View source for Trazodone

{{Drugbox|
|IUPAC_name = ''8-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]<br>-6,8,9-triazabicyclo[4.3.0]nona-2,4,9-trien-7-one''
| image=Trazodone.png
| width=200
| CAS_number=19794-93-5
| ATC_prefix=N06
| ATC_suffix=AX05
| ATC_supplemental=
| PubChem=5533
| DrugBank=APRD00533
| C=19 | H=22 | Cl=1 | N=5 | O=1
| molecular_weight = 371.864 g/mol
| bioavailability= High
| metabolism = Hepatic
| elimination_half-life= 3-6 hours
| excretion = 20% feces,<br>80% urine
| pregnancy_US = C
| legal_status = Unscheduled;<br>Rx only
| routes_of_administration= Oral
}}
{{SI}}
{{CMG}}

==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 antidepressant]]s and [[tetracyclic antidepressant]]s (for a review, see <ref>Haria M, Fitton A, McTavish D., Drugs Aging. 1994 Apr;4(4):331-55.</ref>
[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=8019056&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus 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<ref>Silvestrini B. Trazodone: from the mental pain to the "dys-stress" hypothesis of depression. Clin Neuropharmacol. 1989;12 Suppl 1:S4-10.</ref>. 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-HT receptor|5-HT<sub>2</sub> receptor]] [[receptor antagonist|antagonist]]. However, in contrast to the [[selective serotonin reuptake inhibitor]]s such as [[fluoxetine]] (trade name Prozac), trazodone's antidepressant effects may be due to its antagonistic effect at the 5-HT<sub>2</sub> 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 C<sup>14</sup>-labelled trazodone was found to be excreted in the urine within 72 hours (PMID 1037253). Trazodone is highly protein-bound.<br><br><br><br>

==Uses==

*[[Clinical depression]] with or without anxiety
*Chronic [[insomnia]]<ref>Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994 Jul;151(7):1069-72.</ref><ref>Kaynak H, Kaynak D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Med. 2004 Jan;5(1):15-20.</ref><ref>Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. J Clin Psychiatry. 1990 Sep;51 Suppl:13-7.</ref> (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]]<ref>Mavissakalian M, Perel J, Bowler K, Dealy R. Trazodone in the treatment of panic disorder and agoraphobia with panic attacks. Am J Psychiatry. 1987 Jun;144(6):785-7.</ref>
* [[diabetic neuropathy]]<ref>Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993 Nov;50(11):884-95.</ref>
* [[bulimia nervosa]]<ref>Pope HG Jr, Keck PE Jr, McElroy SL, Hudson JI. A placebo-controlled study of trazodone in bulimia nervosa. J Clin Psychopharmacol. 1989 Aug;9(4):254-9.</ref>
* [[obsessive-compulsive disorder]]<ref>Prasad A. Efficacy of trazodone as an anti obsessional agent. Pharmacol Biochem Behav. 1985 Feb;22(2):347-8.</ref><ref>Pigott TA, L'Heureux F, Rubenstein CS, Bernstein SE, Hill JL, Murphy DL. A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder. J Clin Psychopharmacol. 1992 Jun;12(3):156-62.</ref>
* [[Alcoholism|alcohol withdrawal]]<ref>Roccatagliata G, Albano C, Maffini M, Farelli S. Alcohol withdrawal syndrome: treatment with trazodone. Int Pharmacopsychiatry. 1980;15(2):105-10.</ref><ref>Le Bon O, Murphy JR, Staner L, Hoffmann G, Kormoss N, Kentos M, Dupont P, Lion K, Pelc I, Verbanck P. Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol. 2003 Aug;23(4):377-83.</ref><ref>Borras L, de Timary P, Constant EL, Huguelet P, Eytan A. Successful treatment of alcohol withdrawal with trazodone. Pharmacopsychiatry. 2006 Nov;39(6):232.</ref>
* [[schizophrenia]]<ref>Hayashi T, Yokota N, Takahashi T, Tawara Y, Nishikawa T, Yano T, Furutani M, Fujikawa T, Horiguchi J, Yamawaki S. Benefits of trazodone and mianserin for patients with late-life chronic schizophrenia and tardive dyskinesia: an add-on, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 1997 Jul;12(4):199-205.</ref><ref>Decina P, Mukherjee S, Bocola V, Saraceni F, Hadjichristos C, Scapicchio P. Adjunctive trazodone in the treatment of negative symptoms of schizophrenia. Hosp Community Psychiatry. 1994 Dec;45(12):1220-3.</ref>

==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.){{Fact|date=August 2007}}

==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 [[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. 

Episodes of [[complex partial seizure]]s have been reported in a small number of patients.{{Fact|date=August 2007}} The majority of these patients were already receiving [[anticonvulsant]] therapy for a previously diagnosed seizure disorder.{{Fact|date=August 2007}}

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 [[SSRI discontinuation syndrome|discontinuation syndrome]] if the medication is stopped too quickly. <ref>http://www.aafp.org/afp/20060801/449.html</ref> 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 seizure]]s, and, rarely impaired speech, muscle twitching, numbness, [[dystonia]], [[Euphoria (emotion)|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 [[Cardiac ectopy|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.

==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.

==See also==
*[[nefazodone]]
*[[antidepressant]]s

==Notes==
<div class="references-small">
<references/>
</div>

==References==
*{{cite web | url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=172043 | title=SID 172043 -- PubChem Substance Summary | accessmonthday=17 November | accessyear=2005}}
*{{cite web | url=http://www.rxlist.com/cgi/generic/traz_cp.htm | title=Drug information from Rxlist.com | accessmonthday=16 January | accessyear=2006}}
*{{cite web | url=http://www.mentalhealth.com/drug/p30-d03.html | title=Drug information from Mentalhealth.com | accessmonthday=16 January | accessyear=2006}}
==External links==
*[http://www.pfizer.nl/html/producten/trazolan.htm Pfizer Trazolan Patient Information Sheet] (Dutch)

{{Antidepressants}}


[[Category:Antidepressants]]
[[Category:Drugs]]

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