(British Approved Name Modified, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Note. The following terms have been used as ‘street names’ (see p.vi) or slang names for various forms of trazodone hydrochloride: Sleepeasy.

Pharmacopoeias. In British and US.

BP 2008 (Trazodone Hydrochloride). A white or almost white crystalline powder. Soluble in water sparingly soluble in alcohol practically insoluble in ether. A 1% solution in water has a pH of 3.9 to 4.5. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Trazodone Hydrochloride). A white to off-white crystalline powder. Sparingly soluble in water and in chloroform. Store in airtight containers. Protect from light.

Adverse Effects and Treatment

Trazodone has sedative properties although drowsiness usually disappears on continuing treatment. Other adverse effects occasionally reported include dizziness, headache, nausea and vomiting, weakness, weight loss, tremor, dry mouth, bradycardia or tachycardia, orthostatic hypotension, oedema, constipation, diarrhoea, blurred vision, restlessness, confusional states, insomnia, and skin rash. Although some of these effects are typical of antimuscarinic activity it is reported that trazodone has little antimuscarinic activity compared with tricyclic antidepressants. Animal studies have also indicated that trazodone is less cardiotoxic than the tricyclics. Priapism has been reported on a number of occasions.

Agranulocytosis, thrombocytopenia, and anaemia have been reported rarely. Adverse effects on hepatic function, including jaundice and hepatocellular damage, which may be severe, have also been reported rarely. There have been occasional reports of serotonin syndrome. Neuroleptic malignant syndrome has occurred rarely.

Hyponatraemia possibly due to inappropriate secretion of antidiuretic hormone has been associated with the use of antidepressants, particularly in the elderly.

Symptoms of overdosage include drowsiness, dizziness, vomiting, priapism, respiratory arrest, seizures, and ECG changes. The value of gastric decontamination after overdosage is uncertain. However, activated charcoal may be considered in adults who have taken more than 1 g (children more than 150 mg) and present within 1 hour gastric lavage may also be considered in adults in life-threatening overdoses. Thereafter, symptomatic and supportive therapy should be given as appropriate.

Effects on the cardiovascular system. Although trazodone is considered to cause fewer adverse cardiovascular reactions than the tricyclic antidepressants, they have, nevertheless, been reported in individual patients. In therapeutic doses it has been associated with heart block in a patient with pre-existing cardiovascular disease, as well as in a patient with no ECG abnormalities. Similarly, ventricular arrhythmias have been associated with therapeutic doses of trazodone both in patients with a history of cardiac problems, and with no history of cardiac abnormalities. Atrial fibrillation has been reported in a patient with ischaemic heart disease.

Effects on the eyes. A patient receiving clomipramine and trazodone orally noted excessive blinking whenever the dose of trazodone exceeded or equalled that of clomipramine. When trazodone, but not clomipramine, was withdrawn, blinking became normal within 3 weeks.

Effects on the liver. A mixed hepatocellular-cholestatic liver enzyme pattern has been reported in a patient after about 3 weeks of treatment with trazodone in doses of up to 500 mg daily. The enzyme abnormalities returned to normal 4 weeks after trazodone was stopped but it was suggested that liver enzyme values should be monitored during the first 4 weeks of therapy. A similar case apparently presenting as obstructive jaundice and hepatocellular inflammation, in which the patient had only been receiving 50 mg daily for 2 weeks, has also been described. It was believed that the patient suffered an idiosyncratic drug reaction to trazodone. Further reports of trazodone-induced liver injury include an elderly patient who developed chronic active hepatitis after receiving trazodone 150 mg daily for about 8 months. A case of fatal hepatic necrosis reported in another elderly patient was considered to be due to treatment with trazodone and antipsychotics. The authors of the report noted that up to August 1991 the UK CSM had received 14 reports of adverse effects on the liver associated with trazodone including one episode of fatal hepatic necrosis. In one of 2 later reports of trazodone-induced hepatotoxicity, a female patient with rheumatoid arthritis developed jaundice 18 months after trazodone was added to her existing medications. All drugs were stopped and the patient improved however, an inadvertent rechallenge with trazodone (without any other medication) led to a recurrence of her symptoms which again resolved following trazodone withdrawal. The second case involved a HIV-positive male who was started on methadone, clonidine, and trazodone as part of a detoxification programme 4 days later acute hepatitis and cholestasis was noted and trazodone and clonidine were withdrawn with subsequent resolution of symptoms. The authors considered that trazodone was probably the causative agent.

Effects on mental state. There have been reports of mania, and psychosis with hallucinations associated with the use of trazodone in depressed patients delirium in patients with bulimia nervosa and possible psychosis or hypomania in a patient receiving trazodone-tryptophan treatment for aggression have also been reported.

Effects on sexual function. Trazodone is notable for the number of reports of priapism associated with its use. In most cases, priapism occurred during treatment with standard doses after 1 to 3 weeks of therapy. Several patients required surgery and recovery was not always complete. A review of priapism induced by psychotropic drugs proposed that the effect was related to blockade of alpha-adrenoceptors in the absence of sufficient antimuscarinic activity, criteria fulfilled by the pharmacological profile of trazodone.

Inhibition of ejaculation, and an increase in libido in women and men have also been reported with trazodone therapy. There have also been reports of trazodone-associated priapism of the clitoris.’

Effects on the skin. Individual reports of adverse dermatological reactions to trazodone have included leucocytoclastic vasculitis, erythema multiforme, and exacerbation of psoriasis.

Epileptogenic effect. Tonic-clonic seizures related to trazodone therapy have been reported in 2 patients with no history of seizure disorders.

Overdosage. Reviews have indicated that the incidence of serious toxicity from trazodone overdose alone was low compared with tricyclic antidepressant overdose.

In a review covering 149 overdose cases, only 10 deaths had been reported and in only 1 case was trazodone the sole agent reported to be ingested in this case autopsy revealed an acute myocardial infarction after the patient was stable. The remaining 9 patients also had histories of ingestion of unknown quantities of alcohol, benzodiazepines, or other sedative-hypnotics that may have contributed to their demise. In the surviving 139 patients, 2 cases of respiratory arrest, 2 cases of right bundle branch block, and one case each of priapism, seizure, atrioventricular block, and T-wave inversion were reported. The remaining patients had minor CNS-depressant effects.

In a second review of 88 cases of overdose, no fatalities occurred in the 39 cases where trazodone alone was ingested. However 9 deaths occurred in the remaining 49 cases where trazodone was ingested with other drugs or alcohol.

For a discussion of choice of antidepressant with respect to toxicity in overdosage, see under Depression.

Precautions

Trazodone should be used with caution in patients with cardiovascular disorders, such as ischaemic heart disease, and its use is not recommended in the immediate recovery phase after myocardial infarction. Similarly, it should be used with caution in patients with epilepsy and severe hepatic or renal impairment. Trazodone should be stopped immediately if patients develop signs of hepatic dysfunction or blood dyscrasias. Patients developing inappropriate or prolonged penile erections should also stop trazodone immediately.

Patients should be closely monitored during early antidepressant therapy until significant improvement in depression is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders.

Drowsiness often occurs at the start of trazodone therapy and patients, if affected, should not drive or operate machinery.

As with other antidepressants, trazodone therapy should be withdrawn gradually.

Breast feeding. The American Academy of Pediatrics considers that, although the effect of trazodone on breast-fed infants is unknown, its use by mothers during breast feeding may be of concern since antidepressant drugs do appear in breast milk and thus could conceivably alter CNS function in the infant both in the short and long term.

A study of 6 women each given a single 50-mg dose of trazodone concluded that the exposure of infants to trazodone via breast milk was very small. However, trazodone has been reported to form an active metabolite and it was not known to what extent this metabolite distributed into breast milk.

Porphyria. Trazodone hydrochloride is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Pregnancy. UK licensed drug information states that trazodone should be avoided during pregnancy that for the USA indicates that trazodone should only be used if the benefits to the mother outweigh the risks to the fetus.

For details of outcome in a multicentre study on the use of trazodone during pregnancy, see under Nefazodone.

Interactions

Trazodone should not be given to patients receiving MAOIs or for at least 14 days afterwards. It has also been recommended that any drug liable to provoke a serious reaction (e.g. phenelzine) should not be given within one week of stopping trazodone therapy. For further details of combination antidepressant therapy, see Antidepressants under Interactions of Phenelzine.

It is considered unlikely that trazodone will alter the effects of antihypertensives such as guanethidine some interaction may, however, occur with clonidine. The dose of other antihypertensives may need to be reduced if used with trazodone.

The sedative effects of trazodone may be enhanced by alcohol or other CNS depressants. The potential for interaction between trazodone and general anaesthetics or muscle relaxants exists and some licensed product information recommends that trazodone should be stopped before elective surgery for as long as clinically feasible.

Trazodone may increase plasma concentrations of digoxin or phenytoin and some product information recommends monitoring their serum concentrations if used with trazodone.

Trazodone is metabolised by the cytochrome P450 isoenzyme CYP3A4 and inhibitors of this isoenzyme may limit the elimination of trazodone. Consequently, trazodone may need to be given in reduced doses with drugs known to be potent inhibitors of CYP3A4 such as the azole antifungals itraconazole and ketoconazole, and the HIV-protease inhibitors. CYP3A4 inducers such as carbamazepine may reduce the plasma concentrations of trazodone.

Anticoagulants. For the effect of trazodone on warfarin.

Antiepileptics. Antidepressants may antagonise the activity of antiepileptics by lowering the convulsive threshold. Trazodone may increase plasma concentrations of carbamazepine and phenytoin. Some licensed product information recommends monitoring concentrations of phenytoin if used with trazodone.

Antivirals. In a small study in 10 subjects, the use of low-dose ritonavir (200 mg twice daily for 2 days) with trazodone (50 mg once daily) more than halved the clearance of trazodone resulting in significant increases in its peak plasma concentrations. Adverse reactions were noted in 3 subjects and included dizziness, nausea, hypotension, and syncope.

Ginkgo biloba. Coma, reversible by flumazenil, developed in an 80-year-old woman with Alzheimer’s disease 3 days after starting to take a preparation of ginkgo biloba with trazodone.

Pharmacokinetics

Trazodone is readily absorbed from the gastrointestinal tract although absorption is affected by food. When trazodone is taken shortly after a meal there may be an increase in the amount absorbed, a decrease in the maximum concentration, and a lengthening in the time to maximum concentration compared with the fasting state peak plasma concentrations occur about one hour after a dose when taken on an empty stomach and after about 2 hours when taken with food. Protein binding is reported to be about 89 to 95%.

Trazodone is extensively metabolised in the liver and paths of metabolism include Af-oxidation and hydroxylation. It is metabolised to its active metabolite m-chlorophenylpiperazine via the cytochrome P450 isoenzyme CYP3A4. Trazodone is excreted mainly in the urine almost entirely in the form of its metabolites, either in free or in conjugated form: some is excreted in the faeces via biliary elimination. The elimination of trazodone from the plasma is biphasic, with a terminal elimination half-life of 5 to 9 hours.

Small amounts of trazodone are distributed into breast milk.

Uses and Administration

Trazodone is a triazolopyridine antidepressant chemically unrelated to other classes of antidepressants. It blocks the reuptake of serotonin at presynaptic neurones and has an action at 5-HT1 receptors. Trazodone is also an antagonist at 5-HT_2A/2C receptors. Unlike the tricyclic antidepressants, trazodone does not inhibit the peripheral reuptake of noradrenaline, although it may indirectly facilitate neuronal release. Trazodone blocks central a_radrenoceptors and appears to have no effect on the central reuptake of dopamine. It does not appear to have very significant antimuscarinic properties, but has a marked sedative action.

For the treatment of depression trazodone hydrochloride is given in oral doses of 150 mg daily initially total daily dosage may be increased by 50 mg every 3 or 4 days up to 300 to 400 mg daily if necessary. The daily dosage may be divided throughout the day after food or be given as a single dose at night. Divided daily dosages of up to 600 mg may be given in severe depression in hospitalised patients. A suggested initial dose in elderly and other susceptible patients is 100 mg daily, and total daily doses above 300 mg are unlikely to be needed in these patients.

In the treatment of anxiety, trazodone hydrochloride is given in an initial oral dose of 75 mg daily increasing to 300 mg daily if necessary. As with other antidepressants, trazodone should be withdrawn gradually.

Depression. As discussed on site, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. Trazodone has a different biochemical profile from both the tricyclics and the SSRIs.

Disturbed behaviour. Trazodone has produced beneficial results when tried in various disorders for the control of symptoms such as agitation, aggression, and disruptive behaviour. Some also consider that, in the management of dementia, trazodone might be worth trying in nonpsychotic patients with disturbed behaviour, especially those with mild symptoms or those intolerant of or unresponsive to antipsychotics. However, the evidence for such use is poor a systematic review on the use of trazodone in the treatment of behavioural and psychological symptoms of dementia found that the evidence from randomised, placebo-controlled studies was insufficient for any recommendations to be made. The risk of adverse effects such as sedation and orthostatic hypotension, which may be particularly problematic in the elderly, should also be considered.

Sexual dysfunction. Priapism can occur as an adverse effect of trazodone (see Effects on Sexual Function in Adverse Effects, above) and this has led to trials of oral trazodone for the treatment of erectile dysfunction. Positive responses have been reported, both with yohimbine and alone. However, there appear to have been few controlled studies and a systematic review considered some of these to be either small, brief, or methodologically weak. Meta-analysis of data from 6 studies did notfind trazodone to be superior to placebo but subgroup analysis possibly suggested a better outcome in patients with psychogenic erectile dysfunction and in those given doses of 150 to 200 mg daily.

Substance dependence. The antidepressant, anxiolytic, and sedative properties of trazodone have been reported to have been useful when tried in patients having withdrawal syndromes from a variety of substances including alcohol, cocaine, and benzodiazepines.

Preparations

The United States Pharmacopeia 31, 2008: Trazodone Hydrochloride Tablets.

Proprietary Preparations

Argentina: Taxagon

Austria: Trittico

Belgium: Nestrolan Trazolan

Brazil: Donaren

Canada: Desyrel Trazorel †

Chile: Diapresan Trant Trittico Tronsalan

Czech Republic: Trittico AC

Finland: Azona

Germany: Thombran

Greece: Trittico

Hong Kong: Trittico

Hungary: Depsan Trittico

Ireland: Molipaxin

Israel: Depyrel Trazodil Trittico

Italy: Trittico

Mexico: Sideril

The Netherlands: Trazolan

Poland: Trittico

Portugal: Trazone Triticum

Russia: Trittico

South Africa: Molipaxin

Singapore Trittico

Spain: Deprax

Switzerland: Trittico

Thailand: Desirel Trazo

Turkey: Desyrel

UK: Molipaxin

USA: Desyrel

Venezuela: Trittico.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.

Answer. There are many antidepressants that do not increase blood pressure for MOST adults, but there are always exceptions. For example, the older tricyclic antidepressants (such as imipramine or nortriptyline) typically result in decreased blood pressure. (Children can sometimes have hypertensive reactions to some of the tricyclics, as do a minority of adults). The new antidepressant nefazodone (Serzone) is also unlikely to raise blood pressure, and often will reduce it. This is also true of its close cousin trazodone (Desyrel). Although the MAOIs (monoamine oxidase inhibitors) are associated with hypertensive reactions (very high blood pressure) when an individual goes off the special MAOI diet, these drugs also generally reduce blood pressure. The antidepressants that are most likely to raise blood pressure are venlafaxine (Effexor) and bupropion (Wellbutrin), but this reaction can often be controlled by adjusting the patient’s blood pressure medication.

There is a new antidepressant called citalopram that is expected to be released shortly. It is in the same general class as Prozac and Zoloft (the “SSRIs”), and I have not seen any data yet on its blood pressure effects. My suggestion is to discuss the use of either nefazodone (Serzone) or trazodone (Desyrel) with your doctor.