The Bedtime Solution Mitchell Levy, MD, and Kimberly Mclaren, MD

Cases That Test Your Skills

The bedtime solution Mitchell Levy, MD, and Kimberly McLaren, MD

Depressed and suicidal, Ms. W had not found relief after How would you years of medication trials and electroconvulsive therapy. handle this case? Visit CurrentPsychiatry.com Then her psychiatrists tried a novel intervention. to input your answers and see how your colleagues responded

CASE Refractory depression • nortriptyline for migraine headache pro- Ms. W, age 38, is brought to the emergency de- phylaxis. partment after her son fi nds her unresponsive Some medications were not tolerated, pri- ® and calls 911. Suff ering from worsening depres- Dowdenmarily because Health of increased Media anxiety. Those sion, she wrote a note telling her children good- that were tolerated were adequate trials in bye, and overdosed on zolpidemCopyright from anFor old personalterms of dose titrationuse andonly length. High-dose prescription and her daughter’s opioids. After fl uoxetine (80 mg/d) augmented by risperi- being evaluated and medically cleared in the done (0.375 to 0.5 mg/d) produced the most emergency department, Ms. W was admitted to reliable and signifi cant improvement. the psychiatric unit. Ms. W had 2 courses of electroconvulsive Ms. W has a history of recurrent major de- therapy (ECT) totaling 30 treatments—most pressive disorder that developed after she was recently in 2007—that resulted in signifi cant sexually abused by a relative as a teen. She also memory loss with limited benefi t. Premen- has bulimia nervosa, alcohol dependence, and strual worsening of depression and suicidality posttraumatic stress disorder. She was hospital- were noted. In collaboration with her gynecolo- ized twice for depression and suicidality but had gist, Ms. W was treated with a 3-month trial of not previously attempted suicide. In the mid- leuprolide to suppress her ovarian axis, which to-late 1990s, she had trials of paroxetine, clomi- was helpful. In 2008 she underwent bilateral pramine, lithium, and bupropion. oophorectomy. She has not had symptoms of She was seen regularly in our outpatient mood elevation or psychosis. Family history in- psychiatry clinic for medication management cludes schizophrenia, depression, anxiety, and and supportive psychotherapy. Since being fol- alcoholism. lowed in our clinic starting in early 2005, she has In the months before hospitalization, Ms. had the following medication trials: W had been increasingly depressed and in- • fl uoxetine, citalopram, venlafaxine XR, termittently suicidal, although she did not and duloxetine for depression endorse a specifi c plan or intention to harm • atomoxetine, buspirone, liothyronine, herself because she was concerned about risperidone, and aripiprazole for anti- the impact suicide would have on her chil- depressant augmentation dren. Weight gain with risperidone had reac- • lorazepam, clonazepam, and gabapentin for anxiety Dr. Levy is assistant professor and Dr. McLaren is acting assistant professor, department of psychiatry, University of Washington, Current Psychiatry • zolpidem and trazodone for insomnia Seattle, WA. Vol. 8, No. 12 91

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tivated body image issues, so Ms. W stopped gested that rates of total sleep deprivation- taking this medication 2 weeks before hos- induced mania are likely to be similar to pitalization. Her depression became worse, or less than those reported for antidepres- and she began using her husband’s hydroco- sants. Because sleep deprivation can induce done/acetaminophen prescription. seizures, this therapy is contraindicated for patients with epilepsy or those at risk for What depression treatment would you con- seizures.4 sider next for Ms. W? a) retrial of fl uoxetine and an atypical What adjuncts could help sustain a antipsychotic with a lower potential for depressed patient’s response to partial weight gain, such as aripiprazole sleep deprivation? b) lithium with a tricyclic antidepressant a) light therapy c) bilateral ECT b) lithium Clinical Point d) chronotherapy utilizing sleep deprivation c) antidepressants Sleep deprivation d) sleep-phase advance The authors’ observations e) all of the above is a rapid, eff ective Approximately 40% of patients with ma- treatment for jor depression fail to respond to an initial Researchers have successfully explored depression but antidepressant trial.1 An additional 50% of strategies to reduce the rate of depressive up to 80% of these patients will be treatment-resistant relapse after sleep deprivation, including 1 patients experience to a subsequent antidepressant. Patients coadministering light therapy, antidepres- may be progressively less likely to respond sants, lithium (particularly for bipolar depressive relapse to additional medication trials.2 depression), and sleep-phase advance.4 One of the most rapid-acting and effec- Sleep-phase advance involves shifting the tive treatments for unipolar and bipolar de- sleep-wake schedule to a very early sleep pression is sleep deprivation. Wirz-Justice time and wake-up time (such as 5 PM to et al3 found total or partial sleep depriva- midnight) for 1 day, and then pushing back tion during the second half of the night this schedule by 1 or 2 hours each day until induced rapid depression remission. Re- the patient is returned to a “normal” sleep sponse rates range from 40% to 60% over schedule (such as 10 PM to 5 AM). Research- hours to days.4 Sleep deprivation also can ers have demonstrated that sleep-phase reduce suicidality in patients with season- advance can have antidepressant effects.7 al depression.5 This treatment has not been widely employed, however, because up to 80% of patients who undergo sleep depri- TREATMENT Sleep manipulation vation experience rapid and signifi cant de- Ms. W is continued on fl uoxetine, 80 mg/d. pressive relapse.4 We opt for a trial of partial sleep deprivation Sleep deprivation usually is well toler- and sleep-phase advance for Ms. W because ated. Potential side effects include: of the severity of her depression, her mul- • headache tiple ineff ective or poorly tolerated medica- • gastrointestinal upset tion trials, and limited benefi t from ECT. This • fatigue treatment involves instituting partial sleep • cognitive impairment. deprivation the fi rst night and subsequently Less often, patients report worsening of advancing her sleep phase over the next sev- depressive symptoms and, rarely, suicidal eral days (Table 1, page 96). ideation or psychosis.4 Mania or hypoma- Although she is sleepy the morning after nia are potential complications of sleep partial sleep deprivation, Ms. W reports a loss for patients with bipolar or unipolar marked improvement in her mood, decline Current Psychiatry 92 December 2009 depression. In a review, Oliwenstein6 sug- in hopelessness, and absence of suicidal continued on page 96

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continued from page 92

Table 1 Ms. W’s chronotherapy protocol: Hours permitted for sleep* Day number 12345

Sleep deprivation 9 PM to 2 AM

Sleep-phase 5 PM to 7 PM to 9 PM to 10 PM to advance midnight 2 AM 4 AM 5 AM *Treatment was implemented while Ms. W was hospitalized

ideation. She continues the sleep-phase previously responded to antidepressant aug- advance protocol for the next 3 nights and mentation with an atypical antipsychotic we participates in cognitive-behavioral therapy add aripiprazole and titrate the dosage to 7.5 groups and ward activities. Psychiatric unit mg/d. We also continue ﬂ uoxetine, 80 mg/d, staﬀ support her continued wakefulness dur- and add trazodone, 100 mg at bedtime, and ing sleep manipulation. Because Ms. W had hydroxyzine, 25 mg as needed.

MAINTAINING WELLNESS IN PATIENTS WITH BIPOLAR DISORDER moving beyond eff icacy to effectiveness

FREE 2.0 CME CREDITS FREE PARTICIPATING FACULTY SUPPLEMENT TO Sponsored by 2.0 CME S. Nassir Ghaemi, MD, MPH Available at www.currentpsychiatry.com credits A DOWDEN PUBLICATION October 2009 Director, Mood Disorders and Psychopharmacology Maintaining wellness in Available at Programs patients with Professor of Psychiatry CurrentPsychiatry.com Tufts Medical Center bipolar disorder: Boston, Massachusetts MOVING BEYOND EFFICACY TO Robert M. A. Hirschfeld, MD EFFECTIVENESS Titus H. Harris Chair FACULTY Harry K. Davis Professor S. Nassir Ghaemi, MD, MPH Robert M. A. Hirschfeld, MD Professor and Chairperson Claudia F. Baldassano, MD Department of Psychiatry and Behavioral Sciences University of Texas Medical Branch Galveston, Texas

This supplement was submitted by SciMed and supported by an educational grant from AstraZeneca. It was peer Claudia F. Baldassano, MD reviewed by CURRENT PSYCHIATRY.

Supported by an educational grant from Assistant Professor of Psychiatry Director, Bipolar Outpatient Program Hospital of the University of Pennsylvania A CME-certiﬁ ed supplement enduring from the 2009 CURRENT PSYCHIATRY/AACP Symposium. Philadelphia, Pennsylvania This activity is sponsored by SciMed and supported by an educational grant from AstraZeneca. It was peer reviewed by CURRENT PSYCHIATRY.

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The authors’ observations Table 2 Chronotherapy incorporates manipulations Sleep deprivation for depression: of the sleep/wake cycle such as sleep depri- Possible mechanisms vation and dark or light therapy. It may use combinations of interventions to generate Mechanism Components and sustain a response in patients with de- Alterations to Serotonin, pression. In a 4-week pilot study, Moscovici neurotransmitter norepinephrine, function dopamine11 et al8 employed a regimen of late partial sleep Alterations to Increased gene deprivation, light, and sleep-phase advance endogenous expression14 to generate and maintain an anti depressant circadian pacemaker response in 12 patients. Benedetti et al9 used function a similar regimen plus lithium to successful- Changes in Anterior cingulate, perfusion/activity frontal cortex ly treat bipolar depression and sleep-phase of brain regions regions12,13 Clinical Point advance to continue that response in 50% of Sleep-phase advance patients for 3 months. Circadian rhythms affect the function Table 3 may reduce the of serotonin (5-HT), norepinephrine, and rate of depressive 9,10 Factors that suggest a dopamine. In a manner similar to anti- patient might respond relapse after sleep depressant medications, sleep deprivation to chronotherapy deprivation may up-regulate or otherwise alter these neurotransmitters’ function. In animals, Diurnal mood variation15 sleep deprivation increases serotonin func- Endogenous depression 16 tion.11 Several hypothetical mechanisms including insomnia and anorexia of action for sleep deprivation and other Abnormal dexamethasone suppression17 types of chronotherapies have been sug- High motivation for treatment gested (Table 2).11-14 Bipolar depression (possibly)9 Chronotherapies may affect function in brain pathways, as demonstrated by neuroimaging with positron emission to- with improved sleep-wake cycles related to mography (PET) and functional magnetic depression remission. Bunney and Potkin14 resonance imaging (fMRI). Depression has note the powerful effect of zeitgebers—en- been associated with increased or decreased vironmental agents that reset the body’s brain activity measured by PET or fMRI in internal clock. They suggested that sleep de- regions of the limbic cortex (cingulate and privation may affect the function of “master anterior cingulate) and frontal cortex.12 clock” genes involved in controlling the bio- Wu et al13 examined patients treated for logical clock. These effects on the suprachi- depression with medication and total sleep asmatic nucleus hypothalamic pacemaker deprivation therapy. Response to treatment may improve mood by altering control of was associated with increased function in genetic expression through chromatin re- the cingulate, anterior cingulate, and me- modeling of this master clock circuit. dial prefrontal cortex as measured by PET. Certain factors may increase the likeli- In contrast, mood improvement was asso- hood that a patient may respond to chrono- ciated with reduced baseline activity in the therapy (Table 3).9,15-17 left medial prefrontal cortex, left frontal pole, and right lateral prefrontal cortex. Researchers have noted the convergence OUTCOME Lasting improvement of sleep-wake rhythms and abnormalities Ms. W’s mood improvement is sustained during Current Psychiatry seen in depression and the subsequent link her week-long hospitalization. At discharge she Vol. 8, No. 12 97 continued on page 104

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continued from page 97 Health Care Policy and Research, Public Health Services, U.S. Department of Health and Human Services; 1993. AHCPR Related Resource publication 93-0550. • Wu JC, Kelsoe JR, Schachat C, et al. Rapid and sustained anti- 2. Fava M, Rush JA, Wisniewski SR, et al. A comparison of depressant response with sleep deprivation and chronotherapy mirtazapine and nortriptyline following two consecutive in bipolar disorder. Biol Psychiatry. 2009; 66(3): 298-301. failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163(7):1161-1172. Drug Brand Names 3. Wirz-Justice A, Benedetti F, Berger M. Chronotherapeutics Aripiprazole • Abilify Leuprolide • Lupron (light and wake therapy) in affective disorders. Psychol Med. Atomoxetine • Strattera Liothyronine • Cytomel 2005;35(7):939-944. Bupropion • Wellbutrin Lithium • Eskalith, Lithobid 4. Giedke H, Schwärzler F. Therapeutic use of sleep deprivation Buspirone • BuSpar Lorazepam • Ativan in depression. Sleep Med Rev. 2002;6(5):361-377. Citalopram • Celexa Nortriptyline • Aventyl Clomipramine • Anafranil Paroxetine • Paxil 5. Lam RW, Tam EM, Shiah IS, et al. Effects of light therapy on suicidal ideation in patients with winter depression. J Clin Clonazepam • Klonopin Risperidone • Risperdal, Psychiatry. 2000;61(1):30-32. Duloxetine • Cymbalta Risperdal Consta Fluoxetine • Prozac Trazodone • Desyrel 6. Oliwenstein L. Lifting moods by losing sleep: an Gabapentin • Neurontin Venlafaxine XR • Eﬀ exor XR adjunct therapy for treating depression. Alternative and Complementary Therapies. 2006;12(2):66-70. Hydrocodone/APAP • Vicodin Zolpidem • Ambien Clinical Point Hydroxyzine • Atarax, Vistaril 7. Wehr TA, Wirz-Justice A, Goodwin FK, et al. Phase advance of the circadian sleep-wake cycle as an antidepressant. Science. Chronotherapies Disclosures 1979;206(4419):710-713. The authors report no ﬁ nancial relationship with any 8. Moscovici L, Kotler M. A multistage chronobiologic may work by company whose products are mentioned in this article or intervention for the treatment of depression: a pilot study. J with manufacturers of competing products. Affect Disord. 2009;116(3):201-217. altering the function 9. Benedetti F, Colombo C, Barbini B, et al. Morning sunlight reduces length of hospitalization in bipolar depression. J of serotonin, Affect Disord. 2001;62(3):221-223. is hopeful about the future and does not have norepinephrine, 10. Benedetti F, Barbini B, Colombo C, et al. Chronotherapeutics thoughts of suicide. in a psychiatric ward. Sleep Med Rev. 2007;11(6):509-522. and dopamine At subsequent outpatient visits up to 4 11. Lopez-Rodriguez F, Wilson CL, Maidment NT, et al. Total sleep deprivation increases extracellular serotonin in the rat months after discharge, her depressive symp- hippocampus. Neuroscience. 2003;121(2):523-530. toms remain improved. Patient Health Ques- 12. Mayberg HS. Defi ning the neural circuitry of depression: toward a new nosology with therapeutic implications. Biol tionnaire scores indicate mild depression, but Psychiatry. 2007;61(6):729-730. Ms. W is not suicidal. She maintains a sleep 13. Wu JC, Gillin JC, Buchsbaum MS, et al. Sleep deprivation PET correlations of Hamilton symptom improvement ratings schedule of 10 PM to 6:30 AM and undergoes with changes in relative glucose metabolism in patients with depression. J Affect Disord. 2008;107(1-3):181-186. 10,000 lux bright light therapy, which she 14. Bunney JN, Potkin SG. Circadian abnormalities, molecular began shortly after discharge, for 30 minutes clock genes and chronobiological treatments in depression. Br Med Bull. 2008;86:23-32. every morning. She works more productively 15. Benedetti F, Barbini B, Lucca A, et al. Sleep deprivation hastens in psychotherapy, focusing on her eating dis- the antidepressant action of fl uoxetine. Eur Arch Psychiatry Clin Neurosci. 1997;247(2):100-103. order and anxiety. 16. Vogel GW, Thurmond A, Gibbons P, et al. REM sleep reduction effects on depression syndromes. Arch Gen Psychiatry. References 1975;32(6):765-777. 1. AHCPR Depression Guideline Panel. Clinical practice 17. King D, Dowdy S, Jack R, et al. The dexamethasone guideline number 5. Depression in primary care. Volume 2: suppression test as a predictor of sleep deprivation Treatment of major depression. Rockville, MD: Agency for antidepressant effect. Psychiatry Res. 1982;7(1):93-99.

Bottom Line Deliberately altering depressed patients’ sleep cycle can elevate and improve mood. Ongoing sleep manipulation, light therapy, or medications may be required to sustain response. The mechanisms of action for these treatments may include ‘resetting’ hypothalamic pacemaker activity and gene expression.

Current Psychiatry 104 December 2009

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