Trazodone, sold under many brand names worldwide,[1] is an antidepressant medication.[7] It is used to treat major depressive disorder, anxiety disorders, and in addition to other treatment, alcohol dependence.[7] It is taken by mouth.[7] Common side-effects include dry mouth, feeling faint, vomiting, and headache.[7] More serious side effects may include suicide, unmasking bipolar, irregular heart rate, and priapism.[7] It is unclear if use during pregnancy or breastfeeding is safe.[8] It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class.[9][10] Trazodone also has sedating effects.[11] Trazodone was approved for medical use in the United States in 1981.[7] It is available as a generic medication.[7] The cost in the United Kingdom for the NHS is about 21.23 pounds per month as of 2015.[11] In the United States the whole sale cost is about 4.53 USD per month as of 2018.[12] In 2014 about 26 million prescriptions for the medication were filled in the US.[13] Trazodone has the following medical uses: The primary use of Trazodone is the treatment of major depression. Data from open and double-blind trials suggest the antidepressant efficacy of Trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Also, Trazodone showed anxiolytic properties, low cardiotoxicity, and relatively mild side effects.[17] Because Trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported Trazodone has antidepressant efficacy similar to that of other antidepressants in geriatric patients. However, a side effect of Trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients; thus, this side effect, along with sedation, often makes Trazodone less acceptable for this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, Trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia.[17] Many clinicians use low-dose Trazodone as an alternative to benzodiazepines for the treatment of insomnia. Two recent reviews found that Trazodone is the second most prescribed agent for insomnia, but as most studies have been limited to people with depression, few studies actually support Trazodone's use in primary insomnia.[17] Off-label uses and investigational uses are listed below: Trazodone is available in the form of 50 mg, 100 mg, 150 mg, and 300 mg tablets for oral ingestion.[25][26] Contraindications and precautions for Trazodone include: 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.[28] 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. Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.[29][30] 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. Because of its lack of anticholinergic side effects, Trazodone is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g., in patients with benign prostatic hyperplasia, closed-angle glaucoma, or severe constipation). Trazodone's propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of Trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some patients, probably as a consequence of α1-adrenergic receptor blockade. Mania has been observed in association with Trazodone treatment, including in patients with bipolar disorder, as well as in patients with previous diagnoses of major depression. Compared to the reversible MAOI antidepressant drug moclobemide, significantly more impairment of vigilance occurs with Trazodone.[31] Case reports have noted cardiac arrhythmias emerging in relation to Trazodone treatment, both in patients with pre-existing mitral valve prolapse and in patients with negative personal and family histories of cardiac disease.[32] QT prolongation has been reported with Trazodone therapy. Arrhythmia identified include isolated PVCs, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. Several post-marketing reports have been made 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. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.[citation needed] A relatively rare, but dramatic, side effect associated with Trazodone is priapism, likely due to its antagonism at α-adrenergic receptors.[33] More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with Trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150 mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of Trazodone treatment. Clinical reports have also described Trazodone-associated psychosexual side effects in women, including increased libido, priapism of the clitoris, and spontaneous orgasms.[32][34] Rare cases of idiosyncratic hepatotoxicity have been observed, possibly due to the formation of reactive metabolites.[35] Elevated prolactin concentrations have been observed in patients taking Trazodone.[36] There are reported cases of high doses of Trazodone precipitating serotonin syndrome.[37] There are also reports of patients taking multiple SSRIs with Trazodone and precipitating serotonin syndrome.[38] Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When Trazodone overdoses occur, clinicians should carefully monitor for hypotension, a potentially serious toxic effect. In a report of a fatal Trazodone overdose, torsades de pointes and complete atrioventricular block developed, along with subsequent multiple organ failure, with a Trazodone plasma concentration of 25.4 mg/L on admission.[17][39][40][41] 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, and forced diuresis may be useful in facilitating elimination of the drug, gastric lavage has been shown to not be useful unless done during the first hour after intake.[citation needed] Trazodone is metabolized by CYP3A4, a liver enzyme.[42] 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. Trazodone is generally described as acting as a potent serotonin 5-HT2A and α1-adrenergic receptor antagonist, a weak serotonin reuptake inhibitor (SRI), and a weak antihistamine or histamine H1 receptor inverse agonist.[59] Its 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as a serotonin antagonist and reuptake inhibitor (SARI).[60] Trazodone, both itself and via its major active metabolite meta-chlorophenylpiperazine (mCPP),[61] also binds to a variety of other receptors.[43] It is an antagonist at most or all of the receptors it binds to except the 5-HT1A receptor, where it acts as a partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity.[43][62][63] Conversely, mCPP is a non-selective agonist of most of the serotonin receptors it binds to.[64] A range of weak affinities (Ki) have been reported for Trazodone at the human histamine H1 receptor including 220 nM,[43] 350 nM,[57] 500 nM,[65] and 1,100 nM.[46] Trazodone acts predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.[66] Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak.[66] Hence, Trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs)[66] and is not particularly associated with increased appetite and weight gain, unlike other 5-HT2C antagonists like mirtazapine.[67][68] Moderate 5-HT1A partial agonism is likely to contribute to Trazodone's antidepressant and anxiolytic actions to some extent as well.[62][63][69] The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of Trazodone.[70] Doses of Trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia.[70] Low doses exploit Trazodone's potent actions as a 5-HT2A receptor antagonist, and its properties as an antagonist of H1 and α1-adrenergic receptors, but do not adequately exploit its SERT or 5-HT2C inhibition properties, which are weaker.[70] Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode.[70] Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood.[70] Thus, the ability of low doses of Trazodone to improve sleep in depressed patients may be an important mechanism whereby Trazodone can augment the efficacy of other antidepressants.[70] Trazodone's potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation.[71] Conversely, along with 5-HT2A and H1 receptor antagonism, it may contribute to its efficacy as a hypnotic. Trazodone lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects. mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is the major active metabolite of Trazodone and has been suggested to possibly play a role in its therapeutic benefits.[72][73][74] However, scientific research has not supported this hypothesis, and mCPP may actually antagonize Trazodone's efficacy as well as produce additional side effects.[75][76][77][78][79] Trazodone is well absorbed after oral administration, with mean peak blood levels obtained at about one hour after ingestion. Absorption is somewhat delayed and enhanced by food. The drug is highly protein-bound. Trazodone is extensively metabolized, with three or four major metabolites having been identified in the human body, particularly mCPP,[42] which may contribute to the side effect profile of Trazodone and which probably accounts for Trazodone's serotonergic effects.[80] Levels of Trazodone are about 10-fold those of mCPP with treatment.[81] The mean blood elimination half-life of Trazodone is biphasic: the first phase's half-life is 3 to 6 hours, and the following phase's half-life is 5 to 9 hours. Around 70 to 75% of 14C-labelled Trazodone was found to be excreted in the urine within 72 hours.[82] As a consequence of the production of mCPP as a metabolite, patients administered Trazodone may test positive on EMIT II urine tests for the presence of MDMA ("ecstasy").[83] Trazodone is a triazolopyridine derivative and a phenylpiperazine that is chemically related to nefazodone and etoperidone, each of which are derivatives of it.[84][85][86] Trazodone was discovered in Italy in the 1960s by Angelini Research Laboratories as a second-generation antidepressant.[87][88] 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.[89] In sharp contrast to most other antidepressants available at the time of its development, Trazodone showed minimal effects on muscarinic cholinergic receptors. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) in 1981[90] and was the first non-tricyclic antidepressant approved in the US.[91] Trazodone is the generic name of the drug and its INN, BAN, and DCF, while Trazodone hydrochloride is its USAN, USP, BANM, and JAN.[92][93][94][95] Trazodone has been marketed under a large number of brand names throughout the world.[93][95] Major brand names include Desyrel (worldwide), Molipaxin (IE, UK), Oleptro (US), Trazorel (CA), and Trittico (worldwide).[93][95]