- Email: [email protected]
Understanding cognitive dysfunction in depression in primary and secondary care in the UK: a multi-step consultation with clinicians
P.2.b. Mood disorders and treatment − Affective disorders (clinical) periods [1,2]. It is also a known fact that these patients have poorer empathic responses and deficient social skills persisting even during the remission of the clinical symptoms (consequences of a dysfunctional ability to comprehend and respond to emotional expressions of other people) [3]. These deficits may become important impediments for the social reintegration and recovery of bipolar and schizoaffective patients in remission. Objectives: The purpose of the study was to find potential differences between cognitive impairments, empathic response and emotion recognition abilities of schizoaffective and bipolar patients during the acute manic episode, but also in remission. Methods: The research was conducted on inpatients from the Timisoara Psychiatric Clinic, diagnosed with either bipolar disorder or schizoaffective disorder, according to ICD-10 criteria, and a healthy control group. In order to assess cognitive impairment, we used MoCA (Montreal Cognitive Assessment), a screening test for mild cognitive deficits. The empathic response was appraised using EQ (Empathy Quotient). To measure patients’ ability to understand other people’s mental states we used the revised version of the “Reading the Mind in the Eyes” test (“Eyes test”). Results: The study included 35 inpatients diagnosed with bipolar disorder, 32 inpatients with schizoaffective disorder and 40 healthy subjects (the control group). All inpatients were in acute manic episode upon study entry. The patient group consisted of 39 (68.4%) women and 18 (31.6%) men, with a mean age of 41.32 years (SD = 11.03). The control group was comprised of 19 males (47.5%) and 21 females (52.5%), with a mean age of 40.74 years (SD = 10.82). Statistically significant differences (p < 0.001) were found between the control group and the patients group in regard to executive functions, memory, attention, recall and abstraction. No significant statistical differences were found regarding neurocognitive functions between the two patient groups during the acute manic episode. However, cognitive functions were significantly more impaired (p = 0.04) in schizoaffective patients than in bipolar patients during remission (lower mean scores in bipolar patients regarding all the aforementioned parameters). We found statistically significant differences (p = 0.001) between the patient groups and the control group regarding empathy levels and emotion recognition abilities (lower mean empathy scores and poorer emotion recognition skills than the control group in both bipolar and schizoaffective patients). During the acute manic episode, no significant differences were found concerning the empathic response or the emotion recognition abilities between the two patient groups. Still, during remission, patients with schizoaffective disorder had significantly lower EQ mean scores than bipolar patients (p = 0.02) and gave significantly more incorrect answers in the “Eyes test” (p = 0.003). Conclusions: During euthymic periods, schizoaffective patients have lesser neurocognitive functioning and more severe emotional deficits than bipolar patients. The severity of cognitive and emotional deficits is similar in bipolar and schizoaffective disorder during the acute manic episode. References [1] Simonsen, C., Sundet, K., Vaskinn, A., Ueland, T., Romm, K.L., Hellvin, T., Melle, I., Friis, S., Andreassen, O.A., 2010. Psychosocial function in schizophrenia and bipolar disorder: relationship to neurocognition and clinical symptoms. J. Int. Neuropsychol. Soc. 16 (5), 771–783. [2] Tuulio-Henriksson, A., Per¨al¨a, J., Saarni, S.I., Isomets¨a, E., Koskinen, S., L¨onnqvist, J., Suvisaari, J., 2011. Cognitive functioning in severe psychiatric disorders: a general population study. Eur. Arch. Psychiatry Clin. Neurosci. 261, 447–456.
S399
[3] Derntl, B., Seidem, E.M., Schneider, F., Habel, U., 2012. How specific are emotional deficits? A comparison of empathic abilities in schizophrenia, bipolar and depressed patients. Schizophrenia Research 142:58−64.
P.2.b.035 Understanding cognitive dysfunction in depression in primary and secondary care in the UK: a multi-step consultation with clinicians A.H. Young1 ° , K. Bones2 , G.M. Goodwin3 , J. Harrison4 , C. Katona5 , R.H. McAllister-Williams6 , J. Rasmussen7 , S. Strong8 1 King’s College London, Institute of Psychiatry- Psychology and Neuroscience, London, United Kingdom; 2 Sussex Partnership NHS Foundation Trust, Occupational Therapy and Recovery Practice, Worthing, United Kingdom; 3 Oxford University, Department of Psychiatry, Oxford University, United Kingdom; 4 VU University Medical Center, Alzheimer Center, Amsterdam, The Netherlands; 5 University College London, Division of Psychiatry, London, United Kingdom; 6 Newcastle University, Institute of Neuroscience, Newcastle, United Kingdom; 7 Lingfield, General Practice, Surrey, United Kingdom; 8 Depression Alliance, Support Group, Croydon, United Kingdom Background: Cognitive dysfunction, an important aspect of depression, includes problems with thinking, concentration and memory [1]. Research suggests that cognitive dysfunction is highly prevalent in people with depression and has a significant impact on functioning [2]. However, it remains largely unrecognised, unmonitored and untreated [3]. We aimed to explore understanding of the burden, detection and management of cognitive dysfunction in major depressive disorder in the UK, highlighting priority areas to be addressed. Methods: Using a multi-step process, we obtained and evaluated the views of primary and secondary care experts in depression. In step 1, a multi-stakeholder steering committee (eight psychiatrists, psychologists, primary care physicians, occupational therapy, charity representatives) provided the key themes of burden, detection and management of cognitive dysfunction in depression, and developed ~10−15 statements on each. In step 2, 100 general practitioners (GPs) and 100 psychiatrists indicated their level of agreement with the statements as “strongly disagree”, “disagree”, “don’t know/uncertain”, “agree” or “strongly agree”. High agreement and Very high agreement were defined as >66% and >90%, respectively. In step 3, the steering committee reviewed feedback from step 2 and highlighted priority areas for future education and research. The steering committee was initiated and supported by Lundbeck Ltd, through an educational grant. Lundbeck Ltd did not influence content. Results: There was High/Very high agreement for the majority of statements: 10 of 13 statements related to burden of cognitive dysfunction in depression, seven of nine statements on detection and seven of 12 statements on management. Responses to several statements identified a lack of agreement, suggesting the need for further education, research and clinical guidance. Low agreement (50% agreement) was recorded for the statement Cognitive dysfunction in depression is independent of depressive symptoms: 50% of GPs and 57% of psychiatrists disagreed. Only 40% of GPs and 54% of psychiatrists agreed that More than 30% of patients experience persistent cognitive symptoms despite remission of depressive symptoms. Almost one-third of GPs (29%) disagreed that Cognitive dysfunction in depression is poorly understood
S400
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
by health-care professionals, compared to 15% of psychiatrists. Despite Very high agreement from psychiatrists, over half of GPs (54%) disagreed that Cognitive dysfunction in depression is more likely to be detected in secondary care (eg by psychiatrists) than in primary care (eg by GPs). Four statements relating to evidence for the effects of cognitive behavioural therapy, cognitive training/ behavioural activation, exercise or lifestyle changes on cognitive function in depression scored as low agreement, with 28−51% of physicians responding “Don’t know/uncertain”. Conclusions: These responses from UK physicians confirm that cognitive dysfunction in depression is an important area to address. There were generally high levels of agreement with, and certainty about, statements on burden and detection. Most respondents recognised the marked negative impact that cognitive dysfunction has on outcome and functioning in patients with depression. In contrast, there were generally lower levels of agreement and higher levels of uncertainty about statements on management, likely reflecting the lack of data available in this area. These data gaps should help focus future education and research. References ˚ Ardal, ˚ [1] Hammar, A., G., 2009. Cognitive functioning in major depression − a summary. Front Hum Neurosci 3, 26. [2] McIntyre, R.S., Cha, D.S., Soczynska, J.K., Woldeyohannes, H.O., Gallaugher, L.A., Kudlow, P., Alsuwaidan, M., Baskaran, A., 2013. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety 30, 515–527. [3] Greer, T.L., Kurian, B.T., Trivedi, M.H., 2010. Defining and measuring functional recovery from depression. CNS Drugs 24, 267–284. Disclosure statement: AY has received payment for lectures and advisory boards from all major pharmaceutical companies with drugs used in affective and related disorders is the Lead Investigator for the Embolden Study (AstraZeneca), BCI Neuroplasticity Study and Aripiprazole Mania Study investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth and received grant funding (past and present) from NIMH (USA), CIHR (Canada), NARSAD (USA), Stanley Medical Research Institute (USA), MRC (UK), Wellcome Trust (UK), Royal College of Physicians (Edinburgh, UK), BMA (UK), UBC-VGH Foundation (Canada), WEDC (Canada), CCS Depression Research Fund (Canada), MSFHR (Canada) and NIHR (UK). GG has received payment for consulting/advisory roles from H. Lundbeck, Medscape, MSD, Otsuka, Servier, Sunovion and Takeda received speaker honoraria from H. Lundbeck, Medscape and Servier received payment for clinical trials/research grants from Bailey Thomas Charitable Trust, Wellcome Trust and NIHR has stocks with P1VITAL and received book royalties from Fast Facts: Bipolar Disorder. JH has in the past 3 years received paid consultancy from the following companies and organisations: Abbvie, Alzheon, Amgen, Anavex, AstraZeneca, Avraham, Axon, Axovant, Biogen Idec, Boehringer Ingelheim, Bracket, Catenion, CRF Health, DeNDRoN, ePharmaSolutions, Eisai, Eli Lilly, Forum Pharma (previously EnVivo Pharma), GfHEu, Heptares, Janssen AI, Johnson & Johnson, Kaasa Health, Kyowa Hakko Kirin, H. Lundbeck A/S, MedAvante, Merck, MyCognition, Mind Agilis, Neurocog, Neurim, Neuroscios, Neurotrack, Novartis, Nutricia, Orion Pharma, Pharmanet/i3, Pfizer, Prana Biotech, PriceSpective, Probiodrug, Prophase, Prostrakan, Reviva, Roche, Sanofi, Servier, Shire, Takeda, TCG, TransTech Pharma and Velacor has received payment for CME activities from Medscape and Lundbeck holds options and a patent in Neurotrack and MyCognition, respectively has received royalties from Oxford University Press and Blackwell Publishers and has received research funding from Memorabel. CK has received honoraria, grant funding and consultancy payments from pharmaceutical companies including H. Lundbeck and Eli Lilly. HMW has received speaker fees from AstraZeneca, Bristol Myers-Squibb, Eli Lilly, Ferrer, GlaxoSmithKline, Janssen-Cilag, H. Lundbeck, Merck Sharp & Dohme, Pfizer, Servier, SPIMACO, Sunovian and Wyeth received consultancy fees from AstraZeneca, Bristol Myers-Squibb, Cyberonics, Eli Lilly, Ferrer, JanssenCilag, H. Lundbeck, Merck Sharp & Dohme, MyTomorrow, Servier, Sunovian and Wyeth and received independent investigator-led research support from AstraZeneca, Eli Lilly and Wyeth. JR has received payment for consultancy/advisory boards/Speaker Bureaus from Alzheimer’s Society, Cerestim Ltd, Chase Pharmaceuticals, Edmund de Rothschild, Eli Lilly, H.
Lundbeck, Ono, Otsuka, Pfizer, Roche, Servier, Wellcome Trust and Psinapse, and is a non-executive Director for Cerestim. KB and SS have no conflicts of interest to disclose. This work was supported by Lundbeck Ltd. Lundbeck Ltd did not influence content.
P.2.b.037 Lurasidone for major depressive disorder with mixed features: effect of baseline depression severity on clinical outcome C. Nelson1 , J. Tsai2 ° , Y. Mao3 , A. Pikalov4 , A. Loebel4 of California- San Francisco, Depression Center, San Francisco, USA; 2 Sunovion Pharmaceuticals- Inc., Marlborough MA, USA; 3 Sunovion Pharmaceuticals- Inc., Biometrics, Fort Lee, USA; 4 Sunovion Pharmaceuticals- Inc., Medical Affairs, Marlborough MA, USA
1 University
Introduction: Accumulating evidence indicates that major depressive disorder (MDD), with no prior history of mania or hypomania, but associated with subthreshold hypomanic symptoms (mixed features) is a common clinical presentation. MDD with mixed features has been reported to be associated with greater illness severity, increased frequency of depressive episode recurrence, increased risk for suicide attempt, anxiety disorder and substance abuse comorbidity, greater functional disability and poorer prognosis. The aim of this post-hoc analysis of a 6-week trial of lurasidone in patients with a diagnosis of MDD with mixed features [1] was to evaluate the impact of baseline depression severity on treatment response. Methods: Patients meeting DSM-IV-TR criteria for unipolar major depressive disorder, with a Montgomery-Asberg Depression Rating Scale (MADRS) score 26, who presented with 2 or 3 protocol-defined manic symptoms, were randomized to 6 weeks of double-blind treatment with either lurasidone 20−60 mg/d (N = 109) or placebo (N = 100). To evaluate the effect of illness severity on treatment response, three baseline depression severity groups were defined post-hoc: a moderate severity group (MADRS = 26−30), a marked severity group (MADRS = 31−35), and a high severity group (MADRS36) [2]. For each baseline severity group, baseline to week-6 changes in MADRS total score (primary), Clinical Global Impression, Severity Scale (CGI-S; key secondary), and Young Mania Rating Scale (YMRS) were analyzed using a mixed model for repeated measures analysis. Additional secondary measures of anxiety (Hamilton Anxiety Rating Scale; HAM-A) and functional disability (Sheehan Disability Scale; SDS) were evaluated by ANCOVA (LOCF). Results: At baseline, there were 59 patients who met MADRS criteria for moderate depression severity (mean MADRS total score, 28.6), 95 patients with marked severity (MADRS total, 33.1), and 54 patients with high severity (MADRS total, 38.7). On the primary endpoint, change from baseline to week-6 in MADRS total score, lurasidone treatment effect sizes increased as baseline severity increased from moderate to marked to high, respectively (d = 0.64, P = 0.022; d = 0.72, P = 0.001; d = 1.24, P < 0.0001); a similar effect size trend was observed for improvement at week 6 in the CGI-S score (d = 0.42, P = 0.137; d = 0.57; P = 0.009; d = 0.90; P = 0.002), the YMRS total score (d = 0.39, P = 0.159; d = 0.64, P = 0.003; d = 0.78, P = 0.006), the HAM-A total score (d = 0.70, P < 0.05; d = 0.76, P < 0.001; d = 0.87, P < 0.01), and the SDS total score (d = 0.43, ns; d = 0.70, P < 0.01; d = 0.89, P < 0.05). The mean modal daily dose of lurasidone was similar in the moderate (41.8 mg), marked (39.6 mg) and high (43.6 mg) severity groups.
S399
[3] Derntl, B., Seidem, E.M., Schneider, F., Habel, U., 2012. How specific are emotional deficits? A comparison of empathic abilities in schizophrenia, bipolar and depressed patients. Schizophrenia Research 142:58−64.
P.2.b.035 Understanding cognitive dysfunction in depression in primary and secondary care in the UK: a multi-step consultation with clinicians A.H. Young1 ° , K. Bones2 , G.M. Goodwin3 , J. Harrison4 , C. Katona5 , R.H. McAllister-Williams6 , J. Rasmussen7 , S. Strong8 1 King’s College London, Institute of Psychiatry- Psychology and Neuroscience, London, United Kingdom; 2 Sussex Partnership NHS Foundation Trust, Occupational Therapy and Recovery Practice, Worthing, United Kingdom; 3 Oxford University, Department of Psychiatry, Oxford University, United Kingdom; 4 VU University Medical Center, Alzheimer Center, Amsterdam, The Netherlands; 5 University College London, Division of Psychiatry, London, United Kingdom; 6 Newcastle University, Institute of Neuroscience, Newcastle, United Kingdom; 7 Lingfield, General Practice, Surrey, United Kingdom; 8 Depression Alliance, Support Group, Croydon, United Kingdom Background: Cognitive dysfunction, an important aspect of depression, includes problems with thinking, concentration and memory [1]. Research suggests that cognitive dysfunction is highly prevalent in people with depression and has a significant impact on functioning [2]. However, it remains largely unrecognised, unmonitored and untreated [3]. We aimed to explore understanding of the burden, detection and management of cognitive dysfunction in major depressive disorder in the UK, highlighting priority areas to be addressed. Methods: Using a multi-step process, we obtained and evaluated the views of primary and secondary care experts in depression. In step 1, a multi-stakeholder steering committee (eight psychiatrists, psychologists, primary care physicians, occupational therapy, charity representatives) provided the key themes of burden, detection and management of cognitive dysfunction in depression, and developed ~10−15 statements on each. In step 2, 100 general practitioners (GPs) and 100 psychiatrists indicated their level of agreement with the statements as “strongly disagree”, “disagree”, “don’t know/uncertain”, “agree” or “strongly agree”. High agreement and Very high agreement were defined as >66% and >90%, respectively. In step 3, the steering committee reviewed feedback from step 2 and highlighted priority areas for future education and research. The steering committee was initiated and supported by Lundbeck Ltd, through an educational grant. Lundbeck Ltd did not influence content. Results: There was High/Very high agreement for the majority of statements: 10 of 13 statements related to burden of cognitive dysfunction in depression, seven of nine statements on detection and seven of 12 statements on management. Responses to several statements identified a lack of agreement, suggesting the need for further education, research and clinical guidance. Low agreement (50% agreement) was recorded for the statement Cognitive dysfunction in depression is independent of depressive symptoms: 50% of GPs and 57% of psychiatrists disagreed. Only 40% of GPs and 54% of psychiatrists agreed that More than 30% of patients experience persistent cognitive symptoms despite remission of depressive symptoms. Almost one-third of GPs (29%) disagreed that Cognitive dysfunction in depression is poorly understood
S400
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
by health-care professionals, compared to 15% of psychiatrists. Despite Very high agreement from psychiatrists, over half of GPs (54%) disagreed that Cognitive dysfunction in depression is more likely to be detected in secondary care (eg by psychiatrists) than in primary care (eg by GPs). Four statements relating to evidence for the effects of cognitive behavioural therapy, cognitive training/ behavioural activation, exercise or lifestyle changes on cognitive function in depression scored as low agreement, with 28−51% of physicians responding “Don’t know/uncertain”. Conclusions: These responses from UK physicians confirm that cognitive dysfunction in depression is an important area to address. There were generally high levels of agreement with, and certainty about, statements on burden and detection. Most respondents recognised the marked negative impact that cognitive dysfunction has on outcome and functioning in patients with depression. In contrast, there were generally lower levels of agreement and higher levels of uncertainty about statements on management, likely reflecting the lack of data available in this area. These data gaps should help focus future education and research. References ˚ Ardal, ˚ [1] Hammar, A., G., 2009. Cognitive functioning in major depression − a summary. Front Hum Neurosci 3, 26. [2] McIntyre, R.S., Cha, D.S., Soczynska, J.K., Woldeyohannes, H.O., Gallaugher, L.A., Kudlow, P., Alsuwaidan, M., Baskaran, A., 2013. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety 30, 515–527. [3] Greer, T.L., Kurian, B.T., Trivedi, M.H., 2010. Defining and measuring functional recovery from depression. CNS Drugs 24, 267–284. Disclosure statement: AY has received payment for lectures and advisory boards from all major pharmaceutical companies with drugs used in affective and related disorders is the Lead Investigator for the Embolden Study (AstraZeneca), BCI Neuroplasticity Study and Aripiprazole Mania Study investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth and received grant funding (past and present) from NIMH (USA), CIHR (Canada), NARSAD (USA), Stanley Medical Research Institute (USA), MRC (UK), Wellcome Trust (UK), Royal College of Physicians (Edinburgh, UK), BMA (UK), UBC-VGH Foundation (Canada), WEDC (Canada), CCS Depression Research Fund (Canada), MSFHR (Canada) and NIHR (UK). GG has received payment for consulting/advisory roles from H. Lundbeck, Medscape, MSD, Otsuka, Servier, Sunovion and Takeda received speaker honoraria from H. Lundbeck, Medscape and Servier received payment for clinical trials/research grants from Bailey Thomas Charitable Trust, Wellcome Trust and NIHR has stocks with P1VITAL and received book royalties from Fast Facts: Bipolar Disorder. JH has in the past 3 years received paid consultancy from the following companies and organisations: Abbvie, Alzheon, Amgen, Anavex, AstraZeneca, Avraham, Axon, Axovant, Biogen Idec, Boehringer Ingelheim, Bracket, Catenion, CRF Health, DeNDRoN, ePharmaSolutions, Eisai, Eli Lilly, Forum Pharma (previously EnVivo Pharma), GfHEu, Heptares, Janssen AI, Johnson & Johnson, Kaasa Health, Kyowa Hakko Kirin, H. Lundbeck A/S, MedAvante, Merck, MyCognition, Mind Agilis, Neurocog, Neurim, Neuroscios, Neurotrack, Novartis, Nutricia, Orion Pharma, Pharmanet/i3, Pfizer, Prana Biotech, PriceSpective, Probiodrug, Prophase, Prostrakan, Reviva, Roche, Sanofi, Servier, Shire, Takeda, TCG, TransTech Pharma and Velacor has received payment for CME activities from Medscape and Lundbeck holds options and a patent in Neurotrack and MyCognition, respectively has received royalties from Oxford University Press and Blackwell Publishers and has received research funding from Memorabel. CK has received honoraria, grant funding and consultancy payments from pharmaceutical companies including H. Lundbeck and Eli Lilly. HMW has received speaker fees from AstraZeneca, Bristol Myers-Squibb, Eli Lilly, Ferrer, GlaxoSmithKline, Janssen-Cilag, H. Lundbeck, Merck Sharp & Dohme, Pfizer, Servier, SPIMACO, Sunovian and Wyeth received consultancy fees from AstraZeneca, Bristol Myers-Squibb, Cyberonics, Eli Lilly, Ferrer, JanssenCilag, H. Lundbeck, Merck Sharp & Dohme, MyTomorrow, Servier, Sunovian and Wyeth and received independent investigator-led research support from AstraZeneca, Eli Lilly and Wyeth. JR has received payment for consultancy/advisory boards/Speaker Bureaus from Alzheimer’s Society, Cerestim Ltd, Chase Pharmaceuticals, Edmund de Rothschild, Eli Lilly, H.
Lundbeck, Ono, Otsuka, Pfizer, Roche, Servier, Wellcome Trust and Psinapse, and is a non-executive Director for Cerestim. KB and SS have no conflicts of interest to disclose. This work was supported by Lundbeck Ltd. Lundbeck Ltd did not influence content.
P.2.b.037 Lurasidone for major depressive disorder with mixed features: effect of baseline depression severity on clinical outcome C. Nelson1 , J. Tsai2 ° , Y. Mao3 , A. Pikalov4 , A. Loebel4 of California- San Francisco, Depression Center, San Francisco, USA; 2 Sunovion Pharmaceuticals- Inc., Marlborough MA, USA; 3 Sunovion Pharmaceuticals- Inc., Biometrics, Fort Lee, USA; 4 Sunovion Pharmaceuticals- Inc., Medical Affairs, Marlborough MA, USA
1 University
Introduction: Accumulating evidence indicates that major depressive disorder (MDD), with no prior history of mania or hypomania, but associated with subthreshold hypomanic symptoms (mixed features) is a common clinical presentation. MDD with mixed features has been reported to be associated with greater illness severity, increased frequency of depressive episode recurrence, increased risk for suicide attempt, anxiety disorder and substance abuse comorbidity, greater functional disability and poorer prognosis. The aim of this post-hoc analysis of a 6-week trial of lurasidone in patients with a diagnosis of MDD with mixed features [1] was to evaluate the impact of baseline depression severity on treatment response. Methods: Patients meeting DSM-IV-TR criteria for unipolar major depressive disorder, with a Montgomery-Asberg Depression Rating Scale (MADRS) score 26, who presented with 2 or 3 protocol-defined manic symptoms, were randomized to 6 weeks of double-blind treatment with either lurasidone 20−60 mg/d (N = 109) or placebo (N = 100). To evaluate the effect of illness severity on treatment response, three baseline depression severity groups were defined post-hoc: a moderate severity group (MADRS = 26−30), a marked severity group (MADRS = 31−35), and a high severity group (MADRS36) [2]. For each baseline severity group, baseline to week-6 changes in MADRS total score (primary), Clinical Global Impression, Severity Scale (CGI-S; key secondary), and Young Mania Rating Scale (YMRS) were analyzed using a mixed model for repeated measures analysis. Additional secondary measures of anxiety (Hamilton Anxiety Rating Scale; HAM-A) and functional disability (Sheehan Disability Scale; SDS) were evaluated by ANCOVA (LOCF). Results: At baseline, there were 59 patients who met MADRS criteria for moderate depression severity (mean MADRS total score, 28.6), 95 patients with marked severity (MADRS total, 33.1), and 54 patients with high severity (MADRS total, 38.7). On the primary endpoint, change from baseline to week-6 in MADRS total score, lurasidone treatment effect sizes increased as baseline severity increased from moderate to marked to high, respectively (d = 0.64, P = 0.022; d = 0.72, P = 0.001; d = 1.24, P < 0.0001); a similar effect size trend was observed for improvement at week 6 in the CGI-S score (d = 0.42, P = 0.137; d = 0.57; P = 0.009; d = 0.90; P = 0.002), the YMRS total score (d = 0.39, P = 0.159; d = 0.64, P = 0.003; d = 0.78, P = 0.006), the HAM-A total score (d = 0.70, P < 0.05; d = 0.76, P < 0.001; d = 0.87, P < 0.01), and the SDS total score (d = 0.43, ns; d = 0.70, P < 0.01; d = 0.89, P < 0.05). The mean modal daily dose of lurasidone was similar in the moderate (41.8 mg), marked (39.6 mg) and high (43.6 mg) severity groups.