antidepressants and insomnia

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61Primary Psychiatry MBL Communications

Antidepressants and InsomniaGary K. Zammit, PhD

ABSTRACT

Mood disorders and insomnia are often comorbid conditions,

sharing a complex and bi-directional relationship. Complicating

the situation, mood stabilizers can disrupt sleep in a variety of

different ways depending on a drugs mechanism of action, dos-

age level, and timing of administration. The treatment of comorbid

depression and insomnia can be achieved through the use of a

sedating antidepressant, a combination of two antidepressants,

or a combination of an antidepressant in conjunction with a hyp-

notic. Common practices typically include the concomitant use of

an alerting and a sedating antidepressant. However, the empirical

evidence supporting this approach is limited, and there are few

indicators that sedating antidepressants are efficacious in the

treatment of primary insomnia. This article examines the evidence

supporting the efficacy and safety of mood stabilizers in the treat-

ment of comorbid and primary insomnia.

INTRODUCTION

Psychiatric disorders and chronic insomnia are often comor-bid with each other. The presence of insomnia symptoms inindividuals with a current episode of major depressve disprder(MDD) has been shown to approach 80% to 90%.1-4 Theincidence of comorbid insomnia is higher when anxietycomplicates the clinical presentation, affecting approximately

Needs Assessment:The use of trazodone as an adjunctive therapy for insomnia is

increasing while clinical evidence of the safety and efficacy of this approach is lack-ing. Recent studies of a combination of a hypnotic and an antidepressant offer thepotential for a safer, more efficacious course of action.

Learning Objectives:

List three treatment strategies for depression with comorbid insomnia.

Name the most commonly used adjunctive insomnia therapy for depressed patientstreated with an antidepressant.

Discuss recent research on the efficacy of combining an antidepressant with ahypnotic to treat depression with comorbid insomnia.

Target Audience:Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented inaccordance with the Essentials and Standards of the Accreditation Council for ContinuingMedical Education (ACCME) through the joint sponsorship of the Mount Sinai School ofMedicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accreditedby the ACCME to provide continuing medical education for physicians.

Credit Designation:The Mount Sinai School of Medicine designates this educationalactivity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claimcredit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement:It is the policy of the Mount Sinai Schoolof Medicine to ensure objectivity, balance, independence, transparency, and scientificrigor in all CME-sponsored educational activities. All faculty participating in the plan-ning or implementation of a sponsored activity are expected to disclose to the audienceany relevant financial relationships and to assist in resolving any conflict of interestthat may arise from the relationship. Presenters must also make a meaningful disclo-sure to the audience of their discussions of unlabeled or unapproved drugs or devices.This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair andprofessor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman,MD, editor of Primary Psychiatryand professor of psychiatry at New York UniversitySchool of Medicine. Review Date: March 27, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any

organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-des-ignated accompanying articles, reflect on the information presented, and thencomplete the CME posttest and evaluation found on page 85. To obtain credits,you should score 70% or better. Early submission of this posttest is encouraged:please submit this posttest by May 1, 2010 to be eligible for credit. Release date:May 1, 2008. Termination date: May 31, 2010. The estimated time to complete all threearticles and the posttest is 3 hours.

CLINICAL FOCUSPrimary Psychiatry. 2008;15(5):61-69

3CME

May 2008

Dr. Zammit is president and CEO of Clinilabs, director of the Sleep Disorders Institute, and clinical associate professor at the Columbia University College of Physicians and Surgeons in New York City.

Disclosure: Dr. Zammit is a consultant to Boehringer-Ingelheim, sanofi-aventis, Sepracor, and Takeda; receives research support from Forest, GlaxoSmithKline, Pfizer, sanofi-aventis, Sepracor, Takeda Pharmaceuticals NorthAmerica, Transcept, and Wyeth; and receives honoraria from Takeda.

Acknowledgments: The author would like to thank Ms. Bridget Banas for her assistance in the preparation of this manuscript.

Please direct all correspondence to: Gary Zammit, PhD, Clinilabs, Inc, 423 W. 55th St, 4th Floor, New York, NY 10019; Tel: 212-994-4560; Fax: 212-523-1704; E-mail: [email protected]; Website:

www.clinilabs.com.


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62Primary Psychiatry MBL Communications May 2008

90% with a concurrent anxiety disorder.1 Furthermore, mooddisorder symptoms are typically more pronounced in peoplewith insomnia symptoms.5-10

Insomnia is often a precursor to depression. Several lon-

gitudinal studies have examined the incidence of psychiatricdisorders over periods ranging from 140 years following theinitial diagnosis of insomnia.11-17 In every study completed todate, insomnia has been found to be a significant risk factor forthe subsequent onset of depression, with a greater incidence ofaffective disorder found in people with insomnia. These findingsdo not suggest that insomnia is merely part of a prodrome thatoccurs in close temporal association with affective disorders, asdepression may first appear several years after the initial diagnosisof insomnia. In addition to these findings, it has been shownthat insomnia is a precursor to the recurrence of depression inpatients in remission,18,19 and that persistent sleep disturbance isassociated with non-response to antidepressant therapy.20

While insomnia often precedes the onset of affective illness,symptoms of depression and insomnia may be concurrent.Complicating this picture is the fact that many antidepres-sants used to treat depression disturb sleep, potentiallyexacerbating the relationship between the two disorders. Thetype of sleep disturbance produced by depression pharmaco-therapy varies based on the compounds mechanism of actionand the dosage employed. Effects may include decrements inrapid eye movement (REM) sleep, a lengthening of the timeto sleep onset, and an increase in nocturnal arousals (Table

1). This article reviews the effectiveness and safety of severaltreatment options for comorbid depression and insomnia.

PRESCRIBING PATTERNS

Between 1987 and 1996, the pharmacologic treatmentof insomnia decreased markedly. A recent review21 coveringthis period found that drug mentions (ie, patient contactthat resulted in drug therapy or a mention of drug therapy)fell by >50% for hypnotics, and were down approximately25% for all forms of insomnia pharmacotherapy combined.Antidepressants used for the treatment of insomnia were theonly drug category showing signs of growthtripling in drugmentions over this period.

In 1996, the two drugs mentioned most frequently for the

treatment of insomnia were trazodone, a sedating tricyclic antide-

pressant (TCA), and zolpidem, a non-benzodiazepine hypnotic.

Trazodone is indicated for the treatment of depression, but not

specifically labeled for use as a hypnotic. Over the 10-year periodexamined, the total number of trazodone mentions was steady.21However, mentions associated with antidepressant action fellfrom >70% of all occurrences in 1987 to only 31% in 1996. Incontrast, the number of mentions associated with insomnia rose

from only 6.5% to almost 42% over the same period.The conclusion that the use of sedating antidepressants

for the treatment of insomnia rose between 1987 and 1996 was based on reported medication doses. The therapeutic

daily dosage of trazodone for depression therapy is 150600mg/day. Doses below this level may provide sedative effectsbut are not expected to combat the symptoms of depres-sion. By 1996, two-thirds of all trazodone mentions wereassociated with a daily dose of 100 mgstrongly suggest-ing that antidepressant effects were not the intended results.Furthermore, almost 40% of treatment mentions in 1996were concomitant with the mention of another antidepres-sant. This analysis is consistent with a more recent survey ofpsychiatrists prescribing practices.22 The survey was conduct-ed at a psychopharmacology review course to investigate themanagement of antidepressant-induced side effects. Almost

80% of the survey respondents indicated that they wouldprescribe trazodone to address selective serotonin reuptakeinhibitor (SSRI)-induced insomnia.

TREATMENT OPTIONS

In light of the common use of trazodone as adjunctive insom-nia therapy in depressed patients, it is important to rememberthat several treatment approaches are available. Insomnia comor-bid with depression may be treated using a single hypnotic, asingle antidepressant, a combination of two antidepressants, and

a combination of one antidepressant and one hypnotic.23

Option 1: A Single Hypnotic

There is no evidence to support the treatment of patientswith MDD and comorbid insomnia with a hypnotic medica-tion alone. Even though these medications are highly effica-cious in ameliorating sleep disturbances in a wide range ofpatient populations, neither the older benzodiazepine nor thenewer non-benzodiazepine hypnotics have been shown to beeffective therapy for MDD.

Option 2: A Single AntidepressantA single, sedating antidepressant can be employed as a treat-

ment for both insomnia and depression. Candidates for thistherapeutic approach include the TCAs and several atypicalantidepressants.23 Most of these TCAs inhibit the reuptake ofnoradrenaline and serotonin and block histamine (H)1 recep-tors and 1-adrenoceptors.

24 Amitriptyline and trimipramine,both particularly associated with sedation, also block serotonin(5-HT)2 action.

24 Trazodone is an antagonist at the 1-adrenoceptors, 5-HT1A, and 5-HT2 receptors.

24 Nefazodonehas strong 5-HT2 antagonist properties and mild serotonin


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Antidepressants and Insomnia


reuptake-blocking effects.24 Finally, mirtazapine blocks 5-HT2

receptors, H1 receptors, and 2-adrenoceptors.24

Some practitioners use a single, sedating antidepressant to

treat comorbid depression and insomnia. When administered at

therapeutic doses for depression, these medications are known to

produce sedative side-effects that may be exploited in an effort

to treat insomnia and to provide relief from depression. This

approach has intuitive appeal, as the use of one medication to

TABLE 1

SLEEP EFFECTS OF ANTIDEPRESSANTS*24,86-88

Daily Dosage (mg) Lat TST SWS REM NAW

Effects in

Non-Depressed Patients

TCAs

Amitriptyline T: 100300

S: 25150

Daytime sedation

Clomipramine T: 100250 REM , NAW

Desipramine T: 75200

Doxepin T: 100300

S: 25150

Lat , TST

Imipramine T: 100300 TST , NAW

Nortriptyline T: 50150 TST , daytime sedation

Trimipramine T: 100300

S: 25150

TST

SSRIs

Citalopram T: 2060

Fluoxetine T: 2060 REM

Fluvoxamine T: 100300 TST , REM

Paroxetine T: 2060 Lat , REM

Sertraline T: 50200 Insomnia symptoms

MAOIs

Moclobemide T: 150600 No effect

Phenelzine T: 4590

Tranylcypromine T: 3060

Atypical Antidepressants

Bupropion T: 100450 TST

Mianserin T: 3090

Mirtazapine T: 1545

S: 1530

NAW

Nefazodone T: 150450

S: 50150

TST , NAW

Trazodone T: 150600

S: 25150

REM , NAW

Venlafaxine T: 75375

* Blank spaces indicate no established effect.

Lat=sleep latency; TST=total sleep time; SWS=slow wave sleep; REM=rapid eye movement sleep; NAW=number of awakenings; TCAs=tricyclic antidepressants; T=therapeutic;

S=sedating; decrease; increase; SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxidase inhibitors.

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treat multiple disorders has the advantage of minimizing the risksassociated with drug-drug interactions and may make patientcompliance easier. However, the utility of this approach may belimited by current treatment guidelines and safety concerns.

Option 3: A Combination of Two

Antidepressants

This approach typically involves employing a therapeuticdose of a non-sedating antidepressant (eg, SSRIs, monoamineoxidase inhibitors [MAOIs]) to treat depression, and a lower,non-therapeutic dose of a sedating antidepressant to treatinsomnia. While this strategy has been used with some popu-larity, there are relatively few data demonstrating the safetyand efficacy of this approach.23,25,26

Option 4: A Combination of OneAntidepressant and One Hypnotic

This treatment approach enables clinicians to decouple thetreatment for depression from the treatment of insomnia. Thisapproach represents an important treatment option becauseit is often necessary to experiment with different antidepres-sants, titrate dosage levels, and modify dose timing to findthe most appropriate therapy for an individual with MDD.Employing a hypnotic as an adjunctive treatment enables theclinician to directly and immediately address a patients insom-nia symptoms while still making necessary adjustments to the

pharmacotherapeutic used to treat depression. When present,antidepressant-induced insomnia typically occurs during thefirst 34 weeks of treatment.27 Therefore, addressing sleepcomplaints early may provide rapid relief to the patient andmay also contribute to compliance with depression therapy.

EVIDENCE SUPPORTING THE USE OF

A SINGLE ANTIDEPRESSANT

Efficacy

The SSRIs and MAOIs are generally alerting; these drugstend to exacerbate existing insomnia symptoms or producetreatment-related insomnia (Table 1). As such, they are notconsidered appropriate for addressing insomnia symptoms indepressed patients as monotherapy.

In contrast, the TCAs commonly produce sedation as a sideeffect, even though they also tend to suppress REM sleep likethe SSRIs and MAOIs. Three TCAs appear to offer the great-est potential for combining both antidepressant and hypnoticeffects,24 namely, amitriptyline,28,29 doxepin,28 and trimipra-mine. Improvements were seen in depressed patients treated

with amitriptyline in measures of early morning awakenings,20nocturnal waking,20 and sleep latency30 as compared to theresults produced by imipramine or fluoxetine. Doxepin hasbeen shown to significantly improve Hamilton Rating Scale for

Depression (HAM-D) sleep scores as compared to placebo31

andbupropion.32 Trimipramine has been reported to improve sleepefficiency, increase sleep time, and reduce nocturnal awakeningsas compared to both fluoxetine33 and imipramine.34

The atypical antidepressants most often used to treatdepression and comorbid insomnia are mirtazapine, nefazo-done, and trazodone.24 Mirtazapine has been shown to pro-duce a range of effects on sleep in depressed patients. Rapidimprovements on quality of sleep and other subjective sleepassessments have been seen with mirtazapine as comparedto citalopram,35 while improvements in sleep efficiency andnocturnal distress have been seen relative to both fluoxetine36

or paroxetine treatment.37 It is of interest that HAM-D sleepitem scores have been shown to improve more when patientsare treated with mirtazapine than with either venlafaxine38or paroxetine.39 Nefazodone has also been shown to improveHAM-D sleep item scores relative to treatment with pla-cebo.40 It also produces less nocturnal disturbance than eitherfluoxetine41 or paroxetine.42

Trazodones effects on sleep in depressed patients are perhapsbetter characterized than that of any other sedating antidepres-sant. Two studies have found that, relative to placebo, trazodoneobjectively increases total sleep time, sleep efficiency, and slow

wave sleep (SWS) with limited next-day sedative effects.43,44

It hasalso been shown that trazodone 75 mg results in increases in SWSand improvements in HAM-D scores and subjective assessmentsof daytime alertness.45 Higher doses of trazodone also appear tohave effects on depression and sleep. Trazodone (150400 mg)produces significant improvement in symptoms of depression andchanges in objective measures of sleep architecture.46 Specifically,sleep latency declined, and total sleep time, SWS, and sleep effi-ciency increased following active treatment. Doses of 400600mg produce significant improvements in Montgomery-AsbergDepression Rating Scale (MADRS) scores (>60% reduction),reduce sleep latency, and increase total sleep time and SWS.47

Safety

Employing a sedating antidepressant to treat both depres-sion and comorbid insomnia is appealing because of thereduced opportunity for drug-drug interactions and thepotential increase in patient compliance due to a less complextreatment regimen. However, the available literature suggestscaution should be exercised when considering this approach. A recent conference that reviewed the evidence supportingthe use of both TCAs and SSRIs resulted in a published state-ment suggesting that TCAs are no longer justified as first-line


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antidepressant therapy in most situations.48 This positionreflects concerns about the differential efficacy and safetyprofiles of the TCAs relative to newer therapies.

Two of the three sedating atypical antidepressants reviewed

here are also of questionable value as first-line treatment.First, mirtazapine is indicated for the treatment of depressionbut often is used as an alternative or augmentation therapyfor depression rather than a first-line monotherapy.49 Second,sales of nefazodone have been discontinued in several coun-tries including the United States (branded version) due toconcerns of liver toxicity.

The process of elimination leaves trazodone as the mostlikely candidate for monotherapy in depression with comor-bid insomnia. However, while trazodone is considered to besafer than the TCAs, it remains associated with a series ofsignificant side effects. The most common adverse events seen

with trazodone at doses of 75 mg/day are drowsiness, diz-ziness, dry mouth, nausea, vomiting, constipation, headache,hypotension, and blurred vision.50 A review of published datafrom controlled trials in depressed patients found that 25%to 30% of patients experienced some treatment-emergentadverse event attributed to trazodone.51 Reported discontinu-ation rates from clinical trials were relatively high (25% to60%), with 25% to 50% specifically attributable to adverseevents.50 Most importantly, a recent literature review iden-tified a sizable number of reports of treatment-emergentcardiac events.52 Adverse events noted in clinical studies andcase reports include hypotension, ventricular arrhythmias,

cardiac conduction disturbances, and exacerbation of isch-emic attacks. Torsades de pointes, a prolongation of the QTcinterval, and other cardiac arrhythmias, have been observedin patients treated with trazodone.53-57 Finally, a review ofpsychotropics and priapism found that almost 80% of casesreviewed were associated with trazodone, while the balancewas associated with antipsychotics.58


A COMBINATION OF TWO ANTIDE-

PRESSANTS

Efficacy

Trazodone

Trazodone is the most widely used sedating antidepressantused as adjunctive therapy to other antidepressants. Giventhe frequency with which this treatment course is pursued,it is remarkable that the combination of trazodone and otherantidepressants has not been ardently investigated. Of thestudies that have been conducted, almost all have employed

small samples and, therefore, may be of limited applicabilityto the general population of patients with depression.

In one study,59 trazodone 100 mg or placebo was given topatients (N=12) stable on different SSRIs for a period of 7

days. At the end of this period, trazodone co-therapy signifi-cantly increased total sleep time and SWS, and reduced thenumber of awakenings seen on polysomnography. Anotherstudy60 examined the impact of prescribing trazodone forpatients (N=17) with an incomplete response to fluoxetineor bupropion. In this evaluation, trazodone produced signifi-cantly more improvement than placebo in several subjectivemeasures of sleep.

Trazodone has been added to fluoxetine in one study of agroup of depressed patients (N=8) for the purposes of eitherimproving sleep or as a possible antidepressant potentia-tor.61 Three of the eight patients experienced improvements

in both sleep and depression symptoms. A second group ofpatients on fluoxetine (N=16) was given adjunctive trazo-done for complaints of insomnia.62 All patients had a positivehypnotic response, but five discontinued trazodone due toexcessive sedation.

Trazodone was compared to placebo in depressed patients(N=7) who developed insomnia while treated with the MAOIbrofaromine.63 Trazodone increased SWS and was associatedwith subjective reports of better and deeper sleep. A reviewof MAOI-induced insomnia treated with trazodone found 13case-studies.64 Twelve reported an initial positive response toco-therapy while only nine were able to continue treatment

without intolerable side effects.Depressed patients (N=50) participated in a 4-week study

of the atypical antidepressant venlafaxine with adjunctivetrazodone, as needed, for the development of comorbidinsomnia.65 The timing and dosage of trazodone was left tothe discretion of the clinicians to simulate a naturalistic set-ting. Patients who received adjunctive trazodone had a lowerresponse to venlafaxine monotherapy on MADRS measuresof insomnia and inner tension. Once trazodone was intro-duced, these patients showed improvements in insomniasymptoms but not in other measures of depression.

Other Antidepressants Aside from trazodone, very little information is availableabout the impact on sleep parameters of sedating antidepres-sants used as adjunctive therapy to any of the alerting SSRIsor MAOIs.

Safety

Trazodone

In one study of trazodone as adjunctive therapy for fluox-etine, five of eight patients were unaffected by the additionof trazodone to fluoxetine or had intolerable adverse drug


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reactions.61 In a second study62 of trazodone-fluoxetine co-therapy, all patients reported marked daytime sedation withfive of 16 discontinuing trazodone as a consequence. Theimplications of these case reports suggest that the utility of

the combination of fluoxetine and trazodone may be limitedby adverse effects.

Co-administration of trazodone and brofaromine producedfew adverse events and was well tolerated by study partici-pants.63 A review of several case studies of trazodone-MAOIco-therapy found that one of 13 patients was unable to toler-ate the combination initially and another three discontinuedthis course of treatment due to side effects over a longerperiod of time.64

Serotonin syndrome has been described when trazodonewas prescribed in combination with nefazodone.66 Serotoninsyndrome has also been reported following the use of venla-

faxine and fluoxetine.67

Other Sedating Antidepressants

Co-administration of the atypical antidepressant venlafax-ine and the TCAs clomipramine or imipramine has been welltolerated.68 Venlafaxine has been used as adjunctive therapywhen patients have realized only partial response to the TCA.However, no effects on sleep parameters were reviewed.

Adjunctive paroxetine has been employed to increase theeffectiveness of TCAs (amitriptyline and imipramine) inpatients who had not sufficiently responded after 3 weeks ofmonotherapy.69 This combination increased TCA serum lev-

els as intended and was well tolerated. Effects on sleep werenot reviewed. When used in combination, the SSRI fluoxetine was

shown to increase TCA plasma levels for several members ofthis class of antidepressants.70 This increase was highest withclomipramine and imipramine and less notable with amitrip-tyline. These pharmacokinetic changes did not induce sideeffects in the patients evaluated. The effects on sleep werenot reviewed.


A COMBINATION OF ONE ANTIDE-PRESSANT AND ONE HYPNOTIC

Efficacy

Although numerous drug-drug interaction studies havebeen conducted to evaluate the interaction between hypnot-ics and antidepressants, efforts to evaluate the effectiveness ofco-administration of these treatments on comorbid depres-sion and insomnia are still in the early stages.

The use of zolpidem was examined in SSRI-treated patients

with persistent comorbid insomnia.71 Patients who partici-pated in this study were diagnosed with depression, treatedstably with the SSRIs fluoxetine, sertaline, or paroxetine, andcomplained of sleep onset difficulty or too-short sleep time

at least 3 nights a week and associated with daytime impair-ment. Over a 4-week period, treatment with zolpidem 10 mglengthened sleep time, improved sleep quality, reduced thenumber of awakenings, and improved multiple measures ofdaytime functioning as compared to placebo.

A recent study evaluated the co-administration of eszopi-clone 3 mg with the SSRI fluoxetine in patients with MDDover an 8-week period.72 Compared to fluoxetine alone, thefluoxetine-eszopiclone group demonstrated statistically sig-nificant improvements in all sleep parameters evaluated atall time points. Measures included sleep latency, wake timeafter sleep onset, total sleep time, sleep quality, and depth of

sleep. Importantly, eszopiclone also resulted in a greater treat-ment response to fluoxetine as measured by improvementson the 17-item HAM-D, Clinical Global Impression (CGI)Improvement scale, and CGI Severity scale. Furthermore, asignificantly greater percentage of individuals in the co-thera-py group were classified as responders (59% versus 48%) andremitters (42% versus 33%) at the end of the study.

Safety

In the zolpidem-SSRI-induced insomnia study, adverseevents were similar between the placebo and zolpidem

groups.71 There was no evidence of dependence or withdrawalfrom zolpidem during the placebo substitution period at theconclusion of the study.

Zolpidem drug-drug interaction studies have been con-ducted with two TCAs and two SSRIs.73 Co-administrationof zolpidem and imipramine produced a 20% decrease inpeak levels of imipramine and an additive effect of decreasedalertness. Chlorpromazine in combination with zolpidemproduced no pharmacokinetic interactions; however, decreas-es in alertness and psychomotor performance were potenti-ated. Both of these studies evaluated single-dose interactions

in healthy volunteers. Thus, the results may not be predictivefor chronic administration in depressed patients.Zolpidem-fluoxetine interactions were examined in both

single-dose and multiple-dose studies. A single-dose studyin male volunteers with zolpidem 10 mg and fluoxetine 20mg at steady-state levels did not find any clinically signifi-cant pharmacokinetic or pharmacodynamic interactions.73,74Healthy females participated in a multiple-dose study ofzolpidem and fluoxetine at steady-state concentrations.73 Theonly significant change in this evaluation was a 17% increasein the half-life of zolpidem. No changes in psychomotor per-formance were seen.


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Healthy female volunteers were dosed with sertraline50 mg for 17 days. Once steady-state levels were reached,subjects were dosed for 5 consecutive nights with zolpidem10 mg. The pharmacokinetics of sertraline and N-desmeth-

ylsertraline were unaffected by zolpidem, but zolpidem Cmax was significantly higher (43%) and Tmax was significantlydecreased (53%).

Adverse events and dropout rates were similar between theplacebo and eszopiclone groups in the 8-week eszopiclone-fluoxetine MDD study.72 The frequency of adverse eventscontinued to be similar between both groups during the pla-cebo washout period at the conclusion of study.75 No evidenceof withdrawal effects, rebound insomnia, or rebound depres-sion was observed. A single-dose study of co-administrationof eszopiclone 3 mg with paroxetine 20 mg (7 days) found nopharmacokinetic or pharmacodynamic interactions.73

Zaleplon was evaluated in three single-dose antidepressantdrug interaction studies.73 Zaleplon 20 mg co-administeredwith the TCA imipramine 75 mg potentiated decrements innext-day alertness and psychomotor performance as comparedto either compound administered alone. There was no alterationof the pharmacokinetics of either drug. In two separate studies,neither co-administration of zaleplon with the SSRI paroxetine20 mg (7 days) or with the atypical antidepressant venlafaxine150 mg resulted in any pharmacokinetic or pharmacodynamicchanges to either zaleplon or the antidepressant.

Ramelteon is the newest hypnotic approved for the treatment

of insomnia in the US. It has been evaluated for use in conjunc-tion with two SSRIs. A single-dose of ramelteon 16 mg wasco-administered with fluvoxamine 100 mg (3 days).73 This com-bination increased the area under the curve (AUC)0-infof ramelt-eon by approximately 190-fold, and the Cmax by approximately70-fold. This effect appeared to be specific to fluvoxamine andcytochrome P450 1A2 inhibitors rather than being a class effectwhich could be expected to occur with other SSRIs.

A multiple dose study of co-administration of ramelteon

and sertraline was conducted.76 Ramelteon had no effect onthe systemic availability of sertraline. Decreases in ramelteon AUC and Cmax (23% and 43%, respectively) were deemedclinically irrelevant due to ramelteons highly variable inter-

subject pharmacokinetic profile.

ANTIDEPRESSANTS AND NON-

DEPRESSED PATIENTS

A small number of studies have evaluated the efficacy ofantidepressants in non-depressed, primary insomnia patients.The extremely limited nature of this evidence and the smallscale of most of these studies strongly argues against the use ofantidepressants as hypnotics in non-depressed patients.

The largest study (N=306) reported to date has been the

only placebo-controlled study of trazodone in insomniapatients.77 Over a 2-week period, trazodone improved sleeplatency and total sleep time relative to placebo during thefirst week of treatment only. The loss of efficacy during thesecond week suggests that trazodone is not an appropriateinsomnia treatment choice for non-depressed patients. Noother trazodone studies have been reported in primary insom-nia patients.

A low-dose formulation of doxepin is currently in develop-ment as a hypnotic. Three published studies have examineddoxepins effects in primary insomnia patients. A placebo-controlled, 4-week study of doxepin 2550 mg (N=47) foundthat active treatment improved sleep efficiency and sleepquality over the entire treatment period.78 Notably, morerebound insomnia was observed in the doxepin treatmentgroup during the placebo run-out period. Adverse effectswere comparable between the two groups, but two doxepinpatients discontinued due to adverse effects. In the secondstudy, patients (N=10) were treated with placebo for 1 nightand doxepin 25 mg for 3 weeks.79 Relative to placebo, sleepwas improved after one dose of doxepin during the double-blind phase of the trial. At the end of 3 weeks of open-labeltreatment, doxepin also improved sleep relative to baseline

values. Adverse events and rebound insomnia remained aconcern in some patients. Finally, a 2-night cross-over study80(N=67) was employed to evaluate doxepin 16 mg. All threedoses improved wake time during sleep, total sleep time,and sleep efficiency relative to placebo. The safety profile ofdoxepin was similar to that of placebo with no evidence ofanticholinergic effects, memory impairment, or significanthangover/next-day residual effects.

Two studies evaluated paroxetine in primary insomniapatients. Fifteen insomnia patients were treated for 6 weekswith a flexible dose of paroxetine (median dose=20 mg).81 Atthe end of the treatment period, 11 patients had improved

TABLE 2

HYPNOTICS

DosageSleep

Init iation Sleep Maintenance

Eszopiclone 13 mg + +

Ramelteon 8 mg + -

Zaleplon 520 mg + -

Zolpidem 510 mg

(CR formulation:6.2612.5 mg )

+ -

+ (CR formulation)

+=improvement; -=no consistent effect; CR=controlled release.

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and seven no longer met the diagnostic criteria for insomnia.

Subjective measures of sleep quality and daytime function

were significantly improved, but neither objective nor sub-

jective measures of sleep quantity were consistently changed

with treatment. One participant dropped out due to adverseside effects. A double-blind comparison82 of paroxetine and

placebo in older adults (N=27) found improvements in sub-

jective sleep quality and several measures of daytime function.

Sleep efficiency, sleep latency, and wake time appeared to be

unaffected by active treatment. Both evaluations suggest that

paroxetine is ineffective for treating primary insomnia.

Trimipramine was studied in two groups of primary

insomnia patients.83 It was shown to produce significant

improvements in sleep efficiency, total sleep time, wake time

after sleep onset, sleep quality, and next-day well-being in 19

primary insomnia patients (mean dose=166 mg ). Side effectsincluded dry mouth and the anticholinergic properties of

the drug. No rebound insomnia was observed at either 4 or

14 days following drug discontinuation. A 4-week study84 of

trimipramine (mean dose=100 mg) in 55 insomnia patients

found significant improvements in sleep efficiency but no

impact on total sleep time. Adverse effects were deemed mini-

mal and no rebound insomnia was observed.

One open label study85 of nefazodone in primary insomnia

has been reported. Patients (N=32) were treated with 100

mg nefazodone at bedtime. Over the 4-week period evalu-

ated, this dose could be titrated up to 400 mg dependingon treatment response. At the end of the treatment period

sleep latency was prolonged and there was less SWS relative

to baseline values. The duration of REM sleep was greater

and improvements were seen in subjective Pittsburgh Sleep

Quality Index scores, but overall sleep effects were decidedly

mixed. Furthermore, 12 of 32 participants dropped out of the

study citing either lack of efficacy or intolerable side effects.

CONCLUSION

Mood disorders are frequently comorbid with insomnia.Treatment options to address both conditions simultaneously

include the use of a sedating antidepressant, two antidepres-

sants (one sedating), or an antidepressant in conjunction with

a hypnotic. Although the simultaneous use of two antidepres-

sants is perhaps the most common course of action, it has

not been well studied and is associated with significant safety

concerns. Recent studies suggest that combining an antide-

pressant with a hypnotic may be a more promising, effica-

cious, and safe strategy for the treatment of comorbid mood

disorders and insomnia.PP

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