Trazodone (trade names Desyrel, Molipaxin, Trittico, Thombran, Trialodine) is a psychoactive compound with sedative, anxiolytic, and antidepressant properties. The various manufacturers claim that the antidepressant activity becomes active in the first week of therapy. Trazodone has less prominent anticholinergic (dry mouth, constipation, tachycardia) and adrenolytic (hypotension, male sexual problems) side effects than most tricyclic antidepressants. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body. ... A psychoactive drug or psychotropic substance is a chemical that alters brain function, resulting in temporary changes in perception, mood, consciousness, or behaviour. ... A sedative is a substance that depresses the central nervous system (CNS), resulting in calmness, relaxation, reduction of anxiety, sleepiness, and slowed breathing, as well as slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes. ... An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety. ... Prozac, a selective serotonin reuptake inhibitor (SSRI) Serotonin-norepinephrine reuptake inhibitor, Venlafaxine An antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia (milder depression). ... An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ... This article or section does not cite any references or sources. ... Chemical structure of the tricyclic antidepressant amitriptyline Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. ...

Trazodone is chemically and pharmacologically distinct from tricyclic antidepressants and tetracyclic antidepressants (for a review, see^[1] PMID: 8019056). Lacking the fused ring structures typical of these compounds, trazodone is a triazolopyridine derivative. Chemical structure of the tricyclic antidepressant amitriptyline. ... There are also several chemically unrelated tetracyclic antibiotics based on Tetracycline. ...

History

Trazodone was originally discovered and developed in Italy in the 1960s by Angelini research laboratories as a second-generation antidepressant. This agent was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that clinical depression is associated with a decreased pain threshold.^[2] Trazodone was patented and marketed in many countries all over the world. It was approved by the FDA at the end of 1981. Prozac, a selective serotonin reuptake inhibitor (SSRI) Serotonin-norepinephrine reuptake inhibitor, Venlafaxine An antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia (milder depression). ... On the Threshold of Eternity. ...

Mechanism of action

Trazodone is a serotonin reuptake inhibitor and is also a 5-HT₂ receptor antagonist. However, in contrast to the selective serotonin reuptake inhibitors such as fluoxetine (trade name Prozac), trazodone's antidepressant effects may be due to its antagonistic effect at the 5-HT₂ receptor site (PMID 1365657). In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin, also known as 5-hydroxytryptamine or 5-HT. 5-HT receptors are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin... Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor-agonist coupling. ... SSRI redirects here; for other uses, see SSRI (disambiguation). ... Fluoxetine pills. ...

Pharmacokinetics

Trazodone is well absorbed after oral administration with mean peak blood levels obtained at approximately 1 hour after ingestion. Absorption is somewhat delayed and enhanced by food. The mean blood elimination half-life is biphasic: the first phase's half-life is 3–6 hours, and the following phase's half-life is 5–9 hours. The drug is extensively metabolized with 3 or 4 major metabolites having been identified in man, some of which such as mCPP may contribute to the side effect profile of trazodone. Approximately 70–75% of C¹⁴-labelled trazodone was found to be excreted in the urine within 72 hours (PMID 1037253). Trazodone is highly protein-bound. Tablets containing mCPP confiscated by the DEA in Vernon Hills, Illinois 1-(3-Chlorophenyl)piperazine (or meta-chlorophenylpiperazine, mCPP) is a piperazine-based 5-HT receptor agonist that has been used as a challenge drug in MDMA research. ...

Uses

• Clinical depression with or without anxiety
• Chronic insomnia^[3][4][5] (in some countries, this is an off-label use)
• Fibromyalgia, to control sleeping.
• Control of nightmares or other disturbed sleep
• A sleep aid (with a reduced risk of dependency)

On the Threshold of Eternity. ... This article is about the sleeping disorder. ... Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drugs approved label, most often concerning the drugs indication. ... Fibromyalgia (FM or FMS) is a chronic syndrome (constellation of signs and symptoms) characterized by diffuse or specific muscle, joint, or bone pain, fatigue, and a wide range of other symptoms. ...

Other off-label and investigational uses

• panic disorder^[6]
• diabetic neuropathy^[7]
• bulimia nervosa^[8]
• obsessive-compulsive disorder^[9][10]
• alcohol withdrawal^[11][12][13]
• schizophrenia^[14][15]

Panic Disorder is a psychiatric condition characterized by recurring panic attacks in combination with significant behavioral change or at least a month of ongoing worry about the implications or concern about having other attacks. ... Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. ... Bulimia nervosa, commonly known as bulimia, is an eating disorder and psychological condition in which the subject engages in recurrent binge eating followed by feelings of guilt, depression, and self-condemnation and intentional purging to compensate for the excessive eating, usually to prevent weight gain (see anorexia nervosa). ... Alcoholism is the consumption of, or preoccupation with, alcoholic beverages to the extent that this behavior interferes with the drinkers normal personal, family, social, or work life, and may lead to physical or mental harm. ...

As an SSRI aid

Trazodone is often used in conjunction with selective serotonin reuptake inhibitor, like fluoxetine and has been noted to help with the anxiety that can result from beginning treatment with a SSRI anti-depressant. Trazodone has been prescribed to children as an aid to a SSRI. SSRI redirects here; for other uses, see SSRI (disambiguation). ... Fluoxetine pills. ...

Warnings

• If the patient has a known hypersensitivity to trazodone.
• If the patient is under 18 years of age. (Trazodone use in youth increases the possibility of suicidal thoughts or actions.)^{[citation needed]}

Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. ...

Precautions

Trazodone is metabolised by CYP3A4, a liver enzyme (PMID 9616194). Inhibition of this enzyme by various other substances may delay its degradation, leading to high blood levels of trazodone. CYP3A4 may be inhibited by many other medications, herbs, and foods, and as such, trazodone may interact with these substances. One drug-food interaction is grapefruit juice. Drinking grapefruit juice is discouraged in patients taking trazodone. One glass of grapefruit juice occasionally is not likely to have this effect on most people, but drinking large amounts, or drinking it regularly is proven to affect trazodone's clearance. Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... A drug interaction is a situation in which a substance affects the activity of a drug, i. ... Grapefruit juice is the fruit juice coming from grapefruits. ...

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. Therefore, the number of tablets prescribed at any one time should take into account this possibility, and patients with suicidal ideation should never have access to large quantities of trazodone. For other uses, see Suicide (disambiguation). ... Suicidal ideation is common medical term for the mere thoughts about and of plans of committing suicide, not the actual following through or act itself. ...

Episodes of complex partial seizures have been reported in a small number of patients.^{[citation needed]} The majority of these patients were already receiving anticonvulsant therapy for a previously diagnosed seizure disorder.^{[citation needed]} Complex partial seizures are epileptic attacks which involve a greater degree of impairment of consciousness than simple partial seizures. ... The anticonvulsants, sometimes also called antiepileptics, belong to a diverse group of pharmaceuticals used in prevention of the occurrence of epileptic seizures. ...

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly. ^[16] Care must therefore be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time. SSRI is an acronym that stands for several things: It is a class of antidepressants called selective serotonin reuptake inhibitor SSRI also is used as the stock symbol for Silver Standard Resources Inc. ... SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a condition that can occur during or following the interruption, lowering of dose or discontinuation of regular SSRI or SNRI antidepressant drug usage. ...

Pregnancy and lactation

• Pregnancy : Sufficient data in humans is lacking. The use should be justified by the severity of the condition to be treated.
• Lactation : Sufficient data in humans is also lacking. Additionally, trazodone may be found in the maternal milk in significant concentrations. Women should not breastfeed while taking Trazodone.

Side effects

The most common adverse reactions encountered are drowsiness, nausea/vomiting, headache and dry mouth. Adverse reactions reported include the following: ^{[citation needed]}

Behavioral

Drowsiness, fatigue, lethargy, psychomotor retardation, lightheadedness, dizziness, difficulty in concentration, confusion, uncontrollable laughter, sex drive increase. (Trazodone is also known to cause a "hangover effect" in patients prescribed the drug as a sleep aid: the "Trazodone hangover" generally ceases with regular use after three or four days.) Psychomotor retardation comprises a slowing down of thought and a reduction of physical movements in a person. ...

Neurologic

Tremor, headache, ataxia, akathisia, muscle stiffness, slurred speech, slowed speech, vertigo, tinnitus, tingling of extremities, paresthesia, weakness, complex partial seizures, and, rarely impaired speech, muscle twitching, numbness, dystonia, euphoria, and involuntary movements. For other uses, see Ataxia (disambiguation). ... Akathisia (or acathisia) is an often extremely unpleasant subjective sensation of inner restlessness that manifests itself with an inability to sit still or remain motionless, hence the origin of its name: Greek a (without) + kathesis (sitting). ... Tinnitus (IPA pronunciation: or ,[1] from the Latin word for ringing[2]) is the perception of sound in the human ear in the absence of corresponding external sound(s). ... Complex partial seizures are epileptic attacks which involve a greater degree of impairment of consciousness than simple partial seizures. ... Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. ... Euphoria (Greek ) is a medically recognized emotional state related to happiness. ...

Autonomic

Dry or numb mouth, blurred vision, priapism, diplopia, miosis, nasal congestion, constipation, sweating, urinary retention, increased urinary frequency and incontinence. Priapism (Ancient Greek: ) is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. ... Diplopia, commonly known as double vision, is the perception of two images from a single object. ... Miosis should not be confused with meiosis, the cellular division process involved in sexual reproduction. ...

Cardiovascular

hypertension, tachycardia, palpitations, shortness of breath, apnea, syncope, arrhythmias, prolonged P-R interval, atrial fibrillation, bradycardia, ventricular ectopic activity (including ventricular tachycardia), myocardial infarction and cardiac arrest. For other forms of hypertension, see Hypertension (disambiguation). ... This article or section does not cite any references or sources. ... A palpitation is an abnormal, rapid beating of the heart, brought on by overexertion, disease or drugs. ... Apnea, apnoea, or apnœa (Greek απνοια, from α-, privative, πνεειν, to breathe) is a technical term for suspension of external breathing. ... This article or section does not cite its references or sources. ... A cardiac arrhythmia, also called cardiac dysrhythmia, is a disturbance in the regular rhythm of the heartbeat. ... Atrial fibrillation (AF or afib) is a cardiac arrhythmia (abnormal heart rhythm) that involves the two upper chambers (atria) of the heart. ... Bradycardia, as applied to adult medicine, is defined as a resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. ... Cardiac ectopy is a disturbance of the electrical conduction system of the heart, in which beats arise from the wrong part of the heart muscle. ... Ventricular tachycardia (V-tach or VT) is a fast rhythm that originates in one of the ventricles of the heart. ... Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a disease state that occurs when the blood supply to a part of the heart is interrupted. ...

Rare side effects

Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVC's, ventricular couplets, and in 2 patients short episodes (3 to 4 beats) of ventricular tachycardia. There have also been several post-marketing reports of arrhythmias in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction.

Priapism

Priapism is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. It is often painful. Priapism is considered a medical emergency, which should receive proper treatment by a qualified medical practitioner. Priapism (Ancient Greek: ) is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. ... Priapism (Ancient Greek: ) is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. ...

Gastrointestinal

Nausea, vomiting, diarrhea, gastrointestinal discomfort, anorexia, increased appetite.

Liver

Rare cases of idiosyncratic hepatotoxicity have been observed, possibly due to the formation of reactive metabolites (PMID 15978881). Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver damage. ...

Endocrine

Decrease and, more rarely, increase in libido, weight gain and loss, and rarely, menstrual irregularities, retrograde ejaculation and inhibition of ejaculation. For other uses, see Libido (disambiguation). ... In males, retrograde ejaculation occurs when the fluid to be ejaculated, which would normally exit via the urethra, is redirected towards the urinary bladder. ...

Elevated prolactin concentrations have been observed in patients taking trazodone (PMID 7673654). Prolactin (PRL) is a peptide hormone primarily associated with lactation. ...

Trazodone has been associated with the occurrence of priapism. In approximately 33% of the cases reported, surgical intervention was required and, in a portion of these cases, permanent impairment of erectile function or impotence resulted. Male patients with prolonged or inappropriate erections should immediately discontinue the drug and consult their physician. If the condition persists for more than 24 hours, it would be advisable for the treating physician to consult a urologist or appropriate specialist in order to decide on a management approach. Priapism (Ancient Greek: ) is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. ...

Allergic or toxic

Skin rash, itching, edema, and, rarely, hemolytic anemia, methemoglobinemia, liver enzyme alterations, obstructive jaundice, leukocytoclastic vasculitis, purpuric maculopapular eruptions, photosensitivity and fever. This page is about the condition called edema. ... Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). ... Methemoglobinemia, also known as met-Hb, is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. ... Hypersensitivity vasculitis (or hypersensitivity angiitis or leukocytoclastic vasculitis) is usually due to a hypersensitivity reaction to a known drug, auto-antigens or infectious agents such as bacteria. ...

Miscellaneous

Aching joints and muscles, peculiar taste, hypersalivation, chest pain, hematuria, red, tired and itchy eyes. Drooling (also known as ptyalism) is caused by saliva flowing outside the mouth. ... In medicine, hematuria (or haematuria) is the presence of blood in the urine. ...

Occupational hazards

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired.

Laboratory tests

It is recommended that white blood cell and differential counts should be performed in patients who develop sore throat, fever, or other signs of infection or blood dyscrasia and trazodone should be discontinued if the white blood cell or absolute neutrophil count falls below normal.

Drug interactions

Trazodone may enhance the effects of alcohol, barbiturates and other CNS depressants; patients should be cautioned accordingly as trazodone with the combination of another CNS depressant, can result in extreme tiredness and dizziness.

Increased serum digoxin and phenytoin levels have been reported to occur in patients receiving trazodone concurrently with either of those 2 drugs. Little is known about the interaction between trazodone and general anesthetics; therefore, prior to elective surgery, trazodone should be discontinued for as long as clinically feasible. Digoxin (INN) (IPA: ) is a purified cardiac glycoside extracted from the foxglove plant, Digitalis lanata. ... Phenytoin sodium (marketed as Dilantin® in the USA and as Epanutin® in the UK, by Parke-Davis, now part of Pfizer) is a commonly used antiepileptic. ...

Because it is not known whether an interaction will occur between trazodone and MAO inhibitors, administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAO inhibitor is given concomitantly or has been discontinued shortly before medication with trazodone is instituted.

Because of the absence of experience, concurrent administration of electroconvulsive therapy should be avoided. Electroconvulsive therapy (ECT), also known as electroshock, is a controversial psychiatric treatment in which seizures are induced with electricity for therapeutic effect. ...

Dosage

Treatment should be started with low initial doses of 25 to 50 mg daily in divided doses or in an evening single dose. The dose may be increased slowly to a maximum of 300 mg daily in ambulatory patients and to 600 mg daily in hospitalized patients. Geriatric and emaciated patients should begin with 100 mg daily; this dose may be slowly increased to 300 mg. The duration of treatment should be at least one month. A 50 mg dose is recommended when using Trazodone as a sleep aid.

Overdose

Symptoms

Overdosage of trazodone may cause an increase in incidence or severity of any of the reported adverse reactions, e.g. excessive sedation. Death by deliberate or accidental overdosage has been reported (PMID 15975258, PMID 11603256).

Treatment

There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any patient suspected of having taken an overdosage should be admitted to hospital as soon as possible and the stomach emptied by gastric lavage. Forced diuresis may be useful in facilitating elimination of the drug. Forced diuresis (increased urine formation by diuretics and fluid) may enhance the excretion of certain drugs in urine and is used to treat drug overdose or poisoning of these drugs and hemorrhagic cystitis. ...

See also

• nefazodone
• antidepressants

Nefazodone hydrochloride (trade name Serzone) is an antidepressant drug marketed by Bristol-Myers Squibb. ... Prozac, a selective serotonin reuptake inhibitor (SSRI) Serotonin-norepinephrine reuptake inhibitor, Venlafaxine An antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia (milder depression). ...

Notes

References

• SID 172043 -- PubChem Substance Summary. Retrieved on 17 November, 2005.
• Drug information from Rxlist.com. Retrieved on 16 January, 2006.
• Drug information from Mentalhealth.com. Retrieved on 16 January, 2006.

External links

• Pfizer Trazolan Patient Information Sheet (Dutch)