Despite lack of availability of reliable safety data, trazodone continues to be widely used for insomnia.1–6
Trazodone is a second-generation, atypical antidepressant with complex activity at the serotonergic, α-adrenergic and histaminergic pathways, which accounts for its antidepressant, anxiolytic, and hypnotic effects, respectively.7 This pharmaceutical profile can potentially lead to rare neuropsychiatric manifestations,8–11 especially in the context of polypharmacy, advanced age, and/or systemic illness.
An awareness of these rare but serious adverse reactions is critical, especially in the current practice environment where trazodone use is common and can further escalate given growing safety concerns associated with the use of conventional hypnotics especially in the elderly.6
An 81-year-old right-handed man with medical history significant for borderline (diet-controlled) diabetes mellitus type 2 and restless leg syndrome treated with pramipexole and low dose clonazepam was referred to us for the evaluation of generalized slowness.
The man was discharged from a community hospital approximately 3 weeks earlier after the treatment of community-acquired pneumonia. Around the time of discharge, he was started on trazodone 100 mg for insomnia, with instructions to increase the dose to 150 mg if needed. He returned to his primary care physician within a week of his discharge with complaints of generalized slowness and excessive fatigue. He reported taking trazodone 150 mg for the previous 5 days and sleeping soundly as a result.
He was noted to have diffusely slowed movements including gait, reduced facial expression, and speech volume. A well check conducted on the patient approximately a month earlier by the same physician was negative for any such findings.
He was referred to a general neurologist who diagnosed him with Parkinson disease, and dopamine replacement therapy was prescribed. The patient deferred the prescribed therapy and opted for consultation with a movement disorders neurologist for a second opinion.
Neurological assessment of this gentleman at the movement disorders center revealed mild slowness in information processing but otherwise normal mentation. He had moderate loss of facial expression (hypomimia) and moderate hypophonia without dysarthria. Rest tremor was absent; however, a fine, high-frequency (12–15 Hz) tremor was seen in both hands primarily with posture holding. Mild-moderate rigidity and moderate bradykinesia was present bilaterally and was slightly more pronounced on the left. Gait was slow with small shuffling steps without festination or freezing. Reduced arm swing and en bloc turning were noted. Postural stability testing revealed retropulsion. The remainder of his neurological examination including cranial nerves, motor, sensory, and cerebellar examination revealed only bilateral refractive visual error (corrected with glasses) and very mild sensory (likely diabetic) neuropathy confined to the feet. He was diagnosed as having bradykinetic-rigid parkinsonism meeting the severity criteria of modified Hoehn and Yahr stage 3. Given the subacute onset, a secondary cause was suspected.
The patient refused brain imaging. His laboratory assessment was significant only for a mildly increased hemoglobin A1c. Thyroid and parathyroid function was normal. Toxicology screen was positive for benzodiazepine in the setting of therapeutically prescribed clonazepam for restless leg syndrome.
Given that the patient reported the emergence of symptoms after the recent hospitalization and an earlier review of medications revealed that aside from albuterol inhaler that was continued from the time of hospitalization, the only newly prescribed medication that corresponded to the time frame of interest was trazodone, a trial of trazodone taper was planned.
Trazodone prescription was visually examined and verified as being correctly dispensed during the initial clinic visit. The patient was instructed to reduce trazodone by 25 mg every week. He, however, underwent a faster taper on his own accord and reported being off trazodone within a week. The doses of clonazepam (0.25 mg) and pramipexole (1.5 mg) at bedtime were maintained during this taper. He reported sleep initiation difficulty when trazodone dose was down to 25 mg, which he managed with over-the-counter melatonin intake. The patient reported complete resolution of slowness, stiffness, tremor, and fatigue within 1 week after stopping trazodone.
Reexamination approximately 4 weeks after the discontinuation of trazodone confirmed complete resolution of hypomimia, hypophonia, tremor, and rigidity. Very mild generalized bradykinesia (dramatically improved from the initial presentation) and presumed normal for the patient's age, persisted. Gait also returned to the prehospitalization state (per primary care provider's concurrence) and was significant only for mild reduction in speed and arm swing, as expected for his age.
To our knowledge, this is the first reported case of rapid development of bradykinetic-rigid variety of parkinsonism after brief exposure to moderate doses of trazodone in a nondepressed elderly man.
The literature describes 2 previous cases of trazodone-induced reversible parkinsonism after its prolonged use as an antidepressant.9,10
Our case is unique because (a) it involves a nondepressed person and (b) parkinsonism manifested rapidly within a week of taking trazodone solely as a hypnotic. Trazodone as the likely culprit in this case is supported by the following:
- The patient's baseline examination before trazodone exposure was not consistent with parkinsonism.
- Features of parkinsonism (bradykinesia, rigidity, hypomimia, and hypophonia) developed within 1 week of exposure to trazodone.
- Parkinsonism fully reversed within 1 week of complete withdrawal of trazodone.
Although the exact underlying mechanism causing parkinsonism after the exposure of trazodone in this or any of the previously described cases remains elusive, it likely involves trazodone's inhibitory effect, either directly or via the serotonergic system on striatal dopaminergic neurotransmission.7,8,12–16
It is known that serotonin (5-hydroxytryptamine [5-HT]), via stimulation of 5-HT2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT2A receptors enhances dopaminergic neurotransmission. The antidepressant trazodone is a 5-HT2A and 5-HT2C receptor antagonist.7,16 However, its antagonism at 5-HT2A receptor is more robust than that at 5-HT2C receptors (15-fold difference).7,8 Hence, the differential antagonist effect of trazodone with respect to 5-HT2A versus 5-HT2C receptors “at a certain dose point” could potentially result in inhibition of dopaminergic neurotransmission in the striatonigral region.
In addition, a direct dose-dependent blocking effect of trazodone on postsynaptic striatal D2 dopamine receptors has been demonstrated in the rat model.8
Trazodone is also a serotonin reuptake inhibitor.17 The serotonin system in the animal models has been shown to inhibit the dopaminergic function in the midbrain as well as at the terminal dopaminergic fields in the forebrain.12,14 Trazodone-induced worsening of parkinsonism has been demonstrated in marmoset model.18
Although the observations from the animal studies cannot be assumed to be fully reproducible in humans and the true mechanism of the development of parkinsonism by trazodone remains unclear, the previously mentioned interplay remains potentially thought provoking and should be kept in mind, especially in the current environment where trazodone is being viewed as a potential neuroprotective “wonder drug” for neurodegenerative diseases19 including Parkinson disease. Hence, it is likely to be prescribed more fervently to manage depression, anxiety, or insomnia or even solely for its presumed “neuroprotective effect” in this patient population.
The short duration for the emergence of parkinsonism in our case compared with the previous 2 published cases not only may hypothetically be due to some yet uncharacterized predisposition in this patient but may also reflect possible “less tolerance” for the enhancement of serotonergic neurotransmission and its complex interplay with dopaminergic system in a “nondepressed” and hence chemically “healthier” brain (than a depressed brain), highlighting potentially another unique effect of using antidepressants in nondepressed versus depressed individuals.20
Another key practice point that needs to be underscored is the general lack of awareness among the health care providers regarding drug-induced parkinsonism caused by commonly used antidepressants. A high index of suspicion coupled with careful history can greatly improve clinical recognition of these cases.
Trazodone's use as a hypnotic can cause parkinsonism in nondepressed elderly. All health care providers should be aware of this serious but seemingly fully reversible potential adverse effect.
1. Kaye AD, Sutker PB. Psychiatric and behavioral disorders. In: Anesthesia and Uncommon Diseases
. 6th ed. Philadelphia: Saunders; 2012:444–469.
2. James SP, Mendelson WB. The use of trazodone
as a hypnotic
: a critical review. J Clin Psychiatry
3. Walsh JK. Epidemiology of insomnia
treatment. Presented at: the 41st meeting of the New Clinical Drug Evaluation Unit; May 28–31, 2001; Phoenix, Arizona.
4. Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia
5. Mort JR, Aparasu RR. Prescribing potentially inappropriate psychotropic medications to the ambulatory elderly. Arch Intern Med
6. Ancoli-Israel S. Insomnia
in the elderly: a review for the primary care practitioner. Sleep
7. Marek GJ, McDougle CJ, Price LH, et al. A comparison of trazodone
and fluoxetine: implications for a serotonergic mechanism of antidepressant
action. Psychopharmacology (Berl)
8. Balsara JJ, Jadhav SA, Gaonkar RK, et al. Effects of the antidepressant trazodone
, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. Psychopharmacology (Berl)
9. Albanese A, Rossi P, Altavista MC. Can trazodone
? Clin Neuropharmacol
10. Fukunishi I, Kitaoka T, Shirai T, et al. A hemodialysis patient with trazodone
11. Sotto Mayor J, Pacheco AP, Esperança S, et al. Trazodone
in the elderly: risk of extrapyramidal acute events. BMJ Case Rep
12. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry
13. Haleem DJ. Serotonergic modulation of dopamine neurotransmission: a mechanism for enhancing therapeutics in schizophrenia. J Coll Physicians Surg Pak
14. Ugedo L, Grenhoff J, Svensson TH. Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology (Berl)
15. Govoni S, Racchi M, Masoero E, et al. Extrapyramidal symptoms and antidepressant
drugs: neuropharmacological aspects of a frequent interaction in the elderly. Mol Psychiatry
16. Ghanbari R, El Mansari M, Blier P. Electrophysiological impact of trazodone
on the dopamine and norepinephrine systems in the rat brain. Eur Neuropsychopharmacol
17. Stahl SM. Mechanism of action of trazodone
: a multifunctional drug. CNS Spectr
18. Hamadjida A, Nuara SG, Gourdon JC, et al. Trazodone
alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson's disease. J Neural Transm (Vienna).
2017. doi: 10.1007/s00702-017-1830-8. [Epub ahead of print].
19. Halliday M, Radford H, Zents KAM, et al. Repurposed drugs targeting eIF2α-P–mediated translational repression prevent neurodegeneration in mice. Brain
. 2017;140(6):1768–1783, https://doi.org/10.1093/brain/awx074
20. Willard S, Uberseder B, Clark A, et al. Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates. Neuropharmacology