Trazodone Is Not As Effective As Other Antidepressants in Treating a Patient with Major Depressive Disorder

Case Report Taiwanese Journal of Psychiatry (Taipei) Vol. 26 No. 4 2012 • 311 •

Trazodone Is Not as Effective as Other Antidepressants in Treating a Patient with Major Depressive Disorder

Kah Kheng Goh, M.D.1, Weng-Kin Tam, M.D.1, Winston W. Shen, M.D.1, 2*

Background: Trazodone in clinical use is ineffective because of its sedation to let patient receive an adequate dose for treating a patient with major depressive disorder. We are report a case report to demonstrate this clinical efﬁ cacy issue in the treatment with trazodone. Case Report: A 83-year old male Taiwanese patient had suffered from MDD for six months. He did not response to the treatment of trazodone 150 mg/day for four months, but consequently, he responded to the treatment of milnacipran 100 mg/day or mirtazapine 30 mg/day. Conclusion: Psy- chiatrists in Taiwan should be alert to the fact that trazodone is not as effective as other antidepressants, and that trazodone should not be prescribed as a single antidepressant in treating an MDD patient.

Key words: antidepressant therapy, suicide, venlafaxine, bupropion (Taiwanese Journal of Psychiatry [Taipei] 2012; 26: 311-5)

guideline in the paragraph in describing individu- Introduction al drug trazodone also indicates “other investigators found trazodone to be less effective than other The practice guideline of the American antidepressant medications” [1]. In this case re- Psychiatric Association in the paragraph of intro- port here, we are reporting a case of a major de- ducing antidepressants states “Although some pressive disorder (MDD) patient, who did not re- studies have suggested superiority of one mecha- spond to daily dose of 150 mg of trazodone, but nism of action over another, there are no replica- responded well to antidepressants 100 mg of mil- ble or robust ﬁ ndings to establish a clinically nacipran per day and maybe 30 mg of mirtazapine meaningful difference. For most patients, the ef- per day consequently. fectiveness of antidepressant medications is gen- erally comparable between classes and within classes of medications” [1]. But the same practice

Departments of Psychiatry, Wan Fang Medical Center,1, 2 and School of Medicine,2 Taipei Medical University Received: November 23, 2012; revised: November 26, 2012; accepted: November 26, 2012 *Corresponding author. Department of Psychiatry, TMU-WFMC, 111, Section 3, Shing Long Road, Taiwan 116, Taiwan E-mail: Winston W. Shen • 312 • Trazodone is an Ineffective Antidepressant

then, he was instructed to move up the dose to 100 Case Report mg/day on day 7. At his request, he received es- tazolam 2 mg/day to replace for zolpidem due to An 83-year old male patient had been enjoy- his report of occasional complex behaviors such ing his 17-year retirement life in singing songs at as occasional sleep-walking induced by zolpidem a local karaoke club and making frequent trips un- [2]. He was also instructed to taper off trazodone til eight months previously. When he was seen at by 50 mg every four days, to discontinue estazol- the clinic with his wife in September 2012, he and am 0.5 mg every night, and to continue to take his his wife described his being depressed with severe previous alprazolam 0.5 mg by month t.i.d. At chronic insomnia. He had been treated at a psychi- visit 2 on September 18, two weeks later, the pa- atric clinic at a medical center for more than four tient reported that he had faithfully been taking months with daily trazodone 150 mg, alprazolam medications and had tolerated them well without 1.5 mg and zolpidem 10 mg. He also specifi cally any complaint of side effects except decreased ap- mentioned that he had been taking alprazolam petite, and that he got some appreciable benefi t with the above noted dosage from a non-psychia- especially in the improved insomnia and other trist physician for more than 10 years. MDD symptoms and signs. At visit 4 on October In the mental status examination at clinic 2, another two weeks later, he started to wonder visit 1 on September 4, 2012, the patient presented whether that he could have his milnacipran dis- himself with sad mood, lack of interest, insomnia, continued because of weight loss of 3 kg (from 68 irritability, lack of energy, guilty feeling towards kg to 65 kg) after being on milnacipran for four his wife, inability in concentration, and vague sui- weeks. He was persuaded to stay on milnacipran cidal idea. He was not demented and he denied and he agreed to do so. any delusion and hallucinations. He had stopped At visit 5 on October 11, or day 37 from his singing and travelling in the past six months after fi rst clinic visit here, the patient had showed fur- the onset of his MDD. He had 172 cm in height ther improvement in mood, but still insisted on and 68 kg in weight. He denied any history of ma- having his milnacipran discontinued because he jor operations, drug allergy, or substance abuse. planned to take a sight-seeing gourmet trip to Medical history showed his 20-year history of hy- Japan. As a compromise, we gave him on top of pertension and diabetes mellitus under unknown existing milnacipran 100 mg/day, 30 mg per night oral medications prescribed from a medical clinic of mirtazapine starting three days before his 10- at a different hospital. He reported his depression day trip. At visit 6 on October 24, he came back family history that his sister, four years younger from his 10-day trip, and reported his further im- than the patient, suffered from MDD. She had re- provement under daily combined milnacipran 100 ceived 150 mg/day of trazodone and two benzodi- mg and mirtazapine 30 mg. He also mentioned azepines from our patient’s previous psychiatrist that was pleased to regain his lost body weight of for more than six months, but committed suicide 3 kg. After being offered to have one of two anti- six months previously. depressants discontinued, he chose to stay on mir- At visit 1 on September 4 at the clinic, the tazapine 30 mg/night and stopped taking mil- patient initially received 25 mg/day of milnacip- nacipran after a gradual taper. At visit 7 on ran on days 1-4 and 50 mg/day on days 5 and 6, November 8, he continued to have his remitted Goh KK, Tam WK, Shen WW • 313 •

state from MDD, and received a three-week sup- tients. Of interest, a signifi cant proportion of tra- ply of mirtazapine and alprazolam 0.5 mg t.i.d., zodone was prescribed for mood or anxiety disor- with the instruction to taper off alprazolam 0.5 mg ders without having diagnostic code of sleep per week. His body weight stayed at 68 kg. At disorders [3]. In a set of unpublished data consist- visit 8, November 22, he came back for another ing of 1,750 elder patients, most common antide- follow-up. He continued to do well with his pressant received among elderly depressive inpa- weight kept at 68 kg under 30 mg/night of mirlaz- tients in Taiwan is trazodone (19.0%) [4]. In a epine. He had taken only three 0.5 mg of alpra- further analysis, there is no signifi cant difference zolam in the previous 10 days. between the trazodone prescription rate by psy- chiatrists (24.3%) and that by non-psychiatrist Discussion physicians (26.4%) [4]. Our patient did not respond to the treatment The most salient message in this case report of 150 mg/day of trazodone for at least four is that our patient responded readily to milnacip- months, but responded satisfactorily to milnacipran and mirtazapine at regularly daily approved ran and consequently to mirtazapine. The ineffi - clinical dose, but he did not respond to the treat- cacy issue of trazodone in this case report is sup- ment of daily trazodone 150 mg for six months. ported by the data from two studies [5, 6]. In a The patient got almost remitted after having re- double-blind, placebo-controlled clinical trial ceived a four-week treatment with 100 mg/day of comparing the effi cacy of trazodone (150-400 mg/ milnacipran. We suspect that he would have be- day) versus venlafaxine (75-200 mg/day), both come remitted completely from MDD if he would active treatments have been found to be signifi - stay on milnacipran without his being bothered by cantly more effective than placebo on some mea- the side effect of 3-kg weight loss, and stay on the sures during the short-term study [5]. But venla- milnacipran treatment. We also speculated that the faxine-treated patients are found to be improved patient might be a potential victim of committing signifi cantly in the scores of both cognitive distur- suicide as his sister did if his suicidal idea would bances (items 2, 3, 19, 20, and 21of the Hamilton become stronger in severity while continuing to Rating Scale for Depression) and retardation fac- receive 150 mg/day of trazodone. tors (items 1, 7, 8, and 14) compared to those The use of antidepressants in Taiwan was in treated with placebo, although trazodone-treated an increased trend from 2000 to 2009, but the patients showed signifi cant improvement in sleep speed of the trend in Taiwan was still lower than disturbances (items 4, 5 and 6) compared to other that in other developed countries [3]. In Taiwan, two study groups [5]. Furthermore, patients on fi ve most frequently prescribed antidepressants venlafaxine were most likely to enter the long- are imipramine, trazodone, melitracen/fl upentix- term phase and to remain in the clinical trial lon- ol, doxepin, and fl uoxetine. Of all available anti- gest among those three groups. In another similar depressants, the prescription rate of trazodone is prospective double-blind clinical trial comparing 17.6%, which is number 1 most prescribed single trazodone versus bupropion [6], the investigators antidepressant in Taiwan. Although most common demonstrated that patients treated with trazodone indication for trazadone may be for sleep disorder, have shown improvement from MDD signifi cantly it is still being used for treating depressive pa- compared to those treated with bupropion on day • 314 • Trazodone is an Ineffective Antidepressant

7 because of trazodone’s effect on sleep distur- As shown in the data of published studies bances. But at the end of 42-day treatment, 58% and our experience of treating this patient, trazo- of the bupropion-treated patients at endpoint, and done is not as effective as venlafaxine [5], bupro- 46% of the trazodone-treated patients at endpoint pion [6], milnacipran, and mirtazapine for treating were considered “much improved” or “very much MDD. But low dose of trazodone may be helpful improved,” although in last observation carried as a hypnotic agent [5, 6] which is mediated forward data there is no signifi cant difference [6]. through the blockage of α1-adrenoceptors. As stated previously, the APA’s practice However, our patient did not get improved in his guideline on treating MDD patients pointed out symptom of chronic insomnia under 150 mg/day “... other investigators have found trazodone to be of trazodone and benzodiazepine (alprazolam) less effective than other antidepressant medica- and benzodiazepine receptor agonist (zolpidem). tions [5, 6]. In a review of 18 studies from 1980 Most treatment guidelines for the therapeutic dose through 2003, Mendelson [7] found that trazodo- of trazodone are around 300 mg/day. In fact, al- ne, when compared with various control groups, most all depressed patients cannot tolerate its side did improve sleep. However, it was associated effects of over-sedation when they are given pre- with signifi cant side effects and tolerance may describing treatment guideline dose for treating velop with prolonged use” [1]. This message is MDD. Other than that, most physicians and psy- clearly already stated in a monograph [8]. chiatrists in Taiwan seldom use the treatment Trazodone is a triazolopyridine derivative, guideline dose of trazodone to treat their de- chemically and pharmacologically distinct from pressed patient, which may lead to risk of suicide other antidepressants [9]. It is a weak but specifi c as might have happened in patient’s sister. inhibitor of synaptosomal reuptake of serotonin Therefore, we suggest that trazodone should not (5-HT), with postsynaptic antagonistic action at be prescribed as a single antidepressant in any

5HT1A, 5-HT1C, and 5-HT2 receptors as well as at MDD patients since most of them cannot tolerate

α1-adrenoceptors and to a lesser extent α2- the sedation induced by trazodone under adequate adrenoceptor [9]. Trazodone acts mainly as a dosing.

5-HT2A receptor antagonist to exert its therapeutic The authors recognize the fact that the pa- beneﬁ ts against anxiety and depression [10]. Its tient in this single case report is limited in general- inhibitory effects on serotonin reuptake and izing to other patients. But based on this case and

5-HT2C receptors are relatively weak (about 15- published data [1, 5-8], we would like to call psy- fold lower than for 5-HT2A) and contribute only chiatrist colleagues in Taiwan to do something lightly to its overall effects [9, 10]. Therefore, tra- educationally, or even administratively, to deal zodone does not own similar properties to selec- with the ineffective issue of trazodone because of tive serotonin reuptake inhibitors [10] and is not the huge magnitude of its prescription rate in particularly associated with increased appetite and Taiwan. weight gain, unlike other 5-HT2C antagonists like mirtazapine [11]. Moderate 5-HT1A partial ago- References nism (6-fold lower than 5-HT2A) is also likely to contribute to antidepressant and anxiolytic actions 1. American Psychiatric Association: Practice of trazodone to some extent [12]. Guideline for the Treatment of Patients with Major Goh KK, Tam WK, Shen WW • 315 •

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