Trazodone

Overview
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.

Trazodone is chemically and pharmacologically distinct from tricyclic antidepressants and tetracyclic antidepressants (for a review, see PMID: 8019056). Lacking the fused ring structures typical of these compounds, trazodone is a triazolopyridine derivative.

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 depression is associated with a decreased pain threshold. Trazodone was patented and marketed in many countries all over the world. It was approved by the FDA at the end of 1981.

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).

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.

Uses

 * Clinical depression with or without anxiety
 * Chronic insomnia  (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)

Other off-label and investigational uses

 * panic disorder
 * diabetic neuropathy
 * bulimia nervosa
 * obsessive-compulsive disorder
 * alcohol withdrawal
 * schizophrenia

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.

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.)

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.

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.

Episodes of complex partial seizures have been reported in a small number of patients. The majority of these patients were already receiving anticonvulsant therapy for a previously diagnosed seizure disorder.

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. 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.

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:

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.)

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.

Autonomic
Dry or numb mouth, blurred vision, priapism, diplopia, miosis, nasal congestion, constipation, sweating, urinary retention, increased urinary frequency and incontinence.

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.

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.

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).

Endocrine
Decrease and, more rarely, increase in libido, weight gain and loss, and rarely, menstrual irregularities, retrograde ejaculation and inhibition of ejaculation.

Elevated prolactin concentrations have been observed in patients taking trazodone (PMID 7673654).

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.

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.

Miscellaneous
Aching joints and muscles, peculiar taste, hypersalivation, chest pain, hematuria, red, tired and itchy eyes.

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.

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.

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.

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.