Perospirone Lullan No No No Yes No ? ? +/++ + + + ? - ?
Quetiapine Seroquel Yes Yes Yes Yes Yes ++ +/- - - ++ ++ ++ + Agranulocytosis, leukopenia, neutropenia (0.3%), anaphylaxis, seizures (0.05-0.5%), priapism, tardive dyskinesia (0.1-5%), suicidal ideation, pancreatitis, syncope (0.3-1%)
Remoxipride[66] Roxiam No No Withdrawn No No +/- - + +++/++ - +/- ? - There is a risk of aplastic anaemia risk which is what lead to its removal from the market.
Risperidone Risperdal Yes Yes Yes Yes Yes ++ +/- ++ +++ + ++ + - Syncope (1%), pancreatitis, hypothermia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura, cerebrovascular incident (<5%), tardive dyskinesia (<5%), priapism, neuroleptic malignant syndrome (<1%), Gynomastia, Galactorrhea[67]
Sertindole Serdolect No Yes No ? Yes ++ +/- - ++ - +++ +++ - -
Sulpiride Sulpirid No No Yes Yes Yes + + + +++ - +++ + - Jaundice
Ziprasidone Geodon Yes Yes Yes No Yes - - + + ++ + ++ - Syncope (0.6%), dysphagia (0.1-2%), bone marrow suppression, seizure (0.4%), priapism
Zotepine Nipolept No No No Yes No +++ +++ ++ +++ +++ ++ ++ - Was once used in the UK as is substantiated by the fact that it appears in the BNF58.

Relative efficacy of atypical antipsychotics

Generic Drug Name[68][69][70][71][72] Schizophrenia Mania Bipolar Maintenance Bipolar Depression Adjunct in Major Depressive Disorder
Amisulpride +++ ? ? ? ? (+++ as a dysthymia monotherapy, however)
Aripiprazole ++ ++ ++/+ - +++
Asenapine ++/+ ++ ++ ? (some evidence has suggested efficacy in treating depressive symptoms in mixed/manic episodes[73]) ?
Blonanserin ++ ? ? ? ?
Clozapine +++ ? ? ? ?
Iloperidone + ? ? ? ?
Lurasidone + ? ? +++ ?
Melperone +++/++ ? ? ? ?
Olanzapine +++ +++ ++ - (+++/++ when combined with fluoxetine) ++
Paliperidone ++ ? ? ? ?
Perospirone[74] + ? ? ? ?
Quetiapine ++ ++ +++ +++ ++
Risperidone +++ +++ ++ ? +
Sertindole ++ ? ? ? ?
Ziprasidone ++/+ ++/+ ? ? ?
Zotepine ++ ? ? ? ?

Legend: - clinically insignificant/very mild

+ mild

++ moderate

+++ severe

*Severe side effects; excluding neuroleptic malignant syndrome, tardive dyskinesia, QTc prolongation and metabolic syndrome consequences unless an incidence rate for it via the oral route is known.

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

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 (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.[citation needed]

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)[75] and an absence of sustained prolactin elevation.[42]

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.)[76] 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.[42]

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.[77] 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

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