Trazodone

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Trazodone, [Fig.1] a triazolopyridine derivative belonging to the class of serotonin antagonist an reuptake inhibitors (SARI), is used in the treatment of depression [1] and is currently approved by the FDA to treat major depression [2]. Trazodone has been branded as Desyrel – trazadone hydrochloride (HCl), and its uses, besides its antidepressant activity, include treating medical and psychiatric disorders [3], along with the treatment of post-traumatic stress disorder (PTSD), insomnia, anxiety disorders, obsessive compulsive disorders (OCD), eating disorders, abuse of substances, impediments in cognitive functioning, sexual dysfunction, and particularly in rehabilitation following acute ischemic stroke [3; 4]. Specifically, trazodone HCl [Fig.1] is considered an anti-depressant agent. The way trazodone works is through its antagonism of the serotonin receptor (5-HT2A), alpha 1 and histamine H1 receptors, and this permits the drugs hypnotic effects (at low doses), whilst a high trazodone dose blocks serotonin transporter (SERT) and 5-HT2A allowing for its antidepressant activity [2].  In addition, due to trazodone’s strong antagonistic action at serotonergic type 2 (5-HT2) receptors it is known to quickly improve sleep [5; 1]. Further, trazodone’s pharmacological mode of action is such that a very low dose – 1mg trazodone – can block half of the brain’s 5-HT2A receptors [1].

 

trazodone structure

Figure 1. Structure and formula of trazodone. Trazodone (left) is a dual-acting antidepressant, able to inhibit the serotonin transporter (SERT) and serotonin type II (5-HT2) receptor [6]. Trazodone (C19H22CIN5O) molecular weight of 408.33 [7].

Clear

Trazodone is used for the treatment of depression [2]. Also, trazodone is widely used in treating insomnia due to its capacity to normalise sleep behaviour in depressed patients [6]. Trazodone’s half-life is between 5 and 23 hours [8].

 

Treating Insomnia and sleep

 

It has been identified by Jaffer et al (2017) that a ‘significant number of [clinical] trials have evaluated…the effectiveness of trazodone in the treatment of insomnia.’ The clinical definition of insomnia is a ‘subjective disorder’ in which an overall poor quality sleep pattern is observed for sufferers, increasing the risk of other complications such as hypertension, stroke and mental disorders [9]. Out of 45 studies, it was shown that trazodone was indeed effective in treating insomnia [1]. In addition, trazodone was evaluated as being effective in decreasing sleep latency and increasing the duration of sleep [1]. In a randomised study assessing the individual and combined (using trazodone (100mg)) cognitive behaviour therapy (CBT) on primary insomnia, results showed that both single and combined CBT was effective in treating short-term chronic primary insomnia [10]. Further, a meta-analysis of randomised placebo-controlled trials evaluating trazodone for the treatment of insomnia concluded that trazodone is a well-tolerated hypnotic for patients suffering from primary and secondary insomnia [9]. Trazodone assists primary and secondary insomnia through decreasing stage 1 and REM duration; increasing slow-wave-sleep (SWS) (stages 3 and 4), and improving early morning awakening (EMA) and sleep duration and efficiency [11].

 

Treating anxiety

 

Anxiety, or generalised anxiety disorder (GAD), is a commonly occurring psychiatric condition wherein disproportionate worry interrupts daily life [12]. In addition, anxiety disorders share characteristics of excessive fear; the anticipation of a future threat [13]. Importantly, guidelines suggest that antidepressants are the first-line treatment for GAD [12], and, according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), anxiety disorders include: panic disorders (PD), generalised anxiety disorder (GAD), social anxiety disorder (SAD) and separation anxiety disorder [13]. Table 1 and figure 2 summarise the neurological changes upon perceived anxiety. One study measured the efficacy and tolerability of trazodone [14] administered intravenously in a group of patients diagnosed with Major Depressive Disorder (MDD). Results indicated that trazodone does have a statistically significant impact on the Hamilton Depression rating Scale scores derived from participant responses [14]. Trazodone, in conjunction with – and independent of – panic management was used to assess its effectiveness of panic disorder [15]. However, results displayed that both panic management and trazodone were marginally effective when compared to placebo [15].

Table 1. Anxiety leads to changes in the brain.

Disorder Brain alterations
Anxiety Activation of the fear network: thalamus, amygdala, hippocampus and striatum.
Panic Activation of the brain stem and hypothalamus.
General anxiety Activation of prefrontal cortex and anterior cingulate to threat.
Social anxiety Activation of amygdala, response to social stimuli.

 

trazodone brain

Figure 2. Brain changes associated with trazodone [Image modified from Hanson et al., 2017].

Trazodone use in dogs

 

Interestingly, trazodone is used to decrease anxiety in hospitalised dogs [16]. Previously, trazodone has also been described as treating anxiety disorders – alone or in combination therapy – in dogs, effectively reducing anxiety and improving patient welfare [17]. In a prospective open-label trial experiment, 36 client-owned dogs were recruited to document the calming effect of trazodone hydrochloride (HCl)  after orthopaedic surgery [17]. Results suggested that trazodone was a both safe and efficacious medication that enhanced calmness during the recovery period post-orthopaedic surgery [17].

Dosage

Once  consumed, trazodone peaks in plasma after 1 hour of ingestion, or 2 hours when consumed with food [3]. In an investigation into the pharmacokinetics of trazodone in eight healthy subjects [18], trazodone was administered orally at 100mg [18]. Subjects ingested 100mg trazodone with, and without food and results showed that food intake lowered serum concentrations of trazodone; however, consumption of trazodone in both instances did not affect bioavailability of trazodone, but that trazodone is highly metabolised. This owes to the low recovery in urine of intact trazodone [18]. Single-dose trazodone – 50-100mg/day – was given to 75 depressed patients who experienced sleep disorders [19]. Over two weeks, participants were first given an initial dose of 50mg/day, in which – over the remaining four weeks – this dose rose to 50, 75 and 100mg/day; a total of 6 weeks [19]. Interestingly, results showed trazodone, at a 50-100mg/day dose improved the sleeping disorders experienced by participants, after two weeks of treatment [19]. In this study, trazodone was recommended to be consumed before bedtime [19]. Trazodone’s profile – in a prolonged release context – was compared with paroxetine in treating major depressive disorder (MDD) [20]. Given to 55 patients at a dose of 150-450mg/day, with mean dose being 305mg/day, trazodone – and similarly paroxetine (given to 53 patients) – was concluded as having antidepressant effects [20] over the six-week period. In addition, authors noted that trazodone might be advantageous for depressed individuals with sleeping difficulties [20].

 

Trazodone was administered – starting at 4mg/kg every 12 hours, and increased to 10 to 12mg/kg. Dose did not exceed 300mg per dose [21]. Results indicated that treating hospitalised dogs with trazodone – over a broad dose range – can alleviate some symptoms of stress: lip licking, panting, whining, improving these behaviours after 90 minutes of trazodone treatment [21].

Safety

Out of 200 prescription drugs trazodone HCl was ranked at 29th as most prescribed drug, in 2010 [17]. This has provided a long safety record of use for the antidepressant [17]. However, the synthesis of prolonged-release trazodone tablets in 1981 were marketed in order to limit high (peak) plasma trazodone concentrations [6]. Adverse effects have been recorded with this high peak trazodone plasma concentration, which may interfere with the therapeutic dose of trazodone in depressed patients [6]. Trazodone [acute] overdose has previously been reported in the literature [23] and in the adult population [Zahran et al., 2018]. In one case, an individual suffered from severe depression, and was treated with 100mg/day trazodone and fluvoxamine [23]. Reported cases of trazodone overdose show that dose ranged from 350mg – 8g, with some records of blood plasma concentrations of above 25g/mL [23; 24] – therapeutic concentrations are 1-1.5g/mL [23; 25]. It is also important to note that data on toxic doses in children have not been established [25]. For dogs, where the LD50 of trazodone is 500mg/kg, trazodone overdose is signalled by sedation and hypotension, with seizures and tremors occurring at the serotonin agonist range of 6-8mg/kg [26]. In terms of hepatotoxicity – damage to liver cells – tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) have higher capacity to cause liver damage [27]. Data evaluating whether trazodone demonstrates action against compulsive behaviours has yet to be determined from controlled studies [28]. One randomised, double-blind placebo-controlled study of 50-100mg doses of trazodone on 172 alcohol detoxified patients revealed to have negative consequences for alcoholics – post-detoxification [29]. Authors note that further studies must be conducted to assess trazodone – safety and benefits – on improving sleep for recovering alcoholics [29], and that trazodone is not adequate in treating sleep disturbance in this context [2].

Side effects

Side effects of trazodone include: nausea, anxiety, insomnia, dry mouth, headaches, Dizziness, anorexia, diarrhoea, constipation, tremors and sexual dysfunction [30; 2]. Further, trazodone exhibits less anticholinergic effects indicating that this antidepressant has less cardiotoxic ability when compared with other antidepressants [2]. Trazodone has previously been studied in alcohol-dependent subjects in which results indicated trazodone might reduce relapse rates after acute detoxification [28]. As trazodone is an SSRI and newer antidepressant, it has been attributed to weight gain [27]. A recent ‘SSRI discontinuation syndrome’ has detailed the withdrawal symptoms of which commencement of withdrawal occurs within one week of discontinuation [31]. Symptoms, commonly, range from dizziness, headache nausea and lethargy, which are resolved within 48 hours of recommencement of SSRI uptake [31].

References

[1] Karim Yahia Jaffer, Tiffany Chang, Brigitte Vanle, Jonathan Dang, Alexander J. Steiner, Natalie Loera, Marina Abdelmesseh, Itai Danovitch, and Waguih William Ishak, 2017. trazodone for insomnia: A Systematic Review. Innov Clin Neurosci. 2017;14(7–8):24–34

[2] Letizia Bossini, Ilaria Casolaro, Despoina Koukouna, Federica Cecchini & Andrea Fagiolini, 2012. Off-label uses of trazodone: a review. Expert Opin. Pharmacother. (2012) 13(12):1707-1717.

[3] Hani Raoul Khouzam, 2017. A review of trazodone use in psychiatric and medical conditions. Postgraduate Medicine, 2017. vol. 129, no. 1, 140–148.

[4] Steven P. James, M.D., and Wallace B. Mendelson, M.D. 2004. The Use of Trazodone as a Hypnotic: A Critical Review. Jounral of clinical Psychiatry 65:6.

[5] Adam Wichniak & Aleksandra Wierzbicka & Małgorzata Walęcka & Wojciech Jernajczyk, 2017. Effects of Antidepressants on Sleep. Curr Psychiatry Rep (2017) 19: 63, DOI 10.1007/s11920-017-0816-4.

[6] Andrea Fagiolini, Alessandro Comandini, Mario Catena Dell’Osso, Siegfried Kasper, 2012. Rediscovering Trazodone for the Treatment of Major Depressive Disorder. CNS Drugs (2012) 26:1033–1049, DOI 10.1007/s40263-012-0010-5.

[7] Desyrel, FDA report. Reference ID: 4119349

[8] Public Assessment Report. Medicines and Healthcare products Regulatory Agency.

[9] Xiao-yan Yi, Shi-fen Ni, Mohammad Rasoul Ghadami, Hua-qing Meng, Ming-yan Chen, Li Kuang, Yu-qing Zhang, Li Zhang, Xin-yu Zhou, 2018. Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Medicine 45 (2018) 25-32. https://doi.org/10.1016/j.sleep.2018.01.010.

[10] Lucie Zavesicka, Martin Brunovsky, Jiri Horacek, Milos Matousek, Peter Sos, Vladimir Krajca, & Cyril Hoschl, 2008. Trazodone improves the results of cognitive behaviour therapy of primary insomnia in non-depressed patients. Neuroendocrinol Lett 2008;29(6):101–000.

[11] Zahra Mirsepassi, Shima Saedi, Haleh Behpournia, Behrang Shadloo, Valentin Artounian, Seyyed Taha Yahyavi, Maryam Tabatabaei, Mehdi Soleimani, Sana Khajehpour, Padideh Ghaeli, 2016. Comparing Effects of Melatonin versus Trazodone on Sleep Quality in Major Depressed Patients Receiving Sertraline. J Pharm Care 2016; 4(3-4): 52-57.

[12] Guaiana G, Barbui C, Abouhassan R, 2018. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD012942. DOI: 10.1002/14651858.CD012942.

[13] Christel Hanson, William Modiba, 2017. Overview and management of anxiety disorders. S Afr Pharm J; 84(5):43-50.

[14] Alessio Fiorentini, Chiara Rovera, Alice Caldiroli, Chiara Arici, Cecilia Prunas, Chiara Di Pace, Silvia Paletta, Sara Maria Pozzoli, Massimiliano Buoli, and Carlo Altamura, 2018. efficacy of oral trazodone slow release following intravenous administration in depressed patients: a naturalistic study. riv psichiatr 2018; 53(5): 261-266.

[15] Philip Spinhoven, Evert J. Onstein, Rene A. Klinkhamer, Elise A.M. Knoppert-van der Klein, 1996. Panic Management, Trazodone and a Combination of Both in the Treatment of Panic Disorder. Clinical Psychology and Psychotherapy, vol. 3 (2), 86-92.

[16] Elizabeth A Hoffman, Turi K Aarnes, Carolina H Ricco Pereira, Phillip Lerche, Richard M Bednarski & Mary A McLoughlin, 2018. Effect of oral trazodone on the minimum alveolar concentration of isoflurane in dogs. Veterinary Anaesthesia and Analgesia 2018

[17] Margaret E. Gruen, Simon C. Roe, Emily Griffith, Alexandra Hamilton, and Barbara L. Sherman, 2014. The Use of Trazodone to Facilitate Post-Surgical Confinement in Dogs. J Am Vet Med Assoc. 2014 August 1; 245(3): 296–301. doi:10.2460/javma.245.3.296.

[18] Odd G. Nilsen and Ola Dale, 1992. Single Dose Pharmacokinetics of Trazodone in Healthy Subjects. Pharmacology and Toxicology, 71, 150-153.

[19] Hirobumi Mashiko, Shin-Ichi Niwa, Hisashi Humashiro, Yoshihiro Kaneko, Satoru Suzuki, Yoshihiko Numata, Ryu Horikoshi, and Yoshinori Watanabe, 1999. Effect of trazodone in a single dose before bedtime for sleep disorders accompanied by a depressive state: Dose- finding study with no concomitant use of hypnotic agent. Psychiatry and Clinical Neurosciences (1999), 53, 193–194.

[20] S. Kasper, L. Olivieri, G. Di Loreto  and P. Dionisio, 2005. A comparative, randomised, double-blind study of trazodone prolonged-release and paroxetine in the treatment of patients with major depressive disorder. Current Medical Research and Opinion, vol. 21, no. 8, 2005, 1139–1146.

[21] Shana E. Gilbert-Gregory, Jason W. Stull, Mary Rose Rice, Meghan E. Herron, 2016. Effects of trazodone on behavioural signs of stress in hospitalized dogs. JAVMA, Vol 249, No. 11.

[23] A. de Meester, G. Carbutti, L. Gabriel, JM. Jacques, 2001. Fatal Overdose with Trazodone: Case Report and Literature Review. Acta Clinica Belgica, 2001; 56-4.

[24] Irving Root and Gregory B. Ohlson, 1984. Trazodone Overdose: Report of Two Cases. Journal of Analytical Toxicology, vol.8.

[25] Tharwat El Zahran, Brent W. Morgan, Stephanie Hon, Lloyd Herrington & Robert J. Geller, 2018. Unintentional trazodone overdoses in children 6 years of age: data from poison center over a period of 16 years. CLINICAL TOXICOLOGY https://doi.org/10.1080/15563650.2018.1485928.

[26] Tina A. Wismer, 2000. Antidepressant drug overdoses in dogs. Veterinary Medicine Publishing Group.

[27] Sheng-Min Wang, Changsu Han, Won-Myoung Bahk, Soo-Jung Lee, Ashwin A. Patkar, Prakash S. Masand, and Chi-Un Pae, 2018. Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review. Chonnam Med J 2018;54:101-112.

[28] L. JANIRI, A. HADJICHRISTOS, A. BUONANNO, R. RAGO, P. MANNELLI and S. DE RISIO, 1998. ADJUVANT TRAZODONE IN THE TREATMENT OF ALCOHOLISM: AN OPEN STUDY. Alcohol and Alcoholism vol. 33, no.4, pp. 362-365.

[29] Peter D. Friedmann, MD, MPH, Jennifer S. Rose, Robert Swift, Robert L. Stout, Richard P. Millman, and Michael D. Stein, 2008. Trazodone For Sleep Disturbance After Alcohol Detoxification: A Double-Blind, Placebo-Controlled Trial. Alcohol Clin Exp Res. 2008 September ; 32(9): 1652–1660. doi:10.1111/j.1530-0277.2008.00742.x.

[30] Khushboo and Sharma B, 2017. Antidepressants: Mechanism of Action, Toxicity and Possible Amelioration. J Appl Biotechnol Bioeng 2017, 3(5): 00082.

[31] Peter Haddad, 1998. The SSRI discontinuation syndrome. Journal of Psychopharmacology 12(3): 305-313.

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