Trazodone

Depression The primary use of trazodone is the treatment of unipolar major depression with or without anxiety. 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. 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. 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. Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective. Insomnia Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication. It may also be used to treat antidepressant-related insomnia. Trazodone was the second-most prescribed agent for insomnia in the early 2000s even though most studies of trazodone for the treatment of sleep disturbances have been in depressed individuals. 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. Trazodone slightly improves subjective sleep quality ( = –0.34 to –0.41) and reduces the number of nighttime awakenings ( = –0.31, = –0.51), on average. It appears to increase deep sleep—in contrast to certain other hypnotics. 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. Other disorders Trazodone is often used in the treatment of anxiety disorderssuch as generalized anxiety disorder and panic disorderas well as in post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD). Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders. Benefits for OCD appear to be mild. 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. An extended-release oral tablet formulation at doses of 150mg and 300mg is also available. ==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 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. 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. Thus, care must be taken when coming off the medication, usually by a gradual process of tapering down the dose over time. Suicide Antidepressants may increase the risk of suicidal thoughts and behaviors in children and young adults. Close monitoring for the emergence of suicidal thoughts and behaviors is thus recommended. Sedation Since trazodone may impair the mental or physical abilities required for the 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. Trazodone has been found to impair driving ability. 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. 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 (heart attack). Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia. Priapism A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors. 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. Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms. Others Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites. Elevated prolactin concentrations have been observed in people taking trazodone. They appear to be increased by around 1.5- to 2-fold. Trazodone does not seem to worsen periodic limb movements during sleep. Trazodone is associated with an increased risk of falls in older adults. Pregnancy and lactation Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated. ==Overdose==

There are reported cases of high doses of trazodone precipitating serotonin syndrome. 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. The typical dose is around 150 mg, though some individuals may require higher amounts. However, taking more than 600 mg within 24 hours substantially increases the risk of overdose. 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. ==Interactions==

Cytochrome P450 inhibitors and inducers Trazodone is metabolized by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2. CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP, while CYP2D6 inducers may decrease their concentrations. Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. Fluoxetine, a strong inhibitor of CYP2D6 and a weak or moderate inhibitor of CYP3A4, has been reported to increase levels of trazodone by 1.3- to 1.7-fold and of mCPP by 3.0- to 3.4-fold. Conversely, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although CYP2D6 genotype did correlate with side effects like dizziness and prolonged corrected QT interval. Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone. Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.3-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. By displacing them from the 5-HT2A receptor, serotonin 5-HT2A receptor antagonists can block the hallucinogenic effects of serotonergic psychedelics. Trazodone has been used and discussed extensively online as a trip killer by recreational psychedelic users. It was recommended on the social media website Reddit for such purposes 77times by 2024 with a suggested dose range of 50 to 150mg. Trazodone was one of the most commonly recommended drugs for such purposes, exceeded only by alprazolam, benzodiazepines generally, and quetiapine. ==Pharmacology==

Pharmacodynamics 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. 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. A range of weak affinities (Ki) have been reported for trazodone at the human histamine H1 receptor, including 220nM, and 1,100nM. In contrast to trazodone, mCPP is an agonist of various serotonin receptors. It has relatively low affinity for α1-adrenergic receptors unlike trazodone, but does have high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor. 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. The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100mg/day and 90% at 150mg/day. Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150mg/day. However, it shows differences from certain other antidepressants, like the tricyclic antidepressants, in animals. In addition, trazodone diminishes amphetamine-induced locomotor hyperactivity, although it does not inhibit apomorphine- or amphetamine-induced stereotypy. On the other hand, unlike antipsychotics, trazodone does not produce catalepsy, although it can do so at sufficiently high doses. Trazodone is both a serotonin 5-HT2A and 5-HT2C receptor antagonist, but has about 15-fold greater potency as an antagonist of the 5-HT2A receptor relative to the 5-HT2C receptor. As a result of the preceding actions, trazodone may inhibit striatal dopaminergic neurotransmission. Correspondence to clinical effects Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak. Moderate 5-HT1A partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well. The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone. Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia. 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. Pharmacokinetics Absorption Trazodone is well-absorbed after oral administration. Absorption is somewhat delayed and enhanced by food. Distribution Trazodone is not sequestered into any tissue. The volume of distribution of trazodone is 0.8 to 1.5L/kg. CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP. In any case, there are large interindividual variations in the metabolism of trazodone. 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. In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP. 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. The elimination half-life of extended-release trazodone is 9.1 to 13.2hours. 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. 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. mCPP is glucuronidated and sulfated similarly to other trazodone metabolites. ==Chemistry==

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is structurally related to nefazodone and etoperidone, each of which is a derivative of it. ==History==

Trazodone was developed in Italy, in the 1960s, by Angelini Research Laboratories as a second-generation antidepressant. 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. 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, starting with Italy in 1972 and West Germany in 1977. It was approved by the Food and Drug Administration (FDA) in 1981 and was the first non-tricyclic or MAOI antidepressant approved in the US. ==Society and culture==

Generic names Trazodone is the generic name of the drug and its , , and , while trazodone hydrochloride is its , , , and . Brand names Trazodone has been marketed under a large number of brand names throughout the world. Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide). ==Research==

Trazodone may be effective in the treatment of sexual dysfunction, for instance female sexual dysfunction and erectile dysfunction. A 2003 systematic review and meta-analysis found some indication that trazodone may be useful in the treatment of erectile dysfunction. Besides trazodone alone, a combination of trazodone and bupropion (developmental code names and tentative brand names S1P-104, S1P-205, Lorexys, and Orexa) is under development for the treatment of erectile dysfunction and female sexual dysfunction. As of September 2021, it is in phase 2 clinical trials for these indications. Cochrane reviews found that trazodone was not effective in the treatment of agitation in dementia. Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia. 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. It has been reported to decrease negative symptoms without worsening positive symptoms although improvement in negative symptoms was modest. Trazodone has been studied and reported to be effective in the treatment of bulimia, It might be useful in the treatment of night eating disorder as well. It may also be effective in the treatment of bruxism in children and adolescents. Trazodone may be useful in the treatment of certain chronic pain disorders. Trazodone may be useful in the treatment of fibromyalgia as well as diabetic neuropathy. A 2004 narrative review claimed that trazodone could be used in the treatment of complex regional pain syndrome. Trazodone may also be effective in the treatment of functional gastrointestinal disorders. It may be effective in the treatment of non-cardiac chest pain as well. Trazodone may be useful in promoting motor recovery after stroke. Trazodone is sometimes prescribed to treat premature ejaculation but clomipramine and paroxetine may be more effective. ==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. == See also ==