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The Effects of Antidepressants on Sleep

The Effects of Antidepressants on Sleep

sleep disordersMany psychiatric disorders are accompanied by disturbance of sleep. In addition to resolving sleep-related symptoms through their primary therapeutic effects, many psychiatric medications have secondary effects on sleep that can contribute to their overall therapeutic benefit or sometimes counter them through adverse effects. The antidepressants are a prototypical example of the potentially complex interactions between psychiatric medications and sleep.

It is thought that all approved antidepressants work through modulation of monoamine neurotransmitters, including norepinephrine, dopamine, and serotonin, all of which have been shown to exert prominent effects in regulating sleep-wakefulness and sleep architecture (Table).1 In particular, norepinephrine and serotonin play prominent roles in suppressing REM sleep, while acetylcholine (ACh) plays a key role in the initiation of REM sleep.2 A number of antidepressants affect other neurotransmitter receptors, such as muscarinic ACh, α1-adrenergic, and histamine H1receptors, that are implicated in sleep regulation.3

TCAs

Pharmacological differences among TCAs translate into clinically differentiating features. TCAs such as amitriptyline and doxepin are used in depressed patients who have prominent insomnia. In recent years, clinicians have scaled down the dosages of these antidepressants to well below established ranges to treat insomnia symptoms. Pharmacologically, the TCAs noted for their sleep-enhancing effects are more potent in blocking the serotonin transporter than the norepinephrine transporter, in addition to exerting prominent blockade of histamine H1 receptors.3 Doxepin has been studied at very low dosages in patients with primary insomnia. The studies demonstrate the efficacy of low-dosage doxepin therapy (3 and 6 mg qhs) for alleviating symptoms of insomnia.4 Doxepin is now marketed in the US as Silenor, in 3- and 6-mg dose strengths for primary insomnia.

TABLE

Antidepressants and their effects on sleep physiology

Some TCAs are more activating and have been used to treat a subset of depressed patients who experience hypersomnolence and daytime lethargy. Examples of TCAs in this category include desipramine and protriptyline, agents that are characterized by the selective blockade of norepinephrine presynaptic uptake sites.3 In polysomnographic studies of patients with depression, administration of the activating TCA desipramine has been reported to produce an increase in sleep onset latency, a decrease in sleep efficiency, and a heightened number of awakenings.5 These findings underscore the important lesson that treatment with an antidepressant does not automatically result in improvement in sleep in depressed patients.

The majority of TCAs markedly suppress REM sleep, except for trimipramine, trazodone, nefazodone, bupropion, and mirtazapine.1,6 A clinical consequence of REM suppression can be a change in frequency and intensity of dreaming, as well as a pronounced exacerbation of intense, disturbing dreams related to “REM rebound” on discontinuation. Pulmonary specialists sometimes advocate use of an activating TCA such as protriptyline because it may help suppress REM sleep—when sleep apnea episodes may be accentuated—and also provide benefit for the daytime somnolence that many patients with sleep apnea experience.7

MAOIs

These agents increase concentrations of norepinephrine, dopamine, and serotonin by decreasing their metabolism.8While the MAOIs have demonstrated efficacy in the treatment of depression in general, they especially have been associated with efficacy in the treatment of atypical depression characterized by hypersomnolence as well as by apathy and low energy.9

Tranylcypromine is structurally related to amphetamine and tends to be activating and associated with insomnia. In polysomnographic studies, tranylcypromine has been demonstrated to prolong sleep onset latency and increase awakenings and arousals during sleep.10 Phenelzine is more typically sedating and is less frequently associated with complaints of insomnia. Notably, both have been demonstrated to produce REM suppression, and discontinuation of treatment can be associated with significant REM rebound.6 Selegiline is now available as a skin patch, which may be less likely to cause insomnia.

SSRIs

The SSRIs are characterized by selective inhibition of the presynaptic serotonin transporter, leading to enhanced activity of serotonin at postsynaptic receptors.3 A large number of serotonin receptor subtypes that regulate sleep and wakefulness as well as transitions between specific sleep stages, such as the termination of REM sleep, have been identified.

Because of the complexity of serotonin involvement in sleep-wake regulation, drugs that modulate serotonin activity can produce prominent and sometimes diverse effects on sleep. Some patients who took fluoxetine reported insomnia as an adverse effect, whereas other patients experienced daytime somnolence.11 This same pattern of diverse subjective reports on sleep and wakefulness has been reported in clinical trials with all of the drugs in this class.

While data have been reported most extensively for fluoxetine and paroxetine, class effects of SSRI therapy appear to include increased sleep onset latency and/or an increased number of awakenings and arousals, leading to an overall decrease in sleep efficiency.12,13 Virtually all of the SSRIs examined have been noted to suppress REM sleep.1 Clinically, reports of a change in the frequency, intensity, and content of dreaming can be associated with SSRIs, as well as the occurrence of these symptoms on discontinuation.

Be mindful that treatment of a patient with depression may produce significant improvement in symptoms of depression in general, yet may not address insomnia. In some cases, treatment with an SSRI may produce or exacerbate problems with sleep disturbance. Therefore, a medication that targets insomnia may also be prescribed for patients with depression who are being treated with an SSRI.

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