CNS Drugs

, Volume 23, Issue 4, pp 309–329 | Cite as

Insomnia in Patients with Depression

Some Pathophysiological and Treatment Considerations
  • Ripu D. JindalEmail author
Review Article


The almost ubiquitous sleep disturbances in patients with depression commonly, but not always, subside with the remission of depression. Evidence linking insomnia with the risk of relapses in recurrent depression, as well as suicide, makes optimization of the treatment of insomnia associated with depression a priority. However, most antidepressant agents do not adequately address the sleep complaints in depression: their effects on sleep range from sizeable improvement to equally significant worsening. One approach to the management of insomnia associated with depression is to choose a sedating antidepressant agent such as trazodone, mirtazapine or agomelatine. A second approach is to start with a non-sedating antidepressant (e.g. the selective serotonin reuptake inhibitors, bupropion, venlafaxine or duloxetine); those with a persistent or treatment-emergent insomnia can be switched to a more sedating antidepressant, or offered a hypnotic or cognitive-behavioural therapy as adjunctive treatment. The review discusses the advantages and disadvantages of all treatment options, pharmacological and otherwise


Zolpidem Duloxetine Mirtazapine NREM Sleep Zaleplon 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. The author has received an honorarium for attending an advisory board meeting for Novartis.


  1. 1.
    Horwath E, Johnson J, Weissman MM, et al. The validity of major depression with atypical features based on a community study. J Affect Disord 1992; 26(2): 117–25PubMedCrossRefGoogle Scholar
  2. 2.
    Parker G, Roy K, Mitchell P, et al. Atypical depression: a reappraisal. Am J Psychiatry 2002; 159(9): 1470–9PubMedCrossRefGoogle Scholar
  3. 3.
    Parker G, Malhi G, Hadzi-Pavlovic D, et al. Sleeping in? The impact of age and depressive sub-type on hypersomnia. J Affect Disord 2006; 90(1): 73–6PubMedCrossRefGoogle Scholar
  4. 4.
    Paudel ML, Taylor BC, Diem SJ, et al. Association between depressive symptoms and sleep disturbances in community-dwelling older men. Osteoporotic Fractures in Men Study Group. J Am Geriatr Soc 2008 Jul; 56(7): 1228–35Google Scholar
  5. 5.
    Buysse DJ, Tu XM, Cherry CR, et al. Pretreatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters. Biol Psychiatry 1999; 45(2): 205–13PubMedCrossRefGoogle Scholar
  6. 6.
    Thase ME, Simons AD, Reynolds III CF. Abnormal electroencephalographic sleep profiles in major depression: association with response to cognitive behavior therapy. Arch Gen Psychiatry 1996; 53(2): 99–108PubMedCrossRefGoogle Scholar
  7. 7.
    Dew MA, Reynolds III CF, Houck PR, et al. Temporal profiles of the course of depression during treatment: predictors of pathways toward recovery in the elderly. Arch Gen Psychiatry 1997; 54(11): 1016–24PubMedCrossRefGoogle Scholar
  8. 8.
    Reynolds III CF, Frank E, Houck PR, et al. Which elderly patients with remitted depression remain well with continued interpersonal psychotherapy after discontinuation of antidepressant medication? Am J Psychiatry 1997; 154(7): 958–62PubMedGoogle Scholar
  9. 9.
    Cho HJ, Lavretsky H, Olmstead R, et al. Sleep disturbance and depression recurrence in community-dwelling older adults: a prospective study. Am J Psychiatry 2008 Dec; 165(12): 1543–50PubMedCrossRefGoogle Scholar
  10. 10.
    Dombrovski AY, Cyranowski JM, Mulsant BH, et al. Which symptoms predict recurrence of depression in women treated with maintenance interpersonal psychotherapy? Depress Anxiety 2008; 25(12): 1060–6PubMedCrossRefGoogle Scholar
  11. 11.
    Agargun MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. J Clin Psychiatry 1997; 58(6): 249–51PubMedCrossRefGoogle Scholar
  12. 12.
    Fawcett J, Scheftner WA, Fogg L, et al. Time-related predictors of suicide in major affective disorder. Am J Psychiatry 1990; 147(9): 1189–94PubMedGoogle Scholar
  13. 13.
    Goldstein TR, Bridge JA, Brent DA. Sleep disturbance preceding completed suicide in adolescents. J Consult Clin Psychol 2008 Feb; 76(1): 84–91PubMedCrossRefGoogle Scholar
  14. 14.
    Buysse DJ, Angst J, Gamma A, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 2008 Apr 1; 31(4): 473–80PubMedGoogle Scholar
  15. 15.
    Roane BM, Taylor DJ. Adolescent insomnia as a risk factor for early adult depression and substance abuse. Sleep 2008 Oct 1; 31(10): 1351–6PubMedGoogle Scholar
  16. 16.
    Pigeon WR, Hegel M, Unützer J, et al. Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep 2008 Apr 1; 31(4): 481–8PubMedGoogle Scholar
  17. 17.
    Jindal RD, Thase ME. Treatment of insomnia associated with clinical depression. Sleep Med Rev 2004; 8(1): 19–30PubMedCrossRefGoogle Scholar
  18. 18.
    Thase ME, Carpenter L, Kupfer DJ, et al. Clinical significance of reversed vegetative subtypes of recurrent major depression. Psychopharmacol Bull 1991; 27(1): 17–22PubMedGoogle Scholar
  19. 19.
    Matza LS, Revicki DA, Davidson JR, et al. Depression with atypical features in the National Comorbidity Survey: classification, description, and consequences. Arch Gen Psychiatry 2003; 60(8): 817–26PubMedCrossRefGoogle Scholar
  20. 20.
    Thase ME, Himmelhoch JM, Mallinger AG, et al. Sleep EEG and DST findings in anergic bipolar depression. Am J Psychiatry 1989; 146(3): 329–33PubMedGoogle Scholar
  21. 21.
    Thase ME, Kupfer DJ, Ulrich RF. Electroencephalographic sleep in psychotic depression: a valid subtype? Arch Gen Psychiatry 1986; 43(9): 886–93PubMedCrossRefGoogle Scholar
  22. 22.
    Feinberg M, Carroll BJ. Biological ‘markers’ for endogenous depression: effect of age, severity of illness, weight loss, and polarity. Arch Gen Psychiatry 1984; 41(11): 1080–5PubMedCrossRefGoogle Scholar
  23. 23.
    Frank E, Kupfer DJ, Hamer T, et al. Maintenance treatment and psychobiologic correlates of endogenous subtypes. J Affect Disord 1992; 25(3): 181–9PubMedCrossRefGoogle Scholar
  24. 24.
    Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999; 60(4): 221–5PubMedCrossRefGoogle Scholar
  25. 25.
    Manber R, Rush AJ, Thase ME, et al. The effects of psychotherapy, nefazodone, and their combination on subjective assessment of disturbed sleep in chronic depression. Sleep 2003; 26(2): 130–6PubMedGoogle Scholar
  26. 26.
    Carney CE, Segal ZV, Edinger JD, et al. A comparison of rates of residual insomnia symptoms following pharmacotherapy or cognitive-behavioral therapy for major depressive disorder. J Clin Psychiatry 2007; 68(2): 254–60PubMedCrossRefGoogle Scholar
  27. 27.
    Carskadon MA, Rechtsschaffen A. Monitoring and staging human sleep. In: Kryger MH, Roth T, Demen WC, editors. Principles and practice of sleep medicine. London: W.B. Saunders, 1994Google Scholar
  28. 28.
    Coburn KL, Lauterbach EC, Boutros NN, et al. The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 2006; 18(4): 460–500PubMedCrossRefGoogle Scholar
  29. 29.
    Maquet P. Positron emission tomography studies of sleep and sleep disorders. J Neurol 1997; 244(4 Suppl. 1): S23–8PubMedCrossRefGoogle Scholar
  30. 30.
    Tasali E, Leproult R, Ehrmann DA, et al. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A 2008 Jan 22; 105(3): 1044–9PubMedCrossRefGoogle Scholar
  31. 31.
    Horne J. Human slow wave sleep: a review and appraisal of recent findings, with implications for sleep functions, and psychiatric illness. Experientia 1992; 48(10): 941–54PubMedCrossRefGoogle Scholar
  32. 32.
    Kupfer DJ, Thase ME. The use of the sleep laboratory in the diagnosis of affective disorders. Psychiatr Clin North Am 1983; 6(1): 3–25PubMedGoogle Scholar
  33. 33.
    Benca RM, Obermeyer WH, Thisted RA, et al. Sleep and psychiatric disorders. Arch Gen Psychiatry 1992; 49: 661–8CrossRefGoogle Scholar
  34. 34.
    Jindal RD, Thase ME, Fasiczka AL, et al. Electro-encephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: II. Comparison during remission. Biol Psychiatry 2002; 51(3): 230–6Google Scholar
  35. 35.
    Armitage R. Microarchitectural findings in sleep EEG in depression: diagnostic implications. Biol Psychiatry 1995; 37(2): 72–84PubMedCrossRefGoogle Scholar
  36. 36.
    Jindal RD, Friedman ES, Berman SR, et al. Effects of sertraline on sleep architecture in patients with depression. J Clin Psychopharmacol 2003; 23(6): 540–8PubMedCrossRefGoogle Scholar
  37. 37.
    Terzano MG, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001; 2(6): 537–53PubMedCrossRefGoogle Scholar
  38. 38.
    Lopes MC, Quera-Salva MA, Guilleminault C. Non-REM sleep instability in patients with major depressive disorder: subjective improvement and improvement of non-REM sleep instability with treatment (agomelatine). Sleep Med 2007; 9(1): 33–41PubMedCrossRefGoogle Scholar
  39. 39.
    Farina B, Della Marca G, Grochocinski VJ, et al. Microstructure of sleep in depressed patients according to the cyclic alternating pattern. J Affect Disord 2003; 77(3): 227–35PubMedCrossRefGoogle Scholar
  40. 40.
    Nofzinger EA, Buysse DJ, Miewald JM, et al. Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking. Brain 2002; 125(Pt 5): 1105–15PubMedCrossRefGoogle Scholar
  41. 41.
    Braun AR, Balkin TJ, Wesenten NJ, et al. Regional cerebral blood flow throughout the sleep-wake cycle: an H2(15)O PET study. Brain 1997; 120(Pt 7): 1173–97PubMedCrossRefGoogle Scholar
  42. 42.
    Maquet P, Degueldre C, Delfiore G, et al. Functional neuroanatomy of human slow wave sleep. J Neurosci 1997; 17(8): 2807–12PubMedGoogle Scholar
  43. 43.
    Nofzinger EA, Buysse DJ, Germain A, et al. Alterations in regional cerebral glucose metabolism across waking and non-rapid eye movement sleep in depression. Arch Gen Psychiatry 2005; 62(4): 387–96PubMedCrossRefGoogle Scholar
  44. 44.
    Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161(11): 2126–8PubMedCrossRefGoogle Scholar
  45. 45.
    Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness: I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000; 9(4): 335–52Google Scholar
  46. 46.
    Critchley HD, Corfield DR, Chandler MP, et al. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000; 523 (Pt 1): 259–70PubMedCrossRefGoogle Scholar
  47. 47.
    Steriade M. The corticothalamic system in sleep. Front Biosci 2003; 8: 878–99CrossRefGoogle Scholar
  48. 48.
    Jones BE. The neural basis of consciousness across the sleep-waking cycle. Adv Neurol 1998; 77: 75–94PubMedGoogle Scholar
  49. 49.
    McCarley RW, Massaquoi SG. A limit cycle mathematical model of the REM sleep oscillator system. Am J Physiol 1986; 251 (6 Pt 2): 1011–29Google Scholar
  50. 50.
    Stickgold R, Hobson JA, Fosse R, et al. Sleep, learning, and dreams: off-line memory reprocessing. Science 2001; 294(5544): 1052–7PubMedCrossRefGoogle Scholar
  51. 51.
    Lauer CJ, Riemann D, Wiegand M, et al. From early to late adulthood: changes in EEG sleep of depressed patients and healthy volunteers. Biol Psychiatry 1991; 29(10): 979–93PubMedCrossRefGoogle Scholar
  52. 52.
    Armitage R, Hoffmann R, Trivedi M, et al. Slow-wave activity in NREM sleep: sex and age effects in depressed outpatients and healthy controls. Psychiatry Res 2000; 95(3): 201–13PubMedCrossRefGoogle Scholar
  53. 53.
    Armitage R, Hoffmann R, Emslie G, et al. Sleep micro-architecture in childhood and adolescent depression: temporal coherence. Clin EEG Neurosci 2006; 37(1): 1–9PubMedCrossRefGoogle Scholar
  54. 54.
    Ware JC, Brown FW, Moorad Jr PJ, et al. Effects on sleep: a double-blind study comparing trimipramine to imipramine in depressed insomniac patients. Sleep 1989; 12(6): 537–49PubMedGoogle Scholar
  55. 55.
    Shipley JE, Kupfer DJ, Griffin SJ, et al. Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients. Psychopharmacology (Berl) 1985; 85(1): 14–22CrossRefGoogle Scholar
  56. 56.
    Nofzinger EA, Reynolds III CF, Thase ME, et al. REM sleep enhancement by bupropion in depressed men. Am J Psychiatry 1995; 152(2): 274–6PubMedGoogle Scholar
  57. 57.
    Winkelman JW, James L. Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 2004; 27(2): 317–21PubMedGoogle Scholar
  58. 58.
    Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156(5): 675–82PubMedGoogle Scholar
  59. 59.
    Drevets WC. Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 2000; 126: 413–31PubMedCrossRefGoogle Scholar
  60. 60.
    Germain A, Nofzinger EA, Meltzer CC, et al. Diurnal variation in regional brain glucose metabolism in depression. Biol Psychiatry 2007; 62(5): 438–45PubMedCrossRefGoogle Scholar
  61. 61.
    Nofzinger EA, Buysse DJ, Germain A, et al. Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression. Arch Gen Psychiatry 2004; 61(7): 695–702PubMedCrossRefGoogle Scholar
  62. 62.
    Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005; 58(6): 510–4PubMedCrossRefGoogle Scholar
  63. 63.
    Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. J Clin Psychiatry 1997; 58(8): 348–50PubMedCrossRefGoogle Scholar
  64. 64.
    Marshall NS, Yee BJ, Desai AV, et al. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep 2008; 31(6): 824–31PubMedGoogle Scholar
  65. 65.
    Carley DW, Olopade C, Ruigt GS, et al. Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 2007; 30(1): 35–41PubMedGoogle Scholar
  66. 66.
    Hicks JA, Argyropoulos SV, Rich AS, et al. Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression. Br J Psychiatry 2002; 180: 528–35PubMedCrossRefGoogle Scholar
  67. 67.
    van Bemmel AL, van den Hoofdakker RH, Beersma DG, et al. Changes in sleep polygraphic variables and clinical state in depressed patients during treatment with citalopram. Psychopharmacology (Berl) 1993; 113(2): 225–30CrossRefGoogle Scholar
  68. 68.
    Knab B, Engel RR. Perception of waking and sleeping: possible implications for the evaluation of insomnia. Sleep 1988; 11(3): 265–72PubMedGoogle Scholar
  69. 69.
    Armitage R, Trivedi M, Hoffmann R, et al. Relationship between objective and subjective sleep measures in depressed patients and healthy controls. Depress Anxiety 1997; 5(2): 97–102PubMedCrossRefGoogle Scholar
  70. 70.
    Lader M, Andersen HF, Baekdal T. The effect of escitalopram on sleep problems in depressed patients. Hum Psychopharmacol 2005; 20(5): 349–54PubMedCrossRefGoogle Scholar
  71. 71.
    Luthringer R, Toussaint M, Schaltenbrand N, et al. A double-blind, placebo-controlled evaluation of the effects of orally administered venlafaxine on sleep in in-patients with major depression. Psychopharmacol Bull 1996; 32(4): 637–46PubMedGoogle Scholar
  72. 72.
    Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry 2007; 68(11): 1723–32PubMedCrossRefGoogle Scholar
  73. 73.
    Shelton RC, Prakash A, Mallinckrodt CH, et al. Patterns of depressive symptom response in duloxetine-treated outpatients with mild, moderate or more severe depression. Int J Clin Pract 2007; 61(8): 1337–48PubMedCrossRefGoogle Scholar
  74. 74.
    Pigott TA, Prakash A, Arnold LM, et al. Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin 2007 Jun; 23(6): 1303–18PubMedCrossRefGoogle Scholar
  75. 75.
    Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 2004; 24(4): 389–99PubMedCrossRefGoogle Scholar
  76. 76.
    Kluge M, Schussler P, Steiger A. Duloxetine increases stage 3 sleep and suppresses rapid eye movement (REM) sleep in patients with major depression. Eur Neuropsychopharmacol 2007;17(8): 527–31PubMedCrossRefGoogle Scholar
  77. 77.
    Chalon S, Pereira A, Lainey E, et al. Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects. Psychopharmacology (Berl) 2005; 177(4): 357–65CrossRefGoogle Scholar
  78. 78.
    Loo H, Hale A, D’Haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002; 17(5): 239–47PubMedCrossRefGoogle Scholar
  79. 79.
    Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol 2007; 10(5): 661–73PubMedGoogle Scholar
  80. 80.
    Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2006; 16(2): 93–100PubMedCrossRefGoogle Scholar
  81. 81.
    Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol 2007; 22(5): 283–91PubMedCrossRefGoogle Scholar
  82. 82.
    Quera Salva MA, Vanier B, Laredo J, et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol 2007; 10(5): 691–6PubMedGoogle Scholar
  83. 83.
    Kupfer DJ, Frank E, McEachran AB, et al. Delta sleep ratio: a biological correlate of early recurrence in unipolar affective disorder. Arch Gen Psychiatry 1990; 47(12): 1100–5PubMedCrossRefGoogle Scholar
  84. 84.
    Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M, et al. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005; 63(3): 298–304CrossRefGoogle Scholar
  85. 85.
    Banasr M, Soumier A, Hery M, et al. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry 2006; 59(11): 1087–96PubMedCrossRefGoogle Scholar
  86. 86.
    Montgomery SA, Kennedy SH, Burrows GD, et al. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004; 19(5): 271–80PubMedCrossRefGoogle Scholar
  87. 87.
    Ying SW, Rusak B, Mocaer E. Chronic exposure to melatonin receptor agonists does not alter their effects on suprachiasmatic nucleus neurons. Eur J Pharmacol 1998; 342(1): 29–37PubMedCrossRefGoogle Scholar
  88. 88.
    Ott GE, Rao U, Lin KM, et al. Effect of treatment with bupropion on EEG sleep: relationship to antidepressant response. Int J Neuropsychopharmacol 2004; 7(3): 275–81PubMedCrossRefGoogle Scholar
  89. 89.
    Kavoussi RJ, Segraves RT, Hughes AR, et al. Doubleblind comparison of bupropion sustained release and sertraline in depressed outpatients. J Clin Psychiatry 1997; 58(12): 532–7PubMedCrossRefGoogle Scholar
  90. 90.
    Weihs KL, Settle Jr EC, Batey SR, et al. Bupropion sustained release versus paroxetine for the treatment of depression in the elderly. J Clin Psychiatry 2000; 61(3): 196–202PubMedCrossRefGoogle Scholar
  91. 91.
    Nofzinger EA, Fasiczka A, Berman S, et al. Bupropion SR reduces periodic limb movements associated with arousals from sleep in depressed patients with periodic limb movement disorder. J Clin Psychiatry 2000; 61(11): 858–62PubMedCrossRefGoogle Scholar
  92. 92.
    Mouret J, Lemoine P, Minuit MP, et al. Effects of trazodone on the sleep of depressed subjects: a polygraphic study. Psychopharmacology (Berl) 1988; 95 Suppl.: S37–43CrossRefGoogle Scholar
  93. 93.
    Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. J Clin Psychiatry 1990; 51 Suppl.: 13–7PubMedGoogle Scholar
  94. 94.
    Weisler RH, Johnston JA, Lineberry CG, et al. Comparison of bupropion and trazodone for the treatment of major depression. J Clin Psychopharmacol 1994; 14(3): 170–9PubMedCrossRefGoogle Scholar
  95. 95.
    Beasley Jr CM, Dornseif BE, Pultz JA, et al. Fluoxetine versus trazodone: efficacy and activating-sedating effects. J Clin Psychiatry 1991; 52(7): 294–9PubMedGoogle Scholar
  96. 96.
    Schwetz BA. From the Food and Drug Administration. JAMA 2002; 287(9): 1103PubMedCrossRefGoogle Scholar
  97. 97.
    Leinonen E, Skarstein J, Behnke K, et al. Efficacy and tolerability of mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive disorder. Nordic Antidepressant Study Group. Int Clin Psychopharmacol 1999; 14(6): 329–37CrossRefGoogle Scholar
  98. 98.
    Versiani M, Moreno R, Ramakers-van Moorsel CJ, et al. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. CNS Drugs 2005; 19(2): 137–46PubMedCrossRefGoogle Scholar
  99. 99.
    Guelfi JD, Ansseau M, Timmerman L, et al. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol 2001; 21(4): 425–31PubMedCrossRefGoogle Scholar
  100. 100.
    Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression. J Clin Psychiatry 2000; 61(9): 656–63PubMedCrossRefGoogle Scholar
  101. 101.
    Benkert O, Szegedi A, Philipp M, et al. Mirtazapine orally disintegrating tablets versus venlafaxine extended release: a double-blind, randomized multicenter trial comparing the onset of antidepressant response in patients with major depressive disorder. J Clin Psychopharmacol 2006; 26(1): 75–8PubMedCrossRefGoogle Scholar
  102. 102.
    Ridout F, Meadows R, Johnsen S, et al. A placebo controlled investigation into the effects of paroxetine and mirtazapine on measures related to car driving performance. Hum Psychopharmacol 2003; 18(4): 261–9PubMedCrossRefGoogle Scholar
  103. 103.
    Wingen M, Bothmer J, Langer S, et al. Actual driving performance and psychomotor function in healthy subjects after acute and subchronic treatment with escitalopram, mirtazapine, and placebo: a crossover trial. J Clin Psychiatry 2005; 66(4): 436–43PubMedCrossRefGoogle Scholar
  104. 104.
    Aslan S, Isik E, Cosar B. The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers. Sleep 2002; 25(6): 677–9PubMedGoogle Scholar
  105. 105.
    Winokur A, Sateia MJ, Hayes JB, et al. Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study. Biol Psychiatry 2000; 48(1): 75–8PubMedCrossRefGoogle Scholar
  106. 106.
    Shen J, Chung SA, Kayumov L, et al. Polysomnographic and symptomatological analyses of major depressive disorder patients treated with mirtazapine. Can J Psychiatry 2006; 51(1): 27–34PubMedGoogle Scholar
  107. 107.
    Schmid DA, Wichniak A, Uhr M, et al. Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine. Neuropsychopharmacology 2006; 31(4): 832–44PubMedCrossRefGoogle Scholar
  108. 108.
    Schittecatte M, Dumont F, Machowski R, et al. Effects of mirtazapine on sleep polygraphic variables in major depression. Neuropsychobiology 2002; 46(4): 197–201PubMedCrossRefGoogle Scholar
  109. 109.
    Winokur A, DeMartinis III NA, McNally DP, et al. Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry 2003; 64(10): 1224–9PubMedCrossRefGoogle Scholar
  110. 110.
    Papakostas GI, Thase ME, Fava M, et al. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry 2007; 62(11): 1217–27PubMedCrossRefGoogle Scholar
  111. 111.
    Dording CM, Mischoulon D, Petersen TJ, et al. The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists. Ann Clin Psychiatry 2002; 14(3): 143–7PubMedGoogle Scholar
  112. 112.
    Nierenberg AA, Adler LA, Peselow E, et al. Trazodone for antidepressant-associated insomnia. Am J Psychiatry 1994; 151(7): 1069–72PubMedGoogle Scholar
  113. 113.
    Kaynak H, Kaynak D, Gozukirmizi E, et al. The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Med 2004; 5(1): 15–20PubMedCrossRefGoogle Scholar
  114. 114.
    Glass J, Lanctot KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005; 331(7526): 1169–73PubMedCrossRefGoogle Scholar
  115. 115.
    Cohn JB. Triazolam treatment of insomnia in depressed patients taking tricyclics. J Clin Psychiatry 1983; 44(11): 401–6PubMedGoogle Scholar
  116. 116.
    Scharf MB, Hirschowitz J, Zemlan FP, et al. Comparative effects of limbitrol and amitriptyline on sleep efficiency and architecture. J Clin Psychiatry 1986; 47(12): 587–91PubMedGoogle Scholar
  117. 117.
    Nolen WA, Haffmans PM, Bouvy PF, et al. Hypnotics as concurrent medication in depression: a placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant. J Affect Disord 1993; 28(3): 179–88PubMedCrossRefGoogle Scholar
  118. 118.
    Sussman N. Anxiolytic antidepressant augmentation. J Clin Psychiatry 1998; 59Suppl. 5: 42–8; discussion 9-50PubMedGoogle Scholar
  119. 119.
    Smith WT, Londborg PD, Glaudin V, et al. Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study. Am J Psychiatry 1998; 155(10): 1339–45PubMedGoogle Scholar
  120. 120.
    Smith WT, Londborg PD, Glaudin V, et al. Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? J Affect Disord 2002; 70(3): 251–9PubMedCrossRefGoogle Scholar
  121. 121.
    Barbanoj MJ, Clos S, Romero S, et al. Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers. Neuropsychobiology 2005; 51(3): 134–47PubMedCrossRefGoogle Scholar
  122. 122.
    Kupfer DJ, Reynolds III CF. Management of insomnia. N Engl J Med 1997; 336(5): 341–6PubMedCrossRefGoogle Scholar
  123. 123.
    Perlis ML, McCall WV, Krystal AD, et al. Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiatry 2004; 65(8): 1128–37PubMedCrossRefGoogle Scholar
  124. 124.
    Scharf MB, Roth T, Vogel GW, et al. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 1994; 55(5): 192–9PubMedGoogle Scholar
  125. 125.
    Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies. Int Clin Psychopharmacol 1999; 14(5): 287–303PubMedGoogle Scholar
  126. 126.
    Voshaar RC, van Balkom AJ, Zitman FG. Zolpidem is not superior to temazepam with respect to rebound insomnia: a controlled study. Eur Neuropsychopharmacol 2004; 14(4): 301–6PubMedCrossRefGoogle Scholar
  127. 127.
    Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999; 1(4): 114–20PubMedCrossRefGoogle Scholar
  128. 128.
    Hajak G, Muller WE, Wittchen HU, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003; 98(10): 1371–8PubMedCrossRefGoogle Scholar
  129. 129.
    Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999; 60(10): 668–76PubMedCrossRefGoogle Scholar
  130. 130.
    Roth T, Hull SG, Lankford DA, et al. Intermezzo Study Group. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings. Sleep 2008 Sep 1; 31(9): 1277–84PubMedGoogle Scholar
  131. 131.
    Parrino L, Smerieri A, Giglia F, et al. Polysomnographic study of intermittent zolpidem treatment in primary sleep maintenance insomnia. Clin Neuropharmacol 2008 Jan–Feb; 31(1): 40–50PubMedCrossRefGoogle Scholar
  132. 132.
    Blin O, Micallef J, Audebert C, et al. A double-blind, placebo- and flurazepam-controlled investigation of the residual psychomotor and cognitive effects of modified release zolpidem in young healthy volunteers. J Clin Psychopharmacol 2006; 26(3): 284–9PubMedCrossRefGoogle Scholar
  133. 133.
    Hindmarch I, Legangneux E, Stanley N, et al. A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers. Br J Clin Pharmacol 2006; 62(5): 538–45PubMedCrossRefGoogle Scholar
  134. 134.
    Roth T, Soubrane C, Titeux L, et al. Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med 2006; 7(5): 397–406PubMedCrossRefGoogle Scholar
  135. 135.
    Staner L, Ertle S, Boeijinga P, et al. Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology (Berl) 2005; 181(4): 790–8CrossRefGoogle Scholar
  136. 136.
    Rush CR, Frey JM, Griffiths RR. Zaleplon and triazola in humans: acute behavioral effects and abuse potential. Psychopharmacology (Berl) 1999; 145(1): 39–51CrossRefGoogle Scholar
  137. 137.
    Zammit GK, Corser B, Doghramji K, et al. Sleep and residual sedation after administration of zaleplon, zolpidem, and placebo during experimental middle-of-the-night awakening. J Clin Sleep Med 2006; 2(4): 417–23PubMedGoogle Scholar
  138. 138.
    Vermeeren A, Riedel WJ, van Boxtel MP, et al. Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002; 25(2): 224–31PubMedGoogle Scholar
  139. 139.
    Wagner J, Wagner ML. Non-benzodiazepines for the treatment of insomnia. Sleep Med Rev 2000; 4(6): 551–81PubMedCrossRefGoogle Scholar
  140. 140.
    Hajak G. A comparative assessment of the risks and benefits of zopiclone: a review of 15 years’ clinical experience. Drug Saf 1999; 21(6): 457–69PubMedCrossRefGoogle Scholar
  141. 141.
    Bianchi M, Musch B. Zopiclone discontinuation: review of 25 studies assessing withdrawal and rebound phenomena. Int Clin Psychopharmacol 1990; 5Suppl. 2: 139–45PubMedGoogle Scholar
  142. 142.
    Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26(7): 793–9PubMedGoogle Scholar
  143. 143.
    Roth T, Walsh JK, Krystal A, et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med 2005; 6(6): 487–95PubMedCrossRefGoogle Scholar
  144. 144.
    Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep 2007; 30(8): 959–68PubMedGoogle Scholar
  145. 145.
    Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006; 59(11): 1052–60PubMedCrossRefGoogle Scholar
  146. 146.
    Krystal A, Fava M, Rubens R, et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med 2007; 3(1): 48–55PubMedGoogle Scholar
  147. 147.
    Deacon S, Staner L, Staner C, et al. Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia. Sleep 2007; 30(3): 281–7PubMedGoogle Scholar
  148. 148.
    Walsh JK, Mayleben D, Guico-Pabia C, et al. Efficacy of the selective extrasynaptic GABA(A) agonist, gaboxadol, in a model of transient insomnia: a randomized, controlled clinical trial. Sleep Med 2008 May; 9(4): 393–402PubMedCrossRefGoogle Scholar
  149. 149.
    Walsh JK, Moscovitch A, Burke J, et al. Efficacy and tolerability of indiplon in older adults with primary insomnia. Sleep Med 2007; 8(7-8): 753–9PubMedCrossRefGoogle Scholar
  150. 150.
    Lydiard RB, Lankford DA, Seiden DJ, et al. Efficacy and tolerability of modified-release indiplon in elderly patients with chronic insomnia: results of a 2-week double-blind, placebo-controlled trial. J Clin Sleep Med 2006; 2(3): 309–15PubMedGoogle Scholar
  151. 151.
    Scharf MB, Black J, Hull S, et al. Long-term nightly treatment with indiplon in adults with primary insomnia: results of a double-blind, placebo-controlled, 3-month study. Sleep 2007; 30(6): 743–52PubMedGoogle Scholar
  152. 152.
    Carter LP, Griffiths RR, Suess PE, et al. Relative abuse liability of indiplon and triazolam in humans: a comparison of psychomotor, subjective, and cognitive effects. J Pharmacol Exp Ther 2007; 322(2): 749–59PubMedCrossRefGoogle Scholar
  153. 153.
    Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 2007; 3(5): 495–504PubMedGoogle Scholar
  154. 154.
    Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006; 7(1): 17–24PubMedCrossRefGoogle Scholar
  155. 155.
    Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007; 23(5): 1005–14PubMedCrossRefGoogle Scholar
  156. 156.
    Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry 2006; 63(10): 1149–57PubMedCrossRefGoogle Scholar
  157. 157.
    Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol 2007; 47(4): 485–96PubMedCrossRefGoogle Scholar
  158. 158.
    Baune BT, Caliskan S, Todder D. Effects of adjunctive antidepressant therapy with quetiapine on clinical outcome, quality of sleep and daytime motor activity in patients with treatment-resistant depression. Hum Psychopharmacol 2007; 22(1): 1–9PubMedCrossRefGoogle Scholar
  159. 159.
    Garakani A, Martinez JM, Marcus S, et al. A randomized, double-blind, and placebo-controlled trial of quetiapine augmentation of fluoxetine in major depressive disorder. Int Clin Psychopharmacol 2008 Sep; 23(5): 269–75PubMedCrossRefGoogle Scholar
  160. 160.
    Endicott J, Paulsson B, Gustafsson U, et al. Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: improvements in quality of life and quality of sleep. J Affect Disord 2008 Dec; 111(2–3): 306–19PubMedCrossRefGoogle Scholar
  161. 161.
    Jindal RD, Keshavan MS. Critical role of M3 muscarinic receptor in insulin secretion: implications for psychopharmacology. J Clin Psychopharmacol 2006; 26(5): 449–50PubMedCrossRefGoogle Scholar
  162. 162.
    Walsh JK, Perlis M, Rosentha M, et al. Tiagabine increases slow-wave sleep in a dose-dependent fashion without affecting traditional efficacy measures in adults with primary insomnia. J Clin Sleep Med 2006; 2(1): 35–41PubMedGoogle Scholar
  163. 163.
    Roth T, Wright Jr KP, Walsh J. Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study. Sleep 2006; 29(3): 335–41PubMedGoogle Scholar
  164. 164.
    Walsh JK, Randazzo AC, Stone K, et al. Tiagabine is associated with sustained attention during sleep restriction: evidence for the value of slow-wave sleep enhancement? Sleep 2006; 29(4): 433–43PubMedGoogle Scholar
  165. 165.
    Meolie AL, Rosen C, Kristo D, et al. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med 2005; 1(2): 173–87PubMedGoogle Scholar
  166. 166.
    Bliwise DL, Ansari FP. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep 2007; 30(7): 881–4PubMedGoogle Scholar
  167. 167.
    Morin CM, Koetter U, Bastien C, et al. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 2005; 28(11): 1465–71PubMedGoogle Scholar
  168. 168.
    Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry 1998; 155(8): 1119–21PubMedGoogle Scholar
  169. 169.
    Taibi DM, Landis CA, Petry H, et al. A systematic review of valerian as a sleep aid: safe but not effective. Sleep Med Rev 2007; 11(3): 209–30PubMedCrossRefGoogle Scholar
  170. 170.
    Carman JS, Post RM, Buswell R, et al. Negative effects of melatonin on depression. Am J Psychiatry 1976; 133(10): 1181–6PubMedGoogle Scholar
  171. 171.
    Leibenluft E, Feldman-Naim S, Turner EH, et al. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. J Clin Psychiatry 1997; 58(9): 383–8PubMedCrossRefGoogle Scholar
  172. 172.
    Edinger JD, Wohlgemuth WK, Radtke RA, et al. Does cognitive-behavioral insomnia therapy alter dysfunctional beliefs about sleep? Sleep 2001; 24(5): 591–9PubMedGoogle Scholar
  173. 173.
    Morin CM, Blais F, Savard J. Are changes in beliefs and attitudes about sleep related to sleep improvements in the treatment of insomnia? Behav Res Ther 2002; 40(7): 741–52PubMedCrossRefGoogle Scholar
  174. 174.
    Edinger JD, Wohlgemuth WK, Radtke RA, et al. Dose-response effects of cognitive-behavioral insomnia therapy: a randomized clinical trial. Sleep 2007; 30(2): 203–12PubMedGoogle Scholar
  175. 175.
    Edinger JD, Sampson WS. A primary care “friendly” cognitive behavioral insomnia therapy. Sleep 2003; 26(2): 177–82PubMedGoogle Scholar
  176. 176.
    Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999; 281(11): 991–9PubMedCrossRefGoogle Scholar
  177. 177.
    Jacobs GD, Pace-Schott EF, Stickgold R, et al. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 2004; 164(17): 1888–96PubMedCrossRefGoogle Scholar
  178. 178.
    Morin CM, Bootzin RR, Buysse DJ, et al. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998–2004). Sleep 2006; 29(11): 1398–414PubMedGoogle Scholar
  179. 179.
    Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep 2006; 29(11): 1415–9PubMedGoogle Scholar
  180. 180.
    Manber R, Edinger JD, Gress JL, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep 2008 Apr 1; 31(4): 489–95PubMedGoogle Scholar
  181. 181.
    Vaishnavi S, Gadde K, Alamy S, et al. Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment. J Clin Psychopharmacol 2006; 26(4): 373–8PubMedCrossRefGoogle Scholar
  182. 182.
    Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007; 164(8): 1242–9PubMedCrossRefGoogle Scholar
  183. 183.
    Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005; 66(1): 85–93PubMedCrossRefGoogle Scholar
  184. 184.
    Ninan PT, Hassman HA, Glass SJ, et al. Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 2004; 65(3): 414–20PubMedCrossRefGoogle Scholar
  185. 185.
    Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2007 Dec; 27(6): 614–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.University of Ottawa School of MedicineOttawaCanada

Personalised recommendations