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Atypical antipsychotic

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) largely introduced after the 1970s and 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, irritability in 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 occur. Critics have argued that "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction."

Medical uses
Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, persecutory delusion 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.

Schizophrenia
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 resistant schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. In turn, risperidone, olanzapine, and aripiprazole have been recommended for the treatment of first-episode psychosis.

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, mid-potency 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.

Each drug has its own mechanism, as Dr. Rif S. El-Mallakh, explained regarding the binding site and occupancy with a focus on the dopamine D2 receptor:"In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor. Similarly, despite significant variability in antidepressant response, blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants, or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline—is necessary for these medications to be effective.... Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations. Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%. Since aripiprazole has an intrinsic activity of approximately 30% (i.e., when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls. Clinically, this still appears as the minimal effective dose achieving maximal response without significant parkinsonism despite >90% receptor occupancy."

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

 * Aripiprazole
 * Brexpiprazole
 * Cariprazine
 * Olanzapine
 * Quetiapine
 * Ziprasidone

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

Aripiprazole, brexpiprazole, cariprazine, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States. Cariprazine, Quetiapine, lurasidone, and lumateperone have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Autism
Both risperidone and aripiprazole have received FDA approval for irritability in autism.

Dementia and Alzheimer's disease
Between May 2007 and April 2008, Dementia and Alzheimer's together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. The U.S. Food and Drug Administration requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%. As of now, the only FDA-approved atypical antipsychotic for alzheimer-related dementia is brexpiprazole.

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 if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

Among the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. Kabinoff and colleagues (2003) found that the increase in cardiovascular disease is seen regardless of the treatment received, and that it is instead 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 antipsychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent), 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 antipsychotic 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. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants).

Drug-induced OCD
Many different types of medication can induce in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD.

There are reports that some atypical antipsychotics could cause drug-induced OCD in already schizophrenic patients.

Tardive dyskinesia
All of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.

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

Metabolism
Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the Food and Drug Administration (FDA) required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the risks of hyperglycemia and diabetes with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labeling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity. The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H1 and 5-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.

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.

The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole. In a meta-analysis of 18 antipsychotics, olanzapine and clozapine exhibited the worst metabolic parameters and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign parameters. Aripiprazole, asenapine, ziprazidone and lurasidone have low propensity to cause weight gain. Lumateperone was found to cause minimal weight gain in a long-term 12 month follow-up study.

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. Prescribing topiramate, zonisamide, metformin, GLP-1 receptor agonists, or nizatidine alongside an antipsychotic significantly reduces weight gain.

Despite increasing some risk factors, SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders.

Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacodynamics
The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (DA) 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. It's not possible to affect D2 receptors only in the mesolimbic pathway, but 5-HT2A receptor antagonism reverses these side effects to some extent. Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure and motivation. 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 further compounds these problems. In the nigrostriatal 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.

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. This brake is disrupted through action of a 5-HT2A antagonist, which disinhibits the dopamine neuron, 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. In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. 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. 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. 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.

Brexpiprazole, approved by the US FDA in 2015, has a similar binding profile to aripiprazole as a partial D2 agonist with moderate histamine binding, but with brexipiprazole has a higher affinity for serotonin receptor 5-HT2A

Some effects of 5-HT1A receptor activation include decreased aggressive behavior/ideation, increased sociability, and decreased anxiety and depression. 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, e.g. ziprasidone. Increased norepinephrine can cause increased glucose(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 cariprazine 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.

Terms
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.

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

Legend:

Pharmacokinetics
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.

History
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 for widespread use. During the 1990s, olanzapine, risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The atypical antipsychotic 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 antipsychotics. 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
Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above.

Despite the name "antipsychotics", the drugs are commonly used for a variety of conditions that do not involve psychosis. Some healthcare professionals reported avoiding the name "atypical antipsychotic" when prescribing the drug to patients who had bipolar disorder.

title: Atypical antipsychotic


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Eurovision Song Contest 1987

The Eurovision Song Contest 1987 was the 32nd edition of the annual Eurovision Song Contest. It took place in Brussels, Belgium, following the country's victory at the with the song "J'aime la vie" by Sandra Kim. Organised by the European Broadcasting Union (EBU) and host broadcaster Radio-télévision belge de la Communauté française (RTBF), the contest was held at the Centenary Palace on 9 May 1987 (also Europe Day) and hosted by French-Belgian singer Viktor Lazlo.

Twenty-two countries took part in the contest with and  returning to the competition after their absences the previous year. This set the record for the highest number of competing countries up until that point.

The winner was with the song "Hold Me Now" by Johnny Logan, who had also won the  contest. He became the first performer to have won the Eurovision Song Contest twice.

Location

The contest took place at the Brussels Exhibition Centre (Brussels Expo) in Brussels, Belgium. These are a set of exhibition halls built from 1930 on the Heysel/Heizel Plateau (Heysel Park) in Laeken (northern part of the City of Brussels) to celebrate the centenary of Belgian Independence. The Centenary Palace (Palais du Centenaire, Eeuwfeestpaleis), where the main stage was located, is one of the remaining buildings of the Brussels International Exposition of 1935. Currently, it is still being used for trade fairs, as well as concerts, usually for bigger acts and artists.

Host city selection process
During the selection process of the host city and venue, a joint committee from the two belgium broadcasters was created by EBU. The committee also decided that a potential place for the contest was the Royal Theatre of Antwerp, as both locations proposed by RTBF (the Palais du Centenaire in Brussels and the Patinoire de Coronmeuse in Liege),but they would have required heavy renovation works to meet the proposed tecnical specifications for the contest. Nevertheless, RTBF demanded the event to be held in Brussels with the argument that the city symbolized more than the Belgium capital itself, in addition to its federal functions as the capital of the country (but almost all governing bodies of the European Union also located there). On 6 October 1986, seven months ahead of the contest, RTBF surprisingly and one-sidedly announced that the Palais du Centenaire was chosen as the host venue for the Eurovision Song Contest 1987. The Flemish newspaper Het Laatste Nieuws, published that BRT proposed instead to host the contest at the Cirque Royal, near the Royal Palace of Brussels, adding that RTBF would be solely in charge of organizing the contest if BRT's counteroffer was not chosen. However, RTBF moved forward alone with its plans and confirmed that the Palais du Centenaire was the official contest's host venue. BRT was offended by the choice of Brussels as the host city, and withdrew from the organization, but kept the duties to choose the host's country contestant.

Participating countries
The 1987 Eurovision was the biggest contest to date, and it was also the first in which 22 countries competed. Only, and  failed to compete out of all the countries which had entered the contest in the past. To date, this was the largest number of countries participating in the contest, with the maximum number up until then being 20. As this had never happened, the EBU was forced to review the rules and production calendar after this edition.And fearing that the number would increase again, it was decided that from this edition onwards the maximum number of participants would also be 22.This was a problematic question over the next six years as new and returning nations indicated an interest in participating, but they could not be accommodated.

Returning artists
Bold indicates a previous winner.

Host broadcaster rule
By 1986, Belgium has participated in the Eurovision Song Contest 30 times since making its debut at the first contest in along 6 other countries. Before Sandra Kim's win, Belgium was the only one of the 7 founding countries to have never won the contest and had only twice finished in the top five (with Tonia's fourth place in and Jean Vallée's second place in ).

Sandra Kim's Eurovision victory in 1986 occurred amidst a complex political situation in Belgium. The country was undergoing massive constitutional reforms in which the Belgian state was transitioning from a centralized to a federal system. This was due to rising tensions between the two major linguistic regions of Belgium, Dutch-speaking Flanders and French-speaking Wallonia. Both regions had had independent broadcasters since 1960 (BRT in Flanders and RTBF in Wallonia) but had still agreed to jointly host the contest in the event of a Belgian victory. While the triumph of "J'aime la vie" in 1986 – an entry sent by French-speaking RTBF – reignited a sense of national union across all Belgian regions, the two regional broadcasters weren't able to overcome their disagreements and  joint host the competition. During the production of the event, BRT eventually withdrew from the project and RTBF organised the contest alone as host broadcaster. BRT remained in charge of the selection of the Belgian entry for the contest. As a consequence, the host country images in Eurovision 1987 mostly showed footage of Wallonia.

Budget
Holding the contest in Belgium caused several legal changes in the country's system and forced the implementation of most of the modern rules and regulations on the monetization of public television. This led to the authorization of advertising, sponsorships and marketing actions in the two public channels in the country. As a consequence, the RTBF was also allowed to sell sponsorship quotas for the event, setting a new precedent for the Eurovision Song Contest.

For RTBF, this decision was a relief as the event was almost entirely funded with private funds. This opened the doors to the commercial potential of the event itself, starting a period of modernization and increased interest for the event. Apart from the latent tensions, after the end of the contest the then-president of the BRT Cas Goossens praised RTBF for their "perfect organization" while at the same time regretting that the two broadcasters weren't able to collaborate. He added that the cost of hosting Eurovision would have been difficult to justify to the Flemish taxpayers.

Spokespersons
Each country nominated a spokesperson who was responsible for announcing the votes for their respective country via telephone. Known spokespersons at the 1987 contest are listed below.

 * – An Ploegaerts
 * – Guðrún Skúladóttir
 * – Jan Ellerås
 * – Colin Berry
 * – Ljiljana Tipsarević

12 points
Below is a summary of all 12 points in the final:

Broadcasts
Each participating broadcaster was required to relay the contest via its networks. Non-participating EBU member broadcasters were also able to relay the contest as "passive participants". Broadcasters were able to send commentators to provide coverage of the contest in their own native language and to relay information about the artists and songs to their television viewers. Known details on the broadcasts in each country, including the specific broadcasting stations and commentators are shown in the tables below.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Eurovision Song Contest 1987


text:
Eurovision Song Contest 1986

The Eurovision Song Contest 1986 was the 31st edition of the annual Eurovision Song Contest. It was held in Bergen, Norway, following the country's victory at the with the song "La det swinge" by Bobbysocks! Organised by the European Broadcasting Union (EBU) and host broadcaster Norsk rikskringkasting (NRK), the contest was held at Grieghallen on 3 May 1986 and was hosted by previous Norwegian contestant Åse Kleveland.

Twenty countries took part in this year's contest with and  deciding not to participate and  and  returning. also competed for the first time this year.

The winner was with the song "J'aime la vie" by Sandra Kim. Belgium was the last of the original 7 countries that had competed in the first contest to win. Aged 13, Kim was the youngest ever Eurovision winner. Current rules require Eurovision Song Contest participants to be at least 16, so unless the rule is changed, Kim's record will never be broken. In the lyrics of her song, Kim claimed to be 15 years of age, but after the contest, it was revealed that she was actually 13. , who finished second, appealed for her to be disqualified, but was not successful.

The 1986 contest was a first for Eurovision in that royalty were among the guests—Crown Prince Harald, Crown Princess Sonja, Princess Märtha Louise and Prince Haakon Magnus were all in attendance.

Background

By 1985, Norway had received the unwanted distinction of being "the nul points country," receiving 0 points three times and coming in last six times. When they finally won the 1985 contest, it was a source of pride among the Norwegian population, and the national broadcaster, NRK, took full advantage of being able to showcase Norway and its achievements in front of over 500 million television viewers. By the autumn of 1985, NRK had decided to hold the next year's contest at the Grieghallen in Bergen, turning down other bids from capital Oslo, and main cities of Stavanger, Sandnes and Trondheim. Bergen is the northernmost city to have ever hosted the Eurovision Song Contest.

As this was the first time Norway hosted a Eurovision Song Contest, NRK commissioned a lavish budget for the event, turning Grieghallen into a Viking-esque "ice palace" for the live show, complete with white and pastel neon lights for the stage. In addition, NRK also had a special diamond-encrusted dress made for presenter Åse Kleveland for her opening number. The prized dress, which weighed upwards of 15 pounds (6.8 kg), is still available for viewing at NRK's costuming department at Marienlyst in Oslo.

Åse Kleveland, a well-known folk guitarist and singer, who was President of the Norwegian Association of Musicians and a former Eurovision entrant in, sang the multilingual "Welcome to Music" as the opening act, incorporating English and French primarily, in addition to other European languages. BBC commentator Terry Wogan, at the close of Kleveland's number, dryly remarked, "Katie Boyle (a former Eurovision host for the UK) never sang, did she?"

During her opening remarks, Kleveland said of Norway's road in the contest, "For those of you who have followed Norway's course through the history of the Eurovision Song Contest, you will know that it has been quite thorny, in fact. So, imagine our joy when last year we finally won, and the pleasure we feel today, being able to welcome 700 million viewers to the top of Europe, to Norway, and to Bergen."

The intersong videos introducing each participant, traditionally named 'postcards' were for the only time, represented as actual picture postcards sent from the artists to your own nation. Each video began with clips of various scenic views of a part of Norway, which then 'flipped' to reveal a message of greeting, written in the language of the upcoming song, alongside details of the title, author and composer. The postage stamp on each card (a representation of a genuine Norwegian postage stamp) was linked to the theme of the video content. The postcard then 'flipped' back to the picture side, where the performing artist had been superimposed onto the image. After the video, Åse Kleveland gave details of the entry and introduced the conductors in a mix of English and French, reading from cards represented by the flag of the upcoming country.

The main interval act presented featured Norwegian musicians, a hitherto unknown young woman outside of Norway, Sissel Kyrkjebø and the musician Steinar Ofsdal, accompanied by Norwegian national broadcasting orchestra, Kringkastingsorkesteret (KORK). They opened with the traditional song of the city of Bergen, Udsikter fra Ulriken (also known as "Nystemte'n"), and presented a number of familiar tunes while showing the sights and sounds of Bergen area. Ofsdal played a range of traditional Norwegian folk instruments such as accordion, recorder and hardingfele. This was Kyrkjebø's first performance on an international event, which served as the starting point for a consolidated international career years later.

Participating countries
competed for the first time, as the national broadcaster RÚV had finally cemented their satellite television connections with the rest of Europe.

withdrew, as the contest coincided with Holy Saturday on the Eastern Orthodox Church liturgical calendar. Their entry would have been "Wagon-lit" (Βάγκον λι), performed by Polina, who was backing vocalist of Elpida at the 1979 contest (Elpida represented Cyprus this year). Prior to their withdrawal, they were set to be 18th in the running order between and. Italian broadcaster RAI, on the other hand, decided not to send any delegation to Bergen.

Spokespersons
Each country nominated a spokesperson who was responsible for announcing the votes for their respective country via telephone. Known spokespersons at the 1986 contest are listed below.

 * – Guðrún Skúladóttir
 * – Agneta Bolme Börjefors
 * – Colin Berry

Detailed voting results
The winning song, Belgium's "J'aime la vie", received points from every jury (Belgium received five sets of 12 points; every country awarded Belgium at least five points except for Germany, which gave them just one point). Belgium was the leader in the voting from the results of the second jury out of twenty, in the longest winning stretch during voting since 1974. Switzerland was behind Belgium in nearly every part of the voting, but Belgium had a commanding lead from the very beginning. Traditionally some juries give high points to the host country's entrant, but this did not happen this year; no jury gave Norway's song "Romeo" more than six points out of a possible 12.

Belgium scored an absolute record at the time, with Sandra Kim earning a never seen before number of 176 points (that record remained seven years until the 1993 contest, with Ireland scoring 187 points), an average of 9.26 points per voting nation. Kim received 77.2% of the maximum possible score, which, as of 2023, still ranks 8th among all Eurovision winners.

12 points
Below is a summary of all 12 points in the final:

Broadcasts
Each participating broadcaster was required to relay the contest via its networks. Non-participating EBU member broadcasters were also able to relay the contest as "passive participants". Broadcasters were able to send commentators to provide coverage of the contest in their own native language and to relay information about the artists and songs to their television viewers. Known details on the broadcasts in each country, including the specific broadcasting stations and commentators are shown in the tables below.

title: Eurovision Song Contest 1986


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Partita

Partita (also partie, partia, parthia, or parthie ) was originally the name for a single-instrumental piece of music (16th and 17th centuries), but Johann Kuhnau (Thomaskantor until 1722), his student Christoph Graupner, and Johann Sebastian Bach used it for collections of musical pieces, as a synonym for suite.

Johann Sebastian Bach wrote two sets of partitas for different instruments. Those for solo keyboard the composer published as his Opus 1 (known as the Klavierübung I). One additional suite in B minor, the Overture in the French Style (often simply called French Overture) is sometimes also considered a partita. See Partitas for keyboard (825–830) and choral partitas for organ. The "Partita" in A minor for solo flute (BWV 1013) which takes the form of a suite of four dances, has been given the title "partita" by its modern editors; it is sometimes transposed for oboe.

Bach also wrote three partitas for solo violin in 1720 which he paired with sonatas. (He titled each of them the German Partia, but they came to be called the Italian partita, which was introduced in the Bach Gesellschaft edition in 1879, being the more common term at the time. ) See: Sonatas and partitas for solo violin.

The most prolific composer of partitas for harpsichord was Christoph Graupner, whose works in the form number about 57. The first set was published in 1718 and dedicated to his patron Ernest Louis, Landgrave of Hesse-Darmstadt. The last of his partitas exist in manuscripts dated 1750. They are difficult and virtuosic pieces which exhibit an astonishing variety of musical styles. See: List of harpsichord pieces by Christoph Graupner. The longest partita ever written so far is Shoah for Solo Violin and Sacred Temple by Jorge Grundman, which lasts an hour and a half and was finished in 2016.

Examples
Listed by composer:
 * Johann Paul von Westhoff: Partitas for solo violin
 * Johann Sebastian Bach;
 * Partita for Violin No. 1
 * Partita for Violin No. 2 (1720)
 * Partita for Violin No. 3
 * Partita in A minor for solo flute
 * Christoph Graupner
 * Monatliche Clavier Früchte, GWV 109–120. 12 Partitas for Harpsichord (1722)
 * 45 Partitas for Harpsichord (1718–1750)
 * Luigi Dallapiccola: Partita for orchestra (1932)
 * William Walton: Partita for Orchestra (1957)
 * Krzysztof Penderecki: Partita for Harpsichord and Orchestra (1972)
 * Philip Glass:
 * Partita for Double Bass (2015)
 * Partita No. 1 for Solo Cello, "Songs and Poems"
 * Partita No. 2 for Solo Cello
 * Jorge Grundman
 * Shoah for Solo Violin and Sacred Temple (2016)
 * Stephen Hough: Partita for piano (2019)

Audio files
Johann Kuhnau: a choral partita from 'Biblische Historien'. Here it is called 'Sonata 4' (a programmatic title is added). The tune or cantus firmus is the famous chorale O Haupt voll Blut und Wunden

title: Partita


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Eurovision Song Contest 1985

The Eurovision Song Contest 1985 was the 30th edition of the Eurovision Song Contest, held on 4 May 1985 in the Scandinavium in Gothenburg, Sweden. Organised by the European Broadcasting Union (EBU) and host broadcaster Sveriges Television (SVT), and presented by Lill Lindfors, the contest was held in Sweden following the country's victory at the with the song "Diggi-Loo Diggi-Ley" by Herreys..

Nineteen countries participated in the contest; and  returned after a one-year absence, while the  and, which had participated in the previous year's event, declined to enter due to separate memorial events in those countries coinciding with the date of the contest.

The winner was with the song "La det swinge", composed and written by Rolf Løvland and performed by the group Bobbysocks!. This was Norway's first contest victory, and only the third top five placing for a country which had placed last on six previous occasions, including three times receiving nul points. With a total of 123 points, "La det swinge" remains the lowest scoring winner under the voting system used between and. , Sweden, the and Israel rounded out the top five positions.

Location
The 1985 contest took place in Gothenburg, Sweden, following the country's victory at the with the song "Diggi-Loo Diggi-Ley" performed by Herreys. It was the second time that Sweden had hosted the event, ten years after the previous staging held in the country, when the was held in Stockholm. The chosen venue was the Scandinavium, an indoor arena inaugurated in 1971, home to the Frölunda HC ice hockey team and the venue of the annual Gothenburg Horse Show. The Scandinavium was chosen by host broadcaster Sveriges Television (SVT) from a number of bids submitted by various Swedish cities and venues; among those known to have been considered to stage the contest were the Berwald Hall in Stockholm and the Elmiahallen in Jönköping. The stadium's maximum capacity of 14,000 people was reduced to 8,000 attendees for the contest, in order to provide space for the stage and technical equipment;It should be noted that this contest was the first to be held in a multi-purpose arena and established several broadcasting standards still used in the contest today. Furthermore, until the construction of the Scotiabank Saddledome in 1983, this was the largest arena of its kind in the world and until the 2000 edition this was the largest venue and the largest assembled audience in the history of the contest. During the week leading up to the rehearsals and the televised grand final ,EBU and SVT held the official reception for the participating delegations, which was held on the evening of 1 May at Kronhuset.

Participating countries
Nineteen countries in total participated in the 1985 contest. and both returned following a one-year absence, however the  and, which had competed in the previous year's contest, declined to enter in 1985 as the date of the contest coincided with memorial days in the countries, specifically the Remembrance of the Dead, and the anniversary of the death of Yugoslav president Josip Broz Tito, respectively. It was the first time in the contest's history that there was no entry from the Netherlands, with the nation having previously competed in every event since its.

Several of the participating artists in this year's event had previously competed in past editions of the contest. Izhar Cohen, who had previously won the with the song "A-Ba-Ni-Bi" alongside the group Alphabeta, made a second contest appearance for  at this event; Hot Eyes represented  for a second consecutive year; Al Bano and Romina Power also made a second contest appearance for, having previously competed for the country in ; the two members of 's group Bobbysocks! had previously competed in the event separately, with Hanne Krogh having represented Norway in , and Elisabeth Andreasson previously competing for  in  as a member of the group Chips; Kikki Danielsson, who was also a member of Chips, competed in this event as a solo artist for Sweden; the Swiss duo Mariella Farré and Pino Gasparini had also previously competed in the contest for  on separate entries, with Farré having competed in  as a soloist, while Gasparini had been a member of the Pepe Lienhard Band which had represented Switzerland in ;  Gary Lux competed for  in this event as a solo artist, having previously represented the country in 1983 as a member of the group Westend; and Ireen Sheer, who had twice competed in Eurovision, for  in  and for  in 1978, represented Luxembourg again at this contest alongside five other artists. Additionally, 's Lia Vissi had previously participated as backing vocalist for at the contest on two separate occasions, in  and, the latter as a member of the group the Epikouri, and Rhonda Heath, who was a member of the group Silver Convention that had represented Germany in 1977, returned as a backing vocalist for Austria at this event.

Production and format
The Eurovision Song Contest 1985 was produced by the Swedish public broadcaster Sveriges Television (SVT). Steen Priwin served as executive producer and director, Ingemar Wiberg served as designer, and Curt-Eric Holmquist served as musical director, leading the orchestra. A separate musical director could be nominated by each country to lead the orchestra during their performance, with the host musical director also available to conduct for those countries which did not nominate their own conductor.

Each participating broadcaster submitted one song, which was required to be no longer than three minutes in duration and performed in the language, or one of the languages, of the country which it represented. A maximum of six performers were allowed on stage during each country's performance. Each entry could utilise all or part of the live orchestra and could use instrumental-only backing tracks, however any backing tracks used could only include the sound of instruments featured on stage being mimed by the performers.

The results of the 1985 contest were determined through the same scoring system as had first been introduced in : each country awarded twelve points to its favourite entry, followed by ten points to its second favourite, and then awarded points in decreasing value from eight to one for the remaining songs which featured in the country's top ten, with countries unable to vote for their own entry. The points awarded by each country were determined by an assembled jury of eleven individuals, who were all required to be members of the public with no connection to the music industry, with a recommendation that there should be a balance between the sexes and that half should be under 25 years old. Each jury member voted in secret and awarded between one and five votes to each participating song, excluding that from their own country and with no abstentions permitted. The votes of each member were collected following the country's performance and then tallied by the non-voting jury chairperson to determine the points to be awarded. In any cases where two or more songs in the top ten received the same number of votes, a show of hands by all jury members was used to determine the final placing.

Rehearsals for the participating artists began on 28 April 1985. Two technical rehearsals were conducted for each participating delegation in the week approaching the contest, with countries rehearsing in the order in which they would perform. The first rehearsals of 40 minutes were held on 29 and 30 April, followed by a press conference for each delegation and the accredited press. Each country's second rehearsals were held on 1 and 2 May and lasted 25 minutes total. Three dress rehearsals were held with all artists, two held in the afternoon and evening of 3 May and one final rehearsal in the afternoon of 4 May, with an invited audience present for the second dress rehearsal.

Contest overview
The contest was held on 4 May 1985, beginning at 21:00 (CEST) and lasting 2 hours and 46 minutes. The event was presented by the Swedish singer Lill Lindfors; Lindfors had previously represented Sweden in the, placing second alongside Svante Thuresson with the song "Nygammal vals". Following the confirmation of the nineteen participating countries, a draw was held in Gothenburg on 7 December 1984 to determine the running order (R/O) of the contest.

Lindfors opened the contest with a performance of "My Joy Is Building Bricks of Music", an English version of her song "Musik ska byggas utav glädje", becoming the first contest presenter to perform during the contest. To mark the thirtieth staging of the contest, among the invited audience present was Lys Assia, the contest's first winning artist and representative for in three consecutive contests, in,  and. The interval act featured jazz guitarists Peter Almqvist and Ulf Wakenius, performing as Guitars Unlimited. Lindfors was also part of a memorable moment from the contest, when returning to the stage following the interval act the skirt of her outfit, designed by Christer Lindarw, got caught on the set and ripped off in an apparent wardrobe malfunction, before Lindfors unclipped the top portion of her outfit to reveal a dress; returning to the microphone, she remarked to the audience, "I just wanted you to wake up a little." The trophy awarded to the winning songwriter was presented by the previous year's winning artists Herreys.

The winner was represented by the song "La det swinge", composed and written by Rolf Løvland, and performed by Hanne Krogh and Elisabeth Andreasson as Bobbysocks!. It was Norway's first contest win, and marked a notable turnaround in fortune for the country, which had only placed in the top five on two previous occasions while having placed last six times, including three nul points, at the time of the event, a fact on which Lindfors commented as she interviewed Bobbysocks! on stage following their victory. During the traditional winner's reprise performance, the group sung part of the winning song as its English version "Let It Swing", with the English lyrics also written by Løvland.

Spokespersons
Each country nominated a spokesperson, connected to the contest venue via telephone lines and responsible for announcing, in English or French, the votes for their respective country. Known spokespersons at the 1985 contest are listed below.

 * – Agneta Bolme Börjefors
 * – Colin Berry

Detailed voting results
Jury voting was used to determine the points awarded by all countries. The announcement of the results from each country was conducted in the order in which they performed, with the spokespersons announcing their country's points in English or French in ascending order. The detailed breakdown of the points awarded by each country is listed in the tables below.

Norway's victory at this contest was achieved with the lowest winning score awarded under the voting system used between and. Although the Norwegian entry received the maximum score from eight of the voting countries, almost half of those eligible, the Norwegian entry also received only 27 points from the remaining ten countries which could vote for Norway.

12 points
The below table summarises how the maximum 12 points were awarded from one country to another. The winning country is shown in bold. Norway received the maximum score of 12 points from eight of the voting countries, with Italy receiving three sets of 12 points, Sweden receiving two sets, and France, Germany, Ireland, Israel, Spain and Turkey each receiving one maximum score.

Broadcasts
Each participating broadcaster was required to relay the contest via its networks. Non-participating member broadcasters were also able to relay the contest as "passive participants". Broadcasters were able to send commentators to provide coverage of the contest in their own native language and to relay information about the artists and songs to their television viewers. An estimated maximum audience of over 600 million viewers and listeners was reported in the media around the time of the contest. Known details on the broadcasts in each country, including the specific broadcasting stations and commentators are shown in the tables below.

title: Eurovision Song Contest 1985


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Moon Mullins

Moon Mullins is an American comic strip which had a run as both a daily and Sunday feature from June 19, 1923, to June 2, 1991. Syndicated by the Chicago Tribune/New York News Syndicate, the strip depicts the lives of diverse lowbrow characters who reside at the Schmaltz (later Plushbottom) boarding house. The central character, Moon (short for Moonshine), is a would-be prizefighter—perpetually strapped for cash but with a roguish appetite for vice and high living. Moon took a room in the boarding house at 1323 Wump Street in 1924 and never left, staying on for 67 years. The strip was created by cartoonist Frank Willard.

Origins and history
Frank Henry Willard was born on September 21, 1893, in Anna, Illinois, the son of a physician. He determined to become a cartoonist early in life. After attending the Academy of Fine Arts in Chicago in 1913, he was a staff artist with the Chicago Herald (1914–18), where he drew the Sunday kids' page Tom, Dick and Harry and another strip, Mrs. Pippin's Husband. He next wrote and drew The Outta Luck Club for King Features Syndicate (1919–23).

In The Comics (1947), Coulton Waugh described Willard's art style as "gritty-looking". In 2003, the Scoop newsletter documented the 1923 events that led to the creation of the strip:

"Moon was a tough-talking, if generally good natured, kind of guy who took (and dealt) plenty of punches during his run. And actually, those are very appropriate characteristics. See, back before Moon was created, Frank Willard was working on a strip called The Outta Luck Club for King Features Syndicate. That's when he got the notion that some of his ideas were being slipped to fellow cartoonist George McManus (creator of Bringing Up Father). So, in typical Moon Mullins fashion, Willard approached McManus and gave him a wallop that knocked the latter out cold and got the former fired. That little episode didn't stop Captain Joe Patterson's interest from being piqued, however, and Willard soon set to work on a new strip for the Chicago Tribune Syndicate. That strip was Moon Mullins ..."

"Ah, Moon Mullins! He made a horrible role model but a hilarious star nonetheless—as did his assorted pals ... Adventures included stints in jail, trysts with stolen cars, failed employment opportunities, misunderstandings and plenty of black eyes for all. Yet, there was a certain lightness to all of Moon's debaucheries that made his low-down ways pretty charming ..."

Willard was in tune with the working class characters he created, as noted by David Westbrook in From Hogan's Alley to Coconino County: Four Narratives of the Early Comic Strip:
 * Some comic strip artists laid claim to a similar working-class authenticity by representing themselves in the position of employee. When Frank Willard, author of Moon Mullins, narrates a scene from his workplace, he portrays himself as a rowdy underdog much like The Yellow Kid. He becomes, in effect, the "tricky and roguish" character cited by Gilbert Seldes as the quintessence of the comic strip.

 * I worked for a syndicate manager once who got everybody in the place together once a week and jumped on a desk and gave us 'pep talks.' He didn't give us ideas, but, oh boy, how worn out we were after those pep talks. The guy that applauded the loudest got the most money, and I didn't get much—as he found out who it was who gave him the bird!|30|30|Frank Willard, as related to Martin Sheridan

 * When Brennecke (in "The Real Mission of the Funny Paper" by Ernest Brennecke, from The Century Magazine, March 1924) locates the truth of comic strip realism in the comics' habit of "commenting trenchantly" on "the life of the middle classes," it is comics like The Yellow Kid and artists like Willard that he has in mind...

Characters and story

 * Moon Mullins: With his big eyes, plaid pants, perpetual cigar and yellow derby hat, Moon is an amiable roughneck. He haunts saloons, racetracks and pool halls, mangles the English language with Jazz Age slang, and gets into endless scrapes looking for an easy buck or a hot dame. Moon himself is a low-rent but likeable sort of riff-raff, involved in get-rich schemes and bootleg whiskey, crap games and staying out all night with disreputable friends. None of the roughhousing was fatal or even particularly threatening, however. Indeed, the gentleness of the situational humor behind all the characters' rough edges kept the strip on an even keel. The name "Moonshine" referenced Mullins as a drinker and gambler during Prohibition.
 * Kayo: Moon's street urchin kid brother, who sleeps in an open dresser drawer. Kayo is usually clad in suspenders, polka dot pants and a black derby. Pint-sized Kayo (a play on "K.O.," sportswriters' shorthand for a knockout punch) is wise beyond his years and even a bit of a cynic. His plain-speaking, matter-of-fact bluntness is a frequent source of comedy.
 * Emmy (Schmaltz) Plushbottom: the nosy, lanky, spinsterish landlady who likes to put on airs. She finally married on October 6, 1933, and became Lady Plushbottom. She says "My stars" and "For pity sakes" a lot, but her trademark line—always delivered after a (frequent) putdown—is "I'll smack your sassy face!"
 * (Uncle) Willie: Introduced in 1927, Moon's long lost, no-account uncle wears a checkered suit and is perpetually unshaven. Willie, who would disappear for months at a time, prefers the hobo life—despite being married and half-domesticated. His only occupation seems to be the avoidance of physical labor and confrontations with his formidable wife, Mamie.
 * (Aunt) Mamie: Miss Schmaltz's burly, no-nonsense washwoman and cook. Her rolled-up sleeves reveal a conspicuous star tattoo. She's the only featured character of the working class cast who actually works. Mamie is usually tolerant of her errant husband, but she can be dangerous when riled—much to Willie's dismay.
 * Lord Plushbottom: (aka "Plushie," as Moon calls him.) Willard introduced him because Patterson thought tossing a well-bred Englishman into that shabby crowd had great comic possibilities. Plushbottom initially appeared as a man of wealth, whom Emmy pursued for 10 years before their marriage. Afterward he moved in, in apparently reduced circumstances, but never discarded his evening clothes, spats and top hat for everyday wear.
 * Egypt: Emmy's beautiful flapper niece with the bobbed Louise Brooks coiffure, and Moon's sometime girlfriend.
 * Mushmouth: Moon's pal and much-maligned step-and-fetch-it.
 * Kitty Higgins: the star of Willard's "topper" strip about a precocious little girl and her maid, Pauline. Kitty eventually joined the Moon Mullins cast as Kayo's girlfriend.

After Johnson took over, other characters were added to the cast, including:
 * Professor Byrrd: an erudite, tweed-suited academic
 * Myna Byrrd: the Professor's lovely brunette daughter
 * Miss Swivel: a sexy blonde stenographer, frequently pursued by Moon
 * Mr. Doodle: an eccentric, temperamental artist
 * Joke: a cab driver

The strip was reviewed by Dr. Hermes in Dr. Hermes Retro-Scans: "It was never so hysterical that you felt you just had to clip it and show it to everyone you knew, but Moon Mullins was always enjoyable and funny in a low-key way. Frank Willard's art was better than it's given credit for, very smooth and subtle; but his real strength was in the amusing personalities he gave his characters. (Longtime assistant Ferd Johnson took over after Willard's death in 1958.) "Moonshine" Mullins, as his name hinted, was a shady sort of rogue, always in trouble and often in jail. His little brother Kayo was a tough guy in a derby and turtleneck; everyone remembers him as the kid who slept in a pulled-out dresser drawer. Running the boarding house was sour ol' Emmy Schmaltz (she later married insubstantial Englishman Lord Plushbottom.) Rounding out the continuing cast were the cook Mamie and her less than industrious husband Willie. Moon Mullins is not likely to be adapted into the new big Broadway musical (although you never know), but I always liked it and would like to see it remembered."

- 30

The Sunday page's topper strip, Kitty Higgins, ran from December 14, 1930, to 1973.

Later years
Ferdinand "Ferd" Johnson (1905–1996) began as Willard's assistant a few months after the strip began in 1923. Starting with the lettering, then the backgrounds, Johnson gradually progressed to the point where he was handling the entire operation; but it was only after Willard's death that he began signing it. When Willard died suddenly on January 11, 1958, the Tribune Syndicate hired Johnson to helm the strip. Johnson's first credited strip ran on March 3, 1958. (Frank Willard's tombstone at the Anna Cemetery in Anna, Illinois, is graced with an engraving of Moon Mullins.)

Ferd Johnson was born December 18, 1905, in Spring Creek, Pennsylvania. Johnson became interested in cartooning after winning the Erie (Pennsylvania) Dispatch-Herald cartoon contest at the age of 12. After finishing high school in 1923 he attended the Chicago Academy of Fine Arts, but left school after only three months to take an assistant's job at the Chicago Tribune with Willard. While assisting on Moon Mullins, Johnson remained active with other Tribune projects. He created several comic strip features for the Syndicate—Texas Slim (1925–1928) and Lovey-Dovey (1932)—did sports illustration work, and produced advertising cartoons. In 1940, he revived Texas Slim in Texas Slim and Dirty Dalton (with the companion strip, Buzzy), which ran for 18 years.

By the time he took Moon Mullins, it had evolved from long story continuities to a gag-a-day strip. In 1978, Ferd's son, Tom Johnson, signed on as his assistant. Ferd Johnson stayed with the strip until it came to an end upon his retirement in 1991.

Decline and end
Moon Mullins appeared in 350 papers at its height but declined to 50. Johnson said, "They just kept dropping off because it's so damn old. The new ones come out and the editors want to make room for them, so the old ones get dumped. And Moon sure qualifies that way." In April 1991, the Chicago Tribune dropped the strip, and the Tribune Media Syndicate told Johnson that it was the end. The last strip ran on Sunday, 2 June 1991.

Comic books and reprints
The strip was reprinted in a long-running series of Cupples & Leon books (1927–1937), Big Little Books and comic books for Dell Comics (starting in 1936) and later, the American Comics Group (1947–1948). Dover Publications reprinted a collection of the daily strips in 1976, consisting of the third and fifth Cupples & Leon books. Representative samples of Moon Mullins daily continuity were featured in Great Comics Syndicated by the Daily News-Chicago Tribune (Crown Publishers, 1972), and The Smithsonian Collection of Newspaper Comics (Smithsonian Institution Press/Harry Abrams, 1977). The latter volume also reproduces several full-color Sunday pages. Comic strip historian Bill Blackbeard (1926–2011) edited a series of strip reprints for SPEC Productions.

Moon Mullins merchandise
Moon Mullins merchandising began when agent Toni Mendez arranged a licensing deal for Kayo suspenders. The wave of products that followed included such items as a series of Kellogg's Pep Cereal pins, a Milton Bradley board game (1938), salt and pepper shakers, perfume bottles, Christmas lights, bisque toothbrush holders, a set of German nodder figures, carnival chalkware statues, a wind-up toy handcar, oilcloth and celluloid Kayo dolls, coloring books and a series of jigsaw puzzles (1943).

Kayo Mullins chocolate drink
Kayo Chocolate Drink was the name of a bottled, later canned, chocolate-flavored milk drink. Created in 1929 by Aaron D. Pashkow of Chicago, it was bottled under authority of Chocolate Products, manufactured for decades, and featured Kayo Mullins on its label. It now only sold as a powdered hot chocolate mix distributed by Superior Coffee and Tea and Smucker Foodservice Canada for the foodservice market.

Radio
Moon Mullins was adapted for radio during the 1940s. In the third episode of the series (March 25, 1940), the Plushbottoms trade Moon's only suit to pay for a collect telegram and learn they are owners of a goldmine. In a CBS audition recording dated January 31, 1947, Uncle Willie asks Moon for $10 bail, and Moon teaches the game of Blackjack to Kayo. Lord Plushbottom plans to go to a costume party as an Indian but instead winds up with a suit of armor. Character actor Sheldon Leonard was in the cast.

Animation
Cambria Studios produced two sample episodes of a proposed Moon Mullins syndicated TV series with their Syncro-Vox animation process in the early 1960s, but it did not clear enough television stations to go into production. Comic actor and director Howard Morris was the voice of Moon when the strip was adapted to animation for Archie's TV Funnies (1971–1973), produced by Filmation. Moon and Kayo became one of several rotating segments on the Saturday morning cartoon series. Other comic strip character features in the rotation included Broom-Hilda, Dick Tracy, The Captain and the Kids, Alley Oop, Nancy and Sluggo and Smokey Stover. It was repeated in 1978, without Archie, under the title Fabulous Funnies.

title: Moon Mullins


text:
His

His or HIS may refer to:

Computing

 * Hightech Information System, a Hong Kong graphics card company
 * Honeywell Information Systems
 * Hybrid intelligent system
 * Microsoft Host Integration Server

Education

 * Hangzhou International School, in China
 * Harare International School, in Zimbabwe
 * Hokkaido International School, in Japan
 * Hsinchu International School, in Taiwan
 * Hollandsch-Inlandsche School, a Dutch school for native Indonesians in the Dutch East Indies

Science

 * Angle of His, also known as the esophagogastric angle, at the juncture of the stomach and esophagus
 * Bundle of His, a collection of specialized heart cells
 * Health information system
 * Hospital information system
 * Human identical sequence
 * His-Tag, a polyhistidine motif in proteins
 * Histidine, an amino acid abbreviated as His or H
 * His 1 virus, a synonym of Halspiviridae
 * HIS-1, a long non-coding RNA, also known as VIS1

People

 * Wilhelm His Sr. (1831–1904), Swiss anatomist
 * Wilhelm His Jr. (1863–1934), Swiss anatomist

Places

 * His, Agder, a village in Arendal municipality in Agder county, Norway

Other uses

 * His, the possessive form of the English-language pronoun he
 * H.I.S. (travel agency), a Japanese travel agency
 * His, Haute-Garonne, a commune in the Haute-Garonne department, France
 * B sharp, known as His in some European countries

title: His


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Coining

Coining may refer to:
 * Coining (metalworking), a metalworking process
 * Coining (mint), the production of coins
 * Coining (traditional medicine), dermabrasion practiced in China, Indonesia, and Vietnam
 * Coin counterfeiting
 * Solder ball flattening
 * The creation of a protologism or neologism

title: Coining


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Coinage

Coinage may refer to:
 * Coins, standardized as currency
 * Coining (mint), the process of manufacturing coins
 * COINage, a numismatics magazine
 * Tin coinage, a tax on refined tin
 * Coinage, a protologism or neologism

title: Coinage


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The Silver Chalice

The Silver Chalice is a 1952 English language historical novel by Thomas B. Costain. It is the fictional story of the making of a silver chalice to hold the Holy Grail (itself here conflated with the Holy Chalice) and includes 1st century biblical and historical figures: Luke, Joseph of Arimathea, Simon Magus and his companion Helena, and the apostle Peter.

The story was inspired by the archeological discovery of a 1st-century silver chalice in Antioch (see Antioch Chalice). It is in effect a prequel to the Arthurian Legend, where the search for the Holy Grail plays a conspicuous part.

Two years after its publication, Warner Bros. released a feature adaptation of the book. The film starred Paul Newman, in his first studio role, as Basil the craftsman.

First published in 1952, this classic recounts the story of Basil, a young silversmith, who is commissioned by Luke the Evangelist, a disciple of Christ and biographer of the Apostle Paul, to fashion a holder for the cup Jesus used at the Last Supper.

The Silver Chalice was a top best-selling fiction title of 1953 in the United States, atop The New York Times Best Seller list from September 7, 1952 to March 8, 1953, and remaining 64 weeks on the list until October 25, 1953.

Plot introduction
The Silver Chalice takes place in Judea and other parts of the Roman Empire shortly after the death of Jesus. A young man, Basil, is adopted by a rich man, but loses his fortune when his father dies and his uncle defrauds him, claiming he was purchased as a slave, and sells him. As a slave, he survives by working as an artist and silversmith. He gains his freedom, becomes a Christian and is commissioned to create an outer covering for the cup Jesus drank from at The Last Supper.

The plot of The Silver Chalice centers on the Grail — the cup from which Christ drank at the Last Supper. Tired of “all the Arthurian tripe about the Holy Grail,” Costain imagined his own version of the story. Joseph of Arimathea hires Basil of Antioch, a lowborn artisan, to fashion a beautiful silver casing to hold the plain original cup that Jesus used. The casing is to be decorated with the faces of Jesus and the twelve Apostles. To fulfill the commission, Basil travels throughout the ancient Mediterranean world to meet these men and those who knew them intimately.

Positive
The Silver Chalice was well received when it was published in 1952. The book was on the New York Times Best Seller List from September 7, 1952 to October 25, 1953 for a total of 64 weeks. It was near the top of that list for 6 months.

Also in 1953, Kirkus Reviews said:
 * Mr. Costain's best book of fiction, and one that will put out a strong bid to rival The Robe in success with that market. The subject is an illusive one that has been approached tentatively through the centuries -- the mystery of the holy grail...Occasional pandering to modern taste weakens the fundamental values, perhaps, but insures the larger market. A sure best seller.

After the author's death in 1965, The Canadian Book Review Annual said that:
 * There are a number of anachronisms but, by and large, the novel is a creative introduction to the period and worth a reprint.

title: The Silver Chalice


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Mars effect

The Mars effect is a purported statistical correlation between athletic eminence and the position of the planet Mars relative to the horizon at time and place of birth. This controversial finding was first reported by the French psychologist and "neo-astrologer" Michel Gauquelin. In his book L'influence des astres ("The Influence of the Stars", 1955), Gauquelin suggested that a statistically significant number of sports champions were born just after the planet Mars rises or culminates. He also divided the plane of the ecliptic into twelve sectors, identifying two "key" sectors of statistical significance.

Gauquelin's work was accepted by the psychologist Hans Eysenck among others but later attempts to validate the data and replicate the effect have produced uneven results, chiefly owing to disagreements over the selection and analysis of the data set. Since the phenomenon in question depends upon the daily rotation of the Earth, the availability and accuracy of time and place of birth data is crucial to such studies, as is the criterion of "eminence". Later research claims to explain the Mars effect by selection bias, favouring champions who were born in a key sector of Mars and rejecting those who were not from the sample.

Reception and replication
Gauquelin's work was not limited to the Mars effect: his calculations led him first to reject most of the conventions of natal astrology as it is practised in the modern west but he singled out "highly significant statistical correlations between planetary positions and the birth times of eminently successful people." This claim concerned not only Mars but five planets, correlated with eminence in fields broadly compatible with the traditional "planetary rulerships" of astrology. However, partly because eminence in sport is more quantifiable, later research, publicity and controversy has tended to single out the "Mars effect".

Belgian athletes – the Comité Para
In 1956 Gauquelin invited the Belgian Comité Para to review his findings but it was not until 1962 that Jean Dath corroborated the statistics Gauquelin had presented and suggested an attempt at duplication using Belgian athletes. By this time Gauquelin had published Les Hommes et Les Astres (Men and the Stars, 1960), offering further data. The Comité Para tested the Mars effect in 1967 and replicated it, though most of the data (473 of 535) were still collected by Gauquelin himself. The committee, suspecting that the results might have been an artifact, withheld its findings for a further eight years, then cited unspecified “demographic errors” in its findings. Unpublished internal analyses contradicted this and one committee member, Luc de Marré, resigned in protest. In 1983 Abell, Kurtz and Zelen (see below) published a reappraisal, rejecting the idea of demographic errors, saying, “Gauquelin adequately allowed for demographic and astronomical factors in predicting the expected distribution of Mars sectors for birth times in the general population.”

The Zelen test
In 1975 Paul Kurtz's journal The Humanist published an article on astrology criticizing Gauquelin, to which the latter and his wife Françoise responded. Then Professor Marvin Zelen, a statistician and associate of the recently founded Committee for the Scientific Investigation of Claims of the Paranormal (CSICOP, now known as the Committee for Skeptical Inquiry (CSI)), proposed in a 1976 article in the same periodical that, in order to eliminate any demographic anomaly, Gauquelin randomly pick 100 athletes from his data-set of 2,088 and check the birth/planet correlations of a sample of babies born at the same times and places in order to establish a control group, giving the base-rate (chance) expectation for comparison (The 100 random athletes later expanded into a subsample of 303 athletes).

In April 1977 CSICOP researcher George O. Abell wrote to Kurtz stating that Zelen's test had come out in the Gauquelins' favour. The Gauquelins also performed the test that Professor Zelen had proposed and carried out and found that the chance Mars-in-key-sector expectation for the general population (i.e., non-champions) was about 17%, significantly less than the 22% observed for athletic champions. However the subsequent article by Zelen, Abell and Kurtz did not clearly state this outcome but rather questioned the original data. In a rebuttal of the Gauquelins' published conclusion, Marvin Zelen analysed the composition, not of the 17,000 non-champions of the control group, but of the 303 champions, splitting this secondary subsample (which was already nearly too small to test 22% vs 17%) by eliminating female athletes, a subgroup that gave the results most favourable to Gauquelin, and dividing the remaining athletes into city/rural sections and Parisian/non-Parisian sections.

Before and after publication of Zelen's results astronomer and charter CSICOP member Dennis Rawlins, the CSICOP Council's only astronomer at the time, repeatedly objected to the procedure and to CSICOP's subsequent reporting of it. Rawlins privately urged that the Gauquelins' results were valid and the “Zelen test” could only uphold this and that Zelen had diverted from the original purpose of the control test, which was to check the base rate of births with Mars in the "key" sectors. It appeared to him that the test had minimised the significance of the Mars/key-sector correlations with athletes by splitting the sample of athletes and that the experimenters, who were supposed to be upholding scientific standards, were actually distorting and manipulating evidence to conceal the result of an ill-considered test.

The Kurtz-Zelen-Abell analysis had split the sample primarily to examine the randomness of the 303 selected champions, the non-randomness of which Rawlins demonstrated in 1975 and 1977. Zelen's 1976 "Challenge to Gauquelin" had stated: "We now have an objective way for unambiguous corroboration or disconfirmation ... to settle this question", whereas this aim was now disputed. Rawlins made procedural objections, stating; "... we find an inverse correlation between size and deviation in the Mars-athletes subsamples (that is, the smaller the subsample, the larger the success) – which is what one would expect if bias had infected the blocking off of the sizes of the subsamples".

CSICOP also contended, after reviewing the results, that the Gauquelins had not chosen randomly. They had had difficulty finding sufficient same-week and same-village births to compare with champions born in rural areas and so had chosen only champions born in larger cities. The Gauquelins' original total list of about 2,088 champions had included 42 Parisians and their subsample of 303 athletes also included 42 Parisians. Further, Paris is divided into 20 arrondissements, different economic classes and ethnic groups typically inhabiting different arrondissements. The Gauquelins had compared the 42 Parisian champions (who had been born throughout Paris) to non-champions of only one arrondissement. If the 22% correlation was an artifact partly based on factors such as rural recordkeeping, economic, class or ethnic differences in birth patterns, this fact would be blurred by this non-random selection.

U.S. athletes – CSICOP
At the same time CSICOP began a study of U.S. athletes in consultation with Zelen, Abell and Rawlins. The results, published in 1979 showed a negative result. Gauquelin contended the KZA group demonstrated an overall preference for mediocre athletes and ignored his criteria of eminence and that they included basketball players and people born after 1950.

CFEPP test
In 1994 the results of a major study undertaken by the Committee for the Study of Paranormal Phenomena (Comité pour l’Étude des Phénomènes Paranormaux, or CFEPP) in France found no evidence whatsoever of a "Mars Effect" in the births of athletes. The study had been proposed in 1982 and the committee had agreed in advance to use the protocol upon which Gauquelin insisted. The CFEPP report was “leaked” to the Dutch newspaper Trouw.

In 1990 the CFEPP had issued a preliminary report on the study, which used 1,066 French sports champions, giving full data for the 1,066 as well as the names of 373 who fit the criteria but for whom birth times were unavailable, discussing methodology and listing data-selection criteria. In 1996 the report, with a commentary by J. W. Nienhuys and several letters from Gauquelin to the committee, was published in book form as The Mars Effect – A French Test of Over 1,000 Sports Champions. The CFEPP stated that its experiment showed no effect and concluded that the effect was attributable to bias in Gauquelin's data selection, pointing to the suggestions made by Gauquelin to the committee for changes in their list of athletes. The CFEPP report was criticized by Suitbert Ertel on similar grounds as the American study – for including too many mediocre athletes – and also for using a too high chance-excpectancy level. According to Ertel, a Mars effect could be detected by dividing the athletes into groups of eminence grading.

Statistical explanation
Some researchers argued that Gauquelin did not adjust the statistical significance of the Mars Effect for multiple comparisons and did not address the issue in his publications. Simplified and illustrative showcase argument is explained here: There are 10 celestial bodies and 12 sectors for them to be in. Furthermore, there are 132 combinations of sector pairs and thus 1320 different combinations of a planet with two sectors. There is about a 25% chance to find at least one such combination (of one planet and two sectors) for a random dataset of the same size as Gauquelin's that would yield a result with apparent statistical significance like the one obtained by Gauquelin. This implies that after adjusting for multiple comparisons, the Mars effect is no longer statistically significant even at the modest significance level of 0.05 and is probably a false positive. But the multiple comparisons argument is countered or weakened if it is proven that an effect shows up in more than one study. Some argue that the latter is the case.

Geoffrey Dean has suggested that the effect may be caused by self-reporting of birth dates by parents rather than any issue with the study by Gauquelin. Gauquelin had failed to find the Mars effect in populations after 1950. Dean has put forward the idea that this may be due to increases in doctors reporting the time of birth rather than parents. Information about misreporting was unavailable to Gauquelin at the time. Dean had said that misreporting by 3% of the sample would explain the result.

title: Mars effect