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5HT2c antagonist for individuals with obsessive compulsive disorder
Journal Pre-proof A systematic review of case studies testing a melatonergic agonist/ 5HT2c antagonist for individuals with obsessive compulsive disorder Meredith E. Coles, Matthew H. Goodman
PII:
S0887-6185(19)30499-2
DOI:
https://doi.org/10.1016/j.janxdis.2019.102173
Reference:
ANXDIS 102173
To appear in:
Journal of Anxiety Disorders
Received Date:
7 August 2019
Revised Date:
2 December 2019
Accepted Date:
8 December 2019
Please cite this article as: Coles ME, Goodman MH, A systematic review of case studies testing a melatonergic agonist/ 5HT2c antagonist for individuals with obsessive compulsive disorder, Journal of Anxiety Disorders (2019), doi: https://doi.org/10.1016/j.janxdis.2019.102173
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
A systematic review of case studies testing a melatonergic agonist/ 5HT2c antagonist for individuals with obsessive compulsive disorder
Running Head: AGOMELATINE FOR OCD
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Department of Psychology, State University of New York Binghamton, Binghamton, NY
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Meredith E. Coles, PhD & Matthew H. Goodman, BAa*
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*Corresponding author: Meredith E. Coles. PhD; Email: [email protected]; Phone: 607777-5006; Address: Binghamton University Psychology Department, P.O. Box 6000, 4400 Vestal Parkway East, Binghamton, NY 13902
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OCD is related to disruptions in the timing of sleep Agoemelatine is a melatonergic agonist/ 5HT2c antagonist 10 case studies are reviewed Agomelatine reduced OCD symptoms in patients with sleep disruptions .gomelatine did not changes symptoms in patients without sleep disruptions.
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Highlights
ABSTRACT
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BACKGROUND: Treatments for Obsessive-Compulsive Disorder (OCD) have greatly improved over time. However, some patients do not respond to current interventions and many are left with residual symptoms even if they are ‘responders’. There is increasing evidence that individuals with OCD frequently report delayed bedtimes and are at elevated risk for Delayed Sleep Phase Disorder (DSPD). Therefore, it is logical to ask whether interventions addressing disruptions in sleep timing and circadian rhythms would lead to reductions in OCD symptoms. A prior study
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from our group showed that behaviorally shifting sleep timing resulted in significant symptom reduction in a treatment resistant OCD patient. OBJECTIVES: Extending prior findings, this manuscript presents quantitative data from case studies which tested the use of a pharmacological intervention that targets melatonin receptors. Specifically, the case studies reviewed herein utilized the melatonin analog and melatonergic MT1 and MT2 receptor agonist, Agomelatine. METHODS: A literature review revealed 10 cases which have used Agomelatine
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for OCD. RESULTS: Seven of the cases were reported to have sleep and/or circadian
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disruptions prior to treatment. These cases OCD symptom reductions between 46% to 90%. In contrast, three additional cases without pre-treatment sleep and/or circadian disruptions did not
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respond to the intervention. DISCUSSION: There is growing evidence that disruptions in sleep
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and circadian rhythms may contribute to the maintenance of OCD. Further work is warranted.
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Keywords: obsessive compulsive disorder, sleep timing, circadian rhythms, agomelatine,
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treatment-resistant, review
1. Introduction
Treatments for Obsessive-Compulsive Disorder (OCD) have greatly improved over time
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and there continue to be advances in pharmacological and behavioral interventions. Researchers are working to refine medication dosages and timing of administration (e.g., extended-release methods; (Bloch, McGuire, Landeros-Weisenberger, Leckman, & Pittenger, 2010; Koran et al., 2010), as well as test new, and potentially efficacious platforms for administering Cognitive Behavioral Therapy (CBT; e.g., Internet-Based CBT; (Andersson & Hedman, 2015; Andersson et al., 2014; Patel et al., 2018). Although current first line treatments are beneficial, there is still
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room for improvement. Research suggests that up to one third of patients with OCD are considered treatment-resistant, such that they show little to no response to current first line treatments, serotonin reuptake inhibitors (SRI; (Decloedt & Stein, 2010; Pallanti et al., 2002) or CBT/ERP (cognitive behavioral therapy/exposure and ritual prevention; (Fisher & Wells, 2005;). Furthermore, even patients who are ‘responders’ in that they experience symptom reductions, often continue to have significant OCD symptoms at post-treatment (Skoog & Skoog, 1999;
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Storch, Lewin, De Nadai, & Murphy, 2010).
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One potential new target for OCD intervention is disruptions in sleep and circadian
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rhythms, such as r decreased sleep duration and increased rates of delays in sleep timing (Nota, Sharkey, & Coles, 2015). Decreased sleep duration reflects the homeostatic drive, or how tired
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we feel, and is typically what we think of when we use the word ’sleep’. However, sleep is also influenced by our internal circadian rhythms, internal patterns of function across approximately
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24 hours. For example, in healthya adults, a strong release of melatonin when it gets dark in the evening begins to prepare the body for sleep. Support for a link between circadian disruptions
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and OCD is grounded in data showing that between 17% (Mukhopadhyay et al., 2008) to 42% (Turner et al., 2007) of OCD patients in inpatient programs experience Delayed Sleep Phase Disorder (DSPD). DSPD is a circadian rhythm sleep disorder characterized by delayed bedtimes, such that affected individuals go to bed later and wake up later (Weitzman et al., 1981). The rates
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in OCD are much higher than the rates of 1% to 10% in the general population (Nota, Sharkey, & Coles, 2015). Additionally, these individuals are shown to have more severe OCD and greater resistance to treatment (Donse, Sack, Fitzgerald, & Arns, 2017; Mukhopadhyay et al., 2008; Turner et al., 2007) Disruptions in sleep timing, circadian rhythms of the sleep wake cycle, are associated with impaired attention and decreased self-control (Baird, Coogan, Siddiqui, Donev,
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& Thome, 2012; Lange, Lange, Hauser, Tucha, & Tucha, 2012). There is also some evidence for circadian variations in executive functions including inhibition and flexibility (García, Ramírez, Martínez, & Valdez, 2012), two processes implicated in the maintenance of OCD. Given the elevated rates of disruptions in the timing of sleep and initial evidence that sleep disruptions may be associated with poorer treatment response, it is logical to ask whether
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addressing these circadian disruptions would be beneficial in reducing the severity of OCD. Delayed bedtimes and circadian rhythm desynchronization is an issue that has several validated
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treatment options. Bright light therapy (Rosenthal et al., 1984; Terman et al., 1989) and
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Chronotherapy (Czeisler et al., 1981) are two common interventions. One study, which examined the potential benefits of addressing circadian disruptions in the timing of sleep for OCD (Coles
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& Sharkey, 2011), documented the case of a patient with treatment-resistant OCD and DSPD. After 16 weeks of Chronotherapy to advance the patient’s bedtime, the patient exhibited a 43%
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reduction in symptom severity, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The potential utility in using circadian resynchronization to treat OCD has brought
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researchers’ attention to other methods for potentially adjust circadian rhythms, with one of the methods being the drug, Agomelatine (Pizarro et al., 2014). Agomelatine is unique antidepressant medication that has two primary mechanisms of
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action. First, agomelatine is a 5HT2B and 5HT2C antagonist which influences the noradrenergic and dopaminergic systems along with BDNF (Martinotti et al., 2016). Second, agomelatine is a MT1 and MT2 melatonin agonist designed to address disruptions in circadian rhythms that are often seen in depression and other affective disorders (Brown et al., 1985; Claustrat, Chazot, Brun, Jordan, & Sassolas, 1984; Soutre et al., 1989) . The idea of altering circadian rhythms and correcting delayed bedtimes to reduce symptom severity has been common in affective
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disorders, including bipolar disorder (Tseng et al., 2016), schizophrenia (Aichhorn, StelzigSchoeler, Geresegger, Stuppaeck, & Kemmler, 2007) and seasonal affective disorder (Golden et al., 2005), but use for OCD is relatively novel. The current study was designed to investigate the effects of Agomelatine for individuals with OCD and circadian rhythm disruptions. Specifically, we conducted a systematic review of case studies reporting the use of agomelatine for OCD. Additionally, we compared individuals with OCD with and without comorbid circadian
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disruptions to test our hypothesis that it would only be effective for individuals with sleep
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disruption.
2. Methods
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2.1. Study Selection
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To be included, studies needed to meet the following criteria: (a) diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition or fifth edition (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision,
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2000), or the International Classification of Diseases, ninth revision (ICD-9) or tenth revision (ICD-10); (b) used Agomelatine as a treatment method and (c) and provided a detailed description of individual cases. Studies were excluded based on the following criteria: (a) use of
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an animal sample; (b) subclinical samples; (c) no report of a treatment outcome; (d) not published in English.
2.2. Search Strategy We searched the following databases and search engines during August 2018 for published literature: Pubmed, PsychINFO, and Google Scholar. The search terms were
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(obsessive-compulsive disorder OR OCD OR obsessive compulsive OR compulsions OR obsessive) AND (agomelatine OR melitor OR thymanax OR Valdoxan OR circadian OR chronotherapy OR light box OR delayed sleep OR DSPD OR delayed sleep phase disorder OR bedtime). Melitor, Thymanax, and Valdoxan are brand names for Agomelatine. We also did parallel searches for the variations of the disorder name in combination with the term melatonin. This revealed 73 articles, 29 of which were duplicates, 39 were not relevant based on review of
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the title and abstract and 5 were excluded after reviewing the document. No papers were found
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directly testing melatonin alone as a treatment for OCD.
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2.3. Data Extraction
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The following variables were recorded: (a) Weeks of treatment; (b) dosage, if applicable; (c) age(s) of participants; (e) sex; (f) comorbidity; (g) additional, concurrent treatments; (h)
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sample size; (i) treatment type; (j) pre-treatment and post-treatment Y-BOCS scores. In addition, we also classified individuals as responders if their post-treatment Y-BOCS score was < 16.
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3. Results 3.1. Study selection
The initial search yielded 276 studies after the exclusion of duplicates. An additional 230 studies were excluded after review of the title and abstract. The remaining 46 articles went
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through a full-text review, resulting in 5 articles that were selected to be included in the final review paper based on the previously established inclusion and xclusion criteria. All available case studies were done outside of the United States. This may be due to Agomelatine not being FDA approved. See Figure 1 for the study selection process.
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3.2. Patients The majority of information on agomelatine for treating OCD comes from case studies. Only one study included multiple cases, presenting findings from three cases of individuals with OCD and sleep disturbance and three ‘controls’, individuals with OCD that did not have sleep disturbance (Fornaro, 2011). If patients from both groups show similar reductions in symptoms it would suggest that normalizing sleep is unlikely to be the active mechanism. But, if individuals
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with sleep disruption show larger reductions in symptom severity than those without, this would
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suggest that normalizing sleep may be the mechanism of change. We will now present brief descriptions for each of the 7 patients with sleep disruptions and the 3 control patients who
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received agomelatine but did not have sleep disruption. Additionally, Figure 2 presents basic
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demographic information and pre- and post- treatment Y-BOCS scores for each patient. Patients 1 to 7, shown on the left side represents the cases with sleep disturbance, and patients 8 to10,
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shown on the right side represent the comparison participants. Patients with initial sleep disturbance:
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Patient #1 was a 30-year-old male with OCD (Signorelli et al., 2014). His obsessions included thoughts of contamination and cleanliness, and symptoms first appeared at 24 years of age. The patient was considered treatment-resistant based on prior non-response to multiple SSRIs and benzodiazepine. In addition to OCD, patient #1 met criteria for comorbid insomnia.
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After eight weeks of Agomelatine augmentation at 25mg/daily, his Y-BOCS scores decreased by 46.4%.
Patient #2 was a 22-year-old female whose symptoms first appeared at age 17 and
included contamination obsessions and associated compulsive washing and checking (Berardis et al., 2012). The patient endorsed difficulties sleeping and mild depressive symptoms. Past
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treatments with CBT and multiple medications were reported to have been ineffective and to have caused adverse side effects. After eight weeks of Agomelatine monotherapy at 25mg/daily for two weeks, and then 50mg/daily for the remaining six weeks, Y-BOCS scores were reduced by 90%. Patient #3 was a 17-year-old male with OCD who had multiple trials of pharmacotherapy with SSRIs and TCAs but failed to respond (da Rocha & Correa, 2011). His
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symptoms were characterized by washing and cleaning compulsions. The report stated that the
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patient also met criteria for comorbid depression of moderate severity. After 12 weeks of
Agomelatine augmentation at treatment at 25mg/daily, Y-BOCS scores decreased by 69.4%.
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Patient #4 was a 44-year-old male with OCD characterized by obsessions of losing self-
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control in the presence of other people and belching compulsions (Fornaro, 2011). The patient was considered Serotonin Reuptake Inhibitor (SRI)-refractory, and met for comorbid Impulse
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Control Disorder and Substance Abuse Disorder. He did not meet criteria for a depressive disorder but was rated as having moderate depressive symptoms based on a clinician-
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administered interview. Regarding sleep, patient #4 reported severe insomnia. After 12 weeks of Agomelatine treatment at 50mg/daily, his Y-BOCS score was reduced by 57.1%. Patient #5 was a 25-year-old male whose first OCD symptoms appeared at age 15 (Fornaro, 2011). His symptoms were reported to be severe and consisted of checking and
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repeating behaviors. He was reported to not meet criteria for any comorbid psychiatric conditions (including depression) but was reported to have ongoing disruptions in both sleep and circadian rhythms. Based on a clinician-administered interview, he was rated as having very severe depressive symptoms. Patient #5 was considered SRI-refractory and given Agomelatine. After 12 weeks of Agomelatine treatment at 50mg/daily, his Y-BOCS score dropped by 65.6%.
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Patient #6 was a 33-year-old female who reported initial symptoms around age 24 (Fornaro, 2011). She reported obsessions of losing control around food and met criteria for a diagnosis of OCD. In addition, she reported symptoms consistent with a diagnosis of panic disorder and high levels of sleep disturbance. On a clinician-administered measure, her depressive symptoms were rated as severe but she did not meet criteria for a depression diagnosis. The patient was considered SRI-refractory. After 12 weeks of Agomelatine treatment
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at 50mg/daily, her Y-BOCS scores went down by 63.6%.
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Patient #7 was a 25-year-old female with OCD characterized by fear of contamination and compulsive washing (Berardis et al., 2012). She is reported to have failed to respond to
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previous SSRI and antipsychotic treatments and was considered treatment-resistant. The patient
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reported mild depressive symptoms but did not meet criteria for a depression diagnosis. The patient reported difficulties sleeping related to performance of compulsions at specific times
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reduced by 84.8%.
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during the night. After =12 weeks of Agomelatine augmentation at 25mg/daily, Y-BOCS scores
Patients without initial sleep disturbance Comparison cases included three patients (mean age = 51.3 years; SD = 15.6; 66.7% female) that did not report sleep disruptions of any kind (Fornaro, 2011). Each was considered
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SRI-refractory. All three patients did not respond to Agomelatine treatment, with the largest reduction in Y-BOCS being less than 3 points. Finally, scores at pre and post-treatment were compared between individuals that did
versus did not have sleep disturbance. A 2 Group (sleep disturbance yes vs no) x 2 Timepoint (pre vs post treatment) repeated measures ANOVA revealed significant main effects of both
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group (F (1,8)= 8.49, p=.02) and timepoint (F(1,8)=23.17, p=.001 ). In addition, there was also evidence for a significant interaction between group and timepoint (F (1,8)= 23.17, p=.001). Follow-up within timepoint t-tests showed that the groups were not found to differ significantly before treatment (t (8)= -.21, p=.84) but that the sleep disruption group had significantly lower Y-BOCS scores post-treatment compared to the non-sleep disruption group (t(8)=5.54, p=.001). 4. Discussion
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Our review of the literature revealed seven cases using agomelatine with patients
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experiencing OCD and disruptions in their sleep and/or circadian rhythms and 3 cases of
individuals with OCD without disturbances in sleep/circadian rhythms. Consistent with the
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melatonergic effects of agomelatine, patients with initial sleep disruption showed symptom
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reductions, whereas the 3 patients without sleep/circadian rhythm disruptions did not show changes in symptom severity. Results showed that despite not exhibiting clinical response to
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prior treatments, 8 to 12 weeks of agomelatine lead to reductions in OCD symptom severity for the patients with sleep and/or circadian rhythm disruptions. Furthermore, these patients
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experienced reductions of approximately 50% or more, thereby exceeding typical thresholds for classification as responders (typically 35%, (Mataix-Cols, Lawrence, Wooderson, Speckens, & Phillips, 2009)), and based on clinician-rated severity, all 7 had post-treatment YBOCS scores less than 16 (Mild).
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As noted earlier, in addition to targeting circadian rhythms, agomelatine also acts on 5HT
receptors. The mechanism of action for the cases reported herein is not known. However, findings that OCD symptoms were reduced in individuals with sleep disruption but not in individuals without sleep and/or circadian rhythm disruptions is consistent with its influence on MT1 and MT2 receptors. This suggests that changes in circadian rhythms may be the
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mechanism of action. Further, given that only 1 of the 7 individuals with sleep/circadian disruption had a comorbid depressive disorder it seems unlikely that the effect of agomelatine on these cases were solely due to reductions in depression. The current manuscript was motivated by the growing body of evidence for a link between OCD and difficulty falling asleep until very late. This literature includes a prior case study from our group which showed reductions in OCD symptoms following a behavioral sleep
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intervention to address delayed sleep phase. Specifically, the client demonstrated substantial
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symptom reductions from a behavioral intervention leading to increased synchrony between the patients sleep-wake cycle with the external light-dark period (Coles, Schubert, & Sharkey, 2012).
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Although unclear how circadian rhythms specifically may contribute to the maintenance of
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OCD, several conditions that are frequently comorbid with OCD (e.g., depression, bipolar disorder) are also frequently characterized by disruption in sleep timing (Franzen, Siegle, &
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Buysse, 2008; Harvey, 2008). Furthermore, beyond diagnostic categories, chronobiological research has shown that desynchronized rhythms are associated with several underlying features
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of psychopathology, including impaired attention (Baird, Coogan, Siddiqui, Donev, & Thome, 2012) and decreased self-control (Lange et al., 2012).
Agomelatine has similar properties to several other interventions being piloted for
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treating OCD, such as light boxes and ketamine. Light boxes are well established as a noninvasive treatment for correcting abnormal light/dark cycles with few side effects (Ancoli-Israel, Martin, Kripke, Marler, & Klauber, 2002; Eastman, Suh, Tomaka, & Crowley, 2015) and they have been effective in reducing symptom severity in other psychiatric disorders like Seasonal Affective Disorder (Glickman, Byrne, Pineda, Hauck, & Brainard, 2006). Additionally, the NMDA antagonist Ketamine has also been shown to reestablish circadian rhythm synchrony
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(Duncan et al., 2017; Mihara et al., 2012), and researchers have begun implementing it in the treatment of Major Depressive Disorder (Ladarola, Niciu, & Richards, 2015), suggesting that ketamine can treat depression by shifting circadian rhythms (Morgan, 2017). Few studies have implemented light boxes (Brinkhuijsen, Koenegracht, & Meesters, 2003; Hoflich, Kasper, & Moller, 1992) and Ketamine (Adams, Bloch, & Pittenger, 2017; Rodriguez et al., 2013) to treat OCD; however, those that have each reported significant reductions in symptom severity.
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Finally, in addition to these approaches, use of amber (blue-light blocking) glasses or generic
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melatonin may also be worth testing (we could not locate any existing trials). Testing any of
these interventions will likely help us understand the potential role of circadian disruptions in
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OCD.
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Despite the strengths, the current review has several limitations, with the primary one
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being that the data came from case studies instead of a randomized clinical trial (RCT). Unlike in RCTs, these cases were not randomized, lacked a sufficient number of controls, and could have been susceptible to placebo effects. In addition, given the bias towards publication of
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significant effects, it is impossible to know if there are other studies which did not show symptom reductions from agomelatine and therefore remain unpublished. To the extent this is the case (publication bias), the conclusions drawn from our review would overestimate the utility
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of this approach. In addition to methodological limitations, many of the papers reported that the patients were “treatment resistant” or “refractory” but did not provide details. Variability in how ‘treatment resistance’ was defined limiting the ability to generalize across studies. Another limitation is that the majority of the studies did not administer sleep interviews to assess for sleep disruption or the presence of DSPD. Instead, they relied heavily on self-report. Future studies should consider the use of actigraphy or polysomnography to acquire an objective measure of the
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patients’ sleep cycles, as well as dim light melatonin onset (DLMO) and/or core body temperature to acquire an objective measure of the circadian clock. Finally, future studies can more thoroughly assess how depression might play a role in the sleep disturbance. In the current study comorbid depression diagnoses were rare, suggesting that agomelatine’s effect was not wholly driven by addressing depression. Further, levels of depressive symptoms were generally lower in the group that showed a response to agomelatine (i.e., patients with sleep/circadian
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rhythm disruption) compared to the group that did not respond (i.e., patients without
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sleep/circadian rhythm disruption). For example, Fornaro found that agomelatine was associated with reductions in OCD symptoms in all patients with sleep/circadian rhythm while disruption
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despite the fact that only one met criteria for depression. Further, the three cases that did not
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respond to agomelatine had high levels of depressive symptoms (Fornaro et al, 2011). In conclusion, observations from this review emphasize the potential benefits of future
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investigation into the role of sleep and circadian rhythms in OCD. It is possible that these disruptions may demarcate a new subtype of OCD, and that addressing these disruptions could
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help us improve outcomes. Additionally, furthering our knowledge of how to use circadian rhythm resynchronization techniques, whether independently or to augment other interventions, could optimize these treatments for the sizable subgroup of OCD patients with circadian rhythm
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disruptions. However, more controlled trials are clearly needed.
Conflict of interest: none Declarations of interest: none
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Patel, S. R., Wheaton, M. G., Andersson, E., Rück, C., Schmidt, A. B., La Lima, C. N., … Simpson, H. B. (2018). Acceptability, Feasibility, and Effectiveness of Internet-Based Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder in New York. Behavior Therapy, 49(4), 631–641.
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Rutherford, G., Lithgow, B., Mansouri, B., Sulieman, A., Pouya, O. R., Dastgheib, Z., … Moussavi, Z. (2017). Repetitive Transcranial Magnetic Stimulation (RTMS) as a Treatment for Post-concussion Syndrome. The Canadian Medical and Biological Engineering Society, 40(1). Signorelli, M. S., Concerto, C., Battaglia, E., Costanzo, M. C., Battaglia, F., & Aguglia, E. (2014). Venlafaxine augmentation with agomelatine in a patient with obsessive-compulsive disorder and suicidal behaviors. SAGE Open Medical Case Reports, 2. Simpson, H. B., Zuckoff, A. M., Maher, M. J., Page, J. R., Franklin, M. E., Foa, E. B., … Wang, Y. (2010). Challenges using motivational interviewing as an adjunct to exposure therapy for obsessive-compulsive disorder. Behaviour Research and Therapy, 48(10), 941–948. Skoog, G., Skoog, I. (1999). A 40-Year Follow-up of Patients With Obsessive-compulsive Disorder. Archives of General Psychiatry, 56(2), 121–127.
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Soutre, E., Edouard, S., Belugou, J. -L., Pringuey, D., Candito, M., Krebs, B., … Darcourt, G. (1989). Circadian rhythms in depression and recovery: Evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Research, 28(3), 263–278. Storch, E. A., Lewin, A. B., De Nadai, A. S., & Murphy, T. K. (2010). Defining Treatment Response and Remission in Obsessive-Compulsive Disorder: A Signal Detection Analysis of the Children’s Yale-Brown Obsessive Compulsive Scale. Journal of the American Academy of Child and Adolescent Psychiatry, 49(7), 708–717.
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Terman, M., Terman, J., Quitkin, F., McGrath, P., Stewart, J., Rafferty, B. (1989). Light therapy for SAD: A Review of Efficacy. Neuropsychopharmacology, 2(1), 1-22.
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Turner, J., Drummond, L. M., Mukhopadhyay, S., Ghodse, H., White, S., Pillay, A., & Fineberg, N. A. (2007). A prospective study of delayed sleep phase syndrome in patients with severe resistant obsessive-compulsive disorder. World Psychiatry, 6, 108–111.
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Weitzman, E., Czeisler, C., Coleman, R., Spielman, A., Zimmerman, J., Dement, W., Pollak, C. (1981). Delayed sleep phase syndrome: a chronobiological disorder with sleep-onset insomnia. Archives of General Psychiatry, 38(7), 737-746.
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Zupancic, M., & Guilleminault, C. (2006). Agomelatine: A preliminary review of a new antidepressant. CNS Drugs, 20(12), 981–992.
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Figure captions
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Fig. 1. Search Strategy for the Study Selection
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Fig. 2. Plot of the pre and post Y-BOCS scores of OCD patients with and without sleep/circadian
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rhythm disruptions
Patients with sleep disturbance Sam ple Size
Current medications
Past Medications
Age
Sex
Pre YBO CS
Post YBOCS
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Study
Table 1.
Comorbidity
Sleep/Circadi an Rhythm Disruption
CBT
da Rocha, F.F., & Correa, H. (2011)
n=1
Agomelatine (25mg/daily for 12 weeks), Clomipramine (225 mg/day for 5 months), Risperidone (2mg/day for 6 months), Aripiprazole (100mg/day for 35 days)
1 of 3
Agomelatine (50mg/day for 12 weeks)
Fornaro, M. (2011)
2 of 3
Agomelatine (50mg/day for 12 weeks)
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30
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Agomelatine (50 mg/ day for 8 weeks)
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Fornaro, M. (2011)
n=1
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De Berardis, D. (2012)
Fluvoxamine (up to 200mg/day for 6 months) Fluoxetine (60mg/day* ) Lorazepam (2.5mg/day at bed for 4 weeks) Fluvoxamine (300 mg/day for 10 months), Venlafaxine (225mg/day for 8 months), Lorazepam (2.5 mg/day for 8 months), clomipramine (225 mg/day for 6 months)
28
15
NA
3
Mild Depressive Symptoms but never met criteria for a mood disorder
22
F
30
Difficulty sleeping.
11
“Moderate Depression”
Broadly discuss role of circadian rhythm disruption.
9
Impulse Control disorder. Substance abuse disorder. No depression.
Insomnia
No depression
“Almost constant ‘chronotype’ and ‘sleep’ disruption.
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n=1
Agomelatine (25mg/day for 5 weeks), Venlafaxine (75mg/day for 6 months)
Sertraline (200 mg/day for 7 months)
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Signorelli, M.S., et al. (2014)
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Clomipramine (300mg/day), pimozide (4 mg/day), sertraline (200mg/day)*
Fluvoxamine (250mg/day for 8 months)
17
44
25
M
M
M
36
21
32
11
Insomnia.
Not discussed
Reported one past trial. No benefit.
None reported.
No.
None reported
n=1
Agomelatine (25mg/day for 12 weeks), Escitalopram (30mg/day then tapered off escitalopram)
Duloxetine (120 mg/day for 6 months, Clonazepam (4mg/day for 6 months). Fluvoxamine (300mg/day for 1 year), sertraline (200mg/day for 10 months), alprazolam (1.5mg/day for 6 months), quetiapine (450 mg/day), clomipramine (150mg/day for 3 months)
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1 of 3
Fornaro, M. (2011)
2 of 3
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Fornaro, M. (2011)
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Patients without sleep disturbance
Fornaro, M. (2011)
3 of 3
Agomelatine (50mg/day for 12 weks)
F
Fluoxetine (60mg/day for 6 months)
35
Fluoxetine (60mg/day)*
66
Amitriptyline (300mg/day)*
22
8
Panic Disorder
Mild Depressive Symptoms but never met criteria for a mood disorder
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Agomelatine (50mg/day for 12 weeks)
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De Berardis, D., et al. (2012)
3 of 3
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Fornaro, M. (2011)
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F
33
5
Mean (SD)
28.86 (5.61 )
8.88 (4.02)
CBT (6 months)
Sleep difficulties due to need to perform washing during night at scheduled times.
M
35
36
MDD & Social Anxiety Disorder
F
22
22
None.
No.
F
27
26
Bulimia & Panic Disorder
No.
Mean (SD)
28.00 (6.56 )
28.00 (7.21)
No.
CBT (6 months)
Not reported
Not reported. Yes. “Treated with CBT” “Repetitiv e failures.”
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Notes. * indicates that the duration was not reported or was unclear.
PII:
S0887-6185(19)30499-2
DOI:
https://doi.org/10.1016/j.janxdis.2019.102173
Reference:
ANXDIS 102173
To appear in:
Journal of Anxiety Disorders
Received Date:
7 August 2019
Revised Date:
2 December 2019
Accepted Date:
8 December 2019
Please cite this article as: Coles ME, Goodman MH, A systematic review of case studies testing a melatonergic agonist/ 5HT2c antagonist for individuals with obsessive compulsive disorder, Journal of Anxiety Disorders (2019), doi: https://doi.org/10.1016/j.janxdis.2019.102173
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
A systematic review of case studies testing a melatonergic agonist/ 5HT2c antagonist for individuals with obsessive compulsive disorder
Running Head: AGOMELATINE FOR OCD
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Department of Psychology, State University of New York Binghamton, Binghamton, NY
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Meredith E. Coles, PhD & Matthew H. Goodman, BAa*
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*Corresponding author: Meredith E. Coles. PhD; Email: [email protected]; Phone: 607777-5006; Address: Binghamton University Psychology Department, P.O. Box 6000, 4400 Vestal Parkway East, Binghamton, NY 13902
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OCD is related to disruptions in the timing of sleep Agoemelatine is a melatonergic agonist/ 5HT2c antagonist 10 case studies are reviewed Agomelatine reduced OCD symptoms in patients with sleep disruptions .gomelatine did not changes symptoms in patients without sleep disruptions.
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Highlights
ABSTRACT
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BACKGROUND: Treatments for Obsessive-Compulsive Disorder (OCD) have greatly improved over time. However, some patients do not respond to current interventions and many are left with residual symptoms even if they are ‘responders’. There is increasing evidence that individuals with OCD frequently report delayed bedtimes and are at elevated risk for Delayed Sleep Phase Disorder (DSPD). Therefore, it is logical to ask whether interventions addressing disruptions in sleep timing and circadian rhythms would lead to reductions in OCD symptoms. A prior study
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from our group showed that behaviorally shifting sleep timing resulted in significant symptom reduction in a treatment resistant OCD patient. OBJECTIVES: Extending prior findings, this manuscript presents quantitative data from case studies which tested the use of a pharmacological intervention that targets melatonin receptors. Specifically, the case studies reviewed herein utilized the melatonin analog and melatonergic MT1 and MT2 receptor agonist, Agomelatine. METHODS: A literature review revealed 10 cases which have used Agomelatine
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for OCD. RESULTS: Seven of the cases were reported to have sleep and/or circadian
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disruptions prior to treatment. These cases OCD symptom reductions between 46% to 90%. In contrast, three additional cases without pre-treatment sleep and/or circadian disruptions did not
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respond to the intervention. DISCUSSION: There is growing evidence that disruptions in sleep
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and circadian rhythms may contribute to the maintenance of OCD. Further work is warranted.
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Keywords: obsessive compulsive disorder, sleep timing, circadian rhythms, agomelatine,
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treatment-resistant, review
1. Introduction
Treatments for Obsessive-Compulsive Disorder (OCD) have greatly improved over time
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and there continue to be advances in pharmacological and behavioral interventions. Researchers are working to refine medication dosages and timing of administration (e.g., extended-release methods; (Bloch, McGuire, Landeros-Weisenberger, Leckman, & Pittenger, 2010; Koran et al., 2010), as well as test new, and potentially efficacious platforms for administering Cognitive Behavioral Therapy (CBT; e.g., Internet-Based CBT; (Andersson & Hedman, 2015; Andersson et al., 2014; Patel et al., 2018). Although current first line treatments are beneficial, there is still
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room for improvement. Research suggests that up to one third of patients with OCD are considered treatment-resistant, such that they show little to no response to current first line treatments, serotonin reuptake inhibitors (SRI; (Decloedt & Stein, 2010; Pallanti et al., 2002) or CBT/ERP (cognitive behavioral therapy/exposure and ritual prevention; (Fisher & Wells, 2005;). Furthermore, even patients who are ‘responders’ in that they experience symptom reductions, often continue to have significant OCD symptoms at post-treatment (Skoog & Skoog, 1999;
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Storch, Lewin, De Nadai, & Murphy, 2010).
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One potential new target for OCD intervention is disruptions in sleep and circadian
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rhythms, such as r decreased sleep duration and increased rates of delays in sleep timing (Nota, Sharkey, & Coles, 2015). Decreased sleep duration reflects the homeostatic drive, or how tired
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we feel, and is typically what we think of when we use the word ’sleep’. However, sleep is also influenced by our internal circadian rhythms, internal patterns of function across approximately
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24 hours. For example, in healthya adults, a strong release of melatonin when it gets dark in the evening begins to prepare the body for sleep. Support for a link between circadian disruptions
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and OCD is grounded in data showing that between 17% (Mukhopadhyay et al., 2008) to 42% (Turner et al., 2007) of OCD patients in inpatient programs experience Delayed Sleep Phase Disorder (DSPD). DSPD is a circadian rhythm sleep disorder characterized by delayed bedtimes, such that affected individuals go to bed later and wake up later (Weitzman et al., 1981). The rates
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in OCD are much higher than the rates of 1% to 10% in the general population (Nota, Sharkey, & Coles, 2015). Additionally, these individuals are shown to have more severe OCD and greater resistance to treatment (Donse, Sack, Fitzgerald, & Arns, 2017; Mukhopadhyay et al., 2008; Turner et al., 2007) Disruptions in sleep timing, circadian rhythms of the sleep wake cycle, are associated with impaired attention and decreased self-control (Baird, Coogan, Siddiqui, Donev,
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& Thome, 2012; Lange, Lange, Hauser, Tucha, & Tucha, 2012). There is also some evidence for circadian variations in executive functions including inhibition and flexibility (García, Ramírez, Martínez, & Valdez, 2012), two processes implicated in the maintenance of OCD. Given the elevated rates of disruptions in the timing of sleep and initial evidence that sleep disruptions may be associated with poorer treatment response, it is logical to ask whether
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addressing these circadian disruptions would be beneficial in reducing the severity of OCD. Delayed bedtimes and circadian rhythm desynchronization is an issue that has several validated
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treatment options. Bright light therapy (Rosenthal et al., 1984; Terman et al., 1989) and
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Chronotherapy (Czeisler et al., 1981) are two common interventions. One study, which examined the potential benefits of addressing circadian disruptions in the timing of sleep for OCD (Coles
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& Sharkey, 2011), documented the case of a patient with treatment-resistant OCD and DSPD. After 16 weeks of Chronotherapy to advance the patient’s bedtime, the patient exhibited a 43%
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reduction in symptom severity, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The potential utility in using circadian resynchronization to treat OCD has brought
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researchers’ attention to other methods for potentially adjust circadian rhythms, with one of the methods being the drug, Agomelatine (Pizarro et al., 2014). Agomelatine is unique antidepressant medication that has two primary mechanisms of
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action. First, agomelatine is a 5HT2B and 5HT2C antagonist which influences the noradrenergic and dopaminergic systems along with BDNF (Martinotti et al., 2016). Second, agomelatine is a MT1 and MT2 melatonin agonist designed to address disruptions in circadian rhythms that are often seen in depression and other affective disorders (Brown et al., 1985; Claustrat, Chazot, Brun, Jordan, & Sassolas, 1984; Soutre et al., 1989) . The idea of altering circadian rhythms and correcting delayed bedtimes to reduce symptom severity has been common in affective
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disorders, including bipolar disorder (Tseng et al., 2016), schizophrenia (Aichhorn, StelzigSchoeler, Geresegger, Stuppaeck, & Kemmler, 2007) and seasonal affective disorder (Golden et al., 2005), but use for OCD is relatively novel. The current study was designed to investigate the effects of Agomelatine for individuals with OCD and circadian rhythm disruptions. Specifically, we conducted a systematic review of case studies reporting the use of agomelatine for OCD. Additionally, we compared individuals with OCD with and without comorbid circadian
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disruptions to test our hypothesis that it would only be effective for individuals with sleep
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disruption.
2. Methods
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2.1. Study Selection
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To be included, studies needed to meet the following criteria: (a) diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition or fifth edition (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision,
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2000), or the International Classification of Diseases, ninth revision (ICD-9) or tenth revision (ICD-10); (b) used Agomelatine as a treatment method and (c) and provided a detailed description of individual cases. Studies were excluded based on the following criteria: (a) use of
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an animal sample; (b) subclinical samples; (c) no report of a treatment outcome; (d) not published in English.
2.2. Search Strategy We searched the following databases and search engines during August 2018 for published literature: Pubmed, PsychINFO, and Google Scholar. The search terms were
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(obsessive-compulsive disorder OR OCD OR obsessive compulsive OR compulsions OR obsessive) AND (agomelatine OR melitor OR thymanax OR Valdoxan OR circadian OR chronotherapy OR light box OR delayed sleep OR DSPD OR delayed sleep phase disorder OR bedtime). Melitor, Thymanax, and Valdoxan are brand names for Agomelatine. We also did parallel searches for the variations of the disorder name in combination with the term melatonin. This revealed 73 articles, 29 of which were duplicates, 39 were not relevant based on review of
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the title and abstract and 5 were excluded after reviewing the document. No papers were found
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directly testing melatonin alone as a treatment for OCD.
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2.3. Data Extraction
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The following variables were recorded: (a) Weeks of treatment; (b) dosage, if applicable; (c) age(s) of participants; (e) sex; (f) comorbidity; (g) additional, concurrent treatments; (h)
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sample size; (i) treatment type; (j) pre-treatment and post-treatment Y-BOCS scores. In addition, we also classified individuals as responders if their post-treatment Y-BOCS score was < 16.
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3. Results 3.1. Study selection
The initial search yielded 276 studies after the exclusion of duplicates. An additional 230 studies were excluded after review of the title and abstract. The remaining 46 articles went
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through a full-text review, resulting in 5 articles that were selected to be included in the final review paper based on the previously established inclusion and xclusion criteria. All available case studies were done outside of the United States. This may be due to Agomelatine not being FDA approved. See Figure 1 for the study selection process.
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3.2. Patients The majority of information on agomelatine for treating OCD comes from case studies. Only one study included multiple cases, presenting findings from three cases of individuals with OCD and sleep disturbance and three ‘controls’, individuals with OCD that did not have sleep disturbance (Fornaro, 2011). If patients from both groups show similar reductions in symptoms it would suggest that normalizing sleep is unlikely to be the active mechanism. But, if individuals
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with sleep disruption show larger reductions in symptom severity than those without, this would
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suggest that normalizing sleep may be the mechanism of change. We will now present brief descriptions for each of the 7 patients with sleep disruptions and the 3 control patients who
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received agomelatine but did not have sleep disruption. Additionally, Figure 2 presents basic
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demographic information and pre- and post- treatment Y-BOCS scores for each patient. Patients 1 to 7, shown on the left side represents the cases with sleep disturbance, and patients 8 to10,
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shown on the right side represent the comparison participants. Patients with initial sleep disturbance:
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Patient #1 was a 30-year-old male with OCD (Signorelli et al., 2014). His obsessions included thoughts of contamination and cleanliness, and symptoms first appeared at 24 years of age. The patient was considered treatment-resistant based on prior non-response to multiple SSRIs and benzodiazepine. In addition to OCD, patient #1 met criteria for comorbid insomnia.
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After eight weeks of Agomelatine augmentation at 25mg/daily, his Y-BOCS scores decreased by 46.4%.
Patient #2 was a 22-year-old female whose symptoms first appeared at age 17 and
included contamination obsessions and associated compulsive washing and checking (Berardis et al., 2012). The patient endorsed difficulties sleeping and mild depressive symptoms. Past
AGOMELATINE FOR OCD
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treatments with CBT and multiple medications were reported to have been ineffective and to have caused adverse side effects. After eight weeks of Agomelatine monotherapy at 25mg/daily for two weeks, and then 50mg/daily for the remaining six weeks, Y-BOCS scores were reduced by 90%. Patient #3 was a 17-year-old male with OCD who had multiple trials of pharmacotherapy with SSRIs and TCAs but failed to respond (da Rocha & Correa, 2011). His
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symptoms were characterized by washing and cleaning compulsions. The report stated that the
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patient also met criteria for comorbid depression of moderate severity. After 12 weeks of
Agomelatine augmentation at treatment at 25mg/daily, Y-BOCS scores decreased by 69.4%.
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Patient #4 was a 44-year-old male with OCD characterized by obsessions of losing self-
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control in the presence of other people and belching compulsions (Fornaro, 2011). The patient was considered Serotonin Reuptake Inhibitor (SRI)-refractory, and met for comorbid Impulse
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Control Disorder and Substance Abuse Disorder. He did not meet criteria for a depressive disorder but was rated as having moderate depressive symptoms based on a clinician-
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administered interview. Regarding sleep, patient #4 reported severe insomnia. After 12 weeks of Agomelatine treatment at 50mg/daily, his Y-BOCS score was reduced by 57.1%. Patient #5 was a 25-year-old male whose first OCD symptoms appeared at age 15 (Fornaro, 2011). His symptoms were reported to be severe and consisted of checking and
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repeating behaviors. He was reported to not meet criteria for any comorbid psychiatric conditions (including depression) but was reported to have ongoing disruptions in both sleep and circadian rhythms. Based on a clinician-administered interview, he was rated as having very severe depressive symptoms. Patient #5 was considered SRI-refractory and given Agomelatine. After 12 weeks of Agomelatine treatment at 50mg/daily, his Y-BOCS score dropped by 65.6%.
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Patient #6 was a 33-year-old female who reported initial symptoms around age 24 (Fornaro, 2011). She reported obsessions of losing control around food and met criteria for a diagnosis of OCD. In addition, she reported symptoms consistent with a diagnosis of panic disorder and high levels of sleep disturbance. On a clinician-administered measure, her depressive symptoms were rated as severe but she did not meet criteria for a depression diagnosis. The patient was considered SRI-refractory. After 12 weeks of Agomelatine treatment
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at 50mg/daily, her Y-BOCS scores went down by 63.6%.
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Patient #7 was a 25-year-old female with OCD characterized by fear of contamination and compulsive washing (Berardis et al., 2012). She is reported to have failed to respond to
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previous SSRI and antipsychotic treatments and was considered treatment-resistant. The patient
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reported mild depressive symptoms but did not meet criteria for a depression diagnosis. The patient reported difficulties sleeping related to performance of compulsions at specific times
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reduced by 84.8%.
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during the night. After =12 weeks of Agomelatine augmentation at 25mg/daily, Y-BOCS scores
Patients without initial sleep disturbance Comparison cases included three patients (mean age = 51.3 years; SD = 15.6; 66.7% female) that did not report sleep disruptions of any kind (Fornaro, 2011). Each was considered
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SRI-refractory. All three patients did not respond to Agomelatine treatment, with the largest reduction in Y-BOCS being less than 3 points. Finally, scores at pre and post-treatment were compared between individuals that did
versus did not have sleep disturbance. A 2 Group (sleep disturbance yes vs no) x 2 Timepoint (pre vs post treatment) repeated measures ANOVA revealed significant main effects of both
AGOMELATINE FOR OCD
10
group (F (1,8)= 8.49, p=.02) and timepoint (F(1,8)=23.17, p=.001 ). In addition, there was also evidence for a significant interaction between group and timepoint (F (1,8)= 23.17, p=.001). Follow-up within timepoint t-tests showed that the groups were not found to differ significantly before treatment (t (8)= -.21, p=.84) but that the sleep disruption group had significantly lower Y-BOCS scores post-treatment compared to the non-sleep disruption group (t(8)=5.54, p=.001). 4. Discussion
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Our review of the literature revealed seven cases using agomelatine with patients
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experiencing OCD and disruptions in their sleep and/or circadian rhythms and 3 cases of
individuals with OCD without disturbances in sleep/circadian rhythms. Consistent with the
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melatonergic effects of agomelatine, patients with initial sleep disruption showed symptom
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reductions, whereas the 3 patients without sleep/circadian rhythm disruptions did not show changes in symptom severity. Results showed that despite not exhibiting clinical response to
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prior treatments, 8 to 12 weeks of agomelatine lead to reductions in OCD symptom severity for the patients with sleep and/or circadian rhythm disruptions. Furthermore, these patients
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experienced reductions of approximately 50% or more, thereby exceeding typical thresholds for classification as responders (typically 35%, (Mataix-Cols, Lawrence, Wooderson, Speckens, & Phillips, 2009)), and based on clinician-rated severity, all 7 had post-treatment YBOCS scores less than 16 (Mild).
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As noted earlier, in addition to targeting circadian rhythms, agomelatine also acts on 5HT
receptors. The mechanism of action for the cases reported herein is not known. However, findings that OCD symptoms were reduced in individuals with sleep disruption but not in individuals without sleep and/or circadian rhythm disruptions is consistent with its influence on MT1 and MT2 receptors. This suggests that changes in circadian rhythms may be the
AGOMELATINE FOR OCD
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mechanism of action. Further, given that only 1 of the 7 individuals with sleep/circadian disruption had a comorbid depressive disorder it seems unlikely that the effect of agomelatine on these cases were solely due to reductions in depression. The current manuscript was motivated by the growing body of evidence for a link between OCD and difficulty falling asleep until very late. This literature includes a prior case study from our group which showed reductions in OCD symptoms following a behavioral sleep
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intervention to address delayed sleep phase. Specifically, the client demonstrated substantial
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symptom reductions from a behavioral intervention leading to increased synchrony between the patients sleep-wake cycle with the external light-dark period (Coles, Schubert, & Sharkey, 2012).
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Although unclear how circadian rhythms specifically may contribute to the maintenance of
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OCD, several conditions that are frequently comorbid with OCD (e.g., depression, bipolar disorder) are also frequently characterized by disruption in sleep timing (Franzen, Siegle, &
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Buysse, 2008; Harvey, 2008). Furthermore, beyond diagnostic categories, chronobiological research has shown that desynchronized rhythms are associated with several underlying features
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of psychopathology, including impaired attention (Baird, Coogan, Siddiqui, Donev, & Thome, 2012) and decreased self-control (Lange et al., 2012).
Agomelatine has similar properties to several other interventions being piloted for
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treating OCD, such as light boxes and ketamine. Light boxes are well established as a noninvasive treatment for correcting abnormal light/dark cycles with few side effects (Ancoli-Israel, Martin, Kripke, Marler, & Klauber, 2002; Eastman, Suh, Tomaka, & Crowley, 2015) and they have been effective in reducing symptom severity in other psychiatric disorders like Seasonal Affective Disorder (Glickman, Byrne, Pineda, Hauck, & Brainard, 2006). Additionally, the NMDA antagonist Ketamine has also been shown to reestablish circadian rhythm synchrony
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(Duncan et al., 2017; Mihara et al., 2012), and researchers have begun implementing it in the treatment of Major Depressive Disorder (Ladarola, Niciu, & Richards, 2015), suggesting that ketamine can treat depression by shifting circadian rhythms (Morgan, 2017). Few studies have implemented light boxes (Brinkhuijsen, Koenegracht, & Meesters, 2003; Hoflich, Kasper, & Moller, 1992) and Ketamine (Adams, Bloch, & Pittenger, 2017; Rodriguez et al., 2013) to treat OCD; however, those that have each reported significant reductions in symptom severity.
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Finally, in addition to these approaches, use of amber (blue-light blocking) glasses or generic
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melatonin may also be worth testing (we could not locate any existing trials). Testing any of
these interventions will likely help us understand the potential role of circadian disruptions in
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OCD.
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Despite the strengths, the current review has several limitations, with the primary one
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being that the data came from case studies instead of a randomized clinical trial (RCT). Unlike in RCTs, these cases were not randomized, lacked a sufficient number of controls, and could have been susceptible to placebo effects. In addition, given the bias towards publication of
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significant effects, it is impossible to know if there are other studies which did not show symptom reductions from agomelatine and therefore remain unpublished. To the extent this is the case (publication bias), the conclusions drawn from our review would overestimate the utility
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of this approach. In addition to methodological limitations, many of the papers reported that the patients were “treatment resistant” or “refractory” but did not provide details. Variability in how ‘treatment resistance’ was defined limiting the ability to generalize across studies. Another limitation is that the majority of the studies did not administer sleep interviews to assess for sleep disruption or the presence of DSPD. Instead, they relied heavily on self-report. Future studies should consider the use of actigraphy or polysomnography to acquire an objective measure of the
AGOMELATINE FOR OCD
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patients’ sleep cycles, as well as dim light melatonin onset (DLMO) and/or core body temperature to acquire an objective measure of the circadian clock. Finally, future studies can more thoroughly assess how depression might play a role in the sleep disturbance. In the current study comorbid depression diagnoses were rare, suggesting that agomelatine’s effect was not wholly driven by addressing depression. Further, levels of depressive symptoms were generally lower in the group that showed a response to agomelatine (i.e., patients with sleep/circadian
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rhythm disruption) compared to the group that did not respond (i.e., patients without
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sleep/circadian rhythm disruption). For example, Fornaro found that agomelatine was associated with reductions in OCD symptoms in all patients with sleep/circadian rhythm while disruption
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despite the fact that only one met criteria for depression. Further, the three cases that did not
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respond to agomelatine had high levels of depressive symptoms (Fornaro et al, 2011). In conclusion, observations from this review emphasize the potential benefits of future
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investigation into the role of sleep and circadian rhythms in OCD. It is possible that these disruptions may demarcate a new subtype of OCD, and that addressing these disruptions could
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help us improve outcomes. Additionally, furthering our knowledge of how to use circadian rhythm resynchronization techniques, whether independently or to augment other interventions, could optimize these treatments for the sizable subgroup of OCD patients with circadian rhythm
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disruptions. However, more controlled trials are clearly needed.
Conflict of interest: none Declarations of interest: none
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Figure captions
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Fig. 1. Search Strategy for the Study Selection
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Fig. 2. Plot of the pre and post Y-BOCS scores of OCD patients with and without sleep/circadian
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rhythm disruptions
Patients with sleep disturbance Sam ple Size
Current medications
Past Medications
Age
Sex
Pre YBO CS
Post YBOCS
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Study
Table 1.
Comorbidity
Sleep/Circadi an Rhythm Disruption
CBT
da Rocha, F.F., & Correa, H. (2011)
n=1
Agomelatine (25mg/daily for 12 weeks), Clomipramine (225 mg/day for 5 months), Risperidone (2mg/day for 6 months), Aripiprazole (100mg/day for 35 days)
1 of 3
Agomelatine (50mg/day for 12 weeks)
Fornaro, M. (2011)
2 of 3
Agomelatine (50mg/day for 12 weeks)
M
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30
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Agomelatine (50 mg/ day for 8 weeks)
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Fornaro, M. (2011)
n=1
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De Berardis, D. (2012)
Fluvoxamine (up to 200mg/day for 6 months) Fluoxetine (60mg/day* ) Lorazepam (2.5mg/day at bed for 4 weeks) Fluvoxamine (300 mg/day for 10 months), Venlafaxine (225mg/day for 8 months), Lorazepam (2.5 mg/day for 8 months), clomipramine (225 mg/day for 6 months)
28
15
NA
3
Mild Depressive Symptoms but never met criteria for a mood disorder
22
F
30
Difficulty sleeping.
11
“Moderate Depression”
Broadly discuss role of circadian rhythm disruption.
9
Impulse Control disorder. Substance abuse disorder. No depression.
Insomnia
No depression
“Almost constant ‘chronotype’ and ‘sleep’ disruption.
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n=1
Agomelatine (25mg/day for 5 weeks), Venlafaxine (75mg/day for 6 months)
Sertraline (200 mg/day for 7 months)
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Signorelli, M.S., et al. (2014)
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Clomipramine (300mg/day), pimozide (4 mg/day), sertraline (200mg/day)*
Fluvoxamine (250mg/day for 8 months)
17
44
25
M
M
M
36
21
32
11
Insomnia.
Not discussed
Reported one past trial. No benefit.
None reported.
No.
None reported
n=1
Agomelatine (25mg/day for 12 weeks), Escitalopram (30mg/day then tapered off escitalopram)
Duloxetine (120 mg/day for 6 months, Clonazepam (4mg/day for 6 months). Fluvoxamine (300mg/day for 1 year), sertraline (200mg/day for 10 months), alprazolam (1.5mg/day for 6 months), quetiapine (450 mg/day), clomipramine (150mg/day for 3 months)
33
1 of 3
Fornaro, M. (2011)
2 of 3
25
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Fornaro, M. (2011)
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Patients without sleep disturbance
Fornaro, M. (2011)
3 of 3
Agomelatine (50mg/day for 12 weks)
F
Fluoxetine (60mg/day for 6 months)
35
Fluoxetine (60mg/day)*
66
Amitriptyline (300mg/day)*
22
8
Panic Disorder
Mild Depressive Symptoms but never met criteria for a mood disorder
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Agomelatine (50mg/day for 12 weeks)
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De Berardis, D., et al. (2012)
3 of 3
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Fornaro, M. (2011)
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F
33
5
Mean (SD)
28.86 (5.61 )
8.88 (4.02)
CBT (6 months)
Sleep difficulties due to need to perform washing during night at scheduled times.
M
35
36
MDD & Social Anxiety Disorder
F
22
22
None.
No.
F
27
26
Bulimia & Panic Disorder
No.
Mean (SD)
28.00 (6.56 )
28.00 (7.21)
No.
CBT (6 months)
Not reported
Not reported. Yes. “Treated with CBT” “Repetitiv e failures.”
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Notes. * indicates that the duration was not reported or was unclear.