Sedation: The Ups and Downs of a Side Effect

SPECIAL REPORT: EXPLORING SIDE EFFECTS

Not long ago, tranquilization was an important goal of psychopharmacology, and sedation was integral to this therapeutic effect. Major tranquilizers (ie, antipsychotics) sedated psychosis and mania, while minor ones (ie, benzodiazepines) calmed the anxious mind. Even antidepressants were thought to benefit from sedation, in part because insomnia is a symptom of depression, but also because of concerns that patients might act on suicidal impulses if their energy improved before their depression did.¹

Those ideas were put to rest in the 1990s, as nonsedating medications proved just as effective as their sedating predecessors. Rather than forewarning suicide, early increases in energy and physical activity are actually a predictor of antidepressant response.² Improved functioning is the goal in psychopharmacology, and sedation usually does not contribute to that goal.

Sedation is sometimes desirable and sometimes not. It is desirable when treating insomnia, as long as the sedative effects do not linger into the morning. It can also be life-saving when treating acute agitation in emergency situations. Increased activity does not foretell a positive outcome, and may even be a risk factor for suicide, when it is due to adverse effects like akathisia or mania.

The Best and Worst

The simplest way to manage unwanted sedation is to choose medications that are less likely to cause it. Table 1 ranks psychiatric medications by their sedation risk, based on meta-analyses of clinical trials and data from the US Food and Drug Administration (FDA)^.3-9 Although these analyses arrived at fairly consistent conclusions, Table 1 is still only an approximation. The relative rankings apply within each class, but some classes as a whole are more sedating than others, particularly the antipsychotics.

Surprisingly, the traditional mood stabilizers, particularly lithium, are not nearly as sedating as the antipsychotics. Lithium has been reported to cause sedation in about 1 in 16 to 1 in 27 patients, depending on the study. With most second-generation antipsychotics, this rate is closer to 1 in 5 patients.^6,7 While lithium may not cause much drowsiness, it does cause adverse effects that can be mistaken for sedation, like motoric and cognitive slowing, especially in higher concentrations.

There are 2 nonsedating antidepressants that have stimulant-like properties: bupropion and tranylcypromine. Tranylcypromine is a monoamine oxidase inhibitor (MAOI), but it is structurally related to amphetamine and has dopaminergic effects in the brain. Both of these medications are best dosed in the morning. However, their stimulating effects do not necessarily mean that they will disrupt sleep quality, as we will see later in this review. Table 2 shows the most and least sedating antidepressants within each class.^3,9

Sedation is rarely encountered when treating attention-deficit/hyperactivity disorder (ADHD) with traditional stimulants, but it can be a problem with the nonstimulant treatment options. Sedation is a well-known side effect of the α2 agonists, particularly clonidine, but new data suggests that atomoxetine may also carry a high risk. In clinical trials of atomoxetine, only 1 in 20 patients reported fatigue.⁸ However, in the FDA postmarketing reporting system, atomoxetine ranked second for its propensity to prompt reports of somnolence. (The study ranked atomoxetine against 30 antidepressants since it has an antidepressant structure).⁹ If fatigue was rare in clinical trials of atomoxetine, why did it prompt so many reports of somnolence? The best explanation for this discrepancy is that peak plasma levels of atomoxetine can be 10-fold higher in CYP2D6 poor metabolizers. Therefore, while fatigue may be rare with this drug, it is likely to be quite severe in patients that do experience it.

When it comes to antipsychotics, finding a nonsedating option is like navigating between the fabled Scylla and Charybdis. Patients tend to experience akathisia when we select the less sedating options like lurasidone, risperidone, cariprazine, and aripiprazole. The more sedating ones, such as clozapine, olanzapine, quetiapine, and ziprasidone, are less likely to cause akathisia. When patients cannot tolerate either of these side effects, brexpiprazole and iloperidone are good options, with number needed to harm (NNH) above 30 for both sedation and akathisia.⁴ Lumateperone is also relatively free of akathisia, and its sedative effects are usually manageable with evening dosing.

Evening Dosing

Some medications are so sedating that this adverse effect limits their use. This is particularly true when they are taken in the morning, as is often the case for the short half-life medications that are given in divided doses. Quetiapine (half-life, 6 hours), ziprasidone (7 hours), clozapine (12 hours), and trazodone (5 to 9 hours) were all recommended for twice daily dosing when they were first released, based on the half-lives of the drugs. However, pragmatic physicians soon began dosing these medications at night without any loss of efficacy. This strategy is supported by about a dozen clinical trials comparing evening dosing to divided dosing in patients with schizophrenia and mood disorders.^10-13 Asenapine could also be added to that list, as it was originally recommended to be given in divided doses but has a 24-hour half-life.

Sedation can be an asset when these short half-life medications are given at night, as their sedative effects are generally limited to the hours of sleep. The major risk with this strategy is orthostasis, particularly in older patients. For quetiapine, the extended-release version reduces this risk by smoothing over the peak levels.

Antidotes for Sedation

When switching medications is not an option and evening dosing does not relieve sedation, antidotes may help, but are not consistently helpful. Modafinil and armodafinil improved residual fatigue in both bipolar and unipolar depression, but the benefit was small (effect size = 0.15).¹⁴ These novel stimulants failed to improve fatigue in studies of patients with schizophrenia, although those trials were probably underpowered to detect the difference.¹⁵ Traditional stimulants have even less evidence of benefit and carry more risks. Concerns about tolerance, addiction, psychosis, mania, and cardiovascular risks significantly limit their use.

Sleep Quality and Sedation

Psychiatric medications may cause fatigue through direct sedative effects or by worsening sleep quality. When medications make it difficult for a patient to fall asleep, the effect is usually readily apparent to the patient. When they disrupt sleep quality, the cause is less apparent. Poor sleep quality causes a variety of problems, some of which can be mistaken for symptoms of psychiatric disorders (eg, daytime fatigue, trouble concentrating, irritability, slowed reaction time, and poor problem-solving abilities).

Serotonergic antidepressants can cause both initiation insomnia and restless, fragmented sleep.^3,16 The sedative effects of these antidepressants generally parallel their tendency to disrupt sleep, suggesting that poor sleep quality may be part of the reason that patients feel tired on these medications.

On the other hand, some antidepressants (eg, bupropion, levomilnacipran, and vortioxetine) have low rates of both sedation and insomnia.¹⁶ Despite its stimulating effects, bupropion actually improves sleep quality, increasing slow-wave sleep and reducing REM latency and density.^17,18 Bupropion can cause difficulty falling asleep, but it does so at about the same rate as the selective serotonin reuptake inhibitors (SSRIs).¹⁶ Vortioxetine has not been adequately tested in a sleep lab, but it was shown to normalize sleep architecture in an animal study and, in a post hoc analysis of a clinical study, it improved subjective reports of sleep quality.¹⁸

If a patient needs a sedative to fall asleep, mirtazapine and trazodone both achieve this effect without worsening sleep quality. These antidepressants increase the slow waves that characterize the deepest stage of sleep.³ Likewise, the sedating antipsychotics usually do not worsen sleep quality, and may, in fact, improve it (Table 3).

Quetiapine improved sleep quality, increased sleep efficiency, and reduced nocturnal awakenings in patients with bipolar disorder. Olanzapine, risperidone, and ziprasidone also resulted in improvements in sleep quality, beyond their effects on sleep initiation.19 Lumateperone, which shares a serotonin 5-HT2A receptor antagonist effect with trazodone, was originally developed as a hypnotic before gaining approval in schizophrenia. Taken nightly, in low doses (1-10 mg hs), lumateperone improved sleep without causing next-day sedation.²⁰ These sedating options may provide dual benefits when patients require an antipsychotic for schizophrenia or a mood disorder, but antipsychotics have too many risks to justify their use for insomnia alone.

The Bottom Line

Sedation may not always be desirable, but it is difficult to avoid in psychiatry. Some of the most sedating medications have unique benefits that may justify their use (Table 3).²¹ Evening dosing may improve tolerability, as long as adverse effects that are linked to the peak serum level do not get in the way. Orthostasis, for example, can cause a problem when antipsychotics and some antidepressants (eg, trazodone, mirtazapine, tricyclics, MAOIs) reach peak levels.

On the other hand, it is not necessary to jump to a sedating medication just because a patient has trouble sleeping. Some of these medications, like the SSRIs and the serotonin-norepinephrine reuptake inhibitors, worsen sleep quality. In fact, sleep may improve with an activating medication, either because it deepens sleep quality as bupropion does, or because it helps the patient reset their circadian rhythm. Patients tend to sleep better when they rise at regular times and stay active during the day.

Dr Aiken is an instructor in clinical psychiatry at the Wake Forest School of Medicine and the director of the Mood Treatment Center in Winston-Salem, North Carolina. He is editor-in-chief of The Carlat Psychiatry Report and coeditor of the Bipolar Disorder Section for Psychiatric Times^TM.

References

1. Bourin M, Briley M. Sedation, an unpleasant, undesirable and potentially dangerous side-effect of many psychotropic drugs. Hum Psychopharmacol. 2004;19(2):135-139.

2. Yun L, Fagan M, Subramaniapillai M, et al. Are early increases in physical activity a behavioral marker for successful antidepressant treatment? J Affect Disord. 2020;260:287-291.

3. Goldberg JF, Ernst CL. Managing the Side Effects of Psychotropic Medications. 2nd ed. American Psychiatric Association Publishing; 2019.

4. Citrome L. Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder: absolute risk increase and number needed to harm. J Clin Psychopharmacol. 2017;37(2):138-147.

5. Alberti S, Chiesa A, Andrisano C, Serretti A. Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis. J Clin Psychopharmacol. 2015;35(3):296-303.

6. Ketter TA, ed. Handbook of Diagnosis and Treatment of Bipolar Disorders. American Psychiatric Publishing; 2010.

7. Bai Y, Yang H, Chen G, Gao K. Acceptability of acute and maintenance pharmacotherapy of bipolar disorder: a systematic review of randomized, double-blind, placebo-controlled clinical trials. J Clin Psychopharmacol. 2020;40(2):167-179.

8. Cheng JY, Chen RY, Ko JS, Ng EM. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis. Psychopharmacology (Berl). 2007;194(2):197-209.

9. Eugene AR. Association of sleep among 30 antidepressants: a population-wide adverse drug reaction study, 2004-2019. PeerJ. 2020;8:e8748.

10. Takeuchi H, Powell V, Geisler S, et al. Clozapine administration in clinical practice: once-daily versus divided dosing. Acta Psychiatr Scand. 2016;134(3):234-240.

11. Chengappa KN, Parepally H, Brar JS, et al. A random-assignment, double-blind, clinical trial of once- vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study. Can J Psychiatry. 2003;48(3):187-194.

12. Raatjes B, Dantz B. Trazodone: the forgotten antidepressant. Psychiatr Ann. 2011;41(3):146-157.

13. Riesenberg RA, Baldytcheva I, Datto C. Self-reported sedation profile of quetiapine extended-release and quetiapine immediate-release during 6-day initial dose escalation in bipolar depression: a multicenter, randomized, double-blind, phase IV study. Clin Ther. 2012;34(11):2202-2211.

14. Goss AJ, Kaser M, Costafreda SG, et al. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013;74(11):1101-1107.

15. Saavedra-Velez C, Yusim A, Anbarasan D, Lindenmayer JP. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry. 2009;70(1):104-112.

16. Alberti S, Chiesa A, Andrisano C, Serretti A. Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis. J Clin Psychopharmacol. 2015;35(3):296-303.

17. 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):275-281.

18. Liguori C, Ferini-Strambi L, Izzi F, et al. Preliminary evidence that vortioxetine may improve sleep quality in depressed patients with insomnia: a retrospective questionnaire analysis. Br J Clin Pharmacol. 2019;85(1):240-244.

19. Monti JM. The effect of second-generation antipsychotic drugs on sleep parameters in patients with unipolar or bipolar disorder. Sleep Med. 2016;23:89-96.

20. Calsolaro V, Antognoli R, Okoye C, Monzani F. The use of antipsychotic drugs for treating behavioral symptoms in Alzheimer’s disease. Front Pharmacol. 2019;10:1465.

21. Schatzberg AF, DeBattista C. Schatzberg’s Manual of Clinical Psychopharmacology. 9th ed. American Psychiatric Association Publishing; 2019.❒