Trazodone side effects and how to avoid them

Trazodone side effects include weight gain, sexual dysfunction, and urinary incontinence

Common trazodone side effects | Serious side effects | Weight gain | Sexual dysfunction | Urinary incontinence | Side effects timeline | Contraindications | Warnings | Interactions | How to avoid side effects | How to treat side effects

People are prescribed trazodone hydrochloride to help with depression or anxiety. Trazodone is an older generation antidepressant that is approved to treat major depressive disorder. It has been used to help with anxiety as well, but most commonly is used off-label to take advantage of its tendency to cause sedation and help with insomnia. It belongs to a group of drugs called serotonin antagonist and reuptake inhibitors, drugs that alter brain chemistry to permit greater control over mood. Trazodone affects the body in the same way, so side effects are similar to its better-known cousins like Paxil (paroxetine) and Prozac (fluoxetine). Trazodone is only available as a generic but used to be sold under the brand names Desyrel and Oleptro.

Common side effects of trazodone

The most commonly experienced side effect of trazodone is drowsiness, affecting almost one in four people taking the drug. About one in five people have reported dizziness or high blood pressure. Other common side effects include:

• Dry mouth
• Nervousness
• Tiredness
• Nausea or vomiting
• Headache
• Constipation
• Low blood pressure
• Aches and pains
• Problems with coordination
• Abdominal pain
• Blurred vision
• Confusion
• Problems with concentration
• Tremors
• Red and itchy eyes
• Nasal or sinus congestion
• Edema
• Skin reactions
• Disorientation
• Feeling bad
• Fainting
• Muscle pain
• Trouble sleeping
• Sexual dysfunction
• Weight changes

Serious side effects of trazodone

The most serious adverse effects of trazodone are relatively rare and include:

• Suicidal thoughts and behaviors
• Worsening of depression
• Serotonin syndrome
• High blood pressure
• Orthostatic hypotension
• Heart attack
• Heart rhythm problems
• Angle-closure glaucoma
• Dangerously low sodium levels
• Seizures
• Painful erections (priapism)
• Bleeding
• Withdrawal
• Severe allergic reactions

Weight gain

In clinical trials, approximately one in a hundred people taking trazodone experienced weight gain. Later research indicates the incidence may be as high as 5%, although research suggests that as much as 6% of patients experience weight loss when taking trazodone. No matter what the case, however, always get medical advice whenever weight goes up or down unintentionally when taking a drug. A nutritionist’s advice may be needed.

Sexual dysfunction

Nearly every person who takes an SSRI will experience some reduction in genital sensitivity. For this reason, SSRIs are frequently used off-label to treat premature ejaculation. Impotence, however, is a rare problem in people taking trazodone, occurring in less than 2% of participants in the initial clinical trials. Research indicates that around 1.5% of patients will experience a decrease in sexual desire and less than 1% will have problems with orgasms because of genital numbing. The good news is that most people will experience a return of genital sensitivity, sexual desire, and sexual function when trazodone is stopped. If there are problems with sexual function, get medical advice from the prescriber.

Urinary incontinence

People taking trazodone only rarely experience urinary incontinence as a side effect. It is a reported side effect, but the incidence is between 0% and 1%, depending on the study. If urinary incontinence is a problem, keep in mind that there may be other causes besides trazodone. Talk to a healthcare provider about the best way to proceed.

Trazodone side effects for females

Are women more likely to experience trazodone side effects than men? This question hasn’t been answered. The best that can be said is that people will have individual responses to trazodone. Any adverse effects have to be balanced against the good the drug does, and SSRIs seem to benefit women more than men, though we don’t know why.

How soon do trazodone side effects start?

The serotonin effects of trazodone occur within half an hour of taking a dose, so side effects such as drowsiness, dry mouth, dizziness, trouble sleeping, nausea, urinary incontinence, blurred vision, genital numbing, and similar side effects are sometimes experienced early or even after the first dose. Other side effects, such as sexual dysfunction or weight changes, may develop and worsen over time. Among serious side effects, heart problems can occur early and unexpectedly, particularly changes in the heart’s rhythm. Suicidality and worsening of depression may take longer to manifest but should be monitored for as soon as therapy is started.

How long do trazodone side effects last?

Many of the side effects of trazodone will moderate as time goes by. Trazodone is intended as a time-limited treatment, so most side effects, including sexual dysfunction, can be expected to resolve shortly after the drug is discontinued. However, some problems may take a while to get better, such as weight changes or severe heart problems.

What are the long-term side effects of trazodone?

Even when trazodone is discontinued, people may experience long-term problems from taking the drug. In rare cases, sexual dysfunction persists for a long time after an SSRI is discontinued, a medical condition known as post-SSRI sexual dysfunction. Some serious side effects, such as heart attack, may entail lifelong problems. 

Trazodone contraindications

Because of certain medical conditions, some people cannot safely take trazodone. These include anyone allergic to the drug or who has recently experienced a heart attack.

The FDA has approved trazodone only for use in adults. Safety and efficacy have not been established in patients under 18 years of age. However, some healthcare professionals may prescribe it off-label to children and adolescents. If so, they will need to be closely monitored for worsening depression and suicidality. Trazodone is used with caution in seniors, but there is no evidence of any increased risk of side effects. 

There is no evidence that trazodone is unsafe for women who are pregnant or breastfeeding. Although trazodone does show up in breast milk, there is no evidence that it will harm a nursing baby. Major depressive episodes can be a risk during pregnancy, and the use of trazodone to any antidepressant must consider the benefits to the health of the mother against the unknown risk to the baby.

Trazodone warnings

As with all prescription drugs, trazodone has risks. People need to be aware of these and, in some cases, be more closely monitored for side effects when taking this drug.

Suicidality

The FDA has put a black box warning on trazodone’s drug information sheet warning about the risk of suicidal thoughts and behaviors, particularly in children and young adults. These patients will need to be monitored closely for behavior changes.

Abuse and dependence

The U.S. Food and Drug Administration (FDA) does not consider trazodone to be a drug with the potential for abuse or physical dependence.

Overdose

An overdose of trazodone will require emergency medical care. Depending on the dose, it can cause severe problems that could be life-threatening, particularly when taken with alcohol or sedatives. The most common symptoms of a trazodone overdose are drowsiness or vomiting. 

Withdrawal

The sudden discontinuation of trazodone or any other SSRI can cause withdrawal symptoms such as excessive sweating, nausea, irritability, anxiety, agitation, dizziness, confusion, headache, mood swings, ringing in the ears, and even seizures. When trazodone therapy needs to stop, the doses will gradually decrease over a period of weeks.

Restrictions

Trazodone could worsen some medical conditions. People with these medical conditions can take trazodone, but they will need to be monitored more closely for problems. These include:

• Heart disease or other heart problems
• Electrolyte imbalances
• Bipolar disorder
• Bleeding problems
• Seizure disorders
• Narrow angles or a history of angle-closure glaucoma
• Dehydration
• Liver disease
• Renal impairment

Trazodone interactions

Trazodone can also cause problems when combined with other drugs. In some cases, these issues can be risky enough that healthcare professionals never prescribe trazodone with these other drugs. At the top of the prohibited list are monoamine oxidase inhibitors (MAOIs), a small family of drugs that treat depression or Parkinson’s disease. Allow for at least 14 days to lapse between stopping MAOI treatment and initiating trazodone. Trazodone is also never combined with the antipsychotic medications pimozide or thioridazine, or the HIV/AIDS drug saquinavir.

Because of the risk of serotonin syndrome, a hazardous elevation of serotonin in the brain, healthcare professionals are cautious about combining trazodone with other serotonin-increasing drugs including other antidepressant medications, migraine drugs (triptans), antipsychotics, opioids, anxiety medications, anticonvulsants, anti-nausea drugs, lithium, and some common over-the-counter supplements such as St. John’s wort or tryptophan.

When some drugs are combined with trazodone, the risk of serious adverse effects increases. Combining these drugs will require closer monitoring and vigilance. These include:

• Blood thinners
• NSAIDs
• Sedatives and other central nervous system (CNS) depressants
• Drugs that affect heart rhythm
• Drugs that speed up or slow down the body’s metabolism of trazodone.

How to avoid trazodone side effects

Most people taking trazodone will experience transient side effects. Not all are avoidable, but there are a few ways to minimize problems.

1. Take trazodone as directed

Follow the instructions given by the prescribing healthcare provider. Most people will take a 50–100 mg dose two or three times daily with food. At this frequency, it’s easy to miss a dose or take an extra dose, so it helps to use an alarm or app to make sure doses are taken correctly. If a dose is missed, take it as soon as it’s remembered. If it’s nearly time to take the next dose, skip the missed dose and take the next dose as scheduled. 

2. Inform the prescriber about all medical conditions

The first and best way to avoid problems taking trazodone is to make sure the prescribing healthcare provider has a complete medical history before the first pill is taken. Don’t leave anything out, but make sure that the prescriber knows about:

• Suicidal thoughts
• Heart disease
• Heart rhythm problems, particularly a problem called QT prolongation
• A history of bleeding or blood clotting problems
• A history of seizures
• Dehydration
• Low sodium
• Glaucoma
• Narrow angles in the eye
• Mania or bipolar disorder
• Liver problems
• Pregnancy or pregnancy plans
• Breastfeeding or breastfeeding plans

3.

Tell the doctor about all medications being taken

Drug interactions are another source of side effects when taking trazodone, so tell the prescribing healthcare professional about all prescription drugs, over-the-counter medications, and supplements being taken, especially:

• MAO inhibitors
• Antidepressant medications including other SSRIs, SNRIs, and tricyclic antidepressants
• Medicines that treat anxiety, schizophrenia, or other mental health conditions 
• Seizure medications
• Migraine medications called triptans
• Opioids
• Amphetamines or ADHD medications
• Heart rate medications
• Blood thinners such as warfarin
• NSAIDs
• Over-the-counter supplements such as St. John’s wort or tryptophan

4. Do not quit taking trazodone

If there are problems, talk to a healthcare professional before quitting trazodone. Sudden discontinuation—particularly after months of treatment—could lead to unpleasant withdrawal symptoms.

5. Avoid alcohol

Alcohol will worsen many of the sedative effects of trazodone such as sleepiness, fatigue, and dizziness.

6. Be careful about driving and other risky activities

Speaking of sedative effects, trazodone could make driving and other risky activities more dangerous. Healthcare professionals advise that these activities be put on hold for a few days when first taking trazodone. This allows people to determine if they can drive or perform other activities safely.

7. Avoid NSAIDs

To avoid abdominal problems and possible bleeding events, avoid NSAID pain relievers such as aspirin or ibuprofen. If possible, use acetaminophen instead.

8. Eat a healthy diet

To avoid or minimize weight changes, eat a healthy diet. If weight goes up or down unintentionally, talk to a dietitian or nutritionist.

How to treat side effects of trazodone

Most people will only experience minor problems taking trazodone. The most common is sleepiness and dizziness due to the sedative effects of the drug. Many of these transient side effects get better over time as the body adapts to the drug. Some can be managed by making simple lifestyle changes. Others might require medical attention.

• Sleepiness, dizziness, lightheadedness. These side effects can’t always be avoided but can be managed by removing obstacles in the house that can cause falls, moving carefully, and modifying daily activities.
• Weight changes. If weight goes up or down, talk to a dietitian or nutritionist about the best diet to counter these weight changes.
• Worsening depression or suicidal thoughts

Immediately talk to the prescriber or another mental health professional. Trazodone may need to be stopped.

• Signs of heart problems. Immediately get medical help for any sign of heart problems such as racing heartbeats, fluttering heartbeats, slowed heart rate, shortness of breath, or fainting.
• Low sodium. Call a healthcare professional at any sign of low sodium such as confusion, headache, weakness, or coordination problems.
• Serotonin syndrome. A potentially severe side effect, serotonin syndrome does require emergency medical help. The signs are psychiatric and neurological: agitation, restlessness, hallucinations, tremors, stiff muscles, and problems with coordination. The usual treatment is to stop taking drugs like trazodone that raise serotonin.

Sources

• Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases, The International Journal of Risk & Safety in Medicine
• Gender difference in antidepressant drug response, International Review of Psychiatry
• Post-SSRI sexual dysfunction & other enduring sexual dysfunctions, Epidemiology and Psychiatric Sciences
• Trazodone, Epocrates
• Trazodone hydrochloride drug summary, Prescriber’s Digital Reference
• Trazodone hydrochloride prescribing information, U. S. National Library of Medicine
• Women and depression: Does gender matter?, U.S. Pharmacist

Side effects of trazodone – NHS

Like all medicines, trazodone can cause side effects in some people, but many people have no side effects or only minor ones.

Common side effects

Some of the common side effects of trazodone will gradually get better as your body gets used to it. There are things you can do to help cope with them:

Feeling sleepy or tired

Take trazodone in the evening and try to cut down the amount of alcohol you drink. If you take trazodone twice a day, talk to your doctor. Feeling sleepy should become less of a problem after a few days as your body gets used to the medicine. Do not drive, ride a bike or use tools or machinery if you’re feeling sleepy or tired.

Headaches

Make sure you rest and drink plenty of fluids. Try not to drink too much alcohol. Talk to your doctor if the headaches last longer than a week or are severe.

Feeling sick (nausea)

Try taking trazodone with or after food to see if that helps. It’s best to avoid rich or spicy food while you’re taking this medicine.

Constipation

Eat more high-fibre foods, such as fresh fruit and vegetables and cereals. Try to drink several glasses of water every day. If you can, it may also help to do some exercise.

A dry mouth

Try sugar-free gum or sugar-free sweets.

Tell your doctor if this advice does not help or the side effects do not go away.

Serious side effects

Serious side effects are rare and happen in less than 1 in 1,000 people.

Call your doctor or call 111 now if:

• the whites of your eyes turn yellow, or your skin turns yellow although this may be less obvious on brown or black skin – this can be a sign of liver problems
• you have difficulty pooing (constipation) or you’re unable to pee
• you are bruising more easily than usual or have unexplained bruising
• you get more infections than usual, such as a sore throat or skin infections
• you have a fast, slow or abnormal heartbeat

Immediate action required: Call 999 or go to A&E now if you have:

• a long-lasting and painful erection that lasts longer than 2 hours – this may happen even when you’re not having sex
• a seizure or fit
• thoughts of self-harming or ending your life

Find your nearest A&E

Serious allergic reaction

In rare cases, it’s possible to have a serious allergic reaction (anaphylaxis) to trazodone.

Immediate action required: Call 999 now if:

• your lips, mouth, throat or tongue suddenly become swollen
• you’re breathing very fast or struggling to breathe (you may become very wheezy or feel like you’re choking or gasping for air)
• your throat feels tight or you’re struggling to swallow
• your skin, tongue or lips turn blue, grey or pale (if you have black or brown skin, this may be easier to see on the palms of your hands or soles of your feet)
• you suddenly become very confused, drowsy or dizzy
• someone faints and cannot be woken up
• a child is limp, floppy or not responding like they normally do (their head may fall to the side, backwards or forwards, or they may find it difficult to lift their head or focus on your face)

You or the person who’s unwell may also have a rash that’s swollen, raised, itchy, blistered or peeling.

These can be signs of a serious allergic reaction and may need immediate treatment in hospital.

Sexual side effects

Trazodone can cause problems with ejaculation. Some people say it gives them a higher sex drive, others say it makes it lower.

Other side effects

These are not all the side effects of trazodone. For a full list, see the leaflet inside your medicines packet.

Information:

You can report any suspected side effect using the Yellow Card safety scheme.

Visit Yellow Card for further information.

Page last reviewed: 9 March 2022

Next review due: 9 March 2025

Trazodone (Trittico)

Trazodone is an antidepressant , belongs to the class of SSRIs, has a sedative effect, is used in the treatment of depression

Analogues (generics, synonyms) 90 010

• Trittiko;
• Azona;
• Beneficiary.

Available by prescription, listed in the regular reporting register . Active ingredient: Trazodonum

Prescription form 107-1/y
Latin prescription:
Rp.:Trazodoni 0.1
D.t.d. No. 25 in caps.
S.: Inside, 1 caps. 1 time per day before bed.

Presentation
Long-acting tablets, white or white with a yellowish tint, oval, biconvex, with two parallel notches on both sides.

1 tab. trazodone hydrochloride 150 mg.
Excipients: sucrose – 84 mg, carnauba wax – 24 mg, povidone – 24 mg, magnesium stearate – 6 mg.

10 pcs. – blisters (2) – packs of cardboard.
10 pcs. – blisters (6) – packs of cardboard.

Mechanism of action
SARI antidepressant is a serotonin reuptake inhibitor and 5HT2 receptor antagonist.

Therapeutic indications
Major depressive episodes. Mixed states of depression and anxiety, with or without secondary insomnia.

Directions for use
Orally, swallowed whole, with or without food, with plenty of liquid. The dosage is adjusted by the doctor depending on the disease. The initial daily dose is 150-300 mg divided into 3 doses. Maximum up to 600 mg/day.

Contraindications
Hypersensitivity. Poisoning by alcohol or sleeping pills. Acute myocardial infarction.

Warnings and Precautions
Children <18 years of age, increased risk of suicidal behavior and insufficient safety data. Careful observation, especially in the initial stages and when changing the dose, the risk of suicide / suicidal thoughts. Schizophrenia or other psychotic disorders, risk of worsening psychotic symptoms. Known cardiovascular disorders, including QT interval prolongation. Simultaneously with substances that prolong the QT interval, such as: antiarrhythmic drugs of class IA and III, antipsychotics (derivatives of phenothiazine, pimozide, haloperidol), tricyclic antidepressants, some antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalarial treatment, especially halofantrine), astemizole, mizolastine. Periodic control in: irresistible. heart failure, angina, conduction disturbances or AV block of varying degrees, arrhythmias, recent myocardial infarction, p. congenital long QT interval or bradycardia, epilepsy (avoid sudden increase or decrease in dose), intraocular or intraocular injections, hyperthyroidism, prostatic hypertrophy, acute angle-closure glaucoma, increased intraocular pressure. The elderly are more sensitive to anticholinergic effects. With long-term treatment, gradually reduce the dose to avoid withdrawal symptoms. Suppress that one. when jaundice occurs. The risk of developing serotonergic s. / malignant neuroleptic p.

Liver failure
Caution in severe liver disease, consider periodic monitoring of liver function.

Renal failure
Caution in severe disease.

Interactions
Increases the sedative effect of: alcohol, antipsychotics, hypnotics, sedatives, anxiolytics and antihistamines.
The effect is enhanced by: erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodone.
The effect is reduced by: carbamazepine.
Enhances the action of: muscle relaxants, volatile anesthetics.
Risk of developing serotonin syndrome when taking tricyclic antidepressants.
Increased risk of St. John’s wort toxicity.

Pregnancy
There are limited data (<200 term pregnancies) on the use of trazodone in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/intrauterine development, childbirth or postpartum development at therapeutic doses. As a precautionary measure, it is preferable to avoid the use of trazodone during pregnancy. Appointment to pregnant women should be administered with caution. When using trazodone before delivery, newborns should be monitored for the occurrence of withdrawal syndromes.
Epidemiological evidence suggests that the use of SSRIs during pregnancy, especially in its advanced stages, may increase the risk of persistent pulmonary hypertension in the newborn (PPNH). The observed risk was approximately 5 per 1000 pregnancies. In the general population, there are 1 or 2 cases of EUI for every 1000 births.
Although there are no studies investigating an association with trazodone treatment, this potential risk cannot be ruled out.

Breast-feeding
It is not known if trazodone and its metabolites are excreted in breast milk. A risk to the infant should not be excluded. The decision to continue/discontinue breastfeeding or continue/discontinue trazodone therapy should be made taking into account the benefits of breastfeeding for the baby and the benefits of trazodone treatment for the mother.

Effects on ability to drive
May cause sedation, dizziness. Therefore, patients should be made clear that if they experience sedation or dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.

Adverse reactions
Frequency unknown: blood dyscrasias. Allergic reactions. Syndrome of insufficient secretion of antidiuretic hormone. Hyponatremia, weight loss, anorexia, increased appetite. Suicidal behavior or suicidal thoughts, confusion, insomnia, disorientation, mania, restlessness, nervousness, agitation, frustration, aggressive reaction, hallucinations, nightmares, decreased libido, withdrawal symptoms. Serotonin syndrome, convulsions, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness, agitation, decreased mental acuity, tremor, blurred vision, memory impairment, myoclonus, expressive aphasia, paresthesia, dystonia, taste disturbance. Cardiac arrhythmias, bradycardia, tachycardia, ECG abnormalities. Orthostatic hypotension, hypertension, syncope. Nasal congestion, shortness of breath. Nausea, vomiting, dry mouth, constipation, diarrhea, dyspepsia, abdominal pain, gastroenteritis, increased salivation, colonic paralysis. Liver dysfunction, intrahepatic cholestasis. Skin rash, itching, hyperhidrosis. Pain in the extremities, back pain, myalgia, arthralgia. Urination disorder. Priapism. Weakness, swelling, flu-like symptoms, fatigue, chest pain, fever.

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9 0000 Trazodone (Trittico, Azona) – leaflet: indications, contraindications, side effects

The purpose of the current publication is to review more recent clinical data on the use of trazodone in depression, focusing on the approved dose of 300 mg / day, and to discuss its place in current strategies for the treatment of depression and related conditions, as well as for off-label indications – insomnia and anxiety.

Trazodone is available in many countries around the world in a variety of formulations, including immediate release (IR) tablets, extended release tablets and, in some countries, even as oral drops and injection.

Recently, a new once-daily extended-release formulation of trazodone (150 mg and 300 mg halved tablets) has been developed. This patented delivery technology is able to control the release of trazodone within 24 hours and was developed in an attempt to improve patient adherence to therapy without loss of efficacy and improve tolerability by avoiding the early high plasma concentration peaks seen with conventional IR drugs. Trazadone extended release was approved in the US in early 2010 for the treatment of patients with depression and is in the process of being approved in many European countries.

Through combined serotonergic receptor antagonism and serotonin reuptake inhibition (SSRI), trazodone has also demonstrated unique therapeutic flexibility, leading to its potential use in a wide range of depression-related comorbidities and off-label indications, including insomnia, anxiety, dementia, Alzheimer’s disease, substance abuse, schizophrenia, bulimia, and fibromyorrhea. algia.

PubMed/MEDLINE searched the literature using the following keywords: “trazodone” and “major depressive disorder” as free text. The search was limited to fully published randomized controlled trials, in English only. Each article was assessed for relevance, and only articles published after 1981 (US approval date) were included. Separate searches have been made for the use of trazodone for other indications, including insomnia and anxiety. Again, only fully published randomized controlled trials were included.

Mechanisms of action and pharmacological properties of trazodone

Trazodone is a derivative of triazolopyridine. Although its pharmacological effects in humans are not fully understood, trazodone is believed to have more than one mechanism of therapeutic action, making it a multifunctional drug.

Trazodone: antidepressant, antagonist, serotonin reuptake inhibitor (SSRI)

Trazodone is the first antidepressant with a dual mechanism of action involving serotonin transporter (SERT) inhibition and serotonin type 2 (5-HT2) receptor antagonism (both 5-HT2A and 5-HT2C receptors). Preclinical evidence suggests that the antidepressant activity of SSRIs and SNRIs is most likely due to blockade of serotonin, whereby serotonin exerts its 5-HT1A receptor agonist action. However, this serotonin agonist effect also affects other serotonin receptor subtypes, such as the 5-HT2A and 5-HT2C receptors, which are thought to be responsible for the side effects often associated with SSRI and SNRI therapy, including insomnia, sexual dysfunction, and anxiety. Unlike SSRIs and SNRIs, serotonin antagonist/reuptake inhibitors (SSRIs) such as trazodone provide simultaneous inhibition of SERT and 5-HT2A and 5-HT2C receptor antagonism, avoiding the tolerability problems often associated with 5-HT 2A/2C stimulation. In addition, there have been suggestions that concurrent 5-HT2A/2C antagonism and serotonin inhibition may have a synergistic effect that enhances the antidepressant activity of SARIs and may improve treatment tolerability.

Moreover, trazodone exhibits α1- and α2-adrenergic and histamine H1 receptor antagonistic properties with minimal anticholinergic effects. It is also well known that at low doses (25-100 mg) trazodone has therapeutic activity as a hypnotic. It is known that the action of several neurotransmitter systems, including serotonin, norepinephrine, dopamine, acetylcholine and histamine, are involved in the excitation mechanism. Thus, arousal can be effectively disrupted and sleep induced by inhibition of several of these neurotransmitter systems. The effectiveness of trazodone in this regard may be explained by its ability to inhibit H1 receptors, and the sleep-inducing effect of H1 receptor blockade may be enhanced by simultaneous antagonism of 5-HT2A and α-adrenergic receptors.

Dosage and method of administration

According to the relevant summary of the characteristics of the drug trazodone, therapy should be started with an evening dose (initial dose of 75-150 mg at bedtime). Subsequently, the dose can be increased every 3 days to 300 mg/day, administered in repeated doses after meals (trazodone IR), twice daily (extended release trazodone) or once daily, preferably at bedtime. In hospitalized patients, the dose may be further increased to 600 mg/day on repeated doses. For elderly patients, the initial dose should be reduced to 100 mg/day.

Extended release formulations

In the 1980s, extended-release tablets of trazodone (Roussel Laboratories Ltd., Guildford, UK) [75 and 150 mg tablets] were developed to limit the early and relatively high peak plasma concentrations that are observed with IR tablets. This high peak plasma concentration may be associated with side effects such as drowsiness or hypotension, especially during the first week of treatment. These side effects may limit treatment tolerability and adherence, thereby limiting the use of the therapeutic dose (up to 300 mg/day) in depressed patients.

As reported in the SPC, after a single oral dose of 100 mg of fast-release trazodone, a maximum plasma concentration (max) of 1.2 μg / ml of the drug is achieved, and the time to reach the maximum plasma concentration (t max) is 1 hour. With prolonged release of trazodone after a single oral administration of 75 mg, a maximum concentration of about 0.7 μg / ml is reached with a maximum duration of 4 hours. After a single oral administration of 150 mg of prolonged release trazodone, max Cmax is about 1.2 μg / ml, and max – 4 hours after administration. The half-life is approximately 12 hours.

The half-life of trazodone IR is relatively short (6.6 hours after a single 100 mg dose), so repeated daily dosing is often used to achieve sufficient dose levels for depressed patients, but this dosing regimen can be inconvenient and may result in missed doses and decreased compliance.

More recently, a new once-daily extended-release formulation of trazodone has been developed to further enhance treatment adherence at therapeutic doses and reduce peak plasma concentration and dosing frequency compared to the conventional fast-release formulation. 75 mg increments every 3 days.

Efficacy and tolerability of trazodone in depression

Several direct studies have demonstrated comparable efficacy of trazodone with other drug classes, including TCAs (amitriptyline and imipramine), SSRIs (fluoxetine, paroxetine, sertraline, citalopram and escitalopram), SNRIs (venlafaxine and mirtazapine) and norepinephrine and dopamine reuptake inhibitors (bupropion). Randomized controlled trials of trazodone in elderly people with depression published since 1981 years old

Trazodone versus tricyclic antidepressants (TCAs)

In a series of comparative trials conducted in the 1980s, short-term therapy (4–6 weeks) with trazodone (100–400 mg) was found to be comparable in efficacy to TCAs such as amitriptyline and imipramine. An early randomized, double-blind, placebo-controlled study of elderly patients with unipolar depression demonstrated that the therapeutic efficacy of trazodone was superior to placebo and comparable to that of imipramine after 4 weeks of treatment. A double-blind, randomized trial of trazodone in elderly patients with severe depression reported significant improvements in both the Hamilton Depression Rating Scale (HAM-D) and the Geriatric Depression Scale (GDS), which were similar to those observed in patients treated with amitriptyline and mianserin. In addition, HAM-D and visual analogue scale (VAS) scores were similar between trazodone and amitriptyline in a study of elderly depressed patients.

Trazodone (Trittico) versus second-generation antidepressants

There have been several direct trials of trazodone (dose range 150-450 mg) and second-generation antidepressants in patients with depression. An analysis of head-to-head trials comparing different second-generation antidepressants found that the relative benefit in terms of response was comparable between trazodone and other second-generation antidepressants, including SSRIs, SNRIs, and bupropion.

A small study (n = 27) comparing the antidepressant efficacy and safety of trazodone and the SSRI fluoxetine in elderly depressed patients reported similar improvements in HAM-D scores after 6 weeks of treatment. Significant improvement in HAM-D scores from baseline was also observed with trazodone IR (dose range 50–400 mg/day) and fluoxetine (dose range 20–40 mg/day) in a larger, randomized, double-blind study (n = 126) of outpatients with depression—these improvements in clinical efficacy were similar in the two treatment groups, but HAM sleep disturbance scores were— D improved significantly in the trazodone group than in the fluoxetine group (-2. 7 vs. 1.6; p = 0.001).

More recently, two similar European multicentre, double-blind, randomized trials compared twice-daily long-acting trazodone with paroxetine and sertraline in patients with depression. Efficacy was assessed by measuring change from baseline in the HAM-D, Montgomery Osberg Depression Rating Scale (MADRS) and Clinical Global Impression Severity (CGI-S) after 6 weeks of treatment. The results of these two studies showed that extended release trazodone was as effective as paroxetine and sertraline in reducing depressive symptoms and promoting remission; trazodone may also be of benefit to patients with major depression who have difficulty sleeping or exhibit common sleep disturbances.

The efficacy of venlafaxine SNRIs was compared with that of trazodone in a double-blind, randomized, placebo-controlled trial in 225 patients with depression. Overall, both trazodone (dose range 150-400 mg/day after the titration phase) and venlafaxine (dose range 75-200 mg/day) were significantly more effective than placebo, as measured by changes in HAM-D scores. However, trazodone was associated with greater improvement in HAM-D-associated sleep disturbance factor than venlafaxine, while greater improvement in cognitive impairment and developmental delay was observed with venlafaxine.

In contrast to these results, a double-blind, randomized trial of patients with moderate to severe depression demonstrated that mirtazapine and SNRIs were associated with greater improvement in HAM-D scores compared with trazodone after 6 weeks of treatment.

Trazodone was compared with the norepinephrine-dopamine reuptake inhibitor bupropion in a double-blind, randomized study of outpatients with moderate to severe depression. After 6 weeks, overall efficacy in terms of HAM-D and CGI-S was similar between the trazodone IR and bupropion groups. However, improvements in HAM-D and CGI-S scores at day 7 were significantly greater with trazodone compared with bupropion due to the beneficial effects of trazodone on sleep. At the end of treatment, 46% and 58% of patients were considered to have improved significantly/very much in the trazodone and bupropion groups, respectively.

Trazodone extended release preparations

An extended release formulation (Roussel Laboratories Ltd.) was compared with standard trazodone IR in a double-blind, randomized study of 347 general practitioner patients with MDD. After 6 weeks of treatment (150 mg/day at bedtime for both treatment groups), both treatment groups showed significant improvements from baseline in overall severity, overall improvement, and HAM-D scores. The difference in these improvements was not statistically significant between extended-release trazodone and trazodone IR, but small differences in treatment response rates were in favor of patients receiving extended-release trazodone. Safety, tolerability, and compliance did not differ significantly between the two treatment groups, demonstrating that the new formulation was effective and safe.

The efficacy and safety of extended release trazodone was evaluated in a double-blind, randomized, placebo-controlled trial in 412 patients with MDD (treatment course 6 weeks, dose range 150 to 375 mg/day). The mean maximum daily dose of trazodone administered during the study was 310 mg. The improvement in HAM-D scores was significantly greater with trazodone than with placebo, a difference that was statistically significant after the first week of treatment and persisted throughout the study. Moreover, there was a higher percentage of HAMD-17 responders and a greater decrease in deviations from baseline on the HAMD-17 Depressed Mood Scale, CGI-S, and MADRS total score. In the HAM-D group, the greatest improvement was observed in insomnia, guilt, and depressed mood, while in the MADR group, the greatest improvement was seen in reduced sleep, internal tension, reports of sadness, and suicidal thoughts. Notably, the antidepressant efficacy of trazodone was independent of baseline severity of insomnia and improvement in insomnia. Trazodone was also well tolerated; The most common adverse events were headache and drowsiness. There were no serious treatment-related adverse events or clinically significant ECG or laboratory abnormalities. These results suggest that once-daily long-acting trazodone may be an effective monotherapy option in patients with DMD when administered at an appropriate therapeutic dose (up to 375 mg/day).

Trazodone in special patient populations

Trazodone has been studied for the treatment of depression in a variety of patient populations, including the elderly, pediatric patients, and patients with renal insufficiency.

In elderly depressed patients, comparable efficacy has been reported between trazodone and amitriptyline TCAs. Two double-blind, randomized trials comparing trazodone and the SSRI fluoxetine also reported similar antidepressant efficacy between the two treatments studied. In addition, fluoxetine was associated with a higher incidence of activating side effects (arousal, anxiety, nervousness, insomnia) compared to trazodone. In contrast, sedative effects were reported more frequently with trazodone than with fluoxetine.

Trazodone extended release (Roussel Laboratories Ltd. ) has been evaluated in depressed elderly patients. After 4 weeks of treatment, both controlled-release trazodone and conventional drugs (both given at night as single daily doses starting at 100 mg and increased to 200 mg/day depending on tolerability) were similar in efficacy as measured by changes from baseline on the HAM-D scale and the Global Depression Severity Score. During the first week of treatment, fewer side effects were reported in patients treated with the controlled release drug.

Patients often experience their first episode of depression in early childhood, before the onset of puberty or adolescence. To date, there are no data on the use of trazodone in children and adolescents with depression. In a small open-label study of ten children with chronic tics and Tourette’s syndrome, the combination of haloperidol and trazodone was shown to be effective in improving clinical symptoms. At the end of the study, the Yale Global Tic Severity Scale score was significantly reduced from baseline, and no side effects were reported. However, it should be noted that trazodone is not recommended for use in children under 18 years of age.

Trazodone is extensively metabolized in the liver, but the effects of trazodone in patients with renal or hepatic insufficiency are not well understood. An early study in the late 1970s evaluated the effects of a 12-day treatment with trazodone (75 mg) in patients with mixed neurosis and normal or impaired renal function. Although higher serum concentrations of trazodone were observed in patients with impaired renal function compared with patients with normal renal function, these differences were not statistically significant. As a result, the authors concluded that impaired renal function is not a contraindication to treatment with low doses of trazodone. A recent case of severe liver toxicity leading to fulminant liver failure has been reported following treatment with venlafaxine and trazodone for 4 months.

Given the available data on the use of trazodone in patients with renal or hepatic insufficiency, the labeling of the drug trazodone recommends careful dosing and regular monitoring in patients with hepatic insufficiency, especially in cases of severe hepatic insufficiency and severe renal insufficiency (usually no dose adjustment is required in mild or moderate renal insufficiency).

Trazodone tolerance

Trazodone is generally well tolerated in the treatment of depression, with the most common side effects being drowsiness (hypnotics/sedation), headache, dizziness, and dry mouth.

Drowsiness is the most common side effect of trazodone, with incidence in depressed patients ranging from 5.6% to 22.5% (last estimate shown in the figure).

Trazodone has minimal anticholinergic activity. However, an increased risk of orthostatic hypotension may be associated with trazodone, especially in elderly patients or patients with pre-existing heart disease. This effect, due to the blockade of adrenergic α 1 receptors, is temporary and is associated with the plasma concentration of the drug.

At toxic plasma levels, trazodone may be associated with prolongation of the corrected QT interval (QTc) and torsades de pointes. Even at therapeutic doses, several cases of life-threatening cardiac arrhythmias, including ventricular tachycardia, have been reported in clinical and preclinical studies. Evidence suggests that QT interval prolongation is due to the interaction of trazodone with hERG potassium channels. Concomitant use of trazodone with drugs known to cause cardiac toxicity or prolong the QT interval should be avoided as this may increase the risk of ventricular arrhythmias, including torso de pointe arrhythmia.

Trazodone may also be associated with rare cases of priapism. For this reason, trazodone should be used with caution in men with conditions that may predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia, autonomic nervous system dysfunction, and hypercoagulable states) or in men with an anatomical deformity of the penis (eg, angulation, cavernous fibrosis, or Peyronie’s disease).

Drug interactions have been reported with inhibitors of the cytochrome P450 (CYP) 3A4 enzyme, such as erythromycin, ketoconazole and ritonavir, resulting in increased plasma concentrations of trazodone; conversely, carbamazepine may reduce plasma concentrations of trazodone. Concomitant use with other antidepressants such as TCAs, MAOs or fluoxetine should be avoided due to the risk of serotonin syndrome and cardiovascular side effects. Interactions between trazodone, citalopram and fluoxetine have been studied in 97 patients with depressive syndrome within 1 year. The results showed that the use of citalopram and fluoxetine in combination with trazodone did not significantly affect the concentration of trazodone in the blood serum, and no cases of headache, daytime sedation, fatigue or serotonin syndrome were reported during the study.

Antidepressants increase the risk of suicidal ideation and behavior (suicidality) in children, adolescents, and young adults compared with placebo in short-term studies of MDD and other psychiatric disorders. Cases of suicidal thoughts and suicidal behavior have been reported during trazodone therapy or shortly after cessation of treatment.

Side effects of the antidepressant Trittiko

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