Introduction
Mirtazapine, an antidepressant with multiple receptor effects, is commonly used for the treatment of depression in elderly. It is typically favored in patients suffering from insomnia and weight loss secondary to depression. It is generally considered safe to use in the elderly. Here we report three cases in which use of mirtazapine led to dose-dependent induction of hallucinations. All three patients in this report gave written informed consent to publication in this journal.
Case summaries
Case 1
Mr. A, an 88-year-old Caucasian male, was treated with fluoxetine 20 mg daily for depression. He reported worsening symptoms after his wife passed away. He also reported dry mouth and dizziness, which he attributed to the use of fluoxetine. His past medical history included atrial fibrillation, hypertension, hyperlipidemia, insomnia, coronary artery disease and chronic constipation. His other medications included trazodone, enteric coated aspirin, carvedilol, digoxin, lisinopril, simvastatin, niacin, psyllium, and milk of magnesia. He was cognitively intact and had no hearing problems. Fluoxetine was tapered and mirtazapine was added. It was slowly titrated to 30 mg nightly. Dizziness and dry mouth resolved completely after fluoxetine was stopped. He had a good response to his depression with 30 mg of mirtazapine but continued to have some residual symptoms. The dose was increased to 45 mg to target residual symptoms.
Three days after increasing the dose to 45 mg he developed music hallucinations. He heard “elevator music” throughout the day. Initially he searched for a radio in his house but later accepted that it was not real. He was annoyed by the music. The dose of mirtazapine was reduced to 30 mg and the hallucinations resolved after the second day of dose reduction. He was followed closely and did not have any worsening of depression.
Case 2
Mrs B, a 77-year-old Caucasian woman, presented with depression. Her dog had recently been put to sleep and her room-mate had a worsening physical condition. She had spells of excessive crying, low spirits and decreased energy. She reported chronic insomnia and recent loss of appetite. She also reported feelings of hopelessness and worthlessness but denied suicidal or homicidal ideations. She denied any hallucinations or delusions. Her past medical history included hypertension, hyperlipidemia, osteoporosis, urinary incontinence, mild cognitive impairment and history of falls. Her medications included metoprolol, atorvastatin, multivitamin, calcium, and alendronate. Her baseline labs were within normal limits. Mirtazapine was started at 7.5 mg and increased to 15 mg daily in two weeks. Three days after the increase in dose, she reported seeing a woman in her bed every night and was very upset about this. No prior problems with vision were reported. The patient's daughter reported improvement in crying spells, energy and spirits, but the hallucinations continued. The dose of mirtazapine was decreased to 7.5 mg nightly. The hallucinations stopped, but her symptoms of depression worsened.
Case 3
Mr. C, a 58-year-old Caucasian male, presented with a history of post-traumatic stress disorder (PTSD). He had been a helicopter pilot in Vietnam and had witnessed a helicopter crash in which three of his friends died. He had nightmares and flashbacks three or four times a week. He reported insomnia, hopelessness, and helplessness. He denied any hallucinations or delusions. His past medical history included hyperlipidemia, gastro-esophageal reflux disease and alcohol dependence in sustained full remission. His medications included simvastatin, citalopram, temazepam, and ranitidine. PTSD therapy was administered along with citalopram without much improvement in his symptoms. Mirtazapine was started as an augmentation agent at 15 mg nightly. A week after the mirtazapine was started Mr. B started hearing voices. He thought that the voices were from people in the next apartment. He heard voices talking among themselves. These were not related to his combat experience nor did they have any derogatory content. He denied any command hallucinations. Mirtazapine was discontinued and the hallucinations stopped on the fourth day of discontinuation.
Discussion
Mirtazapine is a tetracyclic antidepressant with noradrenergic and serotonergic activity. It acts as an antagonist of central presynaptic α2-adrenergic inhibitory receptors, where it effectively increases the levels of norepinephrine and serotonin in the synapse. It is a potent antagonist of 5-HT1 and 5-HT3 receptors. It is also a potent antagonist at histamine H1 receptors which leads to sedation, and a moderate peripheral α1-adrenergic antagonist (de Boer, Reference de Boer1995; Stimmel et al., Reference Stimmel, Dopheide and Stahl1997).
The decision to treat depression with mirtazapine is often influenced by its side effect profile. The most common side effect of mirtazapine is somnolence, which may occur in 50% of patients. Weight gain is also commonly observed secondary to increased appetite in 15% of patients. Because of these effects, mirtazapine is commonly used to treat depression in patients with concomitant insomnia and weight loss. Other common side effects include dry mouth, constipation, and dizziness. The relative tolerability of mirtazapine, along with its side effect profile, makes it a first-line medication for many elderly patients suffering from major depression.
These three cases suggest a relationship between mirtazapine use and auditory and visual hallucinations. The appearance of hallucinations in these patients shortly after starting the medication or after an increase in dose, and their resolution shortly after the decrease in the dose or stopping the medication suggest that these effects are drug-induced. The Naranjo criteria used for estimating probability of adverse drug reaction was calculated separately for all three cases (Naranjo et al., Reference Naranjo1981). It does confirm that mirtazapine was the probable cause of hallucination in each case.
Although perceptual abnormalities have not been reported earlier, an association of delirium with the use of mirtazapine has been reported. Bailer et al. (Reference Bailer, Fischer, Kufferle, Stastny and Kasper2000) reported mirtazapine-induced delirium in three patients with organic brain disorders. Normann et al. (Reference Normann, Hesslinger, Frauenknecht, Berger and Walden1997) published a case of mirtazapine-induced delirium in a parkinsonism patient taking levodopa.
The mechanism by which mirtazapine may cause hallucinations is unknown. Three hypotheses have been put forward to explain this. One is the serotonergic delirium hypothesis, the second is the norepinephrine oversensitivity hypothesis and the third is the dopaminergic hypothesis. Bailer et al. (Reference Bailer, Fischer, Kufferle, Stastny and Kasper2000) offer a serotonergic delirium hypothesis as well as a norepinephrine oversensitivity hypothesis to explain the development of delirium in three patients. The case for serotonin being the culprit is weakened as none of the reported patients met criteria for serotonin syndrome, and mirtazapine has even been described as a treatment for serotonin syndrome. Oversensitivity to acute increases of norepinephrine following mirtazapine initiation is a possible explanation as centrally increased nor-epinephrine has been observed in certain types of delirium (Bailer et al., Reference Bailer, Fischer, Kufferle, Stastny and Kasper2000).
Recent studies have shown a pronounced increase in dopamine levels in the frontal cortex of patients being treated with mirtazapine (Nakayama et al., Reference Nakayama, Sakurai and Katsu2004). This occurs, as a result of α2-adrenergic blockade leading to increased co-release of norepinephrine and dopamine from noradrenergic terminals (Millan et al., Reference Millan2000). Dopamine is a likely contributor to psychosis as evidenced by the effect of antipsychotics on central dopamine receptor function (Rogoz et al., Reference Rogoz, Wrobel, Dlaboga and Dziedzicka-Wasylewska2002). Dopamine D2 receptors are thought to play a significant role in the pathophysiology of schizophrenia (Devoto et al., Reference Devoto, Flore, Pira, Longu and Gessa2004). The reported case of mirtazapine-induced delirium in a patient with Parkinson's who was taking levodopa also supports a dopamine hypothesis (Normann et al., Reference Normann, Hesslinger, Frauenknecht, Berger and Walden1997).
Conclusion
Mirtazapine, a common antidepressant used in the elderly, has a relatively safe side effect profile. However, one needs to be cautious when starting the medication or when increasing the dose, particularly with regard to side-effects such as hallucinations.
Conflict of interest
None.
Description of authors’ roles
K. Padala contributed to two case summaries and wrote the paper. P. Padala contributed one case summary and wrote sections of the paper. T Malloy provided critical review to develop the paper. W. Burke provided a critical review of the paper, particularly the discussion section.
