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Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study
Progress in Neuro-Psychopharmacology & Biological Psychiatry 68 (2016) 9–14
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Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study☆ Steven D. Targum a,⁎, Trisha Suppes b, J. Cara Pendergrass a, Sang Lee a, Robert Silva c, Josephine Cucchiaro c, Antony Loebel c a b c
Bracket Global and Clintara, LLC, Boston, MA, United States Stanford University School of Medicine, Palo Alto, CA, United States Sunovion Pharmaceuticals Inc., Fort Lee, NJ and Marlborough, MA, United States
a r t i c l e
i n f o
Article history: Received 16 December 2015 Received in revised form 17 February 2016 Accepted 19 February 2016 Available online 22 February 2016 Keywords: Major depressive disorder Mixed features specifier Subthreshold hypomania Depression subtypes Lurasidone
a b s t r a c t Major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features), has been identified as a distinct nosological entity in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We identified the predominant manic symptoms present at baseline in a multiregional, placebocontrolled trial involving 211 patients with MDD with mixed features (Clinicaltrials.gov NCT01421134). Patients with 2 or 3 DSM-5 criteria defined manic symptoms were eligible for the study. At study baseline, increased talkativeness (pressure to keep talking) and flight of ideas (racing thoughts) were endorsed by approximately 65% of patients and a decreased need for sleep was endorsed by 40% of patients. Approximately 60% of patients also endorsed irritability and distractibility at baseline although these symptoms are not generally counted as part of the “mixed” depression diagnosis as they may overlap with criteria for MDD. Thus, five clinical symptoms characterized the manic presentation in the majority of patients diagnosed as having MDD with “mixed” features in this first placebo-controlled trial examining the use of a psychotropic medication (lurasidone) in this population. Our findings support the designation of MDD with mixed features specifier and suggest that this subpopulation of depressed patients may warrant additional medication beyond antidepressants. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Twenty-five to forty percent of patients with major depressive disorder (MDD) present with concurrent manic symptoms during acute mood episodes that fall short of meeting the criteria for hypomania (bipolar II disorder) or mania (bipolar I disorder) (Judd and Akiskal, 2003; Sato et al., 2003; Benazzi, 2003, 2008; Suppes et al., 2005; Gazalle et al., 2005; McElroy, 2008; Goldberg et al., 2007, 2009; Gonzalez-Pinto et al., 2011; Nusslock and Frank, 2011; Angst et al., 2010, 2011; Merikangas et al., 2011; APA, 2013; Mcintyre et al., 2013, 2015; Targum and Nierenberg, 2011; Koukopoulos et al., 2013; Sani et al., 2014; Zaninotto et al., 2014). The DSM-5 classification added a specifier for depressive disorders to account for subthreshold manic symptoms that occur in acutely depressed patients and designated this new diagnostic category
☆ Funding for this study was provided by Sunovion Pharmaceuticals as part of a quality assurance program conducted under contract to Clintara LLC. ⁎ Corresponding author at: 11 Beacon Street Suite 600, Boston, MA 02108, United States. E-mail address: [email protected] (S.D. Targum).
http://dx.doi.org/10.1016/j.pnpbp.2016.02.007 0278-5846/© 2016 Elsevier Inc. All rights reserved.
major depressive disorder with mixed features (APA, 2013; Hu et al., 2014). Using these criteria in a multi-site survey of 506 acutely depressed MDD patients, McIntyre et al. (2015) reported that 26% of these patients met the “mixed” features specifier. Conventional antidepressants may be ineffective in treating the manic and/or depressive components of “mixed” depression and may even precipitate or exacerbate manic symptoms (Sato et al., 2003; Goldberg et al., 2007; Benazzi, 2008; Zimmermann et al., 2009; Angst et al., 2011; APA, 2013). Consequently, some clinical studies have evaluated the use of atypical antipsychotic medications for patients with “mixed” depression (Patkar et al., 2012; Mcintyre et al., 2013; Suppes et al., 2015). Some researchers believe that this new diagnostic designation is simply a precursor of bipolar disorder and that patients meeting these criteria should be treated as such (Benazzi, 2005; APA, 2013; Zaninotto et al., 2014). Koukopoulos et al. (2013) believe that the DSM-5 designation of MDD with mixed features is inadequate because it does not include psychomotor agitation or irritability as symptoms and may fail to identify many depressed patients who have mixed states. Recently, Sani et al. (2014) reported that psychic agitation, marked irritability, and mood reactivity were common symptoms in a study of 406 MDD patients presenting with mixed depression.
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Ultimately, the value of any change in a diagnostic classification system is to provide a more consistent and clinically meaningful representation of the disorders it attempts to classify and to facilitate earlier diagnostic differentiation to abet more effective treatment strategies (Targum et al., 2008; Stahl, 2013; Hu et al., 2014). One approach to examine the utility of a “new” diagnostic designation is to examine the clinical presentation of patients that clinicians believe meet criteria for the disorder. In the present study, we examined the presence and severity of depressive and manic symptoms in 211 patients with depression with mixed features who participated in a multiregional, placebocontrolled clinical trial. These findings reflect the thorough clinical assessments of investigators in 5 different countries regarding the clinical characteristics of patients meeting the diagnostic criteria for “mixed” depression. 2. Materials and methods This study was done as part of the subject selection approval process for a clinical trial called RESOLVE 1: a randomized, 6-week, doubleblind, placebo-controlled, flexible-dose, parallel group study of lurasidone for the treatment of major depressive disorder with mixed features (Clinicaltrials.gov NCT01421134). Forty-four clinical trial sites located in Russia, Serbia, Ukraine, United Kingdom, and the United States participated in the study between April 2011 and October 2014. A full description of the study design and treatment results has been reported elsewhere (Suppes et al., 2015). In this study, “mixed” depression was defined as a patient who currently met the diagnostic criteria for MDD, was currently experiencing a major depressive episode (diagnosed by DSM IV TR with the current major depressive episode duration of at least 2 weeks but less than 12 months) and who had two or three manic symptoms that occurred on most days over at least the last 2 weeks prior to screening. These criteria differ from the DSM-5 criteria that specified that 3 manic symptoms were required for this diagnosis (APA, 2013). The eligible manic symptoms included the following seven symptoms (per DSM-5): • • • • •
Elevated, expansive mood Inflated self-esteem or grandiosity More talkative than usual or pressure to keep talking Flight of ideas or subjective experience that thoughts are racing Increase in energy or goal-directed activity (either socially, at work or school, or sexually) • Increased or excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted from insomnia).
The diagnosis was confirmed by the Structured Clinical interview for DSM-IV, clinical trial version (SCID-CT) that was modified to include “mixed” features for this study (First et al., 2007). Patients were excluded from the study if they had a lifetime history of any bipolar I manic, mixed manic episode, or psychotic disorder, had treatment resistant depression, or any Axis I or Axis II diagnosis (other than MDD) that was the primary focus of treatment within 3 months of the screen visit (including all anxiety disorders, PTSD, eating disorders, or alcohol or substance abuse or dependence). In addition, eligible patients had a minimum score of 26 on the Montgomery Asberg Depression Rating Scale (MADRS) at screening and baseline utilizing the Structured Interview Guide for the MADRS (Montgomery and Asberg, 1979; Williams and Kobak, 2008). The Young Mania Rating Scale (YMRS) was used to assess manic symptoms; no minimum YMRS entry criterion was used (Young et al., 1978). A “dual” review process was used for diagnostic verification, identification
of excluded psychiatric diagnoses, and confirmatory scoring of the MADRS and YMRS that included audio-digital recording of the key screening instruments and a site-independent review (Targum and Pendergrass, 2014). The study was conducted in compliance with the informed consent regulations of an Institutional Review Board (IRB) and International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) Guidelines at the 44 clinical trial sites. All potential subjects consented to participate in the study and to the use of audio-digital recording instruments for independent clinical review. Raters at all trial sites participated in a standardized, formal rater training and certification program and met minimum qualification standards for inter-rater reliability between raters and demonstration of interviewing competence. The training program included didactic training for all efficacy measures at the investigator meeting or on-line, observation and scoring of expert demonstration MADRS and YMRS interviews with subsequent inter-rater reliability assessment of their scoring performance, and interviewing skills assessment via mock recorded MADRS and YMRS interviews. Audio-digital recording and site-independent scoring of the MADRS and YMRS interviews during the study provided additional opportunities to identify poor ratings performance. Rater remediation was provided when necessary although some raters were ultimately exempted from rating in this study. Statistical analysis included Student's t test and Chi-square analyses to evaluate group differences and examine the frequency of each presenting manic or depressive symptom. 3. Results 211 patients met the study eligibility criteria and were enrolled in the study across 44 clinical trial sites. The study enrolled 62 patients from the United States, 4 from the United Kingdom, 52 from Serbia, 62 from Ukraine, and 31 from the Russian clinical trial sites. The study was conducted between April 2011 and October 2014. 3.1. Characteristics of the enrolled subjects Table 1 lists the demographic and symptom severity scores for the 211 patients who met the entry criteria for “mixed” depression and were randomized in the study. The mean MADRS score was 33.2 ± 4.2 (SD), the mean YMRS score was 10.7 ± 4.5, and the mean Ham-A score was 16.9 ± 6.4 for the study population at the baseline visit. Table 2 presents the individual mean item scores of the MADRS and YMRS as scored by site-based raters at baseline. The MADRS items of Table 1 Patients with “mixed” depression: demographic and clinical characteristics. All subjects Male n (%) Age, years n (SD) Age ≤ 30 n (%) Age 31–50 Age ≥ 51 Race n (%) Black Caucasian Other Number of lifetime major depressive episodes Total number Number with mixed features Duration of current episode, days Major depressive features Concurrent mixed features MADRS score CGI-S score Young Mania Rating Scale (YMRS) score HAM-A total score Sheehan Disability Scale total score
211 64 (30.3%) 44.8 (12.2) 31 (14.7%) 109 (51.7%) 71 (33.6%) 27 (12.8%) 181 (85.8%) 3 (1.4%) Mean (SD) 4.4 (4.0) 2.4 (3.3) 104.1 (83.8) 77.2 (80.5) 33.2 (4.2) 4.5 (0.6) 10.7 (4.5) 16.9 (6.4) 20.2 (5.0)
S.D. Targum et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 68 (2016) 9–14 Table 2 Mean scores on individual MADRS and YMRS items at the baseline visit. Mean (SD) MADRSa MADRS 01 MADRS 02 MADRS 03 MADRS 04 MADRS 05 MADRS 06 MADRS 07 MADRS 08 MADRS 09 MADRS 10
Reported sadness Apparent sadness Inner tension Reduced sleep Reduced appetite Concentration difficulties Lassitude Inability to feel/loss of interest Pessimistic thoughts Suicidal thoughts
4.1 (0.8) 4.4 (0.7) 3.3 (1.0) 4.3 (1.1) 3.0 (1.7) 4.0 (0.9) 3.6 (1.1) 3.7 (0.8) 2.4 (1.2) 0.5 (0.8)
YMRSa YMRS 01 YMRS 02 YMRS 03 YMRS 04 YMRS 05 YMRS 06 YMRS 07 YMRS 08 YMRS 09 YMRS 10 YMRS 11
Elevated mood Increased motor activity/energy Sexual interest Decreased need for sleep Irritability Speech (rate or amount) Language–thought disorder Thought content Disruptive–aggressive behavior Appearance Insight
0.4 (0.7) 1.0 (1.3) 0.2 (0.6) 2.0 (0.9) 1.9 (1.4) 2.1 (2.1) 1.3 (1.0) 0.5 (1.1) 0.7 (1.1) 0.5 (0.6) 0.2 (0.6)
a
n = 211 enrolled subjects (MADRS: Montgomery–Asberg Depression Rating Scale; YMRS: Young Mania Rating Scale).
sadness, decreased sleep, and concentration difficulties were associated with the highest mean item scores. The YMRS items of decreased need for sleep, an increased rate or amount of speech (talkativeness), and irritability were associated with the highest mean item scores. Table 3 lists the past psychiatric hospitalizations and psychopharmacologic treatment history of this population of patients with “mixed” depression. Approximately 10% reported having never received any antidepressant medication prior to this study. One-third of these patients had received mood stabilizers and approximately half had received antipsychotic medication at some time prior to screening. Fig. 1 reveals the number and type of manic symptoms reported by patients on the SCID-CT screening interview. One hundred and thirtythree patients (63.0%) reported two and 78 patients (37.0%) reported three of the seven protocol-specified manic symptoms queried on the SCID-CT as being present for at least two weeks prior to screening. The most frequently reported manic symptoms (flight of ideas or racing thoughts (66.8%), increased talkativeness or pressured speech (61.1%)
Table 3 Treatment history of subjects with “mixed” depressiona. n (%) Previous psychiatric hospitalizations None 1 ≥2 Previous lifetime antidepressant treatments None 1 ≥2 Previous lifetime mood stabilizer treatments None 1 ≥2 Previous lifetime antipsychotic treatments None 1 ≥2
104 (49.3%) 44 (20.9%) 63 (29.9%) 22 (10.4%) 40 (19.0%) 149 (70.6%) 142 (67.3%) 46 (21.8%) 23 (10.9%) 112 (53.1%) 40 (19.0%) 59 (28.0%)
a Reflects hospitalization and psychopharmacologic treatment history preceding the current episode. Treatments were defined as having an adequate dose and adequate duration.
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and decreased need for sleep (40.8%) had the highest individual item baseline severity scores on the Young Mania Rating Scale (Table 2). Reported sadness, apparent sadness, decreased sleep, and concentration difficulties had the highest baseline severity scores on the MADRS (Table 2). Table 4 lists the distribution of specific manic symptoms reported by patients with 2 or 3 eligible symptoms in this study. There was no significant difference between patients reporting 2 or 3 manic symptoms relative to the distribution of reported manic symptoms (Kolmogorov– Smirnov test: p = 0.938). 3.2. Agitation, irritability, and distractibility Psychomotor agitation, irritability, and distractibility are not included as symptoms in the DSM-5 mixed features specifier as these symptoms may overlap with unipolar depression and can therefore be regarded as nonspecific (APA, 2013). A high proportion of patients reported experiencing distractibility (59.2%), irritability (57.3%), and psychomotor agitation (36.5%) at study baseline (Fig. 1). 4. Discussion We examined the clinical characteristics and symptom severity of 211 patients meeting the study protocol criteria for MDD with mixed features as part of the RESOLVE 1 clinical trial of lurasidone treatment in this population. The study design and full study results have been reported elsewhere (Suppes et al., 2015). Most patients entered the study with marked depressive symptoms (mean baseline MADRS score was 33.2 ± 4.2) and mild severity of manic symptoms (mean YMRS score was 10.7 ± 4.5). Thus, the presenting symptomatology is consistent with a clinical condition of acute MDD with subthreshold manic symptoms (“mixed” depression). The most frequent manic symptoms reported on the modified SCIDCT that were present for at least 2 weeks prior to screening and that met the eligibility criteria were flight of ideas (racing thoughts) and increased talkativeness (or pressured speech). These two symptoms were still reported as one of the 2 or 3 eligible manic symptoms by approximately 65% of patients at study baseline. Our data are consistent with Koukopoulos et al. (2013) who reported that flight of ideas and increased talkativeness were the most common “mixed” manic symptoms seen in their acutely depressed patients in their European practice. In addition, 40% of patients reported a reduced need for sleep at the study baseline visit as well. The most commonly reported manic symptoms identified by the SCID-CT diagnostic screen were also identified by the symptomatic rating questionnaires. Data from the individual item analyses of the YMRS (Fig. 1) identified increased talkativeness (increased rate or amount of speech) as the most prominent presenting manic-related symptom in this patient population. Flights of ideas or racing thoughts are subsumed as symptoms under the YMRS item for language–thought disorder. Similarly, the MADRS identified decreased need for sleep as a prominent symptom in these depressed patients. The MADRS and YMRS also identified irritability and distractibility (concentration difficulties) as prominent symptoms in approximately 60% of patients at the screening visit. The DSM-5 criteria specifically exclude psychomotor agitation, irritable mood, and distractibility from the diagnostic criteria for the mixed features specifier stating that these symptoms may overlap with acute depression as part of a major depressive episode (APA, 2013). Koukopoulos and colleagues (2013) have noted that many patients with “mixed” depression present with these symptoms and challenge the validity of the DSM-5 “mixed” features criteria as creating a clinical construct that is rare rather than relevant. According to some authors, the addition of irritability and agitation to the criteria increases the prevalence of “mixed” depressive states from 0 to 12% to a more relevant 33–47% (Angst et al., 2011; Koukopoulos et al., 2013; Koukopoulos and Sani, 2014; Sani et al., 2014). Recently,
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Fig. 1. Frequency of manic and non-specific symptoms endorsed by patients with “mixed” depression.
Sani et al. (2014) validated Koukopoulos' diagnostic criteria for “mixed” depression that includes psychic agitation, irritability, and mood reactivity as common features of this disorder. Our independent data are consistent with these findings and reveal that irritability and distractibility were reported as often as increased talkativeness and flight of ideas and suggest that these symptoms co-exist within the “mixed” depression patient population (Fig. 1). Therefore, it would seem that the identification and treatment of distractibility, irritability, and psychomotor agitation should be considered as part of the overall treatment plan for “mixed” depression. There are some possible limitations in this study that warrant mention. First, the reported data was collected from patients who met the protocol criteria for MDD with mixed features. A possible limitation of
our findings is that we did not include a “control” group of MDD patients without manic features for comparison of non-specific symptoms. Second, patients were included in this study from 44 different clinical trial sites. Inter-rater reliability is always a concern and potential limitation in any multi-site, multi-regional study. To address this concern, all site-based raters successfully completed a rater training and certification program prior to participating in this study and we employed an audio-digital recording surveillance strategy to enhance ratings precision and identify ratings discrepancies during the study. Third, our findings on treatment history (Table 3) require cautious interpretation because the source of information was the depressed subject's report at the screening visit (and any medical records, if available). Future studies might seek more reliable documentation to examine the use of
Table 4 Distribution of manic symptoms among patients reporting 2 or 3 symptoms. Eligible manic symptoms*
SCID 01
SCID 02
SCID 03
SCID 04
SCID 05
SCID 06
SCID 07
2 reported symptoms (n = 133)
11 (8.3%) 27 (34.6%)
5 (3.8%) 8 (10.3%)
73 (54.9%)
89 (67.0%) 51 (65.4%)
31 (23.3%) 27 (34.6%)
19 (14.3%) 14 (17.9%)
46 (34.6%) 40 (51.3%)
3 reported symptoms (n = 78)
55 (70.5%)
Kolmogorov–Smirnov test; p = 0.9375 *Description of eligible manic symptoms from customized SCID-CT: SCID-CT-01: Elevated, expansive mood. SCID-CT-02: Inflated self-esteem or grandiosity. SCID-CT-03: More talkative than usual or pressure to keep talking. SCID-CT-04: Flight of ideas or subjective experience that thoughts are racing. SCID-CT-05: Increase in energy or goal-directed activity (either socially, at work or school, or sexually). SCID-CT-06: Increased or excessive involvement in activities that have a high potential for painful consequences. SCID-CT-07: Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted from insomnia).
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prior clinical history and combination treatments in this patient population. Finally, a possible limitation of this study is that our eligibility criteria were not identical to the recently published DSM-5 criteria that require in part at least 3 of the 7 specified manic symptoms to meet the “mixed” specifier condition (APA, 2013). We accepted 2 or 3 of the 7 possible DSM-5 defined manic symptoms in this study. As noted in Table 4, there was little difference in the clinical characteristics of patients presenting with 2 or 3 manic symptoms. Among the patients presenting with 3 manic symptoms, 70.5% endorsed increased talkativeness, 65.4% endorsed racing thoughts (flight of ideas), and 51.3% of patients endorsed a decreased need for sleep. A clinically relevant and useful diagnostic classification system seeks to identify a group of patients who have common clinical features and who might respond to specific treatment interventions. In clinical practice, it is important to recognize the presence of “mixed” symptoms in patients presenting with primarily acute depressive symptoms. It is not uncommon for manic symptoms to be missed in patients with mood disorders (Angst et al., 2011). In fact, only one-third of the patients in this sample population of “mixed” depression had ever received mood stabilizers (Table 3). In one survey of over 4000 bipolar patients, it took an average of 10 years before the correct diagnosis was made despite multiple consultations (Nusslock and Frank, 2011). The presence of any manic symptoms should alert clinicians to the need for increased vigilance and the possible introduction of additional medications or other changes in the drug regimen (Gazalle et al., 2005; Goldberg et al., 2007; Hu et al., 2014). 5. Conclusion In summary, racing thoughts and increased talkativeness were the two most prominent manic symptoms reported by approximately 65% of patients and decreased need for sleep by 40% of patients with MDD with “mixed” features at study baseline. Distractibility and irritability were also reported by approximately 60% of these patients as well. Hence, a four- or five-symptom cluster characterizes these “mixed” depressed patients within the larger population of patients with MDD. Conventional antidepressants may be ineffective in treating both the depressive and manic symptoms in these “mixed” depressed patients and may even precipitate hypomania. Consequently, the early recognition of “mixed” depression is of vital importance for treatment planning and the use of additional medications may be warranted. Contributors Drs. Targum, Suppes, Pendergrass, Silva, Cucchiaro and Loebel all contributed to the study design, implementation, and data analysis for this study. Mr. Lee contributed to the statistical analysis of the data. All authors have approved this final manuscript. Author disclosures Dr. Targum is an employee of Bracket Global and Clintara LLC, which was working under contract to Sunovion Pharmaceuticals in the conduct of this study. Dr. Targum has received consulting fees, retainers, or travel expenses from Alkermes, BioMarin, Forum Pharmaceuticals, Functional Neuromodulation, Johnson and Johnson PRD, Methylation Sciences Inc., Neurim Pharmaceuticals, One Carbon Therapeutics, Prana Biotechnology Ltd., Resilience Therapeutics, Roche labs, and Sophiris. Dr. Suppes has received funding, medications for clinical grants, consulting fees and/or travel expenses from AstraZeneca, Elan Pharma International, H Lundbeck A/S, Merck, NIMH, VA cooperative studies program, Sunovion Pharmaceuticals, and royalties from UpToDate and Jones and Bartlett (formerly Compact clinical trials).
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Dr. Pendergrass and Mr. Lee are employees of Bracket Global and Clintara. Drs. Silva, Cucchiaro, and Loebel are employees of Sunovion Pharmaceuticals, Inc. Acknowledgements and funding source Funding for this study was provided by Sunovion Pharmaceuticals as part of a quality assurance program conducted under contract to Clintara LLC. The authors listed from Sunovion participated in the study design, analysis, interpretation of data, and in the decision to submit the paper for publication. References American Psychiatric Association., 2013l. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Press, Arlington VA. Angst, J., Cui, L., Swendsen, J., Rothen, S., Cravchik, A., Kessler, R.C., Merikangas, K.R., 2010. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am. J. Psychiatry 167 (10), 1194–1201. Angst, J., Azorin, J.M., Bowden, C.I., Perugi, G., Vieta, E., Gamma, A., et al., 2011. 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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp
Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study☆ Steven D. Targum a,⁎, Trisha Suppes b, J. Cara Pendergrass a, Sang Lee a, Robert Silva c, Josephine Cucchiaro c, Antony Loebel c a b c
Bracket Global and Clintara, LLC, Boston, MA, United States Stanford University School of Medicine, Palo Alto, CA, United States Sunovion Pharmaceuticals Inc., Fort Lee, NJ and Marlborough, MA, United States
a r t i c l e
i n f o
Article history: Received 16 December 2015 Received in revised form 17 February 2016 Accepted 19 February 2016 Available online 22 February 2016 Keywords: Major depressive disorder Mixed features specifier Subthreshold hypomania Depression subtypes Lurasidone
a b s t r a c t Major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features), has been identified as a distinct nosological entity in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We identified the predominant manic symptoms present at baseline in a multiregional, placebocontrolled trial involving 211 patients with MDD with mixed features (Clinicaltrials.gov NCT01421134). Patients with 2 or 3 DSM-5 criteria defined manic symptoms were eligible for the study. At study baseline, increased talkativeness (pressure to keep talking) and flight of ideas (racing thoughts) were endorsed by approximately 65% of patients and a decreased need for sleep was endorsed by 40% of patients. Approximately 60% of patients also endorsed irritability and distractibility at baseline although these symptoms are not generally counted as part of the “mixed” depression diagnosis as they may overlap with criteria for MDD. Thus, five clinical symptoms characterized the manic presentation in the majority of patients diagnosed as having MDD with “mixed” features in this first placebo-controlled trial examining the use of a psychotropic medication (lurasidone) in this population. Our findings support the designation of MDD with mixed features specifier and suggest that this subpopulation of depressed patients may warrant additional medication beyond antidepressants. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Twenty-five to forty percent of patients with major depressive disorder (MDD) present with concurrent manic symptoms during acute mood episodes that fall short of meeting the criteria for hypomania (bipolar II disorder) or mania (bipolar I disorder) (Judd and Akiskal, 2003; Sato et al., 2003; Benazzi, 2003, 2008; Suppes et al., 2005; Gazalle et al., 2005; McElroy, 2008; Goldberg et al., 2007, 2009; Gonzalez-Pinto et al., 2011; Nusslock and Frank, 2011; Angst et al., 2010, 2011; Merikangas et al., 2011; APA, 2013; Mcintyre et al., 2013, 2015; Targum and Nierenberg, 2011; Koukopoulos et al., 2013; Sani et al., 2014; Zaninotto et al., 2014). The DSM-5 classification added a specifier for depressive disorders to account for subthreshold manic symptoms that occur in acutely depressed patients and designated this new diagnostic category
☆ Funding for this study was provided by Sunovion Pharmaceuticals as part of a quality assurance program conducted under contract to Clintara LLC. ⁎ Corresponding author at: 11 Beacon Street Suite 600, Boston, MA 02108, United States. E-mail address: [email protected] (S.D. Targum).
http://dx.doi.org/10.1016/j.pnpbp.2016.02.007 0278-5846/© 2016 Elsevier Inc. All rights reserved.
major depressive disorder with mixed features (APA, 2013; Hu et al., 2014). Using these criteria in a multi-site survey of 506 acutely depressed MDD patients, McIntyre et al. (2015) reported that 26% of these patients met the “mixed” features specifier. Conventional antidepressants may be ineffective in treating the manic and/or depressive components of “mixed” depression and may even precipitate or exacerbate manic symptoms (Sato et al., 2003; Goldberg et al., 2007; Benazzi, 2008; Zimmermann et al., 2009; Angst et al., 2011; APA, 2013). Consequently, some clinical studies have evaluated the use of atypical antipsychotic medications for patients with “mixed” depression (Patkar et al., 2012; Mcintyre et al., 2013; Suppes et al., 2015). Some researchers believe that this new diagnostic designation is simply a precursor of bipolar disorder and that patients meeting these criteria should be treated as such (Benazzi, 2005; APA, 2013; Zaninotto et al., 2014). Koukopoulos et al. (2013) believe that the DSM-5 designation of MDD with mixed features is inadequate because it does not include psychomotor agitation or irritability as symptoms and may fail to identify many depressed patients who have mixed states. Recently, Sani et al. (2014) reported that psychic agitation, marked irritability, and mood reactivity were common symptoms in a study of 406 MDD patients presenting with mixed depression.
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Ultimately, the value of any change in a diagnostic classification system is to provide a more consistent and clinically meaningful representation of the disorders it attempts to classify and to facilitate earlier diagnostic differentiation to abet more effective treatment strategies (Targum et al., 2008; Stahl, 2013; Hu et al., 2014). One approach to examine the utility of a “new” diagnostic designation is to examine the clinical presentation of patients that clinicians believe meet criteria for the disorder. In the present study, we examined the presence and severity of depressive and manic symptoms in 211 patients with depression with mixed features who participated in a multiregional, placebocontrolled clinical trial. These findings reflect the thorough clinical assessments of investigators in 5 different countries regarding the clinical characteristics of patients meeting the diagnostic criteria for “mixed” depression. 2. Materials and methods This study was done as part of the subject selection approval process for a clinical trial called RESOLVE 1: a randomized, 6-week, doubleblind, placebo-controlled, flexible-dose, parallel group study of lurasidone for the treatment of major depressive disorder with mixed features (Clinicaltrials.gov NCT01421134). Forty-four clinical trial sites located in Russia, Serbia, Ukraine, United Kingdom, and the United States participated in the study between April 2011 and October 2014. A full description of the study design and treatment results has been reported elsewhere (Suppes et al., 2015). In this study, “mixed” depression was defined as a patient who currently met the diagnostic criteria for MDD, was currently experiencing a major depressive episode (diagnosed by DSM IV TR with the current major depressive episode duration of at least 2 weeks but less than 12 months) and who had two or three manic symptoms that occurred on most days over at least the last 2 weeks prior to screening. These criteria differ from the DSM-5 criteria that specified that 3 manic symptoms were required for this diagnosis (APA, 2013). The eligible manic symptoms included the following seven symptoms (per DSM-5): • • • • •
Elevated, expansive mood Inflated self-esteem or grandiosity More talkative than usual or pressure to keep talking Flight of ideas or subjective experience that thoughts are racing Increase in energy or goal-directed activity (either socially, at work or school, or sexually) • Increased or excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted from insomnia).
The diagnosis was confirmed by the Structured Clinical interview for DSM-IV, clinical trial version (SCID-CT) that was modified to include “mixed” features for this study (First et al., 2007). Patients were excluded from the study if they had a lifetime history of any bipolar I manic, mixed manic episode, or psychotic disorder, had treatment resistant depression, or any Axis I or Axis II diagnosis (other than MDD) that was the primary focus of treatment within 3 months of the screen visit (including all anxiety disorders, PTSD, eating disorders, or alcohol or substance abuse or dependence). In addition, eligible patients had a minimum score of 26 on the Montgomery Asberg Depression Rating Scale (MADRS) at screening and baseline utilizing the Structured Interview Guide for the MADRS (Montgomery and Asberg, 1979; Williams and Kobak, 2008). The Young Mania Rating Scale (YMRS) was used to assess manic symptoms; no minimum YMRS entry criterion was used (Young et al., 1978). A “dual” review process was used for diagnostic verification, identification
of excluded psychiatric diagnoses, and confirmatory scoring of the MADRS and YMRS that included audio-digital recording of the key screening instruments and a site-independent review (Targum and Pendergrass, 2014). The study was conducted in compliance with the informed consent regulations of an Institutional Review Board (IRB) and International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) Guidelines at the 44 clinical trial sites. All potential subjects consented to participate in the study and to the use of audio-digital recording instruments for independent clinical review. Raters at all trial sites participated in a standardized, formal rater training and certification program and met minimum qualification standards for inter-rater reliability between raters and demonstration of interviewing competence. The training program included didactic training for all efficacy measures at the investigator meeting or on-line, observation and scoring of expert demonstration MADRS and YMRS interviews with subsequent inter-rater reliability assessment of their scoring performance, and interviewing skills assessment via mock recorded MADRS and YMRS interviews. Audio-digital recording and site-independent scoring of the MADRS and YMRS interviews during the study provided additional opportunities to identify poor ratings performance. Rater remediation was provided when necessary although some raters were ultimately exempted from rating in this study. Statistical analysis included Student's t test and Chi-square analyses to evaluate group differences and examine the frequency of each presenting manic or depressive symptom. 3. Results 211 patients met the study eligibility criteria and were enrolled in the study across 44 clinical trial sites. The study enrolled 62 patients from the United States, 4 from the United Kingdom, 52 from Serbia, 62 from Ukraine, and 31 from the Russian clinical trial sites. The study was conducted between April 2011 and October 2014. 3.1. Characteristics of the enrolled subjects Table 1 lists the demographic and symptom severity scores for the 211 patients who met the entry criteria for “mixed” depression and were randomized in the study. The mean MADRS score was 33.2 ± 4.2 (SD), the mean YMRS score was 10.7 ± 4.5, and the mean Ham-A score was 16.9 ± 6.4 for the study population at the baseline visit. Table 2 presents the individual mean item scores of the MADRS and YMRS as scored by site-based raters at baseline. The MADRS items of Table 1 Patients with “mixed” depression: demographic and clinical characteristics. All subjects Male n (%) Age, years n (SD) Age ≤ 30 n (%) Age 31–50 Age ≥ 51 Race n (%) Black Caucasian Other Number of lifetime major depressive episodes Total number Number with mixed features Duration of current episode, days Major depressive features Concurrent mixed features MADRS score CGI-S score Young Mania Rating Scale (YMRS) score HAM-A total score Sheehan Disability Scale total score
211 64 (30.3%) 44.8 (12.2) 31 (14.7%) 109 (51.7%) 71 (33.6%) 27 (12.8%) 181 (85.8%) 3 (1.4%) Mean (SD) 4.4 (4.0) 2.4 (3.3) 104.1 (83.8) 77.2 (80.5) 33.2 (4.2) 4.5 (0.6) 10.7 (4.5) 16.9 (6.4) 20.2 (5.0)
S.D. Targum et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 68 (2016) 9–14 Table 2 Mean scores on individual MADRS and YMRS items at the baseline visit. Mean (SD) MADRSa MADRS 01 MADRS 02 MADRS 03 MADRS 04 MADRS 05 MADRS 06 MADRS 07 MADRS 08 MADRS 09 MADRS 10
Reported sadness Apparent sadness Inner tension Reduced sleep Reduced appetite Concentration difficulties Lassitude Inability to feel/loss of interest Pessimistic thoughts Suicidal thoughts
4.1 (0.8) 4.4 (0.7) 3.3 (1.0) 4.3 (1.1) 3.0 (1.7) 4.0 (0.9) 3.6 (1.1) 3.7 (0.8) 2.4 (1.2) 0.5 (0.8)
YMRSa YMRS 01 YMRS 02 YMRS 03 YMRS 04 YMRS 05 YMRS 06 YMRS 07 YMRS 08 YMRS 09 YMRS 10 YMRS 11
Elevated mood Increased motor activity/energy Sexual interest Decreased need for sleep Irritability Speech (rate or amount) Language–thought disorder Thought content Disruptive–aggressive behavior Appearance Insight
0.4 (0.7) 1.0 (1.3) 0.2 (0.6) 2.0 (0.9) 1.9 (1.4) 2.1 (2.1) 1.3 (1.0) 0.5 (1.1) 0.7 (1.1) 0.5 (0.6) 0.2 (0.6)
a
n = 211 enrolled subjects (MADRS: Montgomery–Asberg Depression Rating Scale; YMRS: Young Mania Rating Scale).
sadness, decreased sleep, and concentration difficulties were associated with the highest mean item scores. The YMRS items of decreased need for sleep, an increased rate or amount of speech (talkativeness), and irritability were associated with the highest mean item scores. Table 3 lists the past psychiatric hospitalizations and psychopharmacologic treatment history of this population of patients with “mixed” depression. Approximately 10% reported having never received any antidepressant medication prior to this study. One-third of these patients had received mood stabilizers and approximately half had received antipsychotic medication at some time prior to screening. Fig. 1 reveals the number and type of manic symptoms reported by patients on the SCID-CT screening interview. One hundred and thirtythree patients (63.0%) reported two and 78 patients (37.0%) reported three of the seven protocol-specified manic symptoms queried on the SCID-CT as being present for at least two weeks prior to screening. The most frequently reported manic symptoms (flight of ideas or racing thoughts (66.8%), increased talkativeness or pressured speech (61.1%)
Table 3 Treatment history of subjects with “mixed” depressiona. n (%) Previous psychiatric hospitalizations None 1 ≥2 Previous lifetime antidepressant treatments None 1 ≥2 Previous lifetime mood stabilizer treatments None 1 ≥2 Previous lifetime antipsychotic treatments None 1 ≥2
104 (49.3%) 44 (20.9%) 63 (29.9%) 22 (10.4%) 40 (19.0%) 149 (70.6%) 142 (67.3%) 46 (21.8%) 23 (10.9%) 112 (53.1%) 40 (19.0%) 59 (28.0%)
a Reflects hospitalization and psychopharmacologic treatment history preceding the current episode. Treatments were defined as having an adequate dose and adequate duration.
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and decreased need for sleep (40.8%) had the highest individual item baseline severity scores on the Young Mania Rating Scale (Table 2). Reported sadness, apparent sadness, decreased sleep, and concentration difficulties had the highest baseline severity scores on the MADRS (Table 2). Table 4 lists the distribution of specific manic symptoms reported by patients with 2 or 3 eligible symptoms in this study. There was no significant difference between patients reporting 2 or 3 manic symptoms relative to the distribution of reported manic symptoms (Kolmogorov– Smirnov test: p = 0.938). 3.2. Agitation, irritability, and distractibility Psychomotor agitation, irritability, and distractibility are not included as symptoms in the DSM-5 mixed features specifier as these symptoms may overlap with unipolar depression and can therefore be regarded as nonspecific (APA, 2013). A high proportion of patients reported experiencing distractibility (59.2%), irritability (57.3%), and psychomotor agitation (36.5%) at study baseline (Fig. 1). 4. Discussion We examined the clinical characteristics and symptom severity of 211 patients meeting the study protocol criteria for MDD with mixed features as part of the RESOLVE 1 clinical trial of lurasidone treatment in this population. The study design and full study results have been reported elsewhere (Suppes et al., 2015). Most patients entered the study with marked depressive symptoms (mean baseline MADRS score was 33.2 ± 4.2) and mild severity of manic symptoms (mean YMRS score was 10.7 ± 4.5). Thus, the presenting symptomatology is consistent with a clinical condition of acute MDD with subthreshold manic symptoms (“mixed” depression). The most frequent manic symptoms reported on the modified SCIDCT that were present for at least 2 weeks prior to screening and that met the eligibility criteria were flight of ideas (racing thoughts) and increased talkativeness (or pressured speech). These two symptoms were still reported as one of the 2 or 3 eligible manic symptoms by approximately 65% of patients at study baseline. Our data are consistent with Koukopoulos et al. (2013) who reported that flight of ideas and increased talkativeness were the most common “mixed” manic symptoms seen in their acutely depressed patients in their European practice. In addition, 40% of patients reported a reduced need for sleep at the study baseline visit as well. The most commonly reported manic symptoms identified by the SCID-CT diagnostic screen were also identified by the symptomatic rating questionnaires. Data from the individual item analyses of the YMRS (Fig. 1) identified increased talkativeness (increased rate or amount of speech) as the most prominent presenting manic-related symptom in this patient population. Flights of ideas or racing thoughts are subsumed as symptoms under the YMRS item for language–thought disorder. Similarly, the MADRS identified decreased need for sleep as a prominent symptom in these depressed patients. The MADRS and YMRS also identified irritability and distractibility (concentration difficulties) as prominent symptoms in approximately 60% of patients at the screening visit. The DSM-5 criteria specifically exclude psychomotor agitation, irritable mood, and distractibility from the diagnostic criteria for the mixed features specifier stating that these symptoms may overlap with acute depression as part of a major depressive episode (APA, 2013). Koukopoulos and colleagues (2013) have noted that many patients with “mixed” depression present with these symptoms and challenge the validity of the DSM-5 “mixed” features criteria as creating a clinical construct that is rare rather than relevant. According to some authors, the addition of irritability and agitation to the criteria increases the prevalence of “mixed” depressive states from 0 to 12% to a more relevant 33–47% (Angst et al., 2011; Koukopoulos et al., 2013; Koukopoulos and Sani, 2014; Sani et al., 2014). Recently,
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Fig. 1. Frequency of manic and non-specific symptoms endorsed by patients with “mixed” depression.
Sani et al. (2014) validated Koukopoulos' diagnostic criteria for “mixed” depression that includes psychic agitation, irritability, and mood reactivity as common features of this disorder. Our independent data are consistent with these findings and reveal that irritability and distractibility were reported as often as increased talkativeness and flight of ideas and suggest that these symptoms co-exist within the “mixed” depression patient population (Fig. 1). Therefore, it would seem that the identification and treatment of distractibility, irritability, and psychomotor agitation should be considered as part of the overall treatment plan for “mixed” depression. There are some possible limitations in this study that warrant mention. First, the reported data was collected from patients who met the protocol criteria for MDD with mixed features. A possible limitation of
our findings is that we did not include a “control” group of MDD patients without manic features for comparison of non-specific symptoms. Second, patients were included in this study from 44 different clinical trial sites. Inter-rater reliability is always a concern and potential limitation in any multi-site, multi-regional study. To address this concern, all site-based raters successfully completed a rater training and certification program prior to participating in this study and we employed an audio-digital recording surveillance strategy to enhance ratings precision and identify ratings discrepancies during the study. Third, our findings on treatment history (Table 3) require cautious interpretation because the source of information was the depressed subject's report at the screening visit (and any medical records, if available). Future studies might seek more reliable documentation to examine the use of
Table 4 Distribution of manic symptoms among patients reporting 2 or 3 symptoms. Eligible manic symptoms*
SCID 01
SCID 02
SCID 03
SCID 04
SCID 05
SCID 06
SCID 07
2 reported symptoms (n = 133)
11 (8.3%) 27 (34.6%)
5 (3.8%) 8 (10.3%)
73 (54.9%)
89 (67.0%) 51 (65.4%)
31 (23.3%) 27 (34.6%)
19 (14.3%) 14 (17.9%)
46 (34.6%) 40 (51.3%)
3 reported symptoms (n = 78)
55 (70.5%)
Kolmogorov–Smirnov test; p = 0.9375 *Description of eligible manic symptoms from customized SCID-CT: SCID-CT-01: Elevated, expansive mood. SCID-CT-02: Inflated self-esteem or grandiosity. SCID-CT-03: More talkative than usual or pressure to keep talking. SCID-CT-04: Flight of ideas or subjective experience that thoughts are racing. SCID-CT-05: Increase in energy or goal-directed activity (either socially, at work or school, or sexually). SCID-CT-06: Increased or excessive involvement in activities that have a high potential for painful consequences. SCID-CT-07: Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted from insomnia).
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prior clinical history and combination treatments in this patient population. Finally, a possible limitation of this study is that our eligibility criteria were not identical to the recently published DSM-5 criteria that require in part at least 3 of the 7 specified manic symptoms to meet the “mixed” specifier condition (APA, 2013). We accepted 2 or 3 of the 7 possible DSM-5 defined manic symptoms in this study. As noted in Table 4, there was little difference in the clinical characteristics of patients presenting with 2 or 3 manic symptoms. Among the patients presenting with 3 manic symptoms, 70.5% endorsed increased talkativeness, 65.4% endorsed racing thoughts (flight of ideas), and 51.3% of patients endorsed a decreased need for sleep. A clinically relevant and useful diagnostic classification system seeks to identify a group of patients who have common clinical features and who might respond to specific treatment interventions. In clinical practice, it is important to recognize the presence of “mixed” symptoms in patients presenting with primarily acute depressive symptoms. It is not uncommon for manic symptoms to be missed in patients with mood disorders (Angst et al., 2011). In fact, only one-third of the patients in this sample population of “mixed” depression had ever received mood stabilizers (Table 3). In one survey of over 4000 bipolar patients, it took an average of 10 years before the correct diagnosis was made despite multiple consultations (Nusslock and Frank, 2011). The presence of any manic symptoms should alert clinicians to the need for increased vigilance and the possible introduction of additional medications or other changes in the drug regimen (Gazalle et al., 2005; Goldberg et al., 2007; Hu et al., 2014). 5. Conclusion In summary, racing thoughts and increased talkativeness were the two most prominent manic symptoms reported by approximately 65% of patients and decreased need for sleep by 40% of patients with MDD with “mixed” features at study baseline. Distractibility and irritability were also reported by approximately 60% of these patients as well. Hence, a four- or five-symptom cluster characterizes these “mixed” depressed patients within the larger population of patients with MDD. Conventional antidepressants may be ineffective in treating both the depressive and manic symptoms in these “mixed” depressed patients and may even precipitate hypomania. Consequently, the early recognition of “mixed” depression is of vital importance for treatment planning and the use of additional medications may be warranted. Contributors Drs. Targum, Suppes, Pendergrass, Silva, Cucchiaro and Loebel all contributed to the study design, implementation, and data analysis for this study. Mr. Lee contributed to the statistical analysis of the data. All authors have approved this final manuscript. Author disclosures Dr. Targum is an employee of Bracket Global and Clintara LLC, which was working under contract to Sunovion Pharmaceuticals in the conduct of this study. Dr. Targum has received consulting fees, retainers, or travel expenses from Alkermes, BioMarin, Forum Pharmaceuticals, Functional Neuromodulation, Johnson and Johnson PRD, Methylation Sciences Inc., Neurim Pharmaceuticals, One Carbon Therapeutics, Prana Biotechnology Ltd., Resilience Therapeutics, Roche labs, and Sophiris. Dr. Suppes has received funding, medications for clinical grants, consulting fees and/or travel expenses from AstraZeneca, Elan Pharma International, H Lundbeck A/S, Merck, NIMH, VA cooperative studies program, Sunovion Pharmaceuticals, and royalties from UpToDate and Jones and Bartlett (formerly Compact clinical trials).
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Dr. Pendergrass and Mr. Lee are employees of Bracket Global and Clintara. Drs. Silva, Cucchiaro, and Loebel are employees of Sunovion Pharmaceuticals, Inc. Acknowledgements and funding source Funding for this study was provided by Sunovion Pharmaceuticals as part of a quality assurance program conducted under contract to Clintara LLC. The authors listed from Sunovion participated in the study design, analysis, interpretation of data, and in the decision to submit the paper for publication. References American Psychiatric Association., 2013l. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Press, Arlington VA. Angst, J., Cui, L., Swendsen, J., Rothen, S., Cravchik, A., Kessler, R.C., Merikangas, K.R., 2010. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am. J. Psychiatry 167 (10), 1194–1201. Angst, J., Azorin, J.M., Bowden, C.I., Perugi, G., Vieta, E., Gamma, A., et al., 2011. 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