|Systematic (IUPAC) name|
|Pregnancy cat.||C (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Mol. mass||371.864 g/mol|
| (what is this?)
Trazodone (also sold under the brand names Desyrel, Oleptro, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico, and Mesyrel) is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a phenylpiperazine compound. Trazodone also has anti-anxiety (anxiolytic) and sleep-inducing (hypnotic) effects. Trazodone has considerably fewer prominent anticholinergic (dry mouth, constipation, tachycardia) and sexual side effects than most of the tricyclic antidepressants (TCAs).
Trazodone was originally discovered and developed in Italy in the 1960s by Angelini Research Laboratories as a second-generation antidepressant. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major 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 Food and Drug Administration (FDA) at the end of 1981.
- Anxiety disorder
- Unipolar depression, with or without anxiety
- Bipolar depression, in some circumstances
- Insomnia (in some countries, this is an off-label use)
- Control of nightmares or other sleep disturbances
Off-label and investigational uses
- Panic disorder
- Diabetic neuropathy
- Bulimia nervosa
- Obsessive-compulsive disorder (OCD)
- Alcohol withdrawal
- Schizophrenia and other psychoses
- Complex regional pain syndrome
Trazodone behaves as an antagonist at all of the following receptors except 5-HT1A where it acts as a partial agonist similarly to buspirone and tandospirone but with greater intrinsic activity in comparison:
- 5-HT1A receptor (Kd = 78 nM)
- 5-HT2A receptor (Ki = 13 nM)
- 5-HT2B receptor (Ki = 74 nM)
- 5-HT2C receptor (Ki = 192 nM)
- α1-adrenergic receptor (Kd = 39 nM)
- α2-adrenergic receptor (Kd = 405 nM)
- H1 receptor (Kd = 725 nM)
- SERT (Kd = 160 nM)
Correspondence to clinical effects
Trazodone acts predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are relatively weak (~15-fold lower than for 5-HT2A) and contribute only lightly to its overall effects. Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs) and is not particularly associated with increased appetite and weight gain, unlike other 5-HT2C antagonists like mirtazapine. Moderate 5-HT1A partial agonism (6-fold lower than 5-HT2A) is likely to contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.
Trazodone's potent α1-adrenergic blockade (~3-fold lower relative to 5-HT2A) may cause some side effects like orthostatic hypotension and sedation. Conversely, along with 5-HT2A antagonism, it may underlie its efficacy as a hypnotic. This seems possible as trazodone's antihistamine activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Trazodone lacks any affinity for the mACh receptors and therefore does not produce anticholinergic side effects.
mCPP, a non-selective serotonin receptor agonist and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits. However, scientific research has not supported this hypothesis, and mCPP may actually antagonize trazodone's efficacy as well as produce additional side effects.
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 the human body, particularly mCPP, which may contribute to the side effect profile of trazodone. mCPP has been shown to activate numerous serotonin receptors, including 5-HT2C. Approximately 70–75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours. Trazodone is highly protein-bound.
- If the patient has a known hypersensitivity to trazodone
- If the patient is under eighteen years of age and combines with other antidepressant medications it may increase the possibility of suicidal thoughts or actions.
Trazodone is metabolized by CYP3A4, a liver enzyme. 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. 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.
Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with medications to control 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. 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. 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.
Adverse reactions reported include the following:
- Headache or heaviness in head
- Nausea, vomiting
- Bad taste in mouth
- Dry mouth
- Stomach pain
- Diarrhea or Constipation
- Changes in appetite or weight
- Weakness or tiredness
- Decreased ability to concentrate or remember things
- Brain fog or "zombie-like" sensations
- Muscle pain
- Blurred vision
- Tired, red, or itchy eyes
- Tinnitus (Ringing in ears)
- Restless leg syndrome
Trazodone can enhance libido and in males, increase erectile function. Compared to the reversible MAOI antidepressant drug moclobemide there is significantly more impairment on vigilance with trazodone.
Serious side effects
|This section does not cite any references or sources. (January 2013)|
- Chest pain (angina)
- Fast, pounding, or irregular heartbeat
- Shortness of breath
- Fever, sore throat, chills, or other signs of infection
- Skin rash
- Difficulty breathing or swallowing (dysphagia)
- Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs (peripheral edema)
- Decreased coordination
- Uncontrollable shaking of a part of the body
- Numbness, burning, or tingling in the arms, legs, hands, or feet
- Dizziness or lightheadedness
- Fainting (syncope)
- Painful erection that lasts longer than normal (priapism)
Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. Arrhythmia identified include isolated PVC's, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. There have also been several post-marketing reports of arrhythmia 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.
Trazodone has been associated with the occurrence of priapism, likely due to its antagonism at α-adrenergic receptors. 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 four hours. In approximately 33% of the cases reported, surgical intervention was performed and, in a portion of these cases, permanent impairment of erectile function or impotence resulted.
It has been concluded that trazodone impairs motor healing in brain-injured rats.
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.
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.
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 two 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 monoamine oxidase inhibitors (MAOI's), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOI 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.
Trazodone adult and geriatric recommended starting dose is 150 mg once daily, it may be increased by 50 mg every three to four days. The dose may be increased slowly to a maximum of 400 mg daily for outpatients and to 600 mg daily in hospitalized patients. Pediatric initial dose should be 25 – 50 mg and may be increased up to 150 mg if necessary. Adult dosage for sedation and sleep aid is 25 – 50 mg. It is recommended that trazodone be given in a divided dose. If necessary just a single dose, in the evening, may be given.
Overdose 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. However, trazodone is often used instead of tricyclic antidepressants because it is very difficult to overdose on. Depressed patients are therefore unlikely to complete suicide with trazodone.
There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any person suspected of having taken an overdosage should be evaluated at a hospital as soon as possible. Activated charcoal, gastric lavage, and forced diuresis may be useful in facilitating elimination of the drug.
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