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Trazodone, sold under many brand names,[1] is an antidepressant medication.[20] It is used to treat major depressive disorder, anxiety disorders, and insomnia.[20] The medication is taken orally.[20]
Common side effects include dry mouth, feeling faint, vomiting, and headache.[20] More serious side effects may include suicide, mania, irregular heart rate, and pathologically prolonged erections.[20] It is unclear if use during pregnancy or breastfeeding is safe.[21] It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class.[22][23] Trazodone also has sedating effects.[24]
Trazodone was approved for medical use in the United States in 1981.[20] It is available as a generic medication.[20] In 2021, it was the 22nd most commonly prescribed medication in the United States, with more than 26 million prescriptions.[25][26]
Medical uses
Depression
The primary use of trazodone is the treatment of unipolar major depression with or without anxiety.[5] Data from open and double-blind trials suggest that the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Furthermore, trazodone has shown anxiolytic properties, low cardiotoxicity, and relatively mild side effects.[27]
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 had antidepressant efficacy similar to that of other antidepressants in geriatric patients. Unfortunately, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients.[28] Therefore, this side effect, along with sedation, often makes trazodone less acceptable for this population compared to 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.[27]
Trazodone is usually used at a dosage of 150 to 300 mg/day for the treatment of depression.[17][13] Lower doses have also been used to augment other antidepressants or when initiating therapy.[17][13] Higher doses, up to 600 mg/day, have been used in more severe cases of depression (in hospitalized patients, for example).[29] Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.[30]
Insomnia
Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication.[31][13][32] It may also be used to treat antidepressant-related insomnia.[33] Trazodone was the second-most prescribed agent for insomnia in the early 2000s even though most studies of trazodone for treatment of sleep disturbances have been in depressed individuals.[13][34][35]
Systematic reviews and meta-analyses published in the late 2010s, including a Cochrane review, found low-dose trazodone to be an effective medication for short-term treatment of insomnia in both depressed and euthymic people.[31][36][37][38] Trazodone slightly improves subjective sleep quality (SMD = –0.34 to –0.41) and reduces the number of nighttime awakenings (MD = –0.31, SMD = –0.51), on average.[36][38] Conversely, it does not appear to affect sleep onset, total sleep time, time awake after sleep onset, or sleep efficiency.[36][38][39] It appears to increase deep sleep—in contrast to certain other hypnotics.[39] The quality of evidence of trazodone for short-term treatment of insomnia was rated as low to moderate.[36][38] There is no evidence available at present to inform long-term use of trazodone in the treatment of insomnia.[38]
The benefits of trazodone for insomnia must be weighed against potential adverse effects, such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others.[31][38] Quality safety data on use of trazodone as a sleep aid are currently lacking.[36][38]
Trazodone is used at low doses in the range of 25 to 150 mg/day for insomnia.[31][40][36][38] Higher doses of 200 to 600 mg/day have also been studied.[31][35]
The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.[41]
Other disorders
Trazodone is often used in the treatment of anxiety disorders — such as generalized anxiety disorder and panic disorder — as well as in post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD).[42][43][32][44][45] Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders.[43][32] However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications is variable and limited.[32][43][42][46][47] Benefits for OCD appear to be mild.[43][32] Trazodone has been used to treat sleep disturbances and nightmares in PTSD.[48][32][43]
Combination with other antidepressants
Trazodone is often used in combination with other antidepressants such as selective serotonin reuptake inhibitors in order to augment their antidepressant and anxiolytic effects and to reduce side effects such as sexual dysfunction, anxiety, and insomnia.[43][13][42][49]
Available forms
Trazodone is provided as the hydrochloride salt and is available in the form of 50 mg, 100 mg, 150 mg, and 300 mg oral tablets.[6] In Italy, it is also available as an oral solution (Trittico 60 mg/mL) with a dosing pipette marked at 25 mg and 50 mg.[50]
An extended-release oral tablet formulation at doses of 150 mg and 300 mg is also available.[51][52]
Side effects
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 people, probably as a consequence of α1-adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone[20] and other antidepressants.[53]
Precautions for trazodone include known hypersensitivity to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions.[54]
While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly.[55] 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.
Suicide
Antidepressants may increase the risk of suicidal thoughts and behaviors in children and young adults. Close monitoring for emergence of suicidal thoughts and behaviors is thus recommended.[56]
Sedation
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. Compared to the reversible MAOI antidepressant drug moclobemide, more impairment of vigilance occurs with trazodone.[57] Trazodone has been found to impair driving ability.[58]
Cardiac
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.[59]
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.[60][61]
Priapism
A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors.[62] 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. Spontaneous orgasms have also been reported with trazodone in men.[63]
Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms.[59][64]
Others
Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.[65]
Elevated prolactin concentrations have been observed in people taking trazodone.[29][66] They appear to be increased by around 1.5- to 2-fold.[29][66]
Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change, and some finding impairment.[67]
Trazodone does not seem to worsen periodic limb movements during sleep.[68]
Trazodone is associated with increased risk of falls in older adults.[28] It has also been associated with increased risk of hip fractures in older adults.[69]
Pregnancy and lactation
Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.[70][71]
Overdose
There are reported cases of high doses of trazodone precipitating serotonin syndrome.[72] There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.[72]
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 low blood pressure, 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.[27][73][74][75]
Interactions
Trazodone is metabolized by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2.[11][76] Its active metabolite meta-chlorophenylpiperazine (mCPP) is known to be formed by CYP3A4 and metabolized by CYP2D6.[11] Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations.[17][13] The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine, enzalutamide, phenytoin, phenobarbital, and St. John's wort may result in decreased trazodone concentrations and increased mCPP concentrations.[17][13][12] CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP while CYP2D6 inducers may decrease their concentrations.[11][17][18] Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. CYP1A2 inhibitors may increase trazodone concentrations while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control), fluoroquinolones (e.g., ciprofloxacin), fluvoxamine, and St. John's wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco.
A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.34-fold, increased area-under-the-curve levels by 2.4-fold, and decreased the clearance of trazodone by 50%.[17][12] This was associated with adverse effects such as nausea, hypotension, and syncope.[17] Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%.[17] The strong CYP2D6 inhibitor thioridazine has been reported to increase concentrations of trazodone by 1.36-fold and concentrations of mCPP by 1.54-fold.[11][77] On the other hand, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although it did correlate with side effects like dizziness and prolonged corrected QT interval.[42][78][79]
Combination of trazodone with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome.[17][13] However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context.[17][13] On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of trazodone and fluoxetine or paroxetine.[11] This may be due to combined potentiation of the serotonin system.[11] However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4.[11][80] Accordingly, fluoxetine has been reported to result in increased levels of trazodone and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively.[11][81]
Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone.[11][82] Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers.[82] Smoking is known to induce CYP1A2, and this may be involved in these findings.[11]
Pharmacology
Pharmacodynamics
| Site | Trazodone | mCPP | Species | Ref |
|---|---|---|---|---|
| SERT | 160–>10,000[84] | 202–432 | Human | [83][85][86] |
| NET | ≥8,500 | ≥1,940 | Human | [86][85] |
| DAT | ≥7,400 | ND | Human | [86][83] |
| 5-HT1A | 96–118 | 44–400 | Human | [83][87][88] |
| 5-HT1B | >10,000 | 89–501 | Human | [83][89] |
| 5-HT1D | 106 | 210–1,300 | Human | [83][88][90] |
| 5-HT1E | >10,000 | ND | Human | [83] |
| 5-HT1F | ND | ND | ND | ND |
| 5-HT2A | 20–45 | 32–398 | Human | [83][91][92][93] |
| 5-HT2B | 74–189 | 3.2–63 | Human | [83][91][94][95] |
| 5-HT2C | 224–402 | 3.4–251 | Human | [91][96][97][93] |
| 5-HT3 | >10,000 | 427 | Human | [83] |
| 5-HT4 | ND | ND | ND | ND |
| 5-HT5A | >10,000 | 1,354 | Human | [83] |
| 5-HT6 | >10,000 | 1,748 | Human | [83] |
| 5-HT7 | 1,782 | 163 | Human | [83] |
| α1 | 12–42 | 97–2,900 | Human | [85][87][88][98] |
| α1A | 153 | 1,386 | Human | [83] |
| α1B | ND | 915 | Human | [83] |
| α1D | ND | ND | ND | ND |
| α2 | 106–490 | 112–570 | Human | [87][85][88][98] |
| α2A | 728 | 145 | Human | [83] |
| α2B | ND | 106 | Human | [83] |
| α2C | 155 | 124 | Human | [83] |
| β | >10,000 | 2,500 | Human | [83][88] |
| β1 | >10,000 | 2,359 | Human | [83] |
| β2 | >10,000 | 3,474 | Human | [83] |
| D1 | 3,730 | 7,000 | Human | [83][88] |
| D2 | ≥3,500 | >10,000 | Human | [83][87][99][88] |
| D3 | 353 | >10,000 | Rat | [83][88] |
| D4 | 703 | ND | Human | [83] |
| D5 | >10,000 | >10,000 | Human | [83][88] |
| H1 | 220–1,100 | 326 | Human | [83][98][87] |
| H2 | 3,290 | ND | Human | [83] |
| H3 | >10,000 | ND | Guinea pig | [83] |
| H4 | >10,000 | ND | Human | [83] |
| mAChRs | >10,000 | >10,000 | Human | [83][99][87][88] |
| nAChRs | >10,000 | >10,000 | Human | [83] |
| σ1 | >10,000 | ND | Rat | [83] |
| σ2 | 536 | 8,350 | Rat | [83] |
| I1 | ND | 759 | Rat | [83] |
| NMDAR (MK-801) |
>10,000 | ND | Rat | [83] |
| VDCCs | >10,000 | 6,043 | Rat | [83] |
| Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. | ||||
Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor.[12][13] More specifically, it is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-adrenergic receptors.[13][12] It is also a ligand of the 5-HT2C receptor with lower affinity than for the 5-HT2A receptor.[12][13] However, it is unknown whether trazodone acts as a full agonist, partial agonist, or antagonist of the 5-HT2C receptor.[12] Trazodone is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity.[83][100][101] A range of weak affinities (Ki) have been reported for trazodone at the human histamine H1 receptor, including 220 nM,[83] 350 nM,[98] 500 nM,[102] and 1,100 nM.[87]
Trazodone has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone.[11][103] In contrast to trazodone, mCPP is an agonist of various serotonin receptors.[104] It has relatively low affinity for α1-adrenergic receptors unlike trazodone, but does high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor.[12] In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA.[12][105][106][81] In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity).[12]
Trazodone's 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type.[42]
Target occupancy studies
Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question.[107][49][12] Roughly half of brain 5-HT2A receptors are blocked by 1 mg of trazodone and essentially all 5-HT2A receptors are saturated at 10 mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100 mg range.[31][40] The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100 mg/day and 90% at 150 mg/day.[17][107] Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150 mg/day.[17][107] Significant occupancy of a number of other sites may also occur.[17][107] However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by trazodone.[12]
| Target | Estimated target occupancy | ||
|---|---|---|---|
| 50 mg/day | 100 mg/day | 150 mg/day | |
| SERT | 75% | 86% | 90% |
| 5-HT1A | 91% | 95% | 97% |
| 5-HT1D | 91% | 95% | 97% |
| 5-HT2A | 97% | 98% | 99% |
| 5-HT2B | 94% | 97% | 98% |
| 5-HT2C | 83% | 91% | 94% |
| 5-HT7 | 39% | 56% | 66% |
| α1A | 88% | 94% | 96% |
| α2A | 61% | 75% | 82% |
| α2C | 88% | 94% | 96% |
| D4 | 62% | 76%
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