Ketamine treatment safety in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.

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Adam Włodarczyk, Wiesław J. Cubała, Maria Węgielnik-Gałuszko, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-42473/v2 This work is licensed under a CC BY 4.0 License Status: Under Review Version 2 posted 11 You are reading this latest preprint version Show more versions Abstract Background and objectives: There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety concerns arise regarding adverse drug reactions and specific subpopulations. The aim of this paper is to investigate the safety of intravenous ketamine treatment concerning dissociative and psychotic measures in TRD inpatients with Major Depressive Disorder (MDD) and Bipolar depression (BP) with somatic comorbidities. Methods: The study population of forty-nine inpatients comprises of MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). This dataset represents an intermittent analysis of an observational study performed for interim modelling of observational learning. The study may be underpowered due to the small sample size. The observations apply to the inhomogeneous TRD population in a single-site with no blinding and are limited to the acute administration. Results: The epilepsy was significantly associated with changes in BPRS over time (p=0.008). Psychotic symptomatology with BPRS scores for comorbid somatic conditions excluding epilepsy turned out to be insignificant (p = 0.198) regardless of the diagnosis. However, for a subgroup of patients with epilepsy substantial fluctuation was seen across all administrations in the time course of the study. Conclusions: In ketamine use, careful consideration of comorbidities and concomitant medication is needed. In ketamine administration, close-clinical supervision is necessary at every visit. Psychotic symptoms must be taken into consideration in planning treatment with TRD patients with epilepsy. Somatic comorbidity may impact dissociative symptomatology. Trial Registration: Study registered: 04DEC2019, clinicaltrials.com no. NCT04226963 https://clinicaltrials.gov/ct2/show/NCT04226963 Psychiatry ketamine treatment resistant depression dissociation psychosis comorbidity safety Background Recent developments in rapid-acting antidepressants use in treatment-resistant depression (TRD) provide robust evidence for ketamine use in Major Depressive Disorder (MDD) and Bipolar Disorder type I (BP) providing an option for rapid remission of symptoms with several concerns on safety and tolerability of the drug {1}. One of the major issues is the risk of adverse events associated with dissociative symptomatology {2}. There is some evidence for dissociative symptoms as the predictor of response in treatment-resistant depression (TRD) (both TRD-MDD and TRD-BP), however, it is limited to very few papers {3}, but even more studies including our own shows that there is no relationship between dissociative symptomatology and depression outcome. Overall, little is known on the course of the dissociative symptomatology in regards to ketamine use in affective disorders {4}. Dissociative states involve symptoms of gaps in memory, out of body experiences and depersonalization, derealization, and identity disturbance {5}. This phenomenon is associated with ketamine administration. Dissociative symptoms cause a wide spectrum of phenomena, however per methodological guidance Clinician-Administeredered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale (BRPS+) are used to represent the overall intensity of the dissociative and potential treatment-emergent psychotic symptomatology {2-4, 6-10}. Little data is available on ketamine use in TRD patients with somatic comorbidities {11}. In line with the measures of depression symptomatology, psychometric safety measures are used to assess dissociation and psychotic phenomena. This study aims to assess safety of intravenous ketamine in course of eight administrations in inpatients with TRD presenting somatic comorbidities. There are many features of the disease that affect ease and difficulty in controlling depression and impact control strategies. A characteristic associated with by far the highest risk of poor outcome compared to others (patient, treatment, or disease) is the absence of complete remission and the presence of residual symptoms after appropriate treatment. This emphasizes the importance of trying to alleviate the symptoms of depression, if possible {12} . Methods The sample selection methods for this study have been described in detail elsewhere {13, 14}. Briefly, the study population comprises of subjects enrolled in a naturalistic safety and efficacy registry protocol for ketamine infusions in TRD. Inpatients diagnosed with a depressive episode in the course of major depression, recurrent depression, or bipolar affective disorder were involved. Patients were interviewed by a clinician psychiatrist to establish the diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria determined using a Mini International Neuropsychiatric Interview (MINI). All participants met the criteria for TRD, defined as an inadequate response to 2 or more antidepressants of different categories (assessed by Massachusetts General Hospital Antidepressant Treatment Response Questionnaire - ATRQ) in course of treatment of that particular episode. Bipolar TRD was defined as a clinically unsatisfactory response following at least two trials of dissimilar medicinal treatments in adequate doses and durations, within a specific phase of bipolar illness {15}. The study followed the rule single-patient and single-rater (the same patient was examined by the same clinician in all of the scales). During the screening patients were rated by the clinician using Montgomery–Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Columbia–Suicide Severity Rating Scale (C-SSRS), The Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS) scales. Safety monitoring was performed by the attending psychiatrist before, during, and post-infusion every 15 minutes up to an hour and a half post-infusion. It included periodic assessment of vital signs (heart rate, body temperature, respiratory rate, blood pressure, oxygen saturation) and mental status examination, including assessment of BPRS and CADSS for the presence of respectively psychotic and dissociative symptoms. In order to demonstrate CADSS and BPRS fluctuations across treatment, CADSS and BPRS scores taken 30 minutes post drug administration were analysed. Only medically stable, able to communicate and provide consent, adult inpatients aged 18-90 were enrolled to study. Some patients were significantly affected by somatic illness, however, all of the patients continued current medication during ketamine treatment without any changes to the substance and/or dosage. The detailed description of antiepileptic medication in patients with epilepsy is presented in Additional File 1. The exclusion criteria included a history of uncontrolled medical conditions, a previous adverse reaction to ketamine, active substance use, pregnancy, or breastfeeding. Somatic comorbidities were defined by the patient's self-reported medical history with corroborated full-passed medical records. Somatic comorbidities relevant to this study group population were: arterial hypertension, diabetes mellitus, hyperlipidaemia, post-stroke patients, and patients with epilepsy (Table 1). This dataset represents the intermittent analysis of an observational study performed for the interim modelling of observational learning. The analyses are set per predefined and equally spaced annual increments for a study duration of 24 months with a population of 120 TRD subjects estimated for inclusion. The study was carried out in accordance with the latest version of the Declaration of Helsinki. For each participant, written consent was obtained after the procedures had been fully explained. The study recruitment procedures were approved by the Ethic Research Committee of the Institution. The study population comprises MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). A subject was defined as a responder at a given time point if the percent improvement from the baseline total MADRS score was at least 50%. The patient was defined as a remitter at a given time point if the total MADRS score was ≤10 points {16}. The final three groups (responders, remitters, and nonremitters) were determined by MADRS score one week after the last ketamine infusion. Table 1. Demographic and clinical variables. N Responder Remitter Non-Responder p V Male sex (%) 21 (42.9) 6 (66.7) 2 (25.0) 13 (40.6) 0.229 0.26 Female sex (%) 28 (57.1) 3 (33.3) 6 (75.0) 19 (59.4) Mean age, in years 50.02 53.11 42.88 50.94 0.336 0.00 Ketamine treatment for: MDD 35 (71.4) 8 (88.9) 5 (62.5) 22 (68.8) 0.475 0.19 BP 14 (28.6) 2 (11.1) 5 (37.5) 7 (31.2) 0.485 0.18 Comorbidity 0.104 0.31 1 21 (42.9) 6 (66.7) 2 (25.0) 13 (40.6) 2 10 (20.4) 2 (22.2) 1 (12.5) 7 (21.9) 3 4 (8.2) 1 (11.1) 2 (25.0) 1 (3.1) Arterial hypertension 16 (32.7) 6 (66.7) 3 (37.5) 7 (21.9) 0.037 0.37 BP 4 (8.2) 1 (11.1) 2 (25.0) 1 (3.1) 0.052 0.66 MDD 12 (24.5) 5 (55.6) 1 (12.5) 6 (18.8) 0.177 0.33 Diabetes mellitus 3 (6.1) 1 (11.1) 2 (25.0) 0 (0) 0.021 0.39 Hyperlipidaemia 9 (18.4) 3 (33.3) 1 (12.5) 5 (15.6) 0.545 0.19 Post-stroke 3 (6.1) 1 (11.1) 0 (0) 2 (6.3) 0.731 0.14 Post-myocardial infarction 0 (0) 0 (0) 0 (0) 0 (0) - - Epilepsy 6 (12.2) 0 (0) 3 (37.5) 3 (9.4) 0.060 0.36 Other 16 (32.7) 2 (22.2) 1 (12.5) 13 (40.6) 0.330 0.24 Coexisting treatment TCA 8 (16.3) 1 (11.1) 1 (13.5) 6 (18.8) 1.000 0.09 SSRIs 23 (46.9) 5 (55.6) 2 (25.0) 16 (50.0) 0.413 0.20 SNRIs 11 (22.4) 2 (22.2) 2 (25.0) 7 (21.9) 1.000 0.03 Other ADTs: 0.749 0.14 1 15 (30.6) 4 (44.4) 2 (25.0) 9 (28.1) 2 3 (6.1) 0 (0) 1 (12.5) 2 (6.3) Antipsychotics 0.806 0.15 1 12 (24.5) 2 (22.2) 1 (12.5) 9 (28.1) 2 5 (10.2) 0 (0) 1 (12.5) 4 (12.5) Mood stabilizers 0.348 0.29 1 15 (30.6) 2 (22.2) 4 (50.0) 9 (28.1) 2 6 (12.2) 1 (11.1) 0 (0) 5 (15.6) 3 1 (2.0) 0 (0) 1 (12.5) 0 (0) N, sample size; p , probability value; V, Cramer’s V; MDD, major depressive disorder; BP, bipolar disorder; TCA, other tricyclic antidepressant; SSRIs, selective serotonin reuptake inhibitors; SNRIs, selective serotonin-noradrenaline reuptake inhibitors; ADTs, antidepressants. Study design: Ketamine infusions All patients continued baseline antidepressants, as well as treatment of chronic somatic diseases during ketamine infusions. This study used an observational design with the administration of eight ketamine intravenous infusions over 4 weeks in TRD subjects. Ketamine was dosed at 0.5 mg/kg based on the patient's actual body weight and infused intravenously over 40 min. Any significant adverse effect (e.g. nausea) was also monitored, either by safety measurements including vital signs or per safety observation by clinical investigators. The ECG was carried out before every second infusion and one week after the last ketamine infusion. One week after the last infusion laboratory tests, ECG, all mentioned scales were performed. Statistical analysis The analyses were conducted using statistical software the IBM SPSS Statistics 25.0. To determine the differences between responders, remitters, and non-responders for sociodemographic variables and the occurrence of diseases and treatment, frequency analyzes were carried out with Fisher's exact test. To determine the differences between measurements, mixed models analysis was used. Analysis of quantitative variables was carried out by the Kruskal-Wallis test. The medium-term rate of change of the analyzed variables was calculated using chain indexes - the harmonic average of all chain indexes was calculated. Based on the medium-term rate of change, the rate of change was calculated for a given variable and the relationships between the dynamics of change between variables were determined. α=0.05 was adopted as the level of significance for this analysis. P-values presented in the current report reflect those obtained from a post hoc Bonferroni analysis. Results Sociodemographic characteristics are displayed in Table 1. Out of 49 patients included in our study, 21 of them had somatic comorbidities. All of the patients were medically stable, including those significantly affected by somatic illness continued current medication during ketamine treatment. A given type of somatic disease was set for the analyses performed as an inter-object factor. The detailed results of the analyses are presented in Table 2 and Table 3. A post hoc, longitudinal analysis showed that the post-dose CADSS and BPRS total score declined over time. Table 2. CADSS scores and somatic comorbidities comorbidities F df p η 2 p comorbidity 1.09 13.556 0.368 0.07 arterial hypertension 0.73 4.408 0.583 0.02 diabetes 0.64 4.439 0.650 0.01 hyperlipidemia 2.35 4.583 0.047 0.05 post-stroke 0.90 4.360 0.471 0.02 epilepsy 1.66 4.426 0.155 0.04 other 0.60 4.517 0.685 0.01 Table 3. BPRS scores and somatic comorbidities comorbidities F df p η 2 p Comorbidity 0,99 9,937 0,460 0,09 arterial hypertension 0,83 3,439 0,495 0,02 diabetes 1,27 3,434 0,288 0,04 hyperlipidemia 0,33 3,464 0,834 0,01 post-stroke 0,87 3,392 0,471 0,03 epilepsy 7,37 3,96 <0,001 0,18 other 0,61 3,439 0,629 0,02 Epilepsy was the only diagnosis significantly associated with changes in BPRS over time. The main effect for BPRS turned out to be significant, F (3.959) = 8.53; p <0.001; η2p = 0.20, similar to the interaction. After considering the Bonferroni correction, simple effects for BPRS for people without epilepsy turned out to be insignificant, F (7.28) = 1.53; p = 0.198; η2p = 0.28, while significant for people with epilepsy, F (7.28) = 3.54; p = 0.008; η2p = 0.47. In patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6, and 8, with higher results obtained for patients with epilepsy. The main effect for CADSS over time turned out to be significant for the diagnosis of hyperlipidemia, F (4.583) = 5.04; p <0.001; η2p = 0.10, similar to interaction. After the Bonferroni correction, simple effects for CADSS for people without hyperlipidemia turned out to be insignificant, F (7.40) = 1.89; p = 0.097; η2p = 0.25 as in case of hyperlipidemia diagnosis, F (7.40) = 1.92; p = 0.092; η2p = 0.25. Discussion The research demonstrates that CNS side effects related to ketamine intravenous infusions occur relatively frequently, especially with some comorbidities with ketamine as add-on treatment. However, they do not require drug discontinuation and overall intravenous ketamine appears to be well-tolerated as an add-on to current psychotropic medication in TRD. In patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6, and 8, with higher results obtained for patients with epilepsy. In each case, both BPRS and CADSS values dropped to zero within 1 hour from the infusion. Although modern antidepressants (Selective Serotonin Reuptake Inhibitors, Serotonin Noradrenaline Reuptake Inhibitors, noradrenergic and specific serotonergic antidepressants) are thought to be safe to use in epilepsy, ‘there is very limited evidence demonstrating a significant effect of antidepressants on depressive symptoms in epilepsy {17, 18} and no data about TRD-MDD treatment in this population. Ketamine has both pro and anti-convulsive properties, however, apart from some sparse data published not long after the FDA registration of Ketalar, there are no controlled human studies of the effect of ketamine in epilepsy in anesthetic or subanesthetic dose {19}. Moreover, recently ketamine has been successfully used in the treatment of status epilepticus , and it has been suggested item has some neuroprotective properties {20}. As a result, we currently don't know what effect could we expect regarding its efficacy in controlling seizures and depression. No data exist on long-term repeated use of ketamine in patients with epilepsy. The occurrence of various psychiatric disorders in people with epilepsy is high, with psychoses affecting 2–9% of patients {21}. In another cross-sectional study by Klaudee et al. (2019) {22} on thai population, from a total of 170 patients with epilepsy 43 (25.3%) fulfilled diagnostic criteria for one or more psychiatric disorders where psychotic disorders were 8.2 %. Other study found that apart from comorbid mood and anxiety disorders, patients with comorbid epilepsy with the interictal dysphoric disorder were also more likely to suffer from psychotic disorder {23}. The symptomatology of mood disorders in epilepsy is often atypical, pleomorphic, and fails to fulfill DSM diagnostic criteria, thus the treatment of mood disorders in epilepsy often requires a non-standard, individual approach {23}. Clinical characteristics of TRD-BP being itself multidimensional and multifaceted so it may be hypothesized that higher scores in psychotic features in course of TRD-BP are not associated with psychotropic intervention but rather with clinical characteristics of both diseases (BP and epilepsy together). There is a need for novel approaches for both TRD-MDD and TRD-BP in people with somatic comorbidities, as they are under-investigated, as most studies focus on healthy participants {24, 25}, i.e. depression is the most frequent comorbid psychiatric disorder in epilepsy {26}. Ketamine is known for its psychomimetic-adverse event potential {2, 27}. However, there is a safety concern regarding treatment with ketamine with comorbidities, while also little is known as for NMDA antagonists for refractory seizures, outcomes were poorly documented in the majority of the studies {28}. Overall, our study is in line with esketamine trials {24, 25, 29, 30}, as it shows to produce no harm with esketamine treatment and all of the patients experienced any persistent dissociative or psychotic symptoms during the follow-up visit. Interestingly, we have found in the literature that irreversible changes reported in rat brain, called ‘Olney's lesions’, developed after ketamine infusion. However, the human brain metabolism is different from rat brain metabolism, therefore such changes may not appear in human brain tissue {31}. There is also evidence that short-term exposure of GABAergic neurons to high doses of ketamine led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still establish long-term transformation of dendritic arbor in differentiated neurons. The study by Vutskits et al. {32, 33} also demonstrated persistent (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that persistent exposure to subanesthetic doses of ketamine, could still damage neuronal maintenance and development, without affecting cell survival. Further studies are needed to explore that matter, not only due to psychomimetic symptomatology present more frequently in people with epilepsy, but also for the possible long-range side-effect of possible ketamine treatment. The presented study provides significant information that in ketamine use, careful consideration of comorbidities and concomitant medication is needed, while ketamine administration close-clinical supervision is necessary at every visit. Somatic comorbidity may impact dissociative symptomatology, and psychotic symptoms, in particular, must be taken into consideration in planning treatment with TRD patients with epilepsy. Limitation The methodological strength of our study was to strengthen the point that the tolerability and general safety of the administration of the drug and that result being in support with some previous ketamine studies mentioned above. However, the study may be underpowered with regard to the small sample size. The research was performed as a single-site study, there was no treatment blinding, during this observational protocol study. The observations apply to treatment-resistant patients and include both, unipolar and bipolar depressed patients. Some concerns remain in terms of establishing an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration while managing long-term safety. The CADSS has limitations as a tool to measure the acute effects of ketamine infusions {34}. Also, was that no CADSS assessment was obtained only once post-dose (30 minutes post-dose) without a few measurements time points, so we could not establish the precise time course of either the peak dissociative symptoms or of their resolution (thus, relying on the esketamine/ketamine literature, it may be expected that these side effects would have resolved by the 2-hour time point, but the data acquired here do not allow that interval. The findings provide support for further consideration of ketamine-related CNS symptomatology into the relevance of these stated in the treatment outcome. With no long-term psychotomimetic side-effects reported it is important to replicate the finding in a larger sample in the long-term safety study design to demonstrate no sequelae. Conclusion The study results demonstrate good safety and tolerability profile of CNS adverse drug reactions with short-term treatment with intravenous ketamine as an add-on intervention to current standard-of-care psychotropic medication in TRD-MDD and TRD-BP inpatients with somatic comorbidities. Although somatic comorbidity may impact dissociative symptomatology, psychotic symptoms must be taken into consideration in planning treatment with TRD patients with epilepsy. We advise careful consideration of comorbidities and concomitant medication is needed, as well as in ketamine administration close-clinical supervision is necessary at every visit. Declarations Ethics approval and consent to participate The studies involving human participants were reviewed and approved by the Independent Ethics Committee of the Medical University of Gdansk NKBBN/172/2017; 172-674/2019, NCT04226963. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Consent for publication N/A Availability of data and material All datasets generated for this study are included in the article/supplementary material. Competing interests Dr. Adam Włodarczyk has received research support from Actavis, Eli Lilly, Minerva Neurosciences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia. Prof. Wiesław Jerzy Cubała has received research support from Actavis, Alkermes, Allergan, Angelini, Auspex, Biogen, Bristol-Myers Squibb, Cephalon, Eli Lilly, Ferrier, Forest Laboratories, Gedeon Richter, GW Pharmaceuticals, Janssen, KCR, Lundbeck, Orion, Otsuka, Sanofi, and Servier; he has served on speakers bureaus for Adamed, Angelini, AstraZeneca, Bristol-Myers Squibb, Celon, GlaxoSmithKline, Janssen, Krka, Lekam, Lundbeck, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, and Zentiva; and he has served as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, and Roche. Dr. Maria Gałuszko-Węgielnik has received research support from: Janssen, Servier, Alkermes, KCR, Lilly, Biogen, Celon; Dr. Mariusz Stanisław Wiglusz has received research support from Acadia, Apodemus, Alkermes, Auspex Pharmaceuticals, Cephalon, Ferrier, Forest Laboratories, Gedeon Richter, GWPharmaceuticals, Janssen, Lundbeck, Orion, Otsuka, Servier; Speaker s Bureau: Lundbeck, Servier. Funding This work is supported by the Medical University of Gdańsk, Poland (Grant No. ST-02-0039/07/221). Authors' contributions Włodarczyk A – manage literature search and analysis, wrote the first draft of the manuscript Cubała WJ – designed the study and wrote the protocol, manage literature searches and analyses. Gałuszko-Węgielnik M – designed the study, wrote the protocol. Wiglusz MS – manage literature searches and analyses All authors contributed to and have approved the final manuscript. Acknowledgments This work is supported by the Medical University of Gdańsk, Poland (Grant No. ST-02-0039/07/221). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. References McIntyre RS, Rodrigues NB, Lee Y, et al. 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Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, Vitagliano D, Blier P, Fava M, Liebowitz M, Ravindran A, Gaillard R, Ameele HVD, Preskorn S, Manji H, Drevets WC, Singh JB. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1), International Journal of Neuropsychopharmacology 2019. Doi: https://doi.org/10.1093/ijnp/pyz039 . Luckenbaugh DA, Niciu MJ, Ionescu DF, Nolan NM, Richards EM, Brutsche NE, Zarate CA. Do the Dissociative Side Effects of Ketamine Mediate Its Antidepressant effects? Journal of Affective Disorders 2014. https://doi.org/10.1016/j.jad.2014.02.017Brief . Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244(4910):1360–2. Bibcode:1989Sci...244.1360O. doi:10.1126/science.2660263. PMID 2660263. Morgan CJA, Muetzelfeldt L, Curran HV. "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study". Addiction 2009;105(1): 121–33. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593. Vutskits L, Gascon E, Potter G, Tassonyi E, et al. "Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture". Toxicology 2007;234(3): 216–26. doi:10.1016/j.tox.2007.03.004. PMID 17418473. van Schalkwyk GI, Wilkinson ST, Davidson L, Silverman WK, Sanacora G. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale. J Affect Disord. 2018 Feb;227:11-16. doi: 10.1016/j.jad.2017.09.023. Epub 2017 Sep 28. PMID: 29045915; PMCID: PMC6248324. Supplementary Files Additionalfile1.pdf Table 4. Antiepileptic treatment in patients with epilepsy. Cite Share Download PDF Status: Under Review Version 2 posted Review # 3 received at journal 07 Feb, 2021 Editorial decision: Major revision 07 Feb, 2021 Review # 1 received at journal 05 Feb, 2021 Review # 2 received at journal 31 Jan, 2021 Reviewer # 3 agreed at journal 10 Jan, 2021 Reviewer # 2 agreed at journal 10 Jan, 2021 Reviewer # 1 agreed at journal 26 Dec, 2020 Reviewers invited by journal 21 Dec, 2020 Editor assigned by journal 20 Dec, 2020 Submission checks completed at journal 20 Dec, 2020 Editor invited by journal 20 Dec, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-42473","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":7038896,"identity":"acd91243-a285-4699-bc0d-93814a17446b","order_by":0,"name":"Adam Włodarczyk","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8549-254X","institution":"Gdanski Uniwersytet Medyczny","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Włodarczyk","suffix":""},{"id":7038897,"identity":"d5d47371-e6c8-4b44-8859-3ba2ded312a9","order_by":1,"name":"Wiesław J. Cubała","email":"","orcid":"","institution":"Gdanski Uniwersytet Medyczny","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wiesław","middleName":"J.","lastName":"Cubała","suffix":""},{"id":7038898,"identity":"2d78c5d5-dd56-4699-b198-d463988b5787","order_by":2,"name":"Maria Węgielnik-Gałuszko","email":"","orcid":"","institution":"Gdanski Uniwersytet Medyczny","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Węgielnik-Gałuszko","suffix":""},{"id":7038900,"identity":"347b0748-7ae2-4b79-b6e8-c8ae549eda23","order_by":3,"name":"Mariusz S. Wiglusz","email":"","orcid":"","institution":"Gdanski Uniwersytet Medyczny","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mariusz","middleName":"S.","lastName":"Wiglusz","suffix":""}],"badges":[],"createdAt":"2020-07-13 19:33:37","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-42473/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-42473/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":13643834,"identity":"ed4b93c1-c773-4502-8152-e363bd396466","added_by":"auto","created_at":"2021-09-17 09:13:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":249279,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-42473/v2/ce40deeb-24aa-4a7b-95eb-fdb2ba9afb47.pdf"},{"id":4775045,"identity":"0119877d-0863-41c3-90f6-2973ee759765","added_by":"auto","created_at":"2021-01-07 11:16:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12316,"visible":true,"origin":"","legend":"Table 4. Antiepileptic treatment in patients with epilepsy.","description":"","filename":"Additionalfile1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-42473/v2/bd276c1e7ffa69564bb15403.pdf"}],"financialInterests":"","formattedTitle":"Ketamine treatment safety in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.","fulltext":[{"header":"Background","content":"\u003cp\u003eRecent developments in rapid-acting antidepressants use in treatment-resistant depression (TRD) provide robust evidence for ketamine use in Major Depressive Disorder (MDD) and Bipolar Disorder type I (BP) providing an option for rapid remission of symptoms with several concerns on safety and tolerability of the drug {1}.\u003c/p\u003e\n\u003cp\u003eOne of the major issues is the risk of adverse events associated with dissociative symptomatology {2}. There is some evidence for dissociative symptoms as the predictor of response in treatment-resistant depression (TRD) (both TRD-MDD and TRD-BP), however, it is limited to very few papers {3}, but even more studies including our own shows that there is no relationship between dissociative symptomatology and depression outcome. Overall, little is known on the course of the dissociative symptomatology in regards to ketamine use in affective disorders {4}. Dissociative states involve symptoms of gaps in memory, out of body experiences and depersonalization, derealization, and identity disturbance {5}. This phenomenon is associated with ketamine administration. Dissociative symptoms cause a wide spectrum of phenomena, however per methodological guidance Clinician-Administeredered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale (BRPS+) are used to represent the overall intensity of the dissociative and potential treatment-emergent psychotic symptomatology {2-4, 6-10}.\u003c/p\u003e\n\u003cp\u003eLittle data is available on ketamine use in TRD patients with somatic comorbidities {11}. In line with the measures of depression symptomatology, psychometric safety measures are used to assess dissociation and psychotic phenomena.\u003c/p\u003e\n\u003cp\u003eThis study aims to assess safety of intravenous ketamine in course of eight administrations in inpatients with TRD presenting somatic comorbidities. There are many features of the disease that affect ease and difficulty in controlling depression and impact control strategies. A characteristic associated with by far the highest risk of poor outcome compared to others (patient, treatment, or disease) is the absence of complete remission and the presence of residual symptoms after appropriate treatment. This emphasizes the importance of trying to alleviate the symptoms of depression, if possible {12}\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe sample selection methods for this study have been described in detail elsewhere {13, 14}. Briefly, the study population comprises of subjects enrolled in a naturalistic safety and efficacy registry protocol for ketamine infusions in TRD. Inpatients diagnosed with a depressive episode in the course of major depression, recurrent depression, or bipolar affective disorder were involved. Patients were interviewed by a clinician psychiatrist to establish the diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria determined using a Mini International Neuropsychiatric Interview (MINI). All participants met the criteria for TRD, defined as an inadequate response to 2 or more antidepressants of different categories (assessed by Massachusetts General Hospital Antidepressant Treatment Response Questionnaire - ATRQ) in course of treatment of that particular episode. Bipolar TRD was defined as a clinically unsatisfactory response following at least two trials of dissimilar medicinal treatments in adequate doses and durations, within a specific phase of bipolar illness {15}. The study followed the rule single-patient and single-rater (the same patient was examined by the same clinician in all of the scales). During the screening patients were rated by the clinician using Montgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Columbia\u0026ndash;Suicide Severity Rating Scale (C-SSRS), The Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS) scales. Safety monitoring was performed by the attending psychiatrist before, during, and post-infusion every 15 minutes up to an hour and a half post-infusion. It included periodic assessment of vital signs (heart rate, body temperature, respiratory rate, blood pressure, oxygen saturation) and mental status examination, including assessment of BPRS and CADSS for the presence of respectively psychotic and dissociative symptoms. In order to demonstrate CADSS and BPRS fluctuations across treatment, CADSS and BPRS scores taken 30 minutes post drug administration were analysed.\u003c/p\u003e\n\u003cp\u003eOnly medically stable, able to communicate and provide consent, adult inpatients aged 18-90 were enrolled to study. Some patients were significantly affected by somatic illness, however, all of the patients continued current medication during ketamine treatment without any changes to the substance and/or dosage. The detailed description of antiepileptic medication in patients with epilepsy is presented in Additional File 1. The exclusion criteria included a history of uncontrolled medical conditions, a previous adverse reaction to ketamine, active substance use, pregnancy, or breastfeeding. Somatic comorbidities were defined by the patient's self-reported medical history with corroborated full-passed medical records. Somatic comorbidities relevant to this study group population were: arterial hypertension, diabetes mellitus, hyperlipidaemia, post-stroke patients, and patients with epilepsy (Table 1).\u003c/p\u003e\n\u003cp\u003eThis dataset represents the intermittent analysis of an observational study performed for the interim modelling of observational learning. The analyses are set per predefined and equally spaced annual increments for a study duration of 24 months with a population of 120 TRD subjects estimated for inclusion. The study was carried out in accordance with the latest version of the Declaration of Helsinki. For each participant, written consent was obtained after the procedures had been fully explained. The study recruitment procedures were approved by the Ethic Research Committee of the Institution. The study population comprises MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963).\u003c/p\u003e\n\u003cp\u003eA subject was defined as a responder at a given time point if the percent improvement from the baseline total MADRS score was at least 50%. The patient was defined as a remitter at a given time point if the total MADRS score was \u0026le;10 points {16}. The final three groups (responders, remitters, and nonremitters) were determined by MADRS score one week after the last ketamine infusion.\u003c/p\u003e\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eTable 1. Demographic and clinical variables.\u003c/p\u003e\n\u003cdiv align=\"center\" style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\n \u003ctable style=\"width: 4.3e+2pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cstrong\u003e\u003cem\u003eN\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cstrong\u003eResponder\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 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style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eFemale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e6 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e19 (59.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eMean age, in years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e50.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e53.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e42.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e50.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eKetamine treatment for:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eMDD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e35 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e8 (88.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e5 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e22 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eBP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e14 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e5 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e7 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.485\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eComorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e21 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e6 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e13 (40.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e10 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eMDD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e6 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (11.1)\u003c/p\u003e\n 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eHyperlipidaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e5 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.545\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.731\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ePost-myocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eEpilepsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e6 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e16 (32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e13 (40.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eCoexisting treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eTCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n 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style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e15 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n 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style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eAntipsychotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.806\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e12 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e9 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e5 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eMood stabilizers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e15 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e9 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e6 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e5 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:70.9pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:35.45pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width:28.35pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 3.5pt 0in 3.5pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;text-align:justify;line-height:115%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eN, sample size; \u003cem\u003ep\u003c/em\u003e, probability value; V, Cramer\u0026rsquo;s V; MDD, major depressive disorder; BP, bipolar disorder; TCA, other tricyclic antidepressant; SSRIs, selective serotonin reuptake inhibitors; SNRIs, selective serotonin-noradrenaline reuptake inhibitors; ADTs, antidepressants.\u003c/p\u003e\u003cbr\u003e\u003cp\u003e\u003cu\u003eStudy design: Ketamine infusions\u0026nbsp; \u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll patients continued baseline antidepressants, as well as treatment of chronic somatic diseases during ketamine infusions. This study used an observational design with the administration of eight ketamine intravenous infusions over 4 weeks in TRD subjects. Ketamine was dosed at 0.5 mg/kg based on the patient's actual body weight and infused intravenously over 40 min. Any significant adverse effect (e.g. nausea) was also monitored, either by safety measurements including vital signs or per safety observation by clinical investigators. The ECG was carried out before every second infusion and one week after the last ketamine infusion. One week after the last infusion laboratory tests, ECG, all mentioned scales were performed.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistical analysis\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe analyses were conducted using statistical software the IBM SPSS Statistics 25.0. To determine the differences between responders, remitters, and non-responders for sociodemographic variables and the occurrence of diseases and treatment, frequency analyzes were carried out with Fisher's exact test. To determine the differences between measurements, mixed models analysis was used. Analysis of quantitative variables was carried out by the Kruskal-Wallis test.\u003c/p\u003e\n\u003cp\u003eThe medium-term rate of change of the analyzed variables was calculated using chain indexes - the harmonic average of all chain indexes was calculated. Based on the medium-term rate of change, the rate of change was calculated for a given variable and the relationships between the dynamics of change between variables were determined. \u0026alpha;=0.05 was adopted as the level of significance for this analysis. P-values presented in the current report reflect those obtained from a post hoc Bonferroni analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSociodemographic characteristics are displayed in Table 1. Out of 49 patients included in our study, 21 of them had somatic comorbidities. All of the patients were medically stable, including those significantly affected by somatic illness continued current medication during ketamine treatment. A given type of somatic disease was set for the analyses performed as an inter-object factor. The detailed results of the analyses are presented in Table 2 and Table 3.\u003c/p\u003e\n\u003cp\u003eA post hoc, longitudinal analysis showed that the post-dose CADSS and BPRS total score declined over time.\u003c/p\u003e\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003eTable 2.\u003c/em\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003eCADSS scores and somatic comorbidities\u003c/em\u003e\u003c/p\u003e\n\u003ctable style=\"width:461.1pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ecomorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003edf\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026eta;\u003csup\u003e2\u003c/sup\u003e\u003csub\u003ep\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ecomorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e13.556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003earterial\u0026nbsp;hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ediabetes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.650\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.8pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ehyperlipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.8pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e2.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.8pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.8pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.8pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003epost-stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.471\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eepilepsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.2pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e4.517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.1pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eTable 3.\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eBPRS scores and somatic comorbidities\u003c/p\u003e\n\u003ctable style=\"width:461.95pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.35pt;border:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ecomorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003edf\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026eta;\u003csup\u003e2\u003c/sup\u003e\u003csub\u003ep\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.35pt;border:solid windowtext 1.0pt;border-top: none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eComorbidity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e9,937\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003earterial\u0026nbsp;hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 16.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ediabetes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e1,27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003ehyperlipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,834\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003epost-stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,471\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eepilepsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e7,37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026lt;0,001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 92.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 16.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e3,439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;text-align:justify;line-height:200%;font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0,02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\u003cp\u003eEpilepsy was the only diagnosis significantly associated with changes in BPRS over time. The main effect for BPRS turned out to be significant, F (3.959) = 8.53; p \u0026lt;0.001; \u0026eta;2p = 0.20, similar to the interaction. After considering the Bonferroni correction, simple effects for BPRS for people without epilepsy turned out to be insignificant, F (7.28) = 1.53; p = 0.198; \u0026eta;2p = 0.28, while significant for people with epilepsy, F (7.28) = 3.54; p = 0.008; \u0026eta;2p = 0.47. In patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6, and 8, with higher results obtained for patients with epilepsy.\u003c/p\u003e\n\u003cp\u003eThe main effect for CADSS over time turned out to be significant for the diagnosis of hyperlipidemia, F (4.583) = 5.04; p \u0026lt;0.001; \u0026eta;2p = 0.10, similar to interaction. After the Bonferroni correction, simple effects for CADSS for people without hyperlipidemia turned out to be insignificant, F (7.40) = 1.89; p = 0.097; \u0026eta;2p = 0.25 as in case of hyperlipidemia diagnosis, F (7.40) = 1.92; p = 0.092; \u0026eta;2p = 0.25.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe research demonstrates that CNS side effects related to ketamine intravenous infusions occur relatively frequently, especially with some comorbidities with ketamine as add-on treatment. However, they do not require drug discontinuation and overall intravenous ketamine appears to be well-tolerated as an add-on to current psychotropic medication in TRD.\u003c/p\u003e\n\u003cp\u003eIn patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6, and 8, with higher results obtained for patients with epilepsy. In each case, both BPRS and CADSS values dropped to zero within 1 hour from the infusion.\u003c/p\u003e\n\u003cp\u003eAlthough modern antidepressants (Selective Serotonin Reuptake Inhibitors, Serotonin Noradrenaline Reuptake Inhibitors, noradrenergic and specific serotonergic antidepressants) are thought to be safe to use in epilepsy, \u0026lsquo;there is very limited evidence demonstrating a significant effect of antidepressants on depressive symptoms in epilepsy {17, 18} and no data about TRD-MDD treatment in this population. Ketamine has both pro and anti-convulsive properties, however, apart from some sparse data published not long after the FDA registration of Ketalar, there are no controlled human studies of the effect of ketamine in epilepsy in anesthetic or subanesthetic dose {19}. Moreover, recently ketamine has been successfully used in the treatment of \u003cem\u003estatus epilepticus\u003c/em\u003e, and it has been suggested item has some neuroprotective properties {20}. As a result, we currently don't know what effect could we expect regarding its efficacy in controlling seizures and depression. No data exist on long-term repeated use of ketamine in patients with epilepsy.\u003c/p\u003e\n\u003cp\u003eThe occurrence of various psychiatric disorders in people with epilepsy is high, with psychoses affecting 2\u0026ndash;9% of patients {21}. In another cross-sectional study by Klaudee et al. (2019) {22} on thai population, from a total of 170 patients with epilepsy 43 (25.3%) fulfilled diagnostic criteria for one or more psychiatric disorders where psychotic disorders were 8.2 %. Other study found that apart from comorbid mood and anxiety disorders, patients with comorbid epilepsy with the interictal dysphoric disorder were also more likely to suffer from psychotic disorder {23}.\u003c/p\u003e\n\u003cp\u003eThe symptomatology of mood disorders in epilepsy is often atypical, pleomorphic, and fails to fulfill DSM diagnostic criteria, thus the treatment of mood disorders in epilepsy often requires a non-standard, individual approach {23}. Clinical characteristics of TRD-BP being itself multidimensional and multifaceted so it may be hypothesized that higher scores in psychotic features in course of TRD-BP are not associated with psychotropic intervention but rather with clinical characteristics of both diseases (BP and epilepsy together).\u003c/p\u003e\n\u003cp\u003eThere is a need for novel approaches for both TRD-MDD and TRD-BP in people with somatic comorbidities, as they are under-investigated, as most studies focus on healthy participants {24, 25}, i.e. depression is the most frequent comorbid psychiatric disorder in epilepsy {26}. Ketamine is known for its psychomimetic-adverse event potential {2, 27}. However, there is a safety concern regarding treatment with ketamine with comorbidities, while also little is known as for NMDA antagonists for refractory seizures, outcomes were poorly documented in the majority of the studies {28}. Overall, our study is in line with esketamine trials {24, 25, 29, 30}, as it shows to produce no harm with esketamine treatment and all of the patients experienced any persistent dissociative or psychotic symptoms during the follow-up visit. Interestingly, we have found in the literature that irreversible changes reported in rat brain, called \u0026lsquo;Olney's lesions\u0026rsquo;, developed after ketamine infusion. However, the human brain metabolism is different from rat brain metabolism, therefore such changes may not appear in human brain tissue {31}. There is also evidence that short-term exposure of GABAergic neurons to high doses of ketamine led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 \u0026mu;g/ml) may still establish long-term transformation of dendritic arbor in differentiated neurons. The study by Vutskits et al. {32, 33} also demonstrated persistent (\u0026gt;24 h) administration of ketamine at concentrations as low as 0.01 \u0026mu;g/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that persistent exposure to subanesthetic doses of ketamine, could still damage neuronal maintenance and development, without affecting cell survival. Further studies are needed to explore that matter, not only due to psychomimetic symptomatology present more frequently in people with epilepsy, but also for the possible long-range side-effect of possible ketamine treatment.\u003c/p\u003e\n\u003cp\u003eThe presented study provides significant information that in ketamine use, careful consideration of comorbidities and concomitant medication is needed, while ketamine administration close-clinical supervision is necessary at every visit. Somatic comorbidity may impact dissociative symptomatology, and psychotic symptoms, in particular, must be taken into consideration in planning treatment with TRD patients with epilepsy.\u003c/p\u003e"},{"header":"Limitation","content":"\u003cp\u003eThe methodological strength of our study was to strengthen the point that the tolerability and general safety of the administration of the drug and that result being in support with some previous ketamine studies mentioned above.\u003c/p\u003e\n\u003cp\u003eHowever, the study may be underpowered with regard to the small sample size. The research was performed as a single-site study, there was no treatment blinding, during this observational protocol study. The observations apply to treatment-resistant patients and include both, unipolar and bipolar depressed patients. Some concerns remain in terms of establishing an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration while managing long-term safety. The CADSS has limitations as a tool to measure the acute effects of ketamine infusions {34}. Also, was that no CADSS assessment was obtained only once post-dose (30 minutes post-dose) without a few measurements time points, so we could not establish the precise time course of either the peak dissociative symptoms or of their resolution (thus, relying on the esketamine/ketamine literature, it\u0026nbsp; may be expected that these side effects would have resolved by the 2-hour time point, but the data acquired here do not allow that interval. The findings provide support for further consideration of ketamine-related CNS symptomatology into the relevance of these stated in the treatment outcome. With no long-term psychotomimetic side-effects reported it is important to replicate the finding in a larger sample in the long-term safety study design to demonstrate no sequelae.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe study results demonstrate good safety and tolerability profile of CNS adverse drug reactions with short-term treatment with intravenous ketamine as an add-on intervention to current standard-of-care psychotropic medication in TRD-MDD and TRD-BP inpatients with somatic comorbidities. Although somatic comorbidity may impact dissociative symptomatology, psychotic symptoms must be taken into consideration in planning treatment with TRD patients with epilepsy.\u003c/p\u003e\n\u003cp\u003eWe advise careful consideration of comorbidities and concomitant medication is needed, as well as in ketamine administration close-clinical supervision is necessary at every visit.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Independent Ethics Committee of the Medical University of Gdansk NKBBN/172/2017; 172-674/2019, NCT04226963. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and material\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll datasets generated for this study are included in the article/supplementary material.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eDr. Adam Włodarczyk has received research support from Actavis, Eli Lilly, Minerva Neurosciences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia.\u003c/p\u003e\n\u003cp\u003eProf. Wiesław Jerzy Cubała has received research support from Actavis, Alkermes, Allergan, Angelini, Auspex, Biogen, Bristol-Myers Squibb, Cephalon, Eli Lilly, Ferrier, Forest Laboratories, Gedeon Richter, GW Pharmaceuticals, Janssen, KCR, Lundbeck, Orion, Otsuka, Sanofi, and Servier; he has served on speakers bureaus for Adamed, Angelini, AstraZeneca, Bristol-Myers Squibb, Celon, GlaxoSmithKline, Janssen, Krka, Lekam, Lundbeck, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, and Zentiva; and he has served as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, and Roche.\u003c/p\u003e\n\u003cp\u003eDr. Maria Gałuszko-Węgielnik has received research support from: Janssen, Servier, Alkermes, KCR, Lilly, Biogen, Celon;\u003c/p\u003e\n\u003cp\u003eDr. Mariusz Stanisław Wiglusz has received research support from Acadia, Apodemus, Alkermes, Auspex Pharmaceuticals, Cephalon, Ferrier, Forest Laboratories, Gedeon Richter, GWPharmaceuticals, Janssen, Lundbeck, Orion, Otsuka, Servier; Speaker s Bureau: Lundbeck, Servier.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis work is supported by the Medical University of Gdańsk, Poland (Grant No. ST-02-0039/07/221).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors' contributions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWłodarczyk A \u0026ndash; manage literature search and analysis, wrote the first draft of the manuscript\u003c/p\u003e\n\u003cp\u003eCubała WJ \u0026ndash; designed the study and wrote the protocol, manage literature searches and analyses.\u003c/p\u003e\n\u003cp\u003eGałuszko-Węgielnik M \u0026ndash; designed the study, wrote the protocol.\u003c/p\u003e\n\u003cp\u003eWiglusz MS \u0026ndash; manage literature searches and analyses\u003c/p\u003e\n\u003cp\u003eAll authors contributed to and have approved the final manuscript.\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAcknowledgments\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis work is supported by the Medical University of Gdańsk, Poland (Grant No. ST-02-0039/07/221).\u003c/p\u003e\n\u003cp\u003eThe funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcIntyre RS, Rodrigues NB, Lee Y, et al. 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Addiction 2009;105(1): 121\u0026ndash;33. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593.\u003c/li\u003e\n\u003cli\u003eVutskits L, Gascon E, Potter G, Tassonyi E, et al. \"Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture\". Toxicology 2007;234(3): 216\u0026ndash;26. doi:10.1016/j.tox.2007.03.004. PMID 17418473.\u003c/li\u003e\n\u003cli\u003evan Schalkwyk GI, Wilkinson ST, Davidson L, Silverman WK, Sanacora G. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale. J Affect Disord. 2018 Feb;227:11-16. doi: 10.1016/j.jad.2017.09.023. Epub 2017 Sep 28. PMID: 29045915; PMCID: PMC6248324.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ketamine, treatment resistant depression, dissociation, psychosis, comorbidity, safety","lastPublishedDoi":"10.21203/rs.3.rs-42473/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-42473/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and objectives: \u003c/strong\u003eThere is evidence for ketamine use in treatment-resistant depression (TRD). Several safety concerns arise regarding adverse drug reactions and specific subpopulations. The aim of this paper is to investigate the safety of intravenous ketamine treatment concerning dissociative and psychotic measures in TRD inpatients with Major Depressive Disorder (MDD) and Bipolar depression (BP) with somatic comorbidities.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe study population of forty-nine inpatients comprises of MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). This dataset represents an intermittent analysis of an observational study performed for interim modelling of observational learning. The study may be underpowered due to the small sample size. The observations apply to the inhomogeneous TRD population in a single-site with no blinding and are limited to the acute administration.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe epilepsy was significantly associated with changes in BPRS over time (p=0.008). Psychotic symptomatology with BPRS scores for comorbid somatic conditions excluding epilepsy turned out to be insignificant (p = 0.198) regardless of the diagnosis. However, for a subgroup of patients with epilepsy substantial fluctuation was seen across all administrations in the time course of the study. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eIn ketamine use, careful consideration of comorbidities and concomitant medication is needed. In ketamine administration, close-clinical supervision is necessary at every visit. Psychotic symptoms must be taken into consideration in planning treatment with TRD patients with epilepsy. Somatic comorbidity may impact dissociative symptomatology.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eStudy registered: 04DEC2019, clinicaltrials.com no. NCT04226963 https://clinicaltrials.gov/ct2/show/NCT04226963\u003c/p\u003e","manuscriptTitle":"Ketamine treatment safety in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2021-01-07 11:16:34","doi":"10.21203/rs.3.rs-42473/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-02-08T00:00:00+00:00","index":3,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThanks for these edits and responses. There are still important details missing from the methods and results/tables that prevent evaluation of the study presented, particularly with regard to the statistical approach and reported results of statistical analyses. Unfortunately, it is not possible to evaluate the results of this study as the manuscript is currently written. Explicit detail is needed.\n\nStats in Table 1 are still unclear. Please explicitly state in the Table footnote what statistical test p-value, etc., corresponds to (e.g., difference in age in responders vs. nonresponders?, association with study outcomes like AEs with age?). If comparing responders, nonresponders, and remitters in the same model, please state that remitters weren't included the nonresponders group.\n\n\"Chain indexes\" still isn't defined. Please state what this method is doing - is it estimating the rate of change in a certain study metric? Why was this approach taken over a regression approach, e.g., correlating time with change in a given study metric? How many time-points were analyzed (e.g., just 2 datapoints pre- and post-treatment, or datapoints for all 8 treatment visits)? Explicit explanation of the statistical approach is needed in the Methods section, and could perhaps be referenced in Results text and Tables as appropriate.\n\nFor Table 2\u00263, do these stats reference a comparison of pre-treatment CADSS/BPRS to post treatment? If so, please add to table title, e.g., \"Change in CADSS scores after ketamine in somatic comorbidities\" or similar.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Major revision","date":"2021-02-08T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-02-06T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\n\nthe paper has been improved, however as it is now still carries major issues. Mainly it is not consistent and some parts are misleading. I think it needs to be clearer and more precise as methods are confused, the title is not consistent with the study, results are too short and unclear, the discussion is not supported by the evidence. \n\n\n\nPlease check my comments in details below:\n\n1. \"Recent developments in rapid-acting antidepressants use in treatment resistant depression (TRD) provide robust evidence for ketamine use in Major Depressive Disorder (MDD) and Bipolar Disorder type I (BP) providing an option for rapid remission of symptoms with several concerns on safety and tolerability of the drug\".\nAs mentioned in my previous comment, the references were not supporting your sentence, both because they were not \"recent\" and because they were not supporting ketamine use. You now changed the reference, using a more recent paper, which solves one of the two issues. However, it is not possible to state that \"robust\" evidence support ketamine use. First, the references you deleted are still valid and present in the literature. For example, the Cochrane review on bipolar disorder concluded: \"Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression.\" Second, the paper you cited cannot be defined as \"robust\" evidence, considering that it is a single retrospective observational study without controls and all other papers (summarized in the systematic review) are reporting difference evidence. I think that you should reconsider your statement. To date the evidence of efficacy are limited (and the evidence on tolerability is concerning).\n2. The methods overall are confused and confusing. Please follow guidelines to report observational studies (STROBE checkilist). First you define the study population (this part is ok), then procedures (ketamine infusions), then outcomes evaluated (what and when and by whom). As it is now, some part of the outcomes are described at the beginning (safety monitoring by clinicians), some others (adverse events) in the ketamine infusion paragraph.\n3. \"Safety monitoring was performed by the attending psychiatrist before, during, and post-infusion every 15 minutes up to an hour and a half post-infusion.\" So as far as I understand, safety was monitored just for 30 minutes? If yes, this needs to be taken into account in the title, in the discussion and in the conclusions. If not, please clarify. I think you should change the tile with \"short term safety\", something that makes the reader understand that you are just providing data for 30 minutes after infusion or one week (in the case of other outcomes). Same in the abstract. In the following section you stated that EEG and EKG were performed after one week. Again, this is very confusing. The reader needs to go up and down the paper to understand which and when different measures were performed.\n\n4. \"This dataset represents the intermittent analysis of an observational study performed for the interim modelling of observational learning. The analyses are set per predefined and equally spaced annual increments for a study duration of 24 months with a population of 120 TRD subjects estimated for inclusion. \" This is misleading, the length of followup is not 24 months. So please clarify and check the next point.\n5. The final three groups (responders, remitters, and nonremitters) were determined by MADRS score one week after the last ketamine infusion. No conclusion based on such a short term follow up can be made. It has been explained in the literature that ketamine and derivates have not an antidepressant effect because they only induce a state (similar to substances of abuse) that hides the depression for few hours.\n6. In patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6, and 8, with higher results obtained for patients with epilepsy. In each case, both BPRS and CADSS values dropped to zero within 1 hour from the infusion.\nyou are describing a sample of 6 patients with epilepsy. The sample resembles more a case series than a real study, any conclusion is not supported.\nmoreover, the paragraph on results need to be expanded. please follow the strobe checklist. results are not clear, occurrences of diagnosis are not reported, main outcome and secondary neither. for example, a reader do not know that patients with epilepsy (your main result) are only 6, unless they check the tables. A better description of results is needed.\n\n7. \"Overall, our study is in line with esketamine trials {24, 25, 29, 30}, as it shows to produce no harm with esketamine treatment and all of the patients experienced any persistent dissociative or psychotic symptoms during the follow-up visit\". this is not fully true. many criticisms on esketamine trials have been published in the last year. Please check Cristea\u0026Naudet Lancet psychiatry (2 papers: 2019 and 2020), Gastaldon et al. 2020 (Epidemiology and Psych Sciences), Turner lancet psych 2019. Moreover a post-marketing analysis on safety concerns for esketamine has been published on psychotherapy and psychosomatics in 2020 (gastaldon et al.) analysing data from the fda database of spontaneous reports. the results showed also that some adverse events last longer than expected.\n\n8.moreover, please avoid the use of the term \"demonstrate\" in the discussion as a small sample and observational study cannot demonstrate any result. \n9. the title needs to identify the type of research you conducted (observational? open lable? lenght of follow up?)\n10. discussion needs to be revised and most of the conclusions are overstatements.\n\n\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **none**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2021-02-01T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nThe revised study remains underpowered to address the research question of treatment safety in TRD and somatic comorbidities. The study is missing actual power analyses. The results from 6 patients with epilepsy among a preliminary dataset from an observational study are more appropriate to publish as case reports or case series.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I am employed by Wayne State University School of Medicine\nI am employed by Wayne Health Physician Group\nI have received funding from Wayne State University School of Medicine\nI have received funding from the American Heart Association\nI have received funding from the National Institutes of Health (USA)\nI have received funding from the McManus Trust**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2021-01-11T01:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-01-11T00:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-27T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-12-22T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-21T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-20T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-20T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-08-06 15:20:50","doi":"10.21203/rs.3.rs-42473/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-12-17T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-12-16T00:00:00+00:00","index":3,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThis report of naturalistic single case study outcomes from a clinical setting seems to still be in \"first draft\" form. There are many grammatical and syntax errors, the table format is nearly uninterpretable, and in many cases the data in the tables doesn't add up. For example:\n N responder remitter nonresponder p V\nMale, sex (%) 21 (42.9) 6 (66.7) 2 (25.0) 13 (40.6) 0.229 0.26\n\nShouldn't \" responder remitter nonresponder\" % all add up to 100?\nDoes the 21 refer to only the males or the 21 with somatic conditions?\n\nThe contribution of concomitant medications like anti-epileptics to the finding seen in patients with epilepsy should be discussed.\n\n\"In patients with epilepsy, significant effects occurred for measurements after the infusion of 1, 6 and 8, with higher results obtained for patients with epilepsy.\"\nWhere is the data for this claim? Table 2 does not contain detailed analyses of outcomes at each infusion as stated.\n\nExtensive editing needs to be done to address statements like this:\n\"The aim of this paper is to investigate the safety and tolerability of Central Nervous System (CNS) in\nrelationship between dissociative measures and psychometric outcomes in course of intravenous\nketamine treatment with comorbidities in treatment refractory inpatients with MDD and BP.\"\nThis doesn't make sense in English.\n\nIn reporting the outcomes form this group, focus on the basic comparisons between the 21 patients with somatic conditions and those 28 without since there is enough statistical power there. How were the treatment or adverse event outcomes different or not between these 2? Within the group as a whole, how did somatic conditions or any demographic factor affect the chance of response, rate of response, or rate of adverse events, etc.? \nThe study is underpowered to examine sublevel relationships like specific somatic conditions. For those cases, shorter case reports or case series are probably more appropriate.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **No competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-11-10T00:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-06T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nthis is an interesting topic. However this study presents several issues from a methodological point of view. did you perform a power analysis? if yes please explain it, if not, why?\nmore comments below:\n1. \"Recent developments in rapid-acting antidepressants use in treatment resistant depression (TRD)\nprovide robust evidence for ketamine use in Major Depressive Disorder\"\nYou mention recent evidence: first, one reference refers to 2000, another to 2010. I would not define this as recent evidence. A third reference you use is a Cochrane review of 2015 in which authors concluded: \"We found limited evidence for ketamine's efficacy over placebo at time points up to one week in terms of the primary outcome, response rate. The effects were less certain at two weeks post-treatment.\".\n2. The aim of this paper is to investigate the safety and tolerability of Central Nervous System (CNS) in relationship between dissociative measures and psychometric outcomes in course of intravenous ketamine treatment with comorbidities in treatment refractory inpatients with MDD and BP. these aims are not clear and they are in contrast with the abstract. is the aim to evaluate dissociation or the general safety? and what about tolerability ? tolerability is the drop out rate due to adverse events, which you did not measured.\n3. All participants met criteria for TRD, defined as inadequate response to 2 or moreantidepressants (assessed by Massachusetts General Hospital Antidepressant Treatment ResponseQuestionnaire - ATRQ) in course of treatment of that particular episode\nUsually at least 2 AD of different categories (eg. SSRI and SNRI)\n4. Maybe I am wrong, but please explain to the reader the rule of the single patient single rater\n\n5. \"Any other significant adverse effect (e.g. nausea) was also monitored.\" How?\n6. Did you calculate a sample size based on power analysis ?\n\na last comment, why didn't you employ some controls?\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **none**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-10-06T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nWłodarczyk and colleagues present a study of the effects of ketamine on depressive symptoms and psychomimetic side effects in patients with treatment-refractory depression and treatment-refractory bipolar disorder. Their aim was to determine whether patients with comorbid somatic disorders were more likely to experience side effects and/or improved depressive symptoms after serial ketamine treatment.\n\nWhile the object of study is interesting, timely, and potentially impactful, the study design, methods, and results are very unclear, which unfortunately prevents proper evaluation of the paper as currently presented. It appears that the main result of the paper is based on 12 patients with epilepsy, and it is unclear whether proper corrections for multiple comparisons or small sample size were taken. Specific comments are below.\n\nPlease briefly define dissociative symptoms, somatic conditions, psychometric outcomes in the Introduction.\n\nMethods section in Abstract describes limitations, but does not describe the experimental or statistical methods applied.\n\nIt would be informative to state the direction of relationship between epilepsy and BPRS change in the abstract (i.e., did BPRS improve?).\n\nMethods p3 middle states that some patients \"significantly affected by somatic illness continued current mediation during ketamine treatment,\" yet at the bottom of p3, it seems that all patients continued current medication (and again in Results section p4). Please clarify. If only some patients continued current medication, please report how many epilepsy patients continued with current medication, as this could have affected reported outcome. In addition, the authors could consider including medication status (continued vs. not) as a nuisance factor in statistical analyses if appropriate.\n\nMethods p4 middle, please describe how patients were categorized as responders, remitters, and non-responders.\n\nMethods p4 middle, please describe the \"chain indexes\" statistical approach, including references to relevant citation(s). Please also include what dependent \u0026 independent variables were studied here, how frequently BPRS was measured, what nuisance factors (age, sex, MDD/BP, etc.) were included, etc.\n\nDoes this chain indexes approach analyze all timepoints in one tests, or is each timepoint measured separately? Please clarify, and include a rationale for approach to multiple comparisons correction.\n\nIn the methods section, please describe how somatic comorbidities were defined and assessed (e.g., medical record review? Patient self-report?), perhaps including references if appropriate.\n\nIn the Methods and/or in a table, please describe how often BPRS and CADSS was assessed (e.g., at each treatment?). Were all these assessments/timepoints included in statistical analyses?\n\nMethods section says statistical threshold was alpha = 0.05, but the Results section refers to a Bonferroni correction. Please clarify.\n\nIt doesn't seem that this study measures the safety and tolerability of ketamine, because it does not appear to measure side effects. Perhaps dissociative symptoms measured with CADSS is the intended side effect to be measured here? If so, this should be made clear in the Abstract, Introduction, and Methods that only one side effect is being studied (e.g., and not cardiac, allergic, or other side effects).\n\nTable 1 is difficult to read, and it is not clear what statistical test is applied in each row (frequency of remitter, responder, non-responder?). This could be added as a footnote in the Table.\n\nTable 2 appears to display results for CADSS, but results associated with BPRS change over time appear to be missing? It would be informative to include mean BPRS at relevant timepoints in a table or chart.\n\nIn Table 2, does this data refer to CADSS post-treatment, or across several treatments? Please clarify.\n\nThis manuscript could benefit from light English-language editing (but this did not affect my ability to review the manuscript). Introduction and Discussion sections could also be more cohesive; both include some single-sentence paragraphs.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-09-14T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-08-11T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-11T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-04T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-07-16T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-07-15T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-07-13T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a0787936-15c9-46e7-820c-ebd046abc617","owner":[],"postedDate":"January 7th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":253111,"name":"Psychiatry"}],"tags":[],"updatedAt":"2020-12-23T23:20:50+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-07 11:16:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-42473","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-42473","identity":"rs-42473","version":["v2"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}