By inhibiting both the serotonin and norepinephrine(Drug information on norepinephrine) transporters, selective SNRIs engage a broader mechanism of action than do SSRIs.8 While significantly fewer polysomnographic studies have been conducted with the selective SNRIs, the general pattern of effects reported are comparable to those seen with SSRIs, including the potential for some disruption of sleep continuity and prominent suppression of REM sleep.1 A recent clinical application of antidepressants to clinical sleep disorders has stemmed from the recognition that broad-spectrum antidepressants have value in the treatment of fibromyalgia.14 Selective SNRIs have been used in patients with this disorder, and the selective SNRI milnacipran has been approved and is now marketed for fibromyalgia.
Trazodone is characterized by serotonin-2 receptor antagonism and weak serotonin reuptake inhibition.8 This effect is noteworthy with respect to sleep physiology, since an increase of serotonin neurotransmission at the serotonin-2 receptor can result in disruption of sleep continuity as well as inhibition of slow wave sleep. In contrast, serotonin-2 receptor antagonists have been shown to decrease sleep onset latency and increase slow wave sleep.
Trazodone also blocks histamine H1 receptors, which can be associated with enhanced sleep and potential for daytime somnolence.15 Trazodone was introduced as an antidepressant with a dosage range of 200 to 600 mg/d in 2 or 3 divided doses. However, trazodone produced prominent daytime somnolence in this dosage range, which made it an unacceptable option for many patients.
Clinicians soon came to recognize that by scaling down the dosage substantially (typically to a range of 50 to 100 mg qhs), trazodone could be used as an adjunctive treatment for improving symptoms of insomnia without causing significant daytime somnolence. Thus, trazodone is now frequently used off-label as add-on therapy to other antidepressant drugs to address residual insomnia.1,16 In some polysomnographic studies, trazodone was seen to increase total sleep time and reduce wakefulness during sleep. In addition, as noted above, trazodone appears to exert minimal effects in suppressing REM sleep.
Nefazodone is structurally similar to trazodone and has a relatively similar pharmacological profile.8 In polysomnographic studies involving depressed patients with prominent insomnia complaints, nefazodone(Drug information on nefazodone) was reported to preserve sleep continuity and to be devoid of REM suppression.12 The clinical use of nefazodone in recent years has been significantly limited by reports of liver toxicity, in some cases involving fatalities. Even though the incidence of this complication is extremely uncommon, its potential severity appears to have significantly reduced nefazodone use in the treatment of depression despite its beneficial sleep profile.
Mirtazapine demonstrates a unique pharmacological profile among the antidepressant drugs, characterized by inhibition of the presynaptic α2-adrenergic receptor as well as blockade of serotonin-2 and serotonin-3 receptors and histamine H1receptors.8 The combination of serotonin-2 and histamine H1 receptor blockade provides a strong basis to anticipate a profile of sleep enhancement; however, there is also potential for daytime somnolence. Polysomnographic studies in depressed patients with prominent insomnia symptoms have reported significant shortening of sleep onset latency and an increase in total sleep time across the full spectrum of mirtazapine(Drug information on mirtazapine)’s antidepressant dosage range, from 15 to 45 mg/d.17 There is also limited evidence of REM suppression with mirtazapine therapy.
Currently, mirtazapine may be selected as monotherapy for depressed patients who have prominent associated insomnia complaints. In other depressed patients, mirtazapine may be added to another primary antidepressant drug to augment the antidepressant response and to address unresolved insomnia. Mirtazapine may be associated with daytime somnolence, which usually resolves after a few days of treatment in some cases but which may be more persistent for some patients. Another vexing problem for some patients treated with mirtazapine is weight gain, which may be significant.
Bupropion is somewhat unique among antidepressant drugs in exerting negligible effects on any parameter of serotonin neurotransmission. Bupropion is selective in blocking presynaptic reuptake of dopamine(Drug information on dopamine) and norepinephrine, but its potency in blocking dopamine and norepinephrine reuptake is limited.3 Increased catecholamine neurotransmission following administration of bupropion appears to lead to complaints of insomnia in some cases.6 Notably, bupropion does not suppress REM sleep, as do most antidepressant drugs, but it actually results in an increase in REM sleep time.18
Neurotransmitters implicated in the mechanism of action of all currently marketed antidepressants have been demonstrated to play important roles in the neurobiological regulation of sleep and wakefulness as well as in the regulation of transitions between the various stages of sleep. In addition, changes in sleep patterns are observed in a large percentage of patients with depression, and unresolved problems with insomnia have been reported to represent the most significant risk factor among residual symptoms of depression in patients who have responded to antidepressant drug therapy.
Knowledge of how different antidepressants are likely to affect parameters of sleep—including latency to sleep onset, maintenance of sleep continuity, and alterations in sleep architecture—can provide an important basis for selecting an appropriate antidepressant drug among the roughly 2 dozen marketed options to most suitably meet the needs of depressed patients.