Personalized treatment of depression based on the patient’s psychopatology: the case for intravenous or intramuscular trazodone in the acute treatment of depression with psychomotor agitation, irritability, or insomnia and the subsequent transition to extended-release Trazodone (Contramid®)

Acute depression with psychomotor agitation or irritability or insomnia is very common and presents significant clinical challenges that require rapid and effective treatment to alleviate symptoms and stabilize patients. Trazodone, a serotonin antagonist and reuptake inhibitor (SARI), is well known for its antidepressant, sedative, and anxiolytic properties, making it an appropriate option for the treatment of depressive symptoms such as agitation, irritability, or insomnia. Intravenous (IV) and intramuscular (IM) administration of trazodone has demonstrated efficacy in the treatment of depressive symptoms in general, and agitation, irritability, and insomnia in particular, providing a fast-acting solution. After stabilization, transitioning patients to extended-release Trazodone (Contramid^®) provides a smooth continuation of therapy with sustained therapeutic benefits and improved patient adherence. This article reviews the clinical utility of IV and IM trazodone in the acute setting and its effect on insomnia, followed by transition to Trazodone XR Contramid^® for long-term treatment.

Introduction

Major depressive disorder (MDD) with symptoms of irritability, psychomotor agitation, or insomnia is a common and severe subtype of depression that requires rapid intervention ^1-5.

These symptoms are common, are among the key symptoms listed in the DSM criteria for the diagnosis of a major depressive episode, and can significantly worsen the prognosis of depression, increase the risk of self-harm, and reduce patients’ overall quality of life ⁵. Despite the recognition of these symptoms, agitation, irritability and insomnia as key symptoms of depression, there remains a significant unmet clinical need for their treatment.

Insomnia is a core symptom of depression that can exacerbate other depressive symptoms and worsen cognitive and emotional functioning, increasing the risk of treatment failure or relapse ^6,7. Many standard antidepressants do not adequately address the sleep disturbances associated with depression, leaving patients with persistent insomnia even after mood symptoms improve. Patients with unresolved insomnia often experience lower treatment adherence due to ongoing fatigue, irritability, and mood instability ⁸. Many clinicians focus on sleep quantity rather than sleep quality, yet sleep architecture disorders play a significant role in the long-term impact of insomnia on overall recovery ⁹. Treating insomnia is essential not only for improving depressive symptoms, but also for restoring patients’ daily functioning and preventing relapse. Trazodone’s sedative and sleep-promoting properties make it a potential candidate for the treatment of both acute and chronic insomnia associated with depression ^10,2,3.

Psychomotor agitation manifests as restlessness, irritability, and an inability to remain still, which can severely impact a patient’s daily life and functioning. Increased agitation often leads to increased distress, disrupts daily activities, and can escalate to impulsive behaviors, including self-harm or suicidal thoughts ¹¹.

Irritability, another common but often under-recognized symptom of depression, is a major contributor to functional impairment in patients. It can manifest as emotional lability, frustration, and quick-tempered outbursts, which can strain personal relationships and negatively impact social and occupational functioning ¹².

Understanding the interplay between psychomotor agitation, irritability, and insomnia is critical for effective diagnosis and treatment, as they significantly affect an individual’s quality of life and overall functioning.

Few pharmacologic options are specifically designed to treat insomnia, agitation, and irritability in depressed patients. Current treatments tend to focus on other core depressive symptoms, often leaving insomnia, agitation, and irritability undertreated, and some clinicians may not recognize these symptoms as key components of depressive disorders, leading to incomplete treatment plans. Further studies are needed to fully understand the mechanisms underlying the symptoms of depression discussed above and to develop targeted therapies that can more effectively treat this symptom.

Although some treatment options exist, they are often used off-label, and their efficacy specifically for agitation, irritability, or insomnia in depression is understudied:

1. antidepressants: although effective for core depressive symptoms, most antidepressants may not adequately address irritability, agitation, or insomnia. In fact, some patients report worsening of these symptoms as a side effect ¹³;
2. mood stabilizers and antipsychotics: both typical and atypical antipsychotics and mood stabilizers are often used off-label, but more research is needed to confirm their effectiveness in treating these specific symptoms while treating other symptoms of depression ¹⁴;
3. benzodiazepines: while benzodiazepines are sometimes used for rapid symptom control, their use is limited by risks such as falls, respiratory depression, particularly in patients with impaired respiratory function, hepatic impairment, or alcohol abuse.

Given these gaps, it is critical to explore pharmacologic options that specifically target agitation, irritability, and insomnia in depression. Trazodone, with its hypnotic, sedative, anxiolytic, and antidepressant properties, has emerged as a potential candidate for treating these symptoms in patients with depressive disorders.

This review will examine the role of intramuscular (IM) or intravenous (IV) trazodone in the treatment of agitation, irritability, and insomnia in acute MDD and its continued use in long-term management with Trazodone XR Contramid^®.

Mechanism of action of trazodone

Trazodone’s unique pharmacological profile makes it particularly suitable for the treatment of depression with psychomotor agitation and insomnia. Classified as a serotonin antagonist and reuptake inhibitor (SARI), trazodone exerts multiple effects:

1. serotonin reuptake inhibition: by blocking serotonin reuptake, trazodone increases serotonin availability, which is key to alleviating depressive symptoms and improving mood stability ^15,3;
2. alpha-1-adrenergic receptor antagonism: this antagonism provides sedative effects, calms agitation, and promotes sleep, particularly in patients who have difficulty initiating and maintaining sleep ^2,3.

Through this diverse mechanism, trazodone not only addresses core depressive symptoms, but also provides significant benefits in calming agitation and improving sleep quality ³

Trazodone in the acute treatment of depression with psychomotor agitation, irritability or insomnia

Patients with MDD very often present with both psychomotor agitation, irritability, and insomnia, which makes treatment more challenging. For example, insomnia exacerbates depressive symptoms and impairs daytime functioning, contributing to mood instability and irritability ².

Efficacy of intramuscular or intravenous trazodone in treating insomnia, irritability, and agitation

Insomnia, irritability, or agitation are key symptoms of depression, and trazodone is known for its efficacy in treating both sleep disturbances and other symptoms of depression, such as agitation. The sedative effects of trazodone, particularly in the IV and IM formulations, make it a valuable option for patients with severe insomnia or psychomotor agitation during acute depressive episodes. Studies have shown that trazodone improves both sleep onset and sleep maintenance as well as irritability or agitation by targeting 5-HT2A receptors and alpha-1 adrenergic receptors ¹⁵.

Intravenous trazodone

The main advantages of intravenous trazodone include

1. - Rapid onset of action: IV trazodone provides immediate bioavailability with noticeable effects within minutes, making it an ideal treatment for acute agitation and insomnia in emergency settings. It calms agitated patients and induces sleep, preventing further escalation of symptoms ⁴.

Intramuscular trazodone

The main advantages of intramuscular trazodone include:

1. - Alternative to IV: IM trazodone offers a slightly delayed but similarly effective onset of action. IM administration can be useful when IV access is not feasible and provides rapid symptom control for both agitation and insomnia in the inpatient setting.
2. - Rapid symptom relief: IM trazodone ensures compliance in acutely distressed individuals and improves sleep outcomes, providing relief from insomnia in patients who are too agitated or anxious to sleep.

Dosing of intravenous and intramuscular trazodone

According to the Italian prescribing information, intravenous or intramuscular trazodone can be prescribed at 100-200 mg (2-4 vials) twice daily. The optimal infusion dose (200 mg twice daily) or intramuscular dose (4 daily IM vials of 50 mg each) is usually reached on day 3 or 4 ¹⁶. In our clinical practice, we usually start patients at 50 mg twice daily on day one, then increase the dose to 50 mg three or four times daily on day two, and then adjust the dose as needed on subsequent days (A Fagiolini, personal communication).

Intravenous vials should be diluted in 250-500 mL of physiological solution for slow intravenous infusion (30-50 drops per minute). During the infusion period and for the next hour, the patient should remain in the supine position ¹⁶. In very elderly or debilitated patients, the recommended starting dose is 100 mg per day, given in divided doses or as a single dose to be taken in the evening. This dose may then be increased as described for the adult dose according to the physician’s judgment based on tolerability and efficacy. In general, single doses greater than 100 mg should be avoided in these patients. Doses greater than 300 mg per day are unlikely to be necessary¹⁶.

Clinical evidence supporting iv/im trazodone for depression with agitation and insomnia

Ballerio et al. ⁴ demonstrated the efficacy of parenteral trazodone in the management of psychomotor activation (PA) in 64 inpatients with bipolar disorder, showing significant improvement in CGI-S scores and overall symptom reduction. The study also noted improvements in sleep quality, particularly in patients with comorbid insomnia ⁴.

In addition, we ^2,3 highlighted trazodone’s ability to improve sleep onset and sleep maintenance in patients with depression, noting its broad therapeutic profile in the treatment of both agitation and insomnia. This makes trazodone a valuable tool in the treatment of depression-related sleep disturbances, particularly in acute settings where immediate intervention is required ².

Transition from IV-IM trazodone to Trazodone Contramid® (extended-release formulation)

Long-term benefits of trazodone XR

In addition to its acute use, oral extended-release Trazodone (Contramid^®) offers long-term benefits for patients with chronic insomnia associated with depression. Fagiolini et al. ² reported that trazodone was effective in improving sleep quality and reducing sleep latency, making it a useful agent for patients with depression-related insomnia. These improvements in sleep were found to be sustained over time, without the sedative hangover often seen with other sedative-hypnotics ².

By addressing both mood and sleep disturbances, trazodone helps to improve overall quality of life and daytime functioning, which are often impaired in patients with MDD and insomnia ².

Long term advantages of extended-release trazodone

The main advantage of XR Contramid^® Trazodone extended release include:

1. Consistent plasma levels: Trazodone XR avoids the peaks and valleys associated with immediate-release formulations, resulting in more consistent therapeutic effects and improved sleep quality ¹⁵.
2. Good tolerability and the possibility of starting treatment at a potentially antidepressant dose of 150 mg ².

In addition to its rapid action in the acute setting, trazodone’s long-term efficacy in the treatment of insomnia associated with depression is well established. By targeting 5-HT2A receptors, trazodone improves sleep continuity and sleep architecture, allowing patients to experience restorative sleep without significant next-day impairment ¹⁵. Unlike traditional sedative-hypnotics, trazodone does not carry the same risk of dependence, making it an appropriate choice for chronic use in the treatment of depression-related insomnia ².

Fagiolini et al. ² reported that patients who switched to Trazodone XR Contramid^® after acute stabilization with IV/IM trazodone not only experienced improvements in their depressive symptoms, but also reported significant improvements in sleep quality. By providing a once-daily dose that maintains consistent levels throughout the day and night, trazodone XR provides a sustained therapeutic effect on both mood and sleep, minimizing the risk of sleep disturbances and daytime sleepiness ².

Optimizing treatment outcomes: combined use of trazodone for insomnia, agitation, and depression

For patients with depression, insomnia, and psychomotor agitation, a two-phase approach using trazodone for both acute symptom relief and long-term stabilization offers significant advantages. This strategy ensures that both mood symptoms and sleep disturbances are effectively addressed, leading to better overall recovery.

Key benefits of combined – sequential trazodone use

The benefits of combined - sequential use of trazodone include

1. - Rapid stabilization: In the acute setting, IV/IM trazodone allows clinicians to quickly address psychomotor agitation and severe insomnia, which are often difficult to manage with oral medications alone ⁴.
2. - Lasting mood improvement: By addressing both mood and sleep simultaneously, trazodone ensures that patients experience sustained improvements in their depressive symptoms, leading to better daytime functioning and overall quality of life ².

Future directions and research needs

While the dual efficacy of trazodone in the treatment of depression, psychomotor agitation, and insomnia is well supported by clinical evidence, further research is needed in several areas:

1. 1. Comparative studies: More research comparing trazodone with other treatments, particularly newer antidepressants and sedative-hypnotics, is needed to fully establish its role in long-term insomnia treatment alongside mood stabilization ^2,3.
2. 3. Personalized treatment: Future research should focus on how to individualize trazodone treatment based on patient characteristics, including age, comorbid conditions, and severity of insomnia and depression. Tailoring trazodone regimens to the specific needs of each patient will further improve outcomes ¹⁵.

Conclusion

Agitation in depression represents a critical unmet need. Addressing this issue requires a multifaceted approach, including improved recognition, targeted research, and the development of effective treatment options. By focusing on this aspect of depression, we can improve patient outcomes and support. Trazodone, both in its parenteral form for acute treatment and in its extended-release formulation for long-term maintenance, offers a comprehensive treatment strategy for patients with major depressive disorder (MDD), particularly those presenting with psychomotor agitation and insomnia. Trazodone’s ability to rapidly stabilize agitation and severe sleep disturbances through IV or IM administration makes it an invaluable tool in the acute care setting. Once stabilized, transitioning to extended-release Trazodone (Contramid^®) ensures long-term therapeutic effects with low risk of sedative hangover or next-day impairment.

Clinical evidence from studies such as Ballerio et al. ⁴ and Fagiolini et al. ² highlight the efficacy of trazodone in improving mood symptoms, sleep quality, and overall patient outcomes. By simultaneously addressing both mood and sleep disturbances, trazodone provides a dual benefit that many other antidepressants do not. Further research is likely to expand trazodone’s role in the treatment of depression with insomnia, solidifying its place as a first-line option for patients with comorbid sleep and mood disorders.

Funding

Unrestricted grant from Angelini Pharma, Spa, Italy and Horizon Europe (HORIZON) Project 101095436 — Optimise andpredict antidepressant efficacy for patient with major depressive disorders using multi-omics analysis and AI-predictive tool (OPADE)

Conflict of interest statement

Andrea Fagiolini is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Boheringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Sunovion, Teva, Viatris

Alessandro Cuomo is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Idorsia, Lundbeck, Janssen, Otsuka, Pfizer, Recordati, Rovi, Teva, Viatris.

Author’s contributions

Both authors contributed to the literature research, analysis, and writing of this manuscript.

Ethical consideration

Not applicable.

Figures and tables

TABLE I. Mechanism of action of trazodone.

Mechanism	Effect
Serotonin reuptake inhibition	Increases serotonin availability, improved mood stability
5-hT2A receptor antagonism	Reduces anxiety, agitation; promotes sleep
Alpha-1 adrenergic receptor antagonism	Provides sedative effects, improves sleep onset

TABLE II. Benefits of IV IM trazodone.

Benefit	Description
Rapid onset of action	Provides noticeable effects within minutes
Manages agitation and insomnia	Effective control over agitation and insomnia in acute settings
Sedative effects	Calms patients, helps manage sleep disturbances
Improved sleep quality	Improves both sleep onset and maintenance

TABLE III. Advantage of extended-release trazodone.

Advantage	Description
Consistent plasma levels	Avoids peaks and troughs associated with immediate-release formulations
Once-daily dosing	Simplifies the dosing regimen, improving patient adherence
Reduced daytime sedation	Provides long-term relief without causing next-day drowsiness
Favorable tolerability	Well tolerated at doses starting from 150 mg