Given the high comorbidity of insomnia and depression and / or anxiety, sedating antidepressants have considerable relevance for treating insomnia. (Note: Sedating antidepressants can effectively treat both depressive and anxious symptoms.) The sleep-promoting properties of the sedating antidepressants, as well as their lack of abuse potential or propensity to induce tolerance, make these agents viable treatment options for chronic insomnia with or without underlying depression and / or anxiety.
Very few well-controlled studies have been undertaken to establish efficacy of antidepressants for insomnia. Nevertheless, physicians continue to prescribe the more-sedating antidepressants for individuals with chronic insomnia who require long-term treatment. This section discusses two sedating antidepressants — trazodone (Aventis’s Molipaxin, Bristol-Myers Squibb’s Desyrel, generics) and mirtazapine (Organon’s Remeron / Remergil / Zispan, generics) — that are commonly prescribed for patients with insomnia with or without comorbid depression.
Mechanism of Action
Trazodone and mirtazapine are often referred to as “second-generation” antidepressants because their development resulted from an effort to improve the pharmacological profiles of the tricyclic antidepressants. Specifically, both trazodone and mirtazapine are more receptor-specific than the traditional tricyclic antidepressants — that is, they have less of an effect at the receptors (e.g., muscarinic, histaminergic) that are responsible for the numerous unwanted side effects associated with the older tricyclic antidepressants (e.g., dry mouth, constipation, blurred vision, urinary retention, cognitive impairment).
Trazodone is a mixed serotonin agonist / antagonist (it blocks 5-HT2a and 5-HT2c receptors) that also blocks alpha-1-adrenergic and histaminergic receptors, and it may stimulate dopaminergic transmission. Researchers believe that trazodone’s ability to block 5-HT2 and alpha-adrenergic receptors provides sleep-enhancing properties. Mirtazapine is referred to as a noradrenergic and specific serotonergic antidepressant because of its potent antagonism of alpha-2-adrenergic, 5-HT2, and 5-НТ3 receptors, which results in increased noradrenergic and 5-HT1-mediated serotonergic neurotransmission. As is the case with trazodone, researchers suspect that mirtazapine’s antagonist activity at 5-HT2 receptors provides sleep-enhancing properties.
Trazodone (Aventis’s Molipaxin, Bristol-Myers Squibb’s Desyrel, generics) has been marketed for depression in most major markets (except France, where it is not available) since the 1980s. Physicians frequently prescribe trazodone off-label for the treatment of chronic insomnia in patients with or without depression. The drug is generally prescribed at lower doses when used to treat insomnia alone.
Trazodone was the first antidepressant to specifically target the serotonin system. As mentioned, trazodone is a mixed serotonin agonist / antagonist (blocks 5-HT2a and 5-HT2c) that also blocks alpha-1-adrenergic and histaminergic receptors and may stimulate dopamine transmission. The drug’s sleep-enhancing properties are believed to result from its action at 5-HT2 receptors and its alpha-adrenergic receptor-blocking properties.
Of the sedating antidepressants used to treat insomnia, trazodone is not just one of the most widely prescribed, but it is also the best studied in clinical trials in patients with secondary insomnia associated with depression; in these trials, the drug has been shown to improve overall sleep efficiency by reducing sleep latency and increasing sleep duration, as well as improving sleep architecture. Trazodone has also been shown to improve sleep in patients with antidepressant-associated insomnia (i.e., insomnia that is persistent, exacerbated, or newly emergent in patients taking nonsedating antidepressants). Additionally, the drug seems to offer an effective alternative for patients with alcohol postwithdrawal syndrome who require hypnotic treatment; in such patients, benzodiazepine-related hypnotics are not an ideal choice because of the potential for cross-tolerance between the benzodiazepines and alcohol.
Trazodone can cause several untoward side effects (e.g., headache, daytime somnolence, dry mouth, hypotension, dizziness, and, in rare cases, priapism [i.e., prolonged and painful erection]) that can lead to a high level of noncompliance among patients. While lowering the dose of the drug helps to alleviate these effects, many patients still have difficulty tolerating trazodone. Nevertheless, the drug’s use for insomnia has steadily increased over the years, and it is generally considered one of the best therapeutic choices when a sedating antidepressant is the drug class of choice for a patient with chronic insomnia.
Mirtazapine (Organon’s Remeron / Remergil / Zispan, generics) was first marketed for depression in the Netherlands in 1994 and has since been marketed for this indication in the United States and Europe. In Japan, mirtazapine is in Phase III trials for depression. Physicians prescribe mirtazapine off-label for the treatment of chronic insomnia in patients with or without depression. The drug is generally prescribed at lower doses when used to treat insomnia alone.
As mentioned earlier, mirtazapine acts as an antagonist at a2-adrenergic inhibitory autoreceptors and heteroreceptors, as well as at 5-HT2 and 5-HT3 receptors; this activity results in increased noradrenergic and 5-HT1-mediated serotonergic neurotransmission. The drug’s sleep-enhancing properties are believed to result from its action at 5-HT2 receptors.
Only small clinical trials have been conducted in individuals with depression to investigate mirtazapine’s sleep-enhancing properties. In a recently published trial, 19 patients with major depressive disorder were randomly assigned to either fluoxetine (20-40 mg / day) or mirtazapine (15-45 mg / day) in a double-blind manner for eight weeks following baseline polysomnographic evaluations taken over two consecutive nights. Follow-up polysomnograms were conducted at weeks 1, 2, and 8 (along with standard depression ratings, which were assessed more frequently).
At study completion, patients receiving mirtazapine (n = 8) had significant improvement in objective sleep physiology measures, whereas those receiving fluoxetine did not. Specifically, improvements in sleep latency, sleep efficiency, and wake time after sleep onset (WASO) reached significance compared with baseline measurements for mirtazapine-treated patients at the two-week time point and continued to improve throughout the remaining weeks. In addition, no significant changes were observed in individual sleep stages or rapid eye movement latency with mirtazapine during the study period; this benefit was in contrast to the fluoxetine group, in which there was a significant increase in stage 1 sleep by week 8 and a significant prolongation of rapid eye movement latency that appeared at week 2 and continued through week 8 (compared to baseline).
In depression trials, increased appetite, weight gain, and somnolence are the most frequently reported side effects associated with mirtazapine.
Common brands (equivalents) of Mirtazapine, which the pharmacists offer you to buy according to your prescription or without a prescription: Afloyan, Amirel, Arintapin, Avanza, Axit, Azapin, Calixta, Ciblex, Combar, Comenter, Depreram, Divaril, Esprital, Lanazapin, Mirap, Miro, Mirta TAD, Mirtabene, Mirtadepi, MirtaLich, Mirtaril, Mirtaron, Mirtastad, Mirtaz, Mirtazelon, Mirtazon, Mirtazza, Mirtel, Mirzalux, Mirzaten, Mizapin, Norset, Noxibel, Promyrtil, Remergil, Remergon, Remeron, Rexer, Tazamel, Vastat, Zismirt, Zispin, Zuleptan.