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== Precautions ==
== Precautions ==


Trazodone is metabolised by [[CYP3A4]], a liver enzyme.<ref name=Rotzinger/> 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 [[drug interaction|interact]] with these substances. One drug-food interaction is [[grapefruit juice]].{{Citation needed|date=January 2010}} 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.
Trazodone is metabolised by [[CYP3A4]], a liver enzyme.<ref name=Rotzinger/> 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 [[drug interaction|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.
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.

Revision as of 23:37, 31 March 2010

Trazodone
Clinical data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityHigh
MetabolismHepatic
Elimination half-life3-6 hours
Excretion20% feces,
80% urine
Identifiers
  • 2-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.039.364 Edit this at Wikidata
Chemical and physical data
FormulaC19H22ClN5O
Molar mass371.864 g/mol g·mol−1
  (verify)

Trazodone (Desyrel, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico) is a psychoactive drug of the piperazine and triazolopyridine chemical classes that has antidepressant, anxiolytic, and hypnotic properties.[2] It has been advertised that its therapeutic benefits become noticeable within the first week of administration. Trazodone has considerably less prominent anticholinergic (dry mouth, constipation, tachycardia) and sympatholytic (hypotension, sexual dysfunction consisting of erectile dysfunction and anorgasmia) side effects in comparison to most of the tricyclic antidepressants (TCAs) and tetracyclic antidepressants (TeCAs).

History

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.[3] 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.

Indications

Off-label and investigational uses

Pharmacology

Binding profile

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:[17][18][19][20][21][22]

It is an inhibitor of the following transporters as well:[23]

The affinities listed are the means of selected values from the references included.

Clinical effects

Trazodone acts predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.[24] Trazodone's inhibitory effects on serotonin reuptake and 5-HT2C receptors are relatively weak (~15-fold lower than 5-HT2A) and contribute only lightly to its overall effects.[24] Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs)[24] and is not particularly associated with increased appetite and weight gain, unlike other 5-HT2C antagonists like mirtazapine.[25][26] 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.[22][27][21]

Trazodone's potent α1-adrenergic blockade (~3-fold lower relative to 5-HT2A) may cause some side effects like orthostatic hypotension and sedation.[28] Conversely, along with 5-HT2A antagonism, it may underlie trazodone's efficacy as a hypnotic. This seems plausible as trazodone's antihistamine activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Notably, trazodone lacks any affinity for muscarinic acetylcholine receptors and therefore does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor agonist is a common active metabolite of trazodone, nefazodone, etoperidone, and mepiprazole, and it has been suggested that it may play a role in trazodone's therapeutic benefits.[29][30][31] However, scientific research has not supported this hypothesis and mCPP may even antagonize trazodone's efficacy as well as produce additional side effects.[32][33][34][35][36]

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 the human body, some of which such as mCPP[37] may contribute to the side effect profile of trazodone. mCCP has been shown to activate numerous serotonin receptors, including 5ht2c. Due to the short half-life of trazodone, if a dose is taken at night, mCCP would be present in the body during the following day, causing symptoms such as anorexia (behavioral symptoms), anxiety, hypolocomotion, headache, and depression. Approximately 70–75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours.[38] Trazodone is highly protein-bound.

Warnings

  • If the patient has a known hypersensitivity to trazodone.
  • If the patient is under 18 years of age and combines with other antidepressant medications it may increase the possibility of suicidal thoughts or actions.[39]

Precautions

Trazodone is metabolised by CYP3A4, a liver enzyme.[37] 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.

Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with other anti seizure medications.[40]

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.[41] 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.

A person who abruptly stops taking trazodone, even in doses as low as 25 mg (common for use as a sleep aid for people with anxiety disorders), may experience adverse mental reactions such as emotional instability, depressed mood, and suicidal thoughts. Although such warnings may be included in printed materials supplied with the drug, physicians prescribing trazodone, particularly those who are not psychiatrists, might not give oral warnings.

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.

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, memory loss, uncontrollable laughter, sex drive decrease.[citation needed]

Neurological

Tremor, headache, ataxia, migraine, 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

Hypotension, 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

Trazodone has rarely 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.

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. 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.

In women, a similar condition of persistent arousal can be caused and is called persistent genital arousal disorder.

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.[42]

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.[43]

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, hypersalivation, chest pain, hematuria, red, tired and itchy eyes.[citation needed] muscle twitches [citation needed]

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.[citation needed]

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 monoamine oxidase inhibitors (MAOIs), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOIs 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 25 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

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.[44][45] However, trazodone is often used instead of tricyclic antidepressants because it is very rarely lethal in overdose. Depressed patients are therefore unlikely to successfully commit suicide with trazodone.[46]

Treatment

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.

See also

References

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  45. ^ de Meester A, Carbutti G, Gabriel L, Jacques JM (2001). "Fatal overdose with trazodone: case report and literature review". Acta Clin Belg. 56 (4): 258–61. PMID 11603256.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ Rakel RE (1987). "The greater safety of trazodone over tricyclic antidepressant agents: 5-year experience in the United States". Psychopathology. 20 (Suppl 1): 57–63. doi:10.1159/000284524. PMID 3321131.
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