March 2010

Treating Persistent Insomnia: Therapy, Meds, or Both?
While cognitive behavioral therapy is probably best for long-term treatment of chronic insomnia, hypnotics can add benefits acutely.

Diet and Depression
Overall dietary pattern may be more important than individual components (such as omega-3 fatty acids) in lowering the risk of depression.

In Brief
Another Negative Trial of Ginkgo biloba for Cognitive Decline; Physical Activity during Pregnancy Has Mixed Results on Postpartum Depression

Carotidynia Associated with SSRIs
Carotidynia may be a rare side effect of selective serotonin reuptake inhibitors and might be more common in migraine sufferers.

Clozapine Hypersalivation: A Negative Study with Ipratropium
In a small, double-blind trial, ipratropium (Atrovent and others) was not effective in decreasing sialorrhea associated with clozapine (Clozaril and others) treatment.

Treating Persistent Insomnia: Therapy, Meds, or Both?

March 2010

Everyone experiences occasional difficulty sleeping. But for some people, insomnia is chronic and disabling. Persistent insomnia impairs daytime functioning, diminishes quality of life, and increases the risk of major depression and hypertension. Many people treat themselves with alcohol or over-the-counter remedies, which have questionable benefits and potentially serious side effects.

The best studied treatments for chronic insomnia are cognitive behavioral therapy (CBT) and pharmacotherapy with benzodiazepine-receptor agonists. Morin and coworkers note that few studies have compared psychotherapy and hypnotic medications directly.1 Limited data suggest that both are effective in the short run, but benefits from a medication stop when a patient stops taking it. As in the treatment of depression, CBT relieves insomnia more slowly than medications, but improved sleep tends to persist over time.2

In 2006, Sivertsen and colleagues reported a greater reduction in total wake time for patients receiving CBT (52%) compared with those taking zopiclone* (4%) after 6 weeks of treatment, as well as a trend for superiority in sleep efficiency and significantly more slow wave sleep (BTP 2007;30:23).3 Total sleep time after 6 months' follow-up had increased significantly in the CBT group but had not changed in the zopiclone group.

Some data suggest that combining CBT and hypnotic medicines produces advantages over using either treatment alone. Morin and coinvestigators conducted a prospective, randomized, controlled trial involving 160 adults with persistent insomnia at a university sleep center in Canada.1 Supported by a grant from the National Institute of Mental Health, this trial addressed the added value of medication combined with CBT over CBT alone for acute treatment of insomnia, as well as the effects of maintenance therapies on long-term outcome. Subjects received either CBT alone or CBT plus zolpidem (Ambien and others), 10 mg at bedtime, for 6 weeks. Then, those who had received CBT alone attended monthly maintenance CBT sessions for 6 months or, for comparison, received no additional treatment. Those treated initially with combined CBT and zolpidem continued with CBT plus zolpidem on an as-needed basis or CBT alone.

Whether used alone or combined with zolpidem, CBT was effective acutely. Patients experienced significant improvement in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (P < .001 for all). Treatment response rates were similar for CBT alone and CBT plus zolpidem (60% and 61%, respectively). The addition of medication to CBT produced modest increases in total sleep time during the 6-week, acute treatment phase. During the 6-month extended phase, combined treatment yielded a higher remission rate (56%) than CBT alone (43%, P = .05).

Due to a shortage of trained cognitive behavioral therapists, CBT may be difficult to obtain in many areas. Vincent and Lewycky conducted a 5-week randomized controlled trial of online CBT—consisting of psychoeducation, sleep hygiene, stimulus-control instruction, sleep restriction treatment, relaxation training, cognitive therapy, and help with medication tapering.4 Of 118 adults with chronic insomnia, online at-home treatment was statistically superior (P = .0001) to a waiting-list control condition. Of patients receiving online CBT, 35% considered themselves much or very much improved, versus only 2% of control subjects. We previously described similar results from a smaller trial of online CBT by Ritterband and colleagues5 (BTP 2009;32:35). Another option is a "stepped-care" approach, which begins with self-administered CBT, followed if necessary by group and then individual CBT.6

A pharmacologic alternative to benzodiazepine-receptor agonists to induce sleep is the use of melatoninergic agonists. These drugs tend to lack hangover or withdrawal effects, and they do not cause dependence.7 But they may have adverse endocrine or immunologic effects and should be avoided in patients with Parkinson's disease.7 The one melatoninergic agonist available in the United States is ramelteon (Rozerem), which binds to types 1 and 2 melatonin receptors in the suprachiasmatic nucleus. Ramelteon's primary effect is the reduction of sleep-onset latency, but this may only occur on the first few nights of treatment.8 Its overall effects on insomnia tend to be modest. More, Richardson and Wang-Weigand report elevated prolactin levels in women treated with ramelteon, which could have unknown long-term consequences.9

Another melatonin 1 and 2 agonist, agomelatine,** is being studied as an antidepressant. It appears to combat insomnia, as well as depression, in patients with major depressive disorder.10

Many antidepressants have been used off-label to treat insomnia—including trazodone (Desyrel and others) and doxepin (Sinequan and others). Goforth contends that very low doses (1 to 6 mg) of doxepin, via strong antagonism of the histamine-H1 receptor, can effectively treat insomnia in some patients.11 At these doses, presumably, anticholinergic and antihistaminic side effects would be modest, but this must be tested prospectively. The widely available antihistamine diphenhydramine (Benadryl and others) is variable in efficacy and often poorly tolerated.

So, how to treat chronic insomnia? CBT (Possibly online) probably affords the best long-term risk compromise. Data from Dr Morin's group1 suggest that combining CBT with the short-term use of a hypnotic can produce added benefits acutely. For the long term, a clinician should consider withdrawing medication to assess whether CBT alone allows continued improvement in sleep patterns. The ratio of risks to benefits for melatoninergic drugs requires further study.

*Racemic zopiclone is not available in the United States. However, the stereoisoform, eszopiclone, is now available as Lunesta.

**Not available in the United States.

1Morin CM, Vallières A, Guay B, Ivers H, Savard J, Mérette C, Bastien C, Baillargeon L: Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: A randomized controlled trial. JAMA 2009;301:2005-2015.

2Riemann D, Perlis ML: The treatments of chronic insomnia: A review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev 2009;13:205-214.

3Sivertsen B, Omvik S, Pallesen S, Bjorvatn B, Havik OE, Kvale G, Nielsen GH, Nordhus IH: Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: A randomized controlled trial. JAMA 2006;295:2851-2858.

4Vincent N, Lewycky S: Logging on for better sleep: RCT of the effectiveness of online treatment for insomnia. Sleep 2009;32:807-815.

5Ritterband LM, Thorndike FP, Gonder-Frederick LA, Magee JC, Bailey ET, Saylor DK, Morin CM: Efficacy of an Internet-based behavioral intervention for adults with insomnia. Arch Gen Psychiatry 2009;66:692-698.

6Espie CA: "Stepped care": A health technology solution for delivering cognitive behavioral therapy as a first line insomnia treatment. Sleep 2009;32:1549-1558.

7Hardeland R: New approaches in the management of insomnia: Weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists. Neuropsychiatr Dis Treat 2009;5:341-354.

8Wang-Weigand S, McCue M, Ogrinc F, Mini L: Effects of ramelteon 8 mg on objective sleep latency in adults with chronic insomnia on nights 1 and 2: Pooled analysis. Curr Med Res Opin 2009;25:1209-1213.

9Richardson G, Wang-Weigand S: Effects of long-term exposure to ramelteon, a melatonin receptor agonist, on endocrine function in adults with chronic insomnia. Hum Psychopharmacol 2009;24:103-111.

10Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, Rybakowski JK, Quera-Salva MA, Wirz-Justice AM, Picarel-Blanchot F, Baylé FJ: Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: A randomized, double-blind comparison with sertraline. J Clin Psychiatry, in press.

11Goforth HW: Low-dose doxepin for the treatment of insomnia: Emerging data. Expert Opin Pharmacother 2009;10:1649-1655.