Trazodone

Source: Wikipedia, the free encyclopedia.

Trazodone
Clinical data
Trade namesDesyrel, Trittico, others[1]
Other namesAF-1161
AHFS/Drugs.comMonograph
MedlinePlusa681038
License data
Dependence
liability		None[2]
Addiction
liability		None[2]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Tmax)[10]
Elimination half-life• Trazodone (IR): 4–15 hours[11][12][13][14]
• Trazodone (ER): 9–13 hours[15][12][13]
• mCPPTooltip meta-Chlorophenylpiperazine: 3–16 hours[11][12][14][16]
ExcretionUrine: 70–75%[7]
Feces: 21%[7]
Identifiers
  • 2-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
JSmol)
Melting point87 °C (189 °F)
  • Clc4cccc(N3CCN(CCCN1/N=C2/C=C\C=C/N2C1=O)CC3)c4
  • InChI=1S/C19H22ClN5O/c20-16-5-3-6-17(15-16)23-13-11-22(12-14-23)8-4-10-25-19(26)24-9-2-1-7-18(24)21-25/h1-3,5-7,9,15H,4,8,10-14H2 checkY
  • Key:PHLBKPHSAVXXEF-UHFFFAOYSA-N checkY
  (verify)

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

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.

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

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]

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

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

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

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

See also: List of adverse effects of trazodone

Because of its lack of

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

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]

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

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

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

Trazodone (and metabolite)[83]
Site Trazodone mCPPTooltip meta-Chlorophenylpiperazine Species Ref
SERTTooltip Serotonin transporter 160–>10,000[84] 202–432 Human [83][85][86]
NETTooltip Norepinephrine transporter ≥8,500 ≥1,940 Human [86][85]
DATTooltip Dopamine transporter ≥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
Tooltip Muscarinic acetylcholine receptors		 >10,000 >10,000 Human [83][99][87][88]
nAChRs
Tooltip Nicotinic acetylcholine receptors		 >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
Tooltip Voltage-dependent calcium channels		 >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

H1 receptor, including 220 nM,[83] 350 nM,[98] 500 nM,[102] and 1,100 nM.[87]

Trazodone has a minor

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]

Estimated occupancy of biological targets by trazodone at different doses[107][49]
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% 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

Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against

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]

Trazodone's potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation.[113] 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 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]

Pharmacokinetics

Absorption

Trazodone is well-

absorbed after oral administration.[12] Its bioavailability is 65 to 80%.[12] Peak blood levels of trazodone occur 1 to 2 hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4 hours.[12][11] Absorption is somewhat delayed and enhanced by food.[citation needed
]

Distribution

Trazodone is not sequestered into any

lipophilic.[11]

Metabolism

The

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).

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 6 hours, and the following phase's half-life (elimination) is 4.1 to 14.6 hours.[11][12][13][14] The elimination half-life of extended-release trazodone is 9.1 to 13.2 hours.[15][12][13] The elimination half-life of mCPP is 2.6 to 16.0 hours 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 72 hours.[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]

Chemistry

Trazodone is a

derivative and a phenylpiperazine that is structurally related to nefazodone and etoperidone, each of which are derivatives of it.[125][126][29]

History

Trazodone was developed in

MAOI antidepressant approved in the US.[131]

Society and culture

Generic names

Trazodone is the

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]

Research

Trazodone may be effective in the treatment of

female sexual dysfunction.[138][139][140] As of September 2021, it is in phase 2 clinical trials for these indications.[138] It has been in this stage of clinical development since at least February 2015.[140]

Trazodone may be useful in the treatment of certain symptoms like

Cochrane reviews found that trazodone was not effective in the treatment of agitation in dementia.[145][146] Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia.[147] Further systematic reviews have found that trazodone may be effective for behavioral and psychological symptoms in dementias such as frontotemporal dementia and Alzheimer's disease.[148][149][150][151][42]

Trazodone has been studied as an

night eating disorder as well.[42] Trazodone might be effective in the treatment of adjustment disorder.[155] It may also be effective in the treatment of bruxism in children and adolescents.[156]

Trazodone may be useful in the treatment of certain

narrative review claimed that trazodone could be used in the treatment of complex regional pain syndrome.[164] Trazodone may also be effective in the treatment of functional gastrointestinal disorders.[165] It may be effective in the treatment of non-cardiac chest pain as well.[166][167]

Trazodone may be useful in promoting motor recovery after stroke.[42][168]

Veterinary use

Trazodone has been used to reduce anxiety and stress, to improve sleep, and to produce sedation in dogs and cats in veterinary medicine.[169][170][171]

See also

References

  1. ^ a b "Trazodone". Drugs.com. Retrieved 9 February 2019.
  2. ^
    ISBN 978-0-8247-4497-7
    .
  3. FDA
    . Retrieved 22 October 2023.
  4. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  5. ^ a b "Desyrel (trazodone HCl)". DailyMed. 19 March 2013. Retrieved 4 April 2022.
  6. ^ a b "Trazodone hydrochloride tablet". DailyMed. 29 June 2021. Retrieved 3 April 2022.
  7. ^ a b c Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Oct 1]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  8. ^ "Trazodone". DrugBank. Retrieved 7 June 2015.
  9. ISBN 978-3-642-18500-7
    .
  10. ^ "MicroMedex DrugPoints – Trazodone". Pharmacy Choice. Retrieved 20 April 2017.
  11. ^
    S2CID 19585113
    .
  12. ^
    S2CID 6068710
    .
  13. ^
    PMID 23192413
    .
  14. ^
    S2CID 36104356
    .
  15. ^
    S2CID 26833385
    .
  16. ISBN 978-1-58562-523-9
    .
  17. ^
    PMID 31379379
    .
  18. ^
    S2CID 45097940
    .
  19. ISBN 978-1-60913-345-0
    .
  20. ^ a b c d e f g h "Trazodone". The American Society of Health-System Pharmacists. 17 March 2021. Retrieved 24 December 2021.
  21. ^ "Trazodone Use During Pregnancy". Drugs.com. Retrieved 7 January 2018.
  22. ISBN 978-0-521-85702-4
    .
  23. ISBN 978-0-7817-6879-5
    .
  24. ISBN 978-0-85711-156-2
    .
  25. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  26. ^ "Trazodone – Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  27. ^
    ISBN 978-1-58562-309-9
    .
  28. ^
    PMID 25735839
    .
  29. ^
    S2CID 265772823
    .
  30. PMID 2211561
    .
  31. ^
    PMID 29552421
    .
  32. ^
    PMID 26088119
    .
  33. PMID 8010365
    .
  34. PMID 15816789
    .
  35. ^
    PMID 16517453
    .
  36. ^
    PMID 29680424
    .
  37. PMID 32714220
    .
  38. ^
    PMID 29761479
    .
  39. ^
    S2CID 243329243
    .
  40. ^
    S2CID 2977125
    .
  41. PMID 27998379
    .
  42. ^
    S2CID 205452630
    .
  43. ^
    S2CID 10638259
    .
  44. S2CID 30562398
    .
  45. ISBN 978-0-85711-084-8
    .
  46. PMID 12804478
    .
  47. S2CID 38329753
    .
  48. S2CID 45471039
    .
  49. ^
    S2CID 53042045
    .
  50. ^ https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000219_022323_RCP.pdf&sys=m0b1l3
  51. PMID 21431085
    .
  52. ^ "Trazodone (Oral Route) Proper Use Clinic". www.mayoclinic.org – Mayo Clinic. Retrieved 11 February 2020.
  53. PMID 26459471
    .
  54. ^ "Webmd.com". Webmd.com. Retrieved 14 March 2014.
  55. PMID 16913164
    .
  56. ^ "FDA – Trazodone Prescribing Information" (PDF).
  57. PMID 2677245
    .
  58. S2CID 3425898
    .
  59. ^
    ISBN 978-1-58562-309-9
    .
  60. ^ "Trazodone Product Monograph" (PDF). 2015.
  61. ^ "Highlights of Prescribing Information" (PDF). U.S. Food and Drug Administration. 2017.
  62. PMID 3573170
    .
  63. S2CID 39522632
    .
  64. PMID 19674253
    .
  65. PMID 15978881
    .
  66. ^
    S2CID 41490922
    .
  67. PMID 34097124
    .
  68. PMID 28822709
    .
  69. S2CID 22681213
    .
  70. PMID 12655908
    .
  71. PMID 3768252
    .
  72. ^ a b Cushing TA (24 April 2018). "Selective Serotonin Reuptake Inhibitor Toxicity". Medscape. WebMD LLC. Retrieved 22 December 2018.
  73. PMID 15975258
    .
  74. S2CID 21487479
    .
  75. PMID 3321131
    .
  76. ^
    PMID 9616194
    .
  77. S2CID 1979283
    .
  78. ^
    S2CID 11521715
    .
  79. ^
    PMID 29061081
    .
  80. PMID 24569517
    .
  81. ^ a b c Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H, Meltzer HY (October 1997). "Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine". Journal of Clinical Psychopharmacology. 17 (5): 358–64.
    PMID 9315986
    .
  82. ^
    PMID 8675966
    .
  83. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  84. ^ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 25 May 2018.
  85. ^
    PMID 9400006
    .
  86. ^
    PMID 9537821
    .
  87. ^
    S2CID 21236268
    .
  88. ^
    S2CID 46730665
    .
  89. S2CID 35553281
    .
  90. PMID 1652050
    .
  91. ^
    S2CID 8938111
    .
  92. PMID 7582481
    .
  93. ^
    PMID 19505264
    .
  94. PMID 11104741
    .
  95. PMID 10498829
    .
  96. PMID 15081042
    .
  97. S2CID 24930608
    .
  98. ^
    PMID 6086881
    .
  99. ^
    PMID 8100134
    .
  100. ^
    S2CID 24965789
    .
  101. ^
    S2CID 27389008
    .
  102. PMID 23357028
    .
  103. ISBN 978-0-7817-6879-5
    .
  104. S2CID 13007057
    .
  105. ^
    PMID 7255270
    .
  106. ^
    S2CID 44968564
    .
  107. ^
    S2CID 28804036
    .
  108. ^
    S2CID 25140746
    .
  109. PMID 12096167
    .
  110. S2CID 7459081
    .
  111. PMID 10065919
    .
  112. ^
    ISBN 978-1-107-68646-5
    .
  113. S2CID 43202340
    .
  114. S2CID 25709000
    .
  115. PMID 2311675
    .
  116. S2CID 38913696
    .
  117. S2CID 901077
    .
  118. PMID 1575270
    .
  119. ^ a b "Trazodone". www.drugbank.ca. Retrieved 31 January 2019.
  120. PMID 11393588.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link
    )
  121. S2CID 21305772
    .
  122. ISBN 978-3-527-62147-7
    .
  123. PMID 21073812
    .
  124. PMID 1037253
    .
  125. ISBN 978-3-527-66445-0
    .
  126. ISBN 978-3-527-64564-0
    .
  127. ISBN 978-0-08-086111-1
    .
  128. ^ Wegener G (30 March 2016). "Ban & Silvestrini's Trazodone". International Network for the History of Neuropsychopharmacology. Archived from the original on 20 March 2017. Retrieved 4 June 2017.
  129. S2CID 34798378
    .
  130. ^ "Trazodone: Common sleep drug is little-known antidepressant". Consumer Reports. August 2015.
  131. ISBN 978-1-4612-4828-6
    .
  132. ISBN 978-1-4757-2085-3
    .
  133. ^
    ISBN 978-3-88763-075-1
    .
  134. ISBN 978-94-011-4439-1
    .
  135. ^ a b c "Trazodone". Drugs.com.
  136. PMID 33967614
    .
  137. S2CID 7499389
    .
  138. ^ a b "Bupropion/Trazodone - AdisInsight".
  139. S2CID 52813769
    .
  140. ^
    S2CID 207477620
    .
  141. PMID 21715413
    .
  142. S2CID 207939482
    .
  143. PMID 25719754
    .
  144. PMID 24899767
    .
  145. PMID 15495135
    .
  146. PMID 21328305
    .
  147. PMID 33189083
    .
  148. S2CID 13491951
    .
  149. S2CID 228158773
    .
  150. S2CID 212417082
    .
  151. S2CID 8766330
    .
  152. ^
    PMID 20807960
    .
  153. PMID 25991654
    .
  154. PMID 14583971
    .
  155. S2CID 219586994
    .
  156. S2CID 209411316
    .
  157. PMID 14583952
    .
  158. S2CID 37252070
    .
  159. PMID 23358935
    .
  160. S2CID 9178257
    .
  161. S2CID 247006915
    .
  162. S2CID 232217908
    .
  163. PMID 28247977
    .
  164. PMID 15948431
    .
  165. PMID 30564156
    .
  166. S2CID 21793648
    .
  167. S2CID 293910
    .
  168. PMID 20032921
    .
  169. PMID 34475580
    .
  170. S2CID 76667125
    .
  171. PMID 29415813
    .

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