Risperdal (psedoscience and the psychiatric equivalent to AIDS/HIV/H4)

Risperidone

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Risperidone

Systematic (IUPAC) name
4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)- 1-piperidyl]ethyl]-3-methyl- 2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one
Identifiers
CAS number	106266-06-2
ATC code	N05AX08
PubChem	CID 5073
IUPHAR ligand ID	96
DrugBank	DB00734
ChemSpider	4895
Chemical data
Formula	C23H27FN4O2
Mol. mass	410.485 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	70% (oral)
Metabolism	Hepatic (CYP2D6-mediated)
Half-life	3–20 hours
Excretion	Urinary
Therapeutic considerations
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral and extended-release intramuscular injection
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Risperidone (pronounced Ris-PEAR-rǐ-dōne) is an atypical antipsychotic used to treat schizophreniaschizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in children with autism. The drug was developed by Janssen-Cilag and first released in 1994^[1]. It is sold under the trade name Risperdal in the Netherlands, United States, Canada, Australia, United Kingdom, Portugal, Spain, Turkey, New Zealand and several other countries, Risperdal or Ridal in New Zealand, Sizodon or Riscalin in India, Rispolept in Eastern Europe, and Russia, and Belivon, or Rispen elsewhere. (including adolescent schizophrenia),

Contents [show] 1 Indications and Uses 2 Availability 3 Side effects 4 Pharmacology 5 References 6 External links

[edit] Indications and Uses

• treatment of schizophrenia in adults
• treatment of schizophrenia in adolescents aged 13-17 years
• alone or in combination with lithium or valproate, for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults
• alone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in children and adolescents aged 10-17 years
• treatment of irritability associated with autistic disorder in children and young adults
• it has also been used as a control drug for people with tourette syndrome and other tic disorders.
• treatment of major depression with psychotic features
• cure persistent or intractable hiccups^[2]

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.^[3]

On August 22, 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youth ages 13–17; it was also approved that same day for treatment of bipolar disorder in youth and children ages 10–17, joining lithium. Risperidone contains the functional groups of benzisoxazolepiperidine as part of its molecular structure. In 2003 the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006 the FDA approved risperidone for the treatment of irritability in children and adolescents with autism.^[4] The FDA’s decision was based in part on a study of autistic children with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic children with mild aggression and explosive behavior without an enduring pattern.^[5] Like other atypical antipsychotics, risperidone has also been used off-label for the treatment of anxiety disorders, such as obsessive-compulsive disorder; severe, treatment-resistant depression with or without psychotic features; tourette syndrome; disruptive behavior disorders in children; and eating disorders, among others. In two small studies risperidone was reported to successfully treat the symptoms of phencyclidine (PCP) psychosis due to acute intoxication^[6] and chronic use.^[7] and

A 2009 Cochrane Library review found no evidence from randomized controlled trials that risperidone is effective for the treatment of attention-deficit hyperactivity disorder (ADHD) in people with intellectual disabilities.^[8] A multi-year UK study by the Alzheimer’s Research Trust suggested that this and other neuroleptic anti-psychotic drugs commonly given to Alzheimer’s patients with mild behavioural problems often made their condition worse. The study concluded that:

“

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy.[9]

”

[edit] Availability

Risperdal 4 mg tablets (UK)

Janssen’s patent on Risperdal expired on December 29, 2003, opening the market for cheaper generic versions of the drug from other companies, and Janssen’s exclusive marketing rights expired on June 29, 2004 (the result of a pediatric extension.)

Risperidone is available as a tablet in 0.25, 0.5, 1, 2, 3 and 4 mg sizes, as an oral solution (30ml, 1 mg/ml), and as a 12.5 mg, 25 mg, 37.5 mg and 50 mg ampoule Risperdal Consta, which is a depot injectionRisperdal M-Tabs and elsewhere as Risperdal Quicklets. administered once every two weeks. It is also available as a wafer known in the United States and Canada as

Risperidone became available as a generic drug in October 2008 from Teva Pharmaceuticals, Dr. Reddy’s Laboratories, Inc. and Patriot Pharmaceutics. The Patriot generic is Janssen Pharmaceutical’s “authorized generic pharmaceutical.”

[edit] Side effects

Risperidone has been associated with weight gain.^[10] Other common side effects include akathisia, sedation, dysphoria, insomnia, sexual dysfunction, low blood pressure, high blood pressure, muscle stiffness, muscletremors, increased salivation, constipation, and stuffy nose. pain,

Many antipsychotics are known to cause hyperprolactinemia which may lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction. However, risperidone is known to increase prolactin to a greater extent than other atypical antipsychotics. Although lactation is possible in both sexes using other antipsychotic drugs, risperidone is the biggest offender.^[11][12][13] It is thought that once risperidone raises prolactin, it may cause prolactinoma, a benign tumor of the pituitary gland. Tumors, in general, are not considered reversible. Medical therapy may help reduce tumor size and restore normal reproduction and pituitary function, however, dopamine agonists^[14] There is a higher association between pituitary neoplasms with use of risperidone and amisulpride than with other antipsychotic agents. are not likely to be prescribed to antipsychotic users, thus, surgery or radiation treatment may be required. This condition may recur if the patient is switched to a different antipsychotic. Risperidone has been known to cause increased thoughts of suicide.

Risperidone can potentially cause tardive dyskinesia (TD),^[15] extrapyramidal symptoms (EPS),^[15] and neuroleptic malignant syndrome (NMS).^[15] Risperidone may also trigger diabetes and more serious conditions of glucose metabolism, including ketoacidosis and hyperosmolar coma, according to an FDA Warning Letter issued to Janssen Pharmaceutica, Inc. on 19-Apr-04.^[16]

[edit] Pharmacology

This drug belongs to a class of antipsychotic drugs known as atypical antipsychotics that have more pronounced serotonin antagonism than dopamine antagonism, but risperidone is unique in this class because it retains dopamine antagonism. It has high affinity for D₂ dopaminergic receptors. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT_2C, linked to weight gain, 5-HT_2A,linked to its antipsychotic action and relief of some of the extrapyramidal side effects (EPS) experienced with the typical neuroleptics.

It reaches peak plasma levels quickly regardless of whether it is administered as a liquid or pill. Risperidone is metabolised fairly quickly, so the potential for nausea subsides usually in two to three hours. However, the active metabolite, 9-hydroxy-risperidone, which has similar pharmacodynamics to risperidone, remains in the body for much longer, and has been developed as an antipsychotic in its own right, called paliperidone.

An intramuscular preparation, marketed as Risperdal Consta, can be given once every two weeks. It is slowly released from the injection site. This method of administration may be used on sanctioned patients who are declining, or consenting patients who may have disorganized thinking and cannot remember to take their daily doses.^[17] Doses range from 12.5 to 50 mg given as an intramuscular injection once every two weeks.

Abilify (Phi)(ability)

Double play on words (Phi, Ability), comp. lexapro

 Aripiprazole

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Aripiprazole

Systematic (IUPAC) name
7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Identifiers
CAS number	129722-12-9
ATC code	N05AX12
PubChem	CID 60795
IUPHAR ligand ID	34
DrugBank	APRD00638
ChemSpider	54790
UNII	82VFR53I78
Chemical data
Formula	C23H27Cl2N3O2
Mol. mass	448.385
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	87%
Protein binding	>99%
Metabolism	liver
Half-life	75h (active metabolite : 94h)
Excretion	feces and urine
Therapeutic considerations
Licence data	EU EMA:Link, US FDA:link
Pregnancy cat.	C (USA)
Legal status	℞ Prescription only
Routes	oral (via tablets, orodispersable tablets, and oral solution); intramuscular
(what is this?)  (verify)Y

Aripiprazole (pronounced /ˌɛərɨˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl; brand names: Abilify, Abilify Discmelt, Aripiprex) is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression. It was approved by the US Food and Drug Administration (FDA) for schizophrenia on November 15, 2002, for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004, as an adjunct for major depressive disorder on November 20, 2007 and to treat irritability in children with autistic disorder in children on 20 November 2009.^[1][2] Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Contents [show] 1 Indications and usage 1.1 Schizophrenia 1.2 Bipolar disorder 1.3 Major depression (Unipolar depression) 1.4 Autism 1.5 Cocaine dependency 2 Pharmacology 3 Pharmacokinetics 4 Patent status 5 Side effects 6 Overdosage 7 Drug interactions 8 Dosage forms 9 Synthesis 10 References 11 External links

[edit] Indications and usage

[edit] Schizophrenia

Aripiprazole has been approved by the FDA for the treatment of schizophrenia.^[3]

[edit] Bipolar disorder

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.^[4] Several double-blind, placebo-controlled trials support this use.^[5][6][7][8] In addition, it is often used as maintenance therapy, either on its own or in conjunction with a mood stabilizer such as lithium or valproate. This use is also supported by a handful of studies.^[9][10]haloperidol at reducing manic symptoms,^{[11][unreliable source?]} and is much better tolerated by patients.^[12] Aripiprazole is at least as effective as
Aripiprazole’s use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness^[13][14] (with one finding a reduction in anhedonia symptoms^[15]), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.^[16] One study reported depression as a side effect of the drug.^[17]

[edit] Major depression (Unipolar depression)

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.^[18] It has not been FDA-approved for use as monotherapy in unipolar depression.

[edit] Autism

In 2009, the United States FDA approved Abilify to treat irritability in persons with autism.^[19] It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, irritability, and temper tantrums in autistic males and females 6–17 years of age.

[edit] Cocaine dependency

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behaviour in animal models without significantly affecting other rewarding behaviours (such as food self-administration). ^[20]

[edit] Pharmacology

D2 Partial Agonist (Ki = 0.34 nM) D3 Antagonist (?)

5-HT1A Partial Agonist (Ki = 0.34 nM) 5-HT2A Antagonist (Ki = 0.8 nM) 5-HT2C Partial Agonist (Ki = 15 nM) 5-HT7 Antagonist (Ki = 39 nM)

SRI (?) Antihistamine (Ki = 61 nM) α-adrenergic antagonist (Ki = 57 nM) mACh receptor antagonist (?)

Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychoticsclozapine, olanzapine, quetiapine, ziprasidone, and risperidone). Rather than antagonizing the D₂ receptor, aripiprazole acts as a D₂ partial agonist (K_i = 0.34 nM).^[21][22] Aripiprazole is also a partial agonist at the 5-HT_1A receptor (K_i = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the 5-HT_2A receptor (K_i = 0.8 nM).^[23][24] It also antagonizes the 5-HT₇ receptor (K_i = 39 nM) and acts as a partial agonist at the 5-HT_2C receptor (K_i = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy.^[25] Aripiprazole has moderate affinity for histamine (K_i = 61 nM) and α-adrenergic (K_i = 57 nM) receptors and for the serotonin transporter, and no appreciable affinity for cholinergic muscarinic receptors.^[26] (e.g.,
D₂ and D₃ receptor occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.^[27][28] Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.^[29]
Recently, it has been demonstrated that in 5-HT₇ receptor knockout mice, aripiprazole does not reduce immobility time in the forced swim test (FST), and actually increases it.^[30][31] This implicates 5-HT₇amisulpride.^[30][31][32] antagonism as playing a major role in aripiprazole’s antidepressant effects, similarly to
Aripiprazole produces 2,3-dichlorophenylpiperazine (DCPP) as a metabolite similarly to how trazodone and nefazodone reduce to 3-chlorophenylpiperazine (mCPP) and niaprazine converts to 4-fluorophenylpiperazine^[33] It is unknown whether DCPP contributes to aripiprazole’s pharmacology in any way, but the possibility cannot be excluded. (pFPP).

[edit] Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. C_max (maximum plasma concentration) is achieved 3–5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.^[26] When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels. This phenomenon is due to the long half life of aripiprazole, and is responsible for many of the adverse side effects that appear after multiple days of dosing (whereas the first dose normally does not cause these side effects).

[edit] Patent status

Otsuka’s US patent on aripiprazole expires on October 20, 2014;^[34] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[4] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.^[35] As of 14 August 2009, this challenge is still in court. (2009 -08-14)^[update]

[edit] Side effects

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Akathisia^[36], headache, unusual tiredness or weakness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, light-headedness, insomnia, sleepiness, shaking, and blurred vision.
Uncontrollable twitching or jerking movements, tremors, seizure, and weight gain. Some people may feel dizzy, especially when getting up from a lying or sitting position, or may experience a fast heart rate.
Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate.)
Aripiprazole also causes sexual dysfunction.
Tardive dyskinesia (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.^[37][38][39])
Stroke (While taking aripiprazole some elderly patients with dementia have suffered from stroke or ‘mini’ stroke.)
Other elderly patients may experience high blood sugar or the onset or worsening of diabetes.
Allergic reaction (such as swelling in the mouth or throat, itching, rash), increased production of saliva, speech disorder, nervousness, agitation, fainting, reports of abnormal liver test values, inflammation of the pancreas, muscle pain, weakness, stiffness, or cramps.

[edit] Overdosage

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these patients were elevated by up to 3-4 fold over normal therapeutic levels, yet no deaths have yet been recorded.^[40]

[edit] Drug interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.^[41] As such, anyone taking Abilify should be aware that their dosage of Abilify may need to be decreased.
Aripiprazole may change the subjective effects of alcohol. One study^[42] found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study^[43] found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.

[edit] Dosage forms

• Intramuscular injection, solution: 7.5 mg/mL (1.3 mL)
• Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
• Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
• Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

[edit] Synthesis

U.S. Patent 5,006,528

)

Lexapro (symbolc misrepresentation)[Lexis-vocabulary, pro-(for, skilled]

Lexapro [Lexis(vocabulary) + Pro]

Escitalopram

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Escitalopram

Systematic (IUPAC) name
(S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Identifiers
CAS number	128196-01-0
ATC code	N06AB10
PubChem	CID 146570
DrugBank	APRD00683
ChemSpider	129277
UNII	4O4S742ANY
Chemical data
Formula	C20H21FN2O
Mol. mass	324.392 g/mol (414.43 as oxalate)
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	80%
Protein binding	~56%
Metabolism	Liver, specifically the enzymes CYP3A4 and CYP2C19
Half-life	27–32 hours
Therapeutic considerations
Pregnancy cat.	C
Legal status	Rx Only (U.S) POM (U.K)
Routes	Oral
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Lexapro tablets

Cipralex brand escitalopram package and tablet sheet

Escitalopram (trade names Lexapro, Cipralex, Seroplex, Lexamil) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment in adults with major depressive disorder, generalized anxiety disorder, social anxiety disorder , or panic disorder. Escitalopram is the S-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity of serotonin reuptake inhibition and has side effects typical for the SSRI class.

Contents [show] 1 History 2 Use in depression 3 Pharmacology 4 Side effects and drug interactions 5 Discontinuation symptoms 6 Controversy 7 References 8 Cited texts 9 See also 10 External links

[edit] History

Escitalopram was developed in a close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.^[1]evergreening“^[2] (also called “lifecycle management”^[3])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of the racemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.^[4] On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.^[5] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.^[6] This pushed the patent expiry from December 7, 2009 to March 14, 2012.

Geodon [geo (earth) + don(dominic)]

LORD

Don, from Latin dominus, is an honorific in Spanish ([don]), Portuguese (Dom, [dõ]), and Italian ([dɔn]). The female equivalent is Doña (Spanish: [ˈdoɲa]), Dona (Portuguese: [ˈdonɐ]), and Donna (Italian: [ˈdɔnna]), abbreviated “Dª” or simply “D.”

Dominus is the Latin word for master or owner.

Ziprasidone

Ziprasidone

Systematic (IUPAC) name
5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]- 6-chloro-1,3-dihydro-2H-indol-2-one
Identifiers
CAS number	146939-27-7
ATC code	N05AE04
PubChem	CID 60854
IUPHAR ligand ID	59
DrugBank	DB00246
ChemSpider	54841
Chemical data
Formula	C21H21ClN4OS
Mol. mass	412.936
Pharmacokinetic data
Bioavailability	100% (intramuscular) 60% (orally)
Metabolism	hepatic (aldehyde reductase)
Half-life	7 hours
Excretion	Urine and feces
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	C(US)
Legal status	℞ Prescription only
Routes	oral, intramuscular
(what is this?)  (verify)Y

Ziprasidone (marketed as Geodon, Zeldox by Pfizer) was the fifth atypical antipsychotic to gain FDA approval (February 2001). In the United States, Ziprasidone is Food and Drug Administration (FDA) approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients. Ziprasidone has also received approval for acute treatment of mania and mixed states associated with bipolar disorder. The brand name Geodon has been suggested to bring to mind the phrase ‘down (don) to earth (geo)’ referring to the goals of the medication.

The oral form of ziprasidone is the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form, on the other hand, is the mesylate salt, ziprasidone mesylate trihydrate, and is provided as a lyophilized powder.

Geodon was one of four drugs which Pfizer in 2009 pleaded guilty to misbranding “with the intent to defraud or mislead”. Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer was found to have illegally promoted four of its drugs for use in conditions that had not been approved by the FDA.^[1]

Contents [show] 1 Pharmacology 2 Pharmacokinetics 3 Adverse effects 4 Off-label uses 5 References 6 External links

[edit] Pharmacology

Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptors, where it is believed to act as an antagonist.^[2] Ziprasidone also displays some inhibition of synaptic reuptake of serotonin and norepinephrine^[2][3], although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it has been theorized that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D₂. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT_2A antagonism is debated among researchers.^[4] Ziprasidone has perhaps the most selective affinity for 5-HT_2A receptors relative to D₂ and 5-HT_2C receptors of any neuroleptic.^[5][6] Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.

[edit] Pharmacokinetics

The systemic bioavailability of ziprasidone administered intramuscularly is 100%, or 60%, administered orally with food. After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. The mean half-life ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

Ziprasidone absorption is not optimally achieved when administered without food. Without a meal preceding dose, the bioavailability of the drug is reduced by approximately 50%.^[7][8]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).^[9] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.^[10][11]

[edit] Adverse effects

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.^[7] It also slightly increases the QTc interval in some patients and increases the risk of a potentially lethal type of heart arrhythmia known as torsades de pointes. Ziprasidone should be used cautiously in patients taking other medications likely to interact with ziprasidone or increase the QTc interval.^[12]

Patients in general will experience loss of focus and motivation as well as blurry vision to the point that stronger doses may cause thoughts of suicide while the medicine is in the patients system. Thoughts of suicide may occur. Typically side effects will start about an hour after ingestion and peak about four to five hours after ingestion. Patient will most likely be unable to operate machinery or drive a vehicle while the medicine is effecting the patient as blurred vision can be quite severe.

Ziprasidone may cause cause dangerous—even fatal—heartbeat irregularities.

Geodon generally adheres to the mid section of the prefrontal cortex. It derives from the ideas and thoughts process in the prefrontal cortex in which determines a treatment diagnosis for psychosis. Those who experience the symptoms of psychosis will experience on-going symptoms such as: lack of sleep, insomnia, and uncontrollable desires and experiences. Geodone adheres and corrects the prefrontal cortex by delivering an enzyme called (enzyme-B). This enzyme corrects the basal ganglia function which coorelates with the B-cortex hemispheres. In other words the enzyme delivers a vital nutrient into the system which is release by the geodome once again, called enzyme-b. The process of Geodon is somewhat confusing as it affects both the basal ganglia and prefrontal cortex. By affecting the basal ganglia the prefrontal cortex does what is called: identity change. This is a process in which enzymes are switched from one section of the brain to another. The prefrontal cortex is mainly involved in spacial recognition which will be slightly alleviated by the geodon. Those who experience spacial recognition problems usually suffer from psychosis.

Ziprasidone is known to cause activation into mania in some bipolar patients.^[13][14][15]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.^[7]

Adverse events reported for ziprasidone include severe chest pains, impaired erectile function and stimulation, sedation, insomnia, orthostasis, life-threatening neuroleptic malignant syndrome, akathisia, and the development of permanent neurological disorder tardive dyskinesia. Rarely, temporary speech disorders may result.

Recently, the FDA required the manufacturers of some atypical antipsychotics include a warning about the risk of hyperglycemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics (namely, olanzapine (Zyprexa)) at causing insulin resistance and weight gain.^{[16][17][18][19]} In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.^[7] Ziprasidone, though, is not a weight loss drug. The weight loss reflected in this study on ziprasidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.^{[citation needed]}clozapine and olanzapine). According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs) (which is significantly lower than other atypicals–

[edit] Off-label uses

In addition to its antipsychotic use, ziprasidone is sometimes prescribed for the treatment of tic disorders. A small study^[20] has supported the efficacy of this use.

Phenethylamine (neurochemistry)(misinformation included)

Phenethylamine

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Phenethylamine

Systematic (IUPAC) name
phenylethan-2-amine
Identifiers
CAS number	64-04-0
ATC code	?
PubChem	CID 1001
ChemSpider	13856352
Chemical data
Formula	C8H11N
Mol. mass	121.18 g/mol
SMILES	eMolecules & PubChem
Synonyms	2-phenylethylamine, β-phenylethylamine, 1-amino-2-phenylethane
Pharmacokinetic data
Metabolism	MAO-A, MAO-B, ALDH, DBH, CYP2D6
Half-life	~5-10 minutes
Therapeutic considerations
Pregnancy cat.	?
Legal status	Uncontrolled
Routes	Oral

Phenethylamine (PEA) is a natural monoamine alkaloid, trace amine, and psychoactive drug with stimulantmammalian central nervous system, phenethylamine is believed to function as a neuromodulatorneurotransmitter. It is biosynthesized from the amino acid phenylalanine by enzymatic decarboxylation. Besides mammals, phenethylamine is found in many other organisms and foods such as chocolate, especially after microbial fermentation. It is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, orally ingested phenethylamine is usually inactive on account of extensive first-pass metabolism by monoamine oxidase (MAO) into phenylacetic acid, preventing significant concentrations from reaching the brain.^[1][2] effects. In the or

The group of phenethylamine derivatives is referred to as the phenethylamines. Substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include stimulants, psychedelics, and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others.

Contents [show] 1 Chemistry 2 Pharmacology 3 Pharmacokinetics 4 Chocolate theory of love 5 See also 6 References 7 External links

[edit] Chemistry

Phenethylamine is an amine, consisting of a benzene ring and an aminoethyl group. It is a colorless liquid at room temperature. Phenethylamine is soluble in water, ethanol, and ether. Similar to other low-molecular-weight amines, it has a fishy odor. Upon exposure to air, it forms a solid carbonate salt with carbon dioxide. Phenethylamine is strongly basic and forms a stable crystalline hydrochloride salt with a melting point of 217 °C. Phenethylamine is also a skin irritant and possible sensitizer.

Phenethylamine has an inactive constitutional isomer 1-phenylethylamine, which itself has two stereoisomers: (R)-(+)-1-phenylethylamine and (S)-(-)-1-phenylethylamine.

[edit] Pharmacology

Phenethylamine, similarly to amphetamine, acts as a releasing agent of norepinephrine and dopamine.^[3][4][5][6] For this reason, it has been called the “body’s endogenous amphetamine”. However when taken orally it is rapidly metabolized.

Low concentrations of endogenous phenethylamine are found in those suffering from attention-deficit hyperactivity disorder (ADHD)^[7] and often in clinical depression, while levels are elevated in schizophrenia.^[8]

Dopamine Dopaminergic system (misinformation included)

 Dopamine

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For other uses, see Dopamine (disambiguation).

Dopamine
IUPAC name[hide] 4-(2-aminoethyl)benzene-1,2-diol
Other names[hide] 2-(3,4-dihydroxyphenyl)ethylamine; 3,4-dihydroxyphenethylamine; 3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine
Identifiers
CAS number	51-61-6 Y, 62-31-7 (hydrochloride)
PubChem	681
ChemSpider	661
UNII	VTD58H1Z2X Y
SMILES	[show] c1cc(c(cc1CCN)O)O
InChI	[show] 1/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
InChI key	[show] VYFYYTLLBUKUHU-UHFFFAOYAA
Properties
Molecular formula	C8H11NO2
Molar mass	153.18 g/mol
Density	1.26 g/cm3
Melting point	128 °C, 401 K, 262 °F
Boiling point	decomposes
Solubility in water	60.0 g/100 ml
Hazards
R-phrases	R36/37/38
S-phrases	S26 S36
(what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)Y
Infobox references

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors—D₁, D₂, D₃, D₄, and D₅—and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area.^[1] Dopamine is also a neurohormonehypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary. released by the

Dopamine is available as an intravenous medication acting on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, because dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson’s disease and dopa-responsive dystonia, L-DOPA, which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.

Contents [show] 1 History 2 Biochemistry 2.1 Name and family 2.2 Biosynthesis 2.3 Inactivation and degradation 3 Functions in the brain 3.1 Anatomy 3.2 Tonic and phasic activity 3.3 Movement 3.4 Cognition and frontal cortex 3.5 Regulating prolactin secretion 3.6 Motivation and pleasure 3.6.1 Reinforcement 3.6.2 Reuptake inhibition, expulsion 3.6.3 Incentive salience 3.6.4 Dopamine, learning, and reward-seeking behavior 3.6.5 Animal studies 3.6.6 The effects of drugs that reduce dopamine activity 3.6.7 Opioid and cannabinoid transmission 3.6.8 Sociability 3.6.9 Processing of pain 3.6.10 Salience 3.6.11 Behavior disorders 3.7 Latent inhibition and creative drive 3.8 Chemoreceptor trigger zone 3.9 Dopaminergic mind hypothesis 4 Links to psychosis 5 Therapeutic use 6 Nonneural functions 6.1 Immunoregulatory 6.2 Peripheral effects 6.3 Renal effects 7 Dopamine and fruit browning 8 See also 9 References 10 External links

[edit] History

Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.^[2] It was named dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). Dopamine’s function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden.^[3] Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but a neurotransmitter as well.

[edit] Biochemistry

Biosynthesis of dopamine

[edit] Name and family

Dopamine has the chemical formula C₆H₃(OH)₂-CH₂-CH₂-NH₂. Its chemical name is “4-(2-aminoethyl)benzene-1,2-diol” and its abbreviation is “DA.”
As a member of the catecholamine family, dopamine is a precursor to norepinephrine (noradrenaline) and then epinephrine (adrenaline) in the biosynthetic pathways for these neurotransmitters.

The effects of drugs that reduce dopamine activity

In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been shown to reduce motivation, cause anhedonia (inability to experience pleasure), and long-term use has been associated with the irreversible movement disorder, tardive dyskinesia.^[26] Furthermore, antipsychotic drugs are associated with weight gain, diabetes, lactation, gynecomastia, drooling, dysphoria, fatigue, sexual dysfunction, and heart rhythm problems. Selective D2/D3 agonists pramipexole and ropinirole, used to treat restless legs syndrome^[27] (RLS), have limited anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

[edit] Opioid and cannabinoid transmission

Opioid and cannabinoid transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking).^[28] This could explain why animals’ “liking” of food is independent of brain dopamine concentration. Other consummatory pleasures, however, may be more associated with dopamine. One study found that both anticipatory and consummatory measures of sexual behavior (male rats) were disrupted by DA receptor antagonists.^[29] Libido can be increased by drugs that affect dopamine, but not by drugs that affect opioid peptides or other neurotransmitters.

[edit] Sociability

Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor-binding is found in people with social anxiety. Traits common to negative schizophrenia (social withdrawal, apathy, anhedonia) are thought to be related to a hypodopaminergic state in certain areas of the brain. In instances of bipolar disorder, manic subjects can become hypersocial, as well as hypersexual.^{[citation needed]} This is credited to an increase in dopamine, because mania can be reduced by dopamine-blocking anti-psychotics.^[30]

[edit] Processing of pain

Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervous system including the spinal cord,^[31] periaqueductal gray (PAG),^[32] thalamus,^[33] basal ganglia,^[34][35] insular cortex,^[36][37] and cingulate cortex.^[38] Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson’s disease.^[39] Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including burning mouth syndrome,^[40] fibromyalgia,^[41][42] and restless legs syndrome.^[43] In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably via activation of neurons involved in descending inhibition.^[44] In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.

[edit] Salience

Dopamine may also have a role in the salience of potentially important stimuli, such as sources of reward or of danger.^[45] This hypothesis argues that dopamine assists decision-making by influencing the priority, or level of desire, of such stimuli to the person concerned.

[edit] Behavior disorders

Deficient dopamine neurotransmission is implicated in attention-deficit hyperactivity disorder, and stimulant medications used to successfully treat the disorder increase dopamine neurotransmission, leading to decreased symptoms.^[46] Consistent with this hypothesis, dopaminergic pathways have a role in inhibitory action control and the inhibition of the tendency to make unwanted actions.^[47]

The long term use of levodopa in Parkinson’s disease has been linked to dopamine dysregulation syndrome.^[48]

[edit] Latent inhibition and creative drive

Dopamine in the mesolimbic pathway increases general arousal and goal directed behaviors and decreases latent inhibition; all three effects increase the creative drive of idea generation. This has led to a three-factor model of creativity involving the frontal lobes, the temporal lobes, and mesolimbic dopamine.^[49]

[edit] Chemoreceptor trigger zone

Dopamine is one of the neurotransmitters implicated in the control of nausea and vomiting via interactions in the chemoreceptor trigger zone. Metoclopramide is a D2-receptor antagonist that functions as a prokinetic/antiemetic.

[edit] Dopaminergic mind hypothesis

The dopaminergic mind hypothesis seeks to explain the differences between modern humans and their hominid relatives by focusing on changes in dopamine.^[50] It theorizes that increased levels of dopamine were part of a general physiological adaptation due to an increased consumption of meat around two million years ago in Homo habilis, and later enhanced by changes in diet and other environmental and social factors beginning approximately 80,000 years ago. Under this theory, the “high-dopamine” personality is characterized by high intelligence, a sense of personal destiny, a religious/cosmic preoccupation, an obsession with achieving goals and conquests, an emotional detachment that in many cases leads to ruthlessness, and a risk-taking mentality. High levels of dopamine are proposed to underlie increased psychological disorders in industrialized societies. According to this hypothesis, a “dopaminergic society” is an extremely goal-oriented, fast-paced, and even manic society, “given that dopamine is known to increase activity levels, speed up our internal clocks and create a preference for novel over unchanging environments.”^[50] In the same way that high-dopamine individuals lack empathy and exhibit a more masculine behavioral style, dopaminergic societies are “typified by more conquest, competition, and aggression than nurturance and communality.”^[50] Although behavioral evidence and some indirect anatomical evidence (e.g., enlargement of the dopamine-rich striatum in humans)^[51] support a dopaminergic expansion in humans, there is still no direct evidence that dopamine levels are markedly higher in humans relative to other apes.^[52] However, recent discoveries about the sea-side settlements of early man may provide evidence of dietary changes consistent with this hypothesis.^[53]

[edit] Links to psychosis

Main article: Dopamine hypothesis of schizophrenia

Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.^[54] Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. Anti-psychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and thereby blocking the effects of the neurochemical in a dose-dependant manner. The older, so-called typical antipsychotics most commonly act on D2 receptors,^[55] while the atypical drugs also act on D1, D3 and D4 receptors.^[56][57] The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,^[58] can temporarily cause psychosis, provides further evidence for this link.^[5

Therapeutic use

Main article: L-DOPA

Levodopa is a dopamine precursor used in various forms to treat Parkinson’s disease and dopa-responsive dystonia. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopa decarboxylase), such as carbidopa or benserazide. Inhibitors of alternative metabolic route for dopamine by catechol-O-methyl transferase are also used. These include entacapone and tolcapone.

Antipsychotics Pseuodoscience Death and Symbolic name fraud

Antipsychotics

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  (Redirected from Major tranquilizers)

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An antipsychotic (or neuroleptic) is a tranquilizing psychiatric medication primarily used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophreniabipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, known as atypical antipsychotics, have been developed more recently, although the first atypical antipsychotic, clozapine, was discovered in the 1950s and introduced clinically in the 1970s. Both generations of medication tend to block receptors in the brain’s dopamine pathways, but antipsychotic drugs encompass a wide range of receptor targets. and

A number of harmful and undesired (adverse) effects have been observed, including lowered life expectancy, weight gain, enlarged breasts and milk discharge in men and women (hyperprolactinaemia), lowered white blood cell count (agranulocytosis), involuntary repetitive body movements (tardive dyskinesia), diabetes, an inability to sit still or remain motionless (tardive akathisia), sexual dysfunction, a return of psychosis requiring increasing the dosage due to cells producing more neurochemicals to compensate for the drugs (tardive psychosis), and a potential for permanent chemical dependence leading to psychosis much worse than before treatment began, if the drug dosage is ever lowered or stopped (tardive dysphrenia).

Temporary withdrawal symptoms including insomnia, agitation, psychosis, and motor disorders may occur during dosage reduction of antipsychotics, and can be mistaken for a return of the underlying condition.^[1][2]

 History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a “chemical lobotomy“. Lobotomy at the time was used to treat many behavioral disorders, including psychosis, although its effect was to markedly reduce behavior and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than the extreme lobotomy-like sedation it was known for. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been discovered by an approach that incorporates this sort of information.

Drug action

All antipsychotic drugs tend to block D₂ receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D₂ receptors in these other pathways is thought to produce some of the unwanted side effects that the typical antipsychotics can produce (see below). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side effects.

Atypical antipsychotic drugs have a similar blocking effect on D₂ receptors. Some also block or partially block serotonin receptors (particularly 5HT_{2A, C} and 5HT_1A receptors):ranging from risperidone, which acts overwhelmingly on serotonin receptors, to amisulpride, which has no serotonergic activity. The additional effects on serotonin receptors may be why some of them can benefit the “negative symptoms” of schizophrenia.^[74]

Controversy

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff.^[81] In an official review commissioned by UK government ministers it was reported that the needless use of anti-psychotic medication in dementia care was widespread and was linked to 1800 deaths per year.^[82][83] In the US, the government has initiated legal action against the pharmaceutical company Johnson and Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic Risperidone (Risperdal) in nursing homes.^[84]

There is some controversy over maintenance therapy for schizophrenia.^[2][85] A review of studies about maintenance therapy concluded that long-term antipsychotic treatment was superior to placebo in reducing relapse in individuals with schizophrenia, although some of the studies were small.^[86] A review of major longitudinal studies in North America found that a moderate number of patients with schizophrenia were seen to recover over time from their symptoms, raising the possibility that some patients may not require maintenance medication.^[85] It has also been argued that much of the research into long-term antipsychotic maintenance may be flawed due to failure to take into account the role of antipsychotic withdrawal effects on relapse rates.^[2]

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. For example in the US, Eli Lilly recently pleaded guilty to violating US laws for over a decade in regard to Zyprexa (olanzapine), and was ordered to pay $1.42 billion to settle criminal and civil allegations, including the biggest criminal fine for an individual corporation ever imposed in US history; while Astrazeneca Seroquel (quetiapine), amidst federal investigations of its marketing practices.^[87] By expanding the conditions for which they were indicated, Astrazeneca’s Seroquel and Eli Lilly’s Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.^[11] is facing about 9,000 personal-injury lawsuits from more than 15,000 former users of

Some critics have also analyzed the use of alleged front organizations and conflicted patient “advocacy” groups funded by pharmaceutical companies that seek to set the mental health agenda, including the use of the law to force people to take antipsychotics against their will, often justified by claims about risk of violence.^[88]

False Prophecy-BEHEADING PROPAGANDA vilifying Islam

Beheadings—Orchestrated FALSE Fulfillment of prophecy to incite fear along with other false allusions. Consider psychotropic or psycho chemical mental incapacitation.  The head was considered the seat of reasoning even in Biblical times.
Revelation 20:3 And cast him into the bottomless pit, and shut him up, and set a seal upon him, that he should deceive the nations no more, till the thousand years should be fulfilled: and after that he must be loosed a little season. 4 And I saw thrones, and they sat upon them, and judgment was given unto them: and I saw the souls of them that were beheaded for the witness of Jesus, and for the word of God, and which had not worshipped the beast, neither his image, neither had received his mark upon their foreheads, or in their hands; and they lived and reigned with Christ a thousand years