Sleeping medicine trazodone: Uses, Side Effects, and Comparison

02.09.202330.06.2023 by alexxlab

Uses, Side Effects, and Comparison

The term insomnia is a descriptive word as opposed to a formal medical term that is used to describe problems with sleep. Insomnia can be used to describe difficulty falling asleep, waking up during the night at some point and being unable to go back to sleep, and significant issues with fatigue and sleepiness after waking.

There are two primary divisions of insomnia.

A person who has difficulty with sleep that is not caused by some other psychological or physical disorder would be categorized as having primary insomnia
A person who has difficulty sleeping due to a medical condition or mental health disorder would be diagnosed with secondary insomnia.

The treatment for primary insomnia is simply to address the sleep issue, whereas the treatment for secondary insomnia would involve addressing the condition that is producing the insomnia and perhaps addressing the insomnia itself medically or behaviorally. Most people suffer from temporary insomnia at some point in their lives, and issues with temporary insomnia that resolve over time are usually not problematic.

Chronic insomnia is defined as insomnia that occurs at least three times a week and has been consistently occurring at least one month.

There are numerous medications designed to address issues with insomnia. Two of the more popular medications are Ambien (zolpidem) and Desyrel or Oleptro (trazodone).

Ambien: What Is It?

Ambien is a sedative or hypnotic (sleep-producing) drug that is prescribed primarily for the treatment of insomnia. Ambien has a mechanism of action that is similar to the mechanism of action of more potent tranquilizers/sedatives like benzodiazepines (e.g., Xanax or Valium).

Ambien is believed to work by increasing the availability of the primary inhibitory neurotransmitter in the brain and spinal cord GABA (gamma-aminobutyric acid). This neurotransmitter is a chemical that is released by the neurons in the brain and spinal cord (referred to as the central nervous system) that reduces the actions of other neurons in the brain. This leads to its ability to produce sedation.

Ambien works relatively quickly compared to many similar drugs, and it has a very short half-life (the time it takes the system to metabolize or reduce the concentration of a drug to half its original concentration). This means that Ambien works quickly, does not remain in the body very long, and can help to induce sleep with lower doses than similar drugs (e.g., benzodiazepines like Xanax). When individuals experience the type of insomnia that does not involve problems falling asleep, but instead involves waking up in the middle of the night and not being able to go back to sleep, higher doses of Ambien or an extended-release version may be used.

Trazodone: What Is It?

Trazodone is not a medication that is primarily designed to produce sleep (a sedative or hypnotic medication). Trazodone was developed as an antidepressant medication. It has an entirely different mechanism of action than Ambien.

Trazodone works by increasing the availability of the neurotransmitter serotonin in the CNS. It is categorized as a serotonin antagonist reuptake inhibitor (SARI), meaning that it primarily blocks the ability of neurons to reabsorb serotonin once it has been released into the central nervous system. This leaves serotonin available in the central nervous system for longer periods of time and theoretically addresses issues with depression.

Because of the chemical composition of trazodone, it has been found to have mild sedating effects, and it is less effective than other antidepressants for the treatment of depression. Therefore, trazodone has found greater utility as a sleep aid than it has as an antidepressant medication.

Comparing Side Effects: Ambien vs Trazodone

Side Effects of Ambien

Lethargy, drowsiness, and daytime sleepiness (particularly in elderly people)
Dizziness, lightheadedness, and/or headache
Nausea and diarrhea
Problems with reaction times and coordination
Problems with remembering new information, particularly the day after using the drug
Rebound insomnia (insomnia that occurs when the person stops using the drug)
Hallucinations (rare)
Parasomnias (very rare), which are troubling disorders of sleep that occur when a person who is sound asleep begins engaging in activities that they would normally perform while they are awake, such as cooking, doing household chores, and even driving
The development of physical dependence on Ambien (tolerance and withdrawal symptoms)

Side Effects of Trazodone

Nausea, vomiting, and diarrhea or constipation
Dizziness, unsteadiness, dry mouth, and/or headache
Fatigue, tingling or numbness in the extremities (arms and legs), or ringing in the ears
Muscle pain, rash, tremors or shaking (mostly in the hands)
Anxiety, difficulty with attention, decreased appetite, and weight loss
Prolonged and painful erections in men
Thoughts of harming oneself (most often in children or adolescents)
Mild physical dependence

Both drugs have the risk for very rare and more serious side effects that would need to be addressed by a physician if they occur. Higher doses are more likely to produce more severe side effects. Trazodone is generally better tolerated in most people than Ambien because trazodone is not specifically designed to produce sedation. However, the actual side effects than any person will experience are difficult to predict, and physicians typically wait and see how the person reacts to the drug.

A Brief Comparison of Trazodone and Ambien as Sleep Aids

Ambien as a sleep aid:

Is effective at helping people fall asleep quicker and stay asleep longer.
Comes in an extended-release version that is effective at helping people stay asleep.
Comes in generic versions (zolpidem) that are inexpensive.

There are some downsides to Ambien.

It may produce next-day drowsiness or cognitive problems.
People develop tolerance to Ambien quickly, meaning they need more of the drug over time for it to be effective.
It has the potential to produce parasomnias.
It is not indicated for people with a history of depression, respiratory problems, kidney disorders, or liver problems.
It is very likely to produce physical dependence.

Trazodone for sleep as a sleep aid:

Is commonly used to treat issues with sleep at lower doses.
Is safer for elderly individuals than other sleep aids.
Has fewer side effects than most drugs used as sleep aids.
Does come in a generic version that is cheaper than Ambien.

There are some downsides to trazodone.

If depression is the issue, higher doses are needed.
Higher doses result in more side effects.
Problems with sexual functioning (particularly males) and suicidality (particularly in younger people).
It is less sedating than Ambien and may not be effective for everyone.

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Physical Dependence

Both Ambien and trazodone use may produce a syndrome of physical dependence (withdrawal symptoms when the person cuts down on using the drug or stops using it altogether). The symptoms of withdrawal associated with Ambien include insomnia, anxiety, flulike symptoms, and stiffness or muscle cramps. The symptoms associated with antidepressant discontinuation syndrome (withdrawal from antidepressants like trazodone) include anxiety, depression, irritability, and mild flulike symptoms.

In general, both withdrawal syndromes are addressed by slowly tapering down the dosage of the drug over time to allow the system to get used to decreasing amounts and then finally discontinuing it altogether. The withdrawal syndrome associated with Ambien is considered to be more severe and more potentially serious than withdrawal from antidepressants like trazodone. Likewise, the potential to develop a withdrawal syndrome is higher with Ambien than it is with trazodone.

Which Is Best?

The data indicates that trazodone will most likely produce fewer side effects and complications than Ambien; however, trazodone may not help some individuals with sleeping. The choice of using trazodone or Ambien is really dependent on the particular needs of the person being treated, their medical history, and the other medications they are taking.

That being said, using medications to treat insomnia is not considered to be the best overall choice. Instead, using Cognitive Behavioral Therapy to help people sleep is a better long-term solution than the use of any medication. For instance, an article in TIME compared the effects of medications and psychotherapy, and came to the conclusion that Cognitive Behavioral Therapy is the best long-term solution to insomnia.

Thus, medications like Ambien, trazodone, and even natural substances like melatonin should only be used as temporary aids for sleep while an individual attempts to address the primary problem that is producing their sleep difficulties. Using behavioral techniques allow the person to address their issue, develop a program of healthy sleep, and continue to implement this program over the long-term without experiencing significant side effects.

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Last Updated on Sep 13, 2022

Dosage, Benefits, Side Effects & Other Risks

Trazodone for Sleep: Dosage, Benefits, Side Effects & Other Risks

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Medically reviewed by Alan Carter, Pharm. D. — By Malini Ghoshal, RPh, MS — Updated on February 18, 2023

Trazodone is an antidepressant that is sometimes prescribed as a sleep aid. It is not addictive and may offer additional benefits over other sleep aids for certain conditions, such as sleep apnea.

Insomnia is more than not being able to get a good night’s sleep. Having trouble falling asleep or staying asleep can affect every aspect of your life, from work and play to your health. If you’re having trouble sleeping, your doctor may have discussed prescribing trazodone to help.

If you’re thinking of taking trazodone (Desyrel, Molipaxin, Oleptro, Trazorel, and Trittico), here’s important information for you to consider.

Trazodone is a prescription medication approved for use by the Food and Drug Administration (FDA) as an antidepressant.

This medicine works in multiple ways in your body. One of its actions is to regulate the neurotransmitter serotonin, which helps brain cells communicate with each other and influences many activities such as sleep, thoughts, mood, appetite, and behavior.

Even at lower doses, trazodone can cause you to feel relaxed, tired, and sleepy. It does this by blocking chemicals in the brain that interact with serotonin and other neurotransmitters, such as, 5-HT2A, alpha1 adrenergic receptors, and h2 histamine receptors.

This effect may be one of the main reasons trazodone works as a sleep aid.

FDA Warning about trazodone
Like many antidepressants, trazodone has been issued a “Black Box Warning” by the FDA.
Taking trazodone has increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. People taking this medication should be closely monitored for worsening symptoms and emergence of suicidal thoughts and behaviors. Trazodone is not approved for use in pediatric patients.

Though the FDA has approved trazodone for use as a treatment for depression in adults, for many years doctors have also prescribed it as a sleep aid.

The FDA approves medications to treat specific conditions based on clinical trials. When doctors prescribe the medicine for conditions other than what was approved by the FDA, it is known as off-label prescribing.

Off-label use of a medication is a widespread practice. Twenty percent of medications are prescribed off-label. Physicians can prescribe medications off-label based on their experience and judgment.

Trazodone is most often prescribed at doses between 25mg to 100mg as a sleep aid.

However, studies show lower dosages of trazodone are effective and may cause less daytime sleepiness and fewer side effects because the drug is short acting.

Experts recommend cognitive behavioral therapy and other behavioral modifications as the first treatment for insomnia and sleep problems.

If these treatment options are not effective for you, your doctor may prescribe trazodone for sleep. Your doctor may also prescribe it if other sleep medications, such as Xanax, Valium, Ativan, and others (short- to medium-acting benzodiazepine medications), haven’t worked for you.

A few advantages of trazodone include:

Effective treatment for insomnia. A 2017 review of studies of trazodone use for insomnia found the medication was effective for primary and secondary insomnia in low doses.
Reduced cost. Trazodone is less expensive than some newer insomnia medicines because it is available generically.
Not addictive. Compared to other medications, such as the benzodiazepine class of medications like Valium and Xanax, trazodone is not addictive.
May help prevent age-related mental decline. Trazodone might help improve slow wave sleep. This may slow certain types of age-related mental decline like memory in older adults.
May be a better choice if you have sleep apnea. Some sleep medications may negatively affect obstructive sleep apnea and sleep arousal. A small 2014 study found that 100mg of trazodone had a positive impact on sleep arousal.

Trazodone may cause some side effects, especially when first starting the medication.

This is not a complete list of side effects. Discuss concerns with your doctor or pharmacist if you feel you are experiencing side effects or have other worries about your medicine.

Some common side effects of trazodone include:

sleepiness
dizziness
fatigue
nervousness
dry mouth
weight changes (in approximately 5 percent of people taking it)

Although rare, trazodone can cause serious reactions. Call 911 or local emergency services if you are experiencing any life-threatening symptoms such as difficulty breathing.

According to the FDA, serious risks include:

Thoughts of suicide. This risk is higher in young adults and children.
Serotonin syndrome. This occurs when too much serotonin builds up in the body and may lead to serious reactions. The risk of serotonin syndrome is higher when taking other medications or supplements that raise serotonin levels such as some migraine medications. Symptoms include:
- hallucinations, agitation, dizziness, seizures
- increased heart rate, body temperature, headaches
- muscle tremor, rigidity, trouble with balance
- nausea, vomiting, diarrhea
Cardiac arrhythmias. The risk of changes in heart rhythm is higher if you already have heart problems.
Priapism. This is a risk of an erection lasting a long time which is painful.
Hypotension. This sudden drop in blood pressure may occur more often when you stand up from sitting.
Increased risk of bleeding. Taking medications that interfere with blood clotting like blood thinner such as Warfarin, Heparin, or Plavix increase this risk.
Mania. Individuals may experience euphoria, hyperactivity, or excessive excitement.
Blurred vision.
Hyponatremia. Sodium imbalance in the blood may occur. Symptoms include:
- headache
- confusion
- weakness
- unsteadiness
- seizures
Discontinuation syndrome. Trazodone, unlike benzodiazepines, is not addictive. However, because your body can become used to trazodone, it is important to talk with your doctor about the best way to slowly stop the medicine. Suddenly stopping trazodone may cause withdrawal symptoms.

Trazodone overdose

There have been reports of overdose with trazodone use. These risks are higher with drinking alcohol, taking benzodiazepines, and other central nervous system depressant drugs that can slow your breathing and reactions.

Drug overdose can be fatal. If you suspect you have taken too much trazodone, call 911 or local emergency services and seek medical attention immediately.

symptoms of overdose
Symptoms of trazodone overdose include:
drowsiness
seizures
vomiting
heart rhythm changes
respiratory arrest (stop breathing)

Trazodone is an older medication approved for use by the FDA in 1981 as an antidepressant. Although trazodone use for sleep is common, according to recent guidelines published by the American Academy of Sleep Medicine, trazodone should not be the first line of treatment for insomnia.

Given in lower doses, it may cause less daytime sleepiness or drowsiness. Trazodone is not addictive, and common side effects are dry mouth, drowsiness, dizziness, and lightheadedness.

Trazodone may offer benefits in certain conditions such as sleep apnea over other sleep aids.

Last medically reviewed on May 24, 2019

How we reviewed this article:

Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations. We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy.

Eckert DJ, et al. (2014). Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. DOI:
10.5665/sleep.3596
Frazer A, et al. (1999). Serotonin Involvement in physiological function and behavior. Basic neurochemistry: Molecular, cellular and medical aspects. 6th edition.
ncbi.nlm.nih.gov/books/NBK27940/
Generali JA, et al. (2015). Trazodone: Insomnia (adults). DOI:
10.1310/hpj5005-367
Jaffer KY, et al. (2017). Trazodone for insomnia: A systematic review.
ncbi.nlm.nih.gov/pmc/articles/PMC5842888/
La AL, et al. (2019). Long-term trazodone use and cognition: A potential therapeutic role for slow-wave sleep enhancers. DOI:
10.3233/JAD-181145
Mayo Clinic Staff. (2016). Insomnia.
mayoclinic.org/diseases-conditions/insomnia/symptoms-causes/syc-20355167
Off-label drugs: What you need to know. (2015).
ahrq.gov/patients-consumers/patient-involvement/off-label-drug-usage.html
Sateia MJ, et al. (2017). New guideline.
aasm.org/resources/clinicalguidelines/040515.pdf
Shin JJ, et al. (2019). Trazodone.
ncbi.nlm.nih.gov/books/NBK470560/
Trazodone hydrochloride drug summary. (n.d.).
pdr.net/drug-summary/Trazodone-Hydrochloride-trazodone-hydrochloride-3033.1692#6
Trazodone package insert. (n.d.).
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What are neurotransmitters. (2017).
qbi.uq.edu.au/brain/brain-physiology/what-are-neurotransmitters

Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

Current Version

Feb 18, 2023

Written By

Malini Ghoshal, RPh, MS

Edited By

Rachael Ajmera, MS, RD

May 24, 2019

Written By

Malini Ghoshal, RPh, MS

Edited By

Rachael Ajmera, MS, RD

Medically Reviewed By

Alan Carter, PharmD

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Medically reviewed by Alan Carter, Pharm. D. — By Malini Ghoshal, RPh, MS — Updated on February 18, 2023

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. Concomitantly with substances that prolong the QT interval, such as: class IA and III antiarrhythmic drugs, antipsychotics (phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalarial treatment, especially halofantrine) , astemizole, mizolastin. 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 effect 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.

Effect 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.

8 (499) 398 – 20 – 68 8 (925) 822 – 88 – 61

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9 0000 Effect of trazodone on sleep in patients taking stimulant antidepressants

1. Introduction

Sleep disturbance is a criterion or one of the main symptoms of depression. More than 70% of women and 80% of men with depression experience problems falling asleep, sleeping or waking up early in the morning [1, 2]. Insomnia can also be a side effect of antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Depressed patients who take SSRIs often complain of persistent sleep disturbances. Antidepressants of this group have a stimulating effect and, by reducing other symptoms of depression, may not only not eliminate pre-existing sleep disorders, but also contribute to their deterioration or provoke insomnia [3, 4]. A total of 35% of patients receiving SSRIs or clomipramine are also taking medications for the treatment of anxiety and sleep disorders [5].

Trazodone is a thiazolopyridine derivative of a sedative antidepressant that is chemically and pharmacologically distinct from SSRIs. The drug has antidepressant, as well as anti-anxiety and hypnotic effects. The effect of trazodone on sleep has been studied in a variety of patients, including patients with sleep disorders and depression, and healthy controls. The drug effectively eliminates depressive symptoms [6] and improves sleep architectonics [7, 8]. In addition, trazodone is an effective hypnotic drug in patients with antidepressant-related sleep disturbances. In an open study of 48 patients with persistent sleep disturbances or worsening insomnia while taking monoamine oxidase inhibitors or other Jacobsen antidepressants [9] used trazodone at a dose of 25-150 mg at night. According to his data, 65% of patients had a complete normalization of sleep, 31% had a partial response to therapy, and 4% had no response. According to Metz and Shader [10], 31% of patients who took trazodone at a dose of 25-75 mg at night for the treatment of insomnia during fluoxetine therapy were forced to stop taking trazodone due to excessive daytime sleepiness. Nierenberg et al. also provided data on clinically significant improvement after taking trazodone in patients with sleep disorders due to antidepressants (fluoxetine or bupropion) [11]. The conclusion was based on the Pittsburgh Sleep Quality Index (PSQI) sleep duration score and the Yale New Haven Hospital Depressive Symptom Inventory score on early morning awakenings. There was also a tendency to improve the quality and duration of sleep on the PSQI subscales.

A limitation of these clinical trials is the lack of polysomnographic (PSG) data and placebo control. The aim of this study is to evaluate the effect of trazodone on subjective and objective sleep measures in patients with depression and sleep disturbances due to treatment with various SSRIs. In a double-blind, placebo-controlled study, it is necessary to investigate whether trazodone can improve sleep in depressed patients receiving SSRI antidepressant therapy, in whom sleep has not returned to normal or sleep disturbances have developed as a result of this therapy.

2. Materials and methods

2.1. Patient selection

Participants in the experiment, aged 20 to 50 years, were selected from among outpatients in a psychiatric clinic. They were diagnosed with a depressive disorder according to the DSMIV criteria. Patients received SSRIs for at least 3 weeks, took antidepressants during the study, complained of new, worsening or untreated sleep disturbance, which continued during the study. A prerequisite for inclusion in the study was a baseline Hamilton Depression Rating Scale (HDRS) score of at least 18.

Exclusion criteria from the study were:

1) concomitant mental illness;

2) alcohol abuse and dependence on other drugs;

3) pregnancy or lactation;

4) any other causes of sleep disturbances, such as periodic leg movements during sleep (RPMS), breathing disorders during sleep (RDS), etc.;

5) ECG signs of cardiac rhythm and conduction disturbances;

6) the development of adverse adverse reactions when taking trazodone in history.

A total of 12 patients aged 42 ± 9 years (range 30 to 59 years; mean age 43.5 years) participated in the study.

Eight patients complained of difficulty falling asleep and maintaining sleep, four described only difficulty falling asleep. Ten patients had previously untreated sleep disturbances, while the remaining two had sleep disturbances during SSRI therapy. For the treatment of depression, various SSRIs have been used in medium therapeutic dosages. Five patients were treated with paroxetine (20 mg/day), three with sertraline (50 mg/day), two with fluoxetine (20 mg/day), and one with citalopram (20 mg/day). One patient was taking venlafaxine (37.5 mg/day), which is a serotonin and norepinephrine reuptake inhibitor.

By the time the study began, the duration of treatment with SSRIs ranged from 4 weeks to 3 months. The mean duration of therapy was 9.0 ± 2.7 weeks (mean 9.5 weeks). For group 1 it was 9.0 ± 2.6 weeks (mean 9.5 weeks), for group 2 it was 9.1 ± 2.9 weeks (mean 9.5 weeks). There were no statistically significant differences between groups 1 and 2 in terms of duration of SSRI treatment (Mann-Whitney U test not significant (NS)).

Half of the randomized patients received placebo in the first phase of treatment, while the other half received trazodone, and vice versa in the second phase of treatment.

2.2. Study Design

During the night of adaptation in the sleep laboratory, the sleep of each patient was assessed and the presence of other causes of insomnia, such as PNMS, RDS, etc. , was monitored. During the following night, baseline PSG (N2) values were recorded. After recording, patients were given 100 mg trazodone (group 1) or placebo (group 2) in phase 1 and vice versa in phase 2. Each phase lasted 7 days, with a 7-day washout period between the two treatment periods.

PSG was performed on nights 3 (N3), 9 (N9), 17 (N17) and 23 (N23) after the start of placebo or trazodone. To study the hypnotic effect, a dosage of 100 mg of trazodone was chosen, which is significantly lower than the dose range recommended for obtaining an antidepressant effect (150–600 mg) [12]. The drug was taken 1 hour before bedtime.

2.3. Subjective data

The HDRS scale was used to assess the severity of depression [13]. The assessment was carried out the night before, during which the baseline PSG values were recorded, the re-assessment was carried out after 9th and 23rd nights. Patients assessed their sleep quality using PSQI based on subjective measures, since sleep quality is a complex clinical structure that is difficult to define and objectively measure. PSQI is a questionnaire for self-assessment of the quality of sleep during the last month. To avoid misinterpretation of the PSQI, some questions have been modified to fit the timing of this study. Because the duration of each treatment phase was only 7 days, PSQI was assessed at baseline and at the end of the study. This study design assumed that all patients would be hypnotic-free at baseline and that patients would have a 50% chance of taking placebo when assessed by PSQI at the end of the study. The study design and clinical assessment of patients are shown in Figure 1. 1

2.4. Polysomnography data

The PSG included two electroencephalogram channels (C3A2, C4A1), two electrooculogram channels, and one chin electromyogram (EMG) channel. Respiratory parameters were recorded by standard measurement of respiratory airflow (oronasal thermistors), respiratory efforts (abdominal and chest strips with strain gauges) and oxygen saturation (pulse oximetry with sensor fixation on the finger). To assess the periodic movements of the legs, EMG was recorded on the right and left m. tibialis during the night of adaptation.

The patients went to bed at their usual time, but the time spent in bed during which all PSG parameters were recorded was 8 hours. The following PSG parameters were assessed: total sleep time (TOS), relative duration of phases + 4” and REM sleep phases, sleep latency, REM sleep latency, sleep efficiency index (SIE), sleep continuity index (SSI), number of awakenings (a activity < 15 s), number of sleep phase changes and average sleep cycle duration. IES was calculated as the ratio of RVR to time spent in bed (the time between turning off and turning on the light), ANN was calculated as the ratio of RVR to the total sleep period (the time from the first falling asleep to the last awakening). PSG records were deciphered by "blind" specialists.

2.5. Statistics

Treatment was prescribed in accordance with the principles of randomization. There were no statistically significant differences between phases 1 and 2 subjects for all PSQI measures and HDRS scores after placebo (Mann-Whitney U test = NS). For this reason, PSG data and HDRS scores were grouped based on trazodone or placebo, regardless of their sequence. The number of patients in both groups was the same, since none of the patients withdrew from the study.

The data were divided into baseline, obtained while taking the drug and while taking placebo. The 14 day time difference between the two groups was not taken into account. Dosage data consisted of test results from the first trazodone group (Arm 1) on observation nights 3–9 and the placebo first group (Arm 2) at observation nights 17–23. The placebo data consisted of the results of the examination in the group that received trazodone first at 17–23 nights of observation (Arm 1) and the group that received placebo first at 3–9th night of observation (group 2).

Subsequent comparisons were made using the Wilcoxon test for paired comparisons. The mean HDRS percent reduction was calculated between the last night of placebo and trazodone and baseline. PSQI scores were tabulated at baseline and end of the study and compared between groups 1 and 2. Baseline polysomnographic sleep parameters were compared with those obtained on the first and last nights of trazodone and placebo. Sleep parameters on the first night of therapy (first effect) were also compared with those on the last night of therapy (short-term effect), after 7 days of trazodone and placebo.

3. Results

3.1. Subjective data

Baseline HDRS score was 23.4 ± 3.7. This indicator decreased to 12.2 ± 3.0 (P < 0.005) points after placebo and to 11.5 ± 4.5 (P < 0.005) points after trazodone, by an average of 46.3 and 49.2% respectively. The effect of trazodone and placebo on mean HDRS score was not significantly different.

At baseline, the mean PSQI was 15.0 ± 2.5 (9 to 19). For group 1 (n = 6), this indicator was 14.6 ± 3.4, for group 2 (n = 6) — 15. 5 ± 1.5 (Mann-Whitney U test = NS). After 3 weeks of trazodone or placebo followed by a withdrawal period, the mean PSQI decreased to a mean of 5.0 ± 1.6 (range 2 to 7) (P < 0.005) and was 4.83 ± 2.14 for group 1 and 5.17 ± 1.17 for group 2. There were no statistically significant differences between the two groups at the end of the study. Mean PSQI values at the end of the study showed a similar improvement in subjective sleep quality in both groups, despite the fact that 50% of patients received placebo for 15 days. Compared to baseline, the change in PSQI was statistically significant for both groups (Wilcoxon test for pairwise comparisons = 0.027). The total PSQI score was 5 or less in half of the patients, 6 in four, and 7 in only two patients. For group 1 - 4.8 ± 2.1 and for group 2 - 5.1 ± 1.1 (Fig. 2).

Side effects: complaints were minimal. While taking trazodone, one patient reported moderate and transient heartburn, while the other two experienced mild sedation in the morning. There were no complaints during the placebo phase.

3.2. Polysomnography data

The initial sleep parameters of patients are given in table. 1. Frequent awakenings (25.1 ± 11.0) and a large number of sleep phase changes (106.2 ± 37.6) led to a decrease in IES (79.8 ± 12.4%) and INS (85.0 ± 9.0%). Mean sleep duration was 382.1 ± 57.9 min, mean sleep latency was 18.8 ± 28.7 min. Slow-wave sleep (SWS) was well maintained (19.5 ± 8.9%), while there was a reduction in REM sleep (13.2 ± 4.9%) and an increase in phase 2 sleep (60.7 ± 11.1% ). On the night of baseline recording, the latency of the REM sleep phase increased (222.9 ± 93.4 minutes).

Trazodone treatment resulted in statistically significant increases in RVR (435 ± 34, P < 0.01), relative duration of 3 + 4 phases (28 ± 14, P < 0.05), IES (90 ± 7%, P < 0.01), INS (94 ± 6%, P < 0.01) and a significant decrease in the proportion of phase 1 (3 ± 1, P < 0.001), the number of awakenings (13 ± 6, P < 0.01) and the number of phase changes (69 ± 21, P < 0. 05) on the first night of therapy (first effect) compared to baseline. At the end of trazodone (short-term effect), there was a trend towards a slight deterioration in sleep parameters compared with the first night of therapy. The values of RVO, IES and INS were 428 ± 39 (P < 0.05), 89 ± 8% (P < 0.05) and 93 ± 7% (P < 0.05), respectively, and still significantly higher than baseline. However, on the last night of trazodone, shortening of phase 1 (3 ± 2%, P < 0.001), fewer awakenings (12 ± 13, P < 0.05), fewer sleep phase changes (64 ± 46, P < 0.01) and an increase in the relative duration of the 3 + 4 phases (31 ± 13%, P < 0.01) were significantly better. Sleep latency decreased from 17 to 14 minutes. The proportion of REM sleep was slightly less on the last night of therapy (16 ± 8%) than on the first night (18 ± 9%), while the REM sleep latency increased from 200 to 230 min.

In conclusion, the significant improvement in sleep parameters that was observed on the first night of trazodone therapy was maintained after 7 days of treatment compared to the reference (baseline) night. Improvement in sleep parameters was more marked on the last night of therapy, but no significant difference was observed between the first and last nights of trazodone.

Placebo did not result in significant changes in sleep parameters on either the first or last night compared to baseline. Sleep latency increased to an average of 24 and 33 minutes on the first and last night of therapy, respectively. Although the number of sleep phases has dropped to 89on the first night of placebo, on the last night it reached 128, which was higher than baseline. The only significant data with placebo was an increase in the number of sleep phase changes on the last night (128 ± 3, P < 0.01) compared with the first (89 ± 36). Sleep parameters for trazodone and placebo therapy are summarized in Table 1. 1.

4. Discussion

The results of this study confirm the earlier conclusion that low-dose trazodone objectively increases sleep duration in patients receiving antidepressant therapy with sleep disorders [11]. Insomnia can be a side effect of some antidepressants, such as SSRIs, or a symptom of depression. Six-day fluoxetine therapy has previously been reported to result in a significant reduction in REM sleep, prolongation of sleep latency and REM sleep latency, without a significant increase in the number of awakenings during the night [15]. Hendricks et al. [16] reported that the use of fluoxetine led to a lengthening of phase 1, suppression of REM sleep, and an increase in REM sleep latency. The results of another fluoxetine study confirmed these findings and also demonstrated a reduction in MVS [17]. Paroxetine, compared with placebo, resulted in a decrease in REM sleep, REM sleep, and IES, and an increase in REM sleep latency and the number of awakenings [18].

Sleep disturbances in depression are well documented. These include an increase in the time spent without sleep as a result of nocturnal awakenings, a decrease in MWS, and a shortening of the latency of REM sleep. At baseline in this study, the HDRS score was 23. 4 ± 3.7, indicating the presence of moderate depression despite SSRI therapy for 9 weeks (minimum 4 weeks). The high HDRS scores in the patients suggest that depression could be the cause of sleep disturbances. Complaints about sleep disturbances that occur during SSRI therapy indicate that sleep problems are a side effect of taking these drugs. Although it is impossible to calculate the percentage of sleep disturbances that result from depression and SSRI therapy, it is only known that both of these components affect sleep.

Baseline PSG data of patients reflect the total effect of SSRI therapy and depression on sleep parameters. A decrease in RVS and IES was revealed, an increase in the number of awakenings while maintaining the AVS. The REM sleep duration decreased (13.2 ± 4.9%), while the REM sleep latency increased (222.0 ± 93.1 min).

Mouret et al. [8] studied polysomnographic changes induced by trazodone 100–600 mg/day in 10 patients with depression who were not taking other drugs. On the first night after taking 100 mg of trazodone, there was an increase in RVO and phase 2, a decrease in sleep latency and the number of awakenings. After increasing the dose over 4 days to 400–600 mg at night, in addition to the improvement in sleep parameters recorded after one day of therapy, an increase in phase 4 and latency of REM sleep was observed. A slight decrease in slow-wave sleep phase 2 (NREM sleep) was noted, but otherwise the findings are consistent with previous studies. After taking 100 mg of trazodone for one week, all improvements in sleep parameters were significant, which manifested itself in a decrease in the duration of phase 1, the number of awakenings, the number of sleep phase changes and an increase in MWS. Improvements in sleep scores in patients were more pronounced than those reported by Mouret et al. after one night of taking the drug. Scharf and Sachais [19] presented the results of a study of six patients with depression who took trazodone 150 mg for 2 days, 200 mg for 2 days, and 250 mg at the end of the first week. They experienced a reduction in sleep latency and an increase in RWS, NREM phase 4 sleep, and REM sleep latency. The described changes in REM sleep parameters after the first day and after 1 week of therapy differed from those observed in patients in this study (who initially showed an increase in REM sleep with a decrease in its latency). REM sleep latency increased from baseline after weekly trazodone.

There have been few polysomnographic studies of the effect of trazodone on sleep parameters in depressed patients taking SSRIs. In this study, trazodone compared with placebo resulted in a significant improvement in sleep parameters with an increase in RWS, MVS, IES, INS, shortening of phase 1, fewer awakenings and sleep phase changes after 1 week of treatment. According to PSG data, there were no significant differences in the effect of trazodone on the first and last nights of dosing. Despite a marked decrease in HDRS scores, none of the sleep parameters were significantly improved by placebo. This means that trazodone resulted in normalization of sleep in patients with depression, regardless of other symptoms of depression, and that the drug was effective after the first night of use.

The PSQI was assessed at the beginning and at the end of the study. None of the patients had taken trazodone before the start of the study, subjective complaints were quite clear. At the end of the study, 50% of patients had not received trazodone for at least two weeks (due to withdrawal and placebo periods). Despite the described situation, there was a significant decrease in the average PSQI score (from 15 to 5). It has previously been reported that a total PSQI score ≤ 5 allowed correct identification of 89.6% of healthy middle-aged individuals in the control group [14]. There was no significant difference in PSQI scores between the two groups at the end of the study, with scores in both groups significantly better than baseline. The fact that the PSQI scores in group 2 improved after 2 weeks of not taking trazodone indicates the importance of frequent re-evaluation of subjective sleep assessment and the subjective effect of attention given to sleep by the research team. However, the question may arise whether an excess effect was observed from the initial (first 7 days) use of trazodone. Although such an effect has never been reported, similar results are often seen in crossover studies, even if they are placebo controlled, as in our case. Nevertheless, PSG data clearly indicate a discrepancy between subjective and objective results. While placebo was associated with improved subjective scores, there was a deterioration in PSG. In this sample, the objective improvement in sleep leveled off within a short period of time (maximum 15 days). These PSG results support the beneficial effects of trazodone in depressed patients.

It was previously noted that persistent insomnia can provoke relapses of depression. These data highlight the importance of treating sleep disorders in these patients. Insomnia can be both a symptom of depression and a side effect of SSRIs. The results of the study suggest that subjective reports of patients may not be a reliable indicator of the severity of sleep disturbance, and therefore there may be a need for polysomnography.

Less severe anticholinergic side effects occur with trazodone compared with tricyclic antidepressants. As a sedative antidepressant, it has a short half-life. The drug was effective in inducing and maintaining sleep during 5 weeks of studies, but little is known about the results of longer therapy [19].].

Trazodone 100 mg resulted in improvements in objective sleep measures in moderately depressed adults treated with low to moderate therapeutic doses of SSRIs after the first dose. There is a need for long-term studies comparing the efficacy and side-effect profile of trazodone and standard hypnotics in the treatment of antidepressant-related sleep disorders.

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