Introduction
Psychomotor disturbance (PMD) in major depressive disorder (MDD) is a complex clinical state characterized by changes in movement, speech, thinking, and cognition (Schrijvers, Hulstijn, & Sabbe, Reference Schrijvers, Hulstijn and Sabbe2008). PMD is more common in severe depression and has been proposed as the core feature of melancholic depression (Parker & Hadzi-Pavlovic, Reference Parker and Hadzi-Pavlovic1996a). There is substantial overlap between melancholic depression and psychotic depression, and not surprisingly PMD is common in psychotic depression (Brodaty et al., Reference Brodaty, Luscombe, Parker, Wilhelm, Hickie, Austin and Mitchell1997; Parker, Hickie, & Hadzi-Pavlovic, Reference Parker, Hickie, Hadzi-Pavlovic, Parker and Hadzi-Pavlovic1996).
Naturalistic follow-up studies found that PMD was associated with poorer long-term outcome of depression (Duggan, Lee, & Murray, Reference Duggan, Lee and Murray1991; Parker, Hickie, & Mason, Reference Parker, Hickie, Mason, Parker and Hadzi-Pavlovic1996). Over several decades, studies have examined whether PMD predicts response to pharmacologic treatment of MDD. For the most part, PMD has been found to predict favorable response to tricyclic antidepressants (TCA) (Laakmann, Blaschke, Engel, & Schvjarz, Reference Laakmann, Blaschke, Engel and Schvjarz1998; Navarro, Gasto, Torres, Marcos, & Pintor, Reference Navarro, Gasto, Torres, Marcos and Pintor2001; Sobin & Sackeim, Reference Sobin and Sackeim1997). In contrast, PMD predicted poorer response or no difference in response to selective serotonin reuptake inhibitors (SSRIs) in nearly all studies that examined this issue (Bondareff et al., Reference Bondareff, Alpert, Friedhoff, Richter, Clary and Batzar2000; Burns et al., Reference Burns, Lock, Edwards, Katona, Harrison, Robertson and Abou-Saleh1995; Chekroud et al., Reference Chekroud, Zotti, Shehzad, Gueorguieva, Johnson, Trivedi and Corlett2016; Flament, Lane, Zhu, & Ying, Reference Flament, Lane, Zhu and Ying1999; Joyce et al., Reference Joyce, Mulder, Luty, McKenzie, Sullivan, Abbott and Stevens2002; Laakmann et al., Reference Laakmann, Blaschke, Engel and Schvjarz1998; Navarro et al., Reference Navarro, Gasto, Torres, Marcos and Pintor2001; Sechter et al., Reference Sechter, Vandel, Weiller, Pezous, Cabanac and Tournoux2004; Taylor et al., Reference Taylor, Bruder, Stewart, McGrath, Halperin, Ehrlichman and Quitkin2006; Ulbricht, Dumenci, Rothschild, & Lapane, Reference Ulbricht, Dumenci, Rothschild and Lapane2018). We know of only one study that has examined the relationship between PMD and relapse of MDD: in a secondary analysis of data from the STAR*D study, Sakurai, Suzuki, Yoshimura, Mimura, and Uchida (Reference Sakurai, Suzuki, Yoshimura, Mimura and Uchida2017) found that both self-reported and observed restlessness at the time of remission of MDD with citalopram predicted relapse during the 12-month follow-up.
To our knowledge, only one study has examined the relationship of PMD with treatment outcome of psychotic depression (Janzing et al., Reference Janzing, Birkenhager, van den Broek, Breteler, Nolen and Verkes2020). In this randomized controlled trial (RCT) that compared imipramine, venlafaxine, and venlafaxine plus quetiapine in the acute treatment of psychotic depression, psychomotor retardation at baseline was associated with a lower frequency of remission in the sample as a whole. The study found no relationship between PMD, treatment arm, and remission, but it was not powered to examine this issue (Janzing et al., Reference Janzing, Birkenhager, van den Broek, Breteler, Nolen and Verkes2020).
The goal of the current analysis was to determine whether PMD is associated with remission and relapse of psychotic depression in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) (NCT01427608) (Flint et al., Reference Flint, Meyers, Rothschild, Whyte, Alexopoulos and Rudorfer2019). Participants in STOP-PD II were treated with open-label sertraline plus olanzapine to reach remission. Those in sustained remission or near-remission were eligible to participate in a 36-week double-blind RCT that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. PMD was quantified with the psychiatrist-rated sign-based CORE (Parker & McCraw, Reference Parker and McCraw2017; Wilhelm, Reference Wilhelm, Parker and Hadzi-Pavlovic1996) at acute phase baseline and at RCT baseline. Based on findings in the literature, we hypothesized that higher CORE total score at acute phase baseline would be associated with a lower frequency of remission/near-remission and higher CORE total score at RCT baseline would be associated with a higher frequency of relapse.
Methods
Participants
The design and methods of STOP-PD II have been previously described (Flint et al., Reference Flint, Meyers, Rothschild, Whyte, Mulsant, Rudorfer and Marino2013). The primary findings of STOP-PD II, pertaining to the risks and benefits of continuing antipsychotic medication among patients with psychotic depression in remission, have been reported (Flint et al., Reference Flint, Meyers, Rothschild, Whyte, Alexopoulos and Rudorfer2019). The study was conducted at four medical centers (University Health Network, Toronto; University of Massachusetts Medical School; University of Pittsburgh School of Medicine; and Weill Cornell Medicine). Using procedures approved by local institutional review boards, written informed consent was obtained from all participants or their substitute decision maker prior to the initiation of any research procedures.
The study had three phases: an acute phase lasting up to 12 weeks, an 8-week stabilization phase, and finally a 36-week RCT. At the time of enrolment in the acute phase of the study, participants were aged between 18 and 85 years, met Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV-TR) (First, Spitzer, Gibbon, & Williams, Reference First, Spitzer, Gibbon and Williams2001) criteria for a current major depressive episode with at least one associated delusion (with or without hallucinations), and had a 17-item Hamilton Depression Rating Scale (HAM-D) (Hamilton, Reference Hamilton1960) total score ⩾21. The study's exclusion criteria included: DSM-IV-TR criteria for lifetime bipolar disorder, any other psychotic disorder, or intellectual disability; DSM-IV-TR criteria for current body dysmorphic disorder or obsessive-compulsive disorder; DSM-IV-TR defined dementia preceding the index episode of depression or a 26-item IQCODE (Jorm, Reference Jorm2004) mean score ⩾4 at acute phase baseline; DSM-IV-TR defined substance abuse or dependence within the preceding 3 months; type 1 diabetes mellitus; neurologic disease that might affect neuromuscular function; and unstable physical illness, although many of the study participants had stable chronic physical problems.
In the acute phase, participants received a combination of open-label sertraline (target dosage of 150–200 mg/day) plus open-label olanzapine (target dosage of 15–20 mg/day). ‘As needed’ lorazepam to a maximum dosage of 3 mg/day and ‘as needed’ benztropine to a maximum dosage of 2 mg/day were the only other psychotropic medications allowed. Participants entered the stabilization phase as soon as they met the study's criteria for remission (see below) or, failing that, met criteria for near-remission (see below) at week 12 of the acute phase. At the end of the 8-week stabilization phase, participants who still met remission or near-remission criteria following open-label treatment with sertraline plus olanzapine, and had a Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, Reference Folstein, Folstein and McHugh1975) score ⩾24, were eligible for the RCT.
All participants continued to take open-label sertraline for the duration of the 36-week RCT. They were randomized under double-blind conditions to either continue olanzapine or switch from olanzapine to identically appearing placebo pills during a protocolized 4-week taper of olanzapine. Participants in the RCT were assessed weekly for the first 8 weeks and once every 4 weeks after that until they reached a study end point: either relapse (the primary outcome), study completion at RCT week 36, or early termination.
Outcomes
Remission and near-remission
Remission was defined as the absence of delusions and hallucinations and a 17-item HAM-D total score of ⩽10 for two consecutive weeks. Near-remission at week 12 of the acute phase was defined as the absence of delusions and hallucinations, a HAM-D score of 11–15 with ⩾50% reduction in baseline HAM-D score, and being rated as ‘very much improved’ or ‘much improved’ on the Clinical Global Impression (CGI) Scale (Guy, Reference Guy and Guy1976).
Near-remission was included as an outcome to allow participants who experienced substantial improvement in depressive symptoms plus remission of psychosis to enter the clinical trial, even though the symptoms may not have reached the conventional HAM-D total score cut point of <8–10 used in studies of non-psychotic depression; this approach reflected ‘real world’ clinical practice.
Relapse
Relapse was the primary outcome in the RCT. Relapse was defined by at least one of the following: (1) a sufficient number of SCID-rated symptoms to meet criteria for a DSM-IV major depressive episode; (2) 17-item HAM-D total score of ⩾18; (3) SCID-rated psychosis (delusions or hallucinations); or (4) other significant clinical worsening defined as: (i) a suicide plan or suicide attempt, (ii) development of SCID-rated symptoms of mania or hypomania, or (iii) psychiatric hospitalization. Although patients with a history of bipolar disorder were not eligible for the study, mania or hypomania was included as an outcome variable because onset of psychotic depression in younger adults may predict subsequent development of bipolar disorder (Salvatore et al., Reference Salvatore, Baldessarini, Khalsa, Amore, Di Vittorio, Ferraro and Tohen2013).
Primary independent variable
PMD was measured with the CORE instrument, administered by trained research psychiatrists, at acute phase baseline and RCT baseline. The CORE is a clinician-administered, sign-based instrument that is intended for use during a clinical interview of a depressed patient and is rated based on observation. It assesses three aspects of PMD in depression: retardation, agitation, and non-interactiveness. The CORE is composed of 18 items, each scored on a 4-point scale based on severity of 0 (absent) to 3 (severe), with a total score range of 0–54 (Wilhelm, Reference Wilhelm, Parker and Hadzi-Pavlovic1996). The CORE total score has satisfactory inter-rater reliability and construct validity as a measure of PMD (Parker & McCraw, Reference Parker and McCraw2017).
Other independent measures
In order to assess the independent association of the CORE total score with remission and relapse, we assessed other relevant clinical variables that had the potential to be included as covariates in analyses of outcome: severity of depression, measured with the 17-item HAM-D (Hamilton, Reference Hamilton1960); severity of psychosis, measured with the delusion and hallucination severity items of the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer & Endicott, Reference Spitzer and Endicott1979); severity of anxiety, measured with the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A) (Zigmond & Snaith, Reference Zigmond and Snaith1983); lifetime medical burden, quantified by the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) (Miller et al., Reference Miller, Paradis, Houck, Mazumdar, Stack, Rifai and Reynolds1992); treatment resistance during the index episode of psychotic depression, defined as an antidepressant plus antipsychotic combination rating score of 3 or higher on the Antidepressant Treatment History Form (ATHF) and/or seven or more treatments of electroconvulsive therapy (ECT) (Oquendo et al., Reference Oquendo, Baca-Garcia, Kartachov, Khait, Campbell and Richards2003); and brain executive function at RCT baseline, measured with the Delis–Kaplan Executive Function Scale (DKEFS) trail making test conditions 4 v. 5 scaled score (measures cognitive flexibility) and DKEFS color word interference condition 3 final weighted scaled score (measures inhibition) (Delis, Kaplan, & Kramer, Reference Delis, Kaplan and Kramer2001). (Neuropsychological tests were not performed at acute phase baseline.) A history of recurrent MDD and duration of the index episode of depression were assessed using the Structured Clinical Interview for DSM-IV-TR (First et al., Reference First, Spitzer, Gibbon and Williams2001).
Data analyses
Spearman's correlations measured the association of (i) the CORE total score at acute phase baseline with frequency of combined remission and near remission, and (ii) the CORE total score at randomization phase baseline with frequency of relapse. Logistic regression analysis was then used to measure the association between the CORE total score and these outcomes, while accounting for relevant covariates that had a statistically significant association with outcome in univariate analyses (correlation or chi-square, as appropriate). The CORE total score was entered into the model first, followed by applicable covariates entered as a block. Variables identified in the literature as having a consistent association with remission or relapse of MDD and which were available in the STOP-PD II data set were selected as potential covariates for the regression models. Potential covariates for remission/near remission were the following acute phase baseline variables: current age, 17- item HAM-D total score, SADS delusion severity score, HADS-A total score, CIRS-G total score, episode duration, and treatment resistance during the index episode of depression (Kemp, Gordon, Rush, & Williams, Reference Kemp, Gordon, Rush and Williams2008; Perlman et al., Reference Perlman, Benrimoh, Israel, Rollins, Brown, Tunteng and Berlim2019; Rush et al., Reference Rush, Kraemer, Sackeim, Fava, Trivedi, Frank and Schatzberg2006). Potential covariates for relapse were age of onset of MDD, history of recurrent MDD, and the following RCT baseline variables: 17- item HAM-D total score, HADS-A total score, CIRS-G total score, DKEFS trail making score, and DKEFS color word interference score (Alexopoulos et al., Reference Alexopoulos, Meyers, Young, Kalayam, Kakuma, Gabrelle and Hull2000; Buckman et al., Reference Buckman, Underwood, Clarke, Saunders, Hollon, Fearon and Pilling2018; Hardeveld, Spijker, De Graaf, Nolen, & Beekman, Reference Hardeveld, Spijker, De Graaf, Nolen and Beekman2010). Additional variables selected as potential covariates were: (i) gender, race, and Hispanic ethnicity for both sets of analyses, and (ii) olanzapine dosage at RCT baseline, given that CORE ratings could be influenced by dosage of olanzapine.
All statistical tests were two-sided, performed at an overall 5% level of significance. Analyses were conducted using SAS 9.4 (© SAS Institute, Cary, NC).
Results
Participant characteristics
Two hundred and sixty-nine participants enrolled in the acute phase of the study. Of these, 126 participated in the RCT. Table 1 presents baseline characteristics of participants enrolled in the acute phase of the study and relevant clinical characteristics of randomized participants at randomization phase baseline.
Characteristics of study participants at acute phase baseline and randomized phase baseline
CIRS-G, Cumulative Illness Rating Scale for Geriatrics; CORE, the CORE assessment of psychomotor change; DKEFS, Delis–Kaplan Executive Function Scale; HADS, Hospital Anxiety and Depression Scale; HAM-D 17, 17-item Hamilton Depression Rating Scale; MMSE, Mini Mental State Examination; SADS, Schedule for Affective Disorders and Schizophrenia.
a ‘Other Race’ includes American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, and unknown or not reported.
b Treatment resistance defined as an antidepressant plus antipsychotic combination rating score of 3 or higher on the Antidepressant Treatment History Form or seven or more treatments of ECT during the current episode of psychotic depression.
c DKEFS trail making test condition 4 v. condition 5 scaled score.
d DKEFS color-word interference test condition 3 final weighted score.
Treatment outcomes
Of the 269 participants enrolled in the study, 167 (62.1%) experienced remission or near remission of the episode of psychotic depression. Of the 126 participants who entered the RCT, relapse occurred in 13 of 64 (20.3%) randomized to sertraline plus olanzapine and 34 of 62 (54.8%) randomized to sertraline plus placebo.
Association of psychomotor disturbance with treatment outcomes
Remission/near remission
Higher CORE total score at acute phase baseline was significantly correlated with a lower frequency of remission/near remission (r s = −0.13, p = 0.042; N = 266).
None of the a priori selected covariates had a statistically significant association with remission/near remission in univariate analyses and, therefore, none were included in the logistic regression analysis. In a logistic regression model that included acute phase baseline CORE as the only explanatory variable, CORE total score was negatively associated with remission/near-remission [χ2[1] = 4.12, p < 0.05; odds ratio (OR) (95% confidence interval (CI)) = 0.97 (0.94–0.99)].
Relapse
Higher CORE total score at RCT baseline was significantly correlated with a higher frequency of relapse in the whole RCT sample (r s = 0.29, p = 0.001; N = 126). Correlations were also significant for relapse in the sertraline plus olanzapine group (r s = 0.33, p = 0.007; n = 64) and sertraline plus placebo group (r s = 0.29, p = 0.02; n = 62).
Of the a priori selected covariates, 17-item HAM-D total score at RCT baseline and history of recurrent MDD were significantly associated with a higher frequency of relapse in univariate analyses (r = 0.24, p = 0.008; N = 126 and χ2[1] = 4.36, p = 0.037, respectively). In a logistic regression model that included HAM-D total score and history of recurrence, CORE total score was the only variable significantly associated with relapse [χ2[1] = 5.64, p < 0.02; OR (95% CI) = 3.62 (1.25–10.49)].
Discussion
In the STOP-PD II clinical trial, PMD at acute phase baseline was associated with a lower frequency of remission/near remission of psychotic depression that was treated with sertraline plus olanzapine. Among participants who remained in remission for 8 weeks and were randomized to sertraline plus olanzapine or sertraline plus placebo, PMD at randomization baseline was associated with a higher frequency of relapse in the whole RCT sample, as well as in each of the two randomized groups. Although statistically significant, the strength of correlation between CORE total score and remission/near-remission was small (Cohen, Reference Cohen1988). On the other hand, CORE score at RCT baseline had a moderate size correlation with relapse (Cohen, Reference Cohen1988).
Our study is the first to examine the relationship between PMD and relapse of psychotic depression. Sakurai et al. (Reference Sakurai, Suzuki, Yoshimura, Mimura and Uchida2017) found that PMD in remitted non-psychotic depression treated with citalopram was associated with a higher rate of relapse during 1-year follow-up, although that study was limited by the retrospective determination of PMD based on a single item of a depression rating scale. The strength of our finding regarding PMD and relapse is that all participants had been in remission of psychosis and remission/near remission of depression for 8 weeks prior to the measurement of PMD, thus minimizing the confound of severity of symptoms, and PMD was measured with a valid and reliable instrument.
In the STOP-PD II clinical trial, the risk of relapse was significantly lower with sertraline plus olanzapine than with sertraline plus placebo (Flint et al., Reference Flint, Meyers, Rothschild, Whyte, Alexopoulos and Rudorfer2019). In the current analysis, the strength of correlation between CORE total score and relapse was similar in each randomized group. Thus, olanzapine did not appear to protect against relapse in those with PMD at randomization baseline, although the study was not powered to test for an interaction between PMD and treatment group with risk of relapse. This finding suggests the need for careful monitoring of patients who have PMD. It also raises the question as to whether adjunctive treatment of psychotic depression with PMD (e.g. the addition of lithium to sertraline plus olanzapine) could decrease the risk of relapse.
As would be expected with remission of depression, median CORE total score was markedly lower at randomization than at acute phase baseline. However, in some participants, CORE remained elevated despite remission/near remission of depression and remission of psychosis. It is possible that PMD was simply a residual symptom/sign of depression, but CORE total score was associated with relapse independent of HAM-D total score. Also, CORE score was associated with lower frequency of remission, whereas severity of depression, psychosis, and anxiety at acute phase baseline were not. Collectively, these findings raise the possibility that PMD is a vulnerability factor for poorer outcome of pharmacologically treated psychotic depression, independent of symptom severity.
Structural and functional neuroimaging studies suggest that PMD in MDD may be related to alterations in cortico-striatal-thalamic circuits, possibly involving changes in white matter integrity (Hyett, Perry, Breakspear, Wen, & Parker, Reference Hyett, Perry, Breakspear, Wen and Parker2018; Liberg & Rahm, Reference Liberg and Rahm2015). Hyett, Breakspear, Friston, Guo, and Parker (Reference Hyett, Breakspear, Friston, Guo and Parker2015) found that patients with PMD-defined melancholic depression had altered functional connectivity between the insular and cortical attentional networks compared with non-melancholic depressed patients who had little/no PMD. Taken together, these imaging data and our clinical data suggest a testable hypothesis: that an altered coupling or imbalance between interoceptive and exteroceptive awareness contributes to vulnerability to relapse of psychotic depression.
The findings of many studies that have examined the relationship between PMD and treatment outcome in MDD are limited by the measurement of PMD. Most studies have used a single item of a depression rating scale, rather than a stand-alone validated measure of PMD, and focused on one aspect of PMD, such as retardation or agitation. Although the study of psychotic depression by Janzing et al. (Reference Janzing, Birkenhager, van den Broek, Breteler, Nolen and Verkes2020) used a stand-alone measure of PMD, the focus was psychomotor retardation. The advantage of the CORE scale, used in our study, is that it incorporates three aspects of PMD: retardation, agitation, and non-interactiveness. Not infrequently, a patient may exhibit more than one of these components in the same interview (Parker & Hadzi-Pavlovic, Reference Parker and Hadzi-Pavlovic1996a). Indeed, psychometric analysis of the CORE found that these components are not independent (Parker & Hadzi-Pavlovic, Reference Parker, Hadzi-Pavlovic, Parker and Hadzi-Pavlovic1996b). Thus, the CORE total score takes into account the full complexity of PMD, not simply one aspect of PMD.
Both PMD and psychotic depression positively predict response to ECT (Heijnen et al., Reference Heijnen, Kamperman, Tjokrodipo, Hoogendijk, van den Broek and Birkenhager2019). Our findings, and the findings of Janzing et al. (Reference Janzing, Birkenhager, van den Broek, Breteler, Nolen and Verkes2020), suggest that the rigorous assessment of PMD in psychotic depression may help guide the choice of treatment for an acute episode of psychotic depression. Several factors influence the choice of pharmacotherapy v. ECT to treat psychotic depression, including patient preference and the availability and accessibility of ECT. However, findings to date suggest that PMD should be considered when deciding on choice of treatment.
The study has some limitations. First, the findings are limited to treatment with sertraline plus olanzapine. Based on findings in non-psychotic depression, it is possible that PMD may not have been associated with worse outcome had the antidepressant been a TCA rather than SSRI. However, Janzing et al. (Reference Janzing, Birkenhager, van den Broek, Breteler, Nolen and Verkes2020) found that PMD predicted a lower rate of remission of psychotic depression treated with either imipramine or venlafaxine. Thus, it is possible that PMD portends worse outcome in the pharmacologic treatment of psychotic depression, regardless of the class of drug used. Second, although our analyses accounted for variables that could confound the relationship between PMD and treatment outcome, selection of variables was limited to those collected in STOP-PD II. History of childhood trauma, personality traits, and quality of interpersonal relationships, which have been found to be relevant to non-remission and/or relapse of MDD (Buckman et al., Reference Buckman, Underwood, Clarke, Saunders, Hollon, Fearon and Pilling2018; Perlman et al., Reference Perlman, Benrimoh, Israel, Rollins, Brown, Tunteng and Berlim2019), were not assessed. In addition, because of the difficulty and limitations in administering neuropsychological tests to persons who are acutely ill with psychotic depression, executive function [which is pertinent to remission (Groves, Douglas, & Porter, Reference Groves, Douglas and Porter2018)] was not measured at acute phase baseline. Third, the analyses were post hoc, since neither the combined acute-stabilization phase nor RCT were powered to test the aims of these analyses.
To conclude, PMD was associated with a lower frequency of remission and a higher frequency of relapse of pharmacologically-treated psychotic depression. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.
Acknowledgements
We thank the members of the STOP-PD II Study Group for their contributions. Members of the STOP-PD II Study Group were: Peter Giacobbe, M.D. and Brenda Swampillai B.Sc. at the University Health Network, Toronto and James Kennedy, M.D. and Bruce Pollock M.D., Ph.D. at the Centre for Addiction and Mental Health, Toronto; Kristina Deligiannidis, M.D., Chelsea Kosma, M.A., Wendy Marsh, M.D. at the University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, MA; Ariel Gildengers, M.D., Joelle Kincman, Ph.D., Meryl Butters, Ph.D., and Michelle Zmuda, M.A. at the University of Pittsburgh School of Medicine, Pittsburgh, PA; and Judith English, M.A., James Kocsis, M.D., Barbara Ladenheim, Ph.D., Vassilios Latoussakis, M.D., and Nikhil Palekar, M.D. at Weill Cornell Medicine of Cornell University and New York Presbyterian Hospital, NY.
Financial support
This study was funded by USPHS grants MH 62446, MH 62518, MH 62565, and MH 62624 from the National Institute of Mental Health (NIMH). Eli Lilly provided olanzapine and matching placebo pills and Pfizer provided sertraline; neither company provided funding for the study.
The National Institute of Mental Health (NIMH) participated in the implementation of this study through the U01 mechanism. NIMH did not participate in the design of the study or the collection, management, or analysis of data. A data safety monitoring board at NIMH provided data and safety monitoring. Neither Eli Lilly nor Pfizer participated in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Conflict of interest
A.J. Flint has received grant support from the U.S. National Institutes of Health, Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, Brain Canada, Ontario Brain Institute, Alzheimer's Association, AGE-WELL, and the Canadian Foundation for Healthcare Improvement. K.S. Bingham receives grant support from the University of Toronto. N.H. Neufeld has received grant support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, and the University of Toronto. G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Allergan, Astra/Zeneca, and Sunovion. B.H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He directly owns stocks of General Electric (less than $5000). Within the past 3 years, he has also received research support from Eli Lilly (medications for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial). He has been an unpaid consultant to Myriad Neuroscience. A.J. Rothschild has received grant or research support from Allergan, Janssen, the National Institute of Mental Health, Otsuka, Eli-Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, is a consultant to Alkermes, GlaxoSmithKline, and Sage Therapeutics, has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012; and, UpToDate® and has received honorarium from Wolters Kluwer (Journal Editor). E.M. Whyte receives grant support from the NIMH and HRSA. A.N. Voineskos receives funding from the NIMH, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto. B.S. Meyers received research support from the NIMH at the time this work was done. P. Marino has no disclosures.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
