Doi:10.1016/j.sleep.2003.06.006

The effects of trazodone on sleep in patients treated Hakan Kaynaka,*, Derya Kaynaka, Erbil Go¨zu¨kırmızıa, Christian Guilleminaultb aDepartment of Neurology, Sleep Disorders Unit, Cerrahpasa Medical School, University of Istanbul, Cerrahpasa, 34303 Istanbul, Turkey bStanford Sleep Disorders Clinic and Research Center, Stanford, CA, USA Received 12 March 2003; received in revised form 25 June 2003; accepted 26 June 2003 Background and purpose: To evaluate the effects of trazodone on subjective and objective measures of sleep in depressed insomnia patients treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs can exacerbate or cause new insomnia while alleviating othersymptoms of depression. Trazodone has been reported to be an effective hypnotic for patients with antidepressant-associated insomnia.
Patients and methods: Twelve female patients were given either 100 mg trazodone or placebo for 7 days in a double-blind crossover design with a 7-day washout period. Polysomnographic recordings were repeated on the 3rd, 9th and 17th, 23rd nights after treatment withtrazodone or placebo. Sleep was assessed by Pittsburgh sleep quality index (PSQI) at the beginning and end of the study. Psychologicalevaluation was done by Hamilton depression rating scale (HDRS).
Results: Trazodone significantly increased total sleep time, percentage of stages 3 þ 4, sleep efficiency index, sleep continuity index and decreased percentage of stage 1, number of awakenings, stage shifts compared to the baseline. This improvement was also obtained after7 days of treatment. The PSQI score was reduced to 5 ^ 1.6 at the end of the study. HDRS was reduced to 11.5 ^ 4.5 with trazodone and to12.2 ^ 3 with placebo.
Conclusion: Trazodone is effective in the treatment of antidepressant-associated insomnia.
q 2003 Elsevier B.V. All rights reserved.
Keywords: Insomnia; Depression; Trazodone; Serotonin reuptake inhibitors; Polysomnography; Hypnotic Trazodone, a sedating triazolopyridine antidepressant, is chemically and pharmacologically different from SSRIs. It Insomnia is a hallmark or core symptom in the majority possesses antidepressant and also some anxiolytic and of depressed patients. It has been estimated that more than hypnotic activities. The effects of trazodone on sleep have 70% of depressed women and 80% of depressed men have been evaluated in a variety of subjects, including patients difficulty falling and/or staying asleep or in early morning with insomnia and depression and normal controls. It has awakenings Insomnia may also occur as a side effect been demonstrated to be effective in resolving depressive of antidepressant treatments such as selective serotonin symptomatology and improving sleep architecture .
reuptake inhibitors (SSRIs). Depressed individuals taking Trazodone has also been reported to be an effective hypnotic SSRIs often report persistent insomnia. These agents are for patients with antidepressant-associated insomnia. Jacob- stimulating antidepressants that can fail to treat preexisting sen gave trazodone, 25 – 150 mg at night, in an open insomnia, exacerbate preexisting insomnia or cause new design to 48 consecutive patients who had persistent or insomnia while alleviating other symptoms of depression worsened insomnia while taking either monoaminooxidase It was reported that a total of 35% of patients inhibitors (MAOIs) or other antidepressants. He found that receiving SSRIs or clomipramine were also taking medi- 65% had complete resolution of insomnia, 31% had partial response and 4% had no response. Metz and Shader reported that 31% of patients who took trazodone at a dose * Corresponding author. Tel.: þ90-212-586-1596; fax: þ90-212-632- of 25 – 75 mg nightly to treat fluoxetine-associated insomnia E-mail address: [email protected] (H. Kaynak).
had to stop taking trazodone because of excessive daytime 1389-9457/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2003.06.006 H. Kaynak et al. / Sleep Medicine 5 (2004) 15–20 sedation. Nierenberg et al. reported that patients taking SSRIs were being used for the treatment of depression, with either fluoxetine or bupropion and having antidepressant- the dosages in the low normal range. Five patients were associated insomnia showed clinically significant improve- taking paroxetine (20 mg/day), three were taking sertraline ment, according to the Pittsburgh index measure of sleep (50 mg/day), two were taking fluoxetine (20 mg/day), and duration and the Yale-New Haven inventory measure of one was taking citalopram (20 mg/day). One patient was early morning awakenings, after taking trazodone. There taking venlafaxine (37.5 mg/day), which is both serotonin was also a trend toward improvement in the Pittsburgh and also norepinephrine reuptake inhibitor.
index subscales for sleep quality and sleep latency.
SSRI treatment duration had ranged from 4 weeks to The above clinical reports are limited by the lack of 3 months at the beginning of the study. The mean duration polysomnographic recordings (PSG) and a placebo control.
of SSRI treatment was 9 ^ 2.7 weeks (median: 9.5 weeks).
The aim of the present study is to evaluate the effects of It was 9 ^ 2.6 (median: 9.5 weeks) in Group 1 and trazodone on subjective and objective measures of sleep in 9.1 ^ 2.9 (median: 9.5 weeks) in Group 2. There was no depressed insomnia patients treated with different SSRIs. It statistical significance between groups 1 and 2 in terms of is a double-blind placebo-controlled study to find out if SSRI treatment (Mann – Whitney U test ¼ NS).
trazodone would improve sleep in depressed patients whose Half of the randomly selected patients took placebo in depression has been treated with SSRIs but in whom the first treatment phase while the other half took trazodone, insomnia was not resolved or insomnia was subsequently and vice versa in the second treatment phase.
During an adaptation night in the sleep laboratory, each patient’s sleep was evaluated and checked for other causes of insomnia, such as PLMS, SRBD, etc. Following theadaptation night, they underwent baseline PSG (N2). After Female subjects between the ages of 20 and 50 were baseline recordings, patients were randomly assigned to recruited from Psychiatry outpatient clinic. All of them had either 100 mg trazodone (Group 1) or matching placebo been diagnosed with major depression according to the tablets (Group 2) in phase 1, and were administered the DSM 4 criteria. They had been treated with SSRIs for at alternative in phase 2. Each phase lasted 7 days, with a least 3 weeks, were receiving antidepressants at the time of washout period of 7 days between the two sets of study, had complaints of new, exacerbated or untreated insomnia, and continued with their treatment during the PSGs were repeated on 3rd (N3), 9th (N9), 17th (N17) study. An initial score of at least 18 on the Hamilton and 23rd (N23) nights after the start of trazodone or placebo depression rating scale (HDRS) was required. The exclusion treatment. A 100 mg dose of trazodone was selected to investigate its hypnotic effect, which is substantially lessthan the 150 – 600 mg dose range recommended for an 1. Suffering from concomitant mental illness other than antidepressant effect . Medications were given 1 h 2. Alcohol abuse and addiction to other drugs3. Pregnancy or lactation 4. Suffering from any other causes of insomnia, such as periodic leg movement during sleep (PLMS), sleep HDRS was used for the evaluation of depression. It related breathing disorders (SRBD), etc.
was done before baseline night and repeated after N9 and 5. Having cardiac conduction delays or arrhythmia in the N23. Sleep was assessed by subjective rating of Pittsburgh sleep quality index (PSQI) as sleep quality represents a 6. Having a history of intolerable adverse reaction to complex clinical construct that is difficult to define and measure objectively. The PSQI is a self-noted questionnairethat assesses sleep quality and sleep disturbance over a A total of 12 female patients with a mean age of 42 ^ 9 1-month period, changed to the time frame used in this study (range: 30 – 59, median: 43.5), responding to inclusion and to avoid misinterpretation of PSQI. Since the treatment exclusion criteria participated in the study and signed phases were only 7 days, PSQI was measured at the baseline and end of the study. This design was implemented with the Eight patients complained of difficulties with falling understanding that all subjects at entry would be free of asleep and maintaining sleep, and four described relatively hypnotics and that at the end of the study there would be a isolated difficulty with falling asleep. Ten patients were 50% chance for the subjects to be on placebo when PSQI suffering from untreated insomnia, while the remaining two was administered. Study design and clinical evaluation of developed insomnia during treatment with SSRSs. Different H. Kaynak et al. / Sleep Medicine 5 (2004) 15–20 Fig. 1. Polysomnographic and clinical evaluation.
condition. PSQI scores were tabulated at the beginning andend of the study and compared between groups 1 and 2. PSG PSG recordings included two EEGs (C3-A2, C4-A1), sleep parameters of baseline night were compared with two EOGs and one chin EMG. Respiration was recorded by those of the first and last treatment nights of trazodone and standard measures of airflow (oro-nasal thermistors), effort placebo. Sleep parameters in the first treatment night (acute (abdominal and thoracic strain gauges) and oxygen effect) were also compared with those in the last treatment saturation (finger pulse oximetry). Leg movements were night (short-term effect), after 7 days of treatment with recorded by right and left tibialis EMGs during the The time of retiring was the same as at home but time in bed was controlled at 8 h in all PSGs. The following PSGparameters were evaluated: total sleep time (TST), percen- tage of stages 1, 2, 3 þ 4 and REM sleep, sleep latency,REM sleep latency, sleep efficiency index (SEI), sleep continuity index (SCI), number of awakenings (# awake; aactivity , 15 s), number of stage shifts (# shifts) and mean The initial HDRS score was 23.4 ^ 3.7. It was reduced duration of each sleep cycle (cycle). SEI is TST per time in to 12.2 ^ 3 ðP , 0:005Þ with placebo and to 11.5 ^ 4.5 bed (from lights out to lights on) and SCI is TST per total ðP , 0:005Þ with trazodone treatment. This represented a sleep period (from the first falling asleep to last awakening).
mean decrease of 46.3 and 49.2%, respectively. The effects All PSG recordings were scored by blinded sleep specialists.
of trazodone and placebo on mean HDRS scores did notdiffer significantly.
The mean global score of the PSQI was 15 ^ 2.5 at the beginning of the study (range: 9 – 19). It was 14.6 ^ 3.4 for The order of the treatments was assigned randomly.
Group 1 ðn ¼ 6Þ and 15.5 ^ 1.5 for Group 2 ðn ¼ 6Þ at entry There was no significant difference between phases 1 and 2 (Mann – Whitney U ¼ NS). After 3 weeks of trazodone/ subjects in the overall PSQI data and HDRS scores after placebo treatment with washout period, it was reduced to placebo treatment (Mann – Whitney U test ¼ NS). There- 5 ^ 1.6 (range: 2 – 7) ðP , 0:005Þ: It was 4.83 ^ 2.14 for fore, PSG data and HDRS scores were grouped based on the Group 1 and 5.17 ^ 1.17 for Group 2. There was no treatment, regardless of the order. There was an equal significant difference between the two groups at the end of number of subjects in each group as none of the subjects the study. According to the last PSQI, there was a similar improvement in subjective sleep quality in both groups, The data were grouped as baseline, drug, and placebo despite the fact that 50% of the subjects had just received conditions. The 14-day time difference between the two placebo for 15 days. Compared to baseline, the change in groups was not taken into consideration. The drug condition PSQI score was significant for both groups (Wilcoxon data consisted of data from the ‘first trazodone’ group matched pair rank test ¼ 0.027). The global PSQI score was (Group 1) on N3-N9 and ‘first placebo’ group (Group 2) on 5 or less in half of the patients, 6 in four patients and 7 in N17-N23. The placebo condition data consisted of data only two patients. It was 4.8 ^ 2.1 for Group 1 and from the first trazodone group on N17-N23 (Group 1) and first placebo group on N3-N9 (Group 2).
Side effects: Complaints were minimum. During the The following comparisons were made using the trazodone intake one subject reported mild and transient Wilcoxon matched pair signed rank test. Mean percentage acid indigestion and two others had mild daytime sedation of reduction in HDRS as of the last treatment nights of in the morning. Neither complaint was mentioned during the placebo and trazodone were compared with the baseline H. Kaynak et al. / Sleep Medicine 5 (2004) 15–20 Fig. 2. Global PSQI scores of patients at the beginning and at the end of the study.
they were still significantly higher than the baselinecondition. However, decreases in stage1 (3 ^ 2%, Baseline sleep parameters of our patients are shown in P , 0:001), number of awakenings (12 ^ 13, P , 0:05) Large numbers of awakenings (25.1 ^ 11) and and number of stage shifts (64 ^ 46, P , 0:01) and stage shifts (106.2 ^ 37.6) led to low SEI (79.8 ^ 12.4%) increases in percentage of stage 3 and 4 (31 ^ 13%, and low SCI (85 ^ 9%). Mean sleep duration was P , 0:01) were more significant in the last treatment 382.1 ^ 57.9 min and mean sleep latency was 18.8 ^ night of trazodone. Sleep latency was reduced from 17 to 28.7 min. Slow wave sleep (SWS) was well preserved 14 min. Percentage of REM sleep was slightly lower in the last night (16 ^ 8%) than in the first (18 ^ 9%), (13.2 ^ 4.9%) and stage 2 was increased (60.7 ^ 11.1%).
while its latency prolonged to 230 from 200 min.
Prolonged REM latency (222.9 ^ 93.4 min) was observed In summary, the significant improvement in sleep parameters in the first night of trazodone administration The administration of trazodone significantly increased was also observed after 7 days of treatment, compared to the TST (435 ^ 34, P , 0:01), percentage of stages 3 þ 4 baseline night. The improvement in sleep parameters was (28 ^ 14, P , 0:05), SEI (90 ^ 7%, P , 0:01) and SCI more marked in the last treatment night, but no significant (94 ^ 6%, P , 0:01) and significantly decreased percen- difference was found between two treatment nights of tage of stage 1 (3 ^ 1, P , 0:001), number of awakenings (13 ^ 6, P , 0:01) and number of stage shifts (69 ^ 21, Placebo treatment produced no significant alterations in P , 0:05) on the first night, compared to the baseline night sleep parameters, either in the first or last night compared to the baseline. Sleep latency was prolonged to a mean of 24 At the end of trazodone treatment period (short term and 33 min in the first and last treatment nights, respec- effect), TST (428 ^ 39, P , 0:05), SEI (89 ^ 8%, tively. Though the number of stage shifts was reduced to 89 P , 0:05) and SCI (93 ^ 7%, P , 0:05) tended to decrease with acute administration, it reached 128 in the last slightly compared to the first treatment night, although treatment night, which was higher than the baseline night.
P values compared to baseline night. aP , 0:05; bP , 0:01; cP , 0:005; dP , 0:001: H. Kaynak et al. / Sleep Medicine 5 (2004) 15–20 The only significant finding with placebo treatment was an awakenings and stage shifts, and augmentation of SWS. The increase in the number of stage shifts during the last night findings in our patients were more marked than those (128 ^ 3, P , 0:01) compared to its acute administration reported by Mouret et al. after only one night of drug intake.
(89 ^ 36). Sleep parameters with trazodone and placebo Scharf and Sachais reported on six depressed patients who took 150 mg doses of trazodone for 2 days, 200 mg for2 days and 250 mg by the end of the first week. Theirsubjects had decreased sleep latency and increased TST, stage 4 NREM sleep and REM latency. The observed effectson REM sleep after the first day and after 1 week of Our study confirms the finding that the administration of treatment were different than those seen in our patients, who a low dose of trazodone objectively improves sleep duration initially had an increase in percentage of REM sleep with a in patients who are being treated with antidepressants and shortening of its latency. REM sleep latency was longer have insomnia . Insomnia may be a side effect of some after 1 week of trazodone than at baseline.
antidepressants such as SSRIs, or may be related to A polygraphic study of the effects of trazodone on sleep depression. It has been reported that 6 days of fluoxetine parameters of depressed patients being treated with daily treatment leads to significant decrease in REM sleep and doses of SSRIs is lacking. In our study, trazodone, increase in sleep latency and REM latency, without a compared to placebo, produced significant improvement significant increase in the number of awakenings during the in sleep parameters with augmentation of TST, SWS, SEI night . Hendricks et al. reported that fluoxetine and SCI and reduction in stage 1, number of awakenings appeared to increase in stage 1, suppress REM sleep and and number of stage shifts after 1 week of treatment; there increase REM latency. Another study done with fluoxetine was no significant difference between the first and last supported these findings and also showed decrease in SWS night effects of trazodone on polysomnographic data.
Paroxetin has been reported to reduce TST, REM sleep Although there was a notable reduction in HDRS, none of and SEI, and increase REM latency and number of the sleep parameters significantly improved with placebo treatment. These findings indicate that trazodone amelio- The sleep disturbances seen in depression are well rated sleep disturbance in depressed patients, independent described. They include increased nocturnal wake time, of changes in depression, and that it was effective after the decreased SWS and shortened REM latency. The mean HDRS score was 23.4 ^ 3.7 at the beginning of our study, The PSQI was administered at the beginning and end of reflecting moderate depression despite SSRI treatment for a our study. None of the subjects had been treated with mean of 9 weeks (minimum 4 weeks). The elevated HDRS trazodone at the outset, and subjective complaints were scores in our patients suggest that depression may have been clear. At the end, 50% of the subjects had not received impacting sleep disturbance. Sleep onset complaints during trazodone for at least 2 weeks (due to washout and placebo SSRI treatment show that sleep problems are a side effect of periods). Despite this situation, the mean PSQI score of our these drugs. Although it is not possible to calculate apercentage of sleep problems arising from depression versus patients was significantly reduced from 15 to 5; it has been SSRIs, we know that both components affect sleep.
previously reported that global PSQI # 5 correctly identified The baseline PSG data of our patients reflects the overall 89.6% of healthy, middle-aged control subjects There effects of SSRIs and depression on sleep parameters. A was no significant difference in PSQI scores between the reduction of TST and SEI, increase in the number of two groups at the conclusion of the study, and the scores awakenings, and preservation of SWS was found. REM were significantly better than those obtained at baseline. The duration was reduced (13.2 ^ 4.9%) while REM latency fact that PSQI scores in Group 2 were improved after 2 weeks without trazodone indicates the importance of close Mouret et al. studied the polysomnographic changes and repetitive subjective evaluations of sleep and the induced by trazodone (100 – 600 mg) in 10 depressed subjective effect of the attention given to the sleep problem patients not taking other medications. On the night by the research team. One may question, however, whether following the first dose of 100 mg trazodone, their patients there is a spillover effect from the initial (first 7 days) use of had increased TST and stage 2 and decreased sleep latency trazodone. Despite the fact that such an effect has never and number of awakenings. When the dose was increased been reported, similar results are often observed in within 4 days to 400 – 600 mg nightly stage 4 and REM crossover design protocols, even with controlled placebo, latency increased in addition to sustained improvement of as in our case. However, the polysomnographic data clearly sleep variables observed after 1 day of treatment. We found show the dissociation of subjective and objective results.
an insignificant decrease in stage 2 NREM sleep, but our When placebo intake was associated with improved findings were otherwise the same. After 1 week of trazodone subjective scores, polysomnographic data showed declines.
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