Trimipramine - Uses, Dosage, Precautions, and Adverse Reactions

Overview:

Trimipramine is an antidepressant widely used to manage two major types of depression that are endogenous and exogenous. Individuals who remain depressed without stress or trauma tend to suffer from endogenous depression. In contrast, exogenous depression occurs in response to a specific external cause, including trauma, financial crisis, or relationship problems.

The drug also has potential anxiolytic and sedative effects. However, it has weak antipsychotic effects in treating anxiety, insomnia, and psychosis. Trimipramine has been categorized as a second-generation tricyclic acid antidepressant (TCA) because it is a weak monoamine reuptake inhibitor. However, the most significant characteristic of the drug is that it does not have antiadrenergic, antiserotonergic, antihistamine, or anticholinergic properties. In simple terms, Trimipramine increases the chemical activities in the brain and helps overcome depression.

Trimipramine Approval History:

Trimipramine was discovered and developed by a French chemical and pharmaceutical company named Rhone-Poulenc. The drug was patented in 1959 and was first introduced in the medical literature in 1961. Trimipramine was first introduced for medical use in Europe in 1966. Finally, the United States (US) Food and Drug Administration (FDA) approved the 25 mg and 50 mg oral capsules of Trimipramine maleate on 1st January 1982. The FDA approved the 100 mg oral capsules on 15th September 1982. Finally, the generic versions of all three formulations were approved on 2nd August 2006.

Efficacy and Safety of Trimipramine:

A clinical trial was done to evaluate Trimipramine's cardiac safety and antipsychotic efficacy. The trial involved 22 patients with depression and cardiac diseases. These patients received Trimipramine of 50 to 200 mg daily for 28 days. The trial results demonstrated that these patients had a baseline decrease in their depression scores. However, a clinically significant change noted during the trial was prolonging the QRS interval. This change became noticeable in the ECG (electrocardiogram), Holter monitor test, and other myocardial function tests. In addition, the patients did not present with any cardiovascular symptoms. Hence, the trial results signify that Trimipramine is efficient in treating depression and would not produce harmful cardiovascular adverse reactions.

How Does Trimipramine Work to Treat Depression?

Trimipramine belongs to the class of tricyclic antidepressants. The drugs in this class have been FDA approved to treat a major depressive disorder, anxiety, insomnia, anxiety, and obsessive-compulsive disorder (OCD). However, the mechanism of action of Trimipramine is different from other TCAs. This is because TCAs directly inhibit the reuptake of norepinephrine and serotonin from the presynaptic terminals. However, Trimipramine only reduces the uptake of serotonin (5-HT) and norepinephrine. Trimipramine is poorly metabolized in the body, which is associated with CYP2D6 polymorphism. In simple terms, Trimipramine elevates the level of substances in the brain that help maintain mental stability.

Effects of Trimipramine on Sleep and Pituitary Hormones:

Trimipramine has atypical pharmacological properties and does not modify sleep in the REM (rapid eye movement). A clinical trial was conducted on ten depressed patients at 75 to 200 mg at night. The trial results demonstrated that the patients improved their sleep patterns, total sleep time, and efficiency. However, there was a decrease in sleep onset latency. Furthermore, there was no suppression of REM sleep. Instead, an increase in the baseline value was noted. Another trial was done on eight patients at a single oral dosage of 75 mg. The patients presented with reduced plasma prolactin concentrations. However, no clinically significant changes were observed in the plasma human growth hormone concentration. Hence, it can be concluded that Trimipramine exerts the same neuroendocrine effects as the ones observed with other neuroleptics.

For Patients:

What Is Depression?

Depression is a common mood disorder prevalent worldwide and can affect people of all age groups. People suffering from this disorder tend to remain sad and lose interest in their surrounding activities. It is also known as major depressive disorder or clinical depression. Some people might find it difficult to carry out their daily activities, whereas others feel they should end their lives. Depression should not be confused with mood swings or emotional stress. Instead, it requires long-term treatment and emotional and mental support. However, people with depression must not get discouraged and consult a psychiatrist to learn about management.

What Are the Symptoms of Depression?

Some people remain depressed, while others might experience the symptoms only once. The signs and symptoms of depression are listed below:

• Feeling tired, hopeless, and sad throughout the day.

• Anger, irritability, or frustration.

• Disturbed sleep cycle leading to insomnia.

• Loss of interest in all the daily activities.

• Loss of appetite.

• Weight loss.

• Lack of energy.

• Agitation or restlessness.

• Difficulty in concentrating on work or making decisions.

• Suicidal thoughts.

• Back pain and headaches.

What Are the Medical Uses of Trimipramine?

Trimipramine is primarily used to treat major depressive disorder and other conditions where sedatives play a significant role. In addition to being an antidepressant, Trimipramine is also an anxiolytic which implies that it helps overcome anxiety. Furthermore, it also helps the patient overcome insomnia or sleep disorders. However, the most significant advantage of Trimipramine is that it does not work like other hypnotics and does not interfere with the normal sleep-wake cycle of a person. In addition, Trimipramine exerts weak antipsychotic effects similar to Clozapine. Hence it can be employed to treat delusional depression, schizophrenia, and other psychotic symptoms.

What Should the Patient Inform the Doctor Before Taking Trimipramine?

Trimipramine is an antidepressant, so the patient must carefully take it. Before taking Trimipramine, the patient must inform the doctor if he or she:

• Is allergic to Trimipramine or any of its ingredients. The patient can consult the doctor or the pharmacist to get a list of the ingredients of Trimipramine.

• Is taking monoamine oxidase (MAO) inhibitors, or has taken the same in the last 14 days. This is because the doctor might avoid administering Trimipramine with MAO.

Some of these drugs include:

• Isocarboxazid.

• Linezolid.

• Methylene blue.

• Phenelzine.

• Selegiline.

• Tranylcypromine.

• Recently had heart failure or heart attack. The doctor might avoid giving Trimipramine in such a situation.

• Has a history of urinary problems, prostate enlargement, seizures, thyroid diseases, and kidney, heart, or liver diseases.

• Is taking or planning to take prescription, herbal, over-the-counter, multivitamins, and mineral supplements.

• Has stopped taking Fluoxetine in the past five weeks. The doctor might change the dosage of the drug or monitor the patient carefully for side effects.

• Is planning to conceive at present or in the future.

• Is above 65 years because Trimipramine is relatively contraindicated in elderly patients.

• Is planning to undergo dental surgery or other surgeries.

Note:

• Trimipramine can make a patient drowsy, so one must avoid driving or operating machinery.

• The patient must avoid consuming alcohol because it can exacerbate the drowsiness associated with this drug.

• The patient must avoid unnecessary sun exposure, increasing skin sensitivity and darkening the skin.

• Trimipramine might cause angle-closure glaucoma, so the patient must undergo an eye examination before taking the drug.

How Should the Patient Take Trimipramine?

Trimipramine is available as capsules, which should be taken orally once or thrice daily. The recommended starting dosage of the drug is 75 mg in two or three divided doses. The patient must take the drug at the same time daily. The doctor will review the patient's condition and modify the dose accordingly. Finally, the dose is adjusted according to the patient's condition and symptoms. The patient must read the prescription label carefully and reach out to his doctor for more clarity. Follow the drug dosage schedule and do not take more or less of the drug. The patient needs to continue taking the drug even if he feels well and should refrain from using it only after consulting the doctor. In case of a missed dose, the patient must take the dose as per the next schedule. However, do not take the double dose as it might cause serious side effects. The drug must be disposed of properly. Do not throw away the drug in household trash or water.

FDA Medication Guide for Antidepressants and Other Suicidal Thoughts:

The patient must carefully read the FDA-approved medication guide that is usually provided with antidepressants. The medication guide describes the risk of suicidal actions and thoughts associated with antidepressants. In addition, the patient must talk to his doctor about the following:

• Benefits of antidepressants.

• Risks associated with antidepressants.

• Other treatment options available for depression and other psychotic conditions.

What Are the Most Important Instructions Associated With Antidepressants?

Studies report that antidepressants stimulate suicidal thoughts and actions in young adults, teenagers, and children during the first few weeks of treatment. Depression is one of the most crucial causes of suicidal actions and thoughts. Some patients are more vulnerable to suicidal tendencies. Patients with a family history of manic-depressive illness or bipolar disorders are more likely to develop suicidal behavior.

How Can a Patient Prevent Suicidal Actions or Thoughts Due to Antidepressants?

• The patient must carefully monitor changes in moods, thoughts, feelings, or behaviors. This is especially important when the doctor changes the dose of the medicines.

• The patient should consult the doctor immediately if he experiences mood swings or changes in thoughts, behavior, or feelings.

• Visit the doctor regularly and keep track of the follow-up visits.

Note - The patient must consult the doctor immediately if he experiences any of the following side effects:

• Suicidal thoughts.

• Multiple attempts to commit suicide.

• Worsening of depression.

• Anxiety.

• Agitation.

• Restlessness.

• Insomnia or inability to fall asleep.

• Panic attacks.

• Worsening of irritability.

• Aggression, violence, or frustration.

• Action on dangerous impulses.

• Mania.

• Unusual variations in mood.

What Is the Important Information Related to Trimipramine?

• The patient must never stop taking antidepressant medications without talking to the doctor. The symptoms might exacerbate by the sudden withdrawal of the drug.

• Antidepressants mainly treat depression and other mental illnesses.

• The patient must discuss all the risk factors with the doctor before initiating the therapy.

• Discuss with the doctor to know in detail about the side effects of antidepressants.

• Keep a list of all the medicines that can interact with Trimipramine to rule out the possibility of drug interactions.

• The parents must consult the doctor to learn more about FDA-approved drugs for children.

For Doctors:

Description:

Trimipramine maleate is 5-(3-dimethylamino-2-methyl propyl)-10,11-dihydro-5H

dibenz (b,f) and azepine acid maleate (racemic form). The capsules are available in 25 mg, 50 mg, and 100 mg containing Trimipramine as the base ingredient. The drug is prepared as a racemic mixture that can be easily resolved into dextrorotatory or levorotatory isomers. Molecular studies indicate that the asymmetric center is responsible for optical isomerism. It is an odorless, cream-colored, and crystalline substance with a melting point of 140 to 144 degrees Celsius. It is almost insoluble in ether, water, acetone, or ethyl alcohol and is freely soluble in methanol and chloroform at 20 degrees Celsius.

Chemical Properties of Trimipramine:

• Molecular Weight - 410.5.

• Molecular Formula - C20H26N2 C4H4O4.

Composition of Trimipramine:

Active Ingredient - Trimipramine maleate.

Inactive Ingredients - Gelatin, lactose, magnesium stearate, black ink, FD and C Blue 1, and titanium dioxide.

Trimipramine 25 mg Dosage Contains the Following:

Benzyl alcohol, D and C yellow 10, FD and C yellow 6, parabens (butyl, propyl, and methyl), sodium lauryl sulfate, sodium propionate, and edetate calcium disodium.

Trimipramine 50 mg Dosage Contains:

Benzyl alcohol, D and C red 28, edetate calcium disodium, FD and C red 40, FD and C yellow

6, parabens (butyl, propyl, and methyl), sodium lauryl sulfate, and sodium propionate.

Clinical Pharmacology:

Trimipramine works against depression along with an anti-anxiety sedative action. However, nothing has been known about the effects of Trimipramine on the central nervous system, that is, the brain and spinal cord. Therefore, Trimipramine should not be confused with amphetamine-type compounds that stimulate the nervous system. Also, the drug does not inhibit the monoamine oxidase system. The pharmacokinetics of Trimipramine was evaluated in 24 young and 24 elderly patients. However, no clinically significant differences were noted during the comparative study.

Indications and Usage:

Trimipramine helps relieve the symptoms of depression. This drug is more likely to act against endogenous depression than exogenous depression. As per the studies on neurotic patients, Trimipramine appeared equivalent to Amitriptyline in patients with moderate depression. In contrast, it is less effective than Amitriptyline in severely depressed patients. Patients who are depressed due to prolonged periods of hospitalization demonstrated equal responses to Trimipramine and Imipramine.

Contraindications:

Monoamine Oxidase Inhibitors (MAOIs):

MAOIs are contraindicated in patients taking Trimipramine or within 14 days of taking Trimipramine because of the serious side effects and a high risk of serotonin-only syndrome. Therefore, Trimipramine patients should not take MAOIs like Linezolid or intravenous Methylene blue because it is contraindicated.

Tricyclic Antidepressants Hypersensitivity:

There is a high possibility of cross-sensitivity between Trimipramine and Dibenzazepines.

Myocardial Infarction:

Trimipramine is contraindicated in patients recovering from myocardial infarction.

Warnings:

Suicide Risk:

Adults and children with the major depressive disorder might experience worsening depression or recurrence of suicidal behavior. They have unusual changes in behavior even if they are not taking antidepressants. Suicide is one of the biggest risks associated with depression. Hence, researchers are concerned about the effects of antidepressants in inducing suicidal thoughts and worsening depression. Pooled analyses from placebo-controlled trials suggest that young adults are at a higher risk of developing suicidal tendencies than children. However, no suicidal tendencies were reported in children during the trial. Though adults presented with suicidal behavior, the number of patients was insufficient to draw conclusive results. Nothing has been known about the prevalence of suicidal tendencies in the long term. Hence, patients treated with antidepressants must be carefully monitored for the clinical worsening of depression symptoms or unusual changes in behavior. The following symptoms have been reported in adults and pediatric patients taking antidepressants:

• Anxiety.

• Panic attack.

• Agitation.

• Insomnia.

• Irritability.

• Hostility.

• Aggressiveness.

• Impulsivity.

• Akathisia or psychomotor restlessness.

• Mania.

• Hypomania.

• Mania.

The doctor must consider altering the therapeutic regimen or permanently discontinuing the drug in patients with worsening depression, severe symptoms, or suicidal thoughts.

Patients With Bipolar Disorders:

Patients with bipolar disorders present with major depressive disorder. If antidepressants are solely used to treat bipolar disorder, the patient is likely to have a maniac disorder. Hence, before initiating the antidepressant therapy, patients must be screened for bipolar disorders, which include a psychiatric history and a family history of depression, suicide, or bipolar disorders. Trimipramine has not been approved to treat bipolar disorders.

Serotonin Syndrome:

Patients taking Trimipramine or other selective serotonin reuptake inhibitors tend to experience life-threatening serotonin syndrome. However, this symptom is mainly seen when other drugs like Lithium, Fentanyl, and Tramadol are taken concomitantly with Trimipramine. These drugs can interrupt serotonin metabolism.

The symptoms of serotonin syndrome are listed below:

• Agitation.

• Hallucinations.

• Coma.

• Delirium.

• Seizures.

• Symptoms of autonomic instability:

  • Tachycardia.

  • Labile blood pressure.

  • Diaphoresis.

  • Dizziness.

  • Flushing.

  • Hyperthermia.

• Neuromuscular symptoms include:

  • Tremors.

  • Rigidity.

  • Hyperreflexia.

  • Myoclonus.

  • Incoordination.

• Gastrointestinal disorders:

  • Vomiting.

  • Nausea.

  • Diarrhea.

General Considerations for Trimipramine Use:

The drug must be used cautiously in cardiovascular patients to avoid arrhythmias, myocardial infarction, strokes, conduction defects, and tachycardia. In addition, patients with the following conditions must stay extra cautious:

• Increased intraocular pressure.

• Medical history of urinary retention.

• Hyperthyroid patients or the ones taking thyroid medications to prevent the risk of cardiovascular toxicity.

• People with a history of epilepsy because Trimipramine lowers the seizure threshold.

• Patients under Guanethidine or similar drugs.

General Precautions:

General precautions are listed below:

• There is a high possibility of suicide in severely depressed patients, which persists until the remission of the condition occurs.

• If a patient with suicidal tendencies cannot be hospitalized, the smallest feasible dose of the drug must be prescribed.

• Patients with schizophrenia might present with activation of psychosis or require dosage reduction. Such patients might also require tranquilizers in their therapeutic regimen.

• Trimipramine must not be administered concomitantly with electroshock therapy to avoid the risk of side effects of therapy. Hence, this treatment must be restricted to patients for whom it is essential.

• The patient must discontinue the drug a few days before the elective surgery.

• Trimipramine should be used cautiously in patients with impaired liver function.

Drug Interactions:

Cimetidine:

It has been observed that Cimetidine interferes with the elimination of TCAs. Hence downward adjustment of the dosage is necessary. Likewise, upward adjustment needs to be done if Cimetidine therapy is discontinued.

Alcohol:

Patients must be informed prior that concomitant use of Trimipramine with alcohol might exaggerate the effects.

Catecholamines or Anticholinergics:

TCAs can exacerbate the effects of catecholamines, and atropine-like effects are more prominent in patients receiving anticholinergics. Hence, care must be taken when

Trimipramine is to be administered with the following:

• Sympathomimetic amines.

• Local decongestants.

• Local anesthetics containing epinephrine.

• Atropine.

• Drugs with an anticholinergic effect.

Medications Metabolized by P450 2D6:

Cytochrome P450 2D6 shows reduced activity in the presence of Trimipramine. Hence the levels of TCAs remain high in the blood.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Semen studies have been done in four patients with schizophrenia and nine patients who are healthy. However, no significant changes were noted in the sperm morphology. Sometimes drugs with a parasympathetic effect, including TCAs, might modify the ejaculation response.

Dosage and Administration:

Patients must be initially given low doses of antidepressants. However, the dosage can be increased gradually. Low doses are usually recommended for pediatric and elderly patients. Similarly, hospitalized patients must take a lower dose and be carefully monitored. However, it is impossible for a doctor to recommend a single dosing schedule for Trimipramine, which is effective in all patients.

Adult Dosage:

Office Patients and Outpatients - Initially, 75 mg per day is given in divided doses, increasing to 150 mg per day. However, the patient is not advised to take more than 200 mg of the drug dose. The drug must be taken during the daytime to obtain the best results.

Hospitalized Patients - Initially, 100 mg per day is given in divided doses. This can be increased slowly to 200 mg daily depending on the tolerance and individual response. If the patient does not show an improvement for two to three weeks, the dosage can be increased to 250 mg.

Geriatric Population:

Initially, a dose of 50 mg per day is divided. Then, the dose can be increased to 100 mg per day.

Overdosage:

Death might occur when Trimipramine is taken in excess. As the management of drug overdose is complicated, the doctor must contact the poison control center for further management.

Manifestations:

Clinical manifestations of Trimipramine overdosage are listed below:

• Cardiac dysrhythmias.

• Hypotension.

• Convulsions.

• CNS depression.

• Changes in the QRS interval in the ECG.

• Confusion.

• Disturbed concentration.

• Hallucinations.

• Dilated pupils.

• Agitation.

• Hyperactive reflexes.

• Stupor.

• Drowsiness.

• Muscle rigidity.

• Vomiting.

• Hypothermia.

• Hyperpyrexia.

Management of Overdose:

• The doctor must obtain an ECG to monitor cardiac functions.

• The patient's airways must be protected to initiate gastric decontamination and establish an intravenous line.

• The patient must be carefully monitored for symptoms of CNS depression, hypotension, cardiac dysrhythmias, and seizures.

• All patients with TCA overdose must receive gastrointestinal decontamination, which includes gastric lavage. Emesis is usually contraindicated.

• Patients with QRS interval prolongation might be given sodium bicarbonate intravenously.

• Sometimes, hemoperfusion might be done to prevent acute refractory cardiovascular instability.

• Intubation is usually done in patients with CNS depression to prevent abrupt deterioration.

• Seizures can be controlled with benzodiazepines or other anticonvulsants.

• Patients must be kept on regular follow-ups.

How Is Trimipramine Supplied?

Trimipramine maleate capsules are supplied as below:

• 25 mg - They are opaque blue and yellow capsules in bottles of 100 with OP and 718 printed.

• 50 mg - They are opaque blue and orange capsules in bottles of 100 with OP and 719 printed.

• 100 mg - They are opaque blue and white capsules in bottles of 100 with OP and 720 printed.

What are the adverse reactions of Trimipramine?

Some of the adverse reactions of Trimipramine are listed below:

• Cardiovascular:

  • Hypotension.

  • Hypertension.

  • Tachycardia.

  • Palpitations.

  • Myocardial infarction.

  • Arrhythmias.

  • Heart block.

  • Strokes.

• Psychiatric:

  • Hallucinations.

  • Disorientation.

  • Delusions.

  • Anxiety.

  • Restlessness.

  • Agitation.

  • Insomnia.

  • Nightmares.

  • Hypomania.

  • Exacerbation of psychosis.

• Neurological:

  • Numbness.

  • Tingling.

  • Paresthesia.

  • Incoordination.

  • Ataxia.

  • Tremors.

  • Peripheral neuropathy.

  • Seizures.

• Allergic Reactions:

  • Skin rashes.

  • Urticaria.

  • Petechiae.

  • Itching.

  • Photosensitization.

  • Swelling of the tongue or face.

• Gastrointestinal:

  • Nausea.

  • Vomiting.

  • Anorexia.

  • Diarrhea.

  • Epigastric distress.

  • Stomatitis.

  • Abdominal pain.

  • Blackish discoloration of the tongue.

Use in Specific Populations:

Pregnancy:

Trimipramine is a pregnancy category C drug that has shown evidence of embryotoxicity and higher incidences of anomalies in animal studies. However, sufficient studies have not been done on pregnant females. Hence the drug must be used in pregnancy only after calculating the risk-benefit ratio.

Pediatric Use:

Nothing has been known about the safety and efficacy of Trimipramine in children. Hence, the risk-benefit ratio must be observed before administering the drug.

Geriatric Population:

As the number of patients above 65 was insufficient, nothing has been known about the safety and efficacy of Trimipramine in the geriatric population.