Antidepressants For The Treatment Of Insomnia

Drugs 2008; 68 (17): 2411-2417 0012-6667/08/0017-2411/$53.45/0

CURRENT OPINION

© 2008 Adis Data Information BV. All rights reserved.

Antidepressants for the Treatment of Insomnia A Suitable Approach? Michael H. Wiegand Department of Psychiatry and Psychotherapy, Sleep Disorders Center, Technical University of Munich, Munich, Germany

Abstract

The popularity of antidepressants in the treatment of insomnia is not supported by a large amount of convincing data, but rather by opinions and beliefs of the prescribing physicians on the advantages of these agents compared with drugs acting on the benzodiazepine receptor or other drugs used for the treatment of insomnia. The existing data do not allow for clear-cut, evidence-based recommendations concerning the use of antidepressants in insomnia. Our conclusions result from a few short-term studies on single agents, clinical experience and inferences from knowledge on the effect of antidepressants in other indications. At present, prescribing antidepressants for short-term treatment of insomnia can be useful if there is some amount of concomitant depressive symptomology or a history of depression, raising the impression that the present insomnia may be a prodromal sign for a new depressive episode. In all other cases, benzodiazepine receptor agonists, especially the nonbenzodiazepines among them (the so-called ‘z drugs’) should be the drugs of choice. For long-term treatment, antidepressants are among the pharmacological options, in addition to other groups of psychotropics. Off-label use of antidepressants may be considered for chronic insomnia if there is a concomitant depressive symptomalogy (which is not so pronounced that an antidepressant treatment with adequate higher doses would be required) and if there is no specific indication for one of the other groups of psychotropics (e.g. dementia-related nocturnal agitation, in which case an antipsychotic would be preferred, or circadian problems, in which case melatonin or a melatonin agonist would be favoured). If antidepressants are used to treat insomnia, sedating ones should be preferred over activating agents such as serotonin reuptake inhibitors. In general, drugs lacking strong cholinergic activity should be preferred. Drugs blocking serotonin 5-HT2A or 5-HT2C receptors should be preferred over those whose sedative property is caused by histamine receptor blockade only. The dose should be as low as possible (e.g. as an initial dose: doxepin 25 mg, mirtazapine 15 mg, trazodone 50 mg, trimipramine 25 mg). Regarding the lack of substantial data allowing for evidence-based recommendations, we are facing a clear need for well designed, long-term, comparative studies to further define the role of antidepressants versus other agents in the management of insomnia.

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For insomnia in general, drugs acting on the benzodiazepine receptor (encompassing benzodiazepines and nonbenzodiazepine benzodiazepine receptor agonists [‘z drugs’]) are commonly considered the treatment of choice because their effectiveness in clinical practice is supported by a lot of substantial data (see clinical review[1] and metaanalyses[2-5]). Especially in acute, short-term, noncomplicated insomnia (e.g. insomnia due to an acute, transient, external stress), drugs acting on the benzodiazepine receptor clearly have the best benefit-risk profile. With respect to long-term insomnia treatment, the use of at least some of these agents is limited by the risk of tolerance and dependency. However, recent data demonstrate that 6 months’ treatment with eszopiclone is efficient over the whole treatment period and there is no evidence of tolerance.[6,7] Similar results were obtained in a 6-month study of zolpidem extended release, which partly implied intermittent (non daily) treatment.[8] In the US, both agents are approved for long-term use. In contrast, the European Medicines Agency has approved all benzodiazepines and z drugs for shortterm use only. Correspondingly, treatment guidelines restrict the duration of treatment. However, in practice, off-label long-term use is widespread. In this unsatisfactory situation, clinicians have several options and the use of antidepressants appears to be rather popular. In the US, the antidepressants trazodone, amitriptyline and mirtazapine are among the most commonly used drugs for chronic insomnia;[9] elsewhere, other sedating antidepressants are used (e.g. in Germany, doxepin, opipramol and trimipramine). Walsh and Schweitzer[10] point out that a great number of antidepressant prescriptions in insomnia are for insomnia that is not related to depression (e.g. primary insomnia or co-morbid insomnia related to conditions other than depression). This clinical practice contrasts with the paucity of substantial data on the effects of antidepressants in insomnia. This is highlighted in several critical articles and guidelines on the topic. The British National Health Service’s Clinical Knowledge Summaries on insomnia clearly state “There is no evidence that antidepressants with sedative properties…help to relieve insomnia in people who do not have depression, and their use risks potential side © 2008 Adis Data Information BV. All rights reserved.

Wiegand

effects”, citing a review in the Drugs and Therapeutics Bulletin.[11] According to Walsh,[12] the popularity of antidepressants in insomnia cannot be based on existing scientific evidence but is due to perceptions and beliefs of the prescribing physicians, who are convinced of some general advantages of antidepressants as a group in this indication compared with drugs acting on the benzodiazepine receptor. Antidepressants are perceived as safer and as having a lower tolerance risk, so that even patients with a specific medical history (e.g. alcohol or benzodiazepine abuse, or dependency in the past) can be treated. When regarding data from long-term studies in patients with depression, it can be concluded that tolerance development is not to be expected, so the treatment can extend over a far longer period of time. When there is a pronounced depressive symptomatology, as well as insomnia, these agents may offer an additional antidepressant action besides sleep promotion. Some physicians may (erroneously) even believe that all or most insomnia is a symptom of depression, so that antidepressant therapy appears to be the treatment of choice. This article does not aim to discuss the issue of pharmacological versus nonpharmacological treatment of chronic insomnia; however, it must be kept in mind that according to the majority of experts, nonpharmacological treatment should be prioritized over drug treatment in chronic insomnia (see Reite et al.[13]). A comparative meta-analysis of pharmacotherapy and behaviour therapy for persistent insomnia[4] found no differences in several parameters relevant to sleep quality, apart from slightly greater reductions on sleep onset latency with nonpharmacological therapy. Most antidepressant drugs affect sleep but, as can be expected from the heterogeneous nature of the drugs summarized under this label, these effects can be extremely different. Recently, Wilson and Argyropoulos,[14] and Mayers and Baldwin[15] reviewed the data on the effects of antidepressants on sleep, both in healthy participants and patients with depression. In the latter group, most antidepressants improve subjectively-rated sleep, irrespective of objective (polysomnographic) sleep measurements, which, in some cases, mirror a worsening of sleep. Drugs 2008; 68 (17)

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Table I. Randomized controlled studies on antidepressants in primary insomnia Drug

Reference

Year

Sample size (enrolled)

Doxepin

Hajak et al.[16]

2001

47

Trazodone

Walsh et al.[17]

1998

589

Trimipramine

Riemann et al.[18]

2002

65

1. Clinical Studies of Antidepressants in Insomnia A more specific overview on studies with chronic insomnia is given by Buscemi et al.[1] There are only three published randomized controlled trials[16-18] on antidepressants in primary insomnia (table I). In a placebo-controlled study in 47 patients[16] (with Diagnostic and Statistical Manual of Mental Disorders [DSM] 4th Edition [DSM-IV] primary insomnia), doxepin was given over 4 weeks in a dose between 25 and 50 mg. In the doxepin-treated patients who completed the study (n = 20), medication significantly increased polysomnographically-measured sleep efficiency after acute and subchronic (4 weeks) intake, compared with the patients completing the study who received placebo (n = 20) without affecting sleep onset latency, which was normal at baseline. Subjectively rated sleep quality and working ability were rated significantly improved by the patients receiving doxepin. No significant group differences in adverse effects were found, but two doxepin-treated patients withdrew from the study because of increased liver enzymes, leukopenia and thrombopenia. In a large-scale multicentre study (n = 589 patients with DSM [3rd Edition, Revised]{DSM-IIIR} primary insomnia), trazodone 50 mg was tested against zolpidem 10 mg and placebo over 2 weeks.[17] Effects were measured by subjective estimations of self-reported sleep onset latency and self-reported sleep duration, based on morning questionnaires (polysomnographic recordings were not performed). After 1 week, both active treatments significantly reduced sleep latency (this was more pronounced with zolpidem than trazodone). After 2 weeks, only the zolpidem group had a significantly shorter sleep onset latency than the placebo group, whereas the trazodone group did not differ from placebo. Both drugs were also rated efficacious in significantly prolonging subjective sleep duration © 2008 Adis Data Information BV. All rights reserved.

Dose range (mg)

Comparator

25–50

Placebo

50

Zolpidem and placebo

25–200

Lormetazepam and placebo

compared with placebo during week 1, but not during treatment week 2. Twelve randomized patients (two placebo, five zolpidem and five trazodone) withdrew from the study because of adverse events (excessive sleepiness, dizziness, drowsiness, headache, vomiting, elevated blood pressure). Treatment-emergent adverse events were reported by 65.4% of placebo patients, 76.5% of zolpidem patients and 75% of trazodone patients, mainly headache and somnolence. Trimipramine, given as a mean dose of 100 mg (range from 25 to 200 mg), was tested against lormetazepam and placebo in 55 patients with insomnia (DSM-III-R primary insomnia or dyssomnia not otherwise classified) over 4 weeks.[18] Trimipramine (n = 18) increased polysomnographically-measured sleep efficiency significantly when compared with placebo, in contrast with lormetazepam. Trimipamine did not change any of the other polysomnographic sleep variables when compared with placebo, whereas lormetazepam reduced the percentage of wake after sleep onset and the percentage of stage 3 sleep, but increased the percentage of rapid eye movement sleep. Comparing trimipramine and lormetazepam, no difference with respect to any of the polysomnographic sleep variables emerged. Several subjective sleep parameters were improved by both of the drugs compared with placebo (Pittsburgh Sleep Quality Index [PSQI[19]] sum score, sleep quality and evening well-being subscales of the SF-A [Schlaffragebogen by G¨ortelmeyer[20]]). In addition, trimipramine improved the ‘feeling rested in the morning’ subscale of the SF-A compared with placebo. In direct comparison, trimipramine was superior to lormetazepam in the ‘evening well-being’ and the ‘feeling rested in the morning’ subscales of the SF-A, whereas the other subjective variables (including the PSQI total score) showed no differences between drugs. Table II summarizes the four existing open-label studies on antidepressants in primary insomnia. Drugs 2008; 68 (17)

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Table II. Open-label studies on antidepressants in primary insomnia Drug

Reference

Year

Sample size (enrolled)

Doxepin

Hajak et al.[21]

1996

10

Nefazodone

Wiegand et al.[22]

2004

32

100–400

Paroxetine

Nowell et al.[23]

1999

15

10–30

Trimipramine

Hohagen et al.[24]

1994

19

25–200

The open-label study on nefazodone[22] demonstrated primarily a favourable effect for some subjective sleep variables (PSQI total score and some PSQI subscales). Polysomnographic variables demonstrated a significant decrease in the number of intermittent awakenings, but also some other less favourable effects: sleep onset latency was significantly prolonged and slow-wave sleep decreased. A high number of patients (11 of 32) withdrew because of adverse effects, mainly absence of expected effect, worsening of insomnia and/or increased nervousness. The open-label study on paroxetine[23] included 15 patients with DSM-IV primary insomnia who were treated with a flexible dose of paroxetine (median dose 20 mg) at bedtime over 6 weeks. Of the 14 patients who completed the study (1 withdrew because of adverse effects), 11 improved with treatment and 7 of these no longer met diagnostic criteria for insomnia. Improvement was clear in subjective sleep variables (PSQI scores), but was not reflected in polysomnographic sleep parameters. This demonstrates the gap between subjective and objective estimations of sleep because polysomnographic studies on paroxetine, like other serotonin reuptake inhibitors (SRIs), notoriously show a worsening of ‘objective’ sleep. The results for doxepin[21] and trimipramine[24] in the respective open-label studies resemble those observed in the controlled trials on these agents subsequently performed and described previously. Thus, it can be concluded that there is evidence for the efficacy of doxepin, trimipramine and trazodone in the short-term treatment of insomnia; the evidence for nefazodone and paroxetine is less convincing. However, there are only two studies directly comparing the effects of an antidepressant with an agent acting on the benzodiazepine receptor (trazodone vs zolpidem and trimipramine vs lormetazepam).[17,18] There is no single study comparing an antidepressant with another drug class in © 2008 Adis Data Information BV. All rights reserved.

Dose range (mg) 25

the long-term treatment of insomnia (e.g. a sedating antipsychotic, antihistamine, melatonin or a melatonin agonist). This is not a major criticism because the same is true for the benzodiazepine receptor agonists. The duration of the studies was in all cases restricted to a few weeks. Therefore, there is no information on long-term efficacy or long-term adverse effects. Thus, a critical evaluation of the usefulness of antidepressants in long-term treatment of insomnia cannot be based on direct evidence from adequate studies. Instead, we have to rely on indirect evidence and unsystematic clinical experience. 2. Potential Advantages and Disadvantages of Antidepressants versus Other Agents Considering antidepressants as a group, the antidepressant component is a possible advantage in many cases where a certain degree of depressed mood accompanies insomnia, without fulfilling criteria of a mood disorder but potentially being positively influenced by an antidepressant (a hypothesis that has not yet been tested). Second, a tolerance development is not expected, permitting long-term use, and there is no abuse or addiction potential. However, the latter advantage is shared with other drug groups used in the treatment of chronic insomnia (e.g. antihistamines, melatonin and melatonin agonists, and antipsychotics). As we now know, the same is true for the nonbenzodiazepine benzodiazepine receptor agonists eszopiclone and zolpidem, which, contrary to former opinion, do not lead to dependency development when administered over several months; these data have led to new perspectives in the treatment of chronic insomnia.[25-27] With antipsychotics and antihistamines, antidepressants share the disadvantage of a broader spectrum of adverse effects, interaction effects and contraindications, compared with drugs acting on the benzoDrugs 2008; 68 (17)

Antidepressants for Insomnia

diazepine receptor. In addition, it must be emphasized that tricyclic antidepressants are potentially lethal in overdose. Sedating antipsychotics have been used for the treatment of insomnia, especially in the elderly. The rationale for their use in this setting is their clinically proven efficacy in complex, acute, often dementiarelated states including insomnia, agitation and disorientation (not related to parasomnias). There is a growing tendency to study these drugs with respect to their effect in the treatment of insomnia. In an open-label pilot study, Wiegand et al.[28] found an impressive sleep-promoting property of quetiapine in very low doses (25–75 mg). 3. Choice of Antidepressant Within the group of antidepressants, the sedating tricyclics trimipramine and doxepin have the advantage of a positive effect in insomnia, proven by controlled clinical trials.[16,18] With respect to doxepin, it could be demonstrated that it preserves nocturnal melatonin secretion patterns,[21] in contrast with flunitrazepam;[29] however, it is not clear in how far these results are generalizable to both sedating tricyclics and benzodiazepinones. However, the strong anticholinergic properties of the tricyclics reduce tolerability, and result in several contraindications and potential interactions, especially in elderly people. The sleep promoting action of tricyclics is mainly based on histamine antagonism, which, regarding the half-lives of the drugs, can lead to hangover effects in the morning, even long-lasting excessive daytime sleepines. The efficacy of trazodone is based on a controlled study.[17] Trazodone lacks anticholinergic effects, which is an advantage; however, there is a higher risk of orthostatic hypotony and ventricular arrhythmias. Evidence-based data on mirtazapine in primary insomnia have not yet been published. Like trazodone, mirtazapine lacks anticholinergic activity; however, there is a spectrum of adverse effects, which include paradoxical agitation and the induction of restless legs symptomatology. It is remarkable that mirtazapine, in addition to its antihistaminergic action, influences sleep positively by inhibiting serotonin 5-HT2A and 5-HT2C receptors; this is a novel sleep-promoting mechanism, which does not cause drowsiness or enhance slow-wave © 2008 Adis Data Information BV. All rights reserved.

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sleep. Quetiapine and agomelatine also have a 5-HT2C inhibiting action. SRIs and antidepressants combining serotonergic and noradrenergic modes of action, as well as bupropion, are not first-choice drugs for insomnia; however, an indirect positive action on subjective sleep is possible when inactivity due to some depressive symptomatology during daytime is part of the problem (this may be the mechanism underlying the paroxetine data[23]). Among the antidepressants that will appear on the market in the future, agomelatine appears promising for insomnia because its mechanism of action does not encompass the antihistaminic pathway (it combines melatonin MT1 and MT2 receptor agonism with 5-HT2C receptor antagonism). Thus far, data on agomelatine indicate a favourable effect on sleep and very good tolerability.[30,31] In the discussion on antidepressants in insomnia, the question of pharmacokinetics, which is so important in benzodiazepines and benzodiazepine receptor agonists, has been neglected. Theoretically, compounds with a shorter half-life should be preferred. The three compounds for which placebocontrolled studies have been performed have rather long half-lives (trimipramine 24 hours; doxepin 15–20 hours [active metabolite 80 hours]; trazodone 9 hours). Mirtazapine and amitriptyline also have long half-lives (20–40 hours and 10–28 hours, respectively). Opipramol and trazodone have shorter half-lives (<9 hours). Agomelatine has an ultra-short half-life of 1–2 hours. The clinical consequences of the large differences have still to be investigated and discussed.[32] When an antidepressant for chronic insomnia appears indicated but is not sufficient for treating severe insomnia symptoms, there is the option of adjunctive eszopiclone and zolpidem, which has proven safe and effective in the treatment of depression (e.g. see Asnis et al.[33] and Becker[34]) as well as in other psychiatric conditions.[35] 4. Conclusion For short-term medication in insomnia, there is no evidence at all of superiority or a better benefitrisk ratio of antidepressants over benzodiazepines and z drugs; thus, the latter should be the treatment Drugs 2008; 68 (17)

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of choice, especially the z drugs, as these can be maintained in patients in whom short-term treatment turns into longer term treatment. At present, prescribing antidepressants (in particular doxepin, mirtazapine, trazodone and trimipramine) for shortterm treatment of insomnia appears useful if there is some amount of concomitant depressive symptomatology or a history of depression, raising the impression that the present insomnia may be a prodromal sign for a new depressive episode; in these cases, a z drug can be added to improve the sleep-promoting effect. For long-term treatment of insomnia, antidepressants are among the pharmacological options, in addition to several other groups of psychotropic drugs, including the z drugs eszopiclone and zolpidem, some antipsychotics, antihistamines, melatonin and melatonin agonists. The existing data do not allow for clear-cut, evidence-based recommendations regarding the use of antidepressants in insomnia; these conclusions result from short-term studies with single agents, from clinical experience and from what is known on the efficacy and tolerability of antidepressants in other indications. Off-label use of antidepressants may be considered for chronic insomnia if there is a concomitant depressive symptomatology (which is not so pronounced that an antidepressant treatment with adequate, higher doses would be required), and if there is no specific indication for one of the other groups of psychotropics (e.g. dementia-related nocturnal agitation, in which case an antipsychotic would be preferred, or circadian problems, in which case melatonin would be favoured). If an antidepressant is used to treat insomnia, a sedating one should be used in preference to activating agents such as SRIs. In general, preference should be given to drugs lacking strong cholinergic activity. Drugs blocking 5-HT2A or 5-HT2C receptors should be used in preference to those with sedative properties caused by histamine receptor inhibition only. Also, in long-term insomnia treatment, antidepressant can be combined with eszopiclone or zolpidem. The dose should be as low as possible (e.g. as an initial dose: doxepin 25 mg, mirtazapine 15 mg, trazodone 50 mg, trimipramine 25 mg). With respect to the prevalence of adverse effects and interaction risks, a continuous monitor© 2008 Adis Data Information BV. All rights reserved.

Wiegand

ing for adverse events is necessary when administering antidepressants; with tricyclic antidepressants, the dangers of (potentially lethal) overdose should be taken into account. Regarding the lack of substantial data allowing for evidence-based recommendations, we are facing a clear need for well designed, long-term comparative studies to further define the role of antidepressants versus other agents in the management of insomnia. Acknowledgements No sources of funding were used to assist in the preparation of this article. The author has received speaker honoraria from AstraZeneca, Cephalon and Servier.

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35. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry 2008; 65: 551-62

Correspondence: Professor Michael H. Wiegand, Department of Psychiatry and Psychotherapy, Sleep Disorders Center, Technical University of Munich, Ismaninger Str. 22, Munich, D-81675, Germany. E-mail: [email protected]

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