Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study
Introduction
Major depressive disorder is a neuropsychiatric condition that consists of core symptoms including a persistently depressed mood, anhedonia, sleep disruption, anergia, poor concentration, guilt, hopelessness, appetite changes, and suicidal ideation. Currently there are no commonly used rapid treatments for depression. Suicide is the 10th leading cause of death in the United States, and is even higher among younger individuals between the ages of 10–24, where it is the second leading cause (Heron, 2013). Untreated depression is known to be associated with suicide risk with estimates that 60% of all suicides are associated with inadequately treated depression (Mann et al., 2005). There is an apparent stratified risk of suicide in those who have been admitted to the inpatient unit for depression, with those who have suicidal thoughts, or suicide attempts, posing the highest lifetime risk of committing suicide (Bostwick and Pankratz, 2000). Depression is a major medical issue both domestically and abroad. Depression is the 4th leading cause of disability in the world and has an approximate lifetime prevalence of 16.5% in the United States (Kessler et al., 2003, Murray and Lopez, 1996). Pharmacotherapy, and psychotherapy are the most commonly used treatments but only approximately 67% of non treatment resistant depressed individuals achieve remission with medications or psychotherapy, taking an average of 5–7 weeks to achieve remission in those who find an effective regimen (Rush et al., 2006). Even electroconvulsive therapy (ECT), which is our most dependable, and effective treatment, still takes 2–3 weeks for therapeutic benefit, and has limited availability and cognitive side effects (Sackeim et al., 2007). Although there are promising newer treatments such as repetitive transcranial magnetic stimulation (rTMS) (George et al., 2014) and ketamine (Caddy et al., 2014), there are at this time no commonly used treatments that rapidly treat depression.
Studies have consistently reported a rapid antidepressant response to total sleep deprivation in both unipolar and bipolar depression, first studied by Pflug and Tolle (1971), and reviewed extensively by (Wu and Bunney, 1990, Wirz-Justice et al., 2005, Benedetti et al., 2007. The clinical utility of this technique is limited however, because responders typically relapse rapidly following recovery sleep. The addition of pharmacotherapy (Benedetti et al., 2001, Colombo et al., 2000, Smeraldi et al., 1999, Martiny et al., 2012, Shelton and Loosen, 1993, Szuba et al., 1994, Wu et al., 2009), sleep phase advance (Riemann et al., 1999, Echizenya et al., 2013), and bright light therapy (Echizenya et al., 2013, Martiny et al., 2012, Martiny et al., 2013, Neumeister et al., 1996, Wu et al., 2009) to sleep deprivation have each demonstrated efficacy in preventing some individuals from relapsing into depression. Some early studies have reported that combined total sleep deprivation, sleep phase advance, and bright light therapy, dubbed Triple Chronotherapy, along with concomitant pharmacotherapy, produces a rapid improvement in depressive symptoms which endures for as long as 9 weeks (Echizenya et al., 2013, Martiny et al., 2012, Wu et al., 2009). If the early, encouraging results of Triple Chronotherapy hold up to further study, the technique represents a near ideal inpatient treatment, as it is inexpensive, relatively easy to carry out, and has minimal side effects.
Despite encouraging early results, only one published report has attempted to use Triple Chronotherapy in suicidal patients, and in that trial only bipolar depressed patients were included. That study used a slightly different variation of chronotherapy that included three nights of sleep deprivation every other night with three light therapy sessions, combined with lithium (Benedetti et al., 2014). The lack of data utilizing Triple Chronotherapy in acutely suicidal patients significantly limits its utility in the United States, where few non-suicidal patients are admitted to the inpatient unit. Furthermore, published trials to this point have excluded those with comorbid illness, which also limits the clinical usefulness of this intervention to a minority of patients. We subsequently sought to determine if adjunctive Triple Chronotherapy was safe and feasible in acutely depressed and suicidal inpatients.
Section snippets
Participants
We included participants with non-psychotic unipolar, or bipolar depression (who were on a therapeutic dose of a mood stabilizer), age 18–75. We excluded patients who were in a mixed state, had active psychosis, had active panic disorder, were actively withdrawing from a substance of abuse, had a history of seizures, or had active unstable medical or neurologic illness.
We recruited participants from inpatient units at the Medical University of South Carolina (MUSC) Institute of Psychiatry (IOP)
Results
As compared to baseline there was a statistically and clinically significant decrease in both clinician, and self rated scales of depression and suicidal ideation. The 17-Item Hamilton depression scale went from an average of 24.7 ± 4.2 SD at day 0, to a final score of 9.4 ± 7.3 SD on day 4. Six out of ten participants met criteria for remission on the Ham17 (60%). Sixty-percent met criteria for response (Fig. 3, Fig. 4). The Columbia Suicide Severity Index went from an average of 19.5 ± 8.5 SD
Discussion
This small, open label pilot study suggests that adjunctive Triple Chronotherapy is safe and tolerable in acutely suicidal, unipolar depressed inpatients. These results complement and extend the recently published study demonstrating safety of another variant of Chronotherapy in suicidal Bipolar Depressed inpatients (Benedetti et al., 2014). This conclusion, along with any conclusion regarding treatment efficacy, must however be made in the context of significant experimental limitations, with
Role of the funding source
Support was provided by the Medical University of South Carolina Resident Research Training Program (DART program), which was funded by National Institute on Drug Abuse (NIDA) R25 DA020537-06 (PI's Back and Brady). Besides providing mentorship that assisted in experimental design and implementation, the funding source did not influence the project.
Author contributions
Gregory L. Sahlem was the Primary investigator of the study. He contributed in experimental design, regulatory procedures, data collection, data analysis, and manuscript preparation.
Benjamin Kalivas contributed in experimental design, data analysis, and manuscript preparation.
James B. Fox contributed in recruitment, and manuscript preparation.
Kayla Lamb contributed to regulatory procedures, and manuscript preparation.
Amanda Roper contributed in experimental design, and manuscript preparation.
Conflict of interest
There is no Conflict of Interest.
Acknowledgments
We would like to thank the acute inpatient team at the Institute of Psychiatry of the Medical University of South Carolina for their tireless effort. Without your help this study could not have occurred. We would also like to thank the Drug Abuse Research Track (DART) program at the Medical University of South Carolina with special thanks to Drs.Back and Brady, along with the grant that supports it (NIDA R25 DA020537-06 (PI's Back and Brady)).
References (38)
- et al.
Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model?
J Psychiatr Res
(2001) - et al.
Chronotherapeutics in a psychiatric ward
Sleep Med Rev
(2007) - et al.
The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research
Psychiatry Res
(1989) - et al.
Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction
Psychiatry Res
(2000) - et al.
Total sleep deprivation followed by sleep phase advance and bright light therapy in drug-resistant mood disorders
J Affect Disord
(2013) - et al.
A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients
Brain Stimul
(2014) Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale
Chest
(1993)- et al.
Bright light therapy stabilizes the antidepressant effect of partial sleep deprivation
Biol Psychiatry
(1996) - et al.
Sleep deprivation accelerates the response to nortriptyline
Prog Neuro-Psychopharmacology Biological Psychiatry
(1993) - et al.
Sustained antidepressant effect of sleep deprivation combined with Pindolol in bipolar depression: a placebo-controlled trial
Neuropsychopharmacology
(1999)
Lithium sustains the acute antidepressant effects of sleep deprivation: preliminary findings from a controlled study
Psychiatry Res
Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder
Biol Psychiatry
Assessment of suicidal intention: the Scale for Suicide Ideation
J Consult Clin Psychol
Combined total sleep deprivation and light therapy in the treatment of drug-resistant bipolar depression: acute response and long-term remission rates
J Clin Psychiatry
Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression
J Clin Psychiatry
Affective disorders and suicide risk: a reexamination
Am J Psychiatry
Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy
Ther Adv Psychopharmacol
A rating scale for depression
J Neurol, Neurosurg psychiatry
Deaths: leading causes for 2010
Natl Vital Stat Rep
Cited by (53)
Sleep spindles in adolescents with major depressive disorder
2024, Journal of Affective DisordersHow to save a life: From neurobiological underpinnings to psychopharmacotherapies in the prevention of suicide
2023, Pharmacology and TherapeuticsBody rhythms/biological clocks
2023, Encyclopedia of Mental Health, Third Edition: Volume 1-3Circadian neuromarkers of mood disorders
2022, Journal of Affective Disorders ReportsSleep deprivation as a treatment for major depressive episodes: A systematic review and meta-analysis
2022, Sleep Medicine ReviewsBiological rhythms and chronotherapeutics in depression
2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry