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 26million prescriptions.[25][26]
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 300mg/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 600mg/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]
Trazodone is used at low doses in the range of 25 to 150mg/day for insomnia.[31][40][36][38] Higher doses of 200 to 600mg/day have also been studied.[31][35]
Trazodone is provided as the
hydrochloridesalt and is available in the form of 50mg, 100mg, 150mg, and 300mg
oraltablets.[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 150mg and 300mg is also available.[51][52]
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. <150mg/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 6,000–9,200mg. 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 25.4mg/L on admission.[27][73][74][75]
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]
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 1mg of trazodone and essentially all 5-HT2A receptors are saturated at 10mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100mg range.[31][40] The occupancy of the
serotonin transporter (SERT) by trazodone is estimated to be 86% at 100mg/day and 90% at 150mg/day.[17][107] Trazodone may almost completely occupy the 5-HT2A and
5-HT2C receptors at doses of 100 to 150mg/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]
Estimated occupancy of biological targets by trazodone at different doses[107][49]
Target
Estimated target occupancy
50mg/day
100mg/day
150mg/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%
83%
H1
84%
91%
94%
Very low (<25–33%): NET, DAT, 5-HT1B, 5-HT1E, 5-HT3, 5-HT5A, 5-HT6, β1, β2, D5, H4, mAChRs, nAChRs. Low (<50%): D1, D2. Not determined: α1B, α2B, D3. Note: Another study estimated much lower occupancies.[12]
Correspondence to clinical effects
This section needs to be updated. The reason given is: Needs to be updated in light of new occupancy studies.. Please help update this article to reflect recent events or newly available information.(October 2020)
Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against
anxiety and
depression.[108] Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak.[108] In relation to these properties, trazodone does not have similar properties to
selective serotonin reuptake inhibitors (SSRIs)[108] and is not particularly associated with increased
appetite and
weight gain – unlike other 5-HT2C antagonists like
mirtazapine.[109][110] Moderate 5-HT1A partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.[100][101][111]
The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.[112] Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia.[112] 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.[112] 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.[112] 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.[112] 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.[112]
mCPP, a non-selective
serotonin receptormodulator and
serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits.[12][105][106][81] However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects.[114][115][116][117][118]
The
metabolic pathways involved in the metabolism are not well-characterized.[17][42] In any case, the
cytochrome P450enzymesCYP3A4,
CYP2D6, and
CYP1A2 may all be involved to varying extents.[11][17][12][18] Trazodone is known to be extensively
metabolized by the liver via
hydroxylation,
N-oxidation, and
N-dealkylation.[11] Several
metabolites of trazodone have been identified, including a
dihydrodiol metabolite (via hydroxylation), a metabolite hydroxylated at the para position of the meta-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen.[11][76] CYP1A2, CYP2D6, and CYP3A4
genotypes all do not seem to predict concentrations of trazodone or mCPP.[42][78][79][120] In any case, there are large
interindividual variations in the metabolism of trazodone.[11] In addition, poor metabolizers of
dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than do extensive metabolizers.[11]
mCPP is formed from trazodone by CYP3A4 and is metabolized via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite).[17][12][18][11] It may contribute to the pharmacological actions of trazodone.[12][17][121] mCPP levels are only 10% of those of trazodone during therapy with trazodone, but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone.[11][122] In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP.[17] 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").[123]
Elimination
The
elimination of trazodone is biphasic: the first phase's half-life (distribution) is 3 to 6hours, and the following phase's half-life (elimination) is 4.1 to 14.6hours.[11][12][13][14] The elimination half-life of extended-release trazodone is 9.1 to 13.2hours.[15][12][13] The elimination half-life of mCPP is 2.6 to 16.0hours and is longer than that of trazodone.[11][12][14] Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled trazodone was found to be excreted in the urine within 72hours.[124] The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form.[119] After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP.[11] mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.[11]
Trazodone was developed in
Italy, in the 1960s, by
Angelini Research Laboratories as a second-generation
antidepressant.[127][128] 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.[129] 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[130] and was the first non-
tricyclic or
MAOI antidepressant approved in the US.[131]
Society and culture
Generic names
Trazodone is the
generic name of the drug and its
INNTooltip International Nonproprietary Name,
BANTooltip British Approved Name, and
DCFTooltip Dénomination Commune Française, while trazodone hydrochloride is its
USANTooltip United States Adopted Name,
USPTooltip United States Pharmacopeia,
BANMTooltip British Approved Name, and
JANTooltip Japanese Accepted Name.[132][133][134][135]
Brand names
Trazodone has been marketed under a large number of brand names throughout the world.[133][135] Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).[133][135]
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