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| Clinical data | |
|---|---|
| Pronunciation | /hæloʊpɛridɒl/ |
| Trade names | Haldol |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682180 |
| Pregnancy category |
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| Routes of administration |
by mouth, IM, IV, depot (as decanoate ester) |
| ATC code | N05AD01 (WHO) |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 60–70% (Oral)[1] |
| Protein binding | ~90%[1] |
| Metabolism | Liver-mediated[1] |
| Biological half-life | 14–26 hours (IV), 20.7 hours (IM), 14–37 hours (oral)[1] |
| Excretion | Biliary (hence in feces) and in urine[1][2] |
| Identifiers | |
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IUPAC name
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| CAS Number | 52-86-8 Y |
| PubChem (CID) | 3559 |
| IUPHAR/BPS | 86 |
| DrugBank | DB00502 Y |
| ChemSpider | 3438 Y |
| UNII | J6292F8L3D Y |
| KEGG | D00136 Y |
| ChEBI | CHEBI:5613 Y |
| ChEMBL | CHEMBL54 Y |
| ECHA InfoCard | 100.000.142 |
| Chemical and physical data | |
| Formula | C21H23ClFNO2 |
| Molar mass | 375.9 g/mol |
| 3D model (Jmol) | Interactive image |
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SMILES
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InChI
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| (verify) | |
Haloperidol, marketed under the trade name Haldol among others, is a typical antipsychotic medication.[3] Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, nausea and vomiting, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal.[3][4][5] It may be used by mouth, as an injection into a muscle, or intravenously. Haloperidol typically works within thirty to sixty minutes. A long-acting formulation may be used as an injection every four weeks in people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.[3]
Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death.[3] When taken during pregnancy it may result in problems in the infant.[3][6] It should not be used in people with Parkinson's disease.[3]
Haloperidol was discovered in 1958 by Paul Janssen.[7] It was made from meperidine.[8] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] It is the most commonly used typical antipsychotic.[10] The yearly cost of the typical dose of haloperidol is about 20 to 800 pounds (30 to 1,250 US dollars) in the United Kingdom.[10][11] The cost in the United States is around 250 US dollars a year.[12]
Contents
- 1 Medical uses
- 1.1 Pregnancy and lactation
- 1.2 Other considerations
- 2 Adverse effects
- 2.1 Contraindications
- 2.2 Special cautions
- 2.3 Interactions
- 3 Overdose
- 3.1 Symptoms
- 3.2 Treatment
- 3.3 Prognosis
- 4 Pharmacology
- 5 Pharmacokinetics
- 5.1 Oral
- 5.2 Intramuscular injections
- 5.3 Intravenous injections
- 5.4 Therapeutic concentrations
- 5.5 Distribution and metabolism
- 6 History
- 6.1 Brand names
- 7 Veterinary use
- 8 References
- 9 External links
Medical uses
Haloperidol is used in the control of the symptoms of:
- Schizophrenia[13]
- Acute psychosis, such as drug-induced psychosis caused by LSD, psilocybin, amphetamines, ketamine,[14] and phencyclidine,[15] and psychosis associated with high fever or metabolic disease
- Hyperactivity, aggression
- Hyperactive delirium (to control the agitation component of delirium)
- Otherwise uncontrollable, severe behavioral disorders in children and adolescents
- Agitation and confusion associated with cerebral sclerosis
- Adjunctive treatment of alcohol and opioid withdrawal
- Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology
- Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea
- Therapeutic trial in personality disorders, such as borderline personality disorder
- Treatment of intractable hiccups[16][17]
- Alcohol-induced psychosis
- Hallucinations in alcohol withdrawal[4]
Haloperidol was considered indispensable for treating psychiatric emergency situations,[18][19] although the newer atypical drugs have gained greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.[20][needs update][21][22][23]
A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.[24]
Pregnancy and lactation
Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the fetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential fetal risk.[13]
Haloperidol, when given to lactating women, is found in significant amounts in their milk. Breastfed children sometimes show extrapyramidal symptoms. If the use of haloperidol during lactation seems indicated, the benefit for the mother should clearly outweigh the risk for the child, or breastfeeding should be stopped.[citation needed]
Other considerations
Skeletal formula of haloperidol decanoate. The decanoate group is highlighted in red.
During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually.[25] In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.[26]
Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly.[citation needed] PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy.[27] Patients responded with doses under even 2 mg in first-episode psychosis.[28] For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.[26]
- Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.[citation needed]
The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks.[29] The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.
Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.[30]
Adverse effects
Sources for the following lists of adverse effects[31][32][33][34]
As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.[35]
With more than 6 months months of use 14% percent of users gain weight.[36]
- Common (>1% incidence)
- Extrapyramidal side effects including:
- Dystonia (continuous spasms and muscle contractions)
- Muscle rigidity
- Akathisia (motor restlessness)
- Parkinsonism (characteristic symptoms such as rigidity)
- Hypotension
- Anticholinergic side effects such as: (These adverse effects are more common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine.)
- Constipation
- Dry mouth
- Blurred vision
- Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis.[35])
- Unknown frequency
- Prolonged QT interval
- Orthostatic hypotension
- Increased respiratory rate
- Anemia
- Visual disturbances
- Headache
- Rare (<1% incidence)
- Jaundice
- Hepatitis
- Cholestasis
- Acute hepatic failure
- Liver function test abnormal
- Hypoglycemia
- Hyperglycemia
- Hyponatremia
- Anaphylactic reaction
- Hypersensitivity
- Agranulocytosis
- Neutropenia
- Leukopenia
- Thrombocytopania
- Pancytopenia
- Psychotic disorder
- Agitation
- Confusional state
- Depression
- Insomnia
- Seizure
- Torsades de pointes
- Ventricular fibrillation
- Ventricular tachycardia
- Extrasystoles
- Bronchospasm
- Laryngospasm
- Laryngeal edema
- Dyspnea
- Nausea
- Vomiting
- Leukocytoclastic vasculitis
- Dermatitis exfoliative
- Urticaria
- Photosensitivity reaction
- Rash
- Itchiness
- Increased sweating
- Urinary retention
- Priapism
- Gynecomastia
- Sudden death
- Face edema
- Edema
- Hypothermia
- Hyperthermia
- Injection site abscess
- Anorexia
- Pulmonary embolism
- Tardive dyskinesia
- Cataracts
- Retinopathy
- Neuroleptic malignant syndrome
Contraindications
- Pre-existing coma, acute stroke
- Severe intoxication with alcohol or other central depressant drugs
- Known allergy against haloperidol or other butyrophenones or other drug ingredients
- Known heart disease, when combined will tend towards cardiac arrest[citation needed]
Special cautions
- Pre-existing Parkinson's disease[37] or dementia with Lewy bodies
- Patients at special risk for the development of QT prolongation (hypokalemia, concomitant use of other drugs causing QT prolongation)
- Impaired liver function, as haloperidol is metabolized and eliminated mainly by the liver
- In patients with hyperthyreosis, the action of haloperidol is intensified and side effects are more likely.
- IV injections: risk of hypotension or orthostatic collapse
- Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.[13]
- Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients. Most of the causes of death were either cardiovascular or infectious in nature. It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients. The drug bears a boxed warning about this risk.[13]
Interactions
- Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased. In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
- Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects
- Levodopa: decreased action of levodopa
- Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)
- Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.[38]
- Guanethidine: antihypertensive action antagonized
- Epinephrine: action antagonized, paradoxical decrease in blood pressure may result
- Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD
- Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).[39]
- Other drugs metabolized by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels[13]
Overdose
Symptoms
Symptoms are usually due to side effects. Most often encountered are:
- Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.
- Hypotension or hypertension
- Sedation
- Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration)
- Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock
- Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time
Treatment
Treatment is merely symptomatic and involves intensive care with stabilization of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can all be tried. Epinephrine is avoided for treatment of hypotension and shock, because its action might be reversed. In the case of a severe overdose, antidotes such as bromocryptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists.[citation needed] ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.[13]
Prognosis
In general, the prognosis of overdose is good, and lasting damage is not known, provided the person has survived the initial phase. An overdose of haloperidol can be fatal.[40]
Pharmacology
Haloperidol, 10-mg oral tablet
Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics.[41] It has effects similar to the phenothiazines.[17] The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis.[42] Haloperidol's negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.
Haloperidol acts on these receptors: (Ki)
- D1 (silent antagonist) — Unknown efficiency[citation needed]
- D5 (silent antagonist) — Unknown efficiency[citation needed]
- D2 (inverse agonist) — 1.55 nM[43]
- D3 (inverse agonist) — 0.74 nM[44]
- D4 (inverse agonist) — 5–9 nM[45]
- σ1 (irreversible inactivation by haloperidol metabolite HPP+) – 3 nM[46]
- σ2 (agonist): 54 nM[47]
- 5HT1A receptor agonist – 1927 nM[48]
- 5HT2A (silent antagonist) – 53 nM[48]
- 5HT2C (silent antagonist) – 10,000 nM[48]
- 5HT6 (silent antagonist) – 3666 nM[48]
- 5HT7 (irreversible silent antagonist) — 377.2 nM[48]
- H1 (silent antagonist) — 1,800 nM[48]
- M1 (silent antagonist) — 10,000 nM[48]
- α1A (silent antagonist) — 12 nM[48]
- α2A (silent antagonist) — 1130 nM[48]
- α2B (silent antagonist) — 480 nM[48]
- α2C (silent antagonist) — 550 nM[48]
- NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 — 2,000 nM[49]
Pharmacokinetics
Oral
The bioavailability of oral haloperidol ranges from 60–70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.[1]
Intramuscular injections
The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours.[1] The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.[50]
Intravenous injections
The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg.[1] The duration of action is four to six hours. If haloperidol is given as a slow IV infusion, the onset of action is slowed, and the duration of action is prolonged.[citation needed]
Haloperidol for injection
Therapeutic concentrations
Plasma levels of four to 25 micrograms per liter are required for therapeutic action. The determination of plasma levels can be used to calculate dose adjustments and to check compliance, particularly in long-term patients. Plasma levels in excess of the therapeutic range may lead to a higher incidence of side effects or even pose the risk of haloperidol intoxication.[citation needed]
The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue,[51] which may explain the slow disappearance of side effects when the medication is stopped.[51][52]
Distribution and metabolism
Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolized in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.[1]
History
Haloperidol was discovered by Paul Janssen.[53] It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.[54][55]
Haloperidol was approved by the U.S. Food and Drug Administration (FDA) on April 12, 1967; it was later marketed in the U.S. and other countries under the brand name Haldol by McNeil Laboratories.[citation needed]
Brand names
Haloperidol is the INN, BAN, USAN, AAN approved name.
It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.[citation needed]
Veterinary use
Haloperidol is also used on many different kinds of animals. It appears to be particularly successful when given to birds, e.g., a parrot that will otherwise continuously pluck its feathers out.[56]
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- ^ Leysen, JE; Janssen, PM; Gommeren, W; Wynants, J; Pauwels, PJ; Janssen, PA (1992). "In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone". Molecular Pharmacology. 41 (3): 494–508. PMID 1372084.
- ^ Malmberg, Åsa; Mikaels, Åsa; Mohell, Nina (1998). "Agonist and Inverse Agonist Activity at the Dopamine D3 Receptor Measured by Guanosine 5′-[γ-Thio]Triphosphate-[35S] Binding". The Journal of Pharmacology and Experimental Therapeutics. 285 (1): 119–26. PMID 9536001.
- ^ Leysen, JE; Janssen, PM; Megens, AA; Schotte, A (1994). "Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity". The Journal of Clinical Psychiatry. 55 (Suppl): 5–12. PMID 7520908.
- ^ Cobos, Enrique J.; Del Pozo, Esperanza; Baeyens, José M. (2007). "Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells". Journal of Neurochemistry. 102 (3): 812–25. doi:10.1111/j.1471-4159.2007.04533.x. PMID 17419803.
- ^ Colabufo, Nicolaantonio; Berardi, Francesco; Contino, Marialessandra; Niso, Mauro; Abate, Carmen; Perrone, Roberto; Tortorella, Vincenzo (2004). "Antiproliferative and cytotoxic effects of some σ2 agonists and σ1 antagonists in tumour cell lines". Naunyn-Schmiedeberg's Archives of Pharmacology. 370 (2): 106–13. doi:10.1007/s00210-004-0961-2. PMID 15322732.
- ^ a b c d e f g h i j k Kroeze, Wesley K; Hufeisen, Sandra J; Popadak, Beth A; Renock, Sean M; Steinberg, Seanna; Ernsberger, Paul; Jayathilake, Karu; Meltzer, Herbert Y; Roth, Bryan L (2003). "H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs". Neuropsychopharmacology. 28 (3): 519–26. doi:10.1038/sj.npp.1300027. PMID 12629531.
- ^ Ilyin, VI; Whittemore, ER; Guastella, J; Weber, E; Woodward, RM (1996). "Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol". Molecular Pharmacology. 50 (6): 1541–50. PMID 8967976.
- ^ "drugs.com".
- ^ a b Kornhuber, Johannes; Schultz, Andreas; Wiltfang, Jens; Meineke, Ingolf; Gleiter, Christoph H.; Zöchling, Robert; Boissl, Karl-Werner; Leblhuber, Friedrich; Riederer, Peter (1999). "Persistence of Haloperidol in Human Brain Tissue". The American Journal of Psychiatry. 156 (6): 885–90. doi:10.1176/ajp.156.6.885. PMID 10360127.
- ^ Kornhuber, Johannes; Wiltfang, Jens; Riederer, Peter; Bleich, Stefan (2006). "Neuroleptic drugs in the human brain: Clinical impact of persistence and region-specific distribution". European Archives of Psychiatry and Clinical Neuroscience. 256 (5): 274–80. doi:10.1007/s00406-006-0661-7. PMID 16788768.
- ^ Healy, David (1996). The psychopharmacologists. 1. London: Chapman and Hall. ISBN 978-1-86036-008-4. [page needed]
- ^ Granger, Bernard; Albu, Simona (2005). "The Haloperidol Story". Annals of Clinical Psychiatry. 17 (3): 137–40. doi:10.1080/10401230591002048. PMID 16433054.
- ^ Lopez-Munoz, Francisco; Alamo, Cecilio (2009). "The Consolidation of Neuroleptic Therapy: Janssen, the Discovery of Haloperidol and Its Introduction into Clinical Practice". Brain Research Bulletin. 79: 130–141. doi:10.1016/j.brainresbull.2009.01.005. PMID 19186209.
- ^ "Veterinary:Avian at Lloyd Center Pharmacy".
External links
- Rx-List.com – Haloperidol
- Medline plus – Haloperidol
- Swiss scientific information on Haldol
- "WHO Model List of Essential Medicines" (PDF) (16th list (updated) ed.). World Health Organization. March 2010. Retrieved 2010-09-14.
- U.S. National Library of Medicine: Drug Information Portal - Haloperidol
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UpToDate Contents
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- 1. 統合失調症に対する薬物療法：持効性抗精神病薬注射製剤 pharmacotherapy for schizophrenia long acting injectable antipsychotic drugs
- 2. 第1世代抗精神病剤：薬理学、投与、および副作用の比較 first generation antipsychotic medications pharmacology administration and comparative side effects
- 3. せん妄および急性錯乱状態：予防、治療、および予後 delirium and acute confusional states prevention treatment and prognosis
- 4. 危篤状態の成人における鎮静鎮痛剤：特性、投与レジメン、および副作用 sedative analgesic medications in critically ill adults properties dosage regimens and adverse effects
- 5. 統合失調症に対する薬物療法：副作用マネージメント pharmacotherapy for schizophrenia side effect management
English Journal
- Pleckstrin homology domain containing 6 protein (PLEKHA6) polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients.
- Spellmann I1, Rujescu D2, Musil R3, Giegling I2, Genius J4, Zill P3, Dehning S3, Cerovecki A3, Seemüller F3, Schennach R3, Hartmann AM3, Schäfer M3, Müller N3, Möller HJ3, Riedel M5.Author information 1Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy. Electronic address: ilja.spellmann@bkh-kaufbeuren.de.2Martin Luther University of Halle (Saale), Department of Psychiatry and Psychotherapy.3Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.4LVR-Hospital Essen, Department of Psychiatry and Psychotherapy.5Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Vinzenz-von-Paul-Hospital Rottweil.AbstractPleckstrin homology domain (PH domain) comprises approximately 120 amino acids and is integrated in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosphatidylinositol (3,4,5)-triphosphate and phosphatidylinositol (4,5)-biphosphate and proteins such as the βγ-subunits of heterotrimeric G proteins and protein kinase C. Associations with psychiatric diseases have not been investigated yet. To identify genes involved in response to antipsychotics, mice were treated with haloperidol (1mg/kg, n=11) or saline (n=12) for one week. By analyzing microarray data, we observed an increase of pleckstrin homology domain containing 6 (PLEKHA6) gene expression. Furthermore, we genotyped 263 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNPs. We found associations between four PLEKHA6 polymorphisms (rs17333933 (T/G), rs3126209 (C/T), rs4951338 (A/G) and rs100900571 (T/C)) and different PANSS subscales at baseline. Furthermore two different polymorphisms (rs7513240 (T/C), rs4951353 (A/G)) were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Our observation of an association between genetic polymorphisms of a protein of the PH domain and psychopathology data in schizophrenic patients might be indicative for an involvement of PLEKHA6 in the pathophysiology of schizophrenia and the therapy response towards antipsychotics.
- Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2014 Jun 3;51:190-5. doi: 10.1016/j.pnpbp.2014.02.006. Epub 2014 Feb 25.
- Pleckstrin homology domain (PH domain) comprises approximately 120 amino acids and is integrated in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosphatidylinositol (3,4,5)-triphosphate and phosphatidylinositol (4,5)-bipho
- PMID 24576533
- Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor.
- Aoyama Y1, Mouri A1, Toriumi K1, Koseki T1, Narusawa S1, Ikawa N1, Mamiya T1, Nagai T2, Yamada K2, Nabeshima T1.Author information 1Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.2The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Meijo University, Nagoya, Japan.AbstractAccumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca2+/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.
- The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP).Int J Neuropsychopharmacol.2014 May;17(5):723-37. doi: 10.1017/S1461145713001466. Epub 2013 Dec 17.
- Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities
- PMID 24345457
- HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation.
- Montalvo-Ortiz JL1, Keegan J1, Gallardo C1, Gerst N2, Tetsuka K2, Tucker C2, Matsumoto M2, Fang D3, Csernansky JG1, Dong H1.Author information 1Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.2Astellas Research Institute of America, Skokie, IL, USA.3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.AbstractAntipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.Neuropsychopharmacology.2014 May;39(6):1469-78. doi: 10.1038/npp.2013.346. Epub 2013 Dec 24.
- Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly i
- PMID 24366052
Related Links
- Learn about the prescription medication Haldol (Haloperidol Injection), drug uses, dosage, side effects, drug interactions, warnings, reviews and patient labeling. ... What are the possible side effects of haloperidol (Haldol)? Get ...
- Haldol. 304 likes · 3 talking about this. Started in 2011. Formerly from Nashville, TN; relocated/reformed in Philadelphia, PA.... ... We haven't used much of this lately, but we have a tour coming up with Pissbath and Vacant Future!
Related Pictures
★リンクテーブル★
| リンク元 | 「ハロペリドール」 |
| 関連記事 | 「haldol」 |
「ハロペリドール」
- 英
- haloperidol
- ラ
- haloperidolum
- 商
- ケセラン、ネオペリドール、ハロマンス、エセックチン、コスミナール、スイロリン、ハロジャスト、ハロステン、ハロミドール、ヨウペリドール、レモナミン、リントン、セレネース、Haldol
- 関
- 抗精神病薬
特徴
- 作用が強力なので統合失調症の急性期によい。
- 催眠作用、自律神経症状、血圧低下などの循環器での急性治療に用いられる。
構造
- C21H23ClFNO2。
作用機序
薬理作用
動態
適応
- 統合失調症
- そう病
注意
禁忌
- 昏睡、重要心不全、パーキンソン病、妊婦
副作用
- フェノチアジン系のクロルプロマジンより抗ムスカリン作用が弱い
相互作用
「haldol」
- 同
- Haldol
- 関
- Haloperidol