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 tranquilizers 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 haloperidol — the most widely used typical antipsychotic — to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson's disease-type movements, body rigidity, and involuntary tremors. However, only a few of the atypicals 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/second generation" as opposed to "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."
- 1 Medical uses
- 2 Adverse effects
- 3 Pharmacology
- 4 History
- 5 Society and culture
- 6 Notes
- 7 References
- 8 Further reading
Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others.
The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of schizophrenia in about 8–15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall. Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia.
There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment.
The choice of which antipsychotic to use for a specific patient 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% of patients, 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 the remaining 20%. Clozapine is considered a first choice treatment for treatment-refactory schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice.
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. 
In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabilizer monotherapy may be attempted first. SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder.
Major depressive disorder
- Quetiapine — the only AAP approved as an adjunct for the treatment of MDD in Australia
- Risperidone Not approved for MDD
- Ziprasidone — which has only demonstrated adjunctive benefit in an open-label study.
Only aripiprazole, olanzapine, and quetiapine have specifically been approved for MDD by the FDA in the United States. Quetiapine and lurasidone have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.
Both risperidone and aripiprazole have received FDA labelling for autism.
Comparison table of efficacy
|Relative efficacy of SGAs|
|Generic Drug Name||Schizophrenia||Mania||Bipolar Maintenance||Bipolar Depression||Adjunct in Major Depressive Disorder|
|Amisulpride||+++||?||?||?||? (+++ as a dysthymia monotherapy, however)|
|Asenapine||+++||++||++||? (some evidence has suggested efficacy in treating depressive symptoms in mixed/manic episodes)||?|
|Olanzapine||+++||+++||++||+++/++ (+++ when combined with fluoxetine)||++|
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. 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 risk. 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. 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 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-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.
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.
Comparison table of adverse effects
|Comparison of side effects for atypical antipsychotics|
|Generic Name||Weight gain||Metabolic Effects||EPS||High
|Sedation||Hypotension / Orthostasis||QTc prolongation||Anti-ACheffects||Other adverse effects|
|Amisulpride||+||+||+||++||-||-||+++||-||Seizures, suicidal ideation|
|Aripiprazole||0‑10%||0‑10%||10-20%||-||10-20%||0‑10%||-||-||Seizures (0.1-0.3%), anxiety, rhabdomyolysis, pancreatitis (<0.1%), agranulocytosis (<1%), leukopenia, neutropenia, suicidal ideation, angioedema (0.1-1%)|
|Asenapine||0‑10%||20%||0‑10%||0‑10%||10-20%||0‑10%||+||-||Immune hypersensitivity reaction, angioedema, suicidal ideation|
|Clozapine||20‑30%||0‑15%||-||-||>30%||20‑30%||+||+++||Seizures (3-5%), agranulocytosis (1.3%), leukopenia, pneumonia, respiratory arrest, angle-closure glaucoma, eosinophilia (1%), thrombocytopenia, Stevens-Johnson syndrome, myocarditis, erythema multiforme and abnormal peristalsis|
|Iloperidone||0‑10%||0‑10%||0‑10%||-||10-20%||0‑10%||++||-||Suicidal ideation (0.4-1.1%), syncope (0.4%)|
|Lurasidone||-||-||>30%||-||20‑30%||-||+||+||Agranulocytosis, seizures (<1%), elevated serum creatinine (2-4%)|
|Melperone||+||+||+/-||-||+/++||+/++||++||-||Agranulocytosis, neutropenia and leukopenia|
|Olanzapine||20‑30%||0‑15%||20‑30%||20‑30%||>30%||0‑10%||+||+||Acute haemorrhagic pancreatitis, immune hypersensitivity reaction, seizures (0.9%), status epilepticus, suicidal ideation (0.1-1%)|
|Paliperidone||0‑10%||-||10-20%||>30%||20‑30%||0‑10%||+/- (7%)||-||Agranulocytosis, leukopenia, priapism, dysphagia, hyperprolactinaemia, sexual dysfunction|
|Perospirone||?||?||>30%||+||+||+||?||-||Insomnia in up to 23%, CPK elevation neuroleptic malignant syndrome|
|Quetiapine||20‑30%||0‑15%||10-20%||-||>30%||0‑10%||++||+||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||+/-||-||-||-||-||+/-||?||-||There is a risk of aplastic anaemia risk which is what led to its removal from the market.|
|Risperidone||10-20%||0‑10%||20‑30%||>30%||>30%||0‑10%||+||-||Syncope (1%), pancreatitis, hypothermia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, hyperprolactinaemia, sexual dysfunction, thrombotic thrombocytopenic purpura, cerebrovascular incident (<5%), tardive dyskinesia (<5%), priapism, neuroleptic malignant syndrome (<1%), gynecomastia, galactorrhea|
|Ziprasidone||0‑10%||0‑10%||0‑10%||-||20‑30%||0‑10%||++||-||Syncope (0.6%), dysphagia (0.1-2%), bone marrow suppression, seizure (0.4%), priapism|
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The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia.
D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. Unfortunately, it’s not possible to affect D2 receptors only in the mesolimbic pathway.[Stahl AP Explained 1 - 1] Fortunately, 5-HT2A receptor antagonism reverses these side effects to some extent.[Stahl AP Explained 1 - 2] Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure, motivation, and the salience of one’s life experience. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism here further compounds these problems. In the nigrostratial pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea.[Stahl AP Explained 1 - 1]
5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release.[Stahl AP Explained 1 - 2] This brake is disrupted through action of a 5-HT2A antagonist, which cuts the brake cable, disinhibiting the dopamine neuron, and stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system.[Stahl AP Explained 1 - 2] In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation.[Stahl AP Explained 1 - 3] Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism.[Stahl AP Explained 1 - 3] When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced.[Stahl AP Explained 1 - 3] Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.[Stahl AP Explained 1 - 3]
Some effects of 5-HT1A receptor activation include decreased aggressive behavior/ideation, increased sociability, and decreased anxiety and depression.[non-primary source needed] 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, for example ziprasidone. Increased norepinephrine can cause increased glucose levels, which is to say blood sugar levels. Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. Inhibition of norepinephrine stabilizes mood in humans. 5-HT6 receptor antagonists improve cognition, learning, and memory. The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, but it creates a risk for a prolonged QTc interval. On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalizes the dopamine level in the brain. This occurs with haloperidol and aripiprazole.
Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilization, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.
Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation.
Note: Unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed.
|Aripiprazole||+||++++ (PA)||+++ (PA)||+ (PA)||+++ (PA)||+||+++||++ (PA)||+||+++ (PA)||++/+||+||-||-||++/+|
|Blonanserin||-||++++||++++||+||-||?||+++||+||+||+/-||+ (RC)||+ (RC)||+||?||-|
|Cariprazine||++++ (PA)||+++++ (PA)||++++ (PA)||+++||++||++||++||-||-||+++|
|Ziprasidone||+++/++||+++||+++||+++/++||+++ (PA)||+++ (PA)||++++||+++(PA)||++||+++||+++/++||++||-||-||++|
|Zotepine||+++/++||+++||++++/+++||+++||++ (PA)||+++||++++||++++ (RC)||++++||++++/+++||+++||+++/++||++ (RC)||++ (RC)||++++|
|No Affinity or No Data|
|RC||Cloned Rat Receptor|
Atypical antipsychotics are most commonly administered orally. Antipsychotics can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood–brain barrier and placental barriers. Once in the brain, the antipsychotics work at the synapse by binding to the receptor. Antipsychotics are completely metabolized in the body and the metabolites are excreted in 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. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released.
|Pharmacokinetic parameters of available atypical antipsychotics|
|Drug||Route(s) of Administration[Note 1]||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)|
|Amisulpride||Oral||12||5.8||16%||Urine (50%), faeces (20%; 70% of this is as unchanged drug)[Note 2]||?||48%||Two peaks: 1 hr & 3-4 hrs post-oral dosing||39±3 (1 hr), 54±4 (3-4 hrs)|
|Aripiprazole||Oral, intramuscular (including depot)||75 (94 for active metabolite)||4.9||99%||Faeces (55%), urine (25%)||CYP2D6 & CYP3A4||87% (Oral), 100% (IM)||3-5||?|
|Asenapine||Sublingual||24||20-25||95%||Urine (50%), faeces (40%)||CYP1A2 & UGT1A4||35% (sublingual), <2% (Oral)||0.5-1.5||4|
|Blonanserin||Oral||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||Oral||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||Oral||?||1340-2800||95%||Urine (45-58%), faeces (20-22%)||CYP2D6 & CYP3A4||96%||2-4||?|
|Lurasidone||Oral||18||6173||99%||Faeces (80%), urine (9%)||CYP3A4||9-19%||1-3||?|
|Melperone||Oral, intramuscular||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||Oral, intramuscular (including depot)||30||1000||93%||Urine (57%), faeces (30%)||CYP1A2, CYP2D6||>60%||6 (Oral)||?|
|Paliperidone||Oral, intramuscular (including depot)||23 (Oral)||390-487||74%||Urine (80%), faeces (11%)||CYP2D6, CYP3A4||28%||24 (Oral)||?|
|Perospirone||Oral||?||?||92%||Urine (0.4% as unchanged drug)||?||?||1.5||1.9-5.7|
|Quetiapine||Oral||6 (IR), 7 (XR)||6-14||83%||Urine (73%), faeces (20%)||CYP3A4||100%||1.5 (IR), 6 (XR)||?|
|Risperidone||Oral, intramuscular (including depot)||3 (EM) (oral), 20 (PM) (oral)||1-2||90%, 77% (metabolite)||Urine (70%), faeces (14%)||CYP2D6||70%||3 (EM), 17 (PM)||?|
|Sertindole||Oral||72 (55-90)||20||99.5%||Urine (4%), faeces (46-56%)||CYP2D6||74%||10||?|
|Ziprasidone||Oral, intramuscular||7 (oral)||1.5||99%||Faeces (66%), urine (20%)||CYP3A4 & CYP1A2||60% (Oral), 100% (IM)||6-8||?|
The first major tranquilizer or antipsychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favor due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged 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), requiring blood monitoring for the patient. 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 atypical anti-psychotic paliperidone was approved by the FDA in late 2006.
The atypical antipsychotics have found favor 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 characteristics of atypical antipsychotics are the decreased incidence of 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 antipsychotics are superior to first generation typical anti-psychotics. Using a number of parameters to assess quality of life, Manchester University researchers found that typical antipsychotics were no worse than atypical antipsychotics. 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.
Society and culture
|Regulatory status of second-generation antipsychotics (SGAs) as of July 2013[update]|
|Generic name||United States
- The route of administration in this category refers to the standard means of administration when the drug is being used in its capacity as an atypical antipsychotic, not for other purposes. For example, amisulpride can be administered intravenously as an antiemetic drug but this is not its standard route of administration when being used as an antipsychotic
- Note these values are from a study in of which amisulpride was intravenously administered
Stahl: AP Explained 1
- Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (January 2009). "Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis". Lancet. 373 (9657): 31–41. doi:10.1016/S0140-6736(08)61764-X. PMID 19058842.
- Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
- "A roadmap to key pharmacologic principles in using antipsychotics". Primary Care Companion to the Journal of Clinical Psychiatry. 9 (6): 444–54. 2007. doi:10.4088/PCC.v09n0607. PMC . PMID 18185824.
- Tyrer P, Kendall T (January 2009). "The spurious advance of antipsychotic drug therapy". Lancet. 373 (9657): 4–5. doi:10.1016/S0140-6736(08)61765-1. PMID 19058841.
- "Respiridone". The American Society of Health-System Pharmacists. Retrieved April 3, 2011.
- Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG (September 2011). "Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis". JAMA. 306 (12): 1359–69. doi:10.1001/jama.2011.1360. PMID 21954480.
- American Geriatrics Society 2012 Beers Criteria Update Expert Panel (April 2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults". Journal of the American Geriatrics Society. 60 (4): 616–31. doi:10.1111/j.1532-5415.2012.03923.x. PMC . PMID 22376048.
- National Collaborating Centre for Mental Health. Gaskell and the British Psychological Society. Schizophrenia: Full national clinical guideline on core interventions in primary and secondary care [PDF]; 2009-03-25.
- Aleman A, Lincoln TM, Bruggeman R, Melle I, Arends J, Arango C, Knegtering H (August 2017). "Treatment of negative symptoms: Where do we stand, and where do we go?". Schizophrenia Research. 186: 55–62. doi:10.1016/j.schres.2016.05.015. PMID 27293137.
- Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P (July 2015). "Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials". Schizophrenia Bulletin. 41 (4): 892–9. doi:10.1093/schbul/sbu170. PMC . PMID 25528757.
- Murray RM, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O; et al. (2016). "Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?". Br J Psychiatry (Submitted manuscript). 209 (5): 361–365. doi:10.1192/bjp.bp.116.182683. PMID 27802977.
- van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
- Kane JM, Correll CU (2010). "Pharmacologic treatment of schizophrenia". Dialogues in Clinical Neuroscience. 12 (3): 345–57. PMC . PMID 20954430.
- Schultz SH, North SW, Shields CG (June 2007). "Schizophrenia: a review". American Family Physician. 75 (12): 1821–9. PMID 17619525.
- Smith T, Weston C, Lieberman J (August 2010). "Schizophrenia (maintenance treatment)". American Family Physician. 82 (4): 338–9. PMID 20704164.
- Siskind D, McCartney L, Goldschlager R, Kisely S (2016). "Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis". Br J Psychiatry. 209 (5): 385–392. doi:10.1192/bjp.bp.115.177261. PMID 27388573.
- Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS (February 2011). "Increasing off-label use of antipsychotic medications in the United States, 1995-2008". Pharmacoepidemiology and Drug Safety. 20 (2): 177–84. doi:10.1002/pds.2082. PMC . PMID 21254289.
- Geddes J, Freemantle N, Harrison P, Bebbington P (December 2000). "Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis". BMJ. 321 (7273): 1371–6. doi:10.1136/bmj.321.7273.1371. PMC . PMID 11099280.
- Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (September 2005). "Effectiveness of antipsychotic drugs in patients with chronic schizophrenia". The New England Journal of Medicine. 353 (12): 1209–23. doi:10.1056/NEJMoa051688. PMID 16172203.
- Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK (April 2006). "Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic". The American Journal of Psychiatry. 163 (4): 611–22. doi:10.1176/appi.ajp.163.4.611. PMID 16585435.
- Voruganti LP, Baker LK, Awad AG (March 2008). "New generation antipsychotic drugs and compliance behaviour". Current Opinion in Psychiatry. 21 (2): 133–9. doi:10.1097/YCO.0b013e3282f52851. PMID 18332660.
- Paczynski RP, Alexander GC, Chinchilli VM, Kruszewski SP (January 2012). "Quality of evidence in drug compendia supporting off-label use of typical and atypical antipsychotic medications". The International Journal of Risk & Safety in Medicine. 24 (3): 137–46. doi:10.3233/JRS-2012-0567. PMID 22936056.
- Owens DC (2008). "How CATIE brought us back to Kansas: A critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia". Advances in Psychiatric Treatment. 14: 17–28. doi:10.1192/apt.bp.107.003970.
- Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, Klein HE (2008). "Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group 'Drugs in Psychiatry' (AGATE)". Neuropsychobiology. 57 (1–2): 80–7. doi:10.1159/000135641. PMID 18515977.
- Whitaker R (2010). Anatomy of an Epidemic. Crown. p. 303.
- Taylor D, Paton C, Kapur S (2012). The Maudsley Prescribing Guidelines (12th ed.). Informa Healthcare. pp. 12–152, 173–196, 222–235.
- Soreff S, McInnes LA, Ahmed I, Talavera F (5 August 2013). "Bipolar Affective Disorder Treatment & Management". Medscape Reference. WebMD. Retrieved 10 October 2013.
- Post RM, Keck P (30 July 2013). "Bipolar Disorder in adults: Maintenance treatment". UpToDate®. Wolters Kluwer Health. Retrieved 10 October 2013.
- Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (December 2010). "Second-generation antipsychotics for major depressive disorder and dysthymia". The Cochrane Database of Systematic Reviews (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID 21154393.
- Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (2013). "Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes". PLoS Medicine. 10 (3): e1001403. doi:10.1371/journal.pmed.1001403. PMC . PMID 23554581.
- Nelson JC, Papakostas GI (September 2009). "Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials". The American Journal of Psychiatry. 166 (9): 980–91. doi:10.1176/appi.ajp.2009.09030312. PMID 19687129.
- Dunner DL, Amsterdam JD, Shelton RC, Loebel A, Romano SJ (July 2007). "Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label, pilot study". The Journal of Clinical Psychiatry. 68 (7): 1071–7. doi:10.4088/jcp.v68n0714. PMID 17685744.
- Maneeton N, Maneeton B, Srisurapanont M, Martin SD (September 2012). "Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials". BMC Psychiatry. 12: 160. doi:10.1186/1471-244X-12-160. PMC . PMID 23017200.
- Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
- Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD (August 2004). "A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features". Journal of Clinical Psychopharmacology. 24 (4): 365–73. doi:10.1097/01.jcp.0000130557.08996.7a. PMID 15232326.
- Roberts RJ, Lohano KK, El-Mallakh RS (September 2016). "Antipsychotics as antidepressants". Asia-Pacific Psychiatry. 8 (3): 179–88. doi:10.1111/appy.12186. PMID 25963405.
- Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR (October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet. 378 (9799): 1306–15. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976.
- Foster A, Dagenais F, Letts G, Rokach J (May 1989). "Metabolism of leukotriene C4 in the anesthetized guinea pig". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 36 (2): 93–6. PMC . PMID 19851515.
- Taylor DM, Cornelius V, Smith L, Young AH (December 2014). "Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis". Acta Psychiatrica Scandinavica. 130 (6): 452–69. doi:10.1111/acps.12343. PMID 25283309.
- Szegedi A, Zhao J, van Willigenburg A, Nations KR, Mackle M, Panagides J (June 2011). "Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials" (PDF). BMC Psychiatry. 11: 101. doi:10.1186/1471-244X-11-101. PMC . PMID 21689438.
- Kishi T, Iwata N (September 2013). "Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials". CNS Drugs. 27 (9): 731–41. doi:10.1007/s40263-013-0085-7. PMID 23812802.
- Stroup TS, Marder S, Stein MB (23 October 2013). "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment". UpToDate®. Wolters Kluwer. Retrieved 10 October 2013.
- Kabinoff GS, Toalson PA, Healey KM, McGuire HC, Hay DP (February 2003). "Metabolic Issues With Atypical Antipsychotics in Primary Care: Dispelling the Myths". Primary Care Companion to the Journal of Clinical Psychiatry. 5 (1): 6–14. doi:10.4088/PCC.v05n0103. PMC . PMID 15156241.
- Uçok A, Gaebel W (February 2008). "Side effects of atypical antipsychotics: a brief overview". World Psychiatry. 7 (1): 58–62. doi:10.1002/j.2051-5545.2008.tb00154.x. PMC . PMID 18458771.
- McKim W (2007). Antipsychotics in Drugs and Behavior: An Introduction to Behavioral Pharmacology. Upper Saddle River, NJ.: Pearson Prentice Hall. pp. 241–60.
- McKim W (2007). Psychomotor Stimulants in Drugs and Behavior: An Introduction to Behavioral Pharmacology. Upper Saddle River, NJ.: Pearson Prentice Hall. pp. 241–60.
- Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC (January 2010). "Impact of FDA black box advisory on antipsychotic medication use". Archives of Internal Medicine. 170 (1): 96–103. doi:10.1001/archinternmed.2009.456. PMC . PMID 20065205.
- Seeman P (February 2002). "Atypical antipsychotics: mechanism of action". Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie. 47 (1): 27–38. PMID 11873706.
- Correll CU, Schenk EM (March 2008). "Tardive dyskinesia and new antipsychotics". Current Opinion in Psychiatry. 21 (2): 151–6. doi:10.1097/YCO.0b013e3282f53132. PMID 18332662.
- "Consensus development conference on antipsychotic drugs and obesity and diabetes". Diabetes Care. 27 (2): 596–601. February 2004. doi:10.2337/diacare.27.2.596. PMID 14747245.
- Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill Professional. pp. 417–455.
- Guenette MD, Giacca A, Hahn M, Teo C, Lam L, Chintoh A, Arenovich T, Remington G (May 2013). "Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model". Schizophrenia Research. 146 (1–3): 162–9. doi:10.1016/j.schres.2013.02.023. PMID 23499243.
- "Comparison of Common Side Effects of Second Generation Atypical Antipsychotics". Facts & Comparisons. Wolters Kluwer Health. Retrieved 2012-03-31. (Subscription required (. ))
- Park YW, Kim Y, Lee JH (December 2012). "Antipsychotic-induced sexual dysfunction and its management". The World Journal of Men's Health. 30 (3): 153–9. doi:10.5534/wjmh.2012.30.3.153. PMC . PMID 23596605.
- Onrust SV, McClellan K (2001). "Perospirone". CNS Drugs. 15 (4): 329–37; discussion 338. doi:10.2165/00023210-200115040-00006. PMID 11463136.
- Holm AC, Edsman I, Lundberg T, Odlind B (June 1993). "Tolerability of remoxipride in the long term treatment of schizophrenia. An overview". Drug Safety. 8 (6): 445–56. doi:10.2165/00002018-199308060-00005. PMID 8329149.
- "Risperdal, gynecomastia and galactorrhea in adolescent males". Allnurses.com. Retrieved 2016-09-30.
- Stahl S. Antipsychotics Explained 1 (PDF). University Psychiatry. Retrieved December 6, 2017.
- Stephen M. Stahl (2008-03-27). Antipsychotics and Mood Stabilizers: Stahl's Essential Psychopharmacology . Books.google.se. p. 105. ISBN 9780521886642. Retrieved 2016-09-30.
- Egerton A, Ahmad R, Hirani E, Grasby PM (November 2008). "Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat". Psychopharmacology. 200 (4): 487–96. doi:10.1007/s00213-008-1226-4. PMID 18597077.
- de Boer SF, Koolhaas JM (December 2005). "5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis". European Journal of Pharmacology. 526 (1–3): 125–39. doi:10.1016/j.ejphar.2005.09.065. PMID 16310183.
- "norepinephrine". Cardiosmart.org. 2010-12-15. Retrieved 2016-09-30.
- Veves A, Malik RA (2008-02-01). Diabetic Neuropathy: Clinical Management. Books.google.se. p. 401. ISBN 9781597453110. Retrieved 2016-09-30.
- "Epinephrine and Norepinephrine". Boundless.com. Retrieved 2016-09-30.
- "Cariprazine - Side Effects, Uses, Dosage, Overdose, Pregnancy, Alcohol". RxWiki.com. Retrieved 2016-09-30.
- "INVEGA® Side Effects - Schizophrenia Treatment – INVEGA® (paliperidone)". Invega.com. 2016-05-17. Retrieved 2016-09-30.
- "Diabetes Update: Hunger is a Symptom". Diabetesupdate.blogspot.se. 2007-08-08. Retrieved 2016-09-30.
- "High & Low Blood Sugar". Healthvermont.gov. Retrieved 2016-09-30.
- "REXULTI® (brexpiprazole) | Important Safety Information". Rexulti.com. Retrieved 2016-09-30.
- Stephen M. Stahl (2008-03-27). Antipsychotics and Mood Stabilizers: Stahl's Essential Psychopharmacology . Books.google.se. p. 172. ISBN 9780521886642. Retrieved 2016-09-30.
- King MV, Marsden CA, Fone KC (September 2008). "A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory". Trends in Pharmacological Sciences. 29 (9): 482–92. doi:10.1016/j.tips.2008.07.001. PMID 19086256.
- Shahid M, Walker GB, Zorn SH, Wong EH (January 2009). "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature". Journal of Psychopharmacology. 23 (1): 65–73. doi:10.1177/0269881107082944. PMID 18308814.
- "Pharmcology Reviews : 200603" (PDF). Accessdata.fda.gov. Retrieved 2016-09-30.
- Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R, Matsumoto K, Nishikawa H, Ueda Y, Toma S, Oki H, Tanno N, Saji I, Ito A, Ohno Y, Nakamura M (July 2010). "Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity". The Journal of Pharmacology and Experimental Therapeutics. 334 (1): 171–81. doi:10.1124/jpet.110.167346. PMID 20404009.
- National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 10]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: "Archived copy". Archived from the original on 2013-11-08. Retrieved 2016-05-16.
- Hemmings HC, Egan TD (2013). Pharmacology and Physiology for Anesthesia: Foundations and Clinical . Books.google.se. p. 209. ISBN 978-1437716795. Retrieved 2016-09-30.
- Margaret Jordan Halter (2014-03-12). Varcarolis' Foundations of Psychiatric Mental Health Nursing: A Clinical . Books.google.se. p. 61. ISBN 9781455728886. Retrieved 2016-09-30.
- Tasman A, Kay J, First MB, Lieberman JA, Riba M (2015-03-30). Psychiatry, 2 Volume Set. John Wiley & Sons. ISBN 978-1-118-84547-9.
- "FDA : Psychopharmacological Drugs Advisory Committee : Briefing Document for ZELDOX CAPSULES (Ziprasidone HCl)" (PDF). Fda.gov. July 19, 2000. Retrieved 2016-09-30.
- Wouters W, Tulp MT, Bevan P (May 1988). "Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors". European Journal of Pharmacology. 149 (3): 213–23. doi:10.1016/0014-2999(88)90651-6. PMID 2842163.
- Horiuchi J, McDowall LM, Dampney RA (November 2008). "Role of 5-HT(1A) receptors in the lower brainstem on the cardiovascular response to dorsomedial hypothalamus activation". Autonomic Neuroscience. 142 (1–2): 71–6. doi:10.1016/j.autneu.2008.06.004. PMID 18667366.
- Weber S, Volynets V, Kanuri G, Bergheim I, Bischoff SC (December 2009). "Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice". International Journal of Obesity. 33 (12): 1339–47. doi:10.1038/ijo.2009.191. PMID 19823183.
- Gobbi G, Janiri L (December 1999). "Clozapine blocks dopamine, 5-HT2 and 5-HT3 responses in the medial prefrontal cortex: an in vivo microiontophoretic study". European Neuropsychopharmacology. 10 (1): 43–9. doi:10.1016/S0924-977X(99)00055-3. PMID 10647096.
- Navari RM (January 2014). "Olanzapine for the prevention and treatment of chronic nausea and chemotherapy-induced nausea and vomiting". European Journal of Pharmacology. 722: 180–6. doi:10.1016/j.ejphar.2013.08.048. PMID 24157985.
- Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina. Archived from the original on November 8, 2013. Retrieved 10 October 2013.
- Culpepper, 2007[verification needed]
- McKim, 2007[verification needed]
- "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.[full citation needed]
- "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.[full citation needed]
- "Daily Med – Home page". U.S. National Library of Medicine. Retrieved 27 November 2013.[full citation needed]
- Deeks ED, Keating GM (January 2010). "Blonanserin: a review of its use in the management of schizophrenia". CNS Drugs. 24 (1): 65–84. doi:10.2165/11202620-000000000-00000. PMID 20030420.
- Product Information: Eunerpan(R), Melperonhydrochlorid. Knoll Deutschland GmbH, Ludwigshafen, 1995.
- Borgström L, Larsson H, Molander L (1982). "Pharmacokinetics of parenteral and oral melperone in man". European Journal of Clinical Pharmacology. 23 (2): 173–6. doi:10.1007/BF00545974. PMID 7140807.
- Product Information: Nipolept(R), zotepine. Klinge Pharma GmbH, Munich, 1996.
- Tanaka O, Kondo T, Otani K, Yasui N, Tokinaga N, Kaneko S (February 1998). "Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects". Therapeutic Drug Monitoring. 20 (1): 117–9. doi:10.1097/00007691-199802000-00021. PMID 9485566.
- Farah A (2005). "Atypicality of atypical antipsychotics". Primary Care Companion to the Journal of Clinical Psychiatry. 7 (6): 268–74. doi:10.4088/PCC.v07n0602. PMC . PMID 16498489.
- Weiden PJ (January 2007). "EPS profiles: the atypical antipsychotics are not all the same". Journal of Psychiatric Practice. 13 (1): 13–24. doi:10.1097/00131746-200701000-00003. PMID 17242588.
- Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW (October 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)". Archives of General Psychiatry. 63 (10): 1079–87. doi:10.1001/archpsyc.63.10.1079. PMID 17015810.
- "Drug Product Database Online Query". Government of Canada, Health Canada, Public Affairs, Consultation and Regions Branch. Retrieved February 1, 2018.
- "Search the TGA website". Australian Government Department of Health, Therapeutic Goods Administration. Retrieved February 2, 2018.
- "European Medicines Agency: Search". European Medicines Agency. Retrieved February 2, 2018. Search
- "Search". Pharmaceuticals and Medical Devices Agency. Retrieved February 2, 2018.
- "Medicines Information: SPC & PILs". Medicines and Healthcare products Regulatory Agency. Retrieved February 2, 2018.
- "Guidance: Antipsychotic medicines". Medicines & Healthcare products Regulatory Agency. August 25, 2005. Retrieved February 2, 2018.
- Elmorsy E, Smith PA (May 2015). "Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics". Biochemical and Biophysical Research Communications. 460 (3): 857–62. doi:10.1016/j.bbrc.2015.03.122. PMID 25824037.
- Simpson GM (September 2005). "Atypical antipsychotics and the burden of disease". The American Journal of Managed Care. 11 (8 Suppl): S235–41. PMID 16180961.
- New antipsychotic drugs carry risks for children (USA Today 2006)
- "NIMH Study to Guide Treatment Choices for Schizophrenia" (Press release). National Institute of Mental Health. September 19, 2005. Archived from the original on September 2, 2013. Retrieved August 18, 2013.