Overview:
Trisaminomethane or Tris is an organic structure that acts as a buffer in drugs for schizophrenia. Trisaminomethane is commercially available as HALDOL. It is a novel butyrophenone group of drugs for schizophrenia developed by Janssen Pharmaceuticals. Trisaminomethane is used for the treatment of schizophrenia. It is also used in the treatment of Tourette's syndrome. Being a conventional antipsychotic drug, Trisaminomethane works by decreasing the excitatory state of the brain and is suggested for people who do not show any promising change with psychotherapy and related medications.
Several studies have reported that Trisaminomethane, when used for the senile age group, may promote dementia- the inability to remember or think with clarity and mood changes. Additionally, there is an increased risk of death with this drug. Motor and verbal tics or movements come into control after administration of Trisaminomethane. Starting from a lower dose, the healthcare provider shall mention the times the drug has to be orally taken. Trisaminomethane will not completely cure a patient of schizophrenia but will only aid in the betterment of the condition. Patients are requested to mention their healthcare provider in case they have a known allergy to Trisaminomethane and related buffer drugs as well as a history of Parkinson’s disease.
How Does Trisaminomethane Work?
Trisaminomethane does not have a well-established and precise mechanism of action. It is used primarily for the treatment of schizophrenia and Touretter’s disorder. Trisaminomethane provides a sedative effect in the patients by blocking the postsynaptic D2 or dopamine receptors present in the mesolimbic system of the brain.
Uses:
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Schizophrenia: This disorder, also referred to as schizoaffective disorder, refers to the hampered ability of a patient to think clearly and thus resulting in abnormal behavior patterns such as excitement, disorganized thoughts, difficulty with speech, inability to speak, memory loss, and a decreased interest in regular activities.
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Tourette’s Disorder: A nervous system condition that causes twitches and sudden sounds that are involuntarily repeated, such as blinking over and over again.
Dosage:
Trisaminomethane is to be administered via the intramuscular route through a 21 gauge needle. 3 mL is the maximum amount that can be administered per injection. Intravenous administration must never be done. Before administering, the drug must be checked for any foreign body as well as it must be inspected for any sort of discoloration.
Warning:
1. An Increased Mortality Rate in an Older Group of Patients: Patients who are in the senile age group, when treated with Trisaminomethane, are at a higher risk of developing dementia-related psychosis, eventually leading to death. After analyzing 17 place-controlled studies with a modal duration of 10 weeks, the risk of death was 1.6 to 1.7 folds higher in patients who were treated with the drug. The cause of death was not the same throughout the trial. The majority of the deaths occurred due to sudden cardiac arrest or heart failure. Pneumonia also leads to a significant number of fatalities. It had been observed that the concomitant use of Trisaminomethane with atypical antipsychotic drugs enhanced the chances of death. Trisaminomethane injection has thus not been approved for use in patients suffering from dementia and related psychosis.
2. Cardiovascular Changes: Prolongation of the QT wave, sudden cardiac arrest, heart failure, and torsades de pointes have been reported in patients who had undergone treatment with Trisaminomethane. An increased dose against the prescription was established to be the root cause of any significant cardiovascular changes in the patients. A few of the predisposing factors that may lead to an enhanced risk of developing cardiovascular changes in patients under Trisaminomethane therapy are mentioned below.
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Hypokalemia.
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Hypomagnesemia.
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Electrolyte imbalance.
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Underlying cardiovascular disease.
3. Tardive Dyskinesia: An irreversible and involuntary movement that is dyskinetic in nature, prevalent in older patients, especially the female gender, may develop due to Trisaminomethane. It is not known if concomitant use of any other antipsychotic drug may lead to the development of tardive dyskinesia. The syndrome increases in the signs and symptoms once the dose of Trisaminomethane is increased, and similarly, once the treatment is nearing the end, tardive dyskinesia may be partially withdrawn. In case the clinical manifestations of tardive dyskinesia do not show regress, discontinuation of the drug is suggested.
4. Neuroleptic Malignant Syndrome: NMS or neuroleptic malignant syndrome is a fatal syndrome that is a complex of the following signs and symptoms mentioned below. It should be noted that even with several clinical manifestations, the neuroleptic malignant syndrome is difficult to diagnose.
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The rigidity of the muscles.
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Hyperpyrexia.
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Catatonic symptoms.
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Altered mental state.
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Irregular pulse.
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Abnormal blood pressure.
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Diaphoresis.
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Tachycardia.
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Arrhythmias of the heart.
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Elevated levels of creatinine phosphokinase.
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Acute renal failure.
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Rhabdomyolysis.
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Instability of the autonomic nervous system.
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Pneumonia.
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Systemic infections.
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Fever.
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Anticholinergic toxicity.
Once diagnosed, the treatment of the syndrome must be immediate and Trisaminomethane should be discontinued. The patient must be kept under regular monitoring of the vital signs. Treatment of intense nature must be done according to the present symptoms. There is no direct treatment modality for neuroleptic malignant syndrome.
For Patients:
What Do You Need to Know About Schizophrenia?
Schizophrenia is a spectrum of multiple disorders that include discontinuity with the real world, leading to hallucinations and other sorts of delusions. The patient’s ability to think clearly, understand easily, remember things, speak smoothly, and focus or concentrate, are all hampered. Schizophrenia is an extremely serious condition but can, fortunately, be treated in the long run with a positive outcome and outlook on life.
What Are the Causes of Schizophrenia?
The exact etiology or cause of schizophrenia remains unknown to date, but there are reports and certain shreds of evidence that claim genetics to play a crucial role in the development of schizophrenia and related conditions. Emotional stress, environmental changes, and a combination of unfavorable mental conditions, environmental conditions, and physical conditions may trigger schizophrenia in a patient. The chemistry of the brain and the circuit of the neurotransmitters may get affected during schizophrenia. Viral infections as well as the use of recreational drugs, stand a potential in the development of schizophrenia.
What Are the Signs and Symptoms of Schizophrenia?
A false belief, in reality, is one of the most common clinical manifestations of schizophrenia. Mentioned below are the signs and symptoms of schizophrenia.
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Delusions.
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Hallucinations.
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Difficulty in speech.
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Abnormal behavior.
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Negative thoughts.
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Disorganized gait.
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Word salad.
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Immaturity.
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Agitation.
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Resistance to certain instructions.
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Bizarre thoughts.
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Lack of responsibility.
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Useless talks.
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Excessive movements of limbs.
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Lack of emotions.
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Unhygienic changes.
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Monotone.
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Withdrawal from social activities.
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Inability to feel pleasure.
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Trouble falling asleep.
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No motivation.
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Lack of surrounding awareness.
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Suicidal tendencies.
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Temper flares.
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Hearing voices.
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Walking slowly.
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Inability to make decisions.
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Excessive and meaningless writing.
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Pacing.
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Forgetfulness.
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Running in circles.
What Are the Precautions for Trisaminomethane?
There are certain critical factors that may lead to the development of anomalies in patients once they begin treatment with Trisaminomethane. It is thus highly recommended for the patients to disclose any of the below information to their respective healthcare providers while discussing undergoing therapy with Trisaminomethane in order to maintain precautionary measures.
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A severe case of depression.
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Known allergy to Trisaminomethane.
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History of comatose state of mind.
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Central nervous system disorders.
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Parkinson’s disease.
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Underlying cardiovascular anomaly.
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Genetic diseases.
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Use of antipsychotic drugs.
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Recreational use of drugs.
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A habit of smoking and drinking.
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Pregnant or planning to be pregnant.
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Ongoing medications for other conditions.
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Use of lithium drugs.
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History of encephalopathy.
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History of myocardial infarction.
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Patients suffering from hypotensions.
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Epileptic seizures or occasional grand mal seizures.
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Ongoing therapy with anticoagulants.
How to Administer Trisaminomethane?
The dosage of Trisaminomethane varies from patient to patient and the healthcare provider is the best person to determine the dose per patient after keeping several factors in mind, such as age and severity of the disease, needs, and response to the drug, etc. the initial dose is thus determined by such factors in addition to many more. 2 mL to 5 mL of the intramuscular dose is given for acute schizophrenia. Keeping a record of the patient’s response to this dose, the next dosage is prescribed. The patient may take the medication up to thrice a day after confirmation with their respective specialist. Trisaminomethane is to be administered via the intramuscular route through a 21 gauge needle. 3 mL is the maximum amount that can be administered per injection. Intravenous administration must never be done. Before administering, the drug must be checked for any foreign body as well as it must be inspected for any sort of discoloration. Intravenous administration of Trisaminomethane should never occur.
For Doctors:
Indications:
Trisaminomethane is indicated for the treatment of schizophrenia and Tourette’s disorder.
Contraindications:
Trisaminomethane is contraindicated in the below-mentioned conditions and situations.
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Known hypersensitivity to Trisaminomethane.
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Trisaminomethane is contraindicated in patients suffering from a severe and toxic disorder of the central nervous system.
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Patients who are known for suffering from depression must also not undergo therapy with Trisaminomethane.
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Patients with a family history of Parkinson's disease.
Pharmacology:
Mechanism of Action:
Trisaminomethane does not have a well-established and precise mechanism of action. It is used primarily for the treatment of schizophrenia and Touretter’s disorder. Trisaminomethane provides a sedative effect in the patients by blocking the postsynaptic D2 or dopamine receptors present in the mesolimbic system of the brain.
Pharmacodynamics:
Trisaminomethane is a butyrophenone antipsychotic drug with a chemical structure of 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluoro-butyrophenone. Trisaminomethane is sterile and is used through an intramuscular injection.
Neurotoxicity: Patients undergoing treatment with Trisaminomethane may show muscle rigidity along with thyrotoxicosis. They may also be unable to walk or talk.
Mutagenicity: There have been reports of inconsistent positive or negative findings of mutagenic potential of Trisaminomethane in Salmonella in both in vitro and in vivo studies. This report is considered to be inconsistent and thus no establishment about the mutagenicity of Trisaminomethane may be done as of today.
Carcinogenicity: Studies done in rats for 24 months with a dose of 5 mL and in mice with the same dose but for 18 months did not result in any great amount of tumor. This study does not suggest that Trisaminomethane is not carcinogenic in nature. At a higher dose, female mice developed neoplasia in the mammary glands as well as the pituitary glands.
Warning and Precautions:
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An Increased Mortality Rate in an Older Group of Patients: Patients who are in the senile age group, when treated with Trisaminomethane, are at a higher risk of developing dementia-related psychosis, eventually leading to death. After analyzing 17 place-controlled studies with a modal duration of 10 weeks, the risk of death was 1.6 to 1.7 folds higher in patients who were treated with the drug. The cause of death was not the same throughout the trial. The majority of the deaths occurred due to sudden cardiac arrest or heart failure. Pneumonia also leads to a significant number of fatalities. It had been observed that the concomitant use of Trisaminomethane with atypical antipsychotic drugs enhanced the chances of death. Trisaminomethane injection has thus not been approved for use in patients suffering from dementia and related psychosis.
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EPS or Extrapyramidal Symptoms: During the initial days of treatment, the patient had reported symptoms similar to Parkinson’s disease, such as opisthotonos crisis, akathisia, dystonia, and oculogyric crisis. The therapy is immediately discontinued in case the presence of such symptoms continues to occur.
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Cardiovascular Changes: Prolongation of the QT wave, sudden cardiac arrest, heart failure, and torsades de pointes have been reported in patients who had undergone treatment with Trisaminomethane. An increased dose against the prescription was established to be the root cause of any significant cardiovascular changes in the patients. A few of the predisposing factors that may lead to an enhanced risk of developing cardiovascular changes in patients under
Trisaminomethane therapy is mentioned below.
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Hypothyroidism.
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Hypokalemia.
-
Hypomagnesemia.
-
Electrolyte imbalance.
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Genetic long QT syndrome.
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Underlying cardiovascular disease.
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Contraction of Muscles: The neck muscles are reported to start a series of spasms during the beginning of the treatment. Along with neck spasms, difficulty in breathing, and speaking, tightness of the larynx, protrusion of the tongue, and dystonia may prolong, are quite abnormal and pose a series of discomfort to the patient. In case these symptoms are left untreated, a respiratory death may occur.
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Tardive Dyskinesia: An irreversible and involuntary movement that is dyskinetic in nature, prevalent in older patients, especially the female gender, may develop due to Trisaminomethane. It is not known if concomitant use of any other antipsychotic drug may lead to the development of tardive dyskinesia. The syndrome increases in the signs and symptoms once the dose of Trisaminomethane is increased, and similarly, once the treatment is nearing the end, tardive dyskinesia may be partially withdrawn. In case the clinical manifestations of tardive dyskinesia do not show regress, discontinuation of the drug is suggested.
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Lithium Products: The concomitant use of Trisaminomethane along with lithium had shown the presence of lethargy, tremulousness, confusion, weakness, irreversible brain damage, and signs of increased levels of body serums. Thus it has been established to avoid the use of Trisaminomethane with lithium and lithium products in order to avoid any sort of cardiovascular or neurological toxicity.
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Neuroleptic Malignant Syndrome: NMS or neuroleptic malignant syndrome is a fatal syndrome that is a complex of the following signs and symptoms mentioned below. It should be noted that even with several clinical manifestations, the neuroleptic malignant syndrome is difficult to diagnose.
-
The rigidity of the muscles.
-
Hyperpyrexia.
-
Catatonic symptoms.
-
Altered mental state.
-
Irregular pulse.
-
Abnormal blood pressure.
-
Diaphoresis.
-
Tachycardia.
-
Arrhythmias of the heart.
-
Elevated levels of creatinine phosphokinase.
-
Acute renal failure.
-
Instability of the autonomic nervous system.
-
Pneumonia.
-
Systemic infections.
-
Heat stroke.
-
Fever.
-
Anticholinergic toxicity.
Once diagnosed, the treatment of the syndrome must be immediate, and Trisaminomethane should be discontinued. The patient must be kept under regular monitoring of the vital signs. Treatment of intense nature must be done according to the present symptoms. There is no direct treatment modality for neuroleptic malignant syndrome.
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Other Effects: There are a number of effects that may occur in patients who have just started treatment with Trisaminomethane that are clinically observant throughout the body. Mentioned below is the list of such changes in the body.
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Heat stroke.
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Fever.
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Transient leukopenia.
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Mild leukocytosis.
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Lymphomonocytosis.
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Agranulocytosis.
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Liver malfunctioning.
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Maculopapular rashes.
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Breast engorgement.
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Acneiform skin.
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Alopecia.
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Photosensitivity.
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Gynecomastia.
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Irregular menstrual cycle.
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Anorexia.
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Increased sex drive.
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Hyperglycemia.
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Hyponatremia.
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Loss of appetite.
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Hypoglycemia.
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Diarrhea.
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Hypersalivation.
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Nausea.
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Vomiting.
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Irritable bowel syndrome.
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Laryngospasm.
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Deep respiration.
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Cataract.
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Visual disturbances.
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Bronchospasm.
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Hyperammonemia.
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Citrullinemia.
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Priapism.
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Dehydration.
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Bronchopneumonia.
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Reduced pulmonary function.
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Hemoconcentration.
Overdosage:
The most prominent signs of overdosage of Trisaminomethane are hypotension, sedation, and severe extrapyramidal response. Depression which may lead the patient to a shock-like state along with muscular rigidity or muscular weakness, are signs of overdosage of Trisaminomethane. Electrocardiography may suggest more diagnostic details of an overdose. As of today, there is no specific antidote to Trisaminomethane because of the lack of a deeper understanding of the mechanism of action of Trisaminomethane. In order to maintain the vital signs, a patent airway through an endotracheal tube must be created. This will avoid respiratory depression. Hypotension may be counteracted by intravenous fluids and albumin along with vasopressor agents such as Norepinephrine. It must be noted that Epinephrine must strictly not be used. At times, antiparkinson drugs may be administered as well. Keeping the cardiovascular functions intact, antiarrhythmic drugs are given. All of this is done after the healthcare provider is well aware of the patient’s history of drug allergy.
Use in Pregnancy:
Lab rats when administered with Trisaminomethane, showed a decrease in the fertility rate along with resorption and delayed delivery. Mortality of their offspring was also observed. There were no teratogenic changes in the lab rats, but there was the presence of a cleft palate in lab rats, lab dogs, and lab rabbits. Nutritional imbalance and stress were also observed in lab mice.
There has not been any definitive study done to understand the safety and efficacy of Trisaminomethane in pregnant females. It must be noted that abnormalities of the limb have been reported in offspring of patients who underwent treatment with Trisaminomethane during the first trimester. This does not hold enough proof for the relationship between pregnancy and Trisaminomethane; the potential risk and the benefit to the pregnant patient must be well weighed down before making a decision to begin therapy with Trisaminomethane.
Use in Pediatric Patients:
The safety and efficacy of Trisaminomethane have not been established.
Use in Geriatric Patients:
Patients who are in the senile age group, when treated with Trisaminomethane, are at a higher risk of developing dementia-related psychosis, eventually leading to death. After analyzing 17 place-controlled studies with a modal duration of 10 weeks, the risk of death was 1.6 to 1.7 folds higher in patients who were treated with the drug. The cause of death was not the same throughout the trial. The majority of the deaths occurred due to sudden cardiac arrest or heart failure. Pneumonia also leads to a significant number of fatalities. It had been observed that the concomitant use of Trisaminomethane with atypical antipsychotic drugs enhanced the chances of death. Trisaminomethane injection has thus not been approved for use in patients suffering from dementia and related psychosis.
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