How does trazodone 50mg function as both an antidepressant and a sleep aid. What are the benefits and risks of using trazodone for sleep disorders. Is trazodone a safe alternative to traditional sleeping pills.

The Dual Nature of Trazodone: Understanding Its Versatility

Trazodone, originally developed as an antidepressant, has found a unique place in modern medicine. Its dual role as both an antidepressant and a sleep aid has intrigued medical professionals and patients alike. But how does a single medication serve these two distinct purposes?

Trazodone’s primary function is to increase natural neurotransmitters in the central nervous system, particularly serotonin. This neurotransmitter plays a crucial role in regulating mood, sleep patterns, appetite, and various other bodily functions. By inhibiting serotonin uptake and stimulating certain nerves, trazodone helps restore the chemical balance in the brain, which is often disrupted in individuals suffering from depression.

However, at lower doses, trazodone’s sedative effects become more prominent, making it an effective option for treating sleep disorders. This dual action has led to its widespread use in treating both depression and insomnia, often simultaneously.

The History and Development of Trazodone

Trazodone’s journey from conception to widespread use is a fascinating tale of pharmaceutical evolution. Developed in Italy during the 1960s, trazodone was initially created to combat depression and anxiety disorders. However, its path to acceptance wasn’t smooth sailing.

Early trials revealed several side effects, including dizziness, fainting, and irregular heartbeat. In rare cases, male patients experienced priapism, a prolonged and painful erection. These adverse reactions initially limited trazodone’s popularity among medical professionals.

Despite these setbacks, researchers and clinicians began to recognize the potential benefits of trazodone, particularly when administered in lower doses. This revelation led to a reevaluation of the drug’s applications and dosage recommendations.

In 1981, trazodone received approval from the U.S. Food and Drug Administration (FDA) under the brand name Desyrel for treating major depressive disorder. Today, it’s also marketed under the brand name Oleptro and is prescribed for various conditions, including sleep disorders, anxiety, and unipolar depression.

Trazodone as a Sleep Aid: Efficacy and Dosage

How effective is trazodone as a sleep aid? For many patients, trazodone induces a relaxed, sleepy feeling, making it an attractive option for those struggling with insomnia. The sedative effects of trazodone can typically be felt within 30 minutes of ingestion, depending on the formulation used.

When prescribing trazodone for sleep disorders, physicians generally recommend a low dose taken at bedtime. This approach helps maximize the sedative effects while minimizing daytime drowsiness. However, it’s important to note that some individuals may experience lingering effects, including sluggishness and fatigue, particularly upon waking.

The typical dosage of trazodone for sleep disorders is lower than that used for depression. While 50-150 mg per day might be prescribed for depression, sleep disorders are often treated with doses as low as 25-100 mg at bedtime.

Comparing Trazodone to Traditional Sleep Medications

• Unlike Ambien, Sonata, and Lunesta, trazodone is not classified as a controlled substance by the FDA.
• Trazodone is typically less expensive than many branded sleep medications and is often covered by insurance plans.
• When used as prescribed, trazodone is generally not considered addictive.
• Physicians have more flexibility in prescribing trazodone, as there are no strict limitations on the number of pills they can prescribe.

Trazodone’s Mechanism of Action in Depression Treatment

How does trazodone work to alleviate depression? Trazodone’s primary mechanism of action involves increasing the levels of natural neurotransmitters in the central nervous system. It specifically targets serotonin, a crucial neurotransmitter that regulates mood, sleep-wake cycles, appetite, digestion, memory, and sexual function.

Many experts believe that depression is linked to an imbalance among the brain’s neurotransmitters, including acetylcholine, norepinephrine, dopamine, and serotonin. While the exact cause of depression is not fully understood, trazodone works by inhibiting the reuptake of serotonin by nerves and stimulating other nerves, effectively increasing serotonin levels in the brain.

It’s important to note that the antidepressant effects of trazodone may take longer to manifest compared to its sedative effects. Patients using trazodone for depression might not notice symptom relief for one to two weeks, and it can take up to four weeks to experience the full benefits of the medication.

Trazodone vs. Other Antidepressants

How does trazodone differ from other antidepressant medications? While all antidepressants aim to affect brain chemistry, their specific targets and mechanisms can vary:

1. Selective Serotonin Reuptake Inhibitors (SSRIs): Examples include Prozac, Zoloft, and Lexapro.
2. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): Such as Cymbalta and Effexor.
3. Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs): Wellbutrin is the primary example.

Trazodone doesn’t fall neatly into any of these categories, which is why it’s often referred to as an “atypical antidepressant.” Its unique mechanism of action sets it apart from more commonly prescribed antidepressants.

Safety Considerations and Potential Side Effects of Trazodone

Is trazodone safe for everyone? Like all medications, trazodone can cause side effects in some individuals. Common side effects may include:

• Drowsiness and fatigue
• Dizziness
• Dry mouth
• Blurred vision
• Weight changes
• Headache

More serious side effects, though rare, can include irregular heartbeat, fainting, and in men, prolonged and painful erections (priapism). It’s crucial for patients to discuss all potential side effects, drug interactions, and possible withdrawal symptoms with their healthcare provider before starting trazodone.

Trazodone is not recommended for pregnant women or those who are breastfeeding. Additionally, there are heightened risks for patients under age 24, particularly concerning mental health. Some young adults may experience an increase in suicidal thoughts when first starting antidepressant treatment.

Trazodone’s Impact on Sleep Architecture

How does trazodone affect sleep patterns? Unlike some sleep medications that can disrupt natural sleep architecture, trazodone has been shown to have a relatively benign effect on sleep stages. Some studies suggest that trazodone may even increase slow-wave sleep, which is crucial for physical restoration and memory consolidation.

Trazodone’s impact on REM (Rapid Eye Movement) sleep appears to be minimal, which is advantageous compared to some other sleep medications that can suppress REM sleep. This preservation of natural sleep patterns contributes to trazodone’s effectiveness as a sleep aid and may explain why many patients report feeling more refreshed upon waking compared to other sleep medications.

Long-term Use of Trazodone for Sleep

Is trazodone suitable for long-term use as a sleep aid? While trazodone is generally considered safe for short-term use in treating insomnia, long-term studies are limited. Some experts caution against prolonged use without regular evaluation by a healthcare provider.

Potential concerns with long-term use include:

• Development of tolerance, requiring higher doses for the same effect
• Difficulty discontinuing the medication due to rebound insomnia
• Possible interactions with other medications
• Increased risk of side effects over time

Patients considering long-term use of trazodone for sleep should work closely with their healthcare provider to monitor its effectiveness and any potential side effects.

Trazodone in Combination Therapy

Can trazodone be used in combination with other medications? Trazodone is sometimes prescribed alongside other antidepressants or anxiety medications. This combination therapy can be particularly effective for patients with complex mental health conditions or those who haven’t responded adequately to single-drug treatments.

For instance, trazodone might be added to an SSRI regimen to help with sleep disturbances that are common in depression. However, combining medications requires careful monitoring by a healthcare provider to avoid potential drug interactions and manage side effects effectively.

Potential Drug Interactions

What medications might interact with trazodone? Some notable interactions include:

• Monoamine Oxidase Inhibitors (MAOIs): Combining trazodone with MAOIs can lead to dangerous increases in serotonin levels.
• Other Serotonergic Drugs: SSRIs, SNRIs, and certain pain medications can increase the risk of serotonin syndrome when combined with trazodone.
• CYP3A4 Inhibitors: Medications that inhibit this liver enzyme can increase trazodone levels in the blood, potentially leading to increased side effects.
• Alcohol: Combining trazodone with alcohol can increase drowsiness and impair cognitive function.

Patients should always inform their healthcare provider about all medications, supplements, and herbal products they are taking to avoid potential interactions.

Trazodone’s Role in Managing Anxiety Disorders

Beyond its applications in depression and insomnia, trazodone has shown promise in managing various anxiety disorders. Its anxiolytic (anti-anxiety) effects are thought to be related to its impact on serotonin levels and its ability to modulate certain serotonin receptors in the brain.

Trazodone may be particularly useful in treating anxiety disorders that are accompanied by sleep disturbances. Its dual action can help alleviate anxiety symptoms while simultaneously improving sleep quality, creating a synergistic effect that can enhance overall treatment outcomes.

Specific Anxiety Disorders

Trazodone has been studied in various anxiety disorders, including:

• Generalized Anxiety Disorder (GAD)
• Panic Disorder
• Social Anxiety Disorder
• Post-Traumatic Stress Disorder (PTSD)

While not always the first-line treatment for these conditions, trazodone can be a valuable option, especially when other treatments have proven ineffective or poorly tolerated.

Trazodone in Geriatric Populations

How effective and safe is trazodone for older adults? Trazodone has gained popularity as a treatment option for elderly patients struggling with depression, anxiety, or sleep disorders. Its relatively mild side effect profile and low risk of addiction make it an attractive choice for this population.

In geriatric patients, trazodone may be preferred over benzodiazepines and other sedative medications due to its lower risk of cognitive impairment and falls. However, dosing must be carefully managed in older adults, who may be more sensitive to the medication’s effects and at higher risk for certain side effects, such as orthostatic hypotension (a sudden drop in blood pressure upon standing).

Considerations for Elderly Patients

• Start with lower doses and titrate slowly
• Monitor for signs of confusion or excessive sedation
• Be aware of potential interactions with other medications commonly used in older adults
• Regularly assess the need for continued treatment

Healthcare providers should conduct a thorough evaluation of an elderly patient’s overall health status, medication regimen, and specific symptoms before prescribing trazodone.

Future Directions and Research

What does the future hold for trazodone research? As our understanding of brain chemistry and mental health disorders continues to evolve, so too does the potential for trazodone and similar medications. Current and future research directions include:

1. Exploring trazodone’s potential in treating other conditions, such as fibromyalgia and chronic pain syndromes
2. Investigating the long-term effects of trazodone use, particularly in sleep disorders
3. Developing new formulations or delivery methods to optimize efficacy and minimize side effects
4. Studying trazodone’s impact on specific subpopulations, such as individuals with comorbid medical conditions
5. Examining the potential neuroprotective effects of trazodone in neurodegenerative disorders

As research progresses, we may gain new insights into trazodone’s mechanisms of action and discover novel applications for this versatile medication.

Emerging Therapeutic Applications

Recent studies have begun to explore trazodone’s potential in treating conditions beyond its traditional uses. Some areas of interest include:

• Neurocognitive disorders: Preliminary research suggests trazodone may have neuroprotective properties that could be beneficial in conditions like Alzheimer’s disease.
• Substance use disorders: Trazodone’s ability to improve sleep and mood may make it a useful adjunct in addiction treatment programs.
• Chronic pain syndromes: The medication’s impact on serotonin levels may help modulate pain perception in certain chronic pain conditions.

While these applications are still in the early stages of research, they highlight the ongoing interest in expanding our understanding of trazodone’s therapeutic potential.

Antidepressant, Sleeping Pill, or Both?

Although trazodone was designed to treat depression and anxiety disorders, the medication is now widely prescribed as a nighttime sleep aid

What is trazodone?

Trazodone was developed in Italy in the 1960s as an antidepressant medication. Due to negative side effects associated with the drug early on—including dizziness, fainting, irregular heartbeat (and in rare cases, priapism in men)—the antidepressant wasn’t widely favored in the medical community. Eventually, however, internists and clinicians recognized potential benefits of the drug, particularly when administered at low doses. In 1981, trazodone (the generic name of the pharmaceutical) was approved by the U.S. Food and Drug Administration (FDA) under the brand name Desyrel for use in treating major depressive disorder. Today, the medication is prescribed under the brand name Oleptro to treat sleep disorders such as insomnia as well as anxiety disorder and unipolar depression.

Does trazodone cause sleepiness?

For many patients, the drug has a sedative effect, inducing a relaxed, sleepy feeling. In prescribing the drug for sleep disorders, physicians typically recommend taking a low dose at bedtime in order to limit the effects of drowsiness. Still, some people report lingering effects, including sluggishness and feeling zapped of energy, particularly upon waking.

How does trazodone help to alleviate depression?

Trazodone increases natural neurotransmitters in the central nervous system, essentially restoring depleted chemicals in the brain. One of these important neurotransmitters—serotonin—regulates our internal clock for resting and being awake, as well as mood, appetite, digestion, memory, sexual function and desire. Many experts believe depression involves an imbalance among the brain’s neurotransmitters (acetylcholine, norepinephrine, dopamine and serotonin.) While the cause of depression is not fully understood, trazodone affects the brain’s neurotransmitters by inhibiting the uptake of serotonin by nerves and stimulating other nerves.

How quickly does the drug take effect?

Patients who take the drug for a sleep disorder can experience the sedative effects within 30 minutes, depending on the type used. Patients who take the drug as an antidepressant may not notice symptom relief for one to two weeks, and it may take up to four weeks to experience the full benefits.

Is it safe to take trazodone to treat depression?

Like all medications, trazodone can cause side effects in some people. Ask your physician to discuss all potential side effects as well as drug interactions and potential withdrawal symptoms associated with the medication.

Do all antidepressant drugs work the same way?

While all antidepressant medications are designed to affect brain chemistry, various pharmaceutical formulations of the drugs have different targets and paths. The most commonly prescribed antidepressants are reuptake inhibitors. Reuptake, as described by WebMD, is “the process in which neurotransmitters are naturally reabsorbed back into nerve cells in the brain after they are released to send messages between nerve cells. ” A reuptake inhibitor, then, keeps levels of neurotransmitters in the gap between nerves, potentially strengthening circuits in the brain that regulate mood. There are three different types: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs). Common SSRIs are Prozac, Zoloft, Paxil, Lexapro, Celexa and Luvox; common SNRIs include Cymbalta and Effexor; and NDRIs are found in only one drug: Wellbutrin.

Because trazodone doesn’t fall under any of these categories, it’s often referred to as an “atypical antidepressant.”

Is it safe to take trazodone for insomnia?

Although trazodone was designed to treat depression and anxiety disorders, the medication is now widely prescribed as a nighttime sleep aid for patients who suffer from acute insomnia.

How is trazodone different from other “sleeping pill” drugs?

Trazodone differs from Ambien, Sonata, Lunesta and other “sleeping pill” medications in a few ways:

• Both Ambien and Lunesta are classified by the FDA as controlled substances because they have the potential for misuse and abuse, including dependence or addiction
• Because trazodone is not a controlled substance, physicians aren’t limited in how many pills they can prescribe
• It’s an inexpensive generic drug covered by most insurance companies
• It’s not considered to be an addictive substance when used as prescribed

Trazodone should not be taken by pregnant women or women who are breastfeeding.

What risks are associated with taking trazodone to treat depression?

There are heightened risks for patients under age 24, particularly with regard to mental health. According to Medline Plus, the following side effects and symptoms can occur among patients under age 24: “new or worsening depression; thinking about harming or killing yourself, or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling asleep or staying asleep; aggressive behavior; irritability; acting without thinking; severe restlessness; and frenzied abnormal excitement.” If any of these symptoms or side effects are experienced, it’s crucial to consult a physician or medical professional immediately.

It’s also imperative that patients know what to avoid while taking SSRIs, SNRIs or other antidepressants. Whether a person has a cold, is having trouble sleeping or is searching for allergy relief, they should talk to their doctor before self-treating with an over-the-counter medication. According to Psychiatry Advisor, one patient who was taking melatonin for insomnia while also prescribed an SSRI woke up with a “headache, dizziness and feeling like his face was on fire”—signs of elevated blood pressure that could have been severe had he taken higher doses. Taking an antidepressant medication in combination with supplements, such as St. John’s wort or aspirin, can increase the likelihood of upper gastrointestinal bleeding. To avoid adverse drug reactions, experts advise making a list of all medications, supplements and other OTC drugs, and sharing it with your physician prior to taking trazodone.

Is it safe to use trazodone with alcohol or other drugs?

Absolutely not. Since both alcohol and trazodone affect the central nervous system, the consequences of mixing the two can be deadly. And mixing the medication with drugs of abuse can result in the onset of serotonin syndrome, a potentially lethal adverse drug reaction. While the potential for trazodone abuse is fairly low, any amount over 600 mg. in 24 hours is an overdose.

What happens if you take too much trazodone? Can it cause serotonin syndrome?

Serotonin syndrome occurs when, according to Mayo Clinic, “high levels of serotonin accumulate in the body.” This is a drug-to-drug interaction involving the over-stimulation of central and peripheral receptors. According to the journal U.S. Pharmacist, “Serotonin syndrome (SS) is caused most often when certain antidepressant agents are taken concurrently with other drugs that modulate synaptic serotonin levels. When patients take two or more antidepressants from different pharmacologic classes, drug-drug interactions may occur; these interactions may lead to potentially severe serotonin toxicity, or serotonin syndrome.” Clinical symptoms of serotonin syndrome can develop within two hours—or up to 24 hours—after taking an increased dose or adding another serotonergic drug.

Signs and symptoms of serotonin syndrome:

• Tremors
• Muscle aches
• Sweating
• Anxiety
• Confusion
• Tachycardia
• Delirium
• Hallucinations
• Seizures
• Renal failure
• Death

What are the side effects of trazodone?

Trazodone usage can cause a decrease in sodium levels in the body, a disruption of the nervous system or serotonin syndrome. The most common side effects include:

• Drowsiness (including feeling groggy the next day)
• Dizziness (including an increased risk of fainting/falling)
• Dry mouth
• Constipation
• Headache
• Fatigue
• Tingling or numbness in hands, arms or legs
• Blurred vision
• Disorientation
• Vertigo
• Nasal congestion
• Shaking
• Anxiety
• Muscle aches
• Prolonged and painful erections lasting longer than six hours (priapism) 
• Abnormally low blood pressure
• Heart rhythm disorders 
• Increased risk of suicidal thoughts and behavior in children and adolescents (even when taken at approved doses for depression)
• Acting on dangerous impulses
• Insomnia (at high doses)
• Weight gain or loss

The drug can stay in a person’s system for 42 hours after the final dose. Higher doses can produce more severe side effects.

Can you become addicted to trazodone?

While the drug is considered non-addictive and non-habit-forming, it should only be taken as prescribed and under a physician’s care in order to avoid misuse. This is especially important for individuals who have a history of substance abuse or other drug addiction. Warning signs of drug misuse include using the sleep aid/antidepressant without a prescription, using the medication at higher doses than prescribed, or snorting or crushing the tablets to speed up the intended effects.

Can you fail a drug test while taking trazodone?

Even though the antidepressant/sleep aid is not classified as a narcotic, it can cause false positives on drug tests. According to the National Center for Biotechnology Information, “The trazodone metabolite meta-Chlorophenylpiperazine [m-CPP] can cause false-positive urine amphetamine immunoassay results.…Further, we found that patients taking trazodone can produce urine with sufficient m-CPP to result in false-positive Amphetamines II results.”

What are trazodone’s withdrawal symptoms?

Although technically a non-addictive substance, regular use of the medication can result in mild physical dependence. For this reason, trazodone withdrawal is a concern. Rather than discontinuing use “cold-turkey,” physicians typically recommend a gradual tapering. This approach is considered a better protocol to avoid potential discomfort associated with trazadone withdrawal syndrome, also known as discontinuation syndrome.

Symptoms of trazodone withdrawal include:

• Agitation
• Confusion
• Rapid mood swings
• Muscle pain
• Weakness
• Dizziness
• Stomach pain
• Sweating
• Insomnia
• Fatigue

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What you need to know

Trazodone ― key points

Trazodone is an antidepressant medication that’s often prescribed for the treatment of insomnia, especially in the USA, where it’s sold under the brand names Oleptro or Desyrel.

In the UK, it’s not a popular choice and its use as a sleeping pill is discouraged by medical professionals, unless it’s being used to treat insomnia alongside anxiety and depression.¹

In this article, we answer the questions we’re frequently asked about trazodone, and we’ll cover:

• what is trazodone?
• why it’s used for insomnia
• why it’s popular in the USA and not the UK
• its effectiveness as a sleeping tablet
• whether its use comes with any risk
• what the alternatives are.

1 in 5 Americans with insomnia are prescribed trazodone

According to figures from 2019, trazodone is the 25th most prescribed drug in the USA, with around five million people having received a prescription for trazodone in this one year alone.²

In fact, trazodone has been one of the most widely prescribed sleep aids in the USA over the past decade³ and 2022 figures suggest that nearly 20% of Americans with insomnia are prescribed this drug to help them sleep. ⁴

Yet trazodone is not licensed as a treatment for insomnia in America and guidelines from the American Association of Sleep Medicine explicitly state that it should not be used for insomnia.⁵

It was developed as an antidepressant medication and is used ‘off-label’ for insomnia. This means that it’s being used to treat a problem that it’s not been licensed for. In the UK it’s also not licensed as a sleeping pill and is not recommended for the treatment of insomnia.⁶

So what is it about trazodone that has led to it being considered a useful sleep medication by some and not others?

In this article we’ll share key facts about the background of this drug, explain why it’s used as a sleep medicine, what the risks of taking it are and whether it is helpful as a treatment for insomnia.

We’ll begin with a look at the history of trazodone and its usage.

What is trazodone?

Trazodone was developed in the 1960s in Italy as a drug to treat depression and has been used to treat major depressive disorder (MDD) since the 1970s. ⁷ It wasn’t until 1981 that it was approved for use in the USA for the treatment of MDD.

It’s not fully known how this drug works, but it’s thought to block nerve cells in the brain from taking up serotonin. Serotonin is a chemical that’s produced in the brain and it’s important for regulating our mood and happiness.

Drugs that increase the levels of serotonin have long been used to treat depression. You may have heard of the more common antidepressant types that work to increase serotonin levels:

• selective serotonin reuptake inhibitors (SSRIs)
• monoamine oxidase inhibitors (MAOIs)
• tricyclic antidepressants (TCAs).

While trazodone does act to increase serotonin levels in the brain, it doesn’t fall into the main antidepressant categories listed above. It’s classed as a regulator of serotonin or, more specifically, it’s a serotonin antagonist and reuptake inhibitor (SARI).

It was the first SARI drug to be approved for usage in the USA and was found to work just as well for relieving symptoms of depression as conventional tricyclic antidepressants, such as amitriptyline which is also given for insomnia. ⁸

Since then, trazodone has also been shown to be just as good or better than several other antidepressants for treating depression, including the popular SSRIs sertraline and paroxetine.⁹¹⁰

Drugs like trazodone only offer relief from the symptoms of insomnia. They can’t get to the root of the problem and won’t treat your sleep disorder.
Sleepstation is different. With our expert support and guidance you can retrain your mind and body for better sleep. So if you’re looking for an effective solution, that doesn’t involve medication, we’re here for you.

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Why is trazodone so popular in the USA?

Firstly, it’s inexpensive.¹¹ It’s been around for a long time so it’s not under patent anymore. This means it can be sold unbranded (in generic form) for relatively little cost, which makes it an affordable choice to prescribe.

Secondly, it’s not considered to be a controlled substance by the US Food and Drug Administration (FDA). Controlled substances are tightly regulated by the US government because they can cause addiction or be abused.

Because trazodone isn’t classified as a controlled substance, it’s possible for doctors to offer it without a limit on how many pills they can prescribe.¹²

Thirdly, a lot of medications for sleep come with dangerous side effects and an increased risk of dependency. While there are risks of side effects with taking trazodone, it’s not thought to be particularly addictive or lead to dependency.

For all the reasons listed above, it may be considered a less risky alternative to many pills you may be aware of that are used as sleep aids, like Ambien, Xanax or Valium.

In the UK, some doctors do prescribe trazodone both for anxiety and depression. It’s not generally prescribed for insomnia unless the person is also experiencing depression or anxiety.¹

Prescription information from the NHS indicates that trazodone is much more expensive than other antidepressants used to treat insomnia, such as mirtazapine,¹³¹⁴ which may be part of the reason why trazodone is not a popular choice in the UK.

So to recap: trazodone is an antidepressant drug that works by increasing levels of serotonin in the brain to improve mood. So how could this drug help people sleep?

Let’s find out.

Trazodone for sleep

A common side effect of taking trazodone is feeling sleepy or tired.³ This side effect is what highlighted the potential for trazodone to be used as a sleep aid.

When used to help people sleep, the dosage of trazodone prescribed differs from other use cases. For depression, it’s usually given at a starting dose of 150mg/day and for anxiety, it’s generally given at 75mg/day.

Depending on what trazodone is being used to treat, the dose range can be anywhere between 75-600mg/day. When it’s given as a sleep aid, it’s given at the lower end of the dose range, generally between 50-100mg/day.

At these doses, it’s thought that trazodone can induce sleepiness that is enough to help people to sleep, but the effects don’t last long enough to affect the person when they wake. ³

We’ve already explained how trazodone can change serotonin levels in the brain, but it also affects the levels of other chemicals that are associated with wakefulness. By blocking these chemicals, trazodone reduces alertness and the end result is that you feel sleepy.¹⁵

So when trazodone is given at lower doses, it can be make you want to sleep. At higher doses, it can boost your mood.

Side effects of trazodone

The most comment side effects of trazodone are considered to be mild, including:

• feeling sleepy or tired
• headaches
• nausea or vomiting
• constipation or diarrhoea
• dry mouth
• dizziness
• weight and appetite changes.¹⁶¹⁷

There are some more serious side effects of trazodone, which are reported to occur rarely and can include:

• changes to heart rhythms
• anaemia or low white blood cells
• suicidal thoughts
• stroke
• hallucinations
• liver problems.

While the FDA doesn’t consider trazodone to be a controlled substance, it does require the manufacturers to add a black box warning which is a label given to substances that carry significant risk of serious or life-threatening side effects.

Trazodone’s black box warning has been mandated because the drug has been shown to increase the risk of suicidal thoughts and behaviours.

As with all medications, if you’re prescribed trazodone you should only take the dose that your doctor has prescribed for you and let your healthcare provider know if you experience any side effects or have any concerns.

You shouldn’t consume alcohol when you’re taking trazodone as the combination of the two can lead to some dangerous effects, including extreme drowsiness and an increased risk of overdose.

Is trazodone addictive?

Trazodone isn’t considered to be addictive. The risk of addiction is lower than with classic antidepressants or sleeping tablets that you may have heard of like Ambien (zolpidem), Lunesta (eszopiclone, similar to zopiclone) or Sonata (zaleplon).

If you stop taking trazodone abruptly, withdrawal symptoms can occur, so it’s recommended to slowly reduce how much you take over a period of time. If you’re taking trazodone, any changes that you might be planning to make should be discussed with your doctor.

Additionally, abrupt trazodone withdrawal can lead to symptoms including insomnia, so if you’ve been taking this drug to help you sleep, then it’s not a good idea to stop taking it suddenly.

Is trazodone a good sleep aid?

Because trazodone wasn’t designed to be a sleeping tablet, there aren’t a huge number of studies that have looked at whether it’s actually useful as a sleep aid and we don’t know much about how long term use may affect people.

Studies tend to look at whether it can improve insomnia in people who are taking trazodone for depression or insomnia linked to another illness (for example in people with cancer, dementia or Parkinson’s disease).¹⁸

It does seem to have some effects on improving how long it takes people to get to sleep and how long people sleep for when taking it. ¹⁹ While this is encouraging, these effects don’t necessarily continue once you stop taking trazodone.

As we’ve already noted, once you stop taking trazodone, you may experience insomnia, so your sleep problem can return or be worse than it was previously. As with all medications taken to aid sleep, the drug won’t treat the sleep problem itself, it can only provide you with some relief from its symptoms.

So you might be asking yourself, “What’s the alternative?” The good news is there’s one treatment that stands head and shoulders above sleeping tablets, getting to the root of your sleep problem and not just masking your symptoms.

Whether in the UK, Europe, Australia or the USA, the experts agree: Cognitive Behavioural Therapy for insomnia (CBTi) is the recommended treatment and should be the first thing you try, before sleep medication.²⁰²¹²²

CBTi is a form of talking therapy specifically developed to treat insomnia and it’s incredibly effective. CBTi works for people who’ve tried other forms of CBT in the past but didn’t find those helpful because it’s very specific and focussed.

Though sadly, due to a lack of professionals trained in CBTi across the world, getting an appointment has often meant spending a long time on waiting lists or paying to see someone privately in a sleep clinic, which can be expensive.

We don’t think that’s acceptable. We believe everyone deserves a good night’s sleep and that everyone should have access to the support they need to sleep well, especially those who need it most. That’s why we developed Sleepstation.

We specialise in CBTi and we deliver it at an affordable price. CBTi has decades of strong scientific evidence to support it and it’s incredibly successful in treating even the most severe forms of insomnia.

Unlike drugs such as trazodone, our sleep solution can get to the root of your sleep problem. We can help you to rebuild your relationship with sleep, ultimately taking back control of your sleep. Our sleep solution is totally medication-free and our results are long-lasting.

Sleepstation’s form of CBTi has been clinically validated and can effectively resolve all types of insomnia, even for people who’ve had insomnia for decades.

Your sleep is incredibly important for maintaining your overall mental and physical wellbeing, so cost and lack of access shouldn’t be a barrier between you and the sleep you deserve.

We made CBTi accessible for everyone, whether your sleep problem is recent or has been a dark cloud over your life for years. We can also help you to reduce or completely stop taking sleeping pills, too.

So if your life feels like it’s on hold because of a sleep problem or you’re relying on sleeping tablets just to get through the night, we’re confident we can provide you with an effective way back to sleeping well without medication. We made it accessible to you, it’s now your choice to decide if you want to improve your sleep.

Summary

• Trazodone has been around as an antidepressant for over 60 years, but it became popular more recently as a sleeping pill.
• Trazodone can have a sedative effect, which is why it’s used to help people sleep.
• Taking trazodone won’t fix a sleep problem.
• Trazodone does have some serious side effects.
• Sleepstation is a drug-free solution with long-lasting results.
• We can help you sleep better, forever.

References

• Common questions about trazodone [Internet]. nhs.uk. 2022 [cited 25 April 2022]. Available here.

  ↑

• Sean P, Kane B. Trazodone – Drug Usage Statistics, ClinCalc DrugStats Database [Internet]. Clincalc.com. 2022. Available here.

  ↑

• Jaffer KY, Chang T, Vanle B, Dang J, Steiner AJ, Loera N et al. Trazodone for insomnia: A systematic review. Innov Clin Neurosci 2017; 14: 24–34.

  ↑

• Pochiero I, Gorini M, Comandini A, Calisti F, Loreto GD, Cattaneo A et al. Real-world characteristics and treatment patterns of patients with insomnia prescribed trazodone in the United States. Clin Ther 2022; 44: 1093–1105.

  ↑

• Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017 Feb 15;13(2):307-49.

  ↑

• Clinical Guidelines on Drug Misuse and Dependence Update 2017 Independent Expert Working Group (2017) Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health

  ↑

• Fagiolini A, Comandini A, Catena Dell’Osso M, Kasper S. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs 2012; 26: 1033–1049.

  ↑

• Georgotas A, Forsell TL, Mann JJ, Kim M, Gershon S. Trazodone hydrochloride: a wide spectrum antidepressant with a unique pharmacological profile. A review of its neurochemical effects, pharmacology, clinical efficacy, and toxicology. Pharmacotherapy 1982; 2: 255–265.

  ↑

• Munizza C, Olivieri L, Di Loreto G, Dionisio P. A comparative, randomized, double-blind study of trazodone prolonged-release and sertraline in the treatment of major depressive disorder. Curr Med Res Opin 2006; 22: 1703–1713.

  ↑

• Kasper S, Olivieri L, Di Loreto G, Dionisio P. A comparative, randomised, double-blind study of trazodone prolonged-release and paroxetine in the treatment of patients with major depressive disorder. Curr Med Res Opin 2005; 21: 1139–1146.

  ↑

• Trazodone: 7 things you should know. [Internet] drugs.com 2022 [cited 25 April 2022]. Available here.

  ↑

• Chao S. Is trazodone a controlled substance? [Internet] drugs.com 2022 [cited 7 March 2022]. Available here.

  ↑

• Cost Comparison Charts. Regional Drug and Therapeutics Centre (Newcastle). 2018 [cited 13 October 2022]. Available here.

  ↑

• English prescribing data (EPD).www.nhsbsa.nhs.uk. Available here. (accessed 13 Oct2022).

  ↑

• Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14(10):536–546.

  ↑

• Shin JJ, Saadabadi A. Trazodone. In: StatPearls [Internet]. StatPearls Publishing, 2022.

  ↑

• Trazodone: MedlinePlus Drug Information [Internet]. Medlineplus.gov. 2022 [cited 7 March 2022]. Available here.

  ↑

• Trazodone: a medicine to treat depression and anxiety [Internet]. nhs.uk. 2022 [cited 7 March 2022]. Available here.

  ↑

• Jaffer KY, Chang T, Vanle B, Dang J, Steiner AJ, Loera N et al. Trazodone for insomnia: A systematic review. Innov Clin Neurosci 2017; 14: 24–34.

  ↑

• Edinger JD, Arnedt JT, Bertisch SM, Carney CE, Harrington JJ, Lichstein KL et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2021; 17: 255–262.

  ↑

• Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res 2017; 26: 675–700.

  ↑

• Insomnia | Health topics A to Z | CKS | NICE [Internet]. Cks.nice.org.uk. 2022 [cited 11 April 2022]. Available here.

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Trazodone (Trittico, Azona) – leaflet: indications, contraindications, side effects depression and related conditions, as well as inappropriate 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, as well as off-label indications including insomnia, anxiety, dementia, Alzheimer’s disease, substance abuse, schizophrenia, bulimia and fibromyalgia.

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 agonist action at the 5-HT1A receptor. 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, thus avoiding the tolerability problems often associated with 5-HT2C stimulation. NT 2A/2C. 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 preparations

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 tolerance and adherence, thus 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 dose of 75 mg, a maximum concentration of about 0.7 μg / ml is reached with a maximum duration of 4 hours. 4 hours after ingestion. 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 decrease in compliance.

More recently, a new once-daily extended-release formulation of trazodone has been developed to further improve adherence to treatment at therapeutic doses and reduce peak plasma concentration and dosing frequency compared to the conventional fast-release formulation. Extended-release trazodone was developed in two doses (tablets scored at 150 and 300 mg) to ensure proper titration, starting at 150 mg/day, in increments of 75 mg 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 seen in patients treated with amitriptyline and mianserin. In addition, HAM-D and visual analog scale (VAS) scores were similar between trazodone and amitriptyline in a study of elderly depressed patients.

Trazodone 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) outpatients with depression – these improvements in clinical performance were similar in the two treatment groups, but HAM-D sleep disturbance scores 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.

Extended release preparations of trazodone

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 trazodone controlled-release formulations and conventional formulations (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 change from baseline on the HAM-D scale and the global assessment of the severity of depression. 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 impairment, the labeling of trazodone recommends careful dosing and regular monitoring in patients with hepatic impairment, especially in cases of severe hepatic impairment and severe renal impairment (usually in mild or moderate renal impairment, dose adjustment is not required).

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 stopping treatment.

Medicines for sleep problems in dementia

Relevance

People with dementia often have trouble sleeping. These may include reduced sleep at night, waking up frequently, walking at night, and excessive sleepiness during the day.

This behavior is highly stressful for caregivers and may be associated with earlier admission of people with dementia to specialized care. Nursing home staff may also find it difficult to care for such people.

Non-drug treatments should be tried first, but they may not work and medications are often used. Because dementia-induced brain changes can be a source of sleep problems, it is unclear whether conventional sleeping pills are effective in people with dementia, and there are concerns that medications may cause significant side effects (harm).

Purpose of this review

In this updated Cochrane Review, we attempted to determine the benefits and overall harms of any medications used to treat sleep problems in people with dementia.

Results of this review

Until February 2020, we searched for well-designed trials that compared any drug used to treat sleep problems in people with dementia with a fake drug (placebo). We consulted with a group of caregivers to help us identify the most important outcomes to look out for in trials.

We found nine trials (649 participants) that looked at four types of drugs: melatonin (five trials), trazodone (one trial), ramelteon (one trial), and orexin antagonists (two trials). Participants in all trials suffered from dementia due to Alzheimer’s disease. The ramelteon trial, one melatonin trial, and both trials of the orexin antagonist were funded by commercial sources. Overall, the evidence was of moderate to low quality, meaning that further research is likely to influence the results.

Participants in the trazodone trial and most of the participants in the melatonin trial had moderate to severe dementia, while participants in the ramelteon and orexin antagonist trials had mild to moderate dementia.

Five trials of melatonin involved 253 people. We found no evidence that melatonin improves sleep in people with Alzheimer’s dementia. The ramelteon trial involved 74 people. The limited information available did not provide evidence that ramelteon was better than placebo. There was no evidence of serious harm associated with the use of these drugs.

Only 30 people participated in the trazodone trial. It showed that a low dose of the sedative antidepressant trazodone (50 mg) taken at night for two weeks could increase total time spent sleeping each night (an average of 43 minutes more during the study) and improve sleep efficiency (percentage sleep time). It may have slightly reduced the amount of time you’re awake at night after you first fall asleep, but we can’t be sure of that effect. This medicine did not affect the frequency of awakenings at night. There was no information on serious harm associated with the use of the drug.

Two trials of orexin antagonists involved 323 people. We found evidence that orexin likely has some beneficial effect on sleep. On average, test participants slept 28 minutes longer at night and spent 15 minutes less time awake after first falling asleep. There was also a slight increase in sleep efficiency, but there was no evidence of an effect on how often the participants woke up. Side effects were no more common in participants who took the medication than in those who took a placebo.

Medications that appeared to have beneficial effects on sleep did not impair participants’ thinking ability, but these studies did not measure participants’ quality of life or look in detail at caregiver outcomes.

Disadvantages of this review

Although we searched, we were unable to find any studies of other sleep medications commonly prescribed for people with dementia. All participants had dementia due to Alzheimer’s disease, although sleep problems are also common in other forms of dementia. None of the trials assessed the duration of uninterrupted sleep, which is very important for caregivers. Only four trials systematically assessed side effects.

We conclude that there are many gaps in the evidence needed to make drug decisions to address sleep problems in dementia.