Psychotropic Medications: Adverse Effects on Sleep

Educational Objectives

The goal of this program is to improve the management of sleep dysfunction in patients who take psychotropic medications. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize sleep problems in patients with
psychiatric disorders.

2. Weigh the beneficial and deleterious effects of
psychotropic medications on sleep.

Summary

Overview: prevalence of insomnia high in patients with major depressive disorder (MDD; especially melancholic form); patients experience frequent awakening and early awakening accompanied by anxiety; melancholic depression characterized by anhedonia, insomnia, and decreased appetite; in patients with untreated depression, polysomnography (PSG) reveals shorter rapid eye movement (REM) latency, longer total REM time, shorter time in deep slow-wave sleep (SWS), and increased number of awakenings compared with controls; separating effects of depression on sleep from those of antidepressant medications difficult

Selective serotonin reuptake inhibitors (SSRIs): patients who take SSRIs report insomnia and somnolence; fluoxetine (Prozac) — best-studied SSRI; findings related to sleep can be extrapolated to other SSRIs; prevalence of activation higher at higher doses (≥60 mg); of sedation higher at lower doses; decrease dose if patient reports insomnia (if appropriate); trazodone — has sedative effect; used to treat insomnia; head-to-head studies of SSRIs scarce; study of patients with MDD found prevalence of sedation higher in those who take trazodone; of activation higher in those who take fluoxetine; findings of PSG — fluoxetine associated with REM suppression, decreased sleep efficiency, increased number of awakenings, and increased number of oculomotor movements (may signify increase in general central arousal); sleep disruption associated with fluoxetine may be related to plasma levels of drug; half-life of fluoxetine long, and drug may accumulate in patients with long-term use (changes in sleep continuity may occur later in treatment)

Serotonin-norepinephrine reuptake inhibitors (SNRIs): patients report insomnia, somnolence, and vivid dreams; venlafaxine and duloxetine best-studied SNRIs; findings of PSG — in patients with MDD who take venlafaxine, findings similar to SSRIs; decreases in sleep continuity, onset of REM latency, and total REM sleep time noted; effects usually noted soon after initiation of treatment and can persist ≈1 mo after discontinuation; periodic limb movements (PLMs) — study of healthy volunteers found venlafaxine associated with PLMs that worsened over time; found rates for PLM >25 in some patients and persistence after discontinuation of drug; duloxetine — associated with similar disruption of sleep

Trazodone: serotonin antagonist and reuptake inhibitor; SSRI effect weak; potent inhibitor of serotonin 2 receptors (results in sedation); rate of use to treat MDD low (doses to treat depression result in sedation); used in smaller doses as hypnotic agent or to counteract deleterious effect of SSRIs on sleep; consider adding trazodone if SSRI causes insomnia; findings of PSG — monotherapy in patients with MDD effective; trazodone increases total sleep time, shortens sleep onset latency, decreases number of awakenings, and increases deep SWS and REM latency

Mirtazapine: serotonin 2-serotonin 3-α2 adrenergic receptor antagonist; sedation reported (drug effective in patients with comorbid depression and insomnia); degree of sedation higher with lower doses; activation higher with higher doses (≥30 mg); findings of PSG — mirtazapine increases total sleep time and sleep efficiency; does not shorten sleep onset latency or affect REM sleep parameters; adverse effects — disturbing dreams and confusion reported; restless legs syndrome (RLS; all antidepressant drugs associated with RLS and PLM, but mirtazapine most often implicated); study of systematic reviews and open-label studies of mirtazapine found that ≤28% of patients reported RLS when specifically asked about it; only ≈0.5% spontaneously reported RLS

Norepinephrine-dopamine reuptake inhibitors (bupropion): associated with insomnia in 11% to 28% of patients; effect on sleep depends on dose, formulation, and condition treated; findings of PSG — unlike majority of other antidepressant drugs, bupropion shortens REM latency and increases total REM sleep time

Tricyclic antidepressants (TCAs): used to treat anxiety, depression, neuropathic pain, insomnia, and pruritus; sedation with tertiary amine TCAs greater than with secondary amine TCAs (eg, greater with amitriptyline than its active metabolite, nortriptyline); tertiary amine TCAs shorten sleep onset latency, improve sleep continuity, and decrease number of awakenings; nortriptyline and desipramine associated with activation (eg, prolong sleep onset latency, decrease sleep efficiency, increase number of awakenings); doxepin approved in 1969 for treatment of MDD and anxiety; later, as topical formulation to treat pruritus; reformulated in 3- and 6-mg doses to treat insomnia; maintains sleep because of its antihistaminergic effects; TCAs suppress REM sleep (prolong REM latency and decrease percentage of time in REM sleep); clomipramine most potent REM suppressant of TCAs; effects of TCAs on sleep persist into treatment; vivid dreams and nightmares reported

Monoamine oxidase inhibitors (MAOIs): rarely prescribed because of adverse effects; effective in treatment of MDD; structurally similar to psychostimulant agents (use in patients with insomnia contraindicated); prolong sleep onset latency, impair sleep continuity, and increase number of nighttime awakenings; associated with hypotension and syncope; effects on sleep begin shortly after initiation of treatment and can persist months or years after discontinuation of treatment; REM rebound may cause vivid dreams and nightmares

Newer antidepressant agents: include vilazodone, levomilnacipran, and vortioxetine; only studies industry-funded; vilazodone and levomilnacipran associated with sleep disturbance; abnormal dreams reported by patients taking vilazodone; vortioxetine not associated with insomnia or somnolence; abnormal dreams reported

Antipsychotic and Hypnotic Agents

Antipsychotic agents: prevalence of sleep dysregulation in schizophrenia high (eg, insomnia); atypical — predominately activating agents include lurasidone and perphenazine (typical antipsychotic agent); activation and sedation with risperidone and aripiprazole equal; olanzapine, quetiapine, ziprasidone, asenapine, and iloperidone predominantly cause sedation; paliperidone and brexpiprazole cause neither activation nor sedation; risk for somnolence — high for clozapine; moderate for olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone; low for aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, and cariprazine; findings of PSG — typical antipsychotic drugs increase total sleep time and sleep efficiency, shorten sleep onset latency, and decrease number of awakenings; clozapine atypical antipsychotic agent with most consistent beneficial effects on sleep, (improved sleep continuity and increased total sleep time); olanzapine and paliperidone consistently found to confer sleep benefits; quetiapine (Seroquel) often used off-label to treat insomnia, but evidence of deleterious effects on sleep found in patients with schizophrenia; findings for risperidone inconsistent; RLS and PLM — prevalence high in patients with schizophrenia who take antipsychotic drugs; differentiating akathisia (restlessness secondary to drug) from primary RLS or PLM important; symptoms of akathisia occur throughout day; RLS and PLM circadian

Hypnotic agents: “Z drugs” popularly associated with parasomnias; evidence suggests that actual incidence low; majority of case reports of parasomnia associated with hypnotic drugs involve polypharmacy and supratherapeutic doses

Readings

DeMartinis NA, Winokur A: Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets 2007 Feb; 6(1):17-29; Doghramji K, Jangro WC: Adverse effects of psychotropic medications on sleep. Sleep Med Clin 2016 Dec;11(4):503-14; Mayers AG, Baldwin DS: Antidepressants and their effect on sleep. Hum Psychopharmacol 2005 Dec;20(8):533-59; Rumble ME et al: Sleep disturbances in mood disorders. Psychiatr Clin North Am 2015 Dec;38(4):743-59; Sutton EL: Psychiatric disorders and sleep issues. Med Clin North Am 2014 Sep;98(5):1123-43; Wichniak A et al: Effects of antidepressants on sleep. Curr Psychiatry Rep 2017 Aug 9;19(9):63; Wichniak A et al: Sleep and antidepressant treatment. Curr Pharm Des 2012;18(36):5802-17.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Jangro presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Jangro was recorded at the 5th Annual Sleep Medicine Symposium: What’s New Under the Moon, presented by Jefferson Sleep Disorder Center, in conjunction with Philadelphia University and Sidney Kimmel Medical College of Thomas Jefferson University, and held November 17, 2018, in Philadelphia, PA. For information about upcoming CME activities presented by the Philadelphia University and Sidney Kimmel Medical College of Thomas Jefferson University, please visit library.jefferson.edu/jeffcme. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS471202

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.