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A multistage chronobiologic intervention for the treatment of depression: A pilot study
Journal of Affective Disorders 116 (2009) 201–207
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
A multistage chronobiologic intervention for the treatment of depression: A pilot study Lucian Moscovici ⁎, Moshe Kotler Beer-Yaakov Mental Health Center, Beer-Ness Campus, affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
a r t i c l e
i n f o
Article history: Received 8 October 2008 Received in revised form 5 January 2009 Accepted 6 January 2009 Available online 20 February 2009 Keywords: Depression Chronobiologic intervention Wake therapy Bright light therapy
a b s t r a c t Background: Most antidepressant medications in current use have several disadvantages: a delayed therapeutic effect, side effects, stigmatization and concerns about safety for the developing fetus during pregnancy. Several chronobiologic techniques which are free of these disadvantages were proposed as an alternative. The current article reports the design and the initial outcome results of a new chronobiologic multistage intervention (CMI) that is comprised of the following techniques: (i) partial sleep deprivation during the second half of the night (wake therapy – WT), (ii) medium (green) wavelength light in combination with dawn simulation (DS), (iii) bright light therapy (BLT), and (iv) sleep phase advance (SPA). Methods: The study was conducted as a set of 12 single-case designs with moderate-to-severe depressive volunteering patients. Depression, anxiety and tension measurements were taken on a daily basis beginning with a baseline measurement (T0), followed by a set of four consecutive morning measurements during the therapeutic intervention (T1–T4),and with a final measurement carried out at the end of 4 weeks of follow-up (T5). Results: A clinically significant rapid improvement of the depressive symptoms was demonstrated and maintained for at least 4 weeks after the end of the intervention. No dropouts or compliance difficulties were observed. Patient satisfaction was high, and other than having to sleep for four nights at the Research and Development Unit, participants were not inconvenienced by the nature of the therapeutic design. Sleepiness in the late afternoon hours was reported by several of the participants, but did not reach a level that interfered with their ability to function. Levels of tension did not show a consistent improvement along the intervention procedure and were not maintained in follow-up. There was some unexpected improvement in the level of anxiety that persisted at follow-up. This latter finding requires further validation by additional studies. Conclusions: These initial findings showed the procedure to be effective and well tolerated. It affords many advantages, such as the achievement of a rapid response, no extinction of the therapeutic effect after 4 weeks of follow-up, safety, high patient compliance and cost effectiveness. These encouraging results warrant validation in further randomized controlled clinical trials. © 2009 Elsevier B.V. All rights reserved.
1. Introduction One of the major disadvantages of most antidepressant medications in current use is a delayed therapeutic effect (National Institute for Clinical Excellence, 2004; Anderson et al., 2000). This period of delay was suggested as being a risk for early dropout (Nemeroff, 2003) and increased suicidal tendency, especially among children and adolescents (US Food and ⁎ Corresponding author. The Research Unit, Beer-Yaakov Mental Hospital, Israel. E-mail address: [email protected] (L. Moscovici). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.01.015
Drug Administration, 2004; Akiskal and Benazzi, 2006). Other disadvantages of pharmacotherapeutic agents are associated with its side effects and drug–drug interactions (Nemeroff et al., 2007), tolerability (Papakostas, 2008), and stigmatization (Interian et al., 2007). Moreover, the treatment of depression with the aid of antidepressant medications during pregnancy and the postpartum period raises unique concerns about safety for the developing fetus as well as the infant (Pearlstein, 2008). Several chronobiologic techniques were proposed as interventional modalities with the purpose of obtaining a rapid, antidepressive effect free of side effects and the other above-
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mentioned disadvantages. We designed an integrative intervention model that combined several chronobiologic techniques and report the results of the initial outcomes in this pilot study. Our chronobiologic multistage intervention (CMI) is comprised of the following techniques: (i) partial sleep deprivation during the second half of the night (wake therapy – WT), (ii) medium (green) wavelength light in combination with dawn simulation (DS), (iii) bright light therapy (BLT), and (iv) sleep phase advance (SPA). Total or partial sleep deprivation (wake therapy – WT) had been previously suggested for obtaining a rapid anti-depressive response within several hours. Several studies that assessed the effectiveness of WT (Giedke and Schwärzler, 2002; Riemann et al., 1995; Wirz-Justice et al., 2005; Wirz-Justice and Van den Hoofdakker, 1999) demonstrated a quick (within hours) and marked improvement in the severity of depressive symptoms among approximately 60% of their patients, irrespective of their depressive diagnostic subtype. Several explanatory mechanisms were proposed for achieving this quick beneficial effect of WT on mood, including the up-regulation of the hippocampal neurogenesis (Grassi-Zucconi et al., 2006), amygdala perfusion (Clark et al., 2006) and increased activation of the prefrontal cortex (Szelenberger et al., 2005). Previous studies provided inconclusive evidence as to whether total or partial sleep deprivation resulted in better outcomes, and the Committee on Chronotherapeutics, under the auspices of the International Society for Affective Disorders (ISAD), recommended that treatment can be total (all night) or partial (second half of the night), both resulting in similar outcomes (Wirz-Justice et al., 2005). From a theoretical perspective, the ‘critical depressogenic theory’ proposed that the second half of the night is considered to be a critical depressogenic period, and that preventing sleep during this period may serve as an anti-depressive intervention (Wehr et al., 1979). Within the CMI, a dawn simulator was used in order to gradually awaken the patient at the beginning of the second half of the night, and than a medium wavelength light spectrum (green 525 nm) was activated in order to keep the patient awake. The rationale behind the use of these components is that the human circadian rhythm system is differentially sensitive to both the gradual increase of white light (Danilenko et al., 2000) as well as to the short-medium (blue-green) wavelength light spectrum (Wright et al., 2004; Horne et al., 1991; Riesenberg et al., 2003). This combination was expected to result in effectively inhibiting levels of melatonin, augmenting levels of cortisol and decreasing the tendency to fall asleep. Since prolonged exposure to blue spectrum or bright white light might produce retinal damage or other adverse effects (Koide et al., 2001; Remé et al., 1998, 2003), we limited our design to the combination of dawn simulation and medium wavelength light spectrum (green 525 nm). Beyond safety reasons, this approach is supported by studies which demonstrate that the exposure to dawn simulation (Avery et al., 2001) and to green light (Benedetti et al., 2003; Stewart et al., 1991) enhances anti-depressive outcomes. According to the Committee on Chronotherapeutics (WirzJustice et al., 2005), daily bright light therapy is one of the ways to prevent relapse into depressive states. The use of BLT following the WT procedure had been described by several groups as a means for preventing relapse and for providing a mood-stabilizing effect (Berger et al., 1997; Neumeister et al., 1996; Praschak-Rieder et al., 1999; Loving et al., 2002). Furthermore, the anti-depressive therapeutic effect of BLT in
seasonal and non-seasonal depression is well known (Golden et al., 2005). BLT was therefore added to the CMI, with the expectation that it would stabilize the therapeutic effect that had been achieved by the other means. Finally, we also inserted SPA, a latent component, into the intervention. A study by Benedetti et al. (2007) found that the antidepressant response to both WT and BLT correlated with a phase advance of the circadian rhythm. According to ‘Lewy's shift delay hypothesis’ (Lewy et al., 2007), affective disorders might be at least partially explained by a mismatch (delay) in the circadian rhythms, more specifically, between those rhythms which are related to the sleep/wake cycle and those that are more tightly coupled to the endogenous circadian pacemaker that is located in the suprachiasmatic nuclei of the hypothalamus. Indeed, SPA had been found to prolong anti-depressive effects in a clinical trial conducted by Benedetti et al. (2001). The inducement of SPA might require specific and additional efforts for the accommodation to an advanced sleep schedule (e.g., Berger et al., 1997). In the CMI, sleep deprivation during the second half of the night spontaneously induced a SPA in the following nights. 1.1. CMI protocol Based on this rationale, the following operative 4 consecutive nights procedure was developed: A. First night – Prolonged sleep deprivation protocol: 21:00 – Patient is allowed to go to sleep as desired. 02:30 – A gradual increase of white light from 0–400 lx (dawn simulation) is activated for 30 min. 03:00–05:30 – A green light (400 lx) is operated using 30 green (525 nm) light emitting diodes (LEDs) light sources. 05:30–06:00 – A 5,000 lx broad spectrum bright light is activated. 06:00–06:30 – The light box is set to 10,000 lx until the end of the session. B. Second night – Short sleep deprivation and advanced sleep phase: 19:00 – The patient is requested to go to sleep earlier. 03:00–03:30 – The dawn simulation white light device is activated. 03:30–05:30 – The green light is activated. 05:30–06:00 – The light box is activated. 06:00–06:30 – The light box is set to 10,000 lx until the end of the session. C. Third night – Same protocol as in night two. D. Fourth night – Same protocol as in the two previous nights. 2. Methods 2.1. Study design The study was conducted as a set of 12 single-case designs. Measurements were taken on a daily basis beginning with a baseline measurement (T0) just before the first intervention night. This was followed by a set of four consecutive morning measurements during the therapeutic intervention (T1–T4), with a final measurement carried out at the end of 4 weeks of follow-up (T5). The purpose of these intensive and frequent measurements was mainly to monitor the pace and course of response to the therapeutic procedure.
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2.2. Population Twelve outpatient participants with depression were recruited in collaboration with peripheral psychiatric and family medicine outpatient clinics. Inclusion criteria were the following: 1. Demonstration of at least four of the main criteria symptoms which are listed for a depressive episode diagnosis (F32) in the ICD-10 (World Health Organization, 1992). 2. Provision of a signed informed consent. Exclusion criteria: 1. The use of pharmacological anti-depressant agents for at least 5 weeks prior to the trial. 2. Retinal disease and/or cataract. 3. Current suicidal thoughts or past suicidal history. 4. A history of psychotic, bipolar affective disorders and alcohol or substance abuse. 2.3. Background data The sample included ten females and two men whose ages ranged between 18 and 70 years (mean= 43.3; SD= 10.12). All participants reported experiencing some degree of depressed mood, loss of interest and enjoyment, and reduced energy leading to increased fatigability and diminished activity for at least 2 weeks before study inclusion. They all also demonstrated at least four of the other symptoms in the ICD-10 criteria for a severe depressive disorder (e.g., reduced concentration and attention, reduced self-esteem and self-confidence, disturbed
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sleep and or diminished appetite). No co-morbidity was reported, with the exception of one participant who reported a prolonged grief reaction after having lost a parent several years earlier. 2.4. Measurements Measurements focused on the severity of symptoms (depression, tension and anxiety), and the instruments used were two clinician rating scales and four patient subjective self-rating scales. The decision to use several measures to rate the same construct (depression) was made in order to increase the level of reliability of the findings. The list of scales that were used along the study is hereby detailed: A. The 21-item version of the clinician rating Hamilton depression scale (HAM-D21) (Hamilton, 1960) was used to assess the severity of depression. It reflects the clinician's impression with scores ranging from 0 (no symptoms at all) to 66 (high level of severity for all symptoms). This measure was completed at T0, T4 and T5. B. The Montgomery–Asberg Depression Clinician Rating Scale (MADRS) (Montgomery and Asberg, 1979) surveys the type and magnitude of symptom burden at the time of completion, and is therefore considered to be a measure of illness severity. Scores are within the range of 0 (least severe) to 60 (most severe): the cutoff point of 31 was suggested as best distinguishing between moderate and severe depression (Müller et al., 2003). This measure was completed at all evaluations (T0–T5).
Fig. 1. Illustration of the course study.
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C. The self-rating depression scale (SDS; Zung, 1965) relates to cognitive, affective, psychomotor, somatic and social– interpersonal aspects of depression. Scores are within the range of 20–80 points with the following suggested clinical cutoff points: mild-to-moderate (50–59), moderate-to-severe (60–69) and severe (N70). This measure was completed at all evaluations (T0–T5). D. Three 5-degree visual analogue scales (VAS) were utilized for self-rating and included a depression VAS (rate the degree of depression you experience), tension VAS (rate the degree of tension you experience) and anxiety VAS (rate the degree of anxiety you experience). The use of these instruments provides an additional state measurement of the levels of experienced distress, thus increasing the findings' reliability. These scales were completed at all evaluations (T0–T5). 2.5. Statistical procedures A set of General Linear models (repeated measures) was conducted in order to establish statistical significance. 2.6. Procedure Patients who fulfilled the study inclusion criteria were referred to the investigator by mental health professionals. Initial contact was established by telephone on the part of potential participants. During these calls, the investigator conducted a brief screening interview and apparently suitable candidates were invited for a complete intake interview in which diagnosis was established and inclusion as well as exclusion criteria were verified. A total of 41 participants were referred to the investigator, 20 were invited for the intake interviews and 12 were included in the experiment. After having established participation suitability, the patients received an extensive explanation about the treatment modality and its conditions, consequences, inconvenience and risks, and were requested to sign an informed consent form. Following the intake interview, the patients went through the intervention protocol at the Research and Development Unit of the Beer–Yaakov Mental Hospital. For further clarifications, the study course is illustrated in Fig. 1. 3. Results The various measurements demonstrated a highly significant and consistent clinical improvement in levels of depression of all 12 participants throughout the therapeutic intervention. This improvement was statistically demonstrated using a repeated measures procedure in relation to the HAM-D21 (F(1,12) = 75.00; pb .001), and did not extinct during the 4 weeks of followup (Table 1, and Figs. 1–4 in Appendix A). Statistically significant improvement was also found in relation to the MADRS scores (F(4,48) =100.56; pb .001), the SDS (F(4,48) =33.88; p b .001) and the depression VAS measure (F(4,48) = 35.85; pb .001). Improvement, as reflected by the clinician rating scales, can also be presented in terms of percentages of improvement and by using the following terminology: ‘Remitters’ are those which HAM-D21 scores b8 and MADRS scores b13. ‘Responders’ are those who demonstrated an improvement of N50%. ‘Partial responders’ are those who improved b50% but N25%, while ‘Non
Table 1 Phase response curve to light. T4
T5
Clinician rating Hamilton Depression Scale 1 23 2 35 3 27 4 38 5 23 6 29 7 33 8 22 9 26 10 30 11 23 12 22
11 17 16 4 9 8 7 12 9 7 7 10
7 27 17 5 8 4 4 7 10 2 2 14
Montgomery–Asberg Depression Clinician Rating Scale 1 25 20 14 8 2 39 24 17 15 3 24 21 13 11 4 35 31 11 10 5 21 16 13 9 6 33 19 12 8 7 35 17 9 7 8 22 10 5 5 9 31 22 15 10 10 35 25 11 8 11 24 19 10 6 12 28 22 14 12
8 13 9 4 4 4 6 4 7 4 5 11
6 18 14 3 4 3 4 8 7 3 5 13
Self-Rating Depression Scale 1 54 46 2 56 42 3 47 46 4 49 46 5 53 41 6 58 41 7 56 42 8 50 49 9 59 54 10 57 50 11 45 44 12 50 47
46 41 45 35 40 37 38 47 44 47 35 44
43 38 44 35 40 33 37 45 35 44 36 40
44 41 40 33 41 26 35 40 35 37 32 41
31 55 47 27 40 31 39 38 34 22 24 42
Depression Visual Analogue 1 3 2 4 3 3 4 3 5 3 6 3 7 3 8 3 9 3 10 3 11 3 12 2
2 0 2 1 1 0 1 2 2 1 1 1
1 0 1 1 1 0 1 2 1 1 0 1
2 1 1 0 1 0 0 1 1 0 0 1
1 2 2 0 2 0 0 2 2 0 0 1
Patient
T0
T1
Scale 2 1 1 2 1 1 1 2 3 2 2 1
T2
T3
Depression scores along the six measurements.
responders’ demonstrated an improvement of less than 25%. In accordance with these definitions, HAM-D21 measurements at T4 revealed 4 remitters, 6 responders and 2 partial responders. T5 scores revealed 7 remitters, 2 responders, 2 partial responders and one non-responder. Even better results were demonstrated by the MADRS scores. 11 remitters and one responder were found at T4. 9 remitters, two responders and one partial responder were found at T5.
L. Moscovici, M. Kotler / Journal of Affective Disorders 116 (2009) 201–207 Table 2 Anxiety and tension scores along the 6 measurements. Patient
T0
T1
T2
T3
T4
T5
Anxiety Visual Analogue Scale 1 2 3 4 5 6 7 8 9 10 11 12
2 3 3 3 3 4 3 3 4 3 2 3
2 0 2 2 1 2 1 2 3 1 2 2
2 0 2 1 1 1 1 2 2 1 0 1
2 0 2 0 1 1 1 2 2 1 0 1
2 0 1 0 1 1 1 1 1 0 0 1
1 1 2 0 1 0 0 2 1 0 0 2
Tension Visual Analogue Scale 1 2 3 4 5 6 7 8 9 10 11 12
3 3 4 2 3 4 4 3 3 3 2 3
3 0 2 2 1 2 3 1 3 1 1 2
2 0 2 1 1 1 2 1 2 1 0 1
2 0 2 0 1 1 2 1 1 1 0 1
2 0 2 0 1 0 1 1 0 0 0 1
2 2 3 1 1 0 2 1 1 0 0 2
Changes in tension and anxiety levels are presented in Table 2. Although anxiety reduction was not an original aim of the CMI, an improvement was also demonstrated in the anxiety VAS (F(4,48) = 34.99; P b.001), and it, too, was maintained at follow-up. A certain improvement in levels of tension was reported by the participants (F(4,48) = 43.56; p b .001), but unlike depression and anxiety, the alleviation in tension levels seemed to diminish to some degree at follow-up. Finally, the study participants were asked to provide feedback regarding their experience during the intervention. There were major three issues that they addressed during the followup interviews. First, they all reported a high level of satisfaction with the rapid improvement in their mood and energy. They did not complain about the need to sleep in a hospital-like environment but four of them reported that they felt a gradually increasing sleepiness beginning at the afternoon and reaching its peak very early in the evening during the intervention days. 4. Discussion The findings of the current pilot study demonstrate a clinically significant rapid improvement of the depressive symptoms as reflected by all the self- and clinician-rating measures that were used. These findings were apparent also in cases of severe depression (MADRSN 31; HAM-D N 30). This desired outcome was maintained for at least 4 weeks after the end of the intervention. There were no dropouts or compliance difficulties. Patient satisfaction, as reported by them in the follow-up interviews, was high, and other than having to sleep for four nights at the Research and Development Unit, they were not inconvenienced by the nature of the therapeutic design. The sleepiness in the late afternoon hours that had been reported by
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several of the participants did not reach a level that interfered with their ability to function and could be indicative of the phase advance effect. Levels of tension, as measured by the selfreport VAS, did not show a consistent improvement along the intervention procedure and were not maintained in follow-up. On the other hand, there was some unexpected improvement in the level of anxiety that persisted at follow-up. This latter finding requires further validation by additional studies. Although some descriptions of side-effects of light therapy and sleep deprivation can include symptoms such as hypomania, irritability, headache, and nausea (Terman and Terman, 2005), menstrual disturbances (Pjrek et al., 2004; Danilenko, 2007), sleepiness, and fatigue (Giedke and Schwarzler, 2002), the participants in the current report did not exhibit any of them (besides late afternoon sleepiness). These findings are very encouraging since they demonstrate a combination of high efficacy, rapid response, little or no side effects, and support the advantages of the CMI for treating moderate-to-severe depression. In a recent literature review (Terman and Terman, 2005), the authors mention the poor compliance of patients to some types of chronobiological interventions. They mention several encountered problems, such as the patients ignoring the alarm clock and considering additional sleep to be the priority of the moment and/or delaying or skipping sessions. These difficulties may represent a conflict between naturally occurring chronobiological processes and rigid sleep schedule protocols for WT and SPA: these may be solved by the some of the procedures that were used in our intervention's design (i.e., the addition of a combination of dawn simulation and green light as well as SPA inducement). This might have facilitated patient compliance due to the match between melatonin secretion, circadian rhythms and the CMI protocol. The timing of the initial light stimulus effect (dawn light) on the first night occurred approximately 5.5 h after bedtime, slightly before a critical time-point along the human phase response curve (PRC) to light (putative core temperature minimum). At that time, the light stimulus is postulated to induce a phase delay response in the circadian rhythm, while our original intention was to induce a phase advance response. Despite this timing, phase advance was actually achieved. An possible explanation for this may stem out of the studies that were conducted by Czeisler (1995), in which it has been suggested that exposure to light during the critical phase of the PRC can reset and even temporary stop the human circadian clock. Indeed, it was demonstrated that if light stimulus is centered near the critical time which coincide with the nadir of the temperature cycle, it results in phase amplitude suppression and leads to large phase shifts (Jewett et al., 1994). In the CMI, light stimulus went on while crossing the putative temperature minimum, into the phase advance period. This reduced the amplitude and thus allowed easier resynchronization of rhythms with 3 nights of stable light treatment. This first night manipulation enabled us to ignore the patients' individual sleeping patterns prior to the intervention, while rapidly adjusting them to the phase advance. Finally, it should be noted that although the CMI is a complex intervention, it was exceptionally easy to conduct and required relatively low-cost technological equipment and little effort on the part of the experimenter, thus showing high levels of cost-effectiveness.
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There are two main limitations to this study. First, there was no control group, and second, the study was comprised of a small non-random sample. Therefore, no comparisons with other intervention or placebo modalities can be made and generalization of the findings should await further studies. In addition, we cannot distinguish between the various components of the intervention in order single out the ones that contributed more to the desired therapeutic effect and which can be omitted. 5. Conclusions
Fig. A3. Improvement in the mean score of the depression visual analog scale (VAS) during the intervention and at follow-up.
This was the first trial of a novel procedure to treat mild-tomoderate depression by means of a multistage chronobiologic intervention. The initial findings showed the procedure to be effective and well tolerated. It affords many advantages, such as the achievement of a rapid response, no extinction of the therapeutic effect after 4 weeks of follow-up, safety, high patient compliance and cost-effectiveness. These encouraging results warrant validation in further randomized controlled clinical trials. Role of funding source This study was conducted without external funding. Conflict of interest The authors declare they have no potential conflict of interest.
Fig. A4. Improvement in the mean score of the clinician rating Hamilton depression scale (HAM-D21) score.
Acknowledgements We thank Yaron Yagil PhD, who kindly assisted with the preparation of the manuscript and Gily Agar MA, for helping us to recruit the patients.
Appendix A
Fig. A1. Improvement in the mean score of the Montgomery–Asberg depression clinician rating scale (MADRS) during the intervention and at follow-up.
Fig. A2. Improvement in the mean score of the self-rating depression scale (SDS) during the intervention and at follow-up.
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
A multistage chronobiologic intervention for the treatment of depression: A pilot study Lucian Moscovici ⁎, Moshe Kotler Beer-Yaakov Mental Health Center, Beer-Ness Campus, affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
a r t i c l e
i n f o
Article history: Received 8 October 2008 Received in revised form 5 January 2009 Accepted 6 January 2009 Available online 20 February 2009 Keywords: Depression Chronobiologic intervention Wake therapy Bright light therapy
a b s t r a c t Background: Most antidepressant medications in current use have several disadvantages: a delayed therapeutic effect, side effects, stigmatization and concerns about safety for the developing fetus during pregnancy. Several chronobiologic techniques which are free of these disadvantages were proposed as an alternative. The current article reports the design and the initial outcome results of a new chronobiologic multistage intervention (CMI) that is comprised of the following techniques: (i) partial sleep deprivation during the second half of the night (wake therapy – WT), (ii) medium (green) wavelength light in combination with dawn simulation (DS), (iii) bright light therapy (BLT), and (iv) sleep phase advance (SPA). Methods: The study was conducted as a set of 12 single-case designs with moderate-to-severe depressive volunteering patients. Depression, anxiety and tension measurements were taken on a daily basis beginning with a baseline measurement (T0), followed by a set of four consecutive morning measurements during the therapeutic intervention (T1–T4),and with a final measurement carried out at the end of 4 weeks of follow-up (T5). Results: A clinically significant rapid improvement of the depressive symptoms was demonstrated and maintained for at least 4 weeks after the end of the intervention. No dropouts or compliance difficulties were observed. Patient satisfaction was high, and other than having to sleep for four nights at the Research and Development Unit, participants were not inconvenienced by the nature of the therapeutic design. Sleepiness in the late afternoon hours was reported by several of the participants, but did not reach a level that interfered with their ability to function. Levels of tension did not show a consistent improvement along the intervention procedure and were not maintained in follow-up. There was some unexpected improvement in the level of anxiety that persisted at follow-up. This latter finding requires further validation by additional studies. Conclusions: These initial findings showed the procedure to be effective and well tolerated. It affords many advantages, such as the achievement of a rapid response, no extinction of the therapeutic effect after 4 weeks of follow-up, safety, high patient compliance and cost effectiveness. These encouraging results warrant validation in further randomized controlled clinical trials. © 2009 Elsevier B.V. All rights reserved.
1. Introduction One of the major disadvantages of most antidepressant medications in current use is a delayed therapeutic effect (National Institute for Clinical Excellence, 2004; Anderson et al., 2000). This period of delay was suggested as being a risk for early dropout (Nemeroff, 2003) and increased suicidal tendency, especially among children and adolescents (US Food and ⁎ Corresponding author. The Research Unit, Beer-Yaakov Mental Hospital, Israel. E-mail address: [email protected] (L. Moscovici). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.01.015
Drug Administration, 2004; Akiskal and Benazzi, 2006). Other disadvantages of pharmacotherapeutic agents are associated with its side effects and drug–drug interactions (Nemeroff et al., 2007), tolerability (Papakostas, 2008), and stigmatization (Interian et al., 2007). Moreover, the treatment of depression with the aid of antidepressant medications during pregnancy and the postpartum period raises unique concerns about safety for the developing fetus as well as the infant (Pearlstein, 2008). Several chronobiologic techniques were proposed as interventional modalities with the purpose of obtaining a rapid, antidepressive effect free of side effects and the other above-
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mentioned disadvantages. We designed an integrative intervention model that combined several chronobiologic techniques and report the results of the initial outcomes in this pilot study. Our chronobiologic multistage intervention (CMI) is comprised of the following techniques: (i) partial sleep deprivation during the second half of the night (wake therapy – WT), (ii) medium (green) wavelength light in combination with dawn simulation (DS), (iii) bright light therapy (BLT), and (iv) sleep phase advance (SPA). Total or partial sleep deprivation (wake therapy – WT) had been previously suggested for obtaining a rapid anti-depressive response within several hours. Several studies that assessed the effectiveness of WT (Giedke and Schwärzler, 2002; Riemann et al., 1995; Wirz-Justice et al., 2005; Wirz-Justice and Van den Hoofdakker, 1999) demonstrated a quick (within hours) and marked improvement in the severity of depressive symptoms among approximately 60% of their patients, irrespective of their depressive diagnostic subtype. Several explanatory mechanisms were proposed for achieving this quick beneficial effect of WT on mood, including the up-regulation of the hippocampal neurogenesis (Grassi-Zucconi et al., 2006), amygdala perfusion (Clark et al., 2006) and increased activation of the prefrontal cortex (Szelenberger et al., 2005). Previous studies provided inconclusive evidence as to whether total or partial sleep deprivation resulted in better outcomes, and the Committee on Chronotherapeutics, under the auspices of the International Society for Affective Disorders (ISAD), recommended that treatment can be total (all night) or partial (second half of the night), both resulting in similar outcomes (Wirz-Justice et al., 2005). From a theoretical perspective, the ‘critical depressogenic theory’ proposed that the second half of the night is considered to be a critical depressogenic period, and that preventing sleep during this period may serve as an anti-depressive intervention (Wehr et al., 1979). Within the CMI, a dawn simulator was used in order to gradually awaken the patient at the beginning of the second half of the night, and than a medium wavelength light spectrum (green 525 nm) was activated in order to keep the patient awake. The rationale behind the use of these components is that the human circadian rhythm system is differentially sensitive to both the gradual increase of white light (Danilenko et al., 2000) as well as to the short-medium (blue-green) wavelength light spectrum (Wright et al., 2004; Horne et al., 1991; Riesenberg et al., 2003). This combination was expected to result in effectively inhibiting levels of melatonin, augmenting levels of cortisol and decreasing the tendency to fall asleep. Since prolonged exposure to blue spectrum or bright white light might produce retinal damage or other adverse effects (Koide et al., 2001; Remé et al., 1998, 2003), we limited our design to the combination of dawn simulation and medium wavelength light spectrum (green 525 nm). Beyond safety reasons, this approach is supported by studies which demonstrate that the exposure to dawn simulation (Avery et al., 2001) and to green light (Benedetti et al., 2003; Stewart et al., 1991) enhances anti-depressive outcomes. According to the Committee on Chronotherapeutics (WirzJustice et al., 2005), daily bright light therapy is one of the ways to prevent relapse into depressive states. The use of BLT following the WT procedure had been described by several groups as a means for preventing relapse and for providing a mood-stabilizing effect (Berger et al., 1997; Neumeister et al., 1996; Praschak-Rieder et al., 1999; Loving et al., 2002). Furthermore, the anti-depressive therapeutic effect of BLT in
seasonal and non-seasonal depression is well known (Golden et al., 2005). BLT was therefore added to the CMI, with the expectation that it would stabilize the therapeutic effect that had been achieved by the other means. Finally, we also inserted SPA, a latent component, into the intervention. A study by Benedetti et al. (2007) found that the antidepressant response to both WT and BLT correlated with a phase advance of the circadian rhythm. According to ‘Lewy's shift delay hypothesis’ (Lewy et al., 2007), affective disorders might be at least partially explained by a mismatch (delay) in the circadian rhythms, more specifically, between those rhythms which are related to the sleep/wake cycle and those that are more tightly coupled to the endogenous circadian pacemaker that is located in the suprachiasmatic nuclei of the hypothalamus. Indeed, SPA had been found to prolong anti-depressive effects in a clinical trial conducted by Benedetti et al. (2001). The inducement of SPA might require specific and additional efforts for the accommodation to an advanced sleep schedule (e.g., Berger et al., 1997). In the CMI, sleep deprivation during the second half of the night spontaneously induced a SPA in the following nights. 1.1. CMI protocol Based on this rationale, the following operative 4 consecutive nights procedure was developed: A. First night – Prolonged sleep deprivation protocol: 21:00 – Patient is allowed to go to sleep as desired. 02:30 – A gradual increase of white light from 0–400 lx (dawn simulation) is activated for 30 min. 03:00–05:30 – A green light (400 lx) is operated using 30 green (525 nm) light emitting diodes (LEDs) light sources. 05:30–06:00 – A 5,000 lx broad spectrum bright light is activated. 06:00–06:30 – The light box is set to 10,000 lx until the end of the session. B. Second night – Short sleep deprivation and advanced sleep phase: 19:00 – The patient is requested to go to sleep earlier. 03:00–03:30 – The dawn simulation white light device is activated. 03:30–05:30 – The green light is activated. 05:30–06:00 – The light box is activated. 06:00–06:30 – The light box is set to 10,000 lx until the end of the session. C. Third night – Same protocol as in night two. D. Fourth night – Same protocol as in the two previous nights. 2. Methods 2.1. Study design The study was conducted as a set of 12 single-case designs. Measurements were taken on a daily basis beginning with a baseline measurement (T0) just before the first intervention night. This was followed by a set of four consecutive morning measurements during the therapeutic intervention (T1–T4), with a final measurement carried out at the end of 4 weeks of follow-up (T5). The purpose of these intensive and frequent measurements was mainly to monitor the pace and course of response to the therapeutic procedure.
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2.2. Population Twelve outpatient participants with depression were recruited in collaboration with peripheral psychiatric and family medicine outpatient clinics. Inclusion criteria were the following: 1. Demonstration of at least four of the main criteria symptoms which are listed for a depressive episode diagnosis (F32) in the ICD-10 (World Health Organization, 1992). 2. Provision of a signed informed consent. Exclusion criteria: 1. The use of pharmacological anti-depressant agents for at least 5 weeks prior to the trial. 2. Retinal disease and/or cataract. 3. Current suicidal thoughts or past suicidal history. 4. A history of psychotic, bipolar affective disorders and alcohol or substance abuse. 2.3. Background data The sample included ten females and two men whose ages ranged between 18 and 70 years (mean= 43.3; SD= 10.12). All participants reported experiencing some degree of depressed mood, loss of interest and enjoyment, and reduced energy leading to increased fatigability and diminished activity for at least 2 weeks before study inclusion. They all also demonstrated at least four of the other symptoms in the ICD-10 criteria for a severe depressive disorder (e.g., reduced concentration and attention, reduced self-esteem and self-confidence, disturbed
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sleep and or diminished appetite). No co-morbidity was reported, with the exception of one participant who reported a prolonged grief reaction after having lost a parent several years earlier. 2.4. Measurements Measurements focused on the severity of symptoms (depression, tension and anxiety), and the instruments used were two clinician rating scales and four patient subjective self-rating scales. The decision to use several measures to rate the same construct (depression) was made in order to increase the level of reliability of the findings. The list of scales that were used along the study is hereby detailed: A. The 21-item version of the clinician rating Hamilton depression scale (HAM-D21) (Hamilton, 1960) was used to assess the severity of depression. It reflects the clinician's impression with scores ranging from 0 (no symptoms at all) to 66 (high level of severity for all symptoms). This measure was completed at T0, T4 and T5. B. The Montgomery–Asberg Depression Clinician Rating Scale (MADRS) (Montgomery and Asberg, 1979) surveys the type and magnitude of symptom burden at the time of completion, and is therefore considered to be a measure of illness severity. Scores are within the range of 0 (least severe) to 60 (most severe): the cutoff point of 31 was suggested as best distinguishing between moderate and severe depression (Müller et al., 2003). This measure was completed at all evaluations (T0–T5).
Fig. 1. Illustration of the course study.
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C. The self-rating depression scale (SDS; Zung, 1965) relates to cognitive, affective, psychomotor, somatic and social– interpersonal aspects of depression. Scores are within the range of 20–80 points with the following suggested clinical cutoff points: mild-to-moderate (50–59), moderate-to-severe (60–69) and severe (N70). This measure was completed at all evaluations (T0–T5). D. Three 5-degree visual analogue scales (VAS) were utilized for self-rating and included a depression VAS (rate the degree of depression you experience), tension VAS (rate the degree of tension you experience) and anxiety VAS (rate the degree of anxiety you experience). The use of these instruments provides an additional state measurement of the levels of experienced distress, thus increasing the findings' reliability. These scales were completed at all evaluations (T0–T5). 2.5. Statistical procedures A set of General Linear models (repeated measures) was conducted in order to establish statistical significance. 2.6. Procedure Patients who fulfilled the study inclusion criteria were referred to the investigator by mental health professionals. Initial contact was established by telephone on the part of potential participants. During these calls, the investigator conducted a brief screening interview and apparently suitable candidates were invited for a complete intake interview in which diagnosis was established and inclusion as well as exclusion criteria were verified. A total of 41 participants were referred to the investigator, 20 were invited for the intake interviews and 12 were included in the experiment. After having established participation suitability, the patients received an extensive explanation about the treatment modality and its conditions, consequences, inconvenience and risks, and were requested to sign an informed consent form. Following the intake interview, the patients went through the intervention protocol at the Research and Development Unit of the Beer–Yaakov Mental Hospital. For further clarifications, the study course is illustrated in Fig. 1. 3. Results The various measurements demonstrated a highly significant and consistent clinical improvement in levels of depression of all 12 participants throughout the therapeutic intervention. This improvement was statistically demonstrated using a repeated measures procedure in relation to the HAM-D21 (F(1,12) = 75.00; pb .001), and did not extinct during the 4 weeks of followup (Table 1, and Figs. 1–4 in Appendix A). Statistically significant improvement was also found in relation to the MADRS scores (F(4,48) =100.56; pb .001), the SDS (F(4,48) =33.88; p b .001) and the depression VAS measure (F(4,48) = 35.85; pb .001). Improvement, as reflected by the clinician rating scales, can also be presented in terms of percentages of improvement and by using the following terminology: ‘Remitters’ are those which HAM-D21 scores b8 and MADRS scores b13. ‘Responders’ are those who demonstrated an improvement of N50%. ‘Partial responders’ are those who improved b50% but N25%, while ‘Non
Table 1 Phase response curve to light. T4
T5
Clinician rating Hamilton Depression Scale 1 23 2 35 3 27 4 38 5 23 6 29 7 33 8 22 9 26 10 30 11 23 12 22
11 17 16 4 9 8 7 12 9 7 7 10
7 27 17 5 8 4 4 7 10 2 2 14
Montgomery–Asberg Depression Clinician Rating Scale 1 25 20 14 8 2 39 24 17 15 3 24 21 13 11 4 35 31 11 10 5 21 16 13 9 6 33 19 12 8 7 35 17 9 7 8 22 10 5 5 9 31 22 15 10 10 35 25 11 8 11 24 19 10 6 12 28 22 14 12
8 13 9 4 4 4 6 4 7 4 5 11
6 18 14 3 4 3 4 8 7 3 5 13
Self-Rating Depression Scale 1 54 46 2 56 42 3 47 46 4 49 46 5 53 41 6 58 41 7 56 42 8 50 49 9 59 54 10 57 50 11 45 44 12 50 47
46 41 45 35 40 37 38 47 44 47 35 44
43 38 44 35 40 33 37 45 35 44 36 40
44 41 40 33 41 26 35 40 35 37 32 41
31 55 47 27 40 31 39 38 34 22 24 42
Depression Visual Analogue 1 3 2 4 3 3 4 3 5 3 6 3 7 3 8 3 9 3 10 3 11 3 12 2
2 0 2 1 1 0 1 2 2 1 1 1
1 0 1 1 1 0 1 2 1 1 0 1
2 1 1 0 1 0 0 1 1 0 0 1
1 2 2 0 2 0 0 2 2 0 0 1
Patient
T0
T1
Scale 2 1 1 2 1 1 1 2 3 2 2 1
T2
T3
Depression scores along the six measurements.
responders’ demonstrated an improvement of less than 25%. In accordance with these definitions, HAM-D21 measurements at T4 revealed 4 remitters, 6 responders and 2 partial responders. T5 scores revealed 7 remitters, 2 responders, 2 partial responders and one non-responder. Even better results were demonstrated by the MADRS scores. 11 remitters and one responder were found at T4. 9 remitters, two responders and one partial responder were found at T5.
L. Moscovici, M. Kotler / Journal of Affective Disorders 116 (2009) 201–207 Table 2 Anxiety and tension scores along the 6 measurements. Patient
T0
T1
T2
T3
T4
T5
Anxiety Visual Analogue Scale 1 2 3 4 5 6 7 8 9 10 11 12
2 3 3 3 3 4 3 3 4 3 2 3
2 0 2 2 1 2 1 2 3 1 2 2
2 0 2 1 1 1 1 2 2 1 0 1
2 0 2 0 1 1 1 2 2 1 0 1
2 0 1 0 1 1 1 1 1 0 0 1
1 1 2 0 1 0 0 2 1 0 0 2
Tension Visual Analogue Scale 1 2 3 4 5 6 7 8 9 10 11 12
3 3 4 2 3 4 4 3 3 3 2 3
3 0 2 2 1 2 3 1 3 1 1 2
2 0 2 1 1 1 2 1 2 1 0 1
2 0 2 0 1 1 2 1 1 1 0 1
2 0 2 0 1 0 1 1 0 0 0 1
2 2 3 1 1 0 2 1 1 0 0 2
Changes in tension and anxiety levels are presented in Table 2. Although anxiety reduction was not an original aim of the CMI, an improvement was also demonstrated in the anxiety VAS (F(4,48) = 34.99; P b.001), and it, too, was maintained at follow-up. A certain improvement in levels of tension was reported by the participants (F(4,48) = 43.56; p b .001), but unlike depression and anxiety, the alleviation in tension levels seemed to diminish to some degree at follow-up. Finally, the study participants were asked to provide feedback regarding their experience during the intervention. There were major three issues that they addressed during the followup interviews. First, they all reported a high level of satisfaction with the rapid improvement in their mood and energy. They did not complain about the need to sleep in a hospital-like environment but four of them reported that they felt a gradually increasing sleepiness beginning at the afternoon and reaching its peak very early in the evening during the intervention days. 4. Discussion The findings of the current pilot study demonstrate a clinically significant rapid improvement of the depressive symptoms as reflected by all the self- and clinician-rating measures that were used. These findings were apparent also in cases of severe depression (MADRSN 31; HAM-D N 30). This desired outcome was maintained for at least 4 weeks after the end of the intervention. There were no dropouts or compliance difficulties. Patient satisfaction, as reported by them in the follow-up interviews, was high, and other than having to sleep for four nights at the Research and Development Unit, they were not inconvenienced by the nature of the therapeutic design. The sleepiness in the late afternoon hours that had been reported by
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several of the participants did not reach a level that interfered with their ability to function and could be indicative of the phase advance effect. Levels of tension, as measured by the selfreport VAS, did not show a consistent improvement along the intervention procedure and were not maintained in follow-up. On the other hand, there was some unexpected improvement in the level of anxiety that persisted at follow-up. This latter finding requires further validation by additional studies. Although some descriptions of side-effects of light therapy and sleep deprivation can include symptoms such as hypomania, irritability, headache, and nausea (Terman and Terman, 2005), menstrual disturbances (Pjrek et al., 2004; Danilenko, 2007), sleepiness, and fatigue (Giedke and Schwarzler, 2002), the participants in the current report did not exhibit any of them (besides late afternoon sleepiness). These findings are very encouraging since they demonstrate a combination of high efficacy, rapid response, little or no side effects, and support the advantages of the CMI for treating moderate-to-severe depression. In a recent literature review (Terman and Terman, 2005), the authors mention the poor compliance of patients to some types of chronobiological interventions. They mention several encountered problems, such as the patients ignoring the alarm clock and considering additional sleep to be the priority of the moment and/or delaying or skipping sessions. These difficulties may represent a conflict between naturally occurring chronobiological processes and rigid sleep schedule protocols for WT and SPA: these may be solved by the some of the procedures that were used in our intervention's design (i.e., the addition of a combination of dawn simulation and green light as well as SPA inducement). This might have facilitated patient compliance due to the match between melatonin secretion, circadian rhythms and the CMI protocol. The timing of the initial light stimulus effect (dawn light) on the first night occurred approximately 5.5 h after bedtime, slightly before a critical time-point along the human phase response curve (PRC) to light (putative core temperature minimum). At that time, the light stimulus is postulated to induce a phase delay response in the circadian rhythm, while our original intention was to induce a phase advance response. Despite this timing, phase advance was actually achieved. An possible explanation for this may stem out of the studies that were conducted by Czeisler (1995), in which it has been suggested that exposure to light during the critical phase of the PRC can reset and even temporary stop the human circadian clock. Indeed, it was demonstrated that if light stimulus is centered near the critical time which coincide with the nadir of the temperature cycle, it results in phase amplitude suppression and leads to large phase shifts (Jewett et al., 1994). In the CMI, light stimulus went on while crossing the putative temperature minimum, into the phase advance period. This reduced the amplitude and thus allowed easier resynchronization of rhythms with 3 nights of stable light treatment. This first night manipulation enabled us to ignore the patients' individual sleeping patterns prior to the intervention, while rapidly adjusting them to the phase advance. Finally, it should be noted that although the CMI is a complex intervention, it was exceptionally easy to conduct and required relatively low-cost technological equipment and little effort on the part of the experimenter, thus showing high levels of cost-effectiveness.
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There are two main limitations to this study. First, there was no control group, and second, the study was comprised of a small non-random sample. Therefore, no comparisons with other intervention or placebo modalities can be made and generalization of the findings should await further studies. In addition, we cannot distinguish between the various components of the intervention in order single out the ones that contributed more to the desired therapeutic effect and which can be omitted. 5. Conclusions
Fig. A3. Improvement in the mean score of the depression visual analog scale (VAS) during the intervention and at follow-up.
This was the first trial of a novel procedure to treat mild-tomoderate depression by means of a multistage chronobiologic intervention. The initial findings showed the procedure to be effective and well tolerated. It affords many advantages, such as the achievement of a rapid response, no extinction of the therapeutic effect after 4 weeks of follow-up, safety, high patient compliance and cost-effectiveness. These encouraging results warrant validation in further randomized controlled clinical trials. Role of funding source This study was conducted without external funding. Conflict of interest The authors declare they have no potential conflict of interest.
Fig. A4. Improvement in the mean score of the clinician rating Hamilton depression scale (HAM-D21) score.
Acknowledgements We thank Yaron Yagil PhD, who kindly assisted with the preparation of the manuscript and Gily Agar MA, for helping us to recruit the patients.
Appendix A
Fig. A1. Improvement in the mean score of the Montgomery–Asberg depression clinician rating scale (MADRS) during the intervention and at follow-up.
Fig. A2. Improvement in the mean score of the self-rating depression scale (SDS) during the intervention and at follow-up.
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